Seres Therapeutics, Inc.

Ladies and gentlemen, thank you for standing by, and welcome to the fourth quarter 2021 Ceres Therapeutics, Inc. earnings conference call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question and answer session. To ask a question during this session, you will need to press star 1 on your telephone. If you require any further assistance, please press star 0. It is now my pleasure to introduce Dr. Carlo Tanzi of Investor Relations.

Thank you and good morning. Our press release with the company's fourth quarter 2021 financial results and a business update became available at 7 a.m. Eastern time this morning and can be found on the investors and news section of the company's website. I'd like to remind you that we'll be making forward-looking statements related to the timing, enrollment, and results of our clinical studies, the anticipated safety profile of our products, the timing of potential regulatory approval of CR109, the success of our agreement with Nestle Health Science, the anticipated market for SIR-109, and the promise and potential impact of any of our microbiome therapeutics. Actual results may differ materially. Additionally, 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. On today's call, with prepared remarks, I'm joined by Eric Schaaf, President and Chief Executive Officer, Dr. Lisa Baumolke, Chief Medical Officer, Dr. Matthew Henn, Chief Scientific Officer, and David Arkowitz, Chief Financial Officer. During the Q&A portion of the call, we will also be joined by Dr. Terry Young, Chief Commercial and Strategy Officer, and Dr. David Agee, Chief Technology Officer. With that, I'll pass the call to Eric.

Thank you, Carlo, and good morning, everyone. 2021 was a very productive year for CERES, where we have made meaningful advancements in our microbiome therapeutics pipeline. At the center of this progress was our lead CER-109 program and our momentum towards an expected BLA filing in the middle of this year. The significance of CER-109 in our successful pivotal clinical data and recurrency to facility infection was recently highlighted by the publication of the Phase III study in the New England Journal of Medicine. We believe that SIR109 has the potential to become the first-ever FDA-approved microbiome therapeutic, a landmark for this emerging class of medicines. Pending SIR109 FDA approval, we believe we have the opportunity to transform the treatment of recurrent C. diff infection. To remind you of our SIR109 efficacy results, our Phase III data demonstrated a significant reduction in the proportion of recurrent C. diff patients experiencing a further recurrence demonstrating superiority versus antibiotics alone. Furthermore, the Phase III data surpassed statistical thresholds that had been communicated to us by the FDA that could allow this single clinical study to fulfill efficacy requirements for a BLA. The FDA had also communicated that our BLA filings should include a safety database of at least 300 subjects receiving the Phase III dose and with a 24-week follow-up. Our SEER-109 open-label study is fully enrolled, and we continue to gather the required safety data. Notably, the SEER-109 open-label study also includes individuals with a first recurrence of C. diff infection, an expansion compared to the Phase III study population, which included only those with multiply recurrent CDI. The combination of first recurrence and multiply recurrent patients across our studies represents a broad segment of patients living with recurrent CDI. As we prepare for a CR109 VLA filing, we are also conducting a CR109 expanded access program. This program is designed to enable adults with a recurrent C. diff infection, including those with a first recurrence, to obtain access to CR109 ahead of a potential FDA product approval. We have continued to make excellent progress towards our planned rolling submission of the BLA, and we continue to plan to complete the full BLA submission, including the required 24-week safety data set, in mid-2022. Given that 0109 has obtained breakthrough therapy designation with the FDA, we anticipate receiving priority review. This would result in an expedited timeline, including a two-month BLA acceptance period, followed by a six-month review period. The approval and launch of CIRA 109 would represent a landmark event for patients living with recurrent CDI and for series. In collaboration with our partners at Nestle Health Science, we continue to prepare for a successful commercial launch. There are approximately 170,000 cases of recurrent CDI in the U.S. per year, and CDI results in over 20,000 deaths per year. Recurrent CDI patients do not have attractive treatment choices today. some of these patients are currently being provided regimens and procedures that are not FDA-approved, including fecal microbiota transplantation and extended courses of antibiotics. Pending product approval, we believe that SIR-109 could address this entire patient group suffering from recurrent CDI. Furthermore, we believe that SIR-109 represents a substantial economic opportunity for CERES. The cost of a patient with recurrent CVI has been estimated to result in approximately $34,000 in annual direct health care expenses, and this does not include the substantial indirect costs associated with this disease. We believe that with a highly attractive CR19 profile and the tremendous level of unmet need, this could translate into significant value for patients, payers, and for the company. Based on our discussions with healthcare practitioners, there is an eagerness for new, safe, effective, and FDA-approved treatment options. We believe CR-109 could provide a transformational new therapeutic option for recurrent CDI, and we are working with urgency to bring our therapeutic forward to the market as quickly as possible. During the fourth quarter, we announced a collaboration with Baxera, a global leader in biopharmaceutical product manufacturing that increases our longer-term SIR19 product supply. This collaboration adds to our existing manufacturing capabilities. Baxera is building a dedicated facility for commercial manufacturing in its new Microbiome Center of Excellence, a manufacturing site dedicated to the production of live biotherapeutic products. We look forward to working with Baxera to expand our current production capacity, which we expect to fully support the initial launch period. With this agreement, we anticipate meeting demand growth beyond the initial phase of launch and under all anticipated commercial uptake scenarios. Beyond the direct benefit that CIDR1 and I demonstrated in recurrent CDI in our Phase III study, we also believe that our data provide important proof of concept for the potential for microbiome therapeutics and infection protection more broadly. In January, we held an investor event that detailed the supporting data and our strategy to address this important opportunity. We believe that infection protection represents a tremendous strategic opportunity for CIRES and we intend to advance additional therapeutic programs in 2022 and beyond. I'd like to now pass the call over to Lisa to discuss our clinical initiatives in more detail.

Thanks, Eric. Since obtaining the initial SEER-109 top-line results in July of 2020, we have presented various data sets at a number of prominent conferences attended by infectious disease physicians and gastroenterologists. More recently in January, we were very pleased to have published the complete phase three study results in the New England Journal of Medicine. The publication highlights study results that demonstrated CR109 to be superior to placebo in reducing CDI recurrence, with 88% of CR109 patients achieving a sustained clinical response, compared to 60% on placebo. This was a highly statistically significant difference. In this study, SIR-109 was also observed to be well tolerated with a side effect profile comparable to placebo and no serious drug-related adverse events observed. The New England Journal publication has had the benefit of increasing physician awareness and interest in SIR-109. As a result of the publication, we have seen a marked increase in the number of inbound inquiries we've received about the program, and we believe that there is a high level of physician interest in incorporating SEER-109, pending FDA approval, into their clinical practice. In addition to demonstrating the opportunity for microbiome therapeutics to impact recurrent CDI, we believe that our SEER-109 data have also provided clear clinical and mechanistic evidence supporting microbiome therapeutics' potential impact on infection protection more broadly. The gastrointestinal tract is known to have an important role in preventing pathogen infection, including from life-threatening pathogens that can harbor antibiotic resistance. Increasing emergence of antibiotic resistance has become a significant public health threat, and new non-antibiotic treatment approaches are desperately needed. Our CR109 data demonstrate that microbiome therapeutics can result in significant restructuring of the gut microbiome, and that these changes can lead to significant reductions in pathogenic bacteria, including those associated with antibiotic resistance. We believe that there are numerous opportunities, in addition to C. diff infection, where we can apply our microbiome therapeutic approach in infection protection. More specifically, we plan to apply our technology toward multiple medically compromised patient groups who are known to be at high risk of life-threatening bacterial infections. Beyond CO109, our next most advanced program in infection protection is CO155, which we are developing for individuals receiving allergenic stem cell transplant. These patients are at very high risk for serious infections as well as graft versus host disease, and we believe that SEER-155 has the potential to address both issues. We have an ongoing Phase 1b trial to assess the safety, microbiome engraftment, and efficacy of SEER-155, working with our partners at Memorial Sloan Kettering and the University of Chicago. The subjects in this study will be undergoing treatment for hematologic malignancies, such as leukemia, Based on historical data, we expect that over 50% of these subjects will experience infection or GVHD. If SEER 155 is able to reduce the incidence of these conditions, we believe we would meaningfully improve health outcomes for these patients. The study is set up with two cohorts. The first cohort, including 10 subjects, is designed to assess safety and engraftment of SEER 155. The second cohort includes 60 patients in a randomized, double-blinded design to further evaluate safety and engraftment, as well as efficacy. This will be measured by assessing the rates of bloodstream infections and acute GVHD. Ideally, we would see a significantly reduced incidence of bloodstream infections and or acute GVHD associated with CL155 administration. The study will help guide future clinical efforts and which outcomes we should target with future studies. Furthermore, positive results in preventing GVHD would support not only pursuing this outcome in future trials, but exploring next steps forward in immune modulation. I'll now pass the call to Matt to further discuss our broader plans in infection protection, as well as our efforts in ulcerative colitis.

Thank you, Lisa. As we highlighted in detail during our January 31st investor event, we believe that both our clinical and preclinical data provide strong evidence supporting the potential for microbiome therapeutics in infection protection. We see the potential to reduce the abundance of targeted pathogens to decrease the potential for pathogen transmission, strengthen epithelial barriers to further reduce the frequency of bloodstream infections, and to modulate immune responses to tackle medical complications such as graft versus host disease. CIRES has developed an integrated platform that has enabled the discovery of novel therapeutic candidates designed to protect patients from infection. We are building on the success of CIR-109 with CIR-155. We've also initiated additional preclinical programs targeting infection protection. These include evaluating opportunities in patients receiving autologous HSTT and designing consortia to deploy in settings such as cancer neutropenia and solid organ transplant, as well as combating the slow pandemic of antimicrobial-resistant infection more broadly. We are driving towards initiating an additional clinical development program in 2023 and progressing additional programs into the clinic over the next few years. Now, moving to our ultracolitis efforts. UC is an area of strategic interest for CERES, and we believe it is a disease that may be particularly well-suited for a microbiome intervention. I'll begin with a recap of our efforts targeting UC and some prior data sets. Last summer, we announced top-line results from our Phase II Eco-Reset Study evaluating CERF-287, a donor-derived investigational microbiome therapeutic candidate in patients with mild to moderate ulcerative colitis. While both dosing regimens of SIR-287 were generally well tolerated, the study did not meet its primary endpoint of improving clinical remission rates compared to placebo. Late last year, we announced additional microbiome drug pharmacology data from the Phase II study that indicated that the engraftment of SIR-287 bacteria was, on average across patients, statistically significant compared to placebo. However, we did not observe metabolomic changes that we had anticipated and that we believe are important for therapeutic impact. In addition to SEER 287, we also continue to evaluate data from our Phase 1B study for SEER 301, a next-generation, rationally designed, cultivated microbiome therapeutic candidate for the treatment of UC. The Phase 1B study is designed to include approximately 65 patients distributed across two cohorts. Preliminary CR301 data has been analyzed from the first cohort, which included 15 subjects. Evaluation of the first cohort data by an independent data safety monitoring board indicated that it would be safe to proceed to the placebo-controlled second cohort. While clinical efficacy was not a defined endpoint in the first cohort, Evaluation of outcome data indicated that no subjects achieved clinical remission using an FDA three-component definition, though there were improvements in one or more individual components of the disease score, including endoscopic, stool frequency, and rectal bleeding subscores. Furthermore, CR3-1 bacteria were observed to engraft in subjects across the trial period, and notably, we observed changes in the metabolic landscape in the gastrointestinal tract. Interestingly, the degree of metabolic changes observed following CR301 administration appeared to be dependent on the baseline metabolic profile of the study subjects. This is an area of particular interest that we continue to explore. UC is known to be a remarkably clinically and biologically heterogeneous disease, and this has hindered the development of various drug efforts for decades. Based on our available CR301 and CR287 data, we believe that certain UC patients may be more receptive to microbiome therapeutics based on definable baseline characteristics. Our research in this area remains ongoing, and we continue to conduct analyses to inform next steps for further development in ulcerative colitis. With that, I'll now turn the call to David to provide an overview of our financials.

Thanks, Matt. The details of our full-year and quarterly financials are included in this morning's press release, so I won't reiterate all the figures here. Series ended the fourth quarter of 2021 with approximately $291 million in cash, cash equivalents, and marketable securities. We are pleased to announce today that we have amended our debt financing agreement with Hercules Capital, providing the company with a debt facility of up to $100 million. This debt financing is a term loan, which we drew down $50 million upon closing last week. This amendment replaces our prior 50 million debt facility with Hercules and approximately 22 million of the proceeds we received last week under the amended agreement will pay off the remaining amount owed. With respect to our operating expenses and efforts over the near term, we continue to be focused on a number of critical SEER 109 related activities, which include preparing and filing the BLA submission, continuing to ramp up manufacturing operations for commercial supply, including increasing longer-term SEER 109 product supply through our Bactera collaboration, and in conjunction with Nestle, continuing and accelerating launch readiness activities. In addition, we continue to invest to advance and expand our pipeline with a focus on infection protection opportunities and further build upon and enhance our platforms and capabilities. As a result of these high-priority and value-generating activities, we expect our expenses to increase in the coming quarters, but at a moderating rate of growth as we have already expanded our capabilities across much of the organization. In summary, we believe the company is well-resourced to prepare for SEER 109 commercialization, drive our ongoing development and preclinical programs, while also deploying resources to continue to advance our research platforms where we believe we have differentiated proprietary and sustainable advantages. I'll now pass the call back to Eric.

Thanks, David. I will conclude our remarks by recapping key 2021 progress milestones, as well as upcoming anticipated value drivers for the year ahead. These include achieving target enrollment in our Serum 109 open label study and our preparation for a BLA filing in the middle of 2022. Continued progress executing on SIR 109 pre-commercial readiness, working closely with Nestle Health Science Amune, including expanded market education efforts. The initiation and ongoing execution of our SIR 109 expanded access program. The expansion of our longer-term commercial supply capabilities, including our collaboration with Vaxera. Continued data analysis to inform future development in ulcerative colitis. SIR 155 study initiation and ongoing execution, and expansion of our efforts targeting infection protection, an area of incredible opportunity to serve patients, which directly builds upon the success of SIR 109. We also continue to strengthen our microbiome research platform and preclinical efforts. In 2022, we expect to advance new microbiome therapeutic candidates towards clinical development and particularly in infection protection, where we believe we have clear clinical and mechanistic data supporting our approach. CIRES is well positioned to lead the microbiome therapeutic field, and we intend to continue to execute on our mission, working hard to improve the lives of patients. With that, now operator, we'll open the call up to questions.

Certainly. As a reminder, to ask a question, you will need to press star 1 on your telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. Our first question comes from the line of Mark Breenenbach with Oppenheimer.

Hi, good morning. This is Jacqueline from Mark, and thanks for taking our questions. My first question is, how is the baseline metabolic profile being defined in 301 study subjects, and how many individual biomarkers are used in this characterization? Thank you.

Good morning and thanks for the question. Matt, do you want to take that one?

Sure. We've been looking at a whole suite of disease-relevant metabolic biomarkers in our UC patients that we had predefined to be important. And in addition to that, we have been looking at and discovering novel biomarkers that we believe are important and relevant for disease based on the data sets that we've generated We haven't spoken and disclosed yet the specifics of the number of biomarkers, but what I can tell you is that we have identified a few biomarkers that are consistent and that we believe could be used potentially for patient stratification and or selection.

Okay, that's good to know. Thanks. And also, do you plan to modify the composition of SIR 301 based on observations from the first 15 patients?

Yeah, so all of our data to date support that the pharmacological properties of SEER 301 are consistent with their design and that the drug is exhibiting pharmacological properties as it was designed to do. So at this time, we do not anticipate any changes to the consortium.

Okay, so my next question is regarding SEER 287. So based on the biomarker profiling, what fraction of mouse moderate UC patients do you think could be good candidates for 287 and 301? And also, is there any difference in the biomarker-defined populations you're considering for continued development of both molecules?

Matt, do you want to start with that one, and I'll throw some comments on top?

Sure. Yeah. So... We do think that the patient subpopulations that we've identified still represent a significant portion of patients with ulcerative colitis. So those that we have identified to be most receptive are somewhere on the order of about 30% to 40% of the patients in the population. We haven't provided any details further than that at this time.

Yeah, I might just add as a larger comment, you know, we are – So learning, iterating, and I think it's worth noting that we have a significant amount of data here with the 287 study results, both clinical and microbiome, now the first 15 subjects of the 301 study. You know, we will continue to learn and adjust from these study results, and we'll follow the data. And I think it's worth noting, if you think back maybe to the 109 experience, after the Phase II study results, You know, we had a lot of confidence in the underlying thesis and a lot of data to support it, but we didn't just say, look, let's run another study and hope that it kind of ends up clinically where we'd like it to. You know, we made a number of adjustments based on data. It turns out that those adjustments, you know, led us to a very positive spot, and that certainly is the process that we have intended to take with our efforts in IBD and UC, and that's what we're doing now.

Great. Thanks. That's really helpful. That's it for me. Thanks again for taking our questions.

Thanks for the questions. Thank you. And our next question comes from the line of Ted Tenthoff with Piper Sandler.

Great. Thank you, guys. Really exciting points for the company. I'm just trying to get a better sense as you prep for the BLA. Obviously, a very strong data set here. And Will you be reporting or presenting the safety data, or will that be something that simply goes into the DLA? And then also, if I may, with respect to the relationship with Nestle, how are you guys working to kind of prep for launch together? Thanks so much.

Yeah, Ted, good morning, and thanks for the questions. Maybe I'll ask Lisa to start with a second, and I'll ask Terry to hit the, sorry, Lisa to start with the first one, And, Terry, to start with the second one, on the first, maybe I'll just start by commenting that, you know, we are still in the process of following these patients out, but maybe, Lisa, you can comment further on the open label study and how we'll track it.

Yeah. So we haven't said yet how we'll make those data public and how to communicate, but I will say that we are eyeing our possibilities in terms of conferences and other ways to disclose as soon as we have that data set finalized.

And then, Terry, can you just comment on our work with Nestle Health Science and some of the pre-commercial work that we have conducted together?

Sure thing. Well, I guess I'd start by highlighting that, you know, we ramped these efforts upon receipt of the data, right, the Phase 3 data, the remarkable data that we had, and then yet again with Nestle after signing the co-commercialization agreement last year. So we've now integrated the team at Nestle into our efforts, and we've worked together to scale both our market education but also our data dissemination efforts. And these are primarily being led in the medical affairs to Lisa's team, and I'll hand it back to her in a minute to comment on that, but also in our market access team. For example, we're developing a robust payer value proposition that is supported by the really strong category-leading profile of 0109, but also the high cost of treating recurrence that Eric highlighted in his remarks today. And, you know, this is treating recurrence after recurrence in these patients. And the options today are quite limited. And Nestle has an existing payer field team to engage this important audience, and we'll be doing that pre-launch in accordance with existing FDA guidance on pre-approval information exchange. So that's a pretty big book of work on the payer front and value proposition front. We also continue to work with them to deepen our understanding of the market opportunity, and we're progressing items like brand positioning efforts, HCP payer and patient segmentation, and branded campaign development. And finally, last year, we launched a broad disease education campaign at ID Week, and we'll be amplifying that campaign as we move throughout 2022. Finally, we're continuing to hire industry-leading commercial talent into both of our organizations. Now, I'd like to ask Lisa specifically to comment on the medical affairs activities in front, particularly in light of the recent publication of the pivotal data in New England Journal of Medicine.

Yes, thanks, Terri. Yeah, so the Medifare's efforts really are spanning a number of areas that you'd expect, including publications. The New England Journal was incredibly impactful with regard to the reception in the physician community, and we've already heard of infectious disease physicians bringing this up on rounds and in their discussions with their colleagues. But the Nestle group is an immune group, are fully integrated as we move through planning further publications, mobilizing the MSLs. They're out there on the ground talking to physicians. There are lots of education activities that are going to be culminating in CME programs. and we're also working with the patient advocacy groups. And we're very pleased with how the Nestle Amune team is blending in and being part of that effort.

Very, very helpful, very thorough answer. I appreciate it, everybody.

Thanks for the question, Ted.

Thank you. And our next question comes from the line of Peyton Bonsack with Cowan.

Hi, good morning, guys, and thanks for taking our questions. I'm on for Joe. So just a real quick question about the expanded access program in the U.S. I was wondering how many patients have been treated through this program, how the demand has been, and whether you can share any details about whether this has been mostly first reoccurrence or multiple reoccurrence patients. Thank you.

Yeah, Peyton, I would say we're just getting started with the expanded access, just having at the end of the year concluded the open label 300-patient bogey that we had been targeting. Lisa, maybe you can comment further.

Yeah, we haven't really given specifics. I can tell you that it's up and running. We have patients enrolled. We have numerous sites across the company. We've tried to strategically place them so that patients can access the site regardless of where they are. And we'll look forward to giving you more information in the future. But we haven't really been specific on numbers yet.

Thank you. That's really helpful. And then maybe a real quick question on the SARE 155 program. I know that when this was talked about previously, it said that the Cohort 2 could begin enrolling before Cohort 1 finishes. Is there a certain level of efficacy that would be required to begin enrolling cohort two? And then also, are there any plans to expand the number of sites where this trial is being conducted, or is it just going to be at the Chicago and MSK sites?

Lisa, maybe you can comment on both. I think one is the protocol structure and progression, and the other is maybe the

Yes. We're at two sites right now and we're intending to increase those. So I think what you're referring to with the first part of your question is that there is a pretty long safety follow-up over the course of actually over an entire year. We don't need to wait for that entire year to start the second cohort. The first has to finish the first set of patients through an initial safety assessment, and at that point we're free to go into the second sector without waiting that entire year of safety follow-up. I think that's what you're probably referring to.

That's exactly it. All right. Thank you so much.

Sure. Thanks for the questions. Thank you. And our next question comes from the line of Chris Shibutani with Goldman Sachs.

Hi, this is Steven on for Chris. Thank you for taking our question. I had one on the 301 program. Do you expect that your label would include language for how many recurrences a patient must have prior to going on 301? And then just if you could comment on the efficacy you're seeing in these patients with first recurrence versus kind of the phase 3 trial population. Thank you.

Steven, I want to make sure that we've got our numbers, our programs right. But the question was 301 around recurrences. Do you mean 109?

Oh, yeah, sorry about that. Okay, all right, no problem.

Yeah, so look, I think what we said before is that The label, of course, will be part of a negotiation that will happen with the FDA as part of the BLA process. You know, we don't want to get ahead of that. At the same time, we absolutely think that medically, and Lisa has and certainly can, again, speak to our view of why we think that recurrent C. diff patients is appropriate for that patient population. And maybe, Lisa, let me hand it to you on that.

Yeah, I think both from a pathophysiology basis as well as how our interactions with physicians are indicating they think about recurrent disease. It pretty much falls into primary disease, primary occurrence, and everything else. And from a pathophysiology standpoint, That first recurrence is the marker and happens because the microbiome is unable to suppress the germination of those spores, and that's the point at which it makes sense to start restructuring. As well, physicians in practice tend to see a C. diff infection as either the first bout or everything else. So for those reasons, we really see this as an appropriate therapy for all recurrent patients. But as Eric said, the label will reflect the negotiations with the agency.

And maybe just to follow, I think you had asked about the percentage of first recurrence that we had seen in the open label. And we haven't disclosed that data, but as Lisa mentioned, we kind of have our eyes on on opportunities once we're past the follow-up period to disclose those data. Got it. Thank you for taking our questions. Sure. Thanks for the question.

Thank you. And our next question comes from the line of John Newman with Canaccord.

Hi there, team. Good morning, and thanks for taking my question. I just had a question about the SEER 301 data. I noticed in your press release as well as in your prepared remarks, you mentioned that Sera 301 did modulate short-chain and medium-chain fatty acids, which is interesting. Many patients actually will take those types of products sort of off-label, but just curious if those types of changes were relatively consistent across the patients. in that first cohort. You did mention that baseline metabolic state affected the changes imparted by 301, but just curious specifically on the short and medium chain fatty acids, if that was somewhat consistent across the patients that you looked at. Thanks.

John, good morning, and thank you for the question. I'm going to hand it to Matt, but I'll do so just with the first qualification that you have to remember we're talking about 15 subjects, right? So it's a pretty limited data set. That said, it's interesting, and we think we're going to learn quite a bit from it. And we are in the process of analyzing some of the data sets that have come from it, but maybe with that I can hand it to Matt.

Yeah, so a couple, morning, John, a couple points. So first, I'm going to start with the same that Eric said. This is 15 subjects in 301, so we need to be cautious in terms of the extrapolation of those results. But I think It's clear that CR301 certainly demonstrated the pharmacological properties that it was designed to exhibit, and certainly short-chain fatty acids and medium-chain fatty acids are one particular metabolite that CR301 is designed and optimized to produce. There are multiple others as well, and the UC patients are certainly a heterogeneous patient population, and you certainly can see variations in the short chain and medium chain fatty acids amongst patients at baseline. I will tell you that that is not the biomarker that we are focused on with respect to our patients and the population that we've identified, but that is certainly an important functional parameter that we continue to assess and evaluate and know that modulating that can be one important mechanism in the context of reducing inflammation in the gut, in the in the gastrointestinal tract. There are multiple others as well that we are focused on. The second part of your question is just a comment on another part of your question, which is a comment that you made of folks taking these sort of compounds, if you will, off-label. What's important is that And I think what's important about our drugs is that it's the bacteria that are producing these. And while you have not seen success with patients previously taking things like bile acids or short-chain fatty acids or other metabolites, through vitamins, et cetera, because, of course, these things need to get to the site of activity and where they need to be. And I think that's one of the clear benefits of our technology is that we're using the bacteria as drugs and the bacteria naturally and have evolved to be at the site where it's most relevant to have those effects. So the bacteria are producing these metabolites at the site that we want them to.

Okay, great.

Thank you. Thanks for the question, John. And our next question comes from the line of Gobind Singh with JMP Securities.

Hey, thanks for taking my questions and congrats on the progress. If I could dig a little bit more into the 301 data, is it possible and would it be accurate to say that the positive metabolic changes seen with 301 were meaningful compared to the changes that were seen with 287 or the lack thereof? And... And since we're talking about metabolic profile, I just wanted to confirm that the engraftment profile with 301 was presumably robust, and I don't know if there's any way to talk about the quantitative difference, if there was any, compared to 287 and how that could maybe tend towards the kind of metabolic changes that you guys are now seeing. This would be a positive indicator. And if there's any feedback or comments that you could share around how metabolic profile, whether baseline or otherwise, and optimizing that could tend towards clinical remission, maybe on a general level or just from data out there. I know there's only 15 patients here. That would be great. Thank you.

Yeah, Gobind, good morning, and thank you for the question. There's a lot there in terms of – in your questions around some of the depths of our microbiome analysis. And, again, I'm going to pass it to Matt, but I'll do so with just the caution that we continue to be in the process of analyzing this data. We are striving to put ourselves in the best position to help patients and, of course, have a return for shareholders based on our efforts in UCs. And we are iterating and we're learning. And there's a number of data sets that we think put ourselves in the position to have more visibility, perhaps, than others as it relates to maximizing our chance of success in UC, but there's a lot for us to do. And maybe Matt can take it there forward.

Yeah, Gobind, I think I heard two questions in your comments. So one was a question about the engraftment of CR301 bacteria in patients post-treatment. And the second was the magnitude of metabolic changes in the CR301 cohort 1 population versus CR287 population. So with respect to engraftment, yes, we did see both rapid and durable engraftment of CR301 bacteria into patients post-treatment. You may recall that... One reason we had this first cohort was that we were testing a novel formulation of the drug where we had bacteria in the drug formulated both in the form of spores as well as in the form of vegetative bacteria. And we wanted to evaluate that formulation in the cohort one study. And I can tell you that we saw both engraftment of spore formulated as well as vegetatively formulated bacteria, which I think is important because it speaks to the strength and the breadth of our manufacturing capabilities at the company. Excuse me. Engraftment, as we have consistently observed across our studies, can have variability from patient to patient, but we certainly consistently get bacteria on board. And importantly, what we have sort of shifting to the Second question you had, the magnitude of metabolic changes. We certainly were able to observe trends and changes and as well as significant differences in multiple predefined metabolites that we think are important and relevant for the treatment of UC and for which CR301 is designed to do. In terms of the magnitude of that, as we noted in the Phase II study of SIR-287, we did not observe these predefined metabolic changes that we had anticipated to, and that was a surprise, whereas in the context of SIR-301, we did. And a good number of those were also significantly changed at multiple different time points in the course of the study. So we saw more meaningful change in the context of SIR-301.

Yeah, so, Gobind, maybe I'll just close by saying, you know, that we will continue to think about, as you often do with a Phase I study, optimizing dose, continuing to analyze the biomarker data that we think is intriguing, and, you know, especially given the heterogeneous disease like you see, thinking about patient segmentation where we can have an impact on the right patient group. So those are the pieces that we are currently continuing to iterate on. Thank you.

Appreciate you guys making advancements in the state.

Thanks for the question. Thank you. And our next question comes from the line of Vernon Bernardino with HC Wainwright.

Hi, everyone. Thanks for taking my questions, and congrats on the process. Looking forward to the VLA midyear. So with CERB 109, The results showed a high sustained clinical response rate, about 88%, yet in a survey you conducted, there's still a significant number or percentage, rather, of prescribers who definitely might not prescribe a SIRT109. What is the driver of their hesitancy, and what kind of efforts do you think during commercialization do you think you could implement to perhaps target that perhaps significant patient population that may not receive SAR109?

Vern, good morning, and thanks for the question. I'm going to ask Terry to comment, but I would say that the conclusion based on the question is we have a very different point of view from what you hypothesized based on the analysis that we did. In fact, we felt extremely favorable in terms of what we heard back from our primary research, but Terry, maybe you can take that one forward.

Yeah, thanks, Eric. I mean, it's a great question, and I would refer you to a slide that is in our current corporate deck that actually illustrates feedback that we've obtained recently from both HCPs and payers. And what you'll see is if you look at the HCP response, it's actually quite remarkable in the positive direction. We have what I would call a sea of green feedback. And this is likelihood to prescribe data, right? So the vast majority of physicians saying that they are probably or definitely will use CR109 within their patient population. And for something that's as transformative and such a new approach to care like CR109, that's actually quite unusual. So I imagine your question is more in the smaller gray percentage that are sort of labeled as a might or might not. Exactly. This is actually very typical, again, in a new category. You get what I call the fence-sitters. So they tend to, you know, you're showing them a profile in research, right, and you're asking them, you know, based on one piece of paper, would you use this in your patient population? And they're just a more cautious physician set. So they want to, for example, hear from their specialist down the street. They want to wait for FDA approval. They want to, you know, understand the data in a little bit more depth. So, you know, these spent sitters don't tend to sit for very long, but that's typically the dynamic that you're dealing with. So how do you deal with it then? It's through the approaches we're taking today around market education from the medical fair standpoint. And, of course, at approval, we can deploy our broader field force as well, publications, conferences, and, of course, the BLA approvals.

And I'm sorry I implied that, you know, I do realize there's a sea of green, and I'm sorry I implied there was a greater hesitancy. It seems like there would be a low bar. I'm sorry, Eric, go ahead.

No, no, I was just going to say I appreciate the clarification. And, you know, I would just say we feel we're starting commercially from a very good spot based on the data. It really comes down to the data more than anything else, right? And, you know, We couldn't be more pleased with the data set that we have. We think it resonated, as we've talked about in the past, in the momentum that we saw, you know, as the open label study was conducted, even amidst the pandemic. We saw it with the acceptance of the manuscript into the New England Journal of Medicine. Lisa has commented earlier and can maybe comment again just in terms of the MediFair side, which we think is really important work that we have to do with our partners in ensuring that that people know about this technology, they know about this profile, and maybe Lisa can comment.

Yeah, no, I think I can't overstate really the impact from the New England Journal paper in in really solidifying the position of the data for so many of the physicians. I think not only within folks who had been watching and wanted to see the whole data set, I think I can also say that we've heard from people who were still somewhat skeptical and still hanging on to or other potential alternatives who have now contacted us and said, now that I've seen that data set in a peer-reviewed, in this particular peer-reviewed journal, and have seen the data for myself, I really am just blown away, and I can't wait to be able to use it. So I think we're well-positioned to be able to do the education that we need to do.

Yes, you are, and thanks for taking my question. And it looks like the publication in your journal mentions you're going to help with the fence sitters. Thank you, and congrats on the progress.

Thanks for the question, Bert. Thank you. I'm showing no further questions. So with that, I'll turn the call back over to management for any further remarks.

So thank you, and I want to thank everyone for joining our call today and for your continued interest in the series. We look forward to keeping you updated on our progress, and with that, we'll conclude. Hope everyone has a great day. Thanks very much.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.