Seres Therapeutics, Inc. (MCRB) Earnings Call Transcript & Summary

Good day, and welcome to the Seres Therapeutics Investor Event. [Operator Instructions] As a reminder, this call is being recorded. I would now like to turn the call over to Carlo Tanzi of Investor Relations. You may begin.

Good morning to everyone on the webcast, and welcome to Seres Therapeutics Infection Prevention Investor Event. We have posted accompanying slides to Seres website, and I encourage you to view those during the presentation. Following our prepared remarks, we will open the call up for a question-and-answer session. We expect today's event to be about 1 hour in duration. Before we get started, I'd like to remind you that we'll be making forward-looking statements, including, but not limiting to, our development plans and the promise and potential impact of microbiome therapeutics in preventing infection as well as others described on Slide 2 in our presentation. These statements are subject to certain risks and uncertainties, which are discussed under the Risk Factors section of our recent SEC filings. Any forward-looking statements made on today's call represent our views as of today only. We may update these statements in the future, but we disclaim any obligation to do so. I'd now like to pass the call to Eric Shaff, Seres' President and CEO, to provide opening remarks.

Thank you, Carlo, and good morning, everyone. I'm very pleased to welcome you to today's discussion. For Seres, Infection Protection represents our next significant focus in discovery and development, pursuing what we believe is the significant potential impact that our microbiome therapeutics may have in providing protection from life-threatening infections to medically compromised patient groups. Seres microbiome approach in infection protection has been clearly validated by data from our lead SER-109 program for recurrent C. difficile infection. During today's presentation, we plan to discuss the tremendous opportunities we see to apply our microbiome therapeutic approach more broadly in infection protection across multiple patient populations and disease areas. Moving to Slide 3. Seres' mission is to transform the lives of patients worldwide with revolutionary microbiome therapeutics. Our company was founded a decade ago, with what was then a remarkable and somewhat audacious question. What if you could use bacteria as therapy. What if it were safe and effective with GMP manufactured and delivered orally. And in the last several years, we have built the discovery, clinical and manufacturing capabilities to make that aspiration a reality. We're very pleased to advance this new modality to where we are now preparing to file a BLA for our first therapeutic candidate, SER-109, for FDA approval. This lead program is supported by a pipeline of promising additional therapeutic candidates as well as our continued efforts to develop differentiated drug discovery and CMC capabilities to support this new field of medicine. Moving to Slide 4. Our belief in the potential for microbiome therapeutics and infection protection stems from the remarkable scientific and clinical data that we've obtained from SER-109 in recurrent C. difficile infection. The success of this program was highlighted earlier this month with the publication of the SER-109 Phase III clinical study results in the New England Journal of Medicine. Recurrent C. difficile is a challenging-to-treat infection that results in 20,000 deaths in the U.S. alone each year. There is a clear need for a new treatment approach to protect individuals against this infection, and we believe that SER-109 has the potential to fundamentally transform how this disease is treated and meaningfully improve patient outcomes. To recap key data from the ECOSPOR III Phase III study, SER-109 delivered a remarkable 88% sustained clinical response rate. Importantly, the study's efficacy results far exceeded a statistical threshold communicated to us by the FDA to enable this trial to fulfill the efficacy requirements for a BLA. The Phase III also provided mechanistic evidence, highlighting its impact on infection protection, and we will discuss those data in a few minutes. The SER-109 safety profile data also were very favorable, and we observed a safety profile comparable to placebo. The favorable safety profile we've observed with our microbiome therapeutics is an important attribute supporting our approach and important dimension of our approach as we consider progressing other pipeline programs forward. Moving to Slide 5. As a company, preparing for a high-quality BLA filing for SER-109 is our top priority. We are pleased with our progress, and we remain on track to complete submission of SER-109 BLA filing in the middle of this year. SER-109 has breakthrough therapy designation and as a result, we expect an accelerated review schedule. This would include a 2-month period for FDA to review and accept the filing and a 6-month review period. In parallel with the preparation for the BLA filing, we have also made extensive preparations to support a successful commercial launch working alongside our commercialization partners at Nestlé Health Science. In addition, we've taken important steps supporting commercial drug supply readiness. This includes planning to ensure adequate SER-109 drug supply under all planned launch scenarios. Moving to Slide 6. We believe that Seres is well positioned to continue to lead the microbiome therapeutics field. We have 3 clear strategic priorities as we look ahead to 2022 and beyond. Our first priority, as previously mentioned, is to advance SER-109 forward as the potential first ever FDA-approved microbiome therapeutic. Second, we plan to leverage what we have learned through SER-109 and apply this knowledge to develop additional therapeutics for infection protection. Our focus today is on the considerable opportunity we see to help patients, leveraging some of the same insights and capabilities we apply to SER-109 in therapeutic adjacencies to C. diff infection. Our third priority is to continue to optimize our plans for further development of microbiome therapeutics for ulcerative colitis. We look forward to providing further updates on these efforts in the short term. Moving to Slide 7. Based on the substantial opportunity we see for our approach in infection protection, we envision a breadth of opportunity to help patients, which we are working to yield a steady stream of pipeline growth. At the foundation of this effort is SER-109, our flagship program for infection protection. Our intent is to double down, triple down and then more within the therapeutic modality where we have had -- where we have demonstrated significant results. SER-109 is scientifically and medically relevant for our future development efforts as our speakers will describe today. Beyond SER-109, we believe there are multiple opportunities to develop microbiome therapeutics to protect medically compromised patient groups from life-threatening infections. Our SER-155 program is currently in a Phase Ib study in patients receiving allogeneic stem cell transplants. These patients are known to be at high risk for serious infections as well as graft-versus-host disease, and we believe that SER-155 has the potential to address both issues. SER-155 is a rationally designed therapeutic candidate that has been specifically designed for this application. Specifically, we expect to apply our drug development know-how to design additional rationally designed drug consortia for other patient populations. This includes a number of serious conditions, cirrhosis, solid organ transplant and cancer neutropenia are several areas of focus. Importantly, in addition to potentially having a transformative impact on how patients with these serious diseases are treated, we believe our approach could also meaningfully address the growing public health threat posed by antimicrobial resistant infections. Before I hand off to our speakers, I'd like to summarize our key messages for today on Slide 8. First, we believe that SER-109 data validates our approach in infection protection and the transformational potential impact that our microbiome therapeutics may have for patients in need. Second, we believe that our mechanistic and therapeutic approach has broad applicability to create a portfolio of medicines, including for other medically compromised patient groups at risk of life-threatening infections. Finally, we're working to create an industry-leading franchise in this therapeutic category. We are leveraging our unique capabilities to discover, develop and manufacture novel therapeutics. Our lead SER-109 program is advancing towards what we expect to be the first approved microbiome therapeutic. We have an ongoing Phase Ib study for SER-155 in patients undergoing HSCT, and we have multiple other therapeutic -- preclinical stage programs for infection protection. I'll also highlight that aside from our partnered SER-109 program, we maintain full global commercial rights to this entire portfolio of programs. We believe these opportunities in infection protection have the potential to result in multibillion-dollar revenue potential and most importantly, we believe that our approach could transform patient lives. I'm joined today by several members of the Seres team, who will speak in more detail about the clinical, scientific and commercial opportunities we see in infection protection. In addition, we are honored to have Dr. Marcel van den Brink from Memorial Sloan Kettering Cancer Center and a member of our Scientific Advisory Board, here to discuss the role of the GI microbiome in infection protection and allogeneic stem cell transplants. Dr. Van den Brink is among the world's foremost experts in the management of patients undergoing HSCT, and he has published extensively on the role of the microbiome in patient outcomes. From Seres management, Dr. Matt Henn, our CSO, will discuss the scientific rationale and pharmacological data supporting microbiome therapeutics for infection protection and our plan for new programs in this area. Dr. Lisa von Moltke, our CMO, will describe the clinical development of SER-155 and share a clinical and regulatory perspective on developing infection protection opportunities. Finally, Dr. Terri Young, our Chief Commercial and Strategy Officer, will describe the commercial opportunities in infection protection and why we believe this to be such an important opportunity. Following these presentations, we will open the call up for questions. I will now pass the call over to Dr. Van den Brink.

Thank you very much, Eric. So maybe I can go immediately to Slide #11, and this is a slide that probably many of you will have seen, but just very quickly to sort of set the whole stage for what we're actually looking at here. We know by now with about 20 or 30 years of research that we are dealing with 2 ecosystems within your body. One are your own cells and the other ones are microbes. And you've probably seen these kind of talks where people tell you that you have about as many microbes as you have human cells but actually the gene content of these microbes is tenfold higher and specifically that most of the microbiome lives within your gut. And then, of course, specifically over the last 15 years or so, almost every month, there is a new study about a link between the ecosystem of your microbiome with some disease or some aspect of health. And we started in that field also in about 2009, and after a few years, we have been partnering actually with Seres, but I just want to state very clearly here that they have never directed in any way what we are studying, what we are doing, it has actually been a very collaborative partnership. So the data that I will be showing you is mostly focused on our data, recent data in an allogeneic bone marrow transplantation. However, I would like to emphasize that at our center now, we have a core that was built around making it possible for many cancer patients to have their microbiome checked and many of my colleagues are now using that to actually monitor changes within the gut flora during certain trials in certain diseases and so on. But anyway, focusing here on allogeneic bone marrow transplantation, just very briefly to tell you what that is. It is a potentially curative therapy for hematological cancers; at this point, mostly leukemias. And it builds on several elements that are summarized here on Slide #12. First thing is the conditioning regimen, which serves 2 purposes: first one is to debulk as much the tumor load; and the second one is to wipe out the hematopoietic system of the patients, which leads to a state of tolerance and creates a niche for the incoming allograft. That allograft is harvested from donor. That is being given on day 0, as you can see on this time line here. And that allograft again serves 2 purposes: first one is to rebuild the whole hematopoietic system that, as I mentioned, was wiped out by the whole conditioning regimen; but second, also to mediate something called graft-versus-tumor and that is mediated by T cells and K cells within the allograft and that actually makes allogeneic bone marrow transplantation such a powerful therapy because that leads, we think, in many cases, to durable CRs. However, there is a flip side to all of this. The first one is that those same T cells that can give you graft-versus-tumor can also lead to graft versus host. And that means when they look at foreign antigens, not just on these tumor cells, but also on normal tissues. So graft versus host is a major problem that we're dealing with. The other thing is that these patients are in a state of pancytopenia for some time and that brings up then the major risk, as you can see in that pie chart there, of infections of all kinds, bacterial, but also viral. Going to the next slide, Slide #13. So over the last 13 years or so, specifically our group, but also others, have demonstrated by now that within the whole cladograms, so all of the taxa of the bacteria that live within your gut, that we can link certain ones with good outcomes and others with bad outcomes. Bad outcomes is indicated in this cladogram with red, good outcomes with blue. And it's basically all clinically relevant outcomes of allogeneic transplant that are somehow linked to that. In many cases, we have mouse modeling also that has given us some in-depth mechanistic insights of how this actually works. Going to the next slide, Slide #14. One of the common features that we have found and many other groups since then is that within the context of an allogeneic transplant, immediately, once these patients come in, there's a drop in the diversity of the microflora. And I'm showing you here data both for allogeneic transplant and for auto transplant from 2 centers, from our center but also from Duke. And you can see how rapid this drop is and how dramatic that is. With the help of Seres, actually, we were able to set up a global study where we took data, where we took patients from all over the world, from a Japanese center and a German center and 2 U.S.A. centers, and analyzed specifically, do we see the same things? Do we see the drop in diversity? And now I'm on Slide 16. And you can see indeed that in the MSK's cohort that we saw that a greater drop in the diversity within the course of allogeneic transplant was linked to worse overall outcomes, and that we could validate that by taking patient data from these other 3 centers together. When we analyze what is the reason for worse outcomes, the primary reason seems to be an increased risk for lethal graft versus host. What was very interesting is that with that drop of the diversity that happens in all these allogeneic bone marrow transplantation patients, you could also see a state of dominance with a certain taxa happening in almost all of these patients, and not just a taxon, you could go all the way to the level of species. And if you look on Slide #17, you see on the left side, you see that increased incidence that we found at all 4 centers of the state of dominance. I should say here that dominance was in our hands defined as more than 1/3 of the whole flora being taken over by one species. But on the right side, you can see that all 4 centers, that the most prominent taxon, species that could actually do that was Enterococcus, which is really fascinating that all over the world, we saw that same species reaching a state of domination. Then if you go to Slide #18, you can see that, that risk of having a state of domination with Enterococcus was, first and most of all, linked to an increased risk for having a bacteremia with Enterococcus. You can see that's a 9-fold increase. We not only found that for Enterococcus, but if you look at the lower part of the table, you see Proteobacteria, E.coli, Pseudomonas, Klebsiella, which are frequent sources of gram-negative bacteremia. If you then look into that table there, you can see that if a patient in the context of allogeneic bone marrow transplantation at one point is being dominated with Proteobacteria that increases the risk for bacteremia fivefold. So just that state of domination already leads to increased bacterial risks. But the other thing that we found, and I'm not going to summarize that here, but you can find that in the papers that we have published is that increased -- or if a patient during the course of allogeneic transplant is being dominated with Enterococcus also leads to an increased risk of graft-versus-host. And that is summarized on Slide #19, where we saw that both for the MSK cohorts, which are the top graphs there and could validate that in the data from the 3 other centers. If I then go to Slide #20, then you can see that the use of broad spectrum antibiotics is certainly one of the reasons why patients can lose their diversity. But I would like to emphasize that, that is not the full story. What we have found in studies that we hope to publish soon is that diet, but also the use of almost any other kind of drug, and these allogeneic transplant patients at any moment are taking 6 or 7 different types of drugs, that can lead to a drop in the diversity. If you now go to Slide #21, then you can see that indeed in the context of allogeneic transplant that the use of specifically broad spectrum antibiotics, and these are the type of antibiotics that are frequently used not just within the context of allogeneic transplant but for any fever and neutropenia that can happen in cancer patients of any kind, those types of broad-spectrum antibiotics do severe damage to the commensal anaerobes. And as you can see in these 2 graphs here, 2 of the commonly used types of broad-spectrum antibiotics are linked to a greater risk of lethal graft-versus-host. So one of the studies that we are doing actually at the moment at our center is in an antibiotic stewardship to minimize the use of those types of antibiotics. Final slide that I would like to show, because I focused so far only on allogeneic transplant, but I hinted already at the fact that we are trying to bring this to other areas within cancer also, is a study that is going to come out soon in Nature Medicine, where we looked at patients getting CAR cells, chimeric antigen receptor T cells, a therapy that you probably know of. And what we found there is that if patients in the month before getting their CAR cells were treated with, again, one of these broad spectrum types of antibiotics, that the outcomes were dramatically worse in this case for patients getting CAR cells for ALL or NHL. So with that, I just want to summarize what I've been trying to tell you here that we see a dramatic loss of the gut microbiome diversity, which is linked to worse outcomes and specifically, in allogeneic bone marrow transplantation to a risk specifically when there's a state of dominance of increased bacteremias and worse lethal graft-versus-host; that some of the factors that lead to the drop in the diversity are certainly the use of broad spectrum antibiotics, but probably more things such as diet and other types of drugs; that there's a clear opening, a clear window here to come with strategies that can improve microbial diversity; and that one of the studies that we have opened, and that will be discussed later is the one with Seres with a product SER-155, you will hear later more about that; that we see a clear avenue from these studies in allogeneic transplant to other areas within cancer, specifically within immunotherapy of cancer. I gave you a hint towards the CAR cells, but you probably know of other studies within checkpoint blockades also. And with that, I think I will start to hand over now to Matt Henn, the Chief Scientific Officer of Seres, who is going to discuss microbiome therapeutic pharmacology.

Great. Thank you, Marcel, for that introduction to the disease area. So good morning, everyone, and I'll be starting on Slide 25. So as Dr. van den Brink described, the gut microbiome impacts a broad range of biology and is important in maintaining health. As an example, the gastrointestinal tract plays an important role in preventing pathogen infection, including that of pathogens that can harbor antibiotic resistance, or AMR. The increasing emergence of AMR is a significant public health threat. It is a slow pandemic. Beneficial microbes in our gut are an important piece of the puzzle in combating infection and AMR. They can be leveraged to transform how we both protect people and treat microbial infection and other diseases more broadly through various functional mechanisms, which I'll touch on through today. Antibiotics as well as other insults can impact beneficial microbes with downstream negative implications. These can include domination by pathogens and/or AMR bacteria and subsequent bacteremia and additional medical complications. Moving to Slide 26. Seres is developing therapeutics that are consortia of multiple species of bacteria that got engraft into the gut, meaning they germinate and vegetatively grow in patients that receive investigational drug. Engraftment is a measure of our drug's pharmacokinetics. We have observed that the engraftment of bacteria from our investigational drugs lead to broader restructuring of the microbiome and modulation of the metabolic landscape of the gut. These are measures of our drug's pharmacodynamics. We have also seen that the bacteria in our investigational drugs produce metabolites that can affect broader functional changes in the gastrointestinal track, both directly and indirectly through changes in host metabolism and immunity. Importantly, we're engrafting several species at the same time with a single investigational drug. This also allows us to attempt to modulate multiple disease relevant pathways with one treatment. Data from our Phase III study of SER-109 shows that this novel therapeutic modality can work successfully in the clinic, and we are leveraging SER-109's strong proof of concept and our unique insights in MoA, PK and PD to target other infections. As illustrated on Slide 27, the profound results from the SER-109 ECOSPOR III trial published in the New England Journal of Medicine highlight the value of our approach. In ECOSPOR III, we observed that SER-109 effectively restructures the host microbiome and changes its function to deliver clinical results. The chart on the left demonstrates the bacteria in SER-109 engrafted rapidly and successfully in the GI of subjects treated. Further, while not shown in this figure, we have observed that the bacteria durably engrafts with SER-109 species observed at the 6-month follow-up time point. Engraftment led to significant restructuring in the microbiome and led to functional changes in the gut. As shown in the chart on the right, we observed significant biologically relevant increases in the concentration of secondary bile acids versus placebo. These changes in bile acids are detrimental to C. difficile germination and growth. Moving to Slide 28. At last year's IDWEEK conference and recently by invitation at the Presidential Advisory Council on Combating Anti-resistant Bacteria, we shared additional ECOSPOR III data as shown in the figure on the left that demonstrate that the treatment with SER-109 rapidly and significantly reduced the abundance of Proteobacteria in patients' guts. As shown in the plot, the Proteobacteria and the Enterobacteriales and Enterobacteriaceae that were most significantly reduced are also significantly associated with more frequent carriage of genes that confer antimicrobial resistance. As you might expect, reducing the abundance of these Proteobacteria leads to significant reductions in the total abundance of microbial-resistant genes in the gut compared to placebo as shown on the right figure. As observed in our extensive preclinical data and in the Phase III clinical data, SER-109 is meaningfully changing the structure and function of the host microbiome while delivering the clinical benefits of preventing recurrent C. difficile infections. In addition, the data also increases our confidence that the targeted reduction of pathogen and the modulation of gastrointestinal metabolic landscape are scalable mechanisms that merits further explorations in populations of medically compromised patients at high risk for medical infections, including AMR infections, for which there are currently limited treatment options. As outlined on Slide 29, over the past decade, Seres has built a differentiated research engine that integrates R&D, CMC and clinical platforms that power novel microbiome discovery and the rational design and development of bacterial consortia drug candidates. We design consortia based on an iterative reverse translational strategy that can elucidate disease-associated biomarkers and targets and drug mechanism of action, PK and PD at high resolution. We utilize high-value clinical data sets combined with advanced data sciences and microbiome analytics to identify microbiome signatures of disease at the resolution of specific species and strains, metabolites and even genes. We then identify and optimize consortia bacteria in our in vitro and ex vivo screening platforms and ecological disease models that have been customized from microbiome drug discovery. Importantly, these in-house capabilities enable us to move from association in the clinic to confirmed causality of the bacteria. Further, our extensive strain library and clinical trials designed to generate translationally rich data sets enable us to assay a broad breadth of biology and continue to generate insights and expand our analytical power to fuel drug design for new indications. As shown on Slide 30, our platform is buttressed by extensive manufacturing capabilities. The strain library that we have built and functionally characterized over the past decade in combination with our manufacturing capabilities provides access to a broad set of bacterial species and functional targets. We can manufacture both donor-derived and rationally designed consortia in-house. We can make both spore and vegetative formulations, allowing us to use more strains in our products that others cannot. We have launched scale manufacturing capabilities to support product needs for multiple clinical assets in parallel and a collaboration with Bacthera to deliver commercial scale manufacturing. Moving to Slide 31. Seres microbiome therapeutics provide a novel, potentially transformative technology for the protection from and treatment of infections, AMR and bacteremia. As noted previously by Dr. van den Brink, a disrupted and gastrointestinal microbiome can lead to domination in the gut by undesirable microbes, the breakdown of the mucosa and epithelia that can lead to an inflammatory state and the development of bloodstream infections resulting from bacterial translocation. Seres consortia is designed to restore colonization resistance to pathogen. Bacteria in our drug candidates can outcompete pathogens and inhibit their growth through nutrient competition and other mechanisms. This can decrease their abundance in the gut, which both reduces the likelihood of patient transmission and the bacterial translocation to the bloodstream. Our drug candidates are designed to also reduce translocation through enhancing epithelial barrier integrity. Additionally, our drug candidates are designed to modulate immune responses with a goal to improve immune homeostasis and reduce inflammation. Through these mechanisms, our therapeutic strategy has the potential to tackle infection and downstream consequence of infection by targeting the root causes that lead to infection, bacteremia and transmission. Our SER-109 data provides clinical proof of concept for deploying our therapeutic technology more broadly to combat microbial infections and AMR. Transitioning now to Slide 32 and our SER-155 program, specifically. As noted previously, Seres has a differentiated platform for the discovery and development of microbiome therapeutics. We have deployed this platform to design SER-155. We analyze multiple longitudinal patient data sets to identify species of interest for 155. We access the data sets Dr. van den Brink was talking about earlier and also from the University of Cologne to identify both bacterial taxa and functional signatures that were depleted post-transplant and associated with reduced risk of bloodstream infection and graft-versus-host disease. We also looked at clinical data from the trials we've conducted to date to understand which species have a high probability to engraft in the GI tract broadly across patients and that had strong associations with modulation of targeted functional pathways. Leveraging our extensive strain library, we screen consortia that were combinations of over 100 different bacterial species. This included screening multiple strains for many species. Our in silico design tools were used to optimize the consortia to exhibit functional properties that promote colonization resistance to VRE and CRE, improve epithelial barrier integrity to prevent bloodstream infection and increase immune homeostasis to reduce the incidence of graft versus host disease. Moving to Slide 33. In the case of SER-155, we designed the consortium to have powerful effect in reducing CRE and VRE abundance. These bacterial species are frequent pathogens in people receiving stem cell transplantation as well as in a broader spectrum of antimicrobial-resistant infections in hospital settings. As Dr. van den Brink described, domination with Enterococcus species is associated with graft versus host disease as well as blood stream infections. So targeting these species can have a significant impact on reducing risks of both infection and graft-versus-host disease. As shown here in mouse models of VRE and CRE colonization, shown on the left and right respectively, where mice are first infected and heavily colonized with VRE and CRE, represented by the red line. Subsequent therapeutic oral administration of SER-155, shown by the blue line, led to significant 2 to 3 log reductions in VRE and CRE titers in the gut compared to untreated mice. Notably, these reductions in VRE and CRE occur rapidly after SER-155 doses. As I mentioned before, our goal is to target multiple functional pathways with one consortium. SER-155 also includes bacteria that produce metabolites that have the potential to prevent bacterial translocation and reduce graft-versus-host disease. As shown on Slide 34, SER-155 is effective in improving epithelial barrier integrity in our in vitro primary colonic membrane assay. In this screening model, an intact epithelial barrier is established and as shown in the left panel, treatment with interferon gamma alone will lead to epithelial damage and permeability. In this model, we include consortia that are designed to not produce the metabolize that we have optimized SER-155 to produce. As you can see, these negative consortia are not protective. In contrast, SER-155 is protective and achieved significantly greater barrier production than both experimental controls. This pharmacological property of SER-155 enhances its potential ability to protect patients from infection, not only by targeting pathogens directly, but also by reducing the ability of pathogens to translocate from the GI tract to the bloodstream. SER-155 was also designed to modulate immune responses. As shown on the right, in germfree mice colonized with SER-155, SER-155 led to differentiation of [ CD4 ] T cells with enrichment for FoxP3 Treg cells and a relative reduction in proinflammatory TH1 and TH17 cell. These results suggest that our consortia are modulating the local immune environment, which has relevance for potential reduction in graft-versus-host disease. Summarizing on Slide 35. Collectively, these functional properties of SER-155 support the potential to transform how we combat bacterial infections in AMR. With SER-155, we see the potential to reduce the abundance of targeted pathogens to prevent pathogen transmission, strengthen epithelial barriers to further reduce frequency of blood stream infections and to modulate immune responses to tackle medical complications such as graft-versus-host disease. Wrapping up on Slide 36. Our integrated platform is helping us accelerate the discovery and development of novel agents to protect patients from infections. We are building on the success of SER-109 by advancing SER-155 into Phase Ib and have initiated multiple additional preclinical programs. These include evaluating opportunities for infection protection in patients receiving autologous HSCT and designing consortia to deploy in settings such as cancer neutropenia and solid organ transplant. We are driving towards initiating additional clinical development program in 2023 and additional programs into the clinic over the next few years. Thank you for your attention, and I'll now pass the call to our Chief Medical Officer, Dr. von Moltke.

Thanks, Matt. Moving to Slide 38. SER-155 is designed for maximal clinical impact. It is a cultivated consortium of human commensal bacterial strains fermented and manufactured in our facilities and formulated for oral delivery. Specific strains were selected using the approach Matt described earlier to target taxa associated with GvHD and bloodstream infections, using species that have a high probability of engrafting in the GI tract based on our clinical experience. This potential therapy is designed to target these 2 important causes of mortality during the first year post-transplant. As shown on Slide 39, we have initiated a Phase Ib trial to assess the safety and efficacy of SER-155 in patients who have received allogeneic stem cell transplants, working with our partners at Memorial Sloan Kettering and the University of Chicago. These patients will be undergoing treatment for hematologic malignancies such as leukemia, and they are a complex and often medically fragile population. We expect that well over 50% of the cohort will experience infection or GvHD. And if we could reduce the incidence of these conditions, we believe we could meaningfully improve the outlook for these patients. And the study is set up with 2 cohorts. The first cohort is designed to assess safety and engraftment of SER-155. We are enrolling 10 subjects to study safety for 18 weeks and 52 weeks post transplant. The second cohort includes 60 patients in a randomized, double-blinded design to further evaluate the safety and engraftment, but also the efficacy of SER-155. The first patient was enrolled in November and recruitment for this trial is ongoing. Moving now to Slide 40. Our trial design allows us to explore a number of outcomes from treatment with SER-155. And as Matt noted, our modality allows us to explore multiple disease-relevant pathways with one consortium, and it is possible that some of the efficacy outcomes could be independent of each other. Both cohorts will give us data on our primary endpoint of safety of SER-155 in this vulnerable population and on whether specific strains engraft. A successful outcome would be a favorable safety profile, which would resemble the safety results seen in the SER-109 Phase III trial. And importantly, it would show that microbiome therapeutics are safe to use in medically compromised populations, including and beyond stem cell recipients. We will also seek to confirm which strains engraft successfully in people taking SER-155. This will guide further efforts in this program and other Seres clinical programs as we continue to learn about which species are most likely to engraft successfully in patients. The second cohort will give us a better understanding of the potential efficacy of SER-155, ultimately guiding future clinical efforts on which outcomes we should target with future studies. Ideally, we would see a significantly reduced incidence of bloodstream infections and acute GvHD in patients taking SER-155. Now this might also translate into improved overall survival, although there are limitations on the interpretation of clinical data from a 60-person cohort. Positive efficacy growth will be important for our company. Observations that SER-155 could reduce the infections will further validate our mechanism and serve to continue to increase our efforts in protection of compromised patients from infections. Positive results in preventing GvHD would demonstrate a clinically significant result [indiscernible] which would support not only pursuing this outcome in future trials, but exploring next steps forward in immune modulation. Results from this trial will also inform our path forward with regulators. We believe that demonstrating a very [ steep ] profile in this population combined with consistently strong safety profile of SER-109 and our other agents should be important as we work with the FDA to establish appropriate precedence for microbiome therapeutics. With the significant unmet medical need and relative rarity of people receiving allogeneic stem cell transplants, we believe that it would be appropriate to seek designations and other opportunities to accelerate discussions with the agency. Finally, if SER-155 is successful in meeting the objectives we have outlined, we believe we could potentially improve outcomes for stem cell transplant patients, which could increase its use across medical conditions where this approach holds promise and the unmet need remains high. With that, I will hand the presentation to Dr. Terri Young to talk about the commercial perspective.

Thanks, Lisa, and good morning, everyone. We'll now move to Slide 42 and start with the best example of the near-term and robust opportunity in infection protection with SER-109. SER-109 was our first foray into an area where current state is a life-threatening and debilitating infection that has substandard answers but far too many patients and resulting in high cost for the health care system. In recurrent C. diff infection, we thought that if you could take a fundamentally different approach from antibiotics, that is pathogen decolonization with a microbiome therapeutic as a means to control for bacterial bad actors, then you could protect patients against future infection while not incurring an increase in antimicrobial resistance. And now we've shown that our approach can achieve what was previously unachievable with antibiotics alone. Very robust Phase III efficacy, a placebo-like safety profile and, importantly, a reduction in pathogens that harbor antibiotic-resistant genes. HCPs and payers are quite enthused about this new approach. And this is shown here in the graph on the right, with the high clinical value rating from payers and high likelihood to prescribe by HCPs for SER-109. So in the wake of this very clear demonstration that profound clinical outcomes can result from pathogen decolonization, we started to think where else might this type of mechanism play well for patients. Are there other areas like this with high unmet need where we can help vulnerable patients against bacterial bad actors. Well, it turns out that there are quite a few places. We're moving to Slide 43 now. We noticed that antimicrobial resistant infections are big and growing threat. And in fact, we continue to see public concern about the slow pandemic that is now considered a Top 10 global public health threat by the World Health Organization. The latest notable mention was a long article in the Lancet earlier this month. And this is happening because of the inability of antibiotics to treat infections without causing increased levels of resistance. For this reason, doctors tend to use new antibiotics very sparingly for treatment and even more sparingly for prophylaxis. Thus, as we've all witnessed, development for new antibiotics has markedly slowed over the past few decades. There is a need for a new approach in this arena that moves beyond the antibiotics. We also noted some recent innovation on the viral front with Merck's PREVYMIS, which is used to protect allo-HSCT patients against viral infection. We found this really interesting because HSCT patients are, in fact, under threat from multiple sources, as you've heard earlier in this program, including bacteria and GvHD. And we had an asset that we thought could play well there. We view PREVYMIS as a bit of a proof source of effective protection against infection being rapidly adopted by physicians and funded by payers. It definitely seems that protecting those allo-HSCT patients from complications has enormous value. And perhaps, this is no surprise if you think about it, even just from the HCP's perspective. Here is a patient who is suffering from cancer that you have the opportunity to give new life to. You complete the transplant, but you are nowhere near out of the woods. There are multiple large and common known threats that still await. Reducing that threat level so that the index cancer treatment, i.e., the transplant, can take hold is of paramount importance to you, the treater, and, of course, to your patient as well. We're on Slide 44 now. Today, both GvHD and infections that affect a high number of these patients cause more time in the hospital and, most importantly, get in the way of better outcome. When these complications occur, we see costs increase significantly with incremental costs approaching nearly $200,000 per patient, and we see high rates of mortality. All this despite the availability and in the case of GvHD, common use, the prophylactic regimen. Clearly, patients, their doctors and payers would all benefit from effective reduction of infections in GvHD. So we're excited about SER-155. Moving to Slide 45. If SER-155 can deliver a safe profile and meaningful risk reduction, it could become a key step in ensuring a successful outcome for these cancer patients. Pursuing reductions in both infections and GvHD to the most prevalent and impactful complication would provide a double benefit. The microbiome modality is logical as you heard earlier, directly addressing the linkage of the gut microbiome to these complications. Importantly, improving patient outcomes would translate to significant economic value for payers. Thus, we believe SER-155 has the potential to become a core part of the armamentarium for physicians treating any of the 9,800 allo-HSCT patients. And it doesn't stop there because there are additional pools of medically compromised patients or bacterial bad actors are further compromising their return to health and the ability of HCPs to address their patients' primary issues. You can see some of these on Slide 46. At Seres, we believe we have the capabilities and knowledge to tackle these with our rationally designed consortia. In the lower part of the slide, you can see a sampling of the areas we're exploring, but this is by no means an exhaustive list. The allo-HSCT population is one of the most expensive DRG, the median per patient cost at 1 year is $400,000, and complications have a meaningfully higher clinical and economic toll. We sought to identify other populations like this, like allo-HSCT, where infection protection could vastly improve clinical and economic outcomes. For example, there are other transplant recipients, autologous HSCT and solid organ transplant and other immunocompromised patient population, such as cancer neutropenia patients. And then there are the chronically ill, many of whom such as cirrhosis patients are at high risk for infection and his frequent interactions with health care facilities may increase the risk of acquiring antimicrobial-resistant infection. We believe that protecting these populations from infections will meaningfully improve their health outcome. Suffice to say that we have multiple paths to a multibillion-dollar franchise, if we're successful here. On Slide 47 and 48, I'll double-click on a few of the examples I just spoke of. First, cancer patients with neutropenia. Neutropenia and resulting infections are common amongst cancer patients, greatly contributing to the 2.8 million annual cancer-related hospitalizations in the U.S. In fact, half of all patients undergoing chemotherapy experience neutropenia, and septicemia was the #1 cause of hospitalization other than the underlying cancer itself. Febrile neutropenia in cancer patients is deadly and costly. Up to 30% of these patients experience major complications, and $2.7 billion is the estimated U.S. total cost of the neutropenia hospitalization. Finally, this complication can result in delay or discontinuation of chemotherapy, again, significantly derailing a cancer patient's potential return to health. Moving to Slide 48. There are 630,000 cirrhosis patients in the U.S., and of those 10% to 15% are hospitalized each year. These patients are highly susceptible to infections because of immune dysfunction and leaky gut, which can lead to infections of the blood and fluid that accumulate in the abdomen as part of the course of the disease. And it doesn't go well for many of these patients once infection takes hold. Sadly, mortality quadruples when they acquire an infection versus when they don't. Finally, increased antibiotic-resistant gene carriage in the gut microbiome due to frequent antibiotic exposure and resulting microbiome disruption is predictive of early hospitalization and death. Like with other areas we've discussed today, the standard of care currently is limited to antibiotic prophylaxis with the typical challenges inherent in that approach. For these patients as well as for the other populations we discussed today, a new approach is needed, one that can effectively decolonize pathogens with a microbiome therapeutic. Now I'll hand it back to Eric to close this out with Slide 49.

Thanks, Terri. As you can see, we are enthusiastic about the opportunity to apply our microbiome therapeutic approach to provide a fundamentally new and potentially transformative approach to infection protection. In the middle of this year, we are looking forward to submitting the SER-109 BLA filing, a tremendous milestone for Seres. We expect SER-109 to lead our infection protection franchise as the first ever approved microbiome therapy for recurrent C. difficile infection. Following SER-109 is our SER-155 program in an ongoing Phase Ib study. This rationally designed therapeutic candidate has the potential to meaningfully improve outcomes in medically compromised individuals undergoing HSCT. We are also evaluating a number of additional therapeutic candidates for development in other areas with great need to protect individuals against infection and society more broadly against the proliferation of antibiotic-resistant pathogens. We believe that all of these efforts have the potential to transform patient management while also creating substantial value. We now look forward to taking your questions.

[Operator Instructions] Our first question comes from Mark Breidenbach with Oppenheimer.

Maybe I can kick it off with one for Dr. van den Brink. I guess I'm wondering when the right time is to treat a patient with a product like SER-155. I imagine this consortium of bacteria would also be susceptible to the antibiotics and other drugs that a patient is on immediately post transplant. How -- when is the right time to deploy 155? And how long would the patient have to stay on treatment?

So that is a fantastic question that we have looked at carefully also. First as a preface, so far, any strategies that people have been thinking of in terms of targeting the microbiome have been for treating late graft-versus-host, and some benefit has been seen there. Our strategy is the only one to really try to prevent it. Getting to your question, the only prophylactic type of antibiotic that we are giving is Cipro or Levaquin, ciprofloxacin or Levaquin. A number of studies by our group and others have actually indicated that, that does relatively little damage to the microflora. In our study, we're going to find out if the -- if actually Cipro will have any impact on the transferred flora from SER-155, but we expect that, that will be compatible. We will start, of course, and you will hear -- and you heard that and can hear many more details from Lisa about that, with this strategy early before the actual date of transplant. And the reason for that is that we think a major benefit from all of this will come to the health of the gut barrier. And you've heard that from Matt also that the flora is so relevant for keeping the mucus layer and the intestinal layer intact. So we think that the maximum benefit will come from having specifically an intact flora in the first week -- the first 2 weeks after a transplant because we know from many studies within mouse and man that, that is the time when graft-versus-host really gets triggered. In that period, the inflammation, the damage to the gut barrier leads to the onset of graft-versus-host, which then clinically will not be visible until 2 or 3 weeks later. I hope that answers your question, but that is our current thinking.

It does. And maybe a question for Lisa. Given this, the design of the Phase Ib trial with the safety cohort followed by the randomized cohort, are we going to have to wait sort of a full 52 weeks after enrollment of cohort 1 before we can even begin enrolling cohort 2? What's sort of like the timing looking like before we can start enrolling patients in the randomized cohort?

Yes. No, we are not waiting the entire time. There are carefully staged points at which there'll be a safety evaluation and there'll be the ability to enroll then on the cohort 2.

Okay. Understood. And maybe one final one for me, probably directed toward Eric. I know we didn't talk about SER-301 and ulcerative colitis much today. But can we realistically expect to see anything from that Phase I trial of 301 in 2022?

Yes, Mark, thanks for the question. Obviously, our focus today is on infection protection. I mean we put out a release at the end of last year saying a couple of things. One was that we saw engraftment in 287, which was a positive. We didn't see some of the metabolic shifts that we had expected to see, which we're currently in the process of unpacking why? I will say that we did see some really intriguing data related to patient subgroup analysis where you can envision maybe an approach where certain patient subgroups may be more amenable to therapy than others. We're continuing to do that analysis and consider the potential implications for 301. So we do expect to get back to you in short order with a plan on that, but we have not provided guidance thereafter. Maybe I can just pivot back to the -- Mark, your first question around when, and I think Dr. van den Brink's answer of early was pretty clear. Maybe I'll just invite Lisa or Matt to make any other comments on that because -- just from the company side.

Sure. Thanks, Eric. So Mark, great question. And the only additional thing I'd add to what Dr. van den Brink said was, we as well have a dosing strategy that takes into account considerations that the patients may be on antibiotic treatment. So that would be the only additional thing that I would add there.

Our next question comes from Joseph Thome with Cowen.

I know towards the end of the presentation, it was indicated additional indications like cancer neutropenia and hospitalized cirrhosis. Are these indications also characterized by an overgrowth of Enterococcus such that SER-155 would potentially also work here? Or would these different indications be kind of discrete formulations and different therapeutics, you think?

Joe, thanks for the question. And maybe I can ask Matt to start.

Joe, yes, it's a great question. So we see multiple additional pools of medically compromised patients where bacterial bad actors are further compromising return of health to folks, and as we said, in settings of HCPs to address patients. So we think more broadly about patients that are on immunosuppressive drugs as well as these various settings where the microbiome has been significantly disrupted to put these patients at risk of the types of infections as well as additional medical complications that we've touched on today. In terms of the -- specifically these particular patient populations, we're actively working to identify the drug targets that we're after, meaning both the specific bacterial and escape pathogens that are dominant in those patient populations as well as any other medical targets that we would want to go after. And we believe and are building a portfolio that would be comprised of SER-155 as well as additional lead candidates.

So Joe, maybe I can just add to that. I think Slide 36 in the deck really kind of lays out the blueprint for how we think about moving forward, considerable unmet need, opportunity to make a difference for patients, really utilizing capabilities and insights that we've demonstrated from 109. So as I said in my prepared remarks, we're thinking about how do we double down, triple down, quadruple down in areas where we have had clinical success, and that's really the approach here. We think there's a depth and breadth of opportunity, which is considerable.

Great. And then maybe one for either the company or Dr. van den Brink, but obviously, reducing graft-versus-host disease is sort of the goal here. Is there any potential that manipulation of the microbiome would affect graft-versus-tumor responses post transplant? Or I guess on the other side, obviously, reducing AEs could potentially, I guess, result in better efficacy. But outside of this AE reduction, is there a reason why manipulation of the microbiome and engraftment of the species would cause a better response for patients?

Well, maybe to your question, Joe, we can invite both Matt and Lisa and Dr. van den Brink to comment. Matt, do you want to go first?

Yes. I mean I think what I would tell you here, Joe, is, first and foremost, keep in mind that our drugs are designed to target multiple different disease relevant patient populations -- patient targets simultaneously. So with SER-155, we're hoping to knock back the various bacteria, repair epithelial, how to prevent translocation as well as modulate host immunity to have an impact on graft-versus-host disease. And while we're seeking to target all of those and have strong data that supports we can, actually successfully targeting any of them could have meaningful success in the clinic. So let me pass it to Marcel to comment further on your question.

Yes, that is a fantastic question. So we published an early study when we had only a smaller cohort where we actually linked a certain taxa, the dominant -- not the dominance, but the presence of a certain taxa with better graft-versus-tumor, in this case, lower relapse risk. So we're certainly hopeful that we might find these kind of links that we find that optimal quadrant where we see taxa that are linked to lower or at least not increased graft-versus-host and better graft-versus-tumor, meaning lower relapse. Currently, we're looking at the whole database that we have now, the much larger cohort and have actually somebody working specifically on that. Theoretically, you could speculate that this is possible. If you find the kind of taxa that will mostly protect the gut from damage because the major problem with a graft-versus-host is gut graft-versus-host. So if you can limit the damage to the gut while still keeping the activation of allo-activated T cells that can lead to graft-versus-tumor intact, so you might be able to find that right balance, and we are hopeful that we can find those kind of taxa that will limit graft-versus-host while optimizing graft-versus-tumor. That is what we're looking for.

Joe, if I can add one additional thing here. Part of what we're seeking to do with our drugs is to induce immune homeostasis. And so I think one of the advantages of our technology is that we can achieve that and anticipate we can achieve that in a clinical setting as well. And where that brings benefits, of course, is that other therapeutics that are out there are more immunosuppressive and that suppression can come with various downstream consequences such as, obviously, relapse with respect to the cancers as well as infections, et cetera. And so I think what we're really driving towards here is that -- is driving that towards that immune homeostasis, which has the potential to have an impact in both areas.

Maybe I can add one more thing. So studies that we hope to publish soon actually indicate that graft-versus-host specifically is more a local phenomenon. So you might see different effects of the gut microbiome systemically as locally T cells leading to graft-versus-host within the gut are not necessarily the same ones that can target within the marrow, for instance, the leukemia cells. So there are a lot of theories based upon data that you can put forward where you might be able to find a way to separate graft-versus-cells from graft-versus-tumor based upon changes within the flora. And that is what we're looking for at the moment.

Our next question comes from Chris Howerton with Jefferies.

I guess what I was curious about, if you could describe a little bit about the reimbursement landscape that we could expect both for SER-109 and then eventually, SER-155. Obviously, both of those might be hospitalized patients. So how should we be thinking about the different payer landscape? And I'll ask again, I know you'll answer me, but I'll ask anyway is, any additional thoughts around pricing for SER-109 would be super helpful.

Yes, Chris. Let me invite Terri to talk about the reimbursement landscape for both.

Sure. So a bit different actually. So SER-109 because of the way that it's administered and the course of the disease, this is a very acute condition, right, where the patient becomes very, very sick very quickly. Many of them, over half are hospitalized, but the vancomycin addresses their symptomatic issues in the presence of the toxin-producing vegetative bacteria pretty quickly. So they tend to be discharged during a vancomycin regimen, and it's after completion of that regimen in the outpatient setting that they would typically receive SER-109. So the vast majority of SER-109 we expect to move through the outpatient benefit. Contrast that with SER-155, the vast majority of prophylactic regimens today for allo-HSCT patients are reimbursed through the inpatient asset. As I mentioned earlier, this is one of the highest DRGs of all DRGs in terms of payments and the substantial cost offset that you could achieve if you're successful in protecting these patients from the serious common complications that we discussed like infections or GvHD. And I guess the final thing I would add on the topic is that we -- as I mentioned earlier, just to reinforce, we view PREVYMIS, the Merck product for viral infection prophylaxis as illustrative that effective protection against infection is rapidly adopted by physicians and funded by payers. So thanks for the question.

Cool. And any advance data on pricing for SER-109?

The SER-109. Right. So for SER-109, we -- I frequently referenced the number and go back to what value you're adding to the system. Right now, these patients recur and recur and recur and it's the bane of HCP's existence. Payers recognize that they don't have good options to prevent recurrences. These patients become very costly because of what I mentioned earlier. They're going in and out of the hospital with every recurrence. So they cost on average $34,000 a year. We haven't guided on pricing yet, but on the back of the Alliance and the agreement we signed with Nestlé Health Sciences, I'm working with my colleagues over there to determine our pricing and contracting strategy as we approach the launch. So more to come on that, but we think we bring substantial value to an area that really does not have good options today as evidenced by the recurrence rates.

Our next question comes from John Newman with Canaccord.

Just wanted to start with a question for Dr. van den Brink. Just curious, in terms of your work and others, is there any correlation between the rate of Enterococcal overgrowth or domination and acute GvHD risk and survival? You've shown from some of the slides that when you see that the enterococcal species are dominant that has a negative effect. Wondering if anyone has ever looked at the rate of that overgrowth if patients that have a very rapid overgrowth tend to fare worse?

So I'm not sure what you mean exactly with the rates, but a number of studies at other centers, Japanese centers, U.S. centers, have indicated that the abundance of Enterococcus in the post-transplant setting, specifically the early post-transplant setting, is just like we found is linked to an increased risk of a graft-versus-host. And in some cases, they found, just like we, that it was even leading to an increased risk of lethal graft-versus-host. So not sure if that answered your question, but this is now a finding that has been validated by a number of centers all over the world.

John, I'll add one thing here as well. Keep in mind, and we've seen this consistently across our portfolio that one, I think, important feature of our therapeutics is that the bacteria engraft and become metabolically active very, very quickly. So certainly, in the context of that ecology in the gut and that continual race against time, basically, our drugs are working very, very quickly. And we also dose and have dosing strategies that help make sure we get a rapid uptake of the drug to establish colonization resistance to the bad actors rapidly.

Great. And I just had a second question, which was, in terms of utilizing a therapeutic like SER-155 after allo transplant, would there be a scenario where down the road, you would investigate longer-term dosing? So for example, after the patient has gotten through the initial period after the transplant, could you investigate a longer-term treatment of maybe a year or 2 afterwards?

John, it's an interesting question, Matt, do you want to comment on that?

Sure, John. So the answer is yes, we could envision those kinds of concepts. It's not something we're specifically evaluating though we are evaluating treatment at multiple different times during this trial in the patient's journey. But certainly, given the safety profile that we have had to date with our drug, you can certainly imagine potentially using drugs like SER-155 on their own or in combination with other therapies and still maintain a safe profile, but this is something that we would certainly have to evaluate in a clinical setting, and we are -- we'll do that ultimately if the data bear out and it makes sense.

Certainly, John -- yes, go ahead, please.

Can I add one thing to that? So we have actually looked at the long-lasting impact of an allogeneic transplant on the microflora. And what we found is, patients 1 year out, even those patients who did really well who were discharged and after that didn't need any kind of antibiotics anymore, one year out, they still have a clear injury to their flora. So yes, I could see that we might treat patients longer, specifically if they're going to be treated at certain time points with antibiotics. But as I told you already, it's not just antibiotics that will do damage to the flora. Many other drugs can do that also. So I can see us, first of all, monitoring closely what is happening post-transplant with the flora, and we might find that every so often we have to treat again or maybe for a longer period. So I could see that happening.

Our next question comes from Keay Nakae with Chardan.

Keay Nakae, Chardan. My question has to do with the conditioning regimen prior to the stem cell transplant. How well understood is it the -- any variation from site to site in that preconditioning regimen? What impacts it has on the ability of the Enterococcus to establish this dominant position?

Maybe I can ask Lisa or Dr. van den Brink to comment on that one.

Yes. Why don't I ask Dr. van den Brink to start, and then I can comment as well.

Right. It's almost like I have paid you to ask this question because we're just finishing up a study that we are submitting in the next week where we have looked again at thousands of patients in terms of the impact of the conditioning regimen on damage to the flora. If you look carefully at the data that I showed you, you saw that the biggest drop in the diversity happened before the allogeneic transplant. So the conditioning regimens are definitely a critical [ or that ] phase of the whole transplant. So we have looked at all the different types of conditioning regimens. And what we have been able to do is put them into 3 categories in terms of how much damage they actually cause to the microbiome. So based upon that, we can stratify, we can classify a little bit what the conditioning regimen damage is to the flora. And that can certainly be used also when we analyze the data of the SER-155 study. Does that answer your question?

Yes. So armed with that knowledge, as you move forward in the study, does that have to be standardized across the sites you use?

So the interesting thing is that we don't necessarily have to standardize by regimen because that would make a multicenter study complicated, right, if we're going to prescribe the exact conditioning regimen. As you might know, within this field, there is a tendency for every center to modify the conditioning regimen somewhat. But by putting them into categories, we think that we can still have a pretty open enrollment when it comes to conditioning regimens.

Yes. And I'll just add that we can stratify for that based on how we enroll. And then as Dr. van den Brink mentioned, when we analyze. So I think we'll be able to control for that.

There are no further questions at this time. I'd like to turn the call back over to management for any closing remarks.

Thank you very much, and thank you for joining us this morning. We look forward to keeping you updated on our progress, and we hope that you have a great week. Thanks very much.

This concludes the program. You may now disconnect. Everyone, have a great day.