I think we're about ready to get started. Welcome, everyone. I'm Josh Schimmer from the Cantor Fitzgerald Biotech Equity Research Team. Very pleased to introduce from Seres, we have Eric Shaff, Chief Executive Officer, Matt Henn, Chief Scientific Officer, Lisa von Moltke, Chief Medical Officer. Eric, I think you're gonna walk us through the presentation, and we'll move over to Q&A.
Great. Well, good afternoon, everybody, and thanks for joining us, and Josh, thanks to you and to Cantor for having us here today. I think it's a great time to be talking about Seres on the heels of our announced transaction with Nestlé Health Science around VOWST, but also after or following our SER-155 data release that we put out last week, so just for background, Seres is a company that's developing novel bacterial therapies for life-threatening infections in medically vulnerable patient populations, and what we'll talk about today revolves around the idea that there are factors that make us more susceptible to infection, right? The significant increase in chronic diseases, the aging of the population, obesity, antibiotic resistance, and immunosuppressive drugs, and other factors.
Modern medical intervention has created significant improvement in many areas of patient care, but therapeutic progress and innovation, while oftentimes life-saving, can also diminish the capacity of the immune system to fight infection. In light of that, we believe that the idea of intervening with live biotherapeutic programs to significantly reduce the risk of infection becomes a particularly powerful and we think important approach. The SER-155 data release, we believe, is a particularly encouraging result, but also strengthens our conviction for something much bigger as we think about where we can potentially apply our technology. We will be making forward-looking statements in today's presentation, and I would refer you to our SEC disclosures, including those that are relevant to the expected transaction with Nestlé around VOWST.
Now, it's been an exciting time at Seres recently with both the VOWST transaction announcement, as well as last week's announcement around the Cohort 2 Phase 1b study results from SER-155, and these are patients that are undergoing allo- HSCT. Now, I started the presentation talking about unmet need. Following our success with VOWST and recurrent C. diff infection and the FDA approval of VOWST, we've worked to continue applying our technology in a particularly extreme or acute example of this need, which is patients undergoing allo-HSCT. A major factor for these patients is complications, which also can include death from bloodstream infections, and we think that there are solutions that are needed that are novel, and bloodstream infections in medically vulnerable patient populations, we think, are the start.
So just to summarize, and we'll talk about this more in detail, SER-155 showed a generally well-tolerated safety profile and was associated with significant reductions in bloodstream infections, systemic antibiotic use, and a reduction or a lower incidence of febrile neutropenia. While these results are early, we're highly encouraged by them, and we'll talk today about why we think they're an important step forward. Now, prior to our announcement of the SER-155 data, we did announce back in August the signing of an agreement to sell our rights to VOWST to Nestlé Health Science, in exchange for substantial, immediate, and future financial consideration.
This transaction improves our balance sheet, will allow us to retire all our debt, and without some of the other obligations associated with VOWST, we think that this allows us to move forward as a company in a more streamlined way, a more efficient way, and better positioned to support the pipeline going forward. Now, what we'll talk about today involves a number of different dimensions, and for us, we live and embrace the idea of using consortia of bacteria as therapy, and I think that sometimes can be known as somewhat of a novel thought.
There's historically been this notion that bacteria can be harmful or maybe perhaps neutral, but the idea that bacteria and the health of the ecosystem of bacteria in your body, and especially what we focus on, which is in the gut, that that consortia, that ecosystem has to be healthy, that is a new concept, right? And the idea is that disruptions to that healthy ecosystem of bacteria can be connected with serious diseases. What we'll talk about today is why we think we're so excited, not just with the validation of VOWST, which certainly starts with our foundation, but certainly SER-155, we think, is the next frontier.
We'll talk about the potential of our cultivated product line, both SER-155, as well as our next program, which is SER-147, for infections, which can be frequent, and severe, and oftentimes deadly in medically vulnerable patient populations. With SER-155, allo-HSCT is where we started, but you can envision thinking about auto, as well as other adjacencies after our initial work in allo-HSCT. Now, our biotherapeutics are consortia of bacteria that are commonly found in the human microbiome, the human GI tract. We know that the ecosystem of bacteria has profound importance into human health. The investments that we've made over the years into our platform allow us to select bacteria based on specific functional properties, which increases our ability to target specific pathogens and host functions.
So we cultivate bacteria in our labs, we formulate them in oral doses, in pills, and then these bacteria then engraft and restructure the GI microbiome to restore critical biology. Now, that biology, we believe, has the potential to impact a broad range of diseases... Our current focus is on preventing life-threatening infections, and we see a broad target population that are medically vulnerable and at high risk for infections and additional complications related to infections. We know that certain bacterial strains in the gut provide critical functions in helping to rebuild damage done by disease treatment, conditioning, and providing incremental protection against further infection. Now, before we move forward, I think it's important to note that this is not a hope or an aspiration. We have proven this technology's capability and potential power to help patients.
We have clinical evidence of our biotherapeutics and the difference that they can make in the clinic and in the real world with VOWST, so VOWST was approved by the FDA in April 2023 to prevent the recurrence of C. diff infection in adults. VOWST has an outstanding clinical profile with an 88% reduction in recurrence, robust efficacy, durability and response, a favorable safety profile, and certainly, of course, an oral formulation, so the success that we showed in VOWST, we think is relevant to show that we can target pathogens in the GI microbiome to prevent other infections in high-risk patients, and with our data in SER-155, we think we've shown the next step in this, which is with patients with allo-HSCT.
Now, I'd also point out that our therapeutics have, and this is across a number of different therapeutic applications, been well tolerated. Remember that these are bacteria that have co-evolved with us over millions of years, specifically, VOWST had a well-tolerated safety profile. We'll discuss the SER-155 profile as well, this time in highly vulnerable patient, patients undergoing cancer transplant, procedures, and if you think about the factors embedded in the probability of clinical progress, the favorable safety profile of our programs, we think is a significant positive factor. Now, I'll also note that Seres has built end-to-end capabilities, intricate, integrated capabilities in discovery, development, manufacturing of live biotherapeutics. This gives us an additional engine to create additional therapeutics, with the ability to target specific pathogens and biological functions.
I'd also offer that in many new treatment modalities, manufacturing quality is, I think, chronically an underestimated capability, a strategic capability. We have a first-in-kind FDA approval under our belts, and there are aspects of our experience with VOWST, including, for one example, developing novel release specs with the FDA, which we think are highly relevant for SER-155 and for our work in other programs. So pipeline quickly, SER-155, SER-147, both of which Seres fully owns after the sale of VOWST. Both of these programs are designed to reduce the incidence of serious bacterial infections and related complications in medically vulnerable patient populations. So let's talk more about SER-155 in patients undergoing allo-HSCT.
These are patients that are undergoing a cancer treatment regimen that significantly impacts the patient's immune system and can leave them uniquely susceptible to serious and potentially fatal infections. There is significant clinical evidence that the gut microbiome is disrupted in these patients. Now, the loss of microbiome diversity is associated with worse clinical outcomes, including bloodstream infections and mortality. Now, mortality, morbidity rates are significant despite the common use of antibiotic prophylaxis, which often causes hospital readmissions and increasing time in ICUs. One of the issues for these patients is not just the infection itself, it's the idea that these infections take them off their course of therapy for the underlying disease. We designed SER-155 to try to prevent the bloodstream infections and associated complications that are harmful in these patients.
Just for background, the SER-155 Phase 1b study included two cohorts. In 2023, we reported promising data from the open label first cohort that showed that SER-155 was generally well tolerated and resulted in successful drug strain engraftment and a reduction in the pathogen domination in the GI microbiome, relative to our historical control cohort that we've worked with, MSK in establishing. The second cohort, which we read out last week, utilized a placebo-controlled design to further evaluate safety, drug strain engraftment, and the incidence of gastrointestinal and bacterial bloodstream infections, as well as related medical consequences such as febrile neutropenia and antibiotic exposure.
We also looked at the incidence of the most severe forms of GvHD, but we also know that with the treatment paradigm that has shifted with the use of PTCy, that those data we did not expect to see those types of infections. So just to go into the data itself, the studies' pre-specified day 100 time point covered a period associated with a high rate of infections and other complications. First and foremost, SER-155 was generally well tolerated throughout this period. Remember that these are patients that are highly immunocompromised, right? One major aim was to confirm that they could be dosed with a live biotherapeutic, so we were pleased with the safety dimension of this profile.
The other primary endpoint was engraftment, and remember, this is an engraftment of our organisms, it's not the transplant engraftment, which was as expected for our bacterial strains and consistent with the Cohort 1 group, and I'll show you one slide in just a minute. Now, there were also a number of meaningful outcomes in the efficacy endpoints as measured through day 100. Patients administered SER-155 experienced a significantly lower rate of bacterial bloodstream infections compared to the placebo group. Febrile neutropenia occurred at a lower incidence in the SER-155 group versus the placebo group, less so than the BSIs. But we also observed a meaningfully lower exposure to systemic antibacterial therapies compared to the placebo group.
Again, due to recent changes in standard of care with the increased use of PTCy, a low rate of GvHD across both study arms. Now, just to dig into the data a little bit deeper, on the BSI side, in the SER-155 arm, two out of 20 patients experienced a BSI versus six out of 14 in the placebo arm. You can see the statistics here, as well as the organisms that we believe are of GI or possibly of GI origin in the allo-HSCT patients. Moving on to antibiotic exposure, in clinical practice, allo-HSCT patients who experience a BSI or febrile neutropenia are aggressively treated, often with broad-spectrum antibiotics, as you can see in the slide.
In our study, we observed a meaningfully lower mean cumulative exposure to systemic antibacterial therapies, with SER-155-treated patients being administered these drugs for a mean duration of about 9.2 days versus 21.1 days for the placebo patients. When we adjust for time on study, as illustrated, the results remain highly meaningful, with a meaningfully lower exposure rate in the SER-155 group versus the placebo group. Now, on the pharmacology side, just to summarize, the study did meet its primary pharmacology, drug strain, engraftment endpoint. The peer-reviewed literature in our preclinical studies support the idea that the abundance of pathogens in the GI tract are associated with bacterial bloodstream infections and other negative pathogen-related clinical outcomes that allo-HSCT patients often experience.
So if you look at the top graph, the SER-155 strains were found to rapidly and robustly engraft in the gastrointestinal tract following the administration of SER-155. The magnitude and the kinetics of this engraftment were similar to what we observed in the Phase 1, Cohort 1 arm, and were highly consistent with our expectations. Importantly, the strains were present through the periods of the greatest susceptibility to bloodstream infections, and the engraftment was actually durable out 100 days following the transplant. Now, if we think about pathogen domination, our ability to detect differences in the pathogen domination in the placebo arm and to compare arms was constrained due to the limited number of placebo stool samples that we're able to collect, about 48% lower than what we had hoped to have.
But if you compare the SER-155 treatment arm to the historical control context, the SER-155, or the cohort that was established by Memorial Sloan Kettering, you can see a lower, a pathogen domination in the SER-155 treatment arm than the historical cohort, as we did see in the one, in the Phase 1, Cohort 1 study as well. So where do we go next? The study data here support the continued development of SER-155 and allo-HSCT. And again, we believe that there is a need for novel approaches for these patients. Based on these results and the significant unmet medical need, we plan to seek a breakthrough therapy designation and engage with the FDA around next steps in advancing SER-155 and allo-HSCT.
If you think about breakthrough, think about unmet need, think about safety, think about clinical signal. More broadly, we believe that the SER-155 Phase 1b study data further validate our corporate strategy to bring new therapies to medically vulnerable patients. Bacterial infections represent a major unmet medical need, and again, think about not just allo, but auto, patients with cancer neutropenia, CAR- T recipients, and other areas where we think our technology may have promise. So if you think about value, and, as we consider the profile of SER-155 and the results that we saw in the Phase 1b study, we think that a drug like SER-155 would be valued by patients and physicians. There are approximately 40,000 allo-HSCT procedures a year worldwide. It's about double for auto.
Infection rates are high, often life-threatening in these immunocompromised patient groups. It's been estimated that infections increase transplant-related treatment costs by approximately $180,000 per patient due to readmissions, prolonged hospital stays, increased time in ICUs. There is significant unmet medical need. We think that SER-155 has the potential to bring value to patients, healthcare providers, and the healthcare system. Viral prophylaxis gives us kind of an interesting data point as a comp. Merck has a drug called PREVYMIS, which provides a safe option to prevent CMV reinfection. About $600 million reported sales in 2023. Nice trajectory, still early in launch, and patients recently expanded to high-risk kidney and transplant patients. PREVYMIS is only for one single type of infection, but nevertheless, has made significant traction.
So we think that this is not a perfect data comp, but nevertheless, an interesting one, for us. Now, it's important to note that SER-155 results provide further evidence to support our strategy. Infections are also frequent, serious, and severe in patients with chronic liver disease, including cirrhosis. In fact, bacterial infections are the leading cause of organ failure and death in patients with cirrhosis, and these infections occur frequently. In one recent study, nearly half of cirrhosis patients experienced a bacterial infection in a six-month period. They are also impacting the healthcare system. They drive longer, more expensive hospital stays. There's an association with these patients, with their GI microbiome, and recent publications show that GI microbiome disruption is frequent and associated with worse clinical outcomes in these patients.
So we've designed SER-147, which is a new biotherapeutic, to prevent specific bacterial infections in these patients. Now, despite the impact of infections, these patients have few therapeutic options. Standard of care in this space is prophylactic use of antibiotics, but only in certain high-risk populations. Even then, prophylaxis isn't working well. Antibiotic resistance is making it less effective, and at least one recent study showed that it did not cause significant improvement in patient survival. So we've designed SER-147 to reduce some of the pathogens most commonly causing bloodstream infections in these patients. Our assays suggest that it is a potent reducer of multiple pathogens, including E. coli, and we're moving to have SER-155 IND ready in the second half of next year, and we're excited about this as the next opportunity.
So just to review, key takeaways for today, we, as a team, have a track record of success with the approval of VOWST, and the sale of VOWST to our partner allows Seres to emerge in a more efficient, more streamlined way. We've got a lower cash burn in the near term and the settlement of key obligations to support the advancement of our cultivated products, starting with SER-155. The data are exciting to us, to our KOLs from SER-155. We believe that there are potential partners that are excited by this readout, both within allo, but also the adjacencies from allo to it, and we're also excited about the signal that we've observed and the positivity that we've received, but also how we can apply it going forward.
And, you know, going forward, we're excited about the opportunities that Seres has. We'll continue to accelerate efforts with SER-155 and allo, including engaging with the FDA to consider breakthrough therapy designation. We'll also evaluate our potential in adjacencies. We continue to see opportunities to prevent life-threatening infections with our biotherapeutics, the potentials and to treat immune-related diseases, other conditions, as you can see outlined on this slide. So I think I took a little bit more than twenty minutes, Josh, but, appreciate again the opportunity to be here, and we're thrilled to take your questions and those from the audience.
All right. Super. Do you wanna come? I think you have the mic if you wanna come sit, or you can stay at the podium. It's your choice. The development of VOWST itself was non-linear, right? So what were some of the lessons along the way in C. diff development that you applied to SER-155, and where do you think you may find similar learnings to optimize the SER-155 product if you think there are opportunities to do so?
Yeah, it's a great question, and I'm, I'll start. Maybe I'll offer Matt and Lisa the chance to chime in. Matt was with Seres since it was an idea on a whiteboard, so I think his perspective is particularly useful. But I might offer a couple of things, Josh. One is, you know, on the heels of really interesting Phase 1 data for what was then SER-109, you know, we thought we had it figured it out, and the reality is that we actually know less about the gut than we do about the brain. In pioneering in any new modality, you have to have a certain humility in how you approach obstacles. We are incredibly proud of how we dealt with what was then a significant miss in the Phase 2 for SER-109.
We took a rigorous, objective, data-driven approach to thinking about why the phase I was successful and why the Phase 2 missed. We considered and rejected dozens of different hypotheses. Ultimately, we followed the data, and we said, based on analytics and insights that Matt and his team had developed in the years from the Phase 1 to the Phase 2, we said: We think we can adjust the dose, and we think we can look at the diagnostic protocol, and we think, we didn't know, that we could come up with a different result. We ended up with a spectacular result that will change C. diff forever.
I think it's the mentality that we take to pioneering new areas like SER-155 next, which is relevant for us and for the team, and I think will put us in the position to be successful going forward, but I might offer my colleagues the chance to comment.
Yeah, just Josh, briefly, specifically, some of the types of data points that we got out of VOWST that I think have informed the SER-155 path forward. So one, both with VOWST and our broader clinical portfolio over the years, we've learned about which bacteria engraft and take up residence in the gut in different patient backgrounds. So that type of information was carried forward into the optimization and design of SER-155. From VOWST, we actually saw, while VOWST was designed and optimized to go after C. diff, we did see signals in the Phase 3 trial of VOWST, where there was reductions of various different pathogens that we knew were problematic in these hematologic stem cell transplant patients.
So taking those insights, we actually then optimized, SER-155, to be able to go after those particular pathogens. So it's information like that, and the last thing that I think we took forward, as well, that I think is particularly relevant from a pharmacology side of thing, is how to dose our drugs and what the right dosing strategies are to get the PK and PD dynamics that we're looking for.
Can we compare and contrast a little what the objectives are in C. diff, kind of on a fundamental basis, compared to in the Allo setting, and then kind of appreciating those objectives, how you've designed each program to really hone in on what you're trying to do?
Sure. Maybe Matt can comment. I'll just start, Josh, by saying SER-155 was not designed for C. diff, and VOWST was not designed for allo-HSCT, and maybe Matt can comment further.
Yeah, so it's in the context of hematologic stem cell transplant patients. You've really got a set of pathogens that can be particularly problematic, particularly during that neutrophil recovery period of time. And those are bacteria, Enterococcus, Klebsiella, E. coli, staph, strep, all known to come to dominate and can come to dominate in the gastrointestinal tract during that critical period of time, and that have been in large cohort studies significantly associated with the development of bloodstream infections and higher risks of that, as well as some other clinical outcomes. So in the context of SER-155, we were designing the drug to be able to go after those pathogens. So that concept is similar to trying to prevent C. diff.
But in the context of SER-155, we also were optimizing that drug to be able to have an impact on the epithelial barrier. Obviously, to get a bloodstream infection, the bacteria have to move from the gut into the bloodstream, and we know that a disrupted microbiome and the functional implications of that have an impact on barrier integrity. And so we have both preclinical data and are now looking at some of the clinical data through plasma biomarkers, host biomarkers to look at if we succeeded in actually having an impact on the barrier as well.
Got it. So you kind of referenced going after C. diff and going after other pathogens. What does that mean? Like, how do you select the microbiome consortia, I guess, to prevent overgrowth of C. diff? And how is that different when you move out of C. diff, and now it's not a single pathogen, it's actually a much broader number of pathogens you're looking to prevent?
Sure. So, look, we look at the gastrointestinal tract, and in particular the microbiome, as an ecosystem of bacteria that are living there. And so in the end, there are certain functional properties that are either promote or inhibit the growth of various different bacteria, and all bacteria aren't created equally. And so what we did in the context of C. diff is we were going after a very specific mechanism, bile acid metabolism, and secondary, in particular, the conversion of primary bile acids to secondary bile acids, 'cause those have an actual implication on both the sporulation as well as the vegetative growth of C. diff. In the context of SER-155, to your point, we're looking at a broader spectrum of bacteria, and what we have done is through various broad screening, preclinical screening efforts, where we y ou know.
We screened over a hundred and forty different strains, representing over a hundred different species of bacteria, some bacteria that aren't even known to the world, that we have in our proprietary strain library. And we designed a set of consortia, that contain bacteria that actually we know can compete with multiple of these different bacteria for things like certain carbon sources, as well as produce compounds that we have found and identified to be inhibitory to some of these different bacteria. So it's really our SER-155, our next generation cultivated consortia. When we take the aggregate data we have and the platform we have, we can really optimize these consortia to go after very specific pharmacology.
How do you measure, and quantify pathogen domination?
Sure. So, pathogen domination in the gut, we use genomic-based methods. So, we use what's called metagenomic sequencing. So, we basically take DNA from stool samples, and basically, we can then, from that DNA, we can determine the relative abundance of the various different bacteria that are present in there. You can also use cultivation methods, as well to do that, and each gives you a slightly different picture, but the genomics gives you a much more holistic picture of what's there.
I know, and Eric, 'cause you flagged the pathogen domination data set is incomplete, but for the data that you do have, what kind of correlation do you see between the dominant pathogen and the bloodstream infection? If- is there a correlation-
Sure
And it not just between the occurrences, but the specific pathogen?
Maybe Lisa can start commenting on the pathogens that we saw as part of the BSIs, as in the Phase 1b, Cohort 2, and then Matt can comment on the mechanism question.
Yeah, I would like to just back up just a teeny bit and add that in addition to targeting specific pathogens, we're also targeting the mucosal barrier injury component in these patients because it's not just the presence of particular bacteria, it's the lack of the barrier and the integrity problem that results in the infections in these people. And so as a result, they're not just getting infected, unfortunately, with the escape pathogens, they're being infected by things that are commonly called mucosal barrier injury organisms, that the CDC keeps a list of, and a lot of oncology patients are infected with those. So as we look at the infections that these patients got, we see things like Pseudomonas, E. coli, some of the typical enterics that you and I would have to worry about as well.
We also see things that are found in the GI tract and increase in abundance in allo-HSCT patients. You and I wouldn't have to worry about it, but they do. And so the medical literature is rich with identification of those pathogens, and we saw some of those as well. So we see things that are known to be found in the GI tract and very possibly found in the GI tract in allo-HSCT patients.
Okay.
So I'll let you talk about the correlation.
Yeah, so there's a well-established literature looking at large cohorts that have actually shown that basically increases in pathogen abundance in the gastrointestinal tract, particularly of Enterococcus and various Enterobacteriaceae species, is associated with these increases in bloodstream infections. There's a very specific set of bacteria, which are the ones that we designed SER-155 towards. In the Cohort 2 study, as Eric pointed out, we unfortunately didn't have a sufficient number of samples in the stool samples in the placebo patients because we lost a lot of those samples for various different reasons. And so we weren't able to look at a comparison between SER-155 versus placebo. The overall rate across the study was very low for these pathogen domination events.
We took the next best step we could, which was look at SER-155 treated patients relative to a reference control cohort that was matched the best we could in terms of sampling time. And there we saw a substantial reduction. We will now, of course, do the more detailed work, looking at individual patient dynamics.