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

Ladies and gentlemen, thank you for standing by, and welcome to the Seres Therapeutics Ulcerative Colitis Webcast. [Operator Instructions] I would now like to introduce your host for this conference call, Mr. Eric Shaff, CEO. You may begin.

Good morning, and welcome to Seres Therapeutics Ulcerative Colitis Investor Webcast. Thank you for spending time with us this morning. We will be reviewing slides alongside our remarks, and we have posted the presentation under the Investors and News section of the Seres website. Our primary goal for today is to provide a better understanding and appreciation of our work to develop novel microbiome therapeutics for ulcerative colitis. We will be discussing our ongoing SER-287 ulcerative colitis Phase IIb study, with top line clinical results expected midyear, followed by additional data later this year. We will also be highlighting SER-301, our next-generation product candidate. We are excited about the prospects for both programs as potentially transformative treatments for patients with UC, and we look forward to diving into these programs in detail today. Moving to Slide 2. We will be making forward-looking statements in today's presentation, so I encourage you to review the Risk Factors section in our last 10-Q. As highlighted on Slide 3, I'm pleased to be joined by a number of my colleagues here today, as well as Professor Stephen Hanauer, who is a leading Gastroenterologist affiliated with the Northwestern School of Medicine and a past President of the American College of Gastroenterology. We are honored to have Dr. Hanauer with us to cover UC pathology, current treatment approaches and the specific needs for new therapies. Following Dr. Hanauer, Dr. Lisa von Moltke, Seres' Chief Medical Officer, will discuss our ongoing SER-287 and SER-301 clinical development efforts as well as the promising clinical data that we have obtained to date. Next, Dr. Matt Henn, our Chief Scientific Officer, will review the scientific basis for microbiome therapeutic candidates in ulcerous colitis. Matt will also discuss the mechanistic differences between SER-287 and SER-301. Following the presentations, we will have a Q&A session that will also include Dr. Dave Ege, Seres' Chief Technology Officer; Dr. Terri Young, Seres' Chief Commercial and Strategy Officer; and David Arkowitz, our Chief Financial Officer. Moving to Slide 4. You will be hearing a great deal of information today about Seres' microbiome therapeutic approach and why we are particularly excited about opportunities to treat ulcerative colitis. I'd like to summarize 4 key points that we intend to highlight. First, Seres is the leader in the development of microbiome therapeutics, leveraging prior clinical success and unique core drug discovery and CMC capabilities. Last summer, we announced the positive results of our SER-109 Phase III study for recurrent C. diff infection. We believe the highly compelling results observed with SER-109 demonstrate the clinical potential of our microbiome therapeutics platform. We continue to apply our core capabilities in microbiome drug development to new areas of medicine, including in UC and in other serious diseases. Second, we believe that UC is a very attractive target for microbiome therapeutics based on the disease pathology, the mechanism of our drugs and the tremendous need for new approaches. For all these reasons, Seres has selected ulcerative colitis as an area of strategic focus. There is a significant need for effective orally administered nonimmunosuppressive treatments. We believe that our microbiome-based therapeutics have the potential to transform the standard of care for UC. We also believe that Seres microbiome therapies could be cornerstones in the treatment of mild-to-moderate UC as well as potentially in more severe forms of the disease. Third, Seres is advancing both SER-287 and SER-301 as differentiated programs for UC. These programs are different in composition and in biological activity. We are advancing a multi-asset strategy that is spearheaded by SER-287, and followed by SER-301, a next-generation therapeutic approach. Finally, we are eagerly looking forward to our SER-287 Phase IIb clinical readout as well as additional microbiome pharmacological data later in the year. We expect that these clinical and microbiome data sets will inform our plans for next steps with our UC programs as well as our future drug development efforts more generally. Moving to Slide 5. Seres has clearly demonstrated that our microbiome therapies have the potential to result in extraordinary clinical data. This was seen in our SER-109 Phase III data in patients with recurrent C. diff infection. In addition to the compelling efficacy data we obtained with SER-109, we also observed a remarkably clean safety profile that was similar to placebo. We believe that this favorable safety profile is an important benefit of our approach and that this may be particularly important in the treatment of ulcerative colitis. Moving to Slide 6 in Seres pipeline. We see broad opportunities for microbiome therapeutics across multiple disease areas. Seres pipeline includes our SER-109 and SER-287 late-stage programs, several earlier stage development programs and also a number of microbiome programs in research and preclinical development. Since 2016, Seres has had a development and commercialization agreement with Nestlé Health Science related to the ex-North American rights for our C. diff and IBD programs, including SER-287 and SER-301. Nestlé Health Science continues to expand their global pharma business, enhance their development and commercialization capabilities, and they have been a great partner for Seres. I would like to comment on our UC franchise strategy and how we have been thinking about the development of our 2 clinical programs, SER-287 and SER-301. We view both as highly promising assets with the potential to transform patient-care in UC, and both are derived from natural commensal bacteria found in the gastrointestinal tract of healthy individuals. There are, however, important differences between the programs. SER-287 is derived from healthy human donors, whereas SER-301 utilizes our next-generation technology and is based on rationally designed, cultivated consortia of bacteria. There are biological differences between these programs that we believe could result in differentiated clinical profiles, and we're looking forward to learning more from our ongoing clinical studies. From a strategic perspective, there are also differences related to drug supply and manufacturing processes. We expect to have the capacity to scale our SER-287 program to meet commercial demand. However, there are cost and logistical advantages with a cultivated product that could be meaningful, especially given the size of the addressable global UC patient population. For these and other reasons, we anticipate a greater emphasis on this next-generation, rationally designed therapeutic approach as we move into the future. Moving to Slide 7. Before I conclude, I would also like to highlight the strength and unique nature of Seres core capabilities. We believe that our differentiated capabilities, especially in drug discovery and manufacturing, provide the company with an ability to develop new microbiome therapeutics that is unique in the field. Since the founding of Seres almost a decade ago, we have made substantial investments in our technology. And this provides the company with a valuable intellectual property as well as unique tools, methodologies and proprietary know-how that continues to fuel our pipeline. Thank you again for joining us this morning. With that, I'm honored to pass the call on to Dr. Hanauer.

Thank you very much. Whoever is moving the slides, the slides are extraordinarily slow. Can I have the next slide, please? And perhaps someone could be anticipating my movement because I still don't see it. Okay. I've been asked in a brief period of time to cover soup-to-nuts ulcerative colitis from a clinician's perspective. Next slide, please. The topics that I'm going to discuss include the pathology, the presentation, the evolving epidemiology, our current options as well as some of the late-stage development candidates that are in late-phase testing. This is an example of a biopsy of a healthy -- can you go to the next slide, please? Next slide please? This is a biopsy from a healthy colon. What you see are the crypts that absorb water. And between the crypts are what are known as chronic inflammatory cells, primarily macrophages and lymphocytes. What you do not see in this slide are neutrophils that are the final arbiter of destruction in the setting of inflammation. On the next slide is an example of an inflamed colon, where you will see eventually -- packed full of neutrophils that actually destroy the crypts, as you can see in the middle on the left, what is known as a crypt abscess, which is a crypt that has been invaded by neutrophils that eventually lead to ulceration of the mucosa. Next slide.

Dr. Han, please go ahead at your pace. These slides are [indiscernible]

Well, my pace is based on the slides. So this is an example, and this was supposed to be an animated slide, of the evolution of a normal mucosa to an inflamed mucosa. And in ulcerative colitis, this is the lining of the bowel that looks as if it has been rubbed by sandpaper. But the bowel has the ability to restore the normal equilibrium in homeostasis and go back to a normal-appearing colon and actually normal-appearing histology when it is appropriately treated. Next slide, please. I wish you guys would anticipate this better. From a clinical perspective, patients are troubled by symptoms of urgency, frequent bowel movements, rectal bleeding, the passage of diarrhea at nighttime and sometimes the inability to distinguish gas from a stool, which leads to incontinence. Ulcerative colitis is a progressive disorder with 10% to 15% of patients requiring removal of the colon for either ineffective management, in the next slide, or due to cancer or other complications of the disease. Next slide, please. The symptoms absolutely impact on the daily lives of patients with frequent bowel movements, the inability to keep jobs, constant sense of fatigue and concerns about their long-term health. While we don't know the cause of these diseases as yet, patients are frequently anxious about the need for removal of the colon. Next slide. Maybe you can just move the slides every 15 seconds. So inflammatory bowel disease has been known for well over 50, 60, 70 years within the West and has really exploded in Western Europe and in North America over the past 50 years. However, it is over the past 20 years that we've seen a marked increase in the risk of developing ulcerative colitis in third world countries where we previously had not seen this. And I will promise you that there is currently more ulcerative colitis in China and in Asia than there is in the West, just based on the extreme big population. But at the present time, it's been estimated by just over 1 million patients have ulcerative colitis. Now what distinguishes ulcerative colitis from health? Under normal situations, we have a quite diverse resident microbiota that leads to a state of immune tolerance. We don't react to the commensal bacteria that are present. We don't react to the food antigens that we're constantly eating. Those sweet rolls that you are having with your coffee and milk this morning, we are tolerant of them. And that is the state of homeostasis. And you see on the left hand, there are no neutrophils present. However, in the state of ulcerative colitis, there is a dysbiosis with a less diverse bacterial population and activated activation of numerous immune cascades that lead ultimately to that figure that I showed you of an ulcerated colon. Next slide. So the concept of ulcerative colitis is really one of complexity. We are currently considering, as are other immune-mediated diseases, pathogenic components that come from the environment, the underlying genetics of individuals, part of the environment is the microbiota and how our immune systems handled the environment and handle the gut microbiota. The number of cascades are really just exemplified on this slide with activation of both the innate and the adaptive immune responses. Next slide, please. So ulcerative colitis is actually a cascade of events. Only about 15% of patients have genetic backgrounds. We know that the increase in the disease around the world is associated with westernization. And westernization includes a number of these different factors, including changes in the diet; including processed and-ultra processed foods; the frequent use of antibiotics, not only in children but also in our food sources such as cattle; the disruption of the mining of the bowel by medications and factors such as nonsteroidal anti-inflammatory drugs; changes in the microbiota. So some individuals develop ulcerative colitis after developing travelers' diarrhea and a number of other stresses, including stress itself and cigarette smoking. So this is really a complex series of events that ultimately lead to the heterogeneous picture of ulcerative colitis. Next slide, please. So our current management of ulcerative colitis is really directed towards suppression of the immuno-inflammatory events. And the pathogenesis is thought to arise from the disruption of the immune tolerance to the healthy gut microbiota that leads to a disruption in this and the less diversity. Now despite the number of agents that we're going to go through, we are troubled by lack of specificity. Many of our agents are used in other diseases as well such as rheumatoid arthritis or psoriasis. And it's interesting, actually, the drugs that actually help one, whereas make another worse. So for instance, while interleukin-17 was a potential target for ulcerative colitis, administering it actually made patients worse, whereas it's a wonderful drug for psoriasis. You will see that despite the panoply of agents that we have, that there really is a modest rate of disease remission and steroid-free remission, and the patients are often asking or requiring nutritional support because of the potential impact on nutrition overall. Next slide, please. I can't apologize because I asked for control and wasn't given it. So how do we approach the treatment of inflammatory bowel disease? You've heard a lot about this moderate-to-severe category. What moderate to severe actually means is patients who have a greater likelihood of developing complications of the disease, including a risk of surgery. And we've identified these factors that separate moderate to severe from mild to moderate, which has a very low risk of colectomy. We usually have used the step-wise approach that was present on the last slide. However, that has recently been altered that individuals who actually present with the factors associated with moderate to severe are escalated more rapidly to more effective therapies. However, in mild-to-moderate disease, we do have a foundational therapy, which is 5-aminosalicylic acid derivatives or mesalamine derivatives. They are effective, as you will see, in about 40% to 60% of patients and have been safe and used for well over 40 years for the treatment and maintenance of remission in mild-to-moderate disease. Next slide, please. So as you all are very aware, there has been a more rapid development of new therapeutics since the advent of biologic therapies with the first biologic being infliximab, introduced in 1998 for Crohn's disease, and then in 2005 for the management of ulcerative colitis. And of course, this has been followed by the development of a number of other TNF inhibitors that have been applied to ulcerative colitis and more recent mechanisms, including interleukin 12 and interleukin 23 therapies that are been available and are evolving. And most recently, actually S1P modulator, but just before that, in 2018, tofacitinib, the first JAK inhibitor that was approved for ulcerative colitis. And as I mentioned, ozanimod has most recently just been approved by the FDA in the past month. So the mesalamine or 5-aminosalicylic acids have been our mainstay treatment for mild-to-moderate ulcerative colitis. They have the advantage of being available in either oral or rectal formulations. In addition, we have utilized immunomodulators, such as thiopurines, azathioprine or mercaptopurine for patients who have responded to corticosteroids that these immunomodulators are now in the setting of moderate-to-severe disease rather than mild-to-moderate. And they are increasingly -- well, they are decreasing in their use because of the baggage and risk of azathioprine with lymphoma in young individuals. Next slide, please. So as I mentioned, mesalamine is a foundational agent but it's been effective in just about half of the individuals. And of the patients who have -- are treated with mesalamine, if they don't respond, they are then escalated into the moderate-to-severe category, which would, as you're going to see, involve steroids or biologics. Next slide. Corticosteroids are the next agent for patients who present with more moderate symptoms or failed therapy with mesalamine. But as you can see, once a patient is started on steroids in ulcerative colitis, 80% of the patients have failed therapy within a year and are on to another therapy. So by the way, when a third-party payer says, "I need to start a patient on steroids," my response is, "Everybody fails steroids eventually." Next slide. The main issue with -- one of the main issues with our current therapies, including steroids, TNF inhibitors, other biologics, JAK inhibitors and the S1P, are the long-term risks of side effects. In particular, infections and a risk of malignancy that include not only lymphoma with immunosuppressives, but also basal cell cancers. And the more that we suppress an individual's immune response, the greater risk of complications. And you guys have seen that, for instance, with tofacitinib, where there is clearly a dose response to toxicity, including infection; malignancy; and in the setting of tofacitinib, blood clots. So our current management has been directed towards post immunosuppression. But as you can see, there is a large gap in our need with even the biologics only providing 40% to 50% remission rates and somewhat lower steroid-free remission rates, which leads to this big unmet need for oral nonimmunosuppressive therapeutic agents. Next slide, please. There are a number of agents that I'm quite certain that you are very familiar with that are emerging from Phase III studies, that include anti-trafficking agents, IL-23 inhibitors, additional S1P modulators and several additional Janus kinase inhibitors. Next slide. I would point out that as these are undergoing Phase III studies, with the current drugs that are available for moderate-to-severe ulcerative colitis, including steroids, immunosuppressives, 2 diff -- 3 different TNF inhibitors, multiple biosimilars, IL-1223 inhibitors, JAK inhibitors and S1P, that's only today. As additional IL-23 inhibitors come onto the market, additional JAK inhibitors and additional S1Ps, you can imagine nearly 20 drugs available in the moderate-to-severe category. On the other hand, very limited development in the mild-to-moderate disease category. And I believe that this is a perfect setting for microbiome-directed therapies. We've recognized that dysbiosis in patients with active inflammatory bowel disease as their disease remits the microbiota revert towards normal, but sometimes not exactly normal, but a therapy that would restore the microbiota and maintain it on a long-term basis without the systemic side effects and actually potential positive effects on the immune system would be very desirable. Next slide. So there are urgent therapeutic gaps, including the lack of specificity, the side effects with the biologic agents and the other agents used in moderate-to-severe disease and limitations in overall efficacy. Next slide. So I think we're coming to the end. And this is my view, and I've emphasized the role in mild-to-moderate disease. The reasons are that there is a large therapeutic gap. The clinical trials in mild to moderate ulcerative colitis have very straightforward validated endpoints that also allow mechanistic studies. There are options of doing head-to-head as well as placebo-controlled trials in this setting. And in mild-to-moderate disease, it avoids a significant confounder, which is corticosteroid therapy. As you've seen in the trials of moderate-to-severe disease, steroids both increase the side effects. They also obscured the readouts from the disease because you can maintain a remission with a patient on steroid, which is different than total withdrawal of steroids for patients. Further, it avoids all the baggage of studies that include patients who are on steroids, immunosuppressives and biologics. And as you are aware, treatment with a biologic impacts on the subsequent responsiveness to other therapies. Once a patient has been treated with a TNF inhibitor, they have about 50% the absolute response rate to the next agent compared to patients who have been bio-naive. And finally, if foundational trials are positive, it will open the door to extensive -- extended studies in other diseases and combinations, including evolution to moderate or refractory disease, maintenance of remission. And from my perspective, the finances, the money is in maintenance therapy, not in inductive therapy as well as expansion to other aspects of IBD, including Crohn's disease, pouchitis and then to other immune-mediated diseases, such as checkpoint inhibitor colitis as well as evidence diseases where there is evidence of a disturbed microbiome, which includes rheumatoid arthritis. It includes psoriasis, it includes Type 1 diabetes, it includes Alzheimer's disease and numerous others. So I think that this is a model that will potentially extend to a wide area of other potential interventions. Now looking at mild-to-moderate disease may have the disadvantage where we have not recruited into this earlier disease for clinical trials. However, if you ask a patient, whether or not they would like to try a probiotic well, let me tell you, 50% of patients are already trying probiotics. So this is a very favorable approach from the patient's perspective. So I personally believe there are a lot of reasons for Seres to focus on this mild-to-moderate category. And I believe that ends my presentation, and I would be delighted to take some questions, and I apologize for the length of this due to slide transitions.

So thank you, Dr. Hanauer, for the comprehensive overview. We're going to hand the call to Lisa. We'll take questions from the group at the end. I just want to note, I appreciate everybody's flexibility with the virtual setup and the lag that we have in the slides. And just a reminder for everyone that the slides are actually available on the website for your review. So Lisa, would you take us forward, please?

Sure. And I echo Eric's thanks to Dr. Hanauer. In this next section, starting on Slide 32, I will provide an update on the clinical studies for SER-287 and SER-301. Those are our 2 ongoing programs for patients with mild-to-moderate ulcerative colitis. Now as Dr. Hanauer indicated, there's a clear need for efficacious and safe treatments in this specific patient population. In this presentation, I will describe our clinical trial experience to date for both programs with a focus on the 287 Phase IIb trial induction readout, which is expected at midyear. Now starting on Slide 33. We'll start with SER-287, which is an investigational oral microbiome therapeutic candidate consisting of a consortium of highly purified Firmicutes spores from healthy screen donors. Spores are hearty and resistant to gastric acid, which allows for GI transit after administration and subsequent germination, replication and engraftment in the gastrointestinal tract. Seres data support that following engraftment, SER-287 may induce compositional and functional changes in the GI microbiome. These microbiome changes may reduce colonic inflammation in ulcerative colitis by modulating multiple cellular inflammatory pathways and without systemic immunosuppression. Moving on to Slide 34. We were very pleased that the Phase Ib study evaluating SER-287 in UC patients was featured on the cover of the January 2021 issue of the Journal Gastroenterology, with clinical trial data presented within the issue. As shown on Slide 35, the SER-287 Phase Ib study design evaluated 2 active dosing regimens, once weekly and once daily, and also explored whether a short 6-day course of vancomycin preconditioning was necessary to create an ecologic niche for optimized engraftment of SER-287 bacteria. The primary endpoints were safety, tolerability and microbiome composition. The study population was active, mild-to-moderate UC patients who are either treatment-naive or had an inadequate response or intolerance to conventional UC treatments. Moving to Slide 36. Daily dosing of SER-287 was associated with an increased rate of clinical remission compared to placebo, as shown here. Clinical remission was defined as indicated on the right and importantly, included blinded, centrally read evaluation of endoscopic remission. The effect was dose-dependent with a numerical advantage for daily dosing over weekly. The necessity of vancomycin preconditioning was supported by bacterial engraftment and clinical remission being highest in the vancomycin daily SER-287 arm. Now on to Slide 37. The SER-287 was well- tolerated with an AE profile comparable to placebo. There were no drug-related SAEs, and AEs were generally mild or moderate in intensity. The SER-287 daily arm had no discontinuations due to an AE and numerically fewer GI AEs than placebo. Moving to Slide 38. After the successful Phase Ib study, Seres progressed into Phase IIb with the ECO-RESET Study, and the study enrolled its last patient in March of this year. The enrollment was 203 subjects with active mild-to-moderate UC. The 3-arm study evaluated 2-dosing regimens of SER-287 against placebo during a 10-week induction period. One active arm used the successful daily dose from the Phase Ib study. And the other active arm utilized that same dose for the first 2 weeks, followed by a lower dose for the remaining 8 weeks. Both active arms began with 6 days of vancomycin preconditioning. The inclusion criteria focused on subjects who had an inadequate response or were intolerant to conventional UC treatments. The primary endpoint is clinical remission after 10 weeks of induction treatment, and the key secondary endpoint is endoscopic improvement, both of which will be the focus of the top line readout in mid-2021. After the induction period, exploratory phases include a placebo-controlled maintenance study for induction period clinical remitters and an open-label phase for induction period non-remitters. As outlined on Slide 39, the ECO-RESET Study was designed in accordance with FDA's guidance on clinical trial endpoints for UC and within the framework of the current paradigm for UC drug approval, which require 2 pivotal induction studies and 1 pivotal maintenance study of notice of potential to combine induction and maintenance periods into a single study. Based upon feedback obtained from the FDA on the ECO-RESET Study design, Seres believes that with compelling results, the study could serve as 1 of 2 required pivotal induction trials supporting a BLA. Now Seres utilized a 3-component modified Mayo Score to define the mild-to-moderate patient population for inclusion into the ECO-RESET Study. This score some stool frequency, rectal bleeding and endoscopic subscores and excluded the physician's global assessment, which the FDA guidance does not recommend as an endpoint measure. Patients were eligible for the study with a 3-component modified Mayo score of 3 to 7 inclusive. The primary endpoint of the study was clinical remission and was defined by the following criteria: a stool frequency subscore of 0 or 1, with at least a 1 point decrease from baseline; a rectal bleeding subscore of 0; an endoscopic subscore of 0 or 1, with at least a 1 point decrease from baseline and as scored by a blinded central reader; and finally, no occurrence of a UC flare during the treatment period. Endoscopic improvement, which is the study's key secondary endpoint, was defined as an endoscopic subscore decrease from baseline of at least 1 point and as scored by a blinded central reader. Now moving to Slide 40. A successful outcome for the Phase IIb study centers on seeing a clear signal of clinical efficacy compared with placebo based on the primary endpoint, secondary endpoints and other data coming from this very rich study. Optimally, secondary clinical endpoints, such as endoscopic and symptomatic benefit, would positively align to support the primary endpoint. These data will be available as part of the top line package in mid-2021. Microbiome data are expected to be available in the second half of 2021. The study will also provide translational data, which may offer mechanistic insights and further understanding of microbiome effects or signatures. It may also identify predictive biomarkers and subpopulations, which derive especially high clinical benefit. Finally, the study data will add to the existing safety and tolerability profile of SER-287, ideally demonstrating ongoing similarity to placebo. Now on to Slide 41. Seres follow-on asset in mild-to-moderate UC is SER-301, an investigational, rationally designed, cultivated consortium of Firmicutes bacterial species. SER-301 has been optimized for drug species engraftment and anti-inflammatory pharmacological properties. Matt will speak further about this later in our program today. As indicated on Slide 42, SER-301 is also targeting a mild-to-moderate UC patient population in a Phase Ib study in Australia and New Zealand. The study is ongoing and being conducted in 2 cohorts, with the primary endpoint for both being safety and tolerability. The first cohort is open label and comprised of 15 patients to gain initial safety and microbiome insights. The second cohort is placebo-controlled with 50 patients, randomized at a ratio of 2:3 placebo to 301 to explore signals of clinical benefit. The induction treatment period for both cohorts is the same and is comparable to the SER-287 IIb study, with 10 weeks of once-daily dosing after a 6-day vancomycin preconditioning period. The study population is active mild-to-moderate UC patients who are either treatment-naïve or had prior inadequate response or intolerance to 5 ASAs, corticosteroids or immunomodulators. A notable difference from the 287 IIb study is that the 301 study excludes patients who have previously been treated with biologics or other advanced therapies for their UC. Now on to Slide 43. Positive data from the -287 ECO-RESET study would facilitate progressing development into Phase III in mild-to-moderate UC. Positive Phase IIb data would also support exploring Seres microbiome therapies for use in moderate-to-severe UC and exploring other indications where we believe our microbiome therapeutic approach could be effective, such as Crohn's disease and pouchitis. Additionally, the existing safety profile observed for Seres microbiome therapeutics suggest they could serve as a well-tolerated component of a combination treatment regimen. So to summarize on Slide 44, Seres has 2 very exciting ongoing clinical studies in patients with mild-to-moderate UC. Coming soon in midyear 2021 is the top line induction readout for the Seres 287 Phase IIb ECO-RESET Study. The data from this study as well as the SER-301 Phase Ib safety study will shape and inform the future clinical development plans for the UC franchise. And with that, I'll pass the presentation over to Matt.

Thank you, Lisa, and good morning, afternoon or evening, depending on where you are joining us from. I'll now take some time to discuss the role of the microbiome in ulcerative colitis and in the pharmacology of Seres UC drug assets. Starting on Slide 46. I hope that at the end of today's talk, you will have an improved understanding of Seres differentiated innovative platforms for drug discovery and development, the integral role that the gastrointestinal microbes and metabolite they generate play in the pathogenesis of ulcerative colitis and IBD more broadly, and how Seres is developing a novel drug modality that can target multiple disease relevant pathways simultaneously to address serious disease. Moving to the next slide. Our understanding of the role of the gastrointestinal microbiome in ulcerative colitis and Crohn's has exploded over the past decade-plus. As seen in the top right corner, a simple search in pub met of articles about IBD and the microbiome shows a growing body of peer-reviewed literature with over 1,200 articles published in 2021 alone. We now know that the microbiome and the interaction of these microbes and metabolites generated by them with human cells and tissues can impact host inflammation and immunity with impact on disease. Moving to Slide 48. Research over the past decade continues to support that individuals with IBD, whether it be UC or Crohn's, can have a gastrointestinal microbiome that differs from those of healthy individuals in terms of the specific bacteria that are found in and that dominate the GI. In adults with IBD, individuals with Crohn's and active UC tend to be most extremely differentiated from healthy individuals, as shown in this PCA plot on the left, where each dot represents the total diversity of the microbiome of an individual. Research further supports that these differences are not just observed in adults but in pediatrics as well. Moving to Slide 49. These differences in the composition of the microbiome in the gut can have profound impact on host cell and tissue functions that are of relevance to IBD. An intact non-disease microbiome and the metabolites generated by these commensal microbes helps maintain inflammatory homeostasis. Microbial-associated metabolites that promote mucosal and epithelial vary integrity can impact the differentiation of various immune cell population, including T cells, macrophages, dendritic cells and B cells, and can signal the production of various cytokines. A disrupted disease microbiome can lead to breakdown in mucin and the dominance of pro-inflammatory bacteria, such as those in the family Enterobacteriaceae that interact with human epithelial cells to promote the production of pro-inflammatory cytokines. Moving to Slide 50. Connecting back to Dr. Hanauer's earlier slide on the role of host immunity in IBD, we know from the [ literature ] and importantly, our own internal clinical and nonclinical data sets, that the bacteria found in the gastrointestinal microbiome and the metabolites they produce are associated with modulation of nearly all of the immune pathways that have been associated with IBD and ulcerative class. The red dots on this slide note all the disease relevant pathways for which we have strong support for a role of the microbiome. The GI microbiome is intimately connected to host immune function. Now transitioned to speaking to the opportunities for microbiome therapeutic approach to UC and specifically, our SER-287 and SER-301 programs in ulcerative colitis. Moving to Slide 52. At Seres, we are not seeking incremental change in the treatment of serious disease, but instead are developing drugs that leverage millions of years of co-evolution between bacteria and our gastrointestinal track with human cells and tissues to fundamentally change how we tackle the complexity of serious unmet medical needs. Our drug candidates are orally formulated consortia of commensal bacteria that are designed to populate the GI, restructuring the microbiome and modulate the metabolic landscape of the gut to target multiple disease-relevant pathways. For nearly a decade, Seres has been pioneering the discovery of these drugs and how to think about drug pharmacokinetics and pharmacodynamics for this novel class of medicines. As shown on Slide 53, our UC assets seek to treat UC by targeting multiple disease-relevant pathways simultaneously; reduce the abundance of pro-inflammatory bacteria, producing immunomodulatory metabolites that improve epithelial barrier integrity and decreasing cytokine-induced inflammation in modulating T-cell populations to impact epithelium inflammation. We anticipate that our drug candidates have applicability both as monotherapy and given the highly favorable safety profile of across our clinical portfolio in combination with other UC therapies. SER-287 and SER-301 are both consortium of bacterial species. SER-287 contains a broad diversity of Firmicutes species and is formulated as scores that are fractionated and purified from donor material. SER-301 is a targeted set of bacterial Firmicutes species that have been optimized for both engraftment in the gastrointestinal track, and the pharmacological properties that are clinical and nonclinical research have identified a potentially important microbiome drivers of clinical remission and endoscopic improvement. The SER-301 consortium is manufactured by cultivation of master cell bank and optimized to include strains with favorable manufacturing properties. Moving to Slide 54. Since Seres inception, we have been building a research engine that can characterize the microbiome and microbiome biomarkers in disease and states of health at high resolution. Our drug discovery and development platforms and capabilities power both the design of consortia of bacteria with specific pharmacological properties and the delineation of the specific mechanisms by which our current drug candidates modulate host function to treat disease. Our platforms integrate insights and microbiome biomarker data from human data, with screening data from human cell-based assays and disease model results from customized in-vivo models to define a high-resolution microbiome signatures in the disease and health. Importantly, our platforms can interrogate the mechanisms of action of microbes both directly in humans to derisk discovery and in combination with nonclinical models to maximize the translatability and probability of success of our lead candidates. Many of our tools are validated for use in late-stage clinical trials, and we have pioneered their use in the derivation of microbiome therapeutic drug pharmacology. Lastly, these capabilities are paired with CMC manufacturing capabilities suitable for late-stage clinical trials and early commercial launch, bringing end-to-end capabilities under a single umbrella that is differentiated from others. These end-to-end capabilities enable us to rapidly move from target identification through clinical development and comprise innovation specific to the development of microbiome therapeutics in each of these areas. Moving to Slide 55. I'll use the remainder of this talk to familiarize all these further with the pharmacology and mechanisms of action of SER-287 and SER-301. Moving to Slide 56. The Phase Ib publication that Lisa pointed out earlier reports on data that support the mechanisms of action of SER-287 and continues to support that our drug candidates can target multiple disease relevant pathways simultaneously. Starting with drug pharmacokinetics on Slide 57. SER-287 bacteria engrafting in subjects. Engraftment was durable post-dosing and was significantly greater in the daily dosing arm, the same arm with the greatest number of clinical remissions. We also demonstrated that preconditioning with vancomycin was an effective strategy to open the ecological niche in the GI to improve the engraftment of SER-287 bacteria. Engraftment analysis showed that while engraftment is robust and durable, it can vary across subjects and not all those species engraft in all subjects. Notably, we have identified multiple bacterial species that are significantly associated with efficacy. These data support a consortium-based approach and are exemplary of the type of data that inform the optimization of SER-301. Moving to drug pharmacodynamics on Slide 58. SER-287 treatment, as shown on the left, results in a broad shift in the overall composition of score and nonscore gut species by 8 weeks post treatment. These data demonstrate that we broadly restructured the microbiome. SER-287 [indiscernible] as represented by the blue bars to the right of the middle line, and decreased the prevalence of different bacterial species denoted by gray bars compared to patients at baseline priority treatment. When we look further into the [indiscernible] find, as shown on the right of the slide, that decreases in pro-inflammatory Enterobacteriaceae are significantly associated with both SER-287 treatment and also clinical remission. Moving to Slide 59. Microbial-mediated metabolites that are known to modulate host inflammation and barrier integrity are significantly associated with both SER-287 treatment and clinical remission as well. In a global analysis, there were 38 metabolites identified that showed significant association with treatment and clinical remission. These included metabolites such as indole, taurine and arachidonate that have also been identified as microbiome signatures of IBD by the large-scale human microbiome projects funded by the NIH. These are examples of metabolites known to be involved in signaling AHR, a pathway involved in barrier integrity and immunomodulation, or that influence neutrophil migration at the epithelium. Moving to Slide 60. Importantly, we have been able to take this further and associate changes in SER-287 bacteria to changes in microbial-associated metabolites to actual changes in gene expression of disease-relevant pathways and intestinal biopsies from treated patients. At the level of pathway modulation, approximately 100 pathways are associated with both SER-287 treatment and clinical remission. These span a range of disease-relevant pathways such as JAK STAT and TNF signaling, differentiating signaling of various T cell populations and cytokine and chemokine signaling. Moving to Slide 61. Using our research engine, we can take these clinical findings and go beyond in-human associations and demonstrate causality of the bacteria in SER-287 driving transcriptional changes in biopsies. Colonic organizer, often referred to as many guts, as they grow to form a complex 3D structure with crypts and diverse cell types. In this proprietary assay, inflammatory conditions are triggered by the addition of interferon gamma. And microbiome consortia are tested for their ability to modulate gene expression in the presence of interferon gamma. As you can see in the table on the right, in vitro, the absence of SER-287 bacteria, these organoids have an inflammatory phenotype expressing various cell death and inflammatory pathways. The addition of -287 reversed the interferon gamma and the signature down regulating all the inflammatory in cell dose pathways shown here. Notably, the gene expression changes observed in human organoids in vitro were highly similar to those observed in biopsies of remitters compared to non-remitters in the SER-287 Phase Ib trial. These results demonstrate causality of SER-287 in the observed clinical remission and support the high translatability of this assay. This is one of many assays that we have customized at Seres for microbiome therapeutic drug discovery that, combined with our in-human high-resolution microbiome biomarker data, differentiate our platform. The SER-287 Phase II trial was designed to be a translationally rich trial. Once the top line clinical data are unblinded, we will work to begin to conduct the microbiome PK and PD analyses and anticipate initial top line microbiome data comparable to what I presented here today in the second half of the year. Moving to Slide 62. Using these types of data, we can design and optimize bacterial consortium to have specific pharmacological properties. SER-301 was optimized by combining insights from the SER-287 Phase Ib as well as insights from across our broad clinical portfolio and additionally, based on rich knowledge of the functional, safety and manufacturing properties of individual bacterial strains in our strain library. Using our research engine, we can both confirm the MOA of clinical assets and iterate on the design of new assets for a broad range of diseases. In the time remaining, I'll provide a few quick examples of such. On Slide 63, I'm showing the ability of both SER-287 and SER-301 to modulate epithelial barrier integrity. In this proprietary assay, barrier permeability of an intact epithelium is assessed. If the barrier's intact, FITC-dextran is retained in the apical compartment, and thus basal fluorescence is low as is shown on the left of the slide. Addition of the pro-inflammatory cytokine, interferon gamma to the basal surface to mimic UC inflammatory condition disrupts the barrier. Addition of SER-287 or [indiscernible] in the presence of interferon gamma decreases barrier damage. Notably, as a negative control, we tested an inflammatory consortium containing strains isolated from UC patients. In this case, the inflammatory consortia failed to protect barrier function further, supporting the specific role of SER-287 bacteria. These results are important because they suggest that SER-301 and SER-287 may improve epithelia barrier integrity in patients even in the presence of inflammatory signaling. This is a distinct mechanism of action from other UC therapies that only target immune inflammatory pathways. The second example I'll use is on Slide 64, is the optimization of consortia for indole production. As noted earlier, indole was associated with both SER-287 treatment and clinical remission. Indole is a known agonist of AHR. Given our extensive strain library and data on the functional properties of these strains, we can design consortia to maximize involve reduction. As you can see here, we can design consortia to produce high or low amounts of indole. Using our broad platform, we can then link these changes to specific impacts on host function. As an example here, I'm showing expression of the SIP [ 181G], which is a gene under the control of AHR and commonly used as a readout for the AHR pathway. Strikingly, we see strong correlation between consortium indole production and [ SIP181 ] expression in our organoid system. The SER-301 consortia has been optimized for a broad range of pharmacological properties, including indole production. As shown on Slide 65 and 66, at Seres, we have been building in-vivo models that are customized for evaluating the pharmacology of microbiome therapeutics. As an example, SER-301 was compared against a composition of pro-inflammatory bacteria isolated from UC patients. As you can see in this model, SER-301, shown in blue, does not increase [ fecal lipocalin ] and favorably modulate Tregs, Th17 and Th1, while the inflammatory UC human microbiome in black does the opposite. On the next slide, we've further innovated developing Avatar human microbiome models. In these models, we can establish a disease human microbiome and state in the mice and then demonstrate that our consortia can restructure the microbiome and reverse the disease state. As you can see here, the inflammatory UC human microbiome, represented in black, increases lipocalin as in the previous example. SER-301, in blue, did not. And the addition of SER-301 after establishing a UC disease microbiome in disease state, shown in purple, significantly reversed the disease state. These data were recently presented in more detail at DDW and given a Poster of Distinction award. I'll close on Slide 67. The field continues to learn about the sweeping role of the microbiome in human health that span from preventing pathogen infection to modulating innate and adaptive immunity and humans. At Seres, we have developed a research engine and platform that allows us to unpack at high resolution; how microbes in the gastrointestinal tract are interacting with one another and human cells and tissues to impact disease; and further, to manufacture under GMP consortium containing a broad breadth of biology. This know-how and technology provides us the opportunity to pursue multiple diseases with high unmet medical needs. These opportunities include numerous diseases, with immediate opportunities in biologically adjacent areas such as fighting antibiotic-resistant bacterial infection and Crohn's disease and additional opportunities that span oncology, autoimmune, metabolic and neurological diseases. With that, I'll thank all of you for your time and turn the session back to Eric.

Thanks, Matt. I want to thank everybody again for your attention today. As you've heard, we are excited about the prospects for Seres investigational microbiome therapeutics to have an important role in the treatment of UC. Our ultimate goal, it's for our medicines to provide patients with a meaningful new treatment option and hopefully, greatly improve their health and their quality of life. With that, operator, let's open the call up for questions.

[Operator Instructions] Our first question comes from Chris Shibutani with Goldman Sachs.

Dr. Hanauer, thank you for participating and for your comments. Curious if you could comment about the importance of the endoscopic improvement endpoint, which is the secondary endpoint for the Phase IIb. What is the bar that you would want to see for this endpoint? And historically, I think for endoscopic improvement, there's been so many variations on scoring systems used. If you can comment there, please.

Well, thank you very much for the question. There's actually been more consilience towards endoscopic improvement along the Mayo Score system since it has been produced by central readers. There was a lot of variation prior to having central readers. But now it's very much standardized. And endoscopic improvement, as you're well aware, has been a component of the approval for both ozanimod, tofacitinib, ustekinumab for this in the setting of ulcerative colitis. So I think utilizing central reading that has been a very acceptable, validated and reproduced endpoint that's now been used for the last 3 drugs, at least, that have been approved for ulcerative colitis.

And what kind of bar would you want to see for this endpoint, particularly for this sort of a study population of mild-to-moderate patients?

Well, you're always -- well at by bar, you're meaning the delta with between drug and placebo.

Correct.

And certainly aiming at a greater than 10% difference, which has been pretty much the bar for the regulatory agencies.

Got it. And then for Lisa, could I just ask you, with the top line readout in July, will we actually see these numbers when you report those top line results, the endoscopic improvement?

Yes. So we will be presenting both the primary endpoint and the key secondary endpoint, which includes the endoscopic information.

And Chris, just to clarify, the guidance that we've provided is mid-2021. That's what we've said so far. Thanks for the questions. And thanks, Lisa and Dr. Hanauer, for the answers.

Next question comes from Chris Howerton with Jefferies.

So for the first one, maybe just a kind of quick housekeeping things. What might -- have you provided powering assumptions for the Phase IIb study? I don't believe you had, but I thought I'd ask. And the second kind of housekeeping one would be when might we expect some data from the 301 study? And then the second question I have is, I'll just throw it to you, Eric, and you can quarter back how you see fit, would be there's been some controversy with respect to the vancomycin pretreatment arm. And there's this trade-off between potential kind of effective, the vancomycin adding to the drug effect; and of course, the increased risk of C. diff in those patients. So I guess some color in terms of how can we have confidence that the FDA is onboard with this trial design and that there won't be any kind of potential controversy with respect to vancomycin pretreatment and future study designs.

Chris, thanks for the 3 separate questions. Let me start with each, and then I'll kick it to Lisa for her perspective. So from a powering perspective, we have not provided details, except to say 200-plus subjects with 3 arms, we think that the study will be powered well to see an effect. We have not provided guidance on 301, except to say that we are currently enrolling in the study in Australia and New Zealand. We're really encouraged by the progress that we've made. I think that, Chris, you know and others that have followed the company, getting through the pandemic was not necessarily a slam dunk, right, especially for studies that are required endoscopies like Seres. The world kind of seized back in last spring. And we weren't really sure that we were going to be able to finish recruiting, never mind getting to a top line result. So I'm incredibly pleased that we're at this point with both studies. And I think it's a testament to a few things. One is just the incredible job that our team has done, that's first. Obviously, the world has rebounded in the availability of endoscopies, not just in the large academic centers, but some of the small GI practices that we work with. I think that we probably got a little bit of a kick from our 109 results, the fact that people said, "Look, this is a technology that can work." But I also think that, I think, has been mentioned earlier today, the mild-to-moderate patient segment that our technology, our microbiome approach could fill a need for patients that don't want to go on the biologics. So -- and then lastly, Chris, and then I'll ask Lisa comment on all 3. Just on the vanco treatment, I think we've talked beforehand, we think it's not the right choice to basically impair a patient's microbiome and not provide restorative therapy. And certainly, if you need evidence to see why that's important, I think the -109 study results are illustrative of why. We have had discussions with the FDA. And to this point, they have not asked for that study. So maybe I can ask Lisa to comment further on all 3.

Yes. No. As Eric said, there are safety concerns that we have around giving these folks vanco without a repair step, and those include C. diff as well as blooms of other pro-inflammatory bacteria. And although there is a literature on various antibiotics used to try to treat both UC and Crohn's disease, I mean it's a very difficult literature to sort through. A lot of the antibiotics -- they're using all different antibiotics, long courses, more intensive courses. Some of the studies looking at vanco actually were also using steroids, pretty high doses of prednisone. So as we look at the literature there, we don't see anything that indicates that a short course, so 6 days of relatively low dose vancomycin, that is 10 weeks before the endpoint, would be a confounder. So that's where we net out on this.

Okay. Very good. Well, thanks so much for the comments. And Eric, I echo the sentiment. Congratulations to your team on a job well done on all the clinical progress, absolutely.

Thanks for the question, Chris. Appreciate it.

Our next question comes from Mark Breidenbach with Oppenheimer.

Maybe one for Dr. Hanauer and one for the company. Just to clarify on one of the earlier answers. You specified a 10% difference between study arms would potentially be exciting to you as a bar to clear in terms of efficacy. Was that just in terms of the endoscopic improvement endpoint? Or was that in terms of clinical remission? And also, I'm wondering if you can just clarify where you, long term, ultimately see microbiome restorative therapy best fitting into the treatment paradigm? Is this something that's best as a stand-alone treatment for patients who don't adequately respond to 5-ASA? Or is this going to be an add-on in combination with frontline 5-ASA or maybe as a maintenance therapy following successful induction? Just what do you see in terms of a long-term fit for this type of drug?

Okay. So to answer the second question, the answer is yes. I think that the most important is probably going to be in maintenance therapy, where we have -- these are chronic diseases. It's been clear that stopping mesalamine or stopping any even TNF inhibitors in the more moderate to severe or biologic therapies lead to relapse in 80% to 90% of patients. So maintenance is -- a safe and effective maintenance therapy is really a significant unmet need. As far as the initial positioning, I've advocated the trials of the microbiome therapy on top of mesalamine as an initial study. But as I said, I think it opens the door, then assuming it is positive, to a head-to-head trial versus mesalamine and the potential of replacing that on a long-term basis. As far as efficacy differences are concerned, I would remind you that the Humira is probably the #1 selling drug financially in ulcerative colitis, is base -- approval was based on a 10% clinical difference without incorporating endoscopy as a co-primary endpoint. As you're aware, moving forward, the FDA has now incorporated both clinical improvement based on patient-reported outcomes of reduction in stool frequency and bleeding as well as endoscopic improvement as co-primary endpoints. And that combination should certainly be a 10% difference. Now as far as it's kind of interesting that in most of the trials, endoscopic improvement has actually been somewhat better than clinical improvement, which emphasizes the fact that symptoms don't actually correlate very well with the endoscopic appearance and is the rationale for why the FDA and other regulatory agencies are now requiring evidence of endoscopic improvement in addition to patient-reported outcomes for approvals in ulcerative colitis.

Okay. That's super helpful. And maybe one for the company, and I'm thinking ahead to future regulatory filings and what would go into the CMC module of the filings. And this applies to SER-109 as well as -287 and others. Just what are your expectations in terms of requirements for in-vitro potency assays? And how to ensure that your drug product potency -- and you have potency and consistency between batches especially from the donor-derived material?

Yes, Mark, it's a little bit of a broad question. And you brought in the dimension of -109. Maybe I'll start, and I'll ask either Matt or Dave or both to comment. But as it relates to 109, remember that our Phase III process was and is our commercial process, and we've been working on these release specs for a significant period of time. We feel that we're in a good position. We have an ongoing dialogue with the FDA. Remember, it's a breakthrough-designated program and orphan-designated program. So that dialogue is -- has been -- continues to be active. And I would just note that we feel that we're on the leading edge of working with the FDA to determine and establish these types of assays. And maybe I can ask Matt to comment further.

Yes. Thanks, Mark, for the question. We've been engaged with the agency for quite some time now, obviously, around our [indiscernible] and the variance [indiscernible] potency assays that are demanded to move our drugs into patients, both in the late-stage as well as in the commercial launch. So we don't anticipate any surprises. We have been building the various different assays that we need, which include a range of means by which we characterize the drug as well as its potency and do involve multiple different assays, both in vitro and direct assays as well. So we feel we're in a strong position. I'll see if Dave has anything he'd like to add.

Eric and Matt, you both answered it very well. And I would just say that we're confident in the consistency of our manufacturing processes, along with what Eric and Matt described.

Our next question comes from Joe Thome with Cowen Company.

First one for the company just in terms of the compelling results that the FDA may look at the determinant business for 1 of 2 pivotal studies. Have you given any additional information as to what would constitute compelling? Is it just a big benefit on the primary or anything else there? And then maybe the second one maybe for Matt. I know we saw that engraftment drove further benefit in patients in the Phase Ib. Did baseline microbiome regulation kind of predisposed patients to respond, I guess, patients that maybe they're also required as this was caused by a greater level of speculation. Do they see a better response? Or is that not possible going to find out at this point?

Yes. Joe, thanks for the question. I'll take the first one quickly, which is we have not disclosed what the definition of compelling is. I think we'll follow the science and the data with the FDA as we always do. Maybe Matt can comment on the engraftment question.

Yes. Sure, Joe. Thanks for the question. So we spend a lot of time in the company understanding what the baseline microbiome looks like in various patients and whether there are patient subpopulations or not in terms of our engraftment dynamics, et cetera. And we continue to refine our understanding of that. A couple of points I'll make with respect to that. One, as I talked about, we decreased significantly, and there was a statistical association with clinical remission as well, the reduction in the pro inflammatory Enterobacteriaceae. And that is certainly one differentiator amongst patients at baseline. Some patients have very high levels of Enterobacteriaceae, others have moderate, moderate levels. But when those bacteria -- those pro-inflammatory bacteria are dominating, we clearly drive them down. And there's an association with clinical remission around that. And with respect to engraftment as well in those patient populations, that's something we spend a lot of time on. And that is an area that I think really differentiates Seres as a company. We have those insights with respect to what bacterial species engraft, in which patient backgrounds. And that's the kind of information that has well been built into SER-301, where all the strains that have been selected to be in the SER-301 consortia are bacterial species and strains that we have clinical evidence in graft in a broad swath of patients.

Our next question comes from John Newman with Canaccord.

Just had 1 question regarding the correlation between clinical remission endoscopic remission for Dr. Hanauer. Dr. Hanauer, how important is that correlation for you as a physician? And do you feel that patients are more sensitive to the results on the clinical remission side or also on the endoscopic remission or both?

Great question. But clearly, patients are interested in how they feel. But what we've learned is that when you treat them to how they feel, it doesn't change the natural course of the disease. In other words, it doesn't change the risk of patients having being hospitalized or undergoing surgery to have their colon removed. On the other hand, when we do treat patients endoscopic remission or endoscopic healing as it's now defined, that does actually change the disease course. So they need to understand that. It's not that different than hypertension. So a patient who has blood pressure of 150 over 100 may not have any symptoms, but are significant risk of heart attacks until you reduce that blood pressure to less than 130 over 80, which has been shown prospectively. So I think that there are many other analogies to this, but -- and with that understanding. And again, I think hypertension is a good example for patients on the emphasis on needing to maintain the blood pressure control, just like we maintain control of the colitis is really an important concept for our patients. Did that clarify?

Yes. Thank you. And then I just had one question for Seres management. It sounds like you have been able to largely ensure that the endoscopies slated for the study have been carried out. Just wondered if you could comment a bit on how you were able to accomplish that? Obviously, you've shown that you can execute clinical studies well based on the -109 results, but just curious if you could talk a little more about how you were able to ensure that the endoscopies took place, especially during this difficult COVID environment.

Yes, John, thanks for the question. I think I've provided a little bit of color beforehand just in the fact that perhaps, we got the benefit from the -109 result. We, of course, got the benefit of having the world rebound, especially in the last couple of months. I do think that we're filling or seeking to fill a niche, an important niche for this patient group. But maybe Lisa can comment more fully on what was an extraordinary effort to try to get to this endpoint. And I would note that we're in a fortunate position now having last patient in and working towards top line results, where we've actually done it before in somewhat of a virtual environment by about last summer with the end results. So there's lessons that we've learned and that have been helpful, I think, continue to be helpful as we work towards that top line result. But maybe Lisa can comment further on your questions.

Yes. No, I think all the glory really go to our ClinOps of organization who really immediately jumped into action to be able to use remote monitoring where it was necessary and to look for alternate arrangements that could be made given the fact that we're doing central readings that are sent out to be evaluated. So it was a lot of hard work and a lot of coordination with the CRO partners was not an easy thing.

Our next question comes from Gobind Singh with JMP.

Thanks to the company for hosting this event, really great, and thanks, Dr. Hanauer, for all your comments. Just 2 questions for you, maybe one for the company. Do you see like clinicians using serum or sequel biomarkers in the setting of mild-to-moderate UC? And if so, what is their value? I don't know if fecal calprotectin or lipocalin or something that you think are useful. And then it's interesting, the FDA is kind of marrying this clinical and endoscopic endpoint recently, more for UC and not for Crohn's. I would be curious to hear your thoughts if you think if we can learn anything about UC there. And what's the relevance, if any, to microbiome therapeutics? And I have a quick follow-up for the company after.

Well, the holy grail of treating any of these diseases is going to be a biomarker that predicts response to any agent which, as you guys are well aware, we do not have at the present time. There's nothing that's going to -- we do not have a biomarker that will predict a response to TNF inhibitor versus an IL-12/23 inhibitor versus the JAK inhibitor. And hence, we see 30% to 40% response rates with any of those different agents. So a predictive biomarker is a holy grail. Where calprotectin comes in is a biomarker that represents or correlates well with endoscopic healing. So we don't have to do an invasive test of putting a scope of a patient to assess responses. So we use calprotectin as an intermediate biomarker to obviate the need for scoping a patient on a very frequent basis because of that good correlation. Let's see, what was the other part of your question?

The marrying of the clinical and endoscopic endpoints, more for UC.

Differentiating from Crohn's disease. I mentioned that mild-to-moderate ulcerative colitis is relatively easy to study because the inflammation in ulcerative colitis is a diffuse and continuous inflammation. So anywhere within the affected field, it's going to look pretty much the same, endoscopically and biopsies. There are mild variations. In contrast, Crohn's disease is much more focal or patchy. So the -- a couple of things. Number one, when you're doing endoscopic assessment, it's a bit more challenging to get a numerical score. When you're doing biopsies, there's a big issue of sampling variation because you could be biopsying a millimeter away from an ulcer, which will look normal versus biopsying an ulcer. So endoscopic and histology have not been as relevant in Crohn's disease, although of late, composite endoscopic scores such as the simple endoscopic score have been utilized now as, again, co-primary endpoints for approval in Crohn's disease, where Crohn's is lacking behind ulcerative colitis is we're getting pretty near to histologic criteria for mucosal healing. So just to clarify, when REMICADE was approved in 2005 for ulcerative colitis, the approval was for endoscopic -- excuse me, was for mucosal healing. And the FDA subsequently realized that the mucosal healing not only represented endoscopy but also represented histology. So for all of the subsequent agents that have been approved to date, the improvement is based on mucosal improvement or endoscopic improvement rather than the concept of healing. We are now seeing combining endoscopy and histology coming together in some of the recent trials. But it is not yet achieved a regulatory necessity to this point, but it's coming in ulcerative colitis.

And for Lisa maybe or whoever in the company, Eric, do you think is best -- what -- how many days are you guys waiting after you finish the 6-day vanco dosing before you give your microbiome therapeutic? And can you just remind us of the primary endpoint for the -287 trial? Is it going to be the pooled arms if you're able to comment? Or is it just one of the arms versus placebo?

Lisa, do you want to comment on the clinical protocol?

Yes. We do 6 days, and then we start the right in the next week with the SER-287. So there's not a big break. And then what was your other question on pooling? Is that...

Yes, I was just wondering if you guys are just pooling your 2 different in -287 arms?

Yes. The primary endpoint will be on -- and the key secondaries, we'll be looking at each arm separately and sequentially.

Got you. And for the day amount, was that kind of less than 48 hours? After you finish the 6-day dosing, you go straight to the therapeutic?

Yes. That's right.

Thanks for the question. And I think we're just at the end of the hour. But maybe, operator, we can take one more quick one.

Our next question is the follow-up question from Chris Shibutani of Goldman Sachs.

For Dr. Hanauer. Can you comment on your thoughts on any of the data or experience in the use of FMT for ulcerative colitis? And then a quick follow-up for the company. Should we think about results that we'll hear about for SER-287 as having any read-across for what we may potentially see in -301? And in what ways could that be different? And with the -301, I know you're enrolling, remind us some perspective on the timing that we could see that data?

So the first question was for me, which is the relevance of fecal transplants in the setting of ulcerative colitis, which, again, as you know, has been quite variable. So my personal interpretation is that, number one, there is a signal that transplant can be helpful. But number two, there's going to be some specificity because many of the successes of the transplant relate to specific donors who have donated their microbiome, whereas other donors have not been as effective. So I think that the mechanistic aspects of the trials that Seres are going to -- are doing is going to help clarify, again, some of the potential targeting of microbiota in individual patients. But I think that it is clearly a signal that there may be -- that there is going to be benefit in individuals. I think part of the other signal is that it looks like some form of maintenance therapy with transplants is going to be more effective than a single transplantation. So identifying donor and patient specificities and also the likely need for long-term therapy, and hence, again, more incentive for an oral replacement therapy.

Yes. Chris, maybe I can put the company lens on the first part of the question, too, which is from a -- if you think about FMC and UC, obviously, the proof of concept that we've talked about, hard to envision a viable commercial approach with repetitive animate colonoscopies and so forth. And of course, we've talked for a long time, particularly in the -109 side relating to the safety dimension of things that we will go through here. But the second part of your question related to -287 and -301 and maybe potentially readthrough. And let me start, and then I'll ask Matt to just add a couple of comments. But we're thrilled to have multiple shots on goal within this space, right? With -287, with -301, each has different biological activity. We think that there's aspects of the trials that are independent of each other. And we expect to learn a great deal from -287 that will inform the development of -301 and beyond. And maybe I can ask Matt to comment further, and then we can close.

Sure, Chris. As I commented in our talk, SER-301 is an optimized cultivated targeted set of pharmacies bacterial species that were optimized for engraftment in the GI and in various pharmacological properties, some of which I talked about today, as well as others. So we know that the bacteria in SER-301 engraft across a majority of patients that we've worked with across our broader portfolio in -287, but including other programs as well. The specific strains in -301 are significantly associated with clinical outcomes and the modulation of key micro mediated metabolite. This includes the production of rare metabolites that are either associated with efficacy in the -287 with Phase Ib, but also that we've identified in our nonclinical assays is important for modulating post epithelium integrity and decreasing inflammation. So in short, with -301, we really anticipate these optimizations to enhance drug activity a broad patient population. And then the other important aspect of 301 is during consortium, is optimized to include strains with highly favorable manufacturing properties and safety attributes. And so these differences in manufacturing afford different advantages in serving larger patient population. So while the drugs have certain are related, they are also differentiated in meaningful ways.

And when might we learn about -301?

We haven't -- Go ahead.

We haven't provided guidance, except to say that we're making great progress in our study in Australia and New Zealand. And as we've done in the past as a company, as we proceed down the line with the study and get a better sense of the slope of the curve, we tend to then provide more guidance and then refine it over time. And I think you can envision that we would do something similar here. So I think we're past time. So I just want to thank everybody again for your interest in Seres. I want to thank again the presenters, including Dr. Hanauer. With that, we'll conclude the call. Thank you, and have a great week.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.