Good morning, everyone. My name is Ted Tenthoff. I'm a Senior Biotech Analyst at Piper Sandler. Before I begin, I'm required to point out certain disclosures regarding the relationship between Piper Sandler and Seres that are located at the back of the room and also at the registration desk. Seres is a leading microbiome therapy company, having developed and sold VOWST for recurrent C. difficile infections in that site. Seres is now developing SER-155 to reduce the incidence of GI infection, bacteremia, and graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplant, and also SER-603 for ulcerative colitis and Crohn's disease. Here with us today from Seres is Marella Thorell, Co-President and CEO, and also Matt Henn, the CSO, and Terri Young, who's the Chief Commercial and Strategy Officer. Thank you all for being with us. Thanks for having us. Maybe you can start off by explaining Seres' core microbiome technology. Describe these therapies and how you design them. Sure. I can start off with that, Ted. Thanks for the question. When we launched Seres, the concept was, how do we actually tap into the therapeutic potential of microbes that live on and in your body? Over the past decade plus, we have seen an incredible explosion of research that has really connected the functional capacity of these microbes, particularly those that live in your gut, with human disease and their ability to modulate very specific pathways. At Seres, we built a platform that enabled us to look at that at very, very high resolution and then to actually design drugs which are actually consortia of bacteria, so collections of bacteria that we designed to have very specific functional properties. In the context of SER-155, as an example, that drug was designed to have the following pharmacologies. One was to basically decolonize pathogens in the gut that are problematic in these patients. Two is to actually repair and protect the epithelial barrier. At the company, we have found a set of microbes that produce metabolites that are very potent at doing that, and as well, there are bacteria in there that have an impact on immune pathways. Seres has developed these drugs, and we have a track record of success. As you pointed out before, we've brought VOWST all the way from inception to commercialization. We are developing innovative technologies, as evidenced by two Breakthrough Therapy designations, one for VOWST and one for SER-155. We feel like we're on a good track. What about manufacturing? Is there any special know-how to produce these microbiome therapies? Sure. There's a lot of unique skills and capabilities that are needed. Again, we're dealing with bacteria that many people haven't cultivated or worked with before. It really starts with our ability to actually cultivate these bacteria and know how to grow them. We have developed over the years with the FDA CMC processes that have allowed us to advance this novel therapeutic, again, from inception all the way through to commercial launch. What we've done with VOWST carries through to and will benefit us in the context of 155. I think a couple of important things I would point out is, one, setting that regulatory precedence. Two is basically, as I noted, dealing with bacteria that many people have never even cultured before in the world. The identity, purity, and potency assays that are needed, as well as then formulations that carry through to long drug stability, et cetera, which are all benefits as you start to think about cost of goods, et cetera, of our drugs. That's really helpful background. Now, Seres' lead program is SER-155 in the allo-HSCT. Can you describe the unmet medical need that SER-155 would address in these patients and the infection risk that these patients face? Absolutely. Let's start by discussing why this problem exists for these patients. Stem cell transplant patients undergo a number of chemotherapy regimens and conditioning regimens that prepare their body to receive the transplant. Unfortunately, this combination of regimens is hugely destructive, not only to the immune system, but to the environment within the gut and the ability of the barrier in the gut to remain intact. What happens as a result is that you have bacterial overgrowth, in particular of bacterial bad actors, that because the barrier is compromised, can then translocate across the barrier into the bloodstream and wreak havoc in these patients. This is a frequent problem. We see reports of roughly in the neighborhood of 4%. That infection rate is on the background of standard of care antibiotic prophylaxis. We saw a similar rate in our phase Ib study in the data. We are seeking to cut that infection rate in half. The other thing I would say about that infection rate is that it's growing as a result of the widespread adoption, particularly in the U.S., of post-transplant cyclophosphamide, which is a regimen that is used to address another complication called graft-versus-host disease. That was recently adopted. There was a data readout a few years back, and the vast majority of transplant centers have incorporated that into their treatment protocol. As a result, infection rates are rising even above the background rate that I referenced. It's a big problem. It's growing. It's frequently fatal because these patients are already so brittle. In fact, infection is the leading cause of death, ranking just behind the cancer itself. I guess the other thing I would say about unmet need is that when we talk to our key external stakeholders, for example, HCPs and U.S. payers, three things emerge. One, they're highly aware of the issue. They're very concerned about the issue. You can see the rating scales we used in our corporate deck and the actual ratings that were given in the studies we conducted. Thirdly, they react very positively to the profile for 155 and say, for a product like 155, we would incorporate that into our treatment protocols as quickly as we could get our hands on the product. Big unmet need, we think we have a really nice solution. Yeah. That's a perfect segue into the phase Ib clinical data that you've reported to date. Maybe you can share that with us. Sure. I'd be happy to. It was very promising data in our phase Ib, which had a placebo-controlled cohort. In that cohort, we saw a 77% relative risk reduction in bloodstream infection between active and placebo. We also saw lower antibiotic use and lower incidence of febrile neutropenia. All indicating positive benefits. It has been very well received by KOLs that we've engaged with, both here in the U.S. where the study was conducted, as well as in Europe. For example, at EBMT, Tandem, and most recently at IDWeek, we've had significant levels of engagement and interest in participating in the phase II study. Importantly, the results were also informative to the FDA in terms of the Breakthrough Therapy designation that we received, which has led to kind of constructive and meaningful interaction with FDA. Importantly, we also have very strong biomarker data that supported the clinical data that we saw. I am going to ask Matt to elaborate a little bit more on what he and his team interrogated and concluded from that. Sure. As I led off with before, 155 was really designed to go after multiple mechanisms of action, one that decolonization of those pathogens in the gut, repairing the barrier, as well as modulating systemic immunity. The SER-155 phase Ib study was a translation study. We were quite excited to actually see clinical translation of all three of those mechanisms of action in the study. We saw reductions in fecal albumin, which is a marker of epithelial barrier damage, where we saw significant reductions of that in patients on 155. We even have data that indicates that it protected from chemotherapy-induced damage, which provides as well thoughts about how you can more broadly think about this drug. We as well saw signals at a systemic level, so not just locally in the gut, where we saw reductions in TNF-alpha, interferon-gamma, IL-17, IL-8, all important markers and trending in a direction of inducing immune homeostasis. We were pretty excited to see those particular results. Both of those sets of results really set us up as well to think more broadly about where we take our technology, particularly in the context of immune-related diseases. Yeah. That's really helpful. And congrats on breakthrough designation. Marella, you guys announced constructive feedback from FDA on the planned upcoming phase II study. Can you provide us some details on sort of what that would look like? Sure. We have had, as I said, very constructive dialogue with the FDA, which has informed the design of our phase II. We are in the latter stage of finalizing that protocol right now. Importantly, the FDA agreed on all of the key design elements, such as the primary endpoint being reduction in bloodstream infections 30 days post allo-HSCT, the stem cell transplant, also the study size, the dosing regimen, and importantly, the interim analysis that we proposed. That was a key element of the study design. The study is estimated to be about 248 patients. The interim analysis, which will be when we are roughly 50% through the population primary endpoint, will be super informative on a couple of measures. Firstly, it will allow us to engage with the FDA on the pivotal study. For example, if there's overwhelming efficacy at that IA, we can speak to FDA about converting the phase II potentially to a registrational study or suspending the phase II at that point and planning and entering into a pivotal study. We are looking forward to that engagement. The IA will be roughly 12 months after the study starts. It is a reasonable timeframe to get meaningful data and to be able to engage. The other piece, not just on the allo-HSCT indication, would we engage with FDA, but also potentially adjacency and other indications, because there is a plethora of different patients who are, due to, as Terri noted, either the conditioning, their treatment for their underlying disease, et cetera, are very vulnerable to bloodstream infections. It is a big problem. One point I want to emphasize in the phase I, we had very good safety data. I mean, the bacteria is commensal bacteria, so you would hope for that. We did have placebo-like safety outcomes in our phase Ib. Yeah. That's really helpful. Before we go to some of those other opportunities, Terri, can you lay out the commercial opportunity for 155 in allo-HSCT? Of course. I'll hearken back to a couple of my previous remarks around the unmet need being high and also the very positive reaction we had from our key stakeholders, HCPs, and even payers with respect to the profile of 155. Those two dynamics, along with two other dynamics that I'll talk about momentarily, I think could give us a very nice tailwind at approval and launch. The other two dynamics that are important is that there are 40,000 of these transplants annually estimated across the globe. They're conducted in a small subset of oncology centers. It's a very tight commercial footprint that we need. It's a very efficient business for us to go get. We can reach and educate these HCPs very rapidly. The fourth aspect is the fact that this is a protocol-driven care delivery system. Basically, each center has what I think of as a recipe book for each patient. It is very prescribed in terms of what treatments are utilized, what chemotherapies are utilized, and what is given and when. The HEMOCs tell us that they can rapidly review a new product and incorporate a new product into those protocols at launch. All of these dynamics give us a great opportunity at launch for rapid and broad adoption across the centers. What do you think about pricing? In terms of pricing, these patients are very, very expensive. A stem cell transplant has been estimated at $400,000 in the U.S. per patient. When an infection occurs, I talked about how brittle the patients were. A lot of times, they're being driven back into the hospital. It's an incremental roughly $200,000. It is not insignificant. That is hitting the hospital's DRG in terms of reimbursement. What payers have told us about 155 is that it will be dispensed in the outpatient setting and therefore reimbursed through the outpatient pharmacy benefit. If you're a hospital, you've got great financial incentives to add 155 to your protocol because you're getting rid of that incremental $200,000 in 40% of your transplants because that's the infection rate. You do not have to pay for it. It's being paid by a completely different payer body. We've got a really strong value proposition with the profile that we have, very costly patients. That sets us up very nicely for a premium price. We've been watching Merck's product, PREVYMIS, with interest. PREVYMIS is a product that's approved in this exact patient population, but to prevent viral infections. There are three things I'll mention about PREVYMIS. Number one, it's doing very well. It grew 30% from 2003 to 2004. It's north of $700 million in net sales, worldwide net sales. It didn't launch that long ago. We hear nothing from HCPs or payers in terms of management of that product or problems accessing it for patients. Where's that price just comparatively, do you know? About $25,000-$27,000. It's dose-dependent, which is why I'm giving a range. Yeah. That's really helpful. Beyond allo-HSCT, what are other areas that you're considering for developing SER-155? You mentioned the broad applicability of this therapy. What would you think would be the triggers to pursue these other indications? Sure. One of the things that struck me when I first started engaging KOLs about SER-155, and this is going back three, four years ago, is they proactively shared with me very early in the interviews that this modality was being discussed at the congresses that they were going to. There is already an understanding of the applicability of the MOA of 155 in this patient population for allo-HSCT. They proactively educated me to say, "Yes, you could use it in allo-HSCT, but this MOA also applies in all these other patient populations I treat, for example, autologous transplants, for example, the broader hematologic malignancy and cancer population who are undergoing chemo regimens and difficult regimens that in the same way compromise the immune system and the composition in the gut and the barrier." This is a very relevant mechanism. If you look at autologous, that's an incremental 60,000 worldwide cases annually. If you look at the broader cancer population, that's 500,000. Even beyond oncology, there are clearly patient populations who are in the same boat where they're immunocompromised and/or they're in an institutional setting where they're exposed to nefarious pathogens that we could help, for example, patients in the ICU, patients in long-term care. We're excited about the opportunity. You asked about the trigger. Maybe Marella could dig into that a little bit. Yeah. As I mentioned earlier, we definitely will be engaging with the FDA at the interim analysis. Certainly something like autologous transplant would rise to the top in terms of an adjacent population. Other indications that would have broader or different applicability would really be driven by commercial opportunity, our strategy, depending upon how we finance the phase II, what does a potential partnership structure look like. Really, the opportunity is multi-billion dollar. We're looking forward to that interim data to help inform that. I know one of the programs outside of infection is along the lines of mucosal barrier immune disruptions. Tell us more about the investigator-sponsored trial that you guys are running in checkpoint-related enterocolitis. What specifically is this firstly? Maybe you can tell us about the impact you're having there. Sure. I can speak to that, Ted. Yeah, we've launched an investigator-sponsored trial in collaboration with longtime collaborators and partners at Memorial Sloan Kettering. Immune checkpoint inhibitors are, as many of you probably know, one of the primary cancer treatments used today. Those cancer treatments are a T-cell biology-based treatment. What we've learned is that there can be severe adverse events that can happen in patients undergoing ICI, particularly that's linked to T-cell biology and epithelial barrier integrity. Those, of course, are two particular areas where 155 mechanisms are specifically targeted, which we have strong preclinical and, as I said earlier, now clinical translational data in the context of allo-HSCT patients. These patients who undergo ICI treatment and develop irEC, it can be quite debilitating. They develop diarrhea in particular. That diarrhea can be quite severe, ranging from kind of all the way from something that will basically hospitalize you to actually kill you. There is an entire range of that. You can have all kinds of other complications, such as perforated colons, major cramping, et cetera. What we are targeting with Memorial Sloan Kettering is a study that is an open-label study that is targeting, evaluating immune-related enterocolitis and essentially diarrhea as an endpoint. We would see success in this trial if we saw a decrease in diarrhea and/or a decrease in corticosteroid use. Current standard of care in these patients is corticosteroids, which, of course, are immunosuppressive. That has a problem because it can actually suppress the cancer treatment itself. The other thing I should point out is this adverse event of diarrhea can be so disruptive that it actually requires patients to come off their cancer treatment. We are also looking at that as well to see if we keep more patients on treatment. That's really interesting. Now, you guys recently unveiled SER-603 to treat UC and Crohn's disease. I've known the company for a long time. I remember you guys were working on this a while ago. Maybe describe 603 and how it's different from earlier attempts. Yeah. Sure. You're right. We've worked in UC from the early days of the company and brought even some other assets into the clinic, as you know. We've really advanced as a company. That was a very early-stage program at the company. We've learned a lot from it as well as all of our other work. A couple of key differentiators between our prior work and now. One, as I talked about earlier, we've been continuing to advance what we call our MbTx platform. Why is that important? We have the ability now as a company to really define specific relationships between specific bacteria and the actual metabolites they produce and the pathways that they're modulating. Why does that matter? It allows us to now design drugs that have increased potency in a way that we couldn't do before. Second is we've been doing a lot of work looking at patient heterogeneity. Particularly in the context of IBD and ulcerative colitis and Crohn's disease, patients are notoriously heterogeneous. Not all patients respond the same to different therapeutics. Actually, through funding from the Crohn's & Colitis Foundation, we have now identified a set of unique microbiome-associated biomarkers that can actually predict response, not just to our own therapeutics, but actually to any advanced biologic. In addition, as I pointed to a little earlier, our prior drug, SER-287, was donor-derived in an early-stage program. Like I said, we can now deliver our drugs in a much more potent way and with much more targeted biology. In a nutshell, we're targeting the right patients with a more potent drug. Essentially, we've advanced that program to the point where we now have preclinical data that can demonstrate that basically SER-603, both as a monotherapy as well as in combination with advanced biologics, can lead to important benefits from efficacy. That's great. When do you think you could get into the clinic? Is this a program you'd likely partner? We are having partnership discussions for all the reasons that Matt mentioned in terms of patient targeting and improving efficacy as a combination therapy. We are having constructive discussions right now. It is something that makes sense to, because of those potential opportunities, to consider for partnership. We are aimed right now at a research collaboration, which would ultimately be the basis for entering into the clinic. Matt, maybe you can outline a little bit about what some of our goals are of an early-stage research. We are actively engaged with a couple of potential partners around a research collaboration. The key features of such a partnership would really be, one, to take those biomarkers that I was talking to you about and deploy them in the context of multiple of their patient population therapeutic modalities. In IBD and Crohn's, there is a well-known efficacy ceiling, right? Drugs are not getting higher than that, right? We believe we know why that is. The partners are very interested in working with us to actually understand if we can boost efficacy numbers in their potential patient populations where they're seeing lower response rates. That's one. The second dimension of it is to then bring forward SER-603, right, in the context of a combination therapy with their therapeutics because we do believe we can both boost efficacy and actually increase durability. That's the other big problem in these patients. A lot of drug switching has to happen in IBD patients because they lose efficacy. We have data now that suggests we could increase durability in those responses. Very cool program. With the minute or so we have left, Seres ended the third quarter with $48 million. You guys have subsequently been tapping the ATM. I think you now have over $50 million. How long does this fund the company? What's it enable you to accomplish? Sure. It funds the company through the second quarter of next year. Right now, our financial and people resources are primarily focused on advancing the phase II for 155 preparatory activities. We have selected a CRO. We are doing study startup activities such as site engagement and feasibility analysis. We are also manufacturing the clinical trial material. Our goal would be to be operationally ready pending the receipt of financing to really be able to get into the clinic in the phase II as quickly as possible. Great. Excellent. Thank you so very much. I appreciate it, Marella. Thank you so much for having us. Appreciate it.