CARB-X & Sepsis Awareness Month

CARB-X & Sepsis Awareness Month

CARB-X & Sepsis Awareness Month

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

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.