Recommended News Category: Podcast

HOSTS: Laura Pavin and Jess Love

Guests: Kevin Outterson, executive director, CARB-X and professor of law, Boston University. Ted Schroeder, CEO, Nabriva Therapeutics. Amanda Starc and Craig Garthwaite, healthcare economists, Kellogg School of Management at Northwestern University.

HOST: Madeleine Finlay

Guest: Dr. Jennifer Rohn, Head of the Centre for Urological Biology at University College Londo

Madeleine Finlay (1:14)

It can start with a suspicious twinge. An urgent need to pee. Tummy pain. Then comes the burn.

Anyone who’s had a urinary tract infection knows how agonizing they can be. Some infections go away on their own. Many need antibiotics.

Simple. Except beneath the surface of this very common infection, there’s a lot of mystery, unanswered questions, and unnecessary suffering. And it gets to the heart of the challenge of tackling antimicrobial resistance.

Carolyn (1:58)

Once you get a recurrent UTI, I’m afraid that the chances of getting another one are quite high. It’s almost as if you don’t clobber it the first time, it’s more likely to get entrenched and come back again and again.

Madeleine Finlay (2:12)

About 20 to 30% of all UTIs recur within about six months. But for some, they never go away.

Carolyn (2:21)

I literally kept a record of how often I was having to go to the loo, and it was eight times in an hour, every hour, every day. And of course, when that happens to you, you withdraw into your own world of pain.

Madeleine Finlay (2:37)

Chronic UTIs also present another problem. Often the infections don’t show up on tests.

Carolyn (2:45)

It was like being slapped in the face, first of all. And at the time, I was naive enough to think, well, the doctor’s know best. And if they’re telling me there’s no infection, then, okay, it must be something else.

Madeleine Finlay (3:00)

But as researchers learn more about the problem bacteria, they’re understanding why our current tests and treatments just aren’t up to scratch.

Jenny Rohn (3:10)

You know, I know it’s a terrifying and awful thing, but it’s also really fascinating, and I have a lot of respect for the bacteria because they are tiny, tiny little things. They’re two microns. They’re tiny little things, and they can bring people to their knees.

And they have so many ways to outmaneuver us.

Madeleine Finlay (3:29)

So today, we’re asking, what’s the latest understanding of UTIs? What’s happening when someone gets a chronic infection? And is there anything on the horizon that could help flush an infection without contributing to our overuse of antibiotics?

From The Guardian, I’m Madeleine Finlay, and this is Science Weekly.

Dr. Jenny Rohn, you’re head of the Center for Urological Biology at University College London. First of all, can you explain what a UTI is and who’s most at risk of one?

Jenny Rohn (4:10)

A UTI is simply an infection of the urinary tract, which is basically your waterworks. That can be your kidney, your bladder, your urethra, which is the little tube that connects the bladder to the outside world. But usually when you hear the term UTI, you’re talking about a bladder infection.

And these are caused by bacteria. There are a lot of bacteria living in your back passage, as we all know. Most of them are friendly, but some of them are not friendly.

And they can, in certain situations, can migrate into the urethra and then up into the bladder and cause problems. And although anyone can get a UTI, it is most common in women, probably because of the anatomy. So our back passage is much closer to the urethra than a man’s back passage.

It can also be very common in children and also in the elderly, things start to equalize a bit and men start getting UTI as much as women. But by and large, this is a disease of women and about one in two women will get one in their lifetime.

Madeleine Finlay (5:04)

Right, so bacteria that migrate from the back passage to the urethra can cause a UTI. But how exactly does that happen? And how does an infection then take hold?

Jenny Rohn (5:16)

So they get up there, they climb up through the urethra and end up in the bladder. So there’s lots and lots of urine and the urine is flowing the wrong direction. It’s trying to wash out all the bacteria.

But these uropathogens or bacteria that cause UTI have all sorts of tricks in order to cling in in this inhospitable environment. So they have sticky appendages that help them to latch on to the bladder wall despite the urination. And they also have ways of hiding from the immune system and from antibiotics.

Two of these ways are, one, they can actually burrow into the bladder wall, which is kind of horrific to think about. So they actually dive into your cells and take up residence inside them. Well, it’s nice and cozy.

There’s plenty of nutrients in there. There’s no antibiotics. There’s no immune system.

Another thing that bacteria can do is they can form these slimy communities known as biofilms on the inside of the bladder wall. And these were also very resistant to antibiotics in the immune system. Those are two that I’ve mentioned, but there are dozens and dozens of strategies they have to get around our defenses and our drugs.

Madeleine Finlay (6:22)

It’s so impressive. And I wonder, once you’ve got this UTI, how do they tend to be diagnosed and how accurate is a diagnosis? How easy is it to pick up that somebody has got a UTI?

Jenny Rohn (6:35)

Diagnosis is definitely a problem. If you have a really raging UTI, you don’t really need diagnosis. You’ll be well aware if you’ve had one that it’s obvious, right?

Your urine is full of cloudy pus, often blood. You’ve got terrible pain when you urinate. Nevertheless, the GP still wants to see some evidence that you’ve got a UTI.

And so what normally happens is you get a dipstick, a little piece of paper is dipped into your urine and it changes color if you’ve got a UTI in theory. And then if it looks like you’ve got a UTI based on the dipstick, they’ll send your urine off for a midstream culture. They try to grow bacteria from your urine.

Now both of these techniques are a little bit flawed and they’re very old fashioned. I want to point out that the midstream urine culture was pretty much invented by Alexander Fleming in the 1920s and things like the dipstick, they don’t work very well. They’re very insensitive.

So imagine you’ve got an infection and a lot of the bugs are actually hiding in biofilms or hiding in your bladder wall. Then the bugs won’t be in your urine or they’ll be in your urine at a very low level. So these tests often fail to pick up a bone a feed a UTI.

It’s kind of like tossing a coin, whether you’re going to test positive for UTI, if you have maybe a lower grade infection that wouldn’t show up in these very old fashioned tests.

Madeleine Finlay (7:51)

A 2017 study found that UTI diagnostic tests gave the wrong result in at least a fifth of cases. For people with chronic UTIs, infections that don’t go away after a typical course of antibiotics, this can be a real problem and make diagnosis very hard. As Carolyn found, she was on a trip up to Scotland in 2015 when she was hit with an initial infection.

Carolyn (8:19)

We got as far as Berwick-on-Tweed, and I suddenly thought, God, I’ve got UTI, how weird, come out of nowhere. And it got worse and worse, and by the time we got up to Edinburgh, I was rushing to the loo, I was in pain, saw a GP there, and I got a call two or three days later to say the test had showed negative, there was no infection, which was really strange.

Madeleine Finlay (8:42)

When her first course of antibiotics didn’t clear the infection, she went back to her GP at home for more tests.

Carolyn (8:48)

My own GP could not identify a UTI. The test kept coming back saying nothing abnormal discovered or contaminated, simply nothing. I was starting to think I was going mad, inventing it all in my head.

Madeleine Finlay (9:05)

So while the tests weren’t picking up Carolyn’s infection, she had to suffer through months and months of living with an unabated UTI.

Carolyn (9:15)

Obviously at that point, you’re thinking, well, how am I going to live like this? You know, I love to go to the theater, I love to do all sorts of things. I couldn’t go anywhere.

Your sex life is an impossibility, like if you’re in that much pain. My life had become so tiny. When you don’t know if you’re going to get any better, it is just horrific.

And depression kicks in. My greatest salvation was finding a group that I could work with and talk to of other women who had similar things. And we’d have lunch in a local pub and everybody would talk about it and help each other.

Madeleine Finlay (9:53)

Then Carolyn found Professor James Malone Lee, who was pioneering research and treatment for chronic UTIs, including the long-term use of antibiotics.

Carolyn (10:04)

I was on antibiotics for three and a half years and gradually, gradually, my symptoms started to get better and I started to have the odd good day.

Madeleine Finlay (10:16)

Today, Carolyn is UTI-free. But despite her success, the long-term use of antibiotics is a fine balance. It doesn’t come without side effects and the risk of antimicrobial resistance.

Currently, the guidelines state that men should be prescribed five to seven days of antibiotics, whereas women are typically given a three-day course. Campaigners like Carolyn argue that this often isn’t enough to clobber that initial infection and prevent UTIs coming back. But if we don’t tackle antimicrobial resistance, we won’t have anything to treat UTIs with.

Back to Jenny.

Jenny Rohn (10:57)

Antimicrobial resistance has been on the rise for the past century. The number one resistant bug at the moment, according to the WHO and a few other studies, is E coli. So E coli is the most common UTI bug.

It’s also the one that’s the most resistant. It’s really a problem. So the more antibiotics humans take and animals, the more drugs are out there in the environment, in the water supply, in the soil.

And then every time a bacteria encounters an antibiotic, those that can resist will survive and those that will die will die. So that just selects, kind of evolutionarily, for a bacteria that are resistant. And then they love spreading these resistance genes around.

They spread on little things called plasmids, little bits of DNA and they’re like business cards. The bacteria can pass them from one to the next, say, hey, I’ve got this really useful bit that allows me to resist penicillin. Would you like it?

If you don’t do something about it, pretty soon we’ll be back to an era where you can’t have an operation, even a routine operation because it will be too risky.

Madeleine Finlay (11:53)

That’s obviously terrifying. So is there anything else that can help treat UTIs or other non-antibiotic treatment options that are on the horizon?

Jenny Rohn (12:04)

There are some pretty good studies with D-mannose. D-mannose is a sugar you can buy over the counter. It prevents certain bacteria from binding to the bladder wall.

It’s got some pretty good data. There’s a little bit of controversy. And equally, cranberry extract.

Again, people go back and forth about whether this is useful, but by and large, the study suggests that it can help a little bit. But these are very sort of modest weapons against UTI. I would consider using them, but they’re not gonna be as good as antibiotics when antibiotics work.

As far as the future, there are a few things on the horizon, disappointingly few, I would say. This whole area has been neglected for decades. There isn’t a lot of research.

There isn’t a lot of drug development, most likely because it’s a women’s disease. People aren’t interested in it, and it’s not necessarily gonna be a blockbuster drug. And maybe there’s no profit margin in it.

But there’s a few things on the line. There’s an interesting new vaccine called Urimune, which has been reporting some excellent findings. I should also mention probiotics.

People are looking at using our good bacteria to fight the bad bacteria. And I think that’s a very promising strategy.

Madeleine Finlay (13:06)

Jenny, this infection is so common. It affects 400 million people every year worldwide. And yet we’re nowhere near the kinds of tests and treatments that we need.

What needs to happen, do you think?

Jenny Rohn (13:21)

This would all start with awareness that it is a serious problem. We need better education at the medical school curriculum. So I teach medical students as my job as a professor and most of them have absolutely no idea that UTI is a complex disease.

In the textbooks, you know, all is well. It’s just a, it’s a trivial disease. You know, you diagnose it this way and you treat it this way.

The students have no idea.

Madeleine Finlay (13:46)

This lack of knowledge around UTIs and chronic infections, not just amongst medical students, but doctors and even sufferers, was something Carolyn and her support group were keen to tackle themselves.

Carolyn (13:59)

We set up a not-for-profit company called Chronic Urinary Tract Infection Campaign, CUTIC. What we’d really like is to see the women’s health strategy expanded to include chronic UTI. And if we get a change of government, we would like the new health minister, whoever that’s going to be, to actually take notice of chronic UTI and be prepared to talk to us and the specialist doctors to have a look at how we can get to the bottom of this disease.

In five years from 2018 to 2023, there have been over 1.8 million admissions for UTI. And these are NHS England’s own statistics. And the NHS mortality rate for UTI is 4%.

So four people in every hundred will die of UTI. And chronic UTI is still not taken seriously.

Madeleine Finlay (14:59)

Finally, Jenny, what advice would you give to maybe somebody listening today who might want to protect themselves from a UTI or perhaps thinks that they have a UTI but isn’t getting the treatment that they feel they need?

Jenny Rohn (15:14)

Well, protection from UTI, there’s no simple answer, but it is widely understood that you do need to have good hygiene. Of course, if you produce feces, you should wipe from front to back. People say it’s useful to urinate before and after sex, and you can understand why, because you can sort of flush out the waterworks.

Drinking lots of water is important. The more you urinate, the more you’ll be facilitating that natural flushing process. Don’t hold your urine in, because it’s known that retaining urine will then set up a situation where you’re sort of fermenting the urine in there.

It should be being flushed out constantly. So don’t hold your urine. As far as if you think you have a UTI, and you’re not sure, and you go to your GP and they fob you off, say, listen, I’ve got these symptoms.

I know that the diagnostic tests are a little bit insensitive. I would like to insist on a second opinion, or I would like you to take the test again. And if the tests come back negative, I’d like to have a course of antibiotics.

And if then it clears up, I know that I had one. I don’t know how successful you’ll be because of antimicrobial resistance. Most GPs are under orders not to give unnecessary antibiotics.

So you might have a fight on your hands. But I know a lot of patients are successful just by advocating for themselves and being quite verbal. So maybe don’t take no for an answer.

Madeleine Finlay (16:36)

A big thanks to Dr Jenny Rohn and to Carolyn. You can find out more about Carolyn’s campaign, CUTIC, at cutic.co.uk. And we’ve put a link to that in the show description.

And if you’ve been following our General Election coverage on the Politics Weekly podcast, you might have noticed that you haven’t heard from our political editor Pippa Crearer and correspondent Kieran Stacey yet this week. Well, they’ve been busy on the campaign trail and they’re going to be back on Thursday with all their insight and a late night analysis of the twists and turns of the last TV debate before the election. So just search for Politics Weekly UK wherever you listen to your podcasts.

And that’s it for today. This episode was produced by me, Madeleine Finlay and Holly Fisher. It was sound designed by Joel Cox and the executive producer is Ellie Beurie.

We’ll be back on Thursday. See you then!

HOST: Maggie Fox

Guest: Kevin Outterson, Executive Director, CARB-X and Professor of Law, Boston University

Maggie Fox (0:01)
Hello and welcome to One World One Health, a place to talk about the planet and our problems. Climate, human health, and animal health are all connected, and the One Health approach recognizes how much all of us on this planet rely on one another. This podcast is brought to you by the One Health Trust, with bite-sized insights into ways to help.

If something’s alive, it’s evolving, and nothing evolves faster than microbes, such as bacteria, viruses, and fungi. They can all quickly change to resist the effects of antibiotics and other drugs used to fight them, something called antimicrobial resistance. These superbugs directly kill more than a million people a year. You might think drug companies are racing one another to bring new antimicrobials to market, but they aren’t.

In this episode, we’re chatting with Kevin Outterson, a professor of Law at Boston University, and the founding Executive Director and Principal Investigator of Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, or CARB-X, a global nonprofit partnership working to speed the development of new life-saving antimicrobials.

Kevin, thanks so much for joining us.

Kevin Outterson (1:16)
I’m glad to be here. Thanks for inviting me.

Maggie Fox (1:18)
So tell us just where we stand. Are drug companies pumping out all sorts of new antibiotics and antimicrobials?

Kevin Outterson (1:25)
The earlier you go in the research and development process, the more optimistic the story will be. If you look at the basic research labs, the universities and the early work being done by lots of the small companies in this space, amazing science, really interesting things. So the problem in my view isn’t predominantly…the bottleneck isn’t scientific, it’s really economic. Then the closer you get to the market, because of these economic difficulties, the more bankruptcies you see, the more companies that are struggling and getting out, the more dire the situation looks. So great science, especially early in the areas that we work at CARB-X, and the economics grind them into the ground when they get closer to reaching patients.

Maggie Fox (2:08)
Now, when you talk about economics, what do you mean? It just doesn’t pay to make these antibiotics?

Kevin Outterson (2:13)
You know, these are extremely valuable drugs to society. But what did you pay for your last antibiotic? I mean, typically, the copay at a Walmart is $4 for an antibiotic. They’re wonderful drugs that are largely very inexpensive. If a company spends 10 or 15 years bringing a brand new antibiotic to market, the first thing that the company wants to do is to sell it, to try to reimburse their investors. But for excellent reasons, all the doctors and the health systems want to keep that antibiotic on the shelf and save it for when we absolutely need it at some point in the future.

We have this situation in which the new antibiotics reach the market, they’re given a label from the World Health Organization as Reserve, hold them in Reserve. It’s wonderful for health and long-term global health, but it’s a disaster for the company. When they get FDA approval, it’s time for them to make money; instead, they watch their antibiotics not sell very much. And so we need to think about a different way to pay for antibiotics because they’re extraordinarily valuable to society. But that’s not been reflected in the way the R&D is being reimbursed.

Maggie Fox (3:20)
Okay, you’ve introduced a lot of ideas here and the idea of keeping a drug in reserve. Let’s go back a little bit and talk about why we need these new drugs and why some of them might be extra special and extra valuable.

Kevin Outterson (3:33)

Well, when you think about every drug class in human history, you know, anti-cancer drugs, or heart disease drugs, or pain drugs, or anything. Probably, the most impactful, the biggest bang on helping human health has been the antimicrobials, led by antibacterials, antibiotics: the most important thing in human history in terms of a drug class.

But unlike most drugs, like cancer drugs, aspirin, or heart disease drugs; these drugs, because of the biological factor of resistance, the fact that evolution causes the bacteria to develop traits that make the antibiotics less effective against them, these are the only drugs in which we need a sustainable, renewable strategy because the moment they’re invented, that’s the peak of their effectiveness, they begin to lose it immediately.

Aspirin was invented more than 100 years ago, it still works great on me, and hopefully on you too. But antibiotics, the best antibiotic we’ve seen, maybe in history, you need to recreate that in every generation, so the R&D challenges are uniquely different in this space.

Maggie Fox (4:35)
And that’s because these microbes quickly develop resistance the minute a drug hits a market. Sometimes some of the microbes are already resistant, right? They are already resistant microbes out there, the drug hits the market, and those are the microbes that then succeed.

Kevin Outterson (4:49)
Yeah, but it’s not instantaneous with bacteria. It’s a slower moving process. The bacterial genome is larger than a virus. So while we saw billions of cases of COVID and a relatively quick emergence of global varieties that may or may not be covered by the vaccines quite as perfectly as we hope, and every year, we get a different flu vaccine because the flu changes remarkably, your bacteria move more slowly.

But you’re right, it is without a doubt that the more you use it, the more resistance develops. And we want these drugs, these antibiotics, to last for 50 or 100 years, not five or 10 or 20 years. And so that means let’s take good care of them. We call that stewardship. Let’s use them only where necessary, let’s not waste them on agricultural uses for which they don’t help or in uses for people for which we don’t need them, [like] taking antibiotics when you have a virus. It doesn’t do you any good, it actually harms your microbiome, and it also accelerates resistance for the rest of us. So we need to protect them because eventually, they will go away. But my goal is, on the stewardship side, we put plans into place so that the next new antibiotic could last for 100 years. That’s a worthy goal.

Maggie Fox (6:01)
And so why can’t a company just develop one that will last longer? Why can’t they come up with the science to make them more flexible?

Kevin Outterson (6:08)
You’re asking a lot from a company that may only have 14 years left on its patent to create a drug that’s going to last 100 years. But there are almost no sales during those first 14 in which the company has the patent. How are they supposed to reimburse the investors for the several 100 million dollars’ worth of R&D that was put into it?

So we have to think about a different way to pay for these drugs. We call those delinked pull incentives. Things like subscription models that are coming out of the United Kingdom and some other G7 countries.

Maggie Fox (6:37)
Why can’t governments just either pay upfront or develop these drugs themselves so the companies don’t have to worry about losing money?

Kevin Outterson (6:44)
The subscription models are paid for by governments, and so the idea of push incentives like CARB-X, that I lead, or pull incentives, like a subscription model. These ultimately are paid for by governments, and especially the governments of the wealthier countries will contribute more.

But maybe your question was, why can’t the government just take over the entire function for antibiotic R&D? And to that, I’d say, I can’t name, at least in the US where I’m most familiar or in Europe, any research-intensive product that is entirely produced by the government without cooperation and partnership with private industry. And maybe you can, but even things that the government provides, like a bridge, they hire private companies to do the engineering and installation. Or the military, which is a very government [centric] function, the government doesn’t build the tank or missile themselves. They recognize the fact that they set the parameters and what’s needed, and then they put it out to bid to private companies who are able to actually execute more efficiently.

So I would like to hear about a research-intensive product that actually is produced entirely by a government and that we’re happy with the way that’s working. I think what’s more likely is public-private partnerships, with government and private industry and academia, public health stakeholders working together to get the sort of antibiotics we really need. Make sure that companies don’t get bankrupt, and make sure we have an adequate supply of these so that the 1.27 million people that The Lancet article tells us are dying each year from resistant bacterial infections, that these people actually have something that works for them, not just in the high-income countries, but everywhere in the world.

Maggie Fox (8:24)
And of course, that’s what you’re trying to do with CARB-X. Can you tell us a little bit about CARB-X?

Kevin Outterson (8:31)

CARB-X is nonprofit. We make grants. We also give the small companies that dominate the space a lot of technical, scientific, and business help, because usually, they’re quite small. They do what they do extraordinarily well if they have 10 or 15 people, but they need additional help. And they’re not getting it today from the rest of the ecosystem. So CARB-X has been awarded over 800 million US dollars since our founding in 2016. We spend that money to support the preclinical from hit to lead all the way to the end of Phase One, a pipeline for therapeutics prevention, including vaccines and diagnostics globally.

We’re funded by three governments, the US, the UK, and Germany, and two foundations, the Wellcome Trust and the Gates Foundation. And collectively, our vision is to ensure that highly innovative antibacterials, these products that are therapeutics, prevention or diagnostics, don’t die in that valley of death, that they actually get the money they need so that it can progress to the end of the Phase One trials.

Maggie Fox (9:32)
So you’re supporting this research and development early in the process. Tell us what the valley of death is.

Kevin Outterson (9:38)
We start at hit to lead, which is that the company has an idea, has some chemistry, a series of drugs that might work, a series of molecules really, and they’re testing it and beginning the early test in the petri dish to find out which one of the many in their lab actually work. It’s very early research. It’s frequently just out of universities. In a healthier market, like cancer, there’s lots of private investment in this preclinical and early clinical space when it begins testing in humans.

Maggie Fox (10:08)
And that’s because cancer drugs make a lot of money. Right?

Kevin Outterson (10:12)
Right, they make a lot of money. That drives not only lots of private investment in the preclinical space, there’s over 1000 cancer products in clinical trials in humans right now. So money does drive the R&D agenda.

Maggie Fox (10:26)
But for antibiotics? Not so much.

Kevin Outterson (10:28)
For antibiotics, there’s a real shortage of truly innovative products in the clinical pipeline, things that are being tested in people today. And WHO has looked at this and declared that it’s grim. And then in the earlier stages, we see lots of amazing science coming out of the universities, things that have been funded by national institutes like the NIH in the US, or their equivalents in many other countries. But these little companies that are spun out need some money to take it from the idea stage until it’s ready to actually be tested in a person. And that is the valley of death for antibacterials right now. There’s no private money to help those companies get over that hurdle. CARB-X is the largest funder in that space.

Where we start at the hit-to-lead stage, we’re about 12 or 13 years away from any sort of approval by the FDA. So we’re developing today supporting at CARB-X, things that are not for tomorrow but are for the next decade and decade after. If you want good drugs in the 2030s and 2040s, you’ll see these projects at CARB-X today. It just takes time.

Maggie Fox (11:36)
You’re a professor of law. Are there legal barriers that people might not think about in the effort to develop better antimicrobials?

Kevin Outterson (11:43)
The way I got into this field was, I was studying the way that intellectual property law, patents, etc, how they function well, and sometimes not so well in drug innovation more generally, and then became fascinated with how they are uniquely challenging when it comes to antibiotics. I don’t think there’s a problem with our patent system with antibiotics. But there’s clearly a problem in the way that we pay for antibiotics, how we reimburse for them. It’s not so much a straight-up legal barrier, but it’s changing the way we think about this.

One analogy is fire protection equipment. I’m sitting at Boston University right now and in the ceiling, there’s fire protection equipment. The people who built that were paid for that equipment decades ago, and the workers who installed it were paid on the day that they installed it. We’re not waiting until there’s a fire that breaks out to pay for the fire protection equipment in my office. We pay for it in advance so that we’re prepared.

For antibiotics, for the first decades and years of antibiotics, we paid for them only after the fire starts, when a patient is sick. And the amazing change that people are embracing is that we need to pay for antibiotics in a different way, thinking about them more as preparedness than response. That is the subscription model that the United Kingdom is pioneering. That is the bill in the United States, the Pasteur Act, and similar efforts in other G7 countries to change the way that we pay for antibiotics. I think that’s the most fundamental legal shift that has to happen.

We’re at a tipping point. Every week that goes by, I hear of another company that calls it quits. And some of these are public companies, and many of them are private, just little, affairs. I wonder how many highly trained antibacterial R&D people are left in the world. A lot of these people, like microbiologists, have skills that can transfer to other areas. There’s only so much of that getting paid that you can take before you need to pay the mortgage. And it’s understandable that this is not a lucrative field that doesn’t attract new talent.

This is a drug class that needs a sustainable plan. We can’t just do one and done for antibacterials. We have to think about how we’re going to do this for generations, and continue research efforts that sustain across our children and grandchildren, and great-grandchildren. Right? So we definitely need to think about this more like a piece of infrastructure. It’s the water pipes in Boston, or it’s a bridge across an important roadway or something because those assets we protect and plan and maintain. But antibiotics — nobody’s really protecting and maintaining it as an infrastructure asset and we should.

Maggie Fox (14:13)
So what can governments globally do? Can the global community help on this?

Kevin Outterson (14:19)
There are two big things that are happening. The first is that the G7, the seven wealthiest countries on Earth, have been working on this issue for some time. Germany headed the G7, they were the presidents last year. They specifically called out CARB-X and GARDP and Secure, a project at WHO, things that need to be supported in order to turn the tide against drug-resistant bacteria. That will continue this year with Japan being the leader and in May, there are several interesting things that Japan may be able to announce as they make progress on this issue.

The second is that the United Nations rarely holds high-level meetings on infectious diseases. And they’re going to have one on September 24 on antimicrobial resistance, which is a follow-through from an earlier meeting a couple of years ago. But it enables the governments of the world to each say, what are we doing ourselves? And what are we doing together to address this problem? So I’m very hopeful for concrete suggestions that follow with funding that have the support not just of the health ministries, but also the financial ministries, the people with money so that collectively we can do something useful against this problem.

Maggie Fox (15:28)
Kevin, thanks so much for joining us.

Kevin Outterson (15:31)
Thank you for having me.

Maggie Fox (15:35)
Listeners can share this podcast which is brought to you by the One Health Trust by email, LinkedIn, or your favorite social media platform.

And let us know what else you’d like to hear about at owoh@onehealthtrust.org. Thanks for listening.

Host: Ethan Rhee

Guest: Su Chiang, PhD, Senior Alliance Manager, CARB-X

00:11 Ethan Rhee
Welcome to the first episode of season two of the Antibiotic Resistance Awareness podcast. I’m your Ethan Rhee. In season two, I hope to bring you more interviews from those who are directly involved with antibiotic resistance. Today’s episode, we will be interviewing Dr. Su Chiang, who is a senior alliance manager at a global nonprofit partnership that accelerates antibacterial products to address drug resistant bacteria. The organization is called CARB-X and it stands for combating antibiotic-resistant bacteria biopharmaceutical accelerator. I would like to welcome Dr. Chiang to the podcast. Hello, Dr. Chiang, thank you for taking time out of your busy schedule to join me on my podcast. Could you give us a brief introduction on your background and career?

00:54 Su Chiang
Yeah, absolutely. Hi, Ethan. Thank you very much for inviting me to your podcast. And thank you for spreading the word about antimicrobial resistance or AMR for short. It’s a very important problem, and I think it’s really important for everyone to know that each of us has a role to play. So thank you so much for doing this. So about me, I started my career with a bachelor’s degree in biochemistry followed by a PhD in molecular microbiology studying Vibrio cholerae. That’s the bacterium that causes cholera. I then did postdoctoral work on mycobacterium tuberculosis, which is the bacterium that causes tuberculosis, before moving into research roles that were away from the lab bench. Initially, I worked on a program funded by NIAID. That’s the National Institute of Allergy and Infectious Disease, that provided research and development resources to researchers across the United States. And then I worked in a university tech transfer office, helping academic researchers move their discoveries into product development and towards commercialization. And then in 2018, just over four years ago, I joined CARB-X at Boston University.

02:11 Ethan Rhee
When I was researching topics for my next podcast episodes, I came across various articles talking about how antibiotic companies were going bankrupt, and that there has been a steady decline in antibiotic discovery, as when I connected with CARB-X I wanted to learn more about why these antibiotic companies are facing these challenges. Could you explain how CARB-X fits into this scenario?

02:31 Su Chiang
Sure, I’d love to. First, there are a couple of points that I’d like to start with to help explain why it has been so difficult to make new antibiotics. Personally, I think most of us, I certainly did for you know, an embarrassingly substantial portion of my career, I think most of us take antibiotics for granted. They were the first wonder drugs, you took them and your bacterial infections were cured. Not that you got a little bit better, not that you lived a few months longer, but people were cured by antibiotics, and they would otherwise have died. Today, antibiotics enable modern medicine, risky procedures like chemotherapy, dialysis, and organ transplants are all much safer procedures because antibiotics are available. And we got used to this situation in the mid 20th century. And we’ve largely forgotten how bad it is when there are no effective antibiotics. So how do antibiotics stop working? Right? And to a first approximation, as soon as patients start taking new antibiotics, bacteria find ways to evolve and escape the activity of those drugs. That’s a natural process that the bacteria undergo to survive. Unfortunately, it means that our existing antibiotics are becoming less effective against bacteria, and we are not developing enough new antibiotics to replace those.

03:59 Ethan Rhee
So if new antibiotics must continually be made to address antibiotic resistance, why has there been a decline in antibiotic discovery?

04:06 Su Chiang
Well, first, funding is a huge problem. You may have heard the number quoted that on average it takes a billion US dollars and more than a decade for a company to develop a new antibiotic. Unfortunately, we as a society, globally, have been under investing for decades in antibacterial research. And as a result of that there’s much less money going into antibiotic R&D compared to for example, cancer. Second, once new antibiotics are approved by regulatory agencies, like the FDA, for example, doctors will reserve them, they’ll save these new antibiotics for situations in which older antibiotics don’t work. This is called stewardship and it’s essential for public health, because it helps to slow the spread of antibiotic resistance. The problem is, while it’s essential for public health, it’s financially disastrous for companies. With low sales volumes and payment policies that don’t reward the true value of antibiotics, it’s difficult for companies to recover the R&D costs that went into creating those new antibiotics. So companies in this area, they can and they do go out of business, even if they succeed in getting a new antibiotic approved. Now, there are efforts ongoing around the world to fix these broken economics of antibiotics. But until that gets done, we need to keep innovation and development going so that the pipeline isn’t empty. And that’s what CARB-X helps to do. So, as you mentioned, CARB-X is a nonprofit. It’s a global nonprofit. It’s based at Boston University. It was founded in 2016. And we have been funded by the US, the United Kingdom and the German governments, the Wellcome Trust, and the Bill and Melinda Gates Foundation. We believe we’re the world’s most scientifically diverse early development pipeline of antibacterial products. And our purpose is to get life-saving products for patients into the pipeline. We support product developers from anywhere in the world who are creating new drugs, new vaccines, rapid diagnostics, and other types of products that address antibiotic resistance. And we take a comprehensive approach, because while antibiotics cure bacterial infections, vaccines help prevent them, and the best infections are the ones that we never have. And as you may have discussed elsewhere in the podcast, as we learned during COVID rapid diagnostics are critical to help slow the spread of disease and rapid diagnostics would help doctors to test at a single medical appointment whether a patient has a bacterial infection, and if so, which antibiotics would be effective.

07:01 Ethan Rhee
I really find stewardship and access to be important and preserving new antibiotic discoveries. In my previous research and interviews, I found that antibiotic stewardship is an effort to gauge and improve how antibiotics are prescribed by clinicians and used by patients. The CDC website says that this is a critical way to effectively treat infections, protect patients from harms caused by unnecessary antibiotic use, and combat antibiotic resistance. Can we talk about that?

07:27 Su Chiang
Yeah, absolutely. This is very important. As mentioned earlier, stewardship means saving antibiotics for situations in which doctors are confident that they will work. And this is in order to slow the development of resistance. This means not using new antibiotics if older ones can cure the infection effectively. And it means using existing antibiotics only when appropriate. I think you’ve mentioned this before, that antibiotics don’t work against viral infections, so they should never be prescribed or used for viral infections. On the other hand, patients who need antibiotics should get them and that’s access. Unfortunately, all over the world, there are patients who are not getting the antibiotics that they need, particularly in low- and middle-income countries. And the goal that we have to achieve is to balance stewardship and access so that vital products are available to patients who need them anywhere in the world, while also slowing the spread of antibiotic resistance to preserve these drugs for future generations.

08:38 Ethan Rhee
So how does CARB-X support this? I see that you developed a Stewardship and Access Guide.

08:44 Su Chiang
Yes, CARB-X and our international partners developed a guide to help our product developers create their own stewardship and access plans so that when they get their antibacterial products to market they can achieve what we call access not excess, for these essential medicines. So an ideal stewardship and access plan must be developed. Or I should say, ideally, the stewardship and access plan should be developed when their product enters pivotal clinical development, meaning that it’s getting pretty close to regulatory approval. And the plan should outline how the company will ensure responsible stewardship and appropriate access in low- and middle-income countries.

09:27 Ethan Rhee
Okay, so as I understand it, companies funded by CARB-X have contractual stewardship and access obligations. So what happens if they can’t meet those obligations?

09:39 Su Chiang
Right. Well, we are all in this together. So responsibility for stewardship and access is shared by companies, governments, funders, industry, health professionals, patients, everybody. And if an individual company can’t meet its stewardship and access obligations, then the Wellcome Trust, which is one of our funders, has access rights that are modeled after the US by dual rights. And very roughly speaking, this means that the Wellcome Trust can step in to help ensure access in low- and middle-income countries, if a CARB-X funded company isn’t able to meet its stewardship and access obligations on its own.

10:25 Ethan Rhee
I see. I saw on your website that there’s quite a list of CARB-X graduates, how are they doing after graduating from the program?

10:33 Su Chiang
We’re very excited that many of our graduated programs continue to progress towards commercial launch. And in fact, two diagnostic products that we supported are now on the market in Europe and seeking FDA approval for the US market. And these are from T2 Biosystems, and from Specific Diagnostics. Specific Diagnostics, which was a private US company, was actually acquired in 2022 bybioMérieux, which is a global leader in in vitro diagnostics. And that was super exciting for us. On the therapeutic side, I’ll just briefly mention two products that are currently in advanced clinical development, post CARB-X. The first is a product called VE303, from Vedanta Bioscience. This is a live biotherapeutic. It’s a mixture of eight bacterial strains that is intended to restore the gut microbiome and prevent recurrent Clostridium difficile infections. This is in phase two clinical trials. And the other product I wanted to mention is called GSK 3882347. This is from GlaxoSmithKline. It’s an orally available small molecule drug that prevents E. Coli from binding to the wall of the bladder. And this is in phase one clinical trials for preventing recurrent urinary tract infections caused by E. coli.

12:00 Ethan Rhee
And those are some interesting names. Well, I think that the work that CARB-X is doing is so unique, and so important, and making sure we have the necessary tools to continue fighting antibiotic resistance. I read that CARB-X has received over 1160 expressions of interest from companies or institutions located in 40 countries in just the first five years. Where do you see CARB-X 10 to 20 years from now?

12:30 Su Chiang
That’s a long time to be looking into the future. So you know, it would be fantastic if economic and societal incentives align, and the antibiotic ecosystem becomes fully self-sustaining on a global basis. Bacteria evolved to escape our medicines, and that’s never going to end. So we have to evolve our efforts. And we’ll never be able to stop either. What CARB-X’s specific role will be over the next decade or two is not something that I’m able to predict. But I can say that we’re always looking to understand what are the most urgent clinical needs, what has gone well, and what could be done better in our own processes. And after the first five years, we’ve implemented targeted funding calls to focus our investments on the most critical gaps in clinical care. We are building portfolio-wide efforts so that we can have benefit across multiple projects. And we’re working with partners to shorten the path between good ideas and real world solutions for AMR. So while I can’t, I really can’t answer your question in any detail, I can say that we will be here doing this as long as we’re needed. And as long as we’re able to.

13:54 Ethan Rhee
Thank you so much Dr. Chiang for joining us here and sharing your knowledge and expertise. We’ve learned so much and I hope to continue as part of the younger generation to keep antibiotic resistance on their minds as they’re navigating through the healthcare system. We hope CARB-X can continue to grow and accelerate important companies discovering AMR products.

14:16 Su Chiang
Thank you so much, Ethan. It’s been a pleasure.

14:18 Ethan Rhee
Thank you. 

14:25 Ethan Rhee
I want to thank Dr. Su Chiang for joining us and a special thank you to Robin Berghaus for helping me get connected with Dr. Chiang for this interview. That is the end of this episode. And don’t forget to click the follow button on Spotify and follow me on Instagram at ARA.podcast. Thanks for listening. This is Ethan Rhee for Antibiotic Resistance Awareness podcast. And that’s a wrap.

Hosts:
Lance Price, PhD, Professor, George Washington University
Matthew Wellington, Public Health Campaigns Director, PIRG

Guest:
Erin Duffy, PhD, Chief of Research and Development, CARB-X

00:14  Matt Wellington
Hey everybody. Welcome to another episode of Superbugs Unplugged. My name is Matt Wellington, I’m the public health campaigns director for PIRG, one of your hosts. And I am joined here by Dr. Lance Price of the Antibiotic Resistance Action Center. My other host for the podcast. Hey, Lance, how’s it going?

00:31  Lance Price
I’m sick.

00:33  Matt Wellington
Yeah, everybody’s sick. My daughter has a pretty nasty case of the croup right now. I don’t know what caused it. I understand that is a side effect of other things like RSV. So who knows what’s going on there. But yeah, things kind of suck right now in terms of illness. They really do. It’s.

00:51  Lance Price
They do. Do you take her outside, too? That fresh air is supposed to help with croup.

01:01  Matt Wellington
Yes. We took her outside this morning a little bit, and she was in her brand-new snowsuit. She’s 14 months old, so she’s running around and walking and we have a snowsuit that’s too big for her. So we have to roll up the sleeves and the legs. And so she looks like an absolute balloon. It’s hilarious. But she was like running around the backyard with her little sunglasses on. It was great. Yeah, but she sounds terrible. It’s kind of scary.

01:28  Lance Price
I’m sorry. It’s very stressful.

01:29  Matt Wellington
Yeah. Did they get you sick or did you get sick on your own?

01:33  Lance Price
Oh, my daughter likes to cough right into my face. It’s pretty awesome. So if you’re yawning, she’ll cough into your mouth. It’s awesome.

01:44  Matt Wellington
Ruby takes her little finger and just kind of puts it in my mouth and twirls it around a little bit. That’s one of her favorite things to do.

01:53  Lance Price
Yeah, kids are gross.

01:55  Matt Wellington
They really don’t understand. Yeah, it’s tough for all daycare classes now. Right now, pretty much.

02:05  Lance Price
I’m excited. I mean, despite being sick, I’m really excited about Erin Duffy, our guest. But you’ve got some news first, don’t you?

02:14  Matt Wellington
Yeah, I’ve got some, some news to share on the antibiotic resistance front. So as we record this episode today, the FDA just came out with their latest report on antibiotics sales to agriculture. It’s the ADUFA report and it’s pretty underwhelming, to be honest. There’s that one less than 1% decrease in the sales of medically important antibiotics to meat producers from 2020 through 2021. So not much of a change at all in either direction. And, you know, that’s been the case pretty much since 2015 when the FDA took the steps. They took on growth promotion and increasing veterinary oversight. After they did that, there was a slight, you know, good decline in sales until 2017. And since then, it’s actually slightly increased, you know, from 2017 through 2021. So it just highlights that the FDA’s approach is not exactly effective right now for reducing antibiotic use for the long term on farms. There’s no, as far as I can tell, no targeted, you know, approach for reducing the use of these drugs. So of course, we’re urging the FDA to take the lead there and to, you know, take some lessons from the European Union. That’s they’ve been able to basically have sales of antibiotics to veterinary medicine in the last ten years. And they did it through setting targets and measuring against their progress. So we are definitely urging the FDA to take a similar step. But yeah, not much, not much else in the report other than not much has changed.

03:56  Lance Price
Are you ever, every time I hear it, I always want to say ADUFA. I don’t know. It’s just got a funny name.

04:02  Matt Wellington
Animal Drug User Fee Act. Yeah, I do feel it’s a very ridiculous outcome.

04:09  Lance Price
Did we ever talk about how from 2016 to 2017 there was this huge jump in therapeutic use? So you see this, you see this, you know, apparent. Well, you see a definite drop in total amount, but then it looks like there’s this big just a shift in what they were calling a bunch of drugs. Right. So they were saying, oh, yeah, these weren’t after all, these weren’t for growth promotion, these were for disease prevention.

04:40  Matt Wellington
Well that’s a good distinction too, you said therapeutic use and the FDA considers disease prevention a therapeutic use, but we do not. To us, therapeutic use means treating disease and disease. You know, preventing disease brought on by industrial farming conditions to me is not a therapeutic use. But we agree to disagree with the FDA on that one. But you’re right, you know, it’s just we see it as, you know, a shift in the labeling. And I think they did tackle the low hanging fruit on antibiotic misuse in their previous actions, but have not really done much of anything since then. So that’s antibiotic resistance in the news, not to be a bummer. But we do have an upbeat episode. We go it was quite a roller coaster. We talk about antibiotic development, we talk about how antibiotic resistance affects lower and middle income countries differently than high income countries. But ultimately we end on a positive note. So even though I have been a little bit of a bummer in my introduction here, I encourage folks to listen to the full episode because you’ll definitely have some hope at the end of it. And we have a special guest joining us, Dr. Erin Duffy. She is the chief of research and development at CARB-X, a global biopharmaceutical accelerator for the discovery and early development of products to prevent, diagnose and treat bacterial infections. So folks might remember we had the executive director of CARB-X, Kevin Outterson, on our previous episode. So Dr. Duffy is his colleague and she is going to take us through some of the more scientific pieces of what CARB-X does. So stick around to hear that episode. But we’re going to take a break right now. We’ll see you when we get back.

06:21  Laura Rogers
Hi, this is Laura Rogers, deputy director of the Antibiotic Resistance Action Center. If you like what you’re hearing, could you do us a favor and rate review and subscribe to the podcast? We really appreciate it. Now, let’s get back to the episode.

06:34  Matt Wellington
Hey, everybody. Welcome back from the break to another episode of Superbugs Unplugged. I’m here with Dr. Lance Price, and Dr. Duffy is our special guest for today. Hey, Dr. Duffy, thanks for joining us.

06:45  Erin Duffy
Hi. Thank you for having me. Happy to be here.

06:48  Matt Wellington
Of course. And so we were lucky enough to chat with one of your colleagues, Kevin Outterson from CARB-X pretty recently. So hopefully our viewers have a little bit of a primer on what CARB-X is. So I wanted to start with just your background. Can you tell us a little bit about yourself?

07:05  Erin Duffy
Sure. So again, Erin Duffy, I am the head of research and development here at CARB-X. I am a chemist by background, trained formally at Yale and spent a little bit of time at Pfizer doing drug discovery right out of a postdoc. But then the meat of my career was actually with a small company founded as Rib-X Pharmaceuticals that became Melinta Therapeutics, a pure play antibiotics company, where our goals were to discover, develop new antibiotics. We did that over about 17 and a half years. And then unfortunately, and I suspect this is going to be part of our conversation once we launched our first antibiotic and commercialized it, we ran into some challenges, market headwinds, which required us to close the research and development shop to focus on market products. And so I left there in 2019 and joined CARB-X.

08:10  Matt Wellington
Awesome. You’ll have to be patient with me with the chemistry it is the only class that I did not do super well on in college, so.

08:18  Lance Price
I didn’t even know chemists could speak. So this is really awesome to microbiologists. You know, we had a lot of competition with us.

08:27  Matt Wellington
Yeah.

08:27  Lance Price
What’s pure play?

08:29  Erin Duffy
Oh, sorry. Pure play. Meaning that we were, which is pretty true of most biotechs, we were solely focused on the development of new antibiotics, not, you know, and oncology agents or whatever, whatever. But we had a foundational technology out of Yale that actually was the subject of a Nobel Prize mid-stream in our company in 2010. Not that I won it, but the founders did. And that was to describe at the atomic level what one of the most prolific targets for antibiotics looked like. And that then allowed us to use that and design new antibiotics against it.

09:09  Lance Price
And I thought you said parallel play. You know, I can see my daughter’s nursery from here and they do a lot of parallel play and I just didn’t know that. I was just imagining chemists all trying to like, you know, almost like shared workspace. Okay.

09:25  Erin Duffy
I’m sorry to disappoint you, but yeah.

09:29  Matt Wellington
Well, I definitely am curious to hear about the challenges, the market challenges. You mentioned before I asked that, as I said, hopefully our listeners are already primed with what CARB-X is, but can you just give us a little bit of what CARB-X is and what we’re all about.

09:43  Erin Duffy
Sure. Absolutely. So I’m sure Kevin told you this, but I’ll remind you what the acronym means, which is combating antimicrobial-resistant bacteria biopharmaceutical accelerator. Those last words are what make the X. And long story short, we are a project at Boston University School of Law that is funded by three international governments. So the U.S., the UK and the German government, as well as two foundations including the Wellcome Trust and the Bill and Melinda Gates Foundation. We’ve been given to date just about $800 million to deploy for the support of companies that are designing and developing new antibiotic attacks, new vaccines and other preventatives against bacterial infections and new diagnostics.

10:36  Matt Wellington
So one thing that and lots of the things Kevin said stuck with me from his interview is that we titled that episode “King of Analogies” because he was just throwing them about left and right. One thing that I came away with was it sounded like CARB-X is doing what I would consider like letting all the flowers grow, right? So it seems like you’re kind of open to every and all approaches to addressing antibiotic resistance, but you all have the strategic goal, like, are you thinking ten years from now we want to have three antibiotics developed, four diagnostic tools in place X, Y and Z? Or is it just throwing spaghetti at the wall, seeing what sticks, which if it is, that’s totally fine. I’m just curious if there is that strategic. Here’s what we want the next ten years.

11:24  Erin Duffy
Yeah. So I’m not the queen of analogies except maybe bad ones, so I’m not going to go there. But I would say that it has evolved. So when Kevin was first awarded this grant in 2016, I would say it was more of the spaghetti on the wall, which is I don’t think Kevin had any idea if ten people would apply, 100 people would apply, 1000 people would apply. And so they had very broad calls of, you know, we do fund only through active funding calls. We can talk about that. If you want to have a very broad, just bring us stuff that might be relevant for antimicrobial resistance. And then as we’ve matured, we’ve built some portfolio analysis tools so that we can look at, you know, the landscape of pathogens and infections that they cause and where we’re heavily invested and where we’re not well invested. And you know what? What sorts of things are in that box, how mature they etc. And then that has allowed us to refine for what we look at. And I think probably the best expression of that is this year in October we launched the first what we’re calling omnibus solicitation or funding call since 2019, and we publish three funding themes and there are very specific funding themes. The first is we’re looking for new oral therapeutics for a variety of infections. The reason for that is all those antibiotics that you know and probably have used with your children. I know you’ve both mentioned young children, things like Zithromax, Augmentin, you know, these are products that are being eroded because of resistance in the community. And so we’re looking to replace those with new antibiotics. So that was one call. The second call was for vaccines, maternal vaccines for neonatal sepsis. Not a huge problem in high income countries, but a massive problem in low middle income countries. These vaccines are very hard to develop. And then the final set of themes was for gonorrhea. And this was a broad based. If you have something for gonorrhea, whether it’s a treatment, a preventative or a diagnostic, we want to hear from you. And this was after a careful analysis of what where the holes are in our current portfolio and where the needs are in the world.

13:55  Matt Wellington
Yeah. Lance, you’re going to jump in.

13:57  Lance Price
Yeah. I mean, no, that’s really exciting. So for the neonatal sepsis, is that primarily E. coli? I know we have a lot of that. And I mean there are E. coli strains that cause neonatal sepsis. You see that in the U.S. But I don’t know about low- and middle-income countries or is it other organisms?

14:16  Erin Duffy
Yeah. So actually, there’s a pretty neat study that was done called BARNARDS. This was work out of Oxford University, Tim Walsh’s lab, supported by the Gates Foundation. And what they found pretty contemporary study was a predominance actually of Klebsiella pneumonia. So if you were to rank pathogens from sort of most likely to cause and do cause neonatal sepsis down, it would sort of go like Klebsiella pneumonia, and maybe said that five more times. And then in fact, E. coli, Acinetobacter baumannii and Staph aureus actually as well. So those are the four main pathogens.

15:01  Lance Price
Tim is amazing, Tim Walsh I mean, this guy.

15:05  Erin Duffy
You could have.

15:06  Lance Price
Him on the show at some point.

15:07  Erin Duffy
I know you do. You do. You do. He’s terrific. Yeah.

15:12  Lance Price
So discover MCR1and then also New Delhi metallic protease. Yeah. Wow. Okay so the end.

15:22  Matt Wellington
Man of the year, Lance gushed about his favorite scientists.

15:25  Lance Price
Oh well he’s an amazing guy. So the oral antibiotics make sense and vaccines. Awesome. And then yeah, the gonorrhea. Let’s talk about gonorrhea a little bit. It’s one of my favorite topics. So super resistant strains now and nearly pan resistant, right?

15:45  Erin Duffy
Yeah, absolutely. You know, there’s you know, we always talk about resistance to classes, but in fact, in the case of gonorrhea, we’re not just down to one class that is effective. We’re down to one antibiotic in one class, and that is the cephalosporin, very old. And it’s an IM injection. It’ll make you think about it if you have to get the injection. But even there, particularly in low- and middle-income countries, the resistance rates are certainly concerning.

16:18  Matt Wellington
So you’ve mentioned lower and middle income countries a few times now. And I know when I was looking at some of the background on your work, CARB-X talks about antibiotic resistance and the burden primarily falling on LMICs. So how does that come into play? You know, obviously we use antibiotics in the U.S. We’ve talked about antibiotic resistance in the US context, but how is it different in LMICs? What are the different challenges? What does it look like?

16:46  Erin Duffy
Oh, well, you know, so I mean, it’s frightening, frankly, is how it looks. But so this year in actually January, I think late January of this year, a really amazing paper was published in The Lancet that sort of commonly known as the GRAM paper. And there for the first time described what the burden looks like worldwide. And also then mortality and morbidity, morbidity associated with bacterial infections. And, you know, the numbers are staggering in and of themselves and I’m sure you talked about that with Kevin, but if you were to plot where those infections happen, they’re not here. Okay? So they are all in low middle income countries. It’s really alarming. And even more alarming than that is the disproportionate burden on children of babies, particularly neonates. It’s shocking.

17:42  Matt Wellington
And what because we did have one of the researchers of that study on the podcast several months ago, and I’m trying to remember what he told me in the interview was partly it’s that it’s just a lack of access to antibiotics in those countries. Is that your take as well, or are there other things coming into play with resistance factors, or is it the case that these people with infections could be easily treated if they happen to live in the United States with these infections? Or is there something else happening?

18:13  Erin Duffy
Well, certainly it is true that access is a major, major, major driver. And that’s because, you again, the health care system is very different. I mean, if you’re a woman who is pregnant and delivering a child, you might drive for two days to go to a place that certainly doesn’t look like any hospital that you or I would ever come into contact with. And so it’s just the levels of the health care system are different. The access to these antibiotics, as you said, is very low, but then also the misuse of antibiotics that we can get drives resistance. And so it’s sort of all of that combined. You know, actually earlier I think Lance mentioned, you know, New Delhi metallo-beta-lactamase, why you think it’s called that because the first patient who showed up with it was from New Delhi. That’s how these things are named. And so anyway, it’s all three of those factors, I think.

19:12  Lance Price
I think, you know, the other thing I was so happy to see your focus on the LMICs, too, is that, you know, we talk about antibiotic resistance undermining modern medicine all the time, right? So that’s, you know, one of the messages that seems to resonate with people. But in low- and middle-income countries, I mean, the antibiotic is modern medicine. And if that fails, you die, right? So that $5 antibiotic doesn’t work. You don’t, you don’t hook people to hundreds of thousands of dollars’ worth of equipment. Right. I mean, so that’s the thing that really strikes me is that these are modern medicine and they’re failing. And so, yeah, well, tell us, how do you when you think about diagnostics, when you think about drugs, how do you know? What is it you’re looking for to support that specifically helps in that context?

20:07  Erin Duffy
Yeah, it’s a great question. You know, and I think it’s so much easier for better or for worse, to have this conversation now. Three years almost. Exactly. And to, you know, COVID, because if you if you roll the clock back to, you know, I believe in May of 2020, if you had a respiratory infection and suspected you might have COVID, you couldn’t get a test, you couldn’t figure out if you had it, there weren’t therapies and there weren’t vaccines. You know, so this is terrifying and it’s sort of the same here. So but in the low and middle income country setting, you need all of these things, but you definitely need a diagnostic. But that diagnostic needs to be, you know, cheap available at the lowest levels of the health care system. So it’s going to be, you know, a blunt instrument. But at least to say, you know, bacterial and maybe, you know, idea what it is and some resistance markers so that you can properly treat, you know, is critical. But then having the right antibiotics or at least enough options for antibiotics once you understand what that is, is key. Now, of course, the third part of this and again, you know, we have code to thank for this is prevention, because you know, the best infection is the one you actually never get. And so if we had good bacterial vaccines available, that I think would be a game changer in low and middle income countries.

21:39  Matt Wellington
I want to ask you about the diagnostics. So what you described that tool where, you know, it says here’s the here’s what the infection is or roughly what the infection might be resistant or not resistant, does that even exist in higher income countries? Like does that is that something physicians have access to here in the U.S.?

21:57  Erin Duffy
At the highest levels of the healthcare system, you know, for different syndromes? And when I say syndromes, I mean infections. Right? And for you have to think about sample types as well. But yes, there are these big systems and then you have these cartridges that you swap in and out. And so it depends. But certainly there are infections for blood sorry, diagnostics for bloodstream infections. After you take the blood and you culture it and say growing the bacteria, then identifying it and saying to what it is susceptible can be done. But that’s at your highest levels of the health care system and it’s not available with all of the infections types and sample types and, you know, whatever that you want. So for instance, in gonorrhea, you know, we have this call. Turns out that it’s really difficult to measure bacteria and things like vaginal swabs and urine. Partially that’s a collection problem. But anyway, so there’s a lot of work to be done and bacterial vaccine and bacterial diagnostics. Now, the good news is for respiratory diseases, we had so many groups, small companies, big companies who dove in to the COVID world in 2020 kind of stopped what they were doing to develop tests for all levels of the healthcare system. Well, those people, you know, they’ve made some really interesting products and now we have the ability to pool them in and hopefully get them excited about what else they can build and build it for, you know, bacterial infections.

23:39  Matt Wellington
Yeah. I mean, the COVID tests amazed me. I just took one this morning. Ready took a little swab, little piece of cardboard and in 15 minutes I knew to a degree whether or not I had COVID. Yeah. So that’s the idea, right? It’s something super simple, cheap that physicians can use. I guess one follow up question I have is how we’re talking about like COVID in particular, you know, versus virus who knows how many potential bacterial infections. So how would you narrow it down in a test like that? Would you develop it for the top three bacterial infections? You might find it in a region. How would that work?

24:19  Erin Duffy
Yeah, it’s a good question. So, I mean, typically these things are more syndrome focused and by that I mean, okay, this is for respiratory tract infections. Okay. And then, you know, you’ll hopefully be able to have enough on the test to be able to determine what the key pathogens. So you’re looking for the key pathogens that cause that syndrome. You know, so, you know, we talked in the case of neonatal sepsis about, you know, the big four, if you’re talking about a lower respiratory infection, you know, a deep pneumonia infection, you know, you’re talking about, you know, things like Klebsiella pneumoniae. We mention that Pseudomonas, staph aureus, you know, it’s a similar grouping. So you’re going to look for that. And then, you know, depending on the sophistication of the tool and again, at what level it sends, that’s where you get into the nitty gritty of. Okay. And it also is carrying X marker where X is something about resistance.

25:20  Lance Price
So I’m curious about the economics of, say, a diagnostic for low- and middle-income countries, because it’s my understanding is that one of the big barriers to bringing new point of care diagnostics into places like the United States is this unpredictable reimbursement. Right. So, you know, if there’s not clear reimbursement, then a doctor’s not going to order it. And if the doctors aren’t going to order, then nobody’s going to produce it. Right. So it seems like the technologies are out there. There needs to be the effort, the investment. And so my understanding of CARB-X is that you do the push piece, so you have this non-dilutive funding at the beginning. But then and you know, we talked a lot with Kevin about, you know, pull incentives, but how would that work in low- and middle-income countries? How would you pull?

26:17  Erin Duffy
Yeah. No, I think these are excellent questions. I’m definitely not the expert to answer these questions, but I will say that that certainly if you’re talking specifically about diagnostics groups who think a lot about this are a group that we work with quite closely called Find. And I don’t know if you’re aware of them, but you know, Geneva based, you know, very big focus on diagnostics for low-income countries across the board, including antimicrobial resistance. But then also the lead at CARB-X of our diagnostics portfolio is a woman called Betsy Wonderly Trainor, super energetic. You know, a really bright gal. And recently she was part of a convening group at the National Academies of Science to start grappling with these questions of reimbursement for diagnostics. So it’s conversation, but it’s certainly something I would say in a less well developed than, for instance, the PASTEUR Act that I’m sure Kevin spent some time talking with you about for treatments.

27:26  Lance Price
Well, I think if anybody can solve this, it’s somebody named Betsy Wonderly Trainor.

27:30  Erin Duffy
I think. Really. I mean, honestly, no, she’s terrific. You know, she’s had a quite a long history of both development and deployment of diagnostics for emerging diseases, including in low- and middle-income countries. So she’s very passionate about it, super connected and really trying to make a difference.

27:55  Matt Wellington
I feel like this is a good, good time. So if you don’t mind, let’s go back to your personal experience with Melinta, right? So we’re talking about the push and pull incentives, the market challenges. Can you give us the details of what happened with the antibiotic at Melinta? Because I think it’s always helpful to have the stories to go along with the principles at play here. So walk us through what happened.

28:19  Erin Duffy
Sure. So I’ll tell you the long version and then we can cut it to the short version.  We have to roll the clock back a little bit. So around 2005 or 2006 at the latest, we actually brought this antibiotic. So our technology, it was all focused on the ribosome, which is, as I mentioned earlier, prolific target for many antibiotics. And we had put our first products that were new ribosomes targeting antibiotics into first in human clinical trials and they were moving along. But we’re a small private company and the investor said you should bring in a more advanced product so that you can get on the market faster. And of course that will allow us to continue to reinvest in R&D. Seems smart. So we brought in this fluoroquinolone that we named delafloxacin, and it’s in the same class as Cipro. Everybody’s heard of Cipro, but it had a better resistance profile and arguably put clinically a better safety profile. And it had been in the hands of Abbott Laboratories, you know, big organization who were developing it. But what happened was around that time there was a company, big company called Aventis, now Sanofi, and they had an antibiotic that was meant to replace Zithromax. It was called Ketek and it was put on the market. And then some idiosyncratic liver toxicity started showing up. And mind you Zithromax is used in kids, your kids, you know, and earaches and bronchitis and sinusitis. And so, these things need to be really safe. So that was a problem. And it really served to shut down the regulatory path for people developing community-based antibiotics. So Abbott got out, gave it back, gave delafloxacin a send back to the people who had created it, which was a Japanese pharmaceutical company. And then we licensed it from them and then we pivoted it towards hospital infections so that we could move it on a regulatory path. But this took some time. Okay? And then we were just about to start. We just finished our Phase two program, which is the first time you demonstrate efficacy in people for the infection you’re trying to cure in 2010. And at that point, the FDA released new guidelines for certain paths towards approval, and that was one of them. And so that caused us to stop. And, you know, because we’re ready to jump into phase three with a plan. So we had to back that up a little bit and took some time. Okay, I’m telling you all this because time is important with the drug, because all those years that you have delays, just eat the patent clock off of your marketing product. Okay. So fast forward 2012. We were trying to raise money in an initial public offering to do those Phase three pivotal trials with delafloxacin. And there was something that was being discussed in Congress called the GAIN Act, which was generate antibiotic incentives now, and the whole story behind that was they recognized that all these companies had a big pause because of Ketek and what happened in the regulatory environment and realized that many of these products would launch after their patent clock had expired. Okay. Not really a great economic story if you think about it. Okay. But GAIN passed and we went and we did our clinical trials. And in 2017, we gained approval. So great. Great approval of our antibiotic. At the same time, we did a reverse merger with an antibiotic company that had run into some challenges with their product that the FDA, this company was called Sempra. They were public and had money but problems and we were not public and needed money to build a marketing team. So was a married match in heaven. So approval of the antibiotic reverse merger. Now we’re a public company, so it’s not bad about that and it’s great. But then we made this decision, which seemed like a really smart decision, which was, well, delafloxacin is meant for the hospital. So you’re going to build a sales force. Why not send those people in with more than one antibiotic in their back? And so we bought three other antibiotics from a company, the medicines company, who decided to divest themselves of antibiotics. I think because of the market conditions. And so now here we are, we have four antibiotics that are on market, two that are launching both important antibiotics and two that have been on the market for a while. It was great and we took on a little debt in addition to the money that we got from the reverse merger to do that. But we were off. We thought this was great. But then the reality of the market conditions that came in and over the next three quarters, the amount of revenue that we received over the four antibiotics was not enough to sustain them on the market. Incredibly. And so that’s when we made the decision in the, I guess, the fourth quarter of 18 to close the research and development shop and find a home for those assets, which we did the preclinical assets, and then to really focus on what we could do to move these antibiotics forward again in oncology company with four branded products for a minute, having this, probably can’t imagine it can you. And so anyway, so then. R&D was closed and then that following year, 2019, in the fourth quarter, actually Melinta filed for Chapter 11 bankruptcy protection. Now, there’s a good news story to that. I have to say, let me just cap this by saying that was sort of the nadir, but now Melinta was brought out of bankruptcy by the group from whom they took the debt, Deerfield and Melinta as a going concern. They’re a focus company with multiple products, including the ones that I mentioned. And so they’re back in business and looking to build, which I think is a good sign.

35:00  Matt Wellington
That was quite a journey. So I think.

35:03  Erin Duffy
Sorry about that.

35:06  Matt Wellington
Reminded me of like it almost was like I felt like there should be like a Hulu documentary special made about this quite, quite a story as you were telling the story, a couple of things stood out for me. You said market conditions several times. You talked about the sales force and it just paints the perfect picture about how the current drug development structure just it does not work for antibiotics. If we want to keep antibiotics effective, it just does not work. You know, sales based on volume, which a company needs, it literally just will not work for antibiotics if we want to keep those drugs effective for the future. So that stood out to me quite a bit.

35:46  Lance Price
Yeah. So I wonder, Erin, how does that of somebody who came out of this, you know, for profit drug world now you’re working with CARB-X. I mean is that shaken your sort of vision of how markets work. I mean what is that Yeah. How does that experience sort of shape your thinking?

36:11  Erin Duffy
Yeah, I mean, it’s a good question. I you know, I guess I’m here because I, you know, I, I believe like, I think we all do that the world needs these products. And, you know, there’s this is a challenge. It’s a different challenge than the scientific challenges that I’m used to tackling. But, you know, somebody has to do this stuff. And thankfully, we have people who are behind us. So we’re curating that pipeline for when. And you know, there are others, including, you know, Kevin, who are working on the how. And I think both need to come together. It’s a puzzle, you know, would have been easy. I’ll tell you to just go to a different therapeutic area. Sadly, when we closed the R&D shop, I had 25 colleagues with whom I worked in New Haven, Connecticut, and I’m proud to say that all of them were gainfully employed shortly after we closed the R&D site. Not a single one of them in antibiotics, not a single one. Okay. So it’s easy to retreat. But I think, you know, we all know we need these things. And I do believe fundamentally smart people and passionate people will help us figure out the other side of the equation.

37:30  Matt Wellington
But it is so clear to me, especially after hearing the story in detail, like it’s a policy problem, obviously there’s a science problem that you’re dealing with, but at the end of the day, it’s a policy problem. We have to figure out the policies that will make this system work. So thank you for sharing the story with us. So I guess pausing for a second, is there anything you wanted to discuss, Dr. Duffy, that we haven’t touched on yet? Because I actually I feel pretty good about where we’re at right now. Lance I don’t know. Is there anything else you wanted to discuss?

38:03  Lance Price
Oh, I could talk for hours. We could do like we could do one of those long podcast recordings. But no.

38:12  Matt Wellington
Yeah. So on your end, Dr. Duffy, anything you feel like you were really burning to talk about that we didn’t ask you?

38:19  Erin Duffy
You know, I think sensing that, that I think we’re still trying to figure out, frankly, because you’re right, it is a policy problem, okay? The science of science. And, you know, I mean, we can tackle hard problems, but the question is, how do you get the non scientists in the world to go yeah, I get it. I mean, it’s good. And I say that because, you know, I think we’ve tried various things. You know, we talk about antibiotics underpin all modern medicine. That’s true. But you know, it’s not at the level that people worry about, know people worried when they felt there were no therapies for COVID. People worried in the eighties and nineties about getting HIV. Okay. So they were activated and motivated and I guess I’m curious to know, you know through all of this if you think there are ways to reach people. I mean we’re talking this obvious podcast hopefully it’ll be out there but how do you make how do you make you know like the gal who’s sitting right now at the dry bar having her hair done, listening to this podcast, because that’s what you do, listening to the dry bar, I think, you know, But like we need to do something about that, you know.

39:44  Matt Wellington
I mean, my, my take and it is a core part of our audience, the salons and barbershops. So we get a lot of play with Superbugs Unplugged there. But my take on the public facing piece of it is if I just sit here and really think about it, I can come up with three immediate family members who have had drug resistant infections. All of them are a little bit different, you know, difference in severity. But one of them was fatal. One of them was nearly fatal. And I think most people, when they really think about it, antibiotic resistance has touched them directly or their loved ones directly, and they don’t even really know that. And I think partly it’s because it’s always couched or, often couched in a larger medical problem. Right. So, you know, a cancer patient surviving cancer and then unfortunately dying from a drug resistant infection is just part of a larger story. And so I think it’s up to folks like me, I’m a non-scientist full disclosure. I’m a non-scientist. So it’s up to people like me, I think, and other advocates to work with physicians in those patients to help tease those stories out and have those physicians tell their stories. But the actual patients tell their stories, too, you know, and we do that every day. I have a great farmer that I work with because we work a lot in agriculture here and trying to reduce antibiotic use there. And he talks about how he had MRSA infection. And I guess his doctor, he was upset with his doctor for not starting antibiotic treatment sooner. And his doctor had a great conversation with him about why he didn’t make that decision, because he doesn’t want to spur antibiotic resistance unnecessarily. And it totally changed this guy’s life. He changed how he produces animals based on it. He switched from a conventional model to now raising his animals without antibiotics. So I think it’s up to I think it’s really about helping physicians to talk about this in a way that is public facing and is understandable to the public, not as just this kind of ambiguous medical problem. And then people me to, you know, put a megaphone in front of them and get it in the media and understand how people understand that if they really think about it, this has already affected them. You know, I think the amoxicillin shortage, I know that’s not necessarily about antibiotic resistance, but it’s giving us a glimpse of what the world will look like without antibiotics. And that has been on headlines all over the country. Right? Amoxicillin shortage. People are freaking out for good reason. What I think we need to do is connect the dots that, yes, and if we don’t act on this soon, you’re going have a lot more to freak out about.

42:19  Lance Price
I think, too, it’s you know, as we see E. coli getting more and more resistant, this is going to become a salon conversation because you’re going to see urinary tract infections that are very, very difficult to treat. And so unfortunately, I mean, I think it’s a crisis. It’s going to lead people to start to feel that. Yeah, unfortunately.

42:45  Erin Duffy
Yeah that’s really good point in the urinary tract infection you know touches so many sort of different levels of people. Right. But you’re you know, to your point about, you know, a lot of young women have, you know, what are, you know, non-complicated urinary tract infections. But we also have not again, because, you know, these markets have not been attractive. We haven’t had a lot of innovation for new oral antibiotics for urinary tract infection. You have a college girl let’s say, gets urinary tract infection. Pretty sure she doesn’t think she’s signing up for 14 days of intravenous antibiotics because all the ones that are oral unfortunately don’t work anymore. So these are all these funny things that seem like, you know, just I’ll just go get an antibiotic. But you can’t.

43:36  Matt Wellington
I mean, gonorrhea, right? Talking about college kids, that’s something to worry about. Not. Yeah, yeah, yeah. So I think I think we just have a lot more work to do to penetrate the public’s consciousness, which is a really hard thing to do. And to Lance’s point, I think unfortunately it often takes a crisis to do it right.

43:55  Lance Price
I think we’ve also, you know, we’ve had 70 years of, you know, faith in technology that’s been reaffirmed whenever there was a new antibiotic. Right. So, you know, we as a society, we’ve been taught to disregard this issue. And what I don’t think that most of society sees is that pattern is coming to a quick change, you know, and.

44:20  Erin Duffy
Know it’s true. You know, I was reading, I don’t know. could have been yesterday, could have been two weeks ago. But there was an article, I think it was in the Wall Street Journal about infrastructure aging where, you know, water treatment and distribution is concerned around the country. Right. Because we haven’t invested in this stuff. Nobody buys a house or rents an apartment thinking I’m not going to have safe water to drink. Right. Nobody in. Okay. People in low- and middle-income countries do, but not in the U.S. Right. But antibiotics are like that water. You don’t think about it. You don’t think when you go to have a, you know, a filling or, you know, to have a hip or a knee replaced or any anything else that, you know, what if what if I get an infection and there’s an antibiotic that works against it? Nobody even thinks about it. Your doctors don’t talk to you about it. You know, you just expect it’s there.

45:13  Lance Price
Yeah, but I mean, I think Matt and I are. We’re going to crack this, you know this. And I don’t really know. I mean, I, I, you know, I listen, there’s a, there’s a podcast that I listen to The Drive and it’s, you know, about longevity. And you know, personal health and how do you, you know, what are the things that you can do to hedge your bet and try to live a little longer? And I think about this all the time. We should be on that podcast because this is what’s going to pull the rug out from under people, right? Because as we get older, you know, no matter how well we’ve taken care of ourselves, we get more and more susceptible to infections. And, you know, I think that this could I don’t want to end on such a negative thing.

45:57  Erin Duffy

No, it’s not. Negativity, actually, which is that, you know, coming back to CARB-X and I mean this as sincerely as I can say it, it is remarkable to me how many high-quality researchers doing really innovative stuff are out there and remain active in this field. Okay. And that’s why we’re here, is to pull that energy and pull what they’re doing. The situation will be fixed. I think, you know, there will be a policy fix. There has to be. And thanks to these people today, 92 different companies and hopefully counting more soon, they’re making it so that the stuff will be there when the policy is fixed. And I think that’s an important message. It’s not like, you know, everybody packed up shop and went somewhere else.

46:46  Lance Price
And people like you, thank you for staying in the fight.

46:50  Matt Wellington
Yeah.

46:50  Erin Duffy
Yeah, I’m honored to do it. It’s good fun.

46:54  Matt Wellington
Well, I think that’s a good place to end. High note. Thank you, Dr. Duffy, for. For joining Lance and I. This has been great. Both said the interview with Kevin and you, I think this is a really great one-two punch to tackle, you know, drug development and antibiotic development and what it’s going to take.

47:12  Erin Duffy
I really appreciate it, and I hope you feel better Lance. Thank you. I look forward to listening. And thanks again.

47:21  Matt Wellington
All right. See you.

47:22  Erin Duffy
Take care.

47:23  Matt Wellington
Bye.

Host: Cary Adams

Guest:Kevin Outterson, Executive Director, CARB-X and Professor of Law, Boston University

Cary Adams: [00:00:02]
Welcome to Let’s Talk Cancer. I’m Cary Adams, the CEO of UICC. Antimicrobial resistance or drug resistance is a serious health threat to humanity. Today, around 1.27 million people die every year as a direct result of drug resistant infections. By 2050, this number could reach 10 million and cost a cumulative $100 trillion of economic output without collective action. Drug resistance occurs when germs are not killed by the medicines designed to destroy them. Why? Because the overuse or misuse of today’s antibiotics and other antimicrobials makes them ineffective over time. They simply don’t work. Drug resistant infections are especially dangerous for cancer patients because the treatment they receive exposes them to a greater likelihood of infection. Few people know that today the infection has become the second leading cause of death in patients with cancer. To mark World Antimicrobial Awareness Week, we speak to Kevin Outterson, executive director of CarbX, an international public-private partnership to accelerate global antibacterial innovation. Kevin, welcome and thank you very much for giving us your time today.

Kevin Outterson: [00:01:23]
Always happy to do anything to help the fight against cancer.

Cary Adams: [00:01:27]
The WHO has added antimicrobial resistance to its list of ten biggest threats to health worldwide. So perhaps to begin with, could you explain why antimicrobial resistance occurs and why it’s becoming such a major health risk?

Kevin Outterson: [00:01:43]
When you think about different types of medicine, antibiotics are probably one of the most important classes of drug in human history. They’ve really done amazing things to extend human lifespan. But most drugs, aspirin, for example, is going to work just as well on you today as it will on our grandchildren in 50 or 100 years. Aspirin will always work. Heart disease drugs will always work. If there’s amazing prevention or cures from cancer, it should always work. The difference is that for anything with a microbial target – antiviral, antibacterial – you have to worry about evolution. You have to worry about the target, the microorganism changing over time and therefore becoming resistant. So for antibiotics, penicillin was an amazing discovery. But as soon as we started using it, we needed to start discovering another penicillin just to avoid falling behind. So it’s different from anything else that we’ve looked at. And we’ve become so used to having these drugs, these amazing miracle, the original miracle drug, that we don’t understand, that we have to work hard just to avoid slipping behind.

Cary Adams: [00:03:08]
We have at UICC, been looking at this for the last year and a half because it was raised with us by certain cancer societies that they were seeing that one in five cancer patients were actually being affected by an infection and many of those led to them being in intensive care as a result of that infection. So what is it about cancer patients specifically that that leaves them open to antibiotic resistance?

Kevin Outterson: [00:03:36]
I published, together with some infectious disease physicians, a review that looked at this issue and the Clinical Journal of the American Cancer Society last year. And but anyone here who’s a survivor of cancer has a friend or family member who’s gone through cancer, you understand how invasive some of the treatments are, the visits to hospital, the openings into the skin that are required for treatments, the fact that some of these treatments suppress or modify your immune system in ways that might be killing the cancer but make you more vulnerable. And so you have to be more careful about the other things in life. You total all these things up and the data shows that while antimicrobial resistance superbugs are a problem for everyone, for people with cancer, the risks are really three times higher that they’ll get a fatal infection from these superbugs because of all the things that cancer treatment does to make you higher risk. Wonderful treatment but like you said before, we want to be careful that the advances in cancer aren’t undermined by the old foe of infection.

Cary Adams: [00:04:48]
UICC is working hard to sensitize the cancer community about this issue because many of the people I talked to are unaware of the challenges that AMR poses to cancer treatment in the future. And we want the cancer community to be ambassadors for the AMR story that they are there talking to governments and and hopefully get them to think differently about how antibiotics are used in their country and around the world. Now, one of the things in your report that you mentioned, you talked about the need for AMR surveillance systems for cancer patients. Perhaps you could give us a little bit more about that because we do struggle as a cancer community anyway with just basic information through cancer registries. Perhaps you could expand on why you think AMR surveillance systems for cancer patients are so important.

Kevin Outterson: [00:05:34]
We were surprised when we did the review just how little detailed data there was that tracked in a careful way using medical records, as well as just top line statistics on the experience of cancer patients with infection and particularly with drug resistant infection. And so when a cancer patient dies, even if the actual cause of death was a drug resistant infection, that’s almost never shown on the death certificate. Something else is almost always there. Maybe the cancer itself, the underlying cause of death. But the proximate cause was the infection that interrupted the course of treatment that may have been working. So we think that there’s a need for a lot more data to understand what is the actual experience of these patients with infection, What sort of drugs are they receiving? Most of those antiinfective drugs, the antibiotics and whatnot are really amazingly inexpensive. There’s been lots of complaints about the cost of cancer therapy, but the antibiotics are like the bargain in this process. But what we don’t know is how many patients with cancer are failing from specific drugs become resistant. And then what are we going to do to make sure that in five or ten years we have a replacement for those things that are failing today?

Cary Adams: [00:07:11]
And your organisation which you’re the founder of I believe CarbX stands for Combating antibiotic-resistant cacteria by a pharmaceutical accelerator, which is a mouthful in itself.

Kevin Outterson: [00:07:24]
You can see why we call ourselves CarbX.

Cary Adams: [00:07:27]
I prefer CarbX, it’s a lot easier for me. It’s a lot easier for me. But I mean, the other side of the coin of this is, okay, we want to see antibiotics used more sensibly around the world, not misused or abused in any way. But also we want to develop new ways in which we can address the issue. So what challenges are there in progressing research and development for new treatments? What are the barriers? Why aren’t we seeing more antibiotics coming onto the market? I mean, we see so much investment and so many companies investing in cancer treatment and care. A lot of new medicines planned to come out in the next five, ten years. What’s stopping us getting new antibiotics?

Kevin Outterson: [00:08:18]
The antibacterial research community often looks over longingly at the pipeline and the money going into cancer. Look how many antibiotics we’ve had in the last decade. Look how many are in the clinical pipeline. It’s So few compared to the amazing work that’s being done over in oncology. And if I had to say one word is the difference: it’s money. There’s great reimbursement. Companies can make money selling cancer drugs or having trouble making money selling antibiotics. The science, amazingly, is remarkable. All of the basic research money that’s been going into the NIH and similar agencies around the world, remarkable new things coming out in the antibacterial world. Science, I don’t think, is the right limiting step. It’s money. We aren’t paying for antibiotics as if they’re valuable to society. We’re doing that for cancer drugs and we’re getting a lot of them as a result. We haven’t done anything similar for antibiotics.

Cary Adams: [00:09:23]
It’s a real challenge, isn’t it? Particularly when you’ve got a medicine, which actually the more it’s used, the less value it is. So that’s an unusual market condition, isn’t it, for a drug or a medicine to come into use in health systems around the world.

Kevin Outterson: [00:09:40]
From the language of economics, we’d call it a negative externality. It would be like a factory that makes something but pollutes all of its neighbours. And antibiotics are a drug class that helps the patient in front of you, but may very well be delivering a less valuable drug. Or, on the flip side, more resistant bacteria to everyone else. And so that calls for being really cautious on how we use these drugs. We don’t want to give them inappropriately to any patient because it could damage their microbiome and it certainly can damage the usefulness of the drug for everybody else, including our children. So we want to be careful with them. And that really is the root of the problem: that a new antibiotic comes to market for excellent reasons, we put them behind glass and we say break glass only in case of emergency. We try to use it as little as possible for the first five or ten or 15 years. But for a company that spent 15 years bringing a product to market, they get FDA approval and then they’re told, let’s use your brand new drug almost with no one for as long as we can. That’s a great answer for public health. It’s a terrible answer for the company. It’s why the majority of them are going bankrupt and leaving the sector. That’s why we have so few new drugs. The reality has penetrated to the boardrooms of the drug companies.

Cary Adams: [00:11:11]
We’re going to have to find another way of rewarding that investment because the standard ROI process doesn’t work.

Kevin Outterson: [00:11:17]
The United Kingdom is doing exactly that. They have pioneered a new way to pay for antibiotics. They’ve selected two antibiotics there. Those contracts are live now. It’s a remarkable first of the world system really paying us a subscription. Let’s pay for the value of having these antibiotics in England without any regard to the volume of sales in the country. So paying for the protection value. There’s a proposed legislation in the US, There’s processes in other G7 countries also looking to do the same. But really the United Kingdom has been the pioneer in the rest of the of the leading countries. Their wealth, the countries of the world need to follow suit.

Cary Adams: [00:11:58]
There are other things as well. What about diagnostics? How is that going? Can you see developments and improvements in the way we can diagnose infections?

Kevin Outterson: [00:12:07]
Diagnostics is a key issue. We learned so much about the importance of diagnostics in COVID. We had both positive and negative experiences. We broke the barrier of getting rapid diagnostics into the hands of people in their homes. There are arguments five years ago that all of us couldn’t be trusted to do these sort of tests at home, that it had to be done in doctor’s office. Well, you know, a couple of billion test results later, I think people are pretty comfortable now with lateral flow SATs, rapid tests and do it all the time now. And so the question is, can we get a diagnostic into the hands of patients and into the hands of treating physicians, not just in the shiny hospitals and capital cities, but everywhere that patients need this information? Because if you could reliably tell a patient you don’t need an antibiotic, you have a viral infection, we save a lot of unnecessary use of antibiotics. And also, if you can tell a doctor this patient, the superbug they have is resistant to everything you would normally give them, and you must get drug X or drug Y, the new things or else die. All of that is amazingly important clinical information, so we’re working hard to get that done. There are economic challenges that are different from what I described with antibiotics, but that are daunting in this space. And I’ll just say the simplest of them is that if an antibiotic is really inexpensive, $5 or $4 a script that you pick up at WalMart, a diagnostic that is designed to encourage you not to take that drug if it’s going to be cost effective just at that patient silo, the diagnostic has to be almost free. You can’t have a $10 diagnostic to save a $5 prescription. So there needs to be some thinking on ways to make the diagnostic free or nearly free, which is what we do with the PCR test. We get billions of those for free from the government because otherwise you’ve put people in an impossible situation. You have to spend more money in order to to save money by not taking the antibiotic when the antibiotic is so cheap.

Cary Adams: [00:14:34]
Let’s move on to the World Antimicrobial Awareness Week 2022. The title of that is Preventing Antimicrobial Resistance Together. So let’s just pick that apart slightly. So it implies obviously, prevention. So what can be done at global and national level to improve infection prevention and to control it? What what is the best practice that you’ve seen around the world?

Kevin Outterson: [00:15:01]
I think the best infection is the one that never happens. To create a brand new drug is really an amazing scientific and technological feat that takes 15 years and lots of money. A similar amount of money spent to improve the quality of the water supply and the sanitation systems in major cities or medium sized cities and poor countries around the world could have an amazing impact. We have vaccines that are effective against some bacteria and some viruses. And getting those vaccines into the arms of people that would benefit from them – which is really almost everybody – is an amazing, cost effective strategy. So while I focus on trying to get new technologies to the market, it’s important that these prevention technologies, whether they be vaccines or clean water, clean food, sanitation, that these are also advanced. It doesn’t matter what the infectious disease threat is, if we have a good primary care system, we can deal with it in the first few months while we try to devise something more specific. And similarly, a lot of the reduction of mortality in the wealthier countries in the 20th century, the early part of the latter part of the 19th was due to things as simple as clean water, as profound and powerful as that. So it doesn’t help if a cancer patient gets 21st or 22nd century technology cancer treatment, but then goes home to a situation in which clean water, clean food and sanitation is not assured. So I believe in prevention. Everyone does. It’s a powerful thing and we need to continue to make the case for it.

Cary Adams: [00:16:49]
Which is great, and in fact, prevention a really common theme with the cancer community as well, because, you know, vaccinations, for example, for HPV, avoiding cervical cancer in the future, reductions in tobacco use, obesity control, all these things. We know 40 to 50% of cancers are caused by modifiable risk factors. So there’s a lot of alignment in the space with our own approach, which is why we need to work on 1. Prevention and 2. early detection. And things are a lot easier then. But let’s move on to this issue. I mean, I’m actually sitting here wearing my light blue jumper. I noticed that you’ve got a light blue shirt on. It’s the colour of AMR awareness represents a multisectoral approach, collaboration against a shared health threat. Why do you think it’s important that, for example, the cancer community and others get together with the AMR community to actually raise this issue and to take it forward?

Kevin Outterson: [00:17:46]
Communities like cancer can help. I live in Boston. There’s a march for a lot of diseases here and causes and they raise great money and you name it. There’s a group for it, many of them cancer, but not just cancer groups. Very effective patient mobilisation. There’s not that many patients who identify as “I’m a survivor from a drug resistant infection”. You know, there are some groups. There’s the Sepsis Alliance, there’s survivors of a Clostridium associated, a bacterial disease that results from use of antibiotics, that destroys the gut microbiome and then creates a terrible form of diarrhea. The cystic fibrosis community in the US this year has made it their top priority to to educate US government on the fact that people suffering from CF are now doing better because the new drugs are much better. But they’re still on their last antibiotic. So to the extent that other patient groups rely on antibiotics, this is a good moment for those groups to also stand up and say, yes, we need to keep this thing going because we don’t want to wake up one day and find out that all the antibiotics don’t work.

Cary Adams: [00:19:06]
I mean, the cancer community is starting to get involved. UICC is lead in that, working with many, many organisations around the world. We have a new publication that we’re sharing to educate the cancer community, But I agree with you. Why should it stop at the cancer community? I mean, any individual who has an illness has to be treated in hospital is probably exactly the same level of risk of getting an infection and then possibly dying of it. So moving away from communities, what about individuals? What can we do individually? Kevin, what should I be doing in the way that I operate? I mean, if I’m offered an antibiotic by my doctor, should I be asking the question “why you are giving this to me?” Should I be challenging that? I mean, what is it that I should be doing?

Kevin Outterson: [00:19:48]
Well, I’d always encourage you to have a reasonable conversation with your doctor about what they’re saying. But if you talk to doctors, they frequently say that they’ll give an antibiotic because the patient is asking for it or that the physician is feeling pressure to do something. There’s a lot of research work that identifies this and articulates how this happens. And in the US, a lot of physicians are rated by the health insurance plan. The patients give them a rating like a Yelp rating or an Airbnb rating. And if a doctor tries to be really strict in not giving antibiotics, all it takes is a couple of patients giving them a 1 for there to be trouble with their reimbursement from health insurance. So we can be informed patients that ask reasonable questions and don’t demand an antibiotic when you have a viral infection. We also have a lot of power as consumers. For years, the Food and Drug Administration tried to regulate the use of antibiotics in the animal agricultural sector in the US, and there was a lot of politics and it didn’t go anywhere fast for decades. The biggest change in the past few years in terms of agricultural use of antibiotics, the United States has been major corporations like McDonald’s and Chick-Fillet and other chain food restaurants and big retailers beginning to announce and then implement transitioning to antibiotic free types of meat and not just having it as an alternative, but making it the default choice, especially for chicken. So our power as consumers is immense. And this change happened at these major corporations because they were listening to their customers and their customers are saying, we would prefer this and and boom – amazing change, something that was politically impossible for decades. And companies are voluntarily doing it to follow their customers. There’s ways to get involved politically to make sure that adequate resources are given to this fight in every country. Drug resistant bacterial infections are killing more people around the world than either HIV or malaria. You’re pretty close to the total of HIV and malaria combined. Just think of the global mobilisation that’s been done against those diseases. That’s part of the reason why drug resistant bacteria kills more, because we’ve been successful in moving those numbers down. But tremendous global effort, lots of political salience stories in the press and everything else. People understand this, these problems that we need to respond to them. We don’t have nearly that level of political, social, emotional mobilisation yet against drug resistant bacteria.

Cary Adams: [00:22:43]
Well, hopefully the cancer community, both for individual level and at community level, can make a difference. Kevin, it’s been great talking to you and thank you very much for giving such great answers to the questions and bringing to light the key challenges we have in this area. UICC will continue to push this around the world to our community. I’m glad that we’re working in partnership. I think this is something that we can really shine a light on and hopefully we can get national governments and global leaders engaged in something that you say is a big threat longer term. So thank you very much for your time, Kevin. Really appreciate it.

Kevin Outterson: [00:23:17]
I appreciate the work the UICC is doing to make sure the safety net of antibiotics is there not just for the cancer patients, but for everybody.

Cary Adams: [00:23:28]
I hope you enjoyed this new episode and if you did, please leave us a review on Apple Podcasts and Spotify. We need to spread the word about antimicrobial resistance and this looming threat to global health, so please do share this episode with others. UICC has a dedicated page to antimicrobial resistance on our website, uicc.org. There you can learn more about AMR and also find a social media toolkit with texts and images for you to download and share with your network.

Host:
Candace DeMatteis, Vice President, Policy & Advocacy, Partnership to Fight Infectious Disease

Guest:
Erin Duffy, PhD, Chief of Research and Development, CARB-X

00:04  Candace DeMatteis
Welcome, everyone. I’m Candace DeMatteis, vice president of policy and advocacy for the Partnership to Fight Infectious Disease. And I’m happy to welcome you to our podcast, Infectious Conversations. Through Infectious Conversations, we’re having discussions with health care professionals, policy and other experts to get a grip on how to squash superbugs. Our goal is to better understand the threat of antibiotic and other antimicrobial resistance, or AMR, the threats that they pose and the need to address them now. We also want to better understand how we can build on lessons that we’ve learned throughout the COVID 19 pandemic and other health care experiences to change the course toward improving health outcomes for everyone. Today, our segment features a discussion with Dr. Erin Duffy, the chief of research and development at CARB-X. Erin is an expert in drug discovery and problem solving in the antibiotic arena. Most of her professional growth was with Melinta Therapeutics. Founded as Rib-X Pharmaceuticals, where over 17 years she became executive vice president, chief scientific officer, and R&D site head. Her entry into the pharmaceutical sector began with Pfizer Central Research. Erin’s formal training was at Yale University, where she completed a Ph.D. in physical, organic chemistry and an HHMI postdoctoral fellowship in computational structural biology. Ooh, nightmares from organic chemistry are coming back. So I’m so good, so excited that we have smart people like you who can not only manage the entry level, but go on to a PhD. We’re so thrilled at PFID to have CARB-X as an active supporter and task force partner. CARB-X is a global nonprofit partnership that supports companies developing antibiotics, vaccines, diagnostics and nontraditional products to address resistant bacterial infections and sepsis. Today, we’re so thrilled to talk to Erin about the CARB-X research portfolio and why it is critical to invest in diverse products and diagnostics that really take a comprehensive approach to help prevent, diagnose and treat sepsis. Erin, thank you so much for joining us today.

02:29  Erin Duffy
Thank you for inviting me. Happy to be here.

02:32  Candace DeMatteis
Well, as I mentioned, we’re thrilled to have you and your expertise will be so invaluable. So let’s talk a little bit more about CARB-X and can you tell us a little bit more about what you do at CARB-X specifically?

02:45  Erin Duffy
Sure. So as you said, we are basically the implementing partner of three international governments and two foundations to not only give financial support, but probably even more importantly, scientific and business support to the groups who are advancing these new potential treatments, prevention and diagnostics for bacterial infections. Now, my role as the head of R&D at CARB-X, we don’t do any research internally, sometimes much to our chagrin. But I have a team of experienced colleagues in all three pillars, and our goal is to shepherd these programs. We build support teams around them that bring expertise that they may lack. I should have said most of our companies are actually really small companies that we support, often maybe 5 to 10 FTEs at most. And typically they are experts at the foundational technologies which are really interesting and varied, but not always, or they are experts at how to take those ideas and translate them into something that will be products. And so what we do is we identify those gaps. We bring in subject matter experts who then sit with these teams on a monthly and a quarterly basis and really help them think through problems and advance through the development stages.

04:14  Candace DeMatteis
So if a company, do they come to you and say, hey, we need help with finding funding or we’re encountering this hurdle in the research process? I’m just curious, did they come to you, too, with the problem identified or is it kind of a two-way street where you also will look and say, how are you dealing with this? And maybe they were like, oh, we didn’t know. If you do that, what would you suggest? How does that work?

04:41  Erin Duffy
Yeah, so I should have said our funding is all through open funding calls, so it’s not a rolling basis. But we’ve let’s see over the course of time here, CARB-X was begun in 2016 and actually commenced the first funding call in September of that year. And so through the years now, we have had eight distinct and unique funding calls through which 92 companies out of over 1000 expressions of interest, but 92 companies or institutes in some cases have come into the portfolio funded by us. And so for those programs and portfolio, we do assemble these companies, support teams right off the bat. And that’s a conversation. It’s, you know, look, we think that these are gaps in your program. What do you think? You know, what do you need? And we try to come to some middle ground so that we’re not overbearing. It is their projects, but we’re giving the support where needed. So that’s sort of one aspect. The other aspect that is both for portfolio but then also for the greater ecosystem. You know, researchers who may not be in portfolio is that my team has begun identifying what we call common challenges that not one company or product developers are facing, but many. And so then we will design a unit of work and work with external researchers to get it done so that then we can hopefully in the ideal sense, you know, unblock a path for many companies that they’ve been struggling with and will publish these results, etc.. So that’s another way that we help is by again identifying problems more on a portfolio level and then trying to do something rapidly that many of them can benefit from.

06:36  Candace DeMatteis
So talk a little bit, if you don’t mind, about why is something like CARB-X needed? Obviously you bring a lot of value, but I’m curious about what was the gap that led to CARB-X being founded? And you talked about different government and private foundation funding as well. So I’m really curious about what was that gap?

06:55  Erin Duffy
Yeah. So, you know, when you introduced me, you know, I spent the most of my career in a little company, you know, begun, as Rib-X Pharmaceuticals and then becoming Melinta Therapeutics. And we were a pure play antibiotic discovery company from day one with a pretty neat technology that had come out of Yale. And the company was begun in 2001. And that was the year that, you know, a new antibiotic called Zyvox trade name Zyvox (linezolid) was launched. And it was the first new antibiotic in many, many years. And there was a lot of excitement around it. And it had both I.V. and oral forms and things looked really great. And in fact, its sales were, you know, in the billion-dollar range or so after a few years of launch. So it looked like a great time to get into antibiotics. We had this neat technology that was going to unlock new ways of bringing antibiotics, etc., but a lot of the big companies started getting out of antibiotics, and it was a mathematics issue really in terms of how much money you’re putting in to research, not that it’s a different in antibiotics to any other therapeutic area. There’s still, you know, the time to do the discovery and then the clinical trials and the launch. So that part isn’t different. It’s what happens on the back end. And if you think about it for a minute, if you take an antibiotic, you’re typically taking it for 5 to 14 days at the most. Not everybody has an infection at the same time. So you don’t have chronic disease and not everybody’s taking it. And so, you know, it’s really a volume problem in terms of the amount of money that you can make. So companies, big companies did the analysis and said, you know, this isn’t an area where we should be trying to create value for our shareholders. So then it was left to all the little companies to do this work. And, you know, there were some other environmental issues that happened. There was a failure of a drug in the mid 2000 and antibiotic that really depressed the regulatory environment. It made it challenging for about four years to really progress new antibiotics through clinical trials and onto the market and so that was tough for your little company. It’s tough to raise money anyway. Now you’ve got a time delay to really advancing your product. And so as many of these companies finally did achieve that goal, including ours, we received FDA approval in 2017 for our first antibiotic, and it launched in January of 18. Exactly three quarters later, we made the decision to shut the antibiotic research and development and I think not many months after that, the company filed for bankruptcy. And we weren’t the only company.

09:51  Candace DeMatteis
But still ultimate financially not successful.

09:56  Erin Duffy
Exactly. And we weren’t the only ones. You know, there was another high-profile bankruptcy, a company called Achaogen and similar story after their first launch. And then a few other companies didn’t go bankrupt, but they were sold or broken up for assets for, frankly, not very much money. So anyway, so you’ve got this problem, but the US government really was a leader here through the ASPR and BARDA. We now know BARDA because of COVID and all that they’ve done there, you know. But BARDA really has two remits, one is to protect Americans and really provide for their health. And the other, of course, is, you know, protecting against bio threats. And many of your big bio threats are bacterial pathogens. And so they had an interest in supporting companies who had a commercial indication. So, you know, urinary tract infections, lung infections, whatever, if they could show activity against potential biowarfare pathogens. So then once that drug was launched, they could bring it into the national stockpile. And so what they were seeing was this decline in innovation, largely because a lot of companies were out and small companies were struggling. And so they said, well, we really need to do something about this. It’s a matter of national security that we have a good stockpile. And so they created this request for proposals and we applied for it and Boston University applied for it. And then, you know, through the PI of CARB-X, Kevin Outterson partnering with BARDA, they encouraged the Wellcome Trust to come in. So those were the first two funders and then subsequently the Bill Melinda Gates Foundation, the UK government and the German government all joined for the same reason, you know, recognizing that, you know, it’s really a matter of national security, if you think about it.

12:03  Candace DeMatteis
Well, we certainly learned what infectious pathogens can do, and it certainly doesn’t discriminate with COVID 19. Absolutely. I want to turn and talk a little bit about one serious problem that we have, and that’s sepsis. As you know, September is Sepsis Awareness Month. And there’s a big gap in what exactly is sepsis. And that said, the awareness month is so important, what causes it, how it can be avoided, and the fallout if it’s not. I mean, it can be quite fatal, as you know. So I understand that at CARB-X, sepsis is an important focus of your research. So can you talk a little bit about why that’s such an important focus in what CARB-X is doing around sepsis?

12:55  Erin Duffy
Sure. So, you know, from just a unmet medical need perspective and I’m sure you saw in the it was late January of this year in The Lancet, there was a really a landmark paper that’s sort of commonly known as the Gram paper, which revealed results from a 2019 study of infections worldwide and what the mortality and morbidity was, and the association with antimicrobial resistance, which is, you know, the challenge here. I mean, you know, bacteria have evolved for the history of time. And as they do, they often render products that had been effective, ineffective, which is why we always need new antibiotic products. People know that now, I think because we talk about COVID variants, it’s kind of the same thing anyway. So in that GRAM paper, one of the things among the many things they highlighted were the syndromes or the indications, things that people present with, disease states, that have the highest mortality. That’s either directly attributable to antimicrobial resistance or associated therewith. And the first category with the highest mortality was lower respiratory tract infections. So hospital associated, bacterial pneumonia, ventilator associated bacterial pneumonia, that sort of thing. But the second was bloodstream infections, which is really what we’re talking about here with sepsis. So you have bloodstream infections. This is when a bacteria gets into the bloodstream, whether it comes from a leaky gut and bacteria then gets into the bloodstream or whether there’s a primary infection site like lung. And again, it gets into the blood. And then once that happens, things progress pretty rapidly to a syndrome that ends up being much more, you know, host directed, meaning the body has cytokine storm strikes trying to fight this infection and things go downhill pretty quickly.

15:11  Candace DeMatteis
Can you talk a little bit, that study that you’re talking about was so important and what a, you know, really, again, highlighted the impact that antimicrobial resistance is having now. And you talked about bloodstream infections or sepsis. But as I understand it in a CARB-X portfolio is not just on the treatment side, but also on the diagnostic side. And that sepsis can be a challenge to diagnose because there are multiple symptoms presenting different people differently. So how is that, what are some innovations around sepsis on the diagnostic side, maybe that CARB-X is following or helping to progress through the pipeline?

15:54  Erin Duffy
Sure. So I should have said and you know, we aim in all of the syndromes where possible to have treatments, preventatives, of course, you know, the best infection is one you never have. So prevention, of course, is very important. And then diagnosis. And again, I think, you know, if we would have had this conversation and even late 2019, you know, most people might have not been able to resonate with this. But with COVID, far before we had the vaccines, you know, we had things that were being explored for treatments. And of course, how important was diagnosis to have it, to not have it? Can I go out and can I not go out, so, you know, all very important anyway so in the area of sepsis or bloodstream infections, you know, we do have programs in all three pillars and I’ll mention all of them. But starting with diagnostics, you know, they’re really, you know, how you how you diagnose an infection in the blood as obviously take a blood sample and then you have to not only look for is it bacterial, okay. So that’s one thing. Is the infection bacterial versus viral, for instance, and then what is the bacterial species? And we call that bacterial identification. So is a staph aureus or MRSA, is that, you know, E. coli or, you know, any of the other big pathogens? So you want to know that. And then the third part is you want to understand what treatments it will be susceptible to. And so that’s called the antibiotic susceptibility testing. And so all of this is important, but a key thing is the time to result, right? Because as I said, you know, sepsis progresses really quickly. And so you need to be able to understand this and then provide a suggestion for treatment in a timeframe that’s meaningful. And so the innovations are sort of three fold, I would say that we’re supporting. The first is, you know, there are two ways to do the analysis of blood. One is what they call host culture. So, you know, you get the blood and you figure out what the bacteria are and then off you go, the others direct from whole blood. And so you can imagine direct from whole blood. It’s like direct mail or whatever that’s faster, that’s challenging. And there’s a lot of technical hurdles with how to process the samples well and then how to be able to have good sensitivity and specificity. Many of our programs in bloodstream infections do in fact emphasize direct from whole blood. And two of the products that were early in our portfolio, one from T-2 biosystems and one from specific diagnostics are both direct from whole blood, and they’re actually marketed in Europe and they’re preparing for their FDA approval. So there’s that. The second thing that those products do is that in addition to the bacterial identification, they also highlight if prominent resistance genes. So you think about this like the variance for a minute, whether it BA4 or BA5 or whatever we’re up to now numbers. And similarly with resistant genes, it can be things like carbapenems. There’s extended beta lactam cases, fluoroquinolone resistant markers. And so they look for those. That’s not the same as automated susceptibility testing. It’ll say there are these resistance genes, so maybe don’t use products from that class, but what it doesn’t say of all of the antibiotics and types of antibiotics that are available, you know, in theory, who can cover the bacteria associated with sepsis? Which ones is this bacteria actually susceptible to? So that’s the other innovation that we’re supporting. And then the third one is all about that turnaround time, how to get it. You know, in the ideal case, definitely less than 8 hours and even less than that. Recognizing that, you’re never going to impact the first antibiotic they give because they’re just going to give you something broad spectrum just to try to get under control. But then how do we manage treatment in a, you know, in the most responsible way? And the sooner you can know this result, the more you can impact that decision.

20:30  Candace DeMatteis
That makes a lot of sense. But it sounds like a lot of complexity and things working together to get that window narrowed and get the right treatment for the patient at the end within that golden time frame, if you will.

20:46  Erin Duffy
Yeah, absolutely. You know, and I have to say, I’m not a diagnostics expert by any means. And if my diagnostics colleagues are listening, they’re cringing at everything I’m saying here. But, you know, the interesting thing about diagnostics, you know, all these areas have their complexities. But with diagnostics, you have the chemistry, right, which is how do I determine what bacteria are there and how am I doing that? But then the other is what is either the box or the cartridge or whatever it is that you put that assay on to do the work? And, you know, these require fundamentally different types of people. You know, you have your biology and chemistry types over here and you have the engineers over here. But both of these pieces have to come together in order to make a product that’s usable at appropriate levels of the health care system. Now, think about it for COVID the very beginning of COVID. Actually, some of our product developers got involved in this and had assays that they could switch to, you know, maybe detecting COVID. This stuff was done on a benchtop, right, with beakers and plungers and whatever, whatever they could do to get it done in hospitals. But then that’s very different from, you know, boxes that can be at your local hospital or your doctor’s office, which is very different from those things we got in the mail. You know, the orange boxes with the little thing on a cartridge. I mean, amazing that you could do that.

22:14  Candace DeMatteis
It really is. And phenomenal in the short time frame. And we’ve seen it develop too. I think sometimes we forget that. But it was truly remarkable. It saved a lot of lives as a result. I’m curious, are you seeing any new trends that you’re in the research and development space of new treatments for infection, anything that’s really kind of more cutting edge or we’ve heard other speakers have talked about phage therapy, for example. That really is kind of a throwback. I learned with our last podcast. But I’m curious, are there other trends that you’re seeing?

22:55  Erin Duffy
Yeah, so I would say three main areas. And again, just staying with the theme of sepsis, recognizing that we fund research for many other syndromes to stay there, you know, meaning in diagnostics for a minute. The next level of I think really cool stuff is to use, you know, everybody’s talking about AI, you know, back when I was a computational scientist, we just used kind of computational science, but now it sounds cooler anyway. That’s really using big data to make predictions about whatever and one of it’s actually two of our diagnostics companies both focused on direct from blood predictions of bloodstream infections are looking at predicting what, again, not only the species, but the resistance is again based on big data and that’s the big data or the genome sequences that they will collate over time and make these predictions. So it’s really cool. I have to say, you know, they’re both early, but they’re certainly their bacterial ID is outstanding. And then, you know, they’re really making great backgrounds and prediction of resistance markers. So that’s a neat space I think, to watch. I think it will fundamentally change, you know, how diagnostics are used and then how treatment is affected in hospitals and centers. So I think that’s a big thing. And the other areas treatment’s been tough. You know, for once you’ve got sepsis just because again, you know, it becomes often more about the host and the inflammatory response than it does the infection at some point. But there’s a really neat company in California called Cellics, and I was literally just talking to them this morning, so they’re fresh on my mind anyway. They have this really cool nano sponge. Okay, so it is therapeutic, but it’s not like a small molecule inhibitor of something and it actually has three different ways it works. But the sum total of it is it basically it’s called a sponge because it attracts bacterial toxins, you know, and then also both pathogen and host inflammatory factors. And so it’s basically sits there and tries to sort of sop up all the bad stuff and do that quickly and effectively. So again, they’re early, but that is really neat. And if that works, I think it would be a terrific addition to the armamentarium. Then you go to prevention. And so there’s a more, I would say, traditional prevention, which is still terrific. You know, the Glaxo Ventures for Global Health has an invasive non type, nontyphoidal salmonellosis (iNTS). It’s a lot of words, vaccine that among the things that invasive non typhoidal salmonellosis (iNTS) causes is sepsis. And this is particularly a challenge in sub-Saharan Africa. And this group is poised to commence clinical trials with this investigational vaccine. So we’re pretty excited about that. And then to your point, we have other products that are focused on decolonization of the gut, of bad bacteria that, you know, in patients, for instance, that have certain hematological cancers or awaiting transplantation or other diseases where they might have a leaky gut, you know, are very much at risk for, you know, bloodstream infections and sepsis. And so there are two approaches. They’re both in our portfolio. One does use bacteriophage, and these are CRISPR-engineered. So CRISPR portion, the subject of the Nobel Prize in chemistry a couple of years ago. And so what these bacteria phage do is they go in and they basically like haul out the bad guys, just cut them out of the gut. So if you think about it in the analogy of a neighborhood, it’s like you get rid of the bad actors in the neighborhood. You have the question, who moves in? But, you know, it’s an interesting idea to remove the bad bacteria. And hopefully what you establish is a healthier gut and then you forestall breakthrough bacteremias. On the other side of the coin are live biotherapeutic products. And there are companies like Vedanta, Boston based company Seres, also a Boston based company, which put both of them who, rather than looking to cut out the bad bacteria, are trying to sort of, you know, knock them out by putting consortia of good bacteria in. So they’re basically replacing bad stuff with good stuff. And again, hoping to restore gut health so that you don’t have these breakthroughs. So a lot of neat innovation and innovation that’s maturing. Seres isn’t a person human study with their product, and we hope Vedanta will be here. You know, in the short term, too. There’s a company, a Danish company in our portfolio using this CRISPR engineered bacteriophage approach for removing E. coli. And this is important for patients with certain cancers. And they’re also in a first in human study looking at safety principally. So a lot of stuff moving closer to patients. Oh, really neat.

28:37  Candace DeMatteis
And also encouraging and exciting. And their approaches are so, so different. That’s very encouraging. One thing I wanted to talk about, too, is like a policy. We understand that Congress has is considering legislation that addressed some of those issues that you were talking about. You’re successful on the R&D side, but then the market just isn’t there to help these companies maintain stability and be financially viable. And we understand that the PASTEUR Act, which is under consideration in Congress, includes incentives for developing some of those new treatments and diagnostics that you were talking about to fight resistant infections. Do you have an opinion based on your experiences of the importance of policies like that?

29:25  Erin Duffy
Oh, yeah, I think they’re huge. You know, we so people talk about, you know, the different strategies to make this a viable therapeutic area and market again in two terms. So there’s the push incentives and that’s funding. So that’s grant funding like what we do. And then advanced development partners like BARDA, I mentioned like the AMR Action Fund that was created by some foundations and most of the Big Pharma, it’s more of a venture fund, but we’ll fund downstream from us and others, GARDP, etc. So these are people giving money to advance these products, to approval and to patients. But then there’s what they call the pull incentives and honestly, it’s like a seesaw. If you don’t have both, you know, it’s actually, you know, so we can pile all the money we want into these innovative products. But if there’s no market at the end, you know, it’s just going to be a disaster. So, you know, we need them. And certainly they’re two different pieces of legislation. The PASTEUR is one that we’re very excited about. It follows, I would say really leadership at the in the UK who built a small version of this and launched it. I think it was last year. And you know, this is kind of like a Netflix model, I guess. So the idea is that if you come with a new product, a therapeutic or preventative or, you know, diagnostic that that meets, you know, really does meet a high unmet need that then the product will basically be bought. So the company then doesn’t build the sales force and do all of that. They’ll be given a certain amount of money upon approval. Well, it won’t all come at once. You will be tiered over time, but it’ll be enough of an incentive that the company can sort of recoup what they invested and hopefully also be encouraged to continue to do this. We think we need these innovations. It also will continue to encourage product developers to focus on the areas where the highest need is. So we think that’s great. You know there is another piece of legislation that was called DISARM and I forget what it’s evolved to now but this is a little different where it’s looking specifically at hospital based products and taking them out of the DRG. The DRG is basically I forget what the letter stand for but basically it’s the whole treatment plan. If you come to the hospital and you present with X, it’s the bed, the nurse, the I.V. bags, the antibiotic, if you need it, and whatever, whatever else. And that all comes with a price tag. So obviously, if your antibiotic is part of that, there’s only so much you can charge for it. Right. And so what this legislation would do would be to take the antibiotic out of the DRG and allow it to be priced for what its value is.

32:40  Candace DeMatteis
I did want to ask, and we typically do this in the podcast as we would close it out, is want to give you a chance. If there are one or two things that people listening to the podcast would walk away with that you hope sticks with them and encourages them to take action either for themselves or, you know, for all of us more broadly on these issues, what would you suggest that they walk away with?

33:07  Erin Duffy
I think number one is we really need this to get done and we just can’t wait and wait and wait. So your voice is very helpful there. But then the other thing to think about, you know, I just don’t think we think about I think I think of antibiotics like running water in a house in a first world country. Right. So when you buy a house or you rent an apartment, do you ever ask, is there running water? Is it something I even think about? The answer is no. And so when you go for, you know, to have a child or, you know, everybody of a certain age and I’m certainly there at this point now is going to be thinking about a knee replacement or a hip replacement or a shoulder replacement or maybe you’re on dialysis or, you know, any of these any time you go into the hospital, you’re having cardiac arterial bypass surgery. None of this. None of this. So all of these medical innovations and oh, by the way, for all those fancy immuno-oncology drugs that we hope are going to be great for cancer patients, somedays none of these is effective if you don’t have a stable store of effective antibiotics and other products. Think about that the next time when you’re going to have your teeth cleaned and they ask you to take an antibiotic the day before, think about why they do that. You know, this is all about, you know, livelihoods that we’ve come to take for granted without these products.

34:38  Candace DeMatteis
You know, great parting thoughts. And Dr. Erin Duffy, thank you so much for all the work you’re doing and for joining us today on Infectious Conversations.

34:48  Erin Duffy
Thank you. It’s been really a pleasure.

Hosts:
Caroline Duell, Director Media & Communications, MTPConnect
Andrew Bowskill, Director Stakeholder Engagement Queensland, MTPConnect

Guest: Richard Alm, PhD, Chief Scientific Officer, CARB-X

00:02  Richard Alm
So upfront, I mean, I’ll say that CARB-X would love to have been accelerated in Australia supporting obviously the Australian ecosystem but also, you know, the Western Pacific as well, because I think there are things going on in New Zealand that we don’t hear about enough. And so I do think an accelerator in this area, you know, geographically this area would be, you know, exceptionally beneficial both to us and CARB-X, but also to the, you know, the greater ecosystem within Australia.

00:45  Caroline Duell
Hello and welcome to the MTPConnect podcast. I’m Caroline Duell, our guest on today’s podcast is Richard Alm. He’s the scientific officer at CARB-X, the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator, which is based at Boston University. CARB-X is a global nonprofit partnership focused on supporting antibacterial research. Richard joined CARB-X following almost 20 years working in drug discovery in large pharmaceutical infection R&D teams and spending some time at a small, antibacterial biotech company. He obtained his Ph.D. in microbiology from the University of Adelaide, and prior to joining industry he held two postdoc positions in the AMR area, one in Australia and one in Canada. It’s a great pleasure to welcome you to the podcast, Richard.

01:35  Richard Alm
Thank you. So happy to be here.

01:38  Caroline Duell
My co-host today is Andrew Bowskill. He’s MTPConnect’s Director of Stakeholder Engagement for Queensland and co-chair of AAMRNET Australia’s Antimicrobial Resistance Network. Hi, Andrew.

01:51  Andrew Bowskill
Hi, Caroline.

01:52  Caroline Duell
Okay, so Richard, you’re originally from Adelaide. Welcome home. What brings you back to Australia for this trip.

02:00  Richard Alm
Yeah. So it’s actually an interesting story. I think that’s one of the positives from out of COVID I guess is the ability to work remotely. And I came back after obviously not being out of travel for two years. I came back for the Lorneinfection meeting in February and presented at that and actually caught up with some people I had used to work with I knew that were happy to see me in person and then spent a couple of weeks. My family’s all still in Adelaide and then when I went back I was given the opportunity from the CARB-X management, whether I wanted to work remotely from Australia for a couple of months and do some outreach as our new funding was coming. And so I came back in May for a little surprise visit to test whether I could function at three in the morning, because obviously the time difference is hot. So I came home for a surprise visit for Mother’s Day, and then came, I guess, early July, and I’ll be here for a couple of months.

03:01  Caroline Duell
Oh, that’s great. Great news. And well, tell us more about CARB-X and how the organization that you’re working for came about and how did you end up there?  It’s a long way from Adelaide.

03:14  Richard Alm
It is. So I am. So first of all, CARB-X. So CARB-X was founded in 2016. It came out of really President Obama’s executive order around combating antibiotic resistant bacteria. And so the order was to make an accelerator and it was competitively bid. And the BU team, led by Kevin Outterson, won the grant from BARDA, which is from the Department of Health and Human Services in the US government, and then raised money from Wellcome Trust. And then three other partners joined shortly after, the governments of Germany and the UK, as well as the Bill and Melinda Gates Foundation. So we have five funders and the initial investment was for five years. So that went through to sort of like 2021 and we’ve just been renewed. So BARDA has just put in another 300 million over ten years and Wellcome Trust has put in, I think 70 million over three. So that’s good news. And so yeah, CARB-X is a very unique model. Uh, funds early, early-stage product development from sort of hit to lead through to first time in human clinical trial on a completely non-dilutive basis. And I’ve been in Boston, based in Boston now for I guess 26 years. So originally I did my PhD in Adelaide and then went to University of Victoria in Canada to my first postdoc with a with an expat Australian who’s chair of the department there he was out of Melbourne and then I came back to the IMB in Queensland to do a second postdoc for three years. And during that time the professor that I was with in Victoria, Trevor Trust, he had been funded by Aster at the time and he got asked to set up a research satellite in Massachusetts. And so he invited me back and that was in 96. And so I said I’d go back for a couple of years and I’m still there. I worked for AstraZeneca for almost 20 years in various roles and responsibilities from early target ID through to support of clinical products. And then when infection sort of ended at AstraZeneca, that was 2015. They exited out of the space and spun out Entasis Therapeutics. I actually went to a small startup company then called Macrolide Pharmaceuticals, where we were just four people at the start. So that was kind of exciting, completely different to having the infrastructure of the Big Pharma. But during that time I was the principal investigator on our CARB-X grant. And so then when that company pivoted away from infection, as a lot of companies unfortunately are doing, it was a chemistry based platform company. They pivoted to awards rare diseases. I reached out to some colleagues that I had known from AstraZeneca that were at CARB-X to see what opportunities were there. And I joined CARB-X then in 2019. So I’ve been there ever since.

06:18  Caroline Duell
What a journey. And you talk about that many companies are moving away from this type of research. So why the focus on AMR for CARB-X and what are the particular challenges for antimicrobials that make an organization like CARB-X so necessary in this research space?

06:38  Richard Alm
Overall, I mean, developing a drug in any therapeutic area is expensive. Developing an antibacterial drug as a therapeutic is equally as expensive, but it’s got some unique challenges to it. One is that you can spend all this time and, you know, estimates are up to $1.3 billion to get a drug from, you know, a compound from the start all the way through to registration. You spend all this money, you know, developing a drug through face to face through clinical trials. And then at the end of it, if it’s approved, the doctors and the regulators say that’s really good. But then the doctors say, well, we want to keep that until we really need it. And so then there’s no revenue for it. And so you spend all this money developing this drug and then it’s put on the shelf until the doctors really need it. And so there’s no income. I think some of the other challenges are when you do the clinical trials, most clinical trials are done as a noninferiority. And so you go against, you know, the standard of care or best available therapy. And so you’re looking for a noninferior. So, you know, worse than that. And so you actually don’t get a claim typically of superiority. And so then the perception I think is, well, you know, I can take a $5 generic or I can take your branded drug, why wouldn’t I take the $5 generic? And so I think the non-inferiority status of how you develop a drug is challenging. And I think then the third dagger, if you like, is that most antibiotics are only taken for 7 to 10 days typically because then the infection is either cleared or the patient has succumbed. And so you don’t have that lifelong your return visits, if you like, if you like, if you’re on a cholesterol or blood pressure medication, you have repeat you have the repeat customer usage concept, whereas with antibacterials you don’t even though a good antibacterial can extend your life by, you know, up to seven years, if you get an infection, a bad infection as a child that’s usually done in the first 7 to 10 days. And then you don’t think about it again. So I think all those challenges together make the profit margins very, very difficult, which is why a lot of countries and I know Australia is also looking at this and looking at pull incentives as well as push incentives. And so CARB-X is an example of a push incentive where governments are giving money and organizations are giving money to increase the amount of pre-clinical work that is ongoing to make sure that there’s a pipeline of products that can be developed and are innovative enough to get around the emerging resistance. But then there’s also a need to fix the other end. And that is, you know, big company, you know, you need big companies to or some big organizations to actually develop the drugs through the expensive phase two and phase three trials and then commercialize them. And I think the way to do that is some sort of reimbursement or, you know, pull incentive. And so different ones are being trialed. And I know Australia is looking at some of the different options there as well, which is great. I think Sweden and the UK have got pilots going and hopefully the PASTEUR Act in in the US will get approved by Congress and that will, you know, put in some sort of strength to the ecosystem so that companies will come back and reinvest in the development of antibacterials because I think they need needed.

10:00  Caroline Duell
CARB-X is an accelerator. Can you tell us how that model works in this marketplace?

10:05  Richard Alm
I’ve never seen a funding model quite like this. So we as in CARB-X, it’s a competitive grant based organization. So we when we have a funding round, the fund has set a size and scope of the funding round. And then we call for applications from all around the world. And it’s a competitive application process. To give you an idea, since 2016, we’ve had I think 1163 applications and funded 90 to 92 projects. So that’s around 8% or something. So it’s quite difficult. I think the good thing that I’m actually proud of at CARB-X, is that even if programs get through to the later stages of the application and don’t get funded, we still provide them with expert feedback from our you know, suite of advisors to help them improve their project. So even if they don’t get funded, they still get, you know, really good feedback on, you know, this is not only what would have helped you in this application, but this is what would help you in your project going forward. So hopefully they can still take that project forward and reapply. And we have had companies come back, reapply and then get funded. So that sort of supports that that notion works. So then once a company is contracted with us, we set up a series of negotiation rounds where we will negotiate a statement of work and we build a what we call a support team around them. Some of the companies we fund, a lot of them are very small, you know, less than ten people, some of them. And so they don’t have all of the expertise and all of the disciplines that they need to take a, you know, compound from hit to lead through to phase one. They don’t have the clinical or the regulatory expertise. And so what CARB-X has done is assembled a panel, if you like, a group of experts in the different areas that we fund. And we will bring those experts to bear. And they will sit on these support teams and work with the companies on a regular basis to add that scientific support around them. So we obviously give them non-dilutive funding, but we also give them a lot of, you know, technical and business development expertise as well as they try and build their company.

12:28  Caroline Duell
I understand, is over $300 million of funding invested into these projects that you’re working with at the moment. That’s a huge boost to the sector all around the world. It takes a lot of money to get an early stage project or a startup company, you know, sort of phase one, really. How much investment is required for these projects?

12:55  Richard Alm
Yes, that’s an interesting question about how much it costs. And obviously, there are some nuances there. CARB-X funds, therapeutics, preventatives and diagnostics. So depending on what pillar you’re of, that of what modality you’re in will have different costs. And also depends where you start. I will also say that, you know, some of the modalities we support like bacteriophages don’t have to do as much toxicology as a small molecule. And so those costs aside, so there’ll be a range of costs. But I would say for your average therapeutic program, if you are if you’re if you’re a company or your organization has multiple assets where some of the infrastructure can be deployed and costed against, you know, different assets, probably 25 to 30 million would probably be the minimum to get you through to, you know, phase 1, first time in human evaluation involved is, that that will depend on how strong your pharmacology package is or whether you pick up any toxicological signals in preclinical studies that you need to then follow up and do you know, more rigorous, tough studies before you progress. But that’s about how much it costs.

14:08  Caroline Duell
You just mentioned phages, and I know this is an interesting area of research around bacterial resistance. Can you just sort of, I guess, explain why antibacterial resistance is such a challenge at the moment?

14:25  Richard Alm
I mean, people have been talking about antimicrobial bacterial resistance for a long time. I think what some of the most pivotal data has come out earlier this year where the large Gram study from IMPE was done actually looked at the burden of attributable mortality to just the resistant part of antimicrobial resistance not just not from bacteria infections but from the resistant infections. I think the numbers like globally, it was like 1.27 million people died due to that were directly attributable to resistant bacterial infections. If you look at those that are associated, you know, associated with bacterial infections, with resistant bacteria infections, the number is almost 5 million. And that’s what they couldn’t attribute it, but it was associated. And that’s the equivalent of, you know, like a jumbo jet crashing every 37 minutes or something, you know, for a year, which, you know, if that was happening, people would pay attention. And yet I think a lot of attention because unlike COVID, which was a very rapid pandemic and very acute antimicrobial drug resistance is a slower moving pandemic. And it’s coming. And a lot of the last resort drugs are now resistances against those. And it’s going to get to a stage, unfortunately, if we’re not careful where simple surgeries, you know, hip replacements, you know, things like that are going to suddenly become, you know, a death sentence. Because if you get an infection, there’ll be nothing to treat it. And so simple surgeries, cancer treatments, all of those things and all those procedures, where we take the presence of an antibiotic for granted, are someday going to become a challenge as the resistance gets worse. And I think as especially in the Gram-negative bacteria as some of the resistance mechanisms have become so widespread, people have either resorted to colistin, which is a very old nephrotoxic drug, that people are still working out how to dose appropriately. It doesn’t get to all body sites as a last resort because that’s the only thing that most things are sensitive to. And now there’s resistance to colistin that is circulating through several mechanisms. And so people have been going back to your question about bacteriophages, the use of bacteriophages has been around for quite a while, mostly in Eastern Europe. I think it’s been picked up again by Western countries. And there’s a lot of activity now about treatment of severe infections with bacteriophage or bacteriophage cocktails, either empirically or personalized, where they will take an individual patient’s infecting bacteria and screen it against panels of bacteriophage and say, this bacteriophage will kill your bacteria. So we’ll dose you with that. And there’s been, you know, a lot of individual case reports where that has been successful. And I think the choice that infectious disease doctors have now is do we do we continue with it on this patient by patient basis or is there potential to move bacteriophage therapy into more of an empiric treatment regimen where you can use a cocktail against a certain pathogen and give it empirically without having to screen against individual patients, you know, isolates. And so I think the field, the bacteriophage therapy field is still working out where best to place it. You know, do you do it in combination with antibiotics? What’s the cadence of dosing? And some of those questions, I think, need to be answered in a randomized clinical trial format where you can robustly ask those clinical research questions. It’s very hard to get those answers when you’re doing one patient at a time. And each patient is very, you know, different. And so there are companies now that are doing, you know, randomized trials with bacteriophage. And I think some of that data will be, you know, will be very useful in directing the field as to where exactly is the best place for these phages to fit into the armamentarium of the infectious disease doctor? I have no doubt they will. The question is, where will they be best deployed?

18:42  Caroline Duell
So there is so many efforts and levels of research involved in this challenge of tackling anti-bacterial resistance. And you are working with a number of these projects, do you feel like you’re really working against the clock here?

19:01  Richard Alm
I do. In many regards. It takes a long time to develop a drug. I think it can take years and then it you know, a project can fall over for reasons that you don’t even predict. I mean, most people think it’s either not going to work or it’s not going to be safe. But there are other reasons that you know, projects can fall over and some of them, unfortunately, aren’t even for science. Some of them are for business reasons. The company might pull out and then try and re-license the asset to someone else and you’ve got to then spend the time to try and, you know, package the data up and find a buyer. So there’s a lot of things that can happen and go wrong between starting a project and getting it even into phase one, which is where CARB-X funds into so as you see all these, you know, rising levels of resistance, you do feel like you’re racing against the clock because it’s only getting worse, it’s not going to get better. And stewardship and infection control that hospitals are putting in place are slowing it down. And they should, you know, continue those policies because they make a huge difference. But, you know, little things like educating the public when and how to take antibiotics is also really important. And that’s all part of stewardship to try and slow down because it is inevitable. Bacteria replicate really frequently. And so evolution takes over and resistance occurs.

20:31  Andrew Bowskill
So you mentioned that CARB-X is a supporter of early stage projects and you’re one of the only financial supporters of those projects. And I’m just wondering, and a lot of those projects, as you called out earlier as well, come from really small organizations or even researchers, and that is still within a medical research institute or in academia. How can they be sort of poached to in development and product development? And what sort of things do you look for in a project to support those researchers and those small companies?

21:11  Richard Alm
First of all, I shouldn’t underestimate the value of research that a lot of governments put in through their funding for basic research. Because basic research is vitally important. CARB-X is a little bit different in that we fund product development research. So we don’t fund basic research at all. And so when we look to fund a program, when the applications come in, we look for applications that have a vision of where they’re going and who, what patient population they want to treat and how they want to get there. And so I think one of the biggest shifts between a lot of academic groups and, you know, to do the basic research over to product development research is really that. And that would be my strongest advice would be if you want to pivot from, you know, from basic to applied research is really think about who do you want to treat and how are we going to treat them because those questions asked early help you frame and design your preclinical research such that you answer those key questions. I think a lot of academic groups and a lot of academic applications, we see that the basic science is there, but they have no idea how to apply that to a clinical development program. So certainly when we have funded academic groups, we have had a couple of grants in Australia with the University of Queensland and what we looked for there was the ability to take that basic science but also have a product development mindset to it. And we always look for, is there an exit strategy? So either the groups that we fund have to have an exit strategy. Is it to out-license the product to certain stage to a group that will continue to develop it, which means that the group that are doing the work initially have to have the mindset to do the right experiments and ask the right questions so that it’s attractive to be out licensed, or are they going to spin out a company and do they have the capacity and the business development expertise around them to do that? And in the case of the group at Queensland, obviously UniQuest has played a role in that in several examples and so that made their application, you know, stand out.

23:40  Andrew Bowskill
So if you are a researcher, if there’s a researcher listening to this and that in an MRI or in academia at the moment, would you think that there’s an advantage for them to spin out into a small company? And if so or not, what do you think are the key attributes of a successful spin out?

24:06  Richard Alm
I think the most successful thing you can get with a small company is the people. I think having worked in both large and small organizations, the smaller the organization, the more important the people are and the way the people interact with each other. And if you’ve got a company of thousands, you interact with your small teams, but not necessarily with everyone in the company. When you’ve got a small company, you interact with everyone. And so that that dynamic and that culture is really, really important. From a scientific standpoint I think if an academic researcher at an MRI as is looking to say, spin out a company, I think they obviously need to get a story down of how their program, their product or future product is going to impact, you know, the health systems and the patients because they’re going to have to go and pitch that and raise money and raising money in this space is is difficult. CARB-X works on a cost share basis so our grants at the moment, some of the existing grants are at a 90/10 contribution. So we’ve been CARB-X has been supplying 90% of preclinical research to 10% cost share from the companies. I think the funders have now moved that to 70/30, which is where it was before COVID. But I mean that’s still a huge boost to them to get 70% non-dilutive money. But you can still have to raise those other funds. And so you have to have a story that you can go out and speak to investors and convince them that your vision is worth them investing in. And a lot of the well, most of the, you know, VC firms that have extremely good due diligence and they know the systems and the ecosystem that they want to invest in. And so you have to have a clear vision and a clear path to get there to warrant these people putting in their money because they want a return on their investment. So I think clear strategy, start with the patient in mind because that’s ultimately where you’re going to get because the VCs are not going to fund basic research, they’re going to fund they want to get to an inflection point where the product can be further developed or or sold off and they can, you know, recoup money on their investment. And so you have to have a clear path towards commercialization.

26:42  Andrew Bowskill
CARB-X has a global accelerator network with various organizations around the world. I was wondering if you could please tell us a bit more about that network and how it works and what those accelerators provide?

26:56  Richard Alm
Yeah, so we have, we have I think now we have six or seven accelerators, some of them are very, very like specialized. Like we have one fund, the foundation for innovative new diagnostics that helps our diagnostics portfolio. And that’s all they do. They do diagnostics. And then we have say C-CAMP in India, which they are an accelerator that goes out in the ecosystem within India and actually sort of encourages and draws out some of the science that is going on in some of the institutes in India and makes them aware of CARB-X. And I will say that since C-CAMP came on board the quality and the number of applications in our funding rounds from Indian institutions has grown dramatically, both in number and in quality. And so I think having an accelerator in a region where, you know, this is what CARB-X is looking for, this is how you can make a competitive application. This is, you know, and coach those groups, especially that are coming out of academia, how to make compelling applications is a key role of a pre award accelerator. The other aspect where we use the accelerators is post award. Some of the accelerators have specific technical expertise that will you know, bring into these support teams. Some of them have good access to regulatory, you know, regulatory agencies in Europe and so they can help if your plan is to, you know, to go in and file in Europe, they can help set up and facilitate interactions with European regulators. And so beyond the you know, once you’ve been awarded a CARB-X grant, these accelerators can also help accelerate, hence the name, but then can also, you know, help further the progress of your program by bringing in expertise and opening up doors and facilitating interactions where a small company might find it difficult. And the accelerators can do that. And so I think of the accelerators as two halves, the ones that help potential applicants frame a better story to get funding, but then also support companies in their portfolio, in the CARB-X portfolio that have been funded. How they can accelerate that by opening doors and creating networks beyond that and both play an important role to make sure there’s a robust pipeline both in the ecosystem as a whole, but in the CARB-X portfolio. Yeah. Specifically.

29:40  Andrew Bowskill
Right. And so and currently there’s no AMR accelerator in Australia nor for that matter in the Western Pacific region. And so you’re aware of the work that AAMRNET has been doing while we’ve been exploring how we could establish AAMRNET as the AMR accelerator here. So it’s the sorts of things that we’ve been doing is engaging internationally, raising awareness about Australia’s capability and capacity and building on its reputation as a single contact point for AMR R&D here in Australia. And we’ve also collaborated with therapeutic innovation Australia on their pipeline accelerator voucher scheme. And thank you for your input and being part of that assessment process on that one. So we just announced the awardees yesterday I think along with TIS. So that’s really exciting. And we’ve also been working with the same team that you support at University of Queensland to hopefully bring the ICARe antimicrobial drug development course to Australia next year, hopefully. And what do you see as the next steps for AAMRNET to get established as Australia’s AMR accelerator and possibly be integrated into the CARB-X global network?

30:56  Richard Alm
So upfront, I mean I’ll say that CARB-X would love to have an accelerator in Australia supporting obviously the Australian ecosystem, but also, you know, the Western Pacific as well because I think there are things going on in New Zealand that we don’t hear about. So I do think an accelerator in this area, you know, geographically this area would be, you know, exceptionally beneficial both to us at CARB-X, but also to the, you know, the greater ecosystem within Australia. And we have two accelerators in our network, the DCIF in Germany as well as C-CAMP in India that are funded from local governments. I mean, I think it would be it would make sense for the Australian Government to understand and recognize the risks that AMR play for the Australian population and see the development of an accelerator as a real investment, not just to develop and encourage and formalize some of the AMR research that’s going on in Australia. And I will say that even in my short time back here a couple of times this year, I wasn’t aware of how much AMR research was going on in Australia. So it’s really pleasing to see and I’m in the AMR field and so for me to see how much there is here that I didn’t know about that needs to get exposed to the world. I mean Australia has, you know, a very good history of doing, you know, good medicinal research and to get that out in such a valuable field as AMR is important. And I think an accelerator would help do that and raise it to an international stage. From a CARB-X perspective, obviously having an accelerator here to understand what CARB-X is looking for, each of our funding rounds and knowing who to contact in all the different research centers and supporting them to put in applications. I mean, the CARB-X grants are fairly large. I think, you know, most of them are on our website, so I won’t put the numbers up, but people can go and look. I mean, but they are significant. And to be honest, even if the development of an accelerator, you know, got one or two of these research grants into Australian, you know, scientific research, that would be more than the cost of funding an accelerator for a decade. So from that point of view, it would be money well spent for the government to step up and put in money to establish a, you know, a bona fide accelerator. And I think the other benefit, you know, just talking now specifically within the CARB-X sphere, a lot of our companies, as you mentioned in the beginning, Bug Works is doing their phase one in Australia. Australia has a reputation for having phase one units that are very good and we’ve had several of our companies within the CARB-X portfolio come and do their trials in Australia, but that’s in the Post Award accelerator. That’s where, you know, if companies are now progressing towards that stage, the connections could be made and the benefits could be directly applied to those companies from members of an accelerator, and that would only help the ecosystem within the clinical research arms of Australia as well. So I think there are multiple benefits of having an accelerator. I think somehow to harness all of the work that’s going on. Australia’s a big country. I think. But there’s, you know, there’s stuff, there’s a lot of stuff going on over in Perth from Brisbane down to Victoria. I mean that’s a lot of geographical area to cover to try and harness all that knowledge and all that, you know, in a central facility, if you like, or a central part of knowledge would be very, very useful, not just for CARB-X grants, but there are other granting bodies, less demand non-dilutive, but there are other, you know, international granting bodies that will, you know, give grants as well. And so it wouldn’t have to you know, it wouldn’t obviously be tied just to supporting CARB-X. It would be able to help these groups get funding from, you know, a lot of other sources as well. But all I can say is we would love to welcome an Australian accelerator into our stable.

35:08  Andrew Bowskill
So great news. Thank you.

35:11  Caroline Duell
You mentioned companies coming to Australia to run their early clinical trials. Why is Australia such a good destination for this type of clinical trial program?

35:25  Richard Alm
Few reasons come to mind. One is obviously, I think the quality of the data that comes out and the access to, you know, rapid assembly of cohorts and then, you know, robust data is obviously what companies look for in terms of their timelines if companies are also fighting against the clock because, you know, the burn rate of finances for small companies is quite quick. So the quicker you can do a clinical trial and not have it drag on, the quicker you get your data. And to be honest, the end of phase one is a very good inflection point for infection companies because you’ve got that preclinical pharmacology, you’ve now got human exposure. If you’re above the know how, you can work out a therapeutic index. And then that’s a really good inflection point to then try and get additional funding to do phase two and three. So I think speed and quality of data is one. The Australian Government also gives a, you know, a tax incentive rebate, which I think a lot of companies, especially the smaller companies, find very attractive. I mean I hear even working in the US, the Australian, you know, phase one companies will do little webcasts and webinars over their advertising themselves. So it’s not just in the therapeutic area of infectious diseases, it’s, you know, it’s a lot of different therapy areas that companies are coming to Australia to do. The early clinical research.

36:47  Andrew Bowskill
You mentioned the CARB-X has supported a couple of projects in Australia already. You talked about the gang at UQIMB and Bug Works have set up an Adelaide’s. There’s also SpeeDx in Sydney. What do you think that Australia and Australian researchers can do to be even more successful when it comes to accessing CARB-X or any other international funding for that matter?

37:15  Richard Alm
So projects that we have funded here, I’ll take SpeeDx to start with. I mean their platform technology is excellent. You know, the program we’re funding is a gonorrhea and chlamydia diagnostic that also picks up resistance very quickly. Obviously the point of care diagnostics for STIs is really important just because of the patient population, you need that out so very quickly. Their technology was quite impressive and they had a path on how to turn their assay platform technology with another partner into a product. The Queensland group had a program when they first came to us that was looking at a product that could kill colistin resistant bacteria. We spoke about colistin earlier as colistin resistance is increasing in the Gram-negative bacteria, something that could kill colistin resistant bacteria is obviously really important because that resistance is only with the amount of usage that colistin is getting now, that resistance is going to spread. They also came in with a very unique proposal around low and low- and middle- income country capability building, which one of our funders, GAMRIF, which is the UK government arm of our funding, is particularly interested in in LMIC or low- and middle-income country applications. And so they fund studies or portions of programs that are directly applicable to LMICs. And so the Queensland group came in with a very unique way of trying to build capability built in, in some of the LMICs. And the UK Government liked that proposal and that was, that was their second, their second grant was to work around how you could use some of their molecules as potentially agents against colistin resistant bacteria with widely available drugs that are already on the market in LMICs and potentiate. So you can repurpose those and reuse them and make them active again. But also with that, they tied in some capability building to help the LMICs researchers understand their problem and how to do molecular epidemiology on site. And that’s now I think if you help but rather than do things for groups like that if you teach them how to do it and they can do it themselves, that brings a lot more value to the whole world really. And so there are two very different programs that we funded here in Australia. When the funders of CARB-X set the scope of the funding around, it’s fairly narrow and will be hopefully announcing our new funding round soon. You know, read those and then I would encourage people within Australia to if you have a program that fits that, you know, reach out to some of the companies within Australia or within the CARB-X portfolio and say, you know, what is it like? We have companies that learn from each other, we have company only webinars, meetings where we will bring out companies together so they can learn from each other. And so that’s a different type of network. But we’re all in this together. And ultimately, as even when I work for AstraZeneca, if your child or your mother gets sick, you don’t really care which company has made the drug that saves their life. I think we owe it to ourselves as a society to make sure that, you know, we help each other be successful. And I think especially in an area where such devastating infections can take the life of someone, we need to help each other. And so, you know, one other thing that we’ve been doing at CARB-X just in the last couple of years, we call them portfolio acceleration tools. If we see several companies dealing with the same issue, we bet we will actually sponsor an activity that brings in data that we can share with those companies, but also to the greater ecosystem. Because, you know, that’s part of what CARB-X is about, is making sure that patients get access to drugs. And if we support the companies that develop them or we support the ecosystem that can develop them outside of our funding, that’s equally important to society. You know, help get off my soapbox now. But I think that that’s really important. And too often companies like don’t share data and then, you know, it’s seen as a competitive advantage if another company has to spend years and years to, you know, go down the same path to find out that, you know, that’s a toxic molecule that’s going to cardiovascular toxic problem or whatever. Whereas we talked about earlier, we’re racing against the clock here. And if you can shave off a couple of years by sharing some data, publishing it, talking to people that are in the same field, you know, I think the time for that level of competitiveness in this field is gone. I think we need to work together. And so I would encourage any applicants in Australia to, you know, speak to the Queensland group or whatever and find out, you know, what they thought CARB-X, what, you know, what they put into their applications and yeah, come to us with the best app application you can generate with this is the patient population we want to treat and this is how we’re going to treat them. This is our vision.

43:07  Andrew Bowskill
It’s a really important point, I think. Yeah. I mean, collaboration is the key, certainly MTPConnect, we stand up there and say, you got to collaborate, you’re going to collaborate, right. And that the whole message of what are we doing this for in the first place? And that’s to ensure patients have access to the right.

43:27  Richard Alm
And I think that shouldn’t be forgotten. There’s the old saying it takes a village to raise a child? I think that’s where AMR research is now. And there’s so many big companies that got out of it. You know, so many little companies are doing the lion’s share of the work now. And they all would benefit from the knowledge. And, you know, the other thing with the big companies leaving the space is that you’re losing a lot of that institutional knowledge. And you mentioned, you know, the eyecare costs that you’re hoping to bring down here next year. I mean, I think part of that is to train the next generation of antimicrobial drug discoveries, because, you know, when old people like me stop, you know, if there’s no one to teach the next generation, then that’s going to have to be relearned. And unfortunately, we don’t have time to relearn how to make, you know, good antimicrobial drugs. And so the continuity of institutional knowledge of how to do it needs to be passed on.

44:31  Andrew Bowskill
And it’s a good segue to the next question, actually. It’s about young people and how can we get more young Australians involved in raising awareness around AMR?

44:44  Richard Alm
So interesting question said you mean young researchers so they research it or just young people in general to be aware of the risks of AMR?

44:55  Andrew Bowskill
I think that everyone needs to be more aware of the threat that AMR poses and in the future. I mean, if we’re running out of antibiotics and to think that someone can’t get chemotherapy or a hip replacement or whatever is, is just incredibly frightening to bear if you stop and think about it. But so yeah. So but yeah, I mean, obviously we need young researchers to get involved as well to try and overcome this. And it’s a village, as you say.

45:30  Richard Alm
I think in terms of general population, I think one of the most important things is the precision of communication. I think COVID has taught us that, you know, populations as a whole can understand scientific principles if they’re communicated fairly clearly. And, you know, unfortunately, COVID has been there’s been good examples and bad examples of that, of how to communicate. But I think if you ignore the bad examples and some of them were quite bad, there were several really good examples of how to talk to the global population, you know, within your country of this is what an infectious disease is, these are the risks, this is how to help. And I think that precision of communication, honest and transparent, is the best way to go. And I think that more and more drug resistant bacteria need to be included in that conversation just at a population level. I think the challenge there is, because it is unlike COVID, it doesn’t affect you so acutely. It’s easy to ignore and, you know, kick the can down the road and, you know, let the next administration worry about it because it’s not our problem. And so I think in terms of the general population, it’s all about you don’t need to put fear into it, but I think you need to be realistic and honest and precise in your communications. That’s for the general population. I think in terms of, you know, if there are researchers going on and you know, where they can choose their career, I mean, microbiology, I’m biased but microbiology is, I think, a fascinating career, working with things you can’t see and watching them evolve and change and adapt basically in real time is is fascinating. And so I think what I’d like to see, you know, some universities I know some are doing this and I applaud them for it is to blend that basic lecture series of microbiology into biotechnology. And how can you turn that basic knowledge into, you know, translate that into medical research? I think the more that you can, you know, not just go to the textbooks and say, learn this remotely, you know, and just, you know, memorize this, memorize this, but actually take that information and translate it and run biotechnology courses or bioengineering or whatever to show students at an early part of their career, maybe as a, you know, undergraduates as to this is how what you’re learning today can be applied, I think gives them a lot of focus and a lot of, you know, excitement about how they could make an impact. And so if you can encourage undergraduates to see how, you know, basic textbooks can really be translated into products, can help the population they will develop technologies that we can’t even think of yet. And so but they need to early on, I mean, when I went through undergraduate, it was, you know, you just learn about bacteria and that was it. It was only really when I ended my postdoc that I was lucky enough to get into industry and see how it’s not just your single discipline. I mean, all through my academic training, it was really just molecular microbiology and that was it. It was only when, you know, you get to a company and you see all these other disciplines, you know, the pharmacology and the biochemistry and the toxicology and how they can all come together and work together. And you have experts from all these different disciplines sitting in the room working on the same problem. Again, it comes back to that collaboration. You all have that singular focus of what can I do with my specific expertise to make this product move forward safely and effectively. That level of broadness in undergraduate would have been a huge advantage to me, rather than taking, you know, six or seven years to come across it. You know, I think for universities or early researchers now, students to get exposure to how other disciplines play a role and what you want to do and how you want to apply I think is important.

49:52  Andrew Bowskill
It’s exciting to think what’s possible in the future, that’s for sure. It really is as scary as AMR is and it’s exciting to think what solutions we can come up with, the new generation can come up with as well. So we can’t talk about anything and we have already a little bit without bringing up the impact of COVID 19 and how the pandemic tested our responsiveness and preparedness around the world to tackle a global crisis in a short term. How do you think the world is currently set to fight against AMR and how can we in Australia be more involved in the global effort?

50:29  Richard Alm
I mean watching it, it was surreal in the States for two years watching COVID evolve because as a microbiologist slash virologist, there was nothing that happened that was surprising. I mean, it was the spread of a, you know, respiratory viruses. It can’t be stopped. And so, you know, I think the speed at which some of the treatments and vaccines came online was breathtaking. Knowing how long it takes to develop those normally. And, you know, I’ve heard people say, well, why did it happen so quickly? It wasn’t done robustly, which is frankly completely untrue. I think one of the biggest things was that because there was money given to the companies that were developing it, you could run trials in parallel without waiting for that, you know. Do I reinvest? Look, let me look at the data. Do I reinvest? Because the money was there? You could do things much faster, which, you know, I’m not saying that that will happen in every case in the AMR, but certainly the availability of funds drives innovation. There’s no question about that. We saw that with COVID. I think as horrific as COVID has been, I think it’s also taught us about preparedness and hopefully put the world on notice that, you know, some of these things, you know, are going to happen again. And how do we prepare, I think with all the molecular testing capability that’s now been deployed around the world to low and middle income countries and to, you know, all different regional centers, I think to have that capacity now to pivot that towards AMR detection and AMR diagnostics would be incredibly useful for both from a surveillance as well as a, you know, just a diagnosis standpoint, but also from a surveillance aspect. If some of that molecular technology that testing can be pivoted towards AMR would be tremendously useful. So I’m hoping that that happens. I think, you know, Australia did really well early on in COVID. I mean I was obviously because my family’s here, I was watching it, I was really impressed at how coordinated Australia was compared to, you know, what was going on in the US at the time, which was, you know, not as coordinated. At some point you get that, you know, that pull of well at which point do you open up again? And I think every country struggled with that. But overall, I think the organization of Australia during COVID was exceptional. I mean, when you come in, you have the sign in QR codes and the contact tracing and the earlier, there was nothing of that in the States. And so, you know, Australia should be really proud I think, of how they handled it and you know, early on and set up those things. In terms of AMR pivoting to that, I think as I said earlier, there is a lot of AMR research going on in Australia. I think having that coordinated and put together to help, not just locally, you know, within Australia but also globally because we do live in a global world. I think that’s one thing COVID has definitely taught us is we’re all so interconnected that it’s not a one country problem. And I don’t think AMR is either. But I do think that the government needs to understand that access, all governments, not just the Australian Government, that access to good antimicrobials is what’s going to prevent an outbreak. And so if you have an outbreak and you don’t have a good antimicrobial, you may not be able to. I mean, the vaccines and stuff came for COVID in, you know, in 12 months they repurposed some antivirals very quickly. I don’t know whether if you had a drug resistant bacterial outbreak that was that widespread, that you could repurpose another drug because they’re already resistant to it. And so I think understanding that you need a consistent pipeline is one of the hardest things it seems to for people to comprehend that you have to prepare years in advance and you need that. You can’t just say, okay, there’s, you know, there’s 20 products in phase one to phase three now that are moving through. If we get three or four drugs out of that will be good because those drugs will you get resistance to those drugs fairly easily. And if you’ve got nothing to replace them, it takes it takes a decade to build that pipeline. And so that’s where CARB-X is really focused, is trying to make sure that there is a sustainable pipeline there with things going into clinical development on a regular basis so that we’re never caught out. And so I think the governments of the world to realize that having a pipeline is what’s important and not just, you know, a drug on the shelf today.

55:38  Andrew Bowskill
It’s a really interesting and unique challenge that AMR sort of poses for the world.

55:45  Caroline Duell
So, Richard, what’s next for CARB-X, given your newly announced funding? What’s the horizon looking like now?

55:51  Richard Alm
Yeah, so we were really proud to get to get the new BARDA Award, which was announced July 1st. I think that was $300 million commitment over ten years, which, you know, I think shows their commitment, you know, to a longer term horizon and Wellcome, which was our another one of our original funders. They came in with more funds as well. I think very shortly within the next few months, hopefully we’ll announce how the scope of our new funding rounds and then we start again with the applications. Some of the discussions we’ve had internally already is, where are the gaps in, you know, in the, the global portfolio as well as our portfolio? What, where are the real gaps? And I think anyone that follows this space can look fairly quickly and say, well, it would be good to have more oral drugs. I think a lot of the drugs are IV based. I think some of the oral drugs that are used commonly, the resistance is getting so high to those that they’re becoming less and less useful. And so to have some good oral drugs for some indications, especially for indications that could be treated out of the hospital. At the moment, if you get a drug-resistant bacteria, even for something as simple as a urinary tract infection, you have to go into hospital to get an I.V. drug. And because there is no oral alternative. And so then you’re now paying hospital costs and the burden on the health care system, you know, at a time when the bed may be better used for someone else, you’ve got someone in there with imminently what would be a treatable outpatient infection if you had an appropriate oral drug. And so I think, you know, there’s an area that I think, you know, I’d like to see more and more attention paid to, you know, getting some oral drugs obviously that hard. I’m not saying they’re easy to develop, but there are things like that that I think hopefully will be, you know, the focus going forward of trying to fill some of the gaps that are in both our pipeline and in the global preclinical pipeline.

58:07  Caroline Duell
Well, we’ll be watching with interest. Richard, thank you so much for joining us today. It’s been a fascinating conversation with you about the challenges of antibacterial research and the work of CARB-X. It’s great to have you back in Australia for a little while and we look forward to staying in touch.

58:25  Richard Alm
Yeah, thank you so much. It’s been lovely.

Host: Steven yang
Guest: Richard Alm, PhD, Chief Scientific Officer, CARB-X

00:12  Steven Yang
Now we know phage therapy is part of the bigger picture of antimicrobial efforts, especially at dealing with the growing threat from antibiotic resistant bacteria. From an investor perspective, to make the right bet, it’s important to have a more comprehensive understanding of the big picture and be able to compare phage therapy horizontally through the other products on the market. I’m Steven Yang, and this is phage therapy today. We’re honored to have Dr. Richard Alm with us on the show today. After his PhD at the University of Adelaide and his post-doctoral work at the University of Victoria and University of Queensland, Dr. Alm served in R&D, a management position at AstraZeneca for 20 years before he became the vice president at Macrolide Pharmaceuticals, now known as Zikani Therapeutics until 2018. Starting in 2019 doctor who is currently the alliance director at CARB-X and a consultant to the World Health Organization. Dr. Alm, thanks for joining us today.

01:18  Richard Alm
Oh, you’re welcome. Nice to be here.

01:20  Steven Yang
Yeah, it’s great to have you here. So I must say, Doctor Alm, going through your career path over here, I feel like you definitely take a few harsh turns over here, both location wise, as well as the career pathway. So I guess I’m always interested, how does our guest, the formative years eventually get you where you are now? I guess also tell us about how you became interested in learning about phage therapy and also what does CARB-X do, what do you guys do over here?

01:54  Richard Alm
Yeah, of course. So, yeah, I mean, going back many years, my career, if you like, has taken a few turns. I had originally wanted to be a veterinary scientist, but growing up in the eighties in Australia, there were very limited options as to the number of universities that would actually teach that. And so for personal reasons, I had wanted to stay in Adelaide and so my dreams of becoming a veterinary surgeon got dashed. And so I found my love in microbiology and so I did my major, my undergraduate microbiology and then did both my honors and my PhD in microbial pathogenesis. And I was lucky enough, I think, during the last year of my PhD, to share a bench with a scientist that was on sabbatical from Canada, and he invited me back to his lab to do a postdoc in Canada. And so I of course accepted, had never left Australia and so came and went to the University of Victoria in British Columbia, which was beautiful. And I spent three years there, after which I went back to Australia, to Queensland to do another postdoctoral fellowship in Pseudomonas Pathogenesis. And during that time the professor that I had worked for in Canada had been getting research funding from Astra. It was before AstraZeneca and he got asked to set up a research satellite in Boston here. And so he called me back in Australia and said, “Will you come back to the United States and travel back across the ocean, work with me again?” And so I did. And my plan was obviously to only come for four or five years. And I’ve been here 23 or so, I’m still here. And so that became Astra, became AstraZeneca. And then unfortunately in 2015, AstraZeneca got out of infection like a lot of the large pharmaceutical companies have. I spent a few years at a small startup where I was involved with CARB-X from the recipient side. We had a CARB-X grant that I was PI on, and then when that company pivoted and got out of anti-infectants again, I joined CARB-X and have been there for two and a half years. And when I joined there, there was one phage company that was in negotiation after having come in an early round, and that was Eligo Biosciences. They were in negotiation. There hadn’t been the contract hadn’t been announced yet, but they were that they were being negotiated. And so when I first started, we had a 2019 funding round, we called it. It was broken up into four parts. And I was responsible for the nontraditional. So the odds and ends that the island of misfit toys I called it, all the bits that didn’t fit into the vaccines or diagnostics or direct acting school molecules. Everything else got bundled into the nontraditional round and that included phage. And so we had I think we had 11 or 12 phage or phage related products supply, of which I think we have a three, a three tiered application stage. And I think six of them made it through to two longform and three of them eventually got funded. So now we have four phage companies in our portfolio. And I had used phage, you know, throughout my formative molecular biology years more as a tool in the lab. I did my Ph.D. on Vibrio cholera. There were the people in the lab that were there working on the first phage of vibrio cholera, that had been isolated from sewage and in low- and middle-income countries. We’re working on phage there, but I’ve never really considered phage as a therapeutic. I’d heard about it in Eastern Europe, but had never really experienced that. I’d rather use it as a molecular biology tool. So I was really excited to see the advancements that have been made in phage and how they had been used and their introduction into Western medicine. And I think that they hold a very unique and specific niche for treatment. We have in CARB-X now I’m pleased to say we have a couple of programs looking at treatment with phage and a couple looking at prevention of infection using phage. And so I think it’s a very exciting field that we’ll still as a community, I think, working out exactly where phage will fit with this, with their therapy. They’re obviously extremely flexible, as you know. And I think there’s many opportunities for how they can impact the treatment of infectious diseases.

06:39  Steven Yang
Wonderful. So I guess before we go into the details of these companies, tell our listeners about what kind of is it private funding, is it public funding CARB-X is.

06:50  Richard Alm
CARB-X was founded in 2016. It was a competitive application put in. The executive director is Kevin Outterson out of the Boston University School of Law. He had been in health policy for years, and he, together with a couple of colleagues, put in an application in response to a call from the federal government that was established under the Obama administration. The Presidential Action Committee Against Combating Antimicrobial-Resistant Bacteria, so PACCARB. And so that sort of was the foundation of CARB-X where the BARDA, which is part of the Health and Human Services Department of the US government, they had put money to form this accelerator to help fund pre-clinical projects in the space. And it was for therapeutics, preventatives and diagnostics and Kevin and his small team in the beginning went out and raised other money from other funders. And so in our first five years we’ve been funded by BARDA from the US Government, but also we have funding from the German and the British government, the UK government and also we have a lot of funding from the Wellcome Trust who were initial partner with BARDA and also from the Bill and Melinda Gates Foundation. And we also get in-kind services from NIAID, which is part of the NIH. And so our companies that we fund get access to the pre-clinical services on a streamlined basis through that offered through NIAID. And so it is, it’s a completely nonprofit. We do, we fund companies through a competitive application process. CARB-X doesn’t take any equity state, so all the funding is non-dilutive, which is good for the companies because I think the companies in this ecosystem struggle because of the economic challenges that selling antibiotics can cause, and it’s a reimbursement model. So it’s quite unique. So it currently for pre-clinical work, CARB-X will put in 90% of the cost and the companies put in 10%. And then as programs move into phase one, which is as far as we as we fund, it’s an 80/20 split where CARB-X would put in 80%. But I will say that it’s more than just the money. A lot of these smaller companies don’t have the broad personnel base within their company where they have expertise in all the disciplines and so every team, every company, the CARB-X funds has a team built around it where we will supply free of charge access to our consultant network. We have about 160 to 200 consultants on retainer that we can draw on across all the different disciplines to provide ad hoc both business and scientific support to these small companies as they progress their program through. And so it’s a very it’s not just, you know, here’s the funding good luck and leave the companies alone. There’s a lot of interaction. People like myself in the R&D team at CARB-X, we get to know our companies and our product developers very well. We work with them and we discuss with them on a monthly basis, sort of what areas they may need support in. And then it’s our job to then go out and try and find that support for them, to help them as much as we can progress their projects. And so it’s a true collaboration, very unique funding model, but a very good one.

10:36  Steven Yang
I think that’s definitely true because especially for those you mentioned, there are pre-clinical companies. So this early stage mentoring is definitely a very big thing. And also the way you fund it, I guess for biotech, you never have enough money.

10:53  Richard Alm
Yeah, true. I mean, I will say that the one thing that having worked for almost 20 years in a large pharma and seeing the unfortunate exit from large pharma of so many infection groups is where I’m nervous that the field is losing some of the institutional knowledge about how to do this type of research. And I think it’s important from an educational aspect to keep some of those people engaged, to try and teach the next generation of antibacterial drug companies.

11:26  Steven Yang
Elaborate a little bit on that.

11:28  Richard Alm
Yeah. So I know that when AstraZeneca got out of the infection space, there were scientists there that had spent 30 years like chemists that knew every class of antibacterial inside and out that had been worked on across the industry. And when they left and then when our infection group of AstraZeneca dissolved, a lot of people went off to other therapy areas. And that knowledge then is lost from the infection, antibacterial space. And so if those people don’t come back to infection, you lose that knowledge. And with so many large companies leaving and, you know, the infection therapeutic area, those people, if they either retire or they go into other therapy areas a lot, go to cancer or metabolic diseases, chemists that discipline knowledge is broad based. So they can go to other therapy areas quite easily. You lose that knowledge of the uniqueness of how to treat infections and how to make molecules that can actually cure bacteria. Because a lot of that, a lot of the uniqueness of the drug discovery aspects in antibacterial research is unique to the bacterial space and so very different to making compounds and drugs for other therapeutic areas, both in terms of the amount of compound that you need to make. So even the process of chemistry is more challenging. Early on, you might have to make kg and kg early on. So you have to start your process chemistry early formulation is challenging because your doses are so high with small molecules. And so there’s a lot of unique challenges in infection that if people that have worked on that leave retired, go to go to another therapeutic area. There’s no training of the younger generation to pick that up and continue to develop it and make progress in the field. Very useful to make sure there’s that continuity of knowledge.

13:35  Steven Yang
Definitely. Yeah. What is a background of all these all the big pharma is leaving the antimicrobial space?

13:43  Richard Alm
You mean why did they get why did they get out?

13:45  Steven Yang
Right.

13:46  Richard Alm
Yeah, that’s a good question. I mean, ultimately the economics of antibacterials are challenging because unlike, you know, heart medicine or, you know, things that you take every day for years and years, antibiotics, antibacterial drugs are used on a very acute short-term basis, you know, really, you know, 10 to 14 days. There’s a few indications where you give them a bit more chronically, but typically they use very acutely. And so that’s one of the challenges. You don’t sell a long, you don’t get a patient for life. You get them for 10 to 14 days. So that’s one challenge. The other challenge is that you spend all this time making a good drug, let’s say, that is active against some of the resistant bacteria. And as soon as you launch it in, the nature is to say, okay, we’re going to leave that until we really need it. And so then they put it on the shelf until you really need that drug. And so then you don’t sell it anyway so that you spend all this time and effort and resource making this drug, and then it gets put on the shelf for that last, you know, last resort antibiotic and it doesn’t get used. So therefore you don’t have the sales. And then the third pillar, if you like, of challenges that a lot of drug sensitive bacteria that cause infections can be treated with generic drugs, which are very cheap. And so inherently people are nervous to use expensive antibiotics when the cheap ones may work a good percentage of the time. And so they now typically try and go to the generic ones first, especially in the hospital situations where all the reimbursements in the US are bundled. And so you basically get reimbursed by the indication as the drugs are used. And so if it’s treatment within a hospital, financially it’s better for the hospital room to use the cheaper drug rather than the expensive drug because they only get paid a certain amount per infection, if you like. And so I think you put all those three together. It’s a very challenging business model. And the times of antibacterial drugs being blockbusters and selling, you know, half a billion to a billion dollars a year of sales are pretty much gone. I think there’s probably only one drug now that is even close to that in yearly sales. And so I think the large companies in the you know, their in their business, they need to show profit to their shareholders. They moved on to they wanted to focus in on different therapeutic areas and infection is one that’s not going to give them the biggest return on investment compared to some of the cancers and stuff.

16:35  Steven Yang
So you’re right, they left the space for smaller companies and also more innovative ways for treatment and sturdy set up the model kind of what is now working for them.

16:48  Richard Alm
And I think that’s what you see now. I mean, I think that if you look at the preclinical pipeline now, it is 80% small and medium sized companies and by small companies I mean less than ten people. I mean there’s a lot of very small micro companies that basically do most of their research through CROs and then and that’s there, they don’t have to pay a lot of salaries because they usually only have one, maybe two assets. And so they go through CROs and they try and move programs through that way. And I think that’s where CARB-X has really been able to help the ecosystem to come in and help those. But you’re right, in terms of the innovation, I think what we’ve seen in the last four or five years is, you know, some of the some of the recent publications that have come out have shown that the preclinical pipeline up to, you know, testing in humans, approximately half of the antibacterial pipeline is now directed against single pathogens. You know, both the CDC and the World Health Organization put out their threats list of their priority pathogens list, you know, against these are the pathogens that that most work should be done on because these are the most challenging bacteria. And researchers have focused on that. And then looked at ways to kill just those specific bacteria. And I think that has led to a lot of nontraditional approaches. And, you know, I mentioned earlier in the podcast about the CARB-X funding round in, you know, when I first joined CARB-X and there were four funding rounds in 2019 and the nontraditional was actually by far the largest in terms of the numbers of applications and the numbers of awarded grants, because there’s a huge amount of diverse and innovative science that’s going on out there. And these small companies working in this nontraditional space have these ideas, but they don’t have the financial resources to try and prosecute those ideas. And I think that’s where push mechanisms like CARB-X are very valuable because it helps develop that science, not just for that particular group, but also for the entire ecosystem. Because everyone learns if you do a certain aspect of science and then you publish it, the whole field learns. And I think that we encourage all our developers to publish their research and talk about it as much as they can, because I think it moves the whole field forward and that’s what we’re going to do as a society.

19:40  Steven Yang
That’s a very big picture you just painted. I know  you mentioned this once or twice. It’s about how some different pathogenically, some of them are more sensitive already to the existing drug, but some of them maybe are some rare pathogen, maybe they’re antibiotic resistance, and where we see phage in this picture?

20:01  Richard Alm
Yeah. So I think there is a growing antibiotic resistance trend. And I think that’s the slow moving tsunami, if you like, of fear among people. You know, that that are in this space because the resistance, the percentage of resistant bacteria are growing. And the more they the higher the percentage of resistant bacteria, the harder they are and the more recalcitrant the treatment options are, because they just they don’t work. And I think that’s where you’ve seen phage therapy sort of grow in the United States, mainly at the moment through emergency use and compassionate use, where patients have been completely untreatable, their infections have been untreatable with multiple different antibiotics that have been tried because the bacteria that’s causing the infection are resistant to all of these drugs. And so as a last resort, people have been using phage therapy. And, you know, the challenge with that is, you know, in many cases, that is a success that that and then a successful treatment, I think, which gives people a lot of confidence that phages can play a really important role in the treatment of MDR infections, multidrug resistant bacterial infections. I think the challenge from a regulatory and a clinical perspective is when you treat a single patient, usually a very vulnerable patient at the, you know, in serious medical need with an underlying infection and you treat them with phage. It’s a one-off customized treatment. And so that treatment has never been evaluated in a randomized clinical trial to understand how to use phage most appropriately in the clinic as an even as an empiric therapy. And so I think as phage therapy graduates and becomes more mainstream and matures in its use, I think what is needed is clinical trial and some of them are ongoing now, which is great to see is randomized clinical trials where you are evaluating key clinical parameters with phage in a controlled fashion in a clinical trial. And I think that will give a broader acceptance to phage being used as a therapy or as a preventative, because it then will get regulatory approval as a broad product rather than a compassionate use product to this particular patient. And I think that’s what the next step the field needs to see. I mean, we’ve seen that clinical benefit, but a lot of those patients are very sick and some of them succumb to their infections. But you don’t know if they have succumbed to their infections because by the time they got the phage treatment, they were in such dire medical need that even the phage couldn’t help them. And so I think you need to understand you. We need to understand as a community where is the best place to position phage and where can they have the maximum benefit for the treatment of these infections? There’s no doubt that they will play a role. The question is finding that patient population or that indication where they can be most useful to the broadest number of patients.

23:43  Steven Yang
Right. So eventually it all goes back to the clinical data.

23:47  Richard Alm
Yeah. And I think the one thing about phage that I mean is everyone that’s worked with phage knows this, but it’s, it’s worth pointing out and that is phage are inherently really specific. They can be specific for a particular species, but also for a particular isolate within that species. And so a lot of these emergency use cases, you have to match the exact isolate that’s causing the infection in that particular patient with that sensitivity to a phage, I think as groups start to strategize and come up with ways to either make larger cocktails of phage so they can be used empirically, that will help cover the maybe the differences within a species of different strains. I think what is still one step beyond that is how can we quickly diagnose the causative agent of an infection so that we know which phage cocktail to give? And I think that’s where diagnostics are a really fast-growing area in infection. Typically, you know, if you go back, you know, years diagnostics was you played out the biological samples and two days later you get what bacteria it is and whether it’s sensitive. And by that time, it’s hard to give care if you’ve already treated the patient empirically until you know exactly what’s causing the infection. I think especially with patients that are extremely sick or extremely vulnerable, you need to have that answer quicker and if you’re going to use a very precise medicine like bacteriophage, then I think you need to know that with more confidence earlier in the treatment cycle so you can make sure you’re putting the right treatment on board. And if that happens to be a phage cocktail that you know that you are putting that the correct phage against the right species. And so I think the combination of the development of diagnostics, rapid diagnostics as well as these broader I’m calling them cocktails, but there could be other engineering aspects that broaden that host range of phage. I think that combined will take phage from treatment of a single patient where you’ve tested a susceptibility of that pathogen to your phage, to a broader, more empiric treatment paradigm where you can diagnose the patient and then treat them empirically with phage at the outset. And I think that will be the paradigm shift that we need in phage therapy.

26:24  Steven Yang
Right. And was that I guess, concern of your when you were making your company valuations in there?

26:30  Richard Alm
So CARB-X is so CARB-X thinks about it two different way. We I mean, we obviously fund diagnostic companies as well. And so we pay attention to with the emerging diagnostic technology platforms out there. And you know, the speed at which you can get the result I want we didn’t choose or not choose which phage companies to invest in based on whether there was a diagnostic available. I mean, I think that that wouldn’t have been the right thing to do. We chose our phage portfolio in the initial instance to capture the breadth of phage research that’s going on. As I said, we have two companies that are looking at using phage in a preventative mode, two that are looking in a therapeutic mode, very different patient populations, different indications and different stages of development. And so our goal at CARB-X was initially to when we stepped into the phage space was to say, let’s take a diversity of approaches and try and understand support these companies. We like this, we like their underlying science. Let’s support these companies. Hopefully get them to the point of evaluating the products enough so maybe we can inform our funders, but also inform the ecosystem what the best direction of travel for phage therapy is. Is there a niche or is it going to be every indication will work with phage if you get the right phage, the right formulation and the right administration, it’ll always work. Or are there specific patient populations where phage is going to be superior to anything else? And so I think rather than putting all our investment into one particular and making out, we knew the answer to that question straight away. We wanted to invest more broadly and try to use our investment to try and advance the field to understand where phage therapy could be most useful.

28:48  Steven Yang
Right. Well, that’s leadership mindset here. Yeah.

28:52  Richard Alm
I can just thank our funders because they supported that.

28:55  Steven Yang
So yeah. So one aspect that is interesting to me is because looking at your phage portfolio, investing through a through a four, you mentioned none of them are phage therapy in the most traditional sense. They’re all using some kind of innovation like locus biosciences, of course. Like they’re trying to do different kind of engineering stuff directly using phage, using this virus specific bacteria to treat bacterial infections. And I’m just wondering, what’s the cost for that? Are you just looking for something that’s more innovative?

29:35  Richard Alm
So we, you mean like the CRISPR engineering?

00;29;40  Steven Yang
Right?

29:41  Richard Alm
Yeah. So there was some evidence that, you know, that locus, the locus had the CRISPR engineering. I mean, we have three CRISPR phage actually in the program, you know, in our programs, different CRISPR systems. But I think that there was some evidence that the use of CRISPR can also increase the speed of killing, which I think is important. I think we didn’t we didn’t certainly didn’t go into our investment saying we only wanted to invest in CRISPR phage. That wasn’t a high priority choice that we made. But I think as we looked at the programs that had the best data package when they applied because obviously the application process that CARB-X is the final stage is where they come in and they present that have submitted a large dossier of written information. But then they come in and present to an advisory board that’s objective outside of CARB-X. And we built an advisory board that had some experience in bacteriophage when they came and presented, it was really to holistically look at the data package and then deliberately try and say, okay, well this is where these different technologies differ. And then if we can’t decide which one is better, well then we should give both a chance to see. Let the data tell us which one is better and be data driven. And so we certainly didn’t go in so we were only going to fund engineered phage. I think that was just serendipity. But I will say that the different CRISPR systems bring different attributes. I think the you know, we have one program that uses phage purely as a non-replicated delivery device, which is a, you know, specific delivery of payload. You know, we have some that will replicate at the site of infection, which I think brings very unique pharmacodynamics and pharmacokinetics, if you like relationship because you’re actually making your product at the site of infection, which for a small molecule never happens. So I think the ability to actually produce more drug at the site of infection will change the way we have to model pharmacodynamic response.

32:21  Steven Yang
Yeah if we’re going to say if there’s something have in common about these companies that have been selected or be their data package will be a little bit more mature compared to the rest.

32:33  Richard Alm
Yeah. So we have well mature so, so certainly there’s a couple that are late stage and so their data package was more mature. There was a I think locus. If you pull them out specifically, their particular program that we’re funding was that it was in a slightly earlier stage but they as a company had had taken one of their products basically into man. So they had demonstrated their ability to take a product into a traditional, more traditional clinical trial. Yeah. So I think it’s a combination of the data package that they had already generated and they presented their underlying thesis as to what patient population they were going to try and treat. And I think people often ask me, what advice do you give to small companies as they’re, you know, developing a product and thinking of applying. And my usual answer is, look, you’ve got to start with the end in mind. Think about the patients you’re trying to treat, what is unique about them and what aspect of that infection do you need to make sure that you can address with your product being a bacteriophage or being, you know, a small molecule or being a vaccine or anything. Think about the patient population because ultimately that’s what’s going to drive the success of your product if you’re making your medicine. And so if you think about, you know, the first step, you have to have the end in mind. The journey may be very different, but the destination, you have to understand your destination. And so I think that certainly with the if you just thinking about out of the sub portfolio stage companies we certainly looked at the differences of indications that those these companies were targeting as well to say, okay, they understood the patient populations, they presented a good thesis as to how they feel that phage would be able to address those patient populations and had a road map of how they were going to, you know, prosecute that project. And so I think it’s a combination of stage of development, data package and vision for how to get to that, you know, to the final product.

35:05  Steven Yang

Great. That’s a very good perspective because I was going to ask you about I guess my original question was going to ask, how do you see the phage has more competitive advantage to compared to other antimicrobial products. But I guess kind of I feel like your answer is going to be it’s really not about competing with each other. It’s really about how each solution should be finding the right target, the right population for treatment.

35:36  Richard Alm
Yeah, that’s definitely part of it. And I think that’s true. I do think that the specificity of phage treatment, I think is also very attractive. You know, as long as we can couple up with high quality and high confidence diagnosis of what’s causing the infection I think over the years, you know, over the last 20 years, we’ve understood a lot more about the risks of broad spectrum killing of bacteria with, say, a small molecule because of the the damage it can do on your microbiome and the dysbiosis that it can cause. And then, you know, obviously the C difficile grow back and stuff. So I think that the precision of killing a bacteriophage is one of its or one of its strongest attributes that if you can go in and, you know, I hate to say surgically remove the pathogen that’s causing the infection and leave everything else untouched. That obviously from a patient perspective is the best outcome because you’re removing that. You know, the organism that’s causing the problem, but you’re leaving everything, everything else untouched so that it doesn’t cause dysbiosis or any other side effects. The question is, how well can we harness that with bacteriophage and, you know, harking back to the diagnosis but I think that knowing which patient populations you can remove enough of the bacteria to allow the patient to recover is also important. And so that’s where it comes to patient populations in my mind. I mean, so if the patient is extremely immunocompromised, you need to understand how much of the infecting pathogen you need to reduce to have the patient recover. I think the phages ability to, certainly some phages ability to penetrate biofilms is important. In some of those volume associated infections, small molecules often can’t penetrate that. And so I think having bacteriophage in those types of infections is also important. And it may be that a combination of small molecule and bacteriophage is going to be the best treatment. Right. And so I think that, again, in the confines of a controlled clinical trial to understand that combination therapy of phage plus traditional antibiotic is going to be something that’s worth studying, because that may ultimately be, you know, the best treatment for patients. You get that, you know, fast, fast killing by the bacteriophage and then and then the more prolonged effect of an antibacterial. And there’s also evidence to say that there can be some synergy, which is, you know, which is really good for the patient. So I think there are many attributes we need to understand about bacteriophage, but I think that they will play an important role as we move forward.

38:47  Steven Yang
That’s something we’re all happy to hear. Well, we are running a little late on time, Dr. Alm. But before we let you go today, final question. Is CARB-X still accepting new applications? And if yes, what recommendation would you give to the people just entering the market to prepare?

39:06  Richard Alm
Yeah. So I think the answer is CARB-X. The original grant to CARB-X was a five-year grant from BARDA. And that’s coming to an end back in the middle of 2021, BARDA announced a broad agency competitive application code for biopharmaceutical accelerate, which is what CARB-X was and their commitment to fund such an accelerator for ten years, which is a tremendous commitment by the U.S. government. Now, the group at Boston University, we applied for that and we’re waiting. And so hopefully, I mean, they will certainly be a biopharmaceutical accelerator, whether it’s the group at Boston University or another one that they choose is unknown yet. But I think that whichever group gets that, there will be application calls immediately because as that new funding comes in, then there will be money to spend on innovative emerging technologies. In terms of the advice that I would give anyone that’s applying for these types of funds, it’s probably, probably multi-pronged. I think it’s you know, I’ve already mentioned come in with a knowledge about the patient population you’re trying to treat. I think that’s you know, having the end in mind is very important. It doesn’t matter even if you’re early and hit lead, you may not have your full clinical development strategy developed. You almost won’t. But you still should have a vision as to where you want to go. Be extremely conscious about presenting pertinent data and have, you know, the application is confidential and so be as data rich as you can, acknowledge what gaps you have and come up with a plan as how to most expeditiously fill those gaps with data that can convince you one way or another. I think, you know, all of us scientists realize that not everything is going to work every time. The best product developers know how to take data and pivot and understand where they can improve rather than just being blunt. Never be afraid to get the right answer right. Even if that answer may not be what you want to hear for the development of your product, it’ll inform the next generation of your product, which will be even better. Right? Right. Science is an iterative learning process and I think we all need to learn from that. So I think that’s my advice. I think start with patient in mind. Be as data rich as you can, acknowledge your gaps and how you’re going to fill them.

41:49  Steven Yang
Great. Wonderful. Yeah. Well, thanks so much for joining us today, Dr. Alm. And I guess good luck to all the companies in your portfolio.

41:57  Richard Alm
It’s been my pleasure. It’s been wonderful. I think going on this journey with CARB-X and seeing so many innovative technologies and I hope to be able to continue doing that.

42:08  Steven Yang
That’s Dr. Richard Alm. I’m Steven Yang, and this is phage therapy today. Thanks again for your support and listening to our podcast, if you like it. Follow us and give us five stars in the end. Happy holidays.

Host: Gunnar Esiason
Guest: Kevin Outterson, Executive Director, CARB-X and Professor of Law, Boston University

00:31 Gunnar Esiason
Welcome to the State of Health, the podcast where patients put healthcare decision makers and thought leaders in the hot seat. I’m Gunnar Esiason. Today’s show carries on the antibiotic resistance series. So far, you’ve heard from patient advocates about living with an antibiotic resistant infection, politicians who are trying to fix the antibiotic market disincentives at the heart of the crisis, an investor putting money into companies with the hope that policymakers can make antibiotic development sustainable, and scientists at the bench who are working to develop tomorrow’s antibacterial technologies. Past episodes in the antibiotic resistance series are already in your feed. Today, we learned about the public private partnership that is hoping to launch a new generation of antibiotics. Kevin Outterson, the executive director of Boston based CARB-X joins the show to tell us a little bit about the early-stage antibiotic landscape, the massive amounts of capital that governments and nonprofit organizations are trying to move into biotech companies to keep the antibiotic pipeline alive, and his hopes for the next generation of antibiotics. Let’s talk about the state of antibiotic developers. Kevin, Thanks for coming on the show.

01:49 Kevin Outterson
I’m glad to be here. Thanks for inviting me.

01:51 Gunnar Esiason
What is CARB-X? And what role does it play in the antibiotic ecosystem?

01:57 Kevin Outterson
We actually have a very central role, we take these amazing things that are coming out of university labs from around the world that have been funded by governments, basic science, and we translate them to a product that has completed the first stage of testing in humans, the Phase One testing. And we do that for anything that touches, you know, antibiotics. Both antibiotics and prevention therapy, as well as diagnostics. And we’re entirely nonprofit. We’re based at Boston University. I’m a professor there. We operate globally, we’re funded by governments and foundations and our entire purpose in life is to stop this drought of no outstanding antibacterial innovation in the last several decades, and to really get things that are transformative to patients into the pipeline.

02:48 Gunnar Esiason
How does a law professor end up leading in a global R&D program?

02:57 Kevin Outterson
A lot of what you do in my position is to bring together partnerships, you know, we have five different funders, three governments, US, UK, and Germany, two foundations, the Wellcome Trust and the Gates Foundation. And we worked with 92 different product developer companies all around the world at this point in our first five years. That’s a lot of negotiations and a lot of deals to pull things together, a lot of partnership. And what I did as a practicing attorney, was actually healthcare transactions pulling things together. How I got interested in this is that when I first became a professor, I wrote this — law professors love to write — I wrote this long article, you know, 90 pages on all the things that work and don’t work in drug innovation. But something bothered me because a key assumption in that entire article, 90 pages published in one of Yale’s journals, was that when the drug actually became generic, it would still be just as useful as the day it started. That’s a foundational assumption. But I put a footnote that said, but for antibiotics and things like that, that degrade with use over time, that wouldn’t be true. And went on to finish the article, the articles not about antibiotics, just that one footnote. But it began to bother me, and that basically, everything that works in drug innovation might be upside down and not work for antibiotics. I just became increasingly obsessed. 20 years later, here I am. You have to be careful where your curiosity takes you sometimes, you might be surprised where you end up.

04:45 Gunnar Esiason
I need to address the elephant in the room. I did my undergrad at Boston College and the fact that we can get someone from BC and BU on the same podcast together, I think proves that we could achieve anything in the world.

05:01 Kevin Outterson
It’s like the Yankees and Red Sox. That’s the level of patriots that we’re talking about here.

05:07 Gunnar Esiason
Yeah and exactly for listeners who may not be familiar with the Boston University and Boston College rivalry definitely is a deep rooted rivalry. But nonetheless, it’s exciting to have you on the program. So question about CARB-X again.

Does CARB-X purchase equity, like a traditional biotech venture capital firm?

05:33 Kevin Outterson
No, we don’t. We use the language of investment. And we’re run by you know, all the people who work with us have a lot of industry experience. We make decisions like a venture fund or a business development arm of large pharma would, but we’re entirely nonprofit. We don’t take any equity stake in the companies. What we’re trying to do is to address a global market failure. The fact that these companies can’t make money in antibiotics for, you know, kind of baked into how they’re made today. And so we’re trying to advance that pipeline, improve its quality, improve the innovation potential and, and then hopefully hand it off to people that can take it across the finish line, because we end at the end of the phase one trial. So we’re charitable, we make grants, but we think like a venture capitalist.

06:22 Gunnar Esiason
I would imagine that a venture investor sees CARB-X grant into it into a company or technology, that would be inviting, right, that sort of essentially, is de-risking the earliest stages of adult development to some degree?

06:40 Kevin Outterson
We’ve received 1100 applications around the world and run an elaborate scientific and business due diligence process over time, in a funded 92 companies out the back door. So you know, there’s a lot of investors who are interested in this space who say that our CARB-X due diligence engine helps them to focus on as much smaller and abroad companies. We save them time, by having sifted the world and boiled the ocean to come down with a few. Also, they like the fact that we bring them not only cash grants, but also a lot of technical and scientific and business support. A lot of these companies are really small, that I mean 10 or 15 people. And they have outsourced most of their other work. They need the sort of support that you could get out of a large global company, but they can’t afford it. So we provide the money, but we also have a global network of more than 100, now, experts around the world, mostly people that used to work for large drug companies, but are now retired. And we pay for those folks so that they can provide their advice and help to these companies for free.

8:00 Gunnar Esiason
Why do antibiotic makers need CARB-X? How does drug development work? What are those key infrastructure pieces that CARB-X is providing?

08:27 Kevin Outterson
It’s everything you mentioned (regulatory, clinical trial know how) and then in the earlier phases, just the taking a molecule so you know, you’ll read frequently, in a paper, that published in a Nature or Science, somebody discovered a new antibiotic in the in the soils of Maine, you know, or whatever, from the deep sea trench and they they’ve, but what they mean when they say that is that somebody has found something that in a glass dish, and the petri dish kills bacteria, right? Taking that, and translating that into whether it can help mice, you know, who have bacterial infections that can help other animals have bacterial infections, and eventually be proven to help humans with bacterial infections. That process of preclinical development has many ways that things can go off the rails. And a well run project, you might start with 30 such early preclinical projects and end up with one actual drug at the end of the day. So our goal is to help them understand what they don’t know. And to the extent that we have people within our network that we can provide to them, that will give them a menu. Here’s five people that know a lot about the issue that you’re facing. Pick one and we’ll take care of it, we’ll pay for the cost. So we’re here to accelerate, you know, CARB-X stands for … “acceleration” is the X. And we want to help these companies not die from being ground into economic dust because the economics are so bad. We want to see this really great science move forward.

10:14 Gunnar Esiason
Is there anything out there that’s exciting when we consider traditional antibiotic treatment? Are there things out there that CARB-X looks at? Are there things that CARB-X just doesn’t look at? Or is it more of an all-encompassing look at the space?

10:41 Kevin Outterson
Yeah, in a way, this is a question of which of my children do I love the most right? But I’ll answer it, you know, it’s been my entire life. I’m 59 years old, but it’s been since 1962, that we discovered the world discovered a new class against the worst bacteria that actually got approved by the FDA. That’s along the last discovery that was approved by the FDA my entire life. And almost everything 36 out of the 37 therapeutics in our portfolio today would qualify as the first such thing in my entire life, 36 out of 37 therapeutics. And the last one is also very exciting, but it happens to be from a known class. So what we’re doing is extraordinary innovation, you know, any one of those that makes it through will be the biggest news in six decades in antibacterial innovation. But there’s, there’s a wide variety, I mean, there’s things as unusual as phages, you know, viruses that eat and attack bacteria, ones that are engineered to detect specific bacteria, and to kill them to entirely new chemical classes, things that have never been used before, and therefore go after different targets in the bacteria, and therefore, there’s probably not pre existing resistance to that. And then all sorts of other things that people just called non-traditionals because they’re completely different approaches, you know, somebody would attack a biofilm, you know, in a wound or an infection are in the lungs. Biofilms are like defensive structures that bacteria build in order to make it harder, easier for them to live and also harder for antibiotics to penetrate. For anti-virulence compounds that are designed not so much to kill the bacteria, but to make it, you know, less dangerous to the humans. So, anything we touch is likely to be the most innovative thing that we’ve seen in the approved drug categories for the last five or six decades.

13:34 Gunnar Esiason
Now let’s talk about the actual antibiotic market. Sort of maybe the reason CARB-X is in existence or the reason that it needs to help some of these companies. And something that we’ve spent a lot of time talking about on the podcast for the last couple of weeks. But what is standing in the way of antibiotic drug developers and a sustainable market?

13:55 Kevin Outterson
You think about any product that you have in your life, like your cell phone, you know, new technology we can adopt. And usually the new technology is expensive, but there’s no good reason for the government to limit our access to the iPhone 11 or 12. Right. There might be a good budget reason for me not to buy it but it’s our choice. And the new technology sells not only high prices, but high volumes. For antibiotics, we have an excellent reason not to use it today. You know, the newest antibiotic, we would love to actually use it as little as possible for as long as possible, keeping it on the shelf and still use the ones we have today for as long as they last, and drag it out. Now that’s a wonderful answer for public health. It’s the correct answer. Let’s save the new antibiotics for the future. But think about it for the company. They’ve got 10 to 14 years of patent life by the time they get approved by the FDA. They need to make sales in that first decade or else they’re dead. But what actually needs to happen from a societal standpoint is to sell almost none of the antibiotics for the first decade, great for society, instant bankruptcy for the company. So, you know, if the cell phone had to be, you know, we had to absolutely hold on to our old phones until they absolutely died. And they could prove to a doctor that we needed another one, I think we’d have a broken cell phone innovation market, I’d still be using the things that look like bricks from the 80s. So that’s the basic problem. This is a product that we want to save and not spend today. So there are other things like that in the world, you know that, if you’re in a commercial building, you’re you know, or the university, the University is filled with fire extinguisher equipment embedded in the ceilings, right, and then the walls, you pay for that in advance, hoping to never need it. You don’t pay for that once a fire is broken out, you pay for decades ahead to prevent a fire. And so we need to shift the way that we’re thinking about paying for antibiotics, instead of paying for per pill based on volume based on need today, we need to pay for them more like fire extinguishers or fire departments or preparedness. And that’s the shift that the PASTEUR Act makes in my mind,

16:24 Gunnar Esiason
Then you’re talking about preparedness here. And I think the world has certainly learned a hard lesson over the last 18 months for, you know what failing to invest in preparedness could look like and it’s, you know, coming from somebody who’s lived with infectious diseases entire life, it’s I can’t say it’s super shocking. But it’s definitely something that I think is an important message to be sending right now. But you mentioned the PASTEUR act. Another thing that we’ve talked about on the podcast the last couple of weeks, sort of a legislative item going through Congress right now that we’ve had, you know, both Senator Young and Senator Bennett, the co-sponsors of the bill on the podcast.

Can you talk about PASTEUR, and then there’s also another bill out there the DISARM Act? You know, are they complements? You know, what’s different between them? You know, it’s, it seems like there is some hunger or some appetite to sort of fix this problem from a policy level too.

17:28 Kevin Outterson
I’m a big fan of the PASTEUR Act. And it really answers the questions. I’ve been asking in my academic work for the past 20 years, right? How can we pay for antibiotics based on their value to society, even if we don’t want to use them very much for the first five or 10 years? And the genius of PASTEUR is that the answer is let’s do a subscription. This is like Netflix, you know, whether you watch no shows, or binge 24/7, or you lose track of the rest of your life, there is a paid subscription. And so PASTEUR would set high standards, a few drugs will qualify. And in the federal government pays in advance for them, even if we don’t need very many of them. The company goes away satisfied. The research and development gets reimbursed. We have these drugs ready. We don’t have to use them at any time. But they’re ready for the future. And we are prepared. Right. So I think it’s a brilliant idea. I applaud Senators Young and Bennett and the House sponsors as well, Doyle and Ferguson. It’s a great piece of work. And it has real potential. As we look at the pandemic bill that will eventually go through Congress this year. To understand that, yes, we want to fight the battle against COVID. But we don’t want to just focus everything on the last war. We need to remember that the biggest branch of the tree of life, you know that the most numerous thing that has species and on the earth are bacteria, and they’re the longest foe of humanity think the plague think cholera. And today antimicrobial resistance. We need to also be prepared for bacteria and PASTEUR will do that. You also asked about DISARM. There was a clever idea in 1983 during the Reagan administration to save money for Medicare. Everyone thought it was a great idea. It’s been adopted around the world. It’s when the hospital gets paid in Medicare, they get a single payment for everything that happens at the hospital. So you know, the hospital bed, you know, in the nurse and the drugs you need while you’re in the hospital, and the food unfortunately, were included in that bundle payment. And it saved money for Medicare without a doubt, but it had an unintended consequence. It punished any hospital that uses a branded on patent antibiotic because they will lose money on that patient. Right. So what DISARM is designed to do is to fix that problem to eliminate that unintended consequence of Ronald Reagan’s 1983 reform to Medicare and put them more in a level financial playing field. These ideas are complimentary, you DISARM is more of a let’s fix what’s broken about how Medicare pays for drugs. And PASTEUR is more about let’s dramatically change our societal valuation of antibiotics and pay for value, not volume, and do so in a way that helps the company survive. So I’m a fan of PASTEUR. I’m a fan of DISARM, I think they absolutely work together. But the one that has a chance of moving forward now, I’m told I’m not a political expert, is PASTEUR. And so that’s where my focus lies.

22:09 Gunnar Esiason
Now, I want to go back to CARB-X for a second. What does CARB-X represent? You know, it’s not so often you hear about a fund set up with, you know, public capital or money from foundations to invest in private biotechnology companies. Of course, my life is very close to one such nonprofit organization that invests in biotechnology companies. But what but what does CARB-X really represent for the life sciences and for, you know, global innovation?

22:40 Kevin Outterson
Most of the companies that we support are extremely small. And most of them have reported to us that if we had not been able to support this project, either the project would have died, or the company itself would have died. You see many antibiotic companies because of this market issue that I’ve described, which has become acute in the past five years. Switching to other things, that they’re taking people that that are smart microbiologists, and they’ll move over to viruses or Coronavirus to hepatitis C, hepatitis B, or leave infection entirely. And, and go over to a field that has lots of money like immune oncology. So think about infrastructure, where we are losing the human capacity to develop antibacterial drugs, because the teams of scientists who do that, who know how to do that their organizations have been ground down by terrible economics of the past decade. And so CARB-X is there to just find the most amazing projects that advance them so that they finish their first human trials and are ready to go on to the later round of human trial development. And, and also, you know, indirectly we’re keeping alive the planet’s ability to do this, you know, that the last estimate I saw put up by the German government a couple of years ago, there may only be 600 – 800 PhD scientists left in the world who know what they’re doing, and are able to develop an antibiotic. And a lot of them, I have to say, are nearing retirement age, have a lot of gray hair. And, we need younger, newer scientists, the next generation to join this effort. And it’s hard if all the money for research and for grants and for the companies is in everything, but.

24:46 Gunnar Esiason
You know, it’s the things are you’re saying there I think echo a lot of what Henry Skinner said on the podcast a couple of weeks ago, and he shared a similar fear in that the next generation antibiotic developers is, you know, hinging on really a desire or, you know, hope, hopeful desire for people to get involved in the basic, the basic groundwork of science to do this. So I think it’s a nice sort of link to a past show. And I’ll finish I’ll finish today’s episode with the same question that I asked. I asked Henry from the AMR Action Fund, what does CARB-X need to achieve, to mean that it was a success?

25:31 Kevin Outterson
I told you earlier that it’s been six decades since we’ve had the discovery of a drug that actually was a first in class against the worst bacteria approved by the FDA. In a long time, we’re loaded with such things at CARB-X. I want to see one or two or three or four entirely new classes, groundbreaking things, have them come through the CARB-X portfolio, be approved by the FDA and EMA in Europe, and actually being used sparingly in the patients that need them. To make that happen, and make it sustainable, I think requires the PASTEUR Act, because, you know, even if we paid for all the costs to get the product all the way to the to the FDA approval, you still need a company you need somebody to keep that drug ready and alive and keep doing research on it. So that improves. And PASTEUR I think is that essential link in what’s out there. And so, you know, it’s interesting, our work is we start like 15 years before a drug would be approved. That’s how long it takes to go through this process, as you’re well aware, having spent a lot of time looking at research. And but so we might still be, been around for five years, we might still be five or 10 years away from that first moment. But we can certainly see a change, you know, years ago, the pipeline was characterized by the WHO and Pew Charitable Trust as fragile and weak. And now everyone recognizes that what’s coming through the CARB-X pipeline is amazing. We are grateful for all the little companies doing that work, a couple of big companies with mainly little ones. And I’m especially grateful for people like the NIH, NIAID, who’s just funded this basic research for decades, and we’re able to build upon that, and bring it to patients.

27:32 Gunnar Esiason
I think it’s a, you made an insightful comment there that the amount of time that it takes from you know, getting from the test tube to the patient is we always like to say is just so extraordinary. And you know, I’ve lived it on one hand, and then I think the first time I ever actually built a cash flow model to project what that looks like you see them in an Excel spreadsheet, it’s just like a whole different mindset required to look at it. And I think you’re right that people see it for almost like in this very unique position. On one side, we have like the high flying sexy biotech industry that’s developing and cranking out precision medications that have just been, you know, absolutely life changing for people with CF. And then on the other side, you know, we are relying on those antibiotics that have, you know, been around since the 60s and haven’t really been, you know, iterated upon to a point where they’re materially different. And I look at my own life, right, you know, I’ve gone through first, second, third line antibiotics and now I’m all the way down to last on antibiotics is my only my only remaining options so it’s a personal issue for me, it’s a personal issue for a lot of my friends, my entire patient community and I think the things that CARB-X is doing alongside the AMR Action funding, hopefully our policymakers in Washington if they can get on board with this really do have the potential to make a meaningful change. So with that, I just want to say go ahead

29:02 Kevin Outterson
The CF foundation as you know works with several companies that CARB-X supports, you know, we have been actively looking for several years now any new drug getting new chemistry come in the CARB-X, you know, we evaluated for whether it can have a specifically helpful impact in the CF world and the foundation’s been really helpful in that process for many years. And also know the foundation has been helpful as it is a voice of patients who need new antibiotics in Congress and in Washington. And I applaud that effort. It’s absolutely vital that that continue. I’m grateful for what the foundation is doing. And what you’re doing.

29:50 Gunnar Esiason
Well, thanks, Kevin. I do appreciate the comments and I appreciate you coming on the episode. Good luck with the work and I look forward to seeing what CARB-X is able to do. You know, once we’re able to sort out this policy mess and the reimbursement issue from Washington.

30:09 Kevin Outterson
CARB-X.org Go look at the companies that we’re supporting and the amazing sciences going forward.