Synlogic, Inc.

Good morning, and welcome to CineLogic's second quarter 2021 conference call. At this time, all participants are in a listen-only mode. Later, there will be a question and answer session at the end of this call. Please be advised that this call is being recorded. I would now like to turn the call over to Daniel Roseanne, Head of Finance and Investor Relations. Please proceed.

Thank you, Operator. Good morning, and thanks for joining us on today's conference call. This morning we issued a press release which outlines our second quarter 2021 financial results and additional business updates. The release is available on the investor section of our website at SynlogicTX.com. Joining me in this call are Dr. Aoife Brennan, President and Chief Executive Officer, and Dr. David Hava, Chief Scientific Officer. Other members of the management team will also be available during the Q&A. This morning Aoife will provide a review of second quarter highlights and recent progress, Dave will share the latest advancements in applying our synthetic biotic platform to phenylketonuria, and IFA will then return to provide an update on our metabolic portfolio, including enteric hyperoxaluria. Finally, I will summarize our financial results for the quarter. Following our prepared remarks, we will open the call for your questions. As we begin, I'd like to remind everyone that comments today may include forward-looking statements made under the Private Securities Litigation Reform Act of 1995. These forward-looking statements are made as of the date hereof and are subject to numerous factors, assumptions, risks, and uncertainties which change over time. Actual results could differ materially from those contained in any forward-looking statement as a result of various factors, including those described under the heading forward-looking statements in Synlogic's press release from earlier today or under the heading risk factors in Synlogic's most recent Form 10-K or in later filings with the SEC. then logic cautions you not to place undue reliance on any forward-looking statement. Now, I'd like to turn the call over to Issa.

Thanks, Dan. Good morning, everyone, and thank you for joining us. I'm thrilled to share with you today updates on our recent execution and progress across the portfolio, as well as our financial results from the second quarter of 2021. Before we dive in, and as I'm sure you're already aware, I wanted to first thank Dr. Richard Rees for all of his contributions over the last few years serving as Synlogix Chief Medical Officer. We wish Richard the best in his new endeavors. As our programs continue to build momentum, we remain in good hands with a highly experienced executive team. I'm personally excited to tap into my CMO roots as we initiate a search for a CMO who can lead our growing clinical development organization and shepherd our programs as they transition to later phases of development. Now back to the business. We're executing on our plans to demonstrate the clinical potential of our synthetic biotic platform in 2021. With proof of mechanism established in our two lead metabolic programs, a strengthened balance sheet, and an exciting new partnership, we are well positioned to deliver proof of concept in multiple high-value indications. Like all companies with ongoing clinical studies, we continue to watch the impact of the COVID-19 pandemic and particularly the Delta variant carefully, especially on clinical sites in the southeastern United States. We're pleased that our team continues to execute with the singular goal of developing synthetic biotic medicines which provide meaningful treatments for patients with serious diseases. Let me turn to those programs now. I'll begin with our PKU program. We believe patients living with PKU continue to need additional treatment options to manage this devastating disease, and we believe that an efficacious oral therapy, regardless of genotype, remains one of the most attractive clinical profiles. This is why we've been executing on our plan to evaluate our lead PKU candidate, CINB1618, in a Phase II clinical study we call Symphony. We're thrilled to recently publish the compelling proof-of-mechanism results for our Phase I study of CINB1618 in nature metabolism, and the Symphony study is on track to deliver data later this year. This quarter, we also took another important step forward by initiating the phase one study of CINB 1934. CINB 1934 is an evolved strain of CINB 1618. And in a moment, Dave will tell you more about the science behind our PKU program. Let me tell you why we developed CINB 1934. It's because we never stopped asking the question, how much more efficacy can we deliver for patients? Synthetic biology tools are progressing rapidly, and our team has access to the best of those tools both internally and through our network of collaborators. By deploying a new suite of directed evolution tools to SynB 1618, we were able to generate a candidate which may have even more fee-consuming capacity and move rapidly into the clinic. In enteric hyperoxaluria, we also see a significant opportunity to make a meaningful difference in the lives of patients. CINB 8802, our other lead metabolic program, is designed to consume the toxic metabolite oxalate in the GI tract in patients with enteric hyperoxaluria, a leading cause of oxalate nephropathy and recurrent kidney stones for which there are no approved therapies. As we previously communicated, CINB-8802 has demonstrated the ability to consume oxalate in the GI tract of healthy volunteers, exhibiting a robust and dose-responsive urinary oxalate reduction. We are now evaluating the oxalate-lowering potential of CINB-8802 in a Phase Ib study in patients with enteric hyperoxaluria following Roux-en-Y gastric bypass surgery. This study gives us an opportunity to demonstrate a highly clinically attractive profile. We are taking the learnings from our co-lead metabolic program and applying them to novel approaches to address other diseases in which a GI-based approach may be relevant, including inherited and acquired metabolic disorders, as well as autoimmune conditions. We recently entered into a research collaboration agreement with Roche, for the discovery of a novel synthetic biotic medicine for the treatment of inflammatory bowel disease, or IBD. IBD remains an area of high unmet need in which new approaches are urgently needed. We're delighted to be working with an organization with unparalleled depth in immunology and look forward to exploring the potential of synthetic biotic medicines in IBD. Our team has done a tremendous job executing across multiple programs, during what continues to be trying times for all of us in 2021. This resilience and teamwork have set the stage for multiple meaningful readouts in 2021. Thanks to our careful capital stewardship, these milestones occur well within our cash window. In summary, 2021 has been an incredibly exciting year for the company. We now have demonstrated proof of mechanism in humans from both our lead metabolic programs in PKU and enteric hyperoxyurea. We initiated a phase one study of a next generation strain in our PKU portfolio and initiated an exciting new partnership in immunomodulation. We have the opportunity to demonstrate proof of concept in our co-lead program and advance our mission to bring the transformative power of synthetic biology to medicine. Now, let me turn the call over to Dave to go deeper into our PKU program. Dave?

Thank you, Aoife. It's my role today to share the exciting science which underpins our PKU program and our next generation strain, SYNB1934. Before I do, let me remind you of the challenges faced by PKU patients and caregivers. PKU is an inherited metabolic disease in which children are born without the ability to metabolize phenylalanine, or Phe. Consuming even modest amounts of dietary Phe causes irreversible neurocognitive deficits in patients with PKU. Despite the availability of dietary management and approved treatments, a large proportion of patients struggle to maintain blood feed levels in the target range required to avoid this irreversible damage. It is clear to us that both current and emerging treatment options continue to leave too many patients behind. And so we have set as our target product profile a safe, tolerable, reversible, and oral therapy, which would reduce plasma fee levels for PKU patients regardless of underlying genotype. The scientific hypothesis behind our approach is quite simple. It is well understood that reducing the dietary consumption of phenylalanine reduces plasma fee levels in patients with PKU. Our team has built on that biology to introduce a synthetic biotic medicine into the GI tract, which is specifically designed to consume fee and break it down to produce TCA and HA. TCA, or transcinnamic acid, is cinnamate. HA is a further breakdown product of TCA. Both are generally regarded as safe substances which are harmlessly excreted from the body. These measurable biomarkers, TCA and HA, are key because they allow us to determine the fee-lowering potency of our strains in a consistent manner. across in vitro, in vivo, healthy volunteer, and patient studies. As you know, our first generation PKU candidate, CINB 1618, has shown promising activity with dose-dependent increases in TCA seen in healthy volunteers. This indicates that the strain is consuming fee in the GI tract at escalating levels that correspond closely with how much CINB 1618 were administering. Based on this observation, we have moved CINB 1618 into Phase II clinical development. However, our scientific team at Synlogic has continued to ask how much fee-consuming activity can we engineer into a synthetic biotic medicine, especially as synthetic biology tools have advanced rapidly in the time since 1618 was engineered. That curiosity led us to CINB 1934, a strain that has been evolved from CINB 1618 with the potential to provide increased fee-lowering efficacy for patients living with PKU. Preclinical in vivo and in vitro studies demonstrated a greater than two-fold improvement in the ability of CINB 1934 to consume and break down fee compared to CINB 1618. CINB 1934 was developed using a directed evolution approach, using a biosensor engineered into a tool strain, which was designed to respond to TCA. This allowed us to generate hundreds of variants of the fee-consuming enzyme PAL and to test their whole cell activity in a translationally relevant environment. After multiple rounds of selection, we chose the top candidate strains and confirmed their increased activity in simulated GI compartments in vitro and in vivo in non-human primates, which is the most predictive animal model for humans. This approach resulted in a doubling of fee-consuming activity between CINB 1934 and CINB 1618, which we are now seeking to confirm in phase one. This rapid progression of CINB 1934, which went from candidate selection to first in human dosing in less than eight months, demonstrates the speed and power of our synthetic biotic platform. While we evaluate CINB 1934, We also continue to progress the Symphony I Phase II proof of concept study with utmost care and attention. Our goals in this study are to demonstrate the potential of CYMB1618 to lower blood fee in adult PKU patients and to validate our pharmacodynamic model to better understand the relationship between the strain biomarkers we have spoken about and plasma fee lowering in a disease setting. Patients in Symphony have no therapeutic options They are ineligible, inappropriate for, or unresponsive to existing therapies. These are patients left behind by today's limited treatment options. The study is powered to detect 20% reduction in plasma fee. PKU patients and investigators tell us that 20% fee reductions in an oral, tolerable, and reversible therapeutic, which is effective for Cuvon non-responders, would be a welcome treatment option. In summary, the Phase I Multiple Ascending Dose Study of CINB1934 will evaluate the safety, tolerability, and feed consumption activity of CINB1934, including a head-to-head comparison with CINB1618 in healthy volunteers using biomarkers of feed consumption. Based on the data from the head-to-head comparison, as well as results of the ongoing Phase II study of CINB1618 in patients with PKU, Synlogic plans to select one therapeutic strain for late-stage development. Data from both studies are expected by the end of 2021. The willingness of advocates, caregivers, and patients to engage with us and other sponsors is critical to advancing new treatment options for this devastating disease. We want to thank them for their partnership. Let me now turn the call over to Aoife to share progress in enterokyproxylurea.

Thank you, Dave, and congratulations to your team on the tremendous progress in bringing potential new treatments to patients with PKU. Now, let me turn to our co-lead metabolic program, SINB 8802 in enteric hyperoxaluria. Enteric hyperoxaluria, which we just call HOX, is a devastating condition with no treatment option in which dangerously high levels of urinary oxalate lead to progressive kidney damage. It often occurs as a result of a primary insult to the bowel leading to fat malabsorption, such as inflammatory bowel disease, short bowel syndrome, or as a result of surgical procedures, such as bariatric weight loss surgery. If left untreated, the dangerously high levels of urinary oxalate cause recurrent kidney stone formation, nephrocalcinosis, and progressive damage resulting in chronic kidney disease. Since oxalate is present in many healthy foods, Enteric hyperoxaluria is almost impossible to control with diet alone. That means these patients are at risk for serious kidney complications. For most patients, enteric hyperoxaluria isn't a standalone problem. Because the pathogenic absorption of oxalate is a result of an underlying bowel disorder, this means in clinical practice, it is patients who already have the complexity of living with short bowel syndrome, chronic pancreatitis, IBD, or who have undergone bariatric surgery, who now have to face the devastating challenge of recurrent and chronic kidney stones. In this patient population, the pain and disruption of recurrent kidney stones is a significant challenge in their overall care. There are approximately 75,000 to 90,000 patients with enteric hyperoxaluria and recurrent chronic kidney stones, a high risk of significant kidney damage in the United States. They have no treatment options today, and we believe the synthetic biotic platform could provide a meaningful new approach. Meeting the needs of this population led us to develop CYMB-8802, an oral synthetic biotic medicine which metabolizes the toxic substance oxalate in the GI tract and converts it into formate, which is harmlessly excreted from the body. As you may recall, we have demonstrated 8802 proof of mechanism in a dietary hyperoxyurea study. We have now moved to Part B of that study in which CINB 8802 will be evaluated for the potential to lower urinary oxalate in enteric hyperoxyurea patients. Let me walk you through both parts of this study. The primary outcome of Part A of the Phase 1 study was safety and tolerability which would be used to select a dose for further study in patients with enteric hyperoxiduria in Part B of the trial. We completed dosing of five cohorts in Part A of the study. In the efficacy analysis, the percent change for baseline urinary oxalate levels was 28.6% compared to placebo at the 3E11 live cell dose, a clinically meaningful level of oxalate degradation. This dose was well tolerated and is being used in Part B of the study. Similar to our prior programs, we did not observe any systemic toxicity, and there were no SAEs or serious adverse events at any dose. Adverse events were generally mild to moderate, GI-related, and transient. We found that a dose ramp significantly improved the tolerability profile. CINDY-8802 is a non-colonizing, non-reproducing strain and cleared from subjects after cessation of dosing. We were thrilled to see substantial urinary oxalate lowering across multiple dosing cohorts. This consistent and dose-responsive result is very encouraging. In Part B of the study, patients with enteric hyperoxaluria post-RUON-Y gastric bypass surgery who have dangerously high levels of urinary oxalate will be assessed in a crossover design. We have chosen a dose of 3E11 live cells for Part B of the trial. We believe this dose could provide a clinically meaningful reduction in urinary oxalate levels in this population. In parallel, we will also continue to evaluate CYMB8802 in additional cohorts of healthy volunteers as we explore further optimization of dose and dose frequency. Overall, this study will inform an enormous amount as we progress CINV8802 through clinical development. We will better understand not only the activity of CINV8802 in dietary hyperoxaluria disease model, but also in patients with enteric hyperoxaluria itself, as well as the degree of colonic activity and the potential for less frequent dosing. Moving forward, we believe the regulatory and clinical path in this indication is relatively straightforward. with significant precedent by sponsors in related diseases, such as primary hyperoxaluria, for the importance of urinary oxalate as one critical endpoint. Our initial efficacy assessments will evaluate clinically relevant reductions in urinary oxalate levels, and feedback from our key investigators suggests greater than 20% lowering in patients would be clinically meaningful. Lowering dangerously high levels of urinary oxalate is the only way to reduce the risk of disease progression and reduce or eliminate oxalate nephropathy. We're pleased that CIMBY 8802 has demonstrated the potential to lower urinary oxalate levels in healthy volunteers with dietary hyperoxaluria. We're looking forward to advancing the program rapidly into patients and providing additional data later this year. As we move forward with both of our lead metabolic programs in PKU and enteric hyperoxiduria, I will come back to you with more information as the studies unfold. Now, let me hand the call over to Dan to briefly run through our financial results. Dan?

Thank you, Lisa, and good morning, everyone. This morning, we released our financial results for the second quarter, ended June 30, 2021, and I'd like to review the highlight of those results with you now. Research and development expenses were $10.7 million for the three months ended June 30, 2021, compared to $12.9 million for the corresponding period in 2020. The R&D expense for the three months ended June 30, 2021, consisted primarily of costs related to our collaboration with Ginkgo Bioworks for the optimization of synthetic biotic medicines, as well as clinical study activities associated with CINB 1618 and CINB 8802, the ongoing CINB 1891 Phase 1 study, and the initiation of the CINB 1934 Phase 1 study. General and administrative expenses were $4.1 million for the second quarter of 2021, compared to $3.5 million for the same period in 2020. For the second quarter of 2021, the company reported a consolidated net loss of $14.5 million, or 28 cents per share, compared to a net loss of $15.5 million, or $0.44 per share for the corresponding period in 2020. Revenue was $0.2 million for the second quarter of 2021 compared to $0.4 million for the same period in 2020. Revenue was due to the recently initiated collaboration with Roche for the discovery of a novel synthetic biotic medicine for the treatment of IBD. Now, turning to the balance sheet. Zoologic ended the second quarter of 2021 with $115.5 million in cash, cash equivalents, and short-term investments, compared to $100.4 million as of December 31, 2020. Under our current operating plan, we expect our cash and cash equivalents will be sufficient to fund the company through the second half of 2023. This will enable Synlogic to advance our clinical programs through important data readouts over the coming months. Thank you for your attention. and we look forward to keeping you updated on future calls. I'll now turn the call back over to Aoife to wrap up.

Thank you, Dan. Our team has made tremendous progress across all of our programs, both in and outside the clinic. We're executing effectively and with a sense of urgency. We look forward to demonstrating proof of concept in our co-lead programs in PKU and enteric hyperoxaluria later this year. We will now open the call for questions.

Thank you. To ask a question, you'll need to press star 1 on your telephone. To withdraw your question, press the pound key. And our first question comes from Ram Savaraju with HC Wainwright. Your line is open.

Hi, this is Irma speaking on behalf of HC Wainwright. Thanks for taking our questions. So in terms of the Symphony I Phase II trial for 16-18 and the Phase I for 19-34, can we expect a combined data release at the same time later this year, together with your announcement of your selection for one of the compounds for development?

Yeah, so thanks so much for the question. It's very difficult for us to predict exactly when those readouts will come. We know that they're both on track for the second half of this year. I think it really will depend on how exactly the timing falls, whether we can make a single announcement or would have to do two separate announcements. So I can't give you a straight answer to your question other than to let you know that they will fall soon. within the second half of this year, if all continues to plan.

Okay, makes sense. We were just curious. And if 1934, you know, is indeed selected, what kinds of bridging studies would need to be done to move to a pivotal status? And is the formulation of 1934 already optimized or not?

Yeah, so the... The nice thing about 1934 is it's very similar to 1618. We use the same enzyme pathways. It's just with an optimized version of the gene for PAL. So we were really able to leverage a lot of the work that we had done for 1618 as we were developing 1934. I think that's evidenced by how quickly it moved from clinical candidate to IND to being in the clinic. And we anticipate that it will continue to benefit from kind of having a lead program that's very, very similar. Right now, the phase one study is being done with a Lyo formulation of 1934. So we were able to go into the clinic with already kind of having taken that big step to Lyo. And we anticipate that it will move very, very quickly thereafter. In terms of what we would need to do before initiating the phase three study, should we decide to switch to 1934, We haven't provided a lot of guidance in terms of the specific steps. Suffice it to say that we think that it can move very, very rapidly because of being able to take advantage of all of the learnings we've had with 1618. And of course, you know, any regulatory plan would be subject to agreement with the FDA and other regulators. So that's kind of all we can say at this time.

Okay, thanks for the clarification. And just finally regarding business development, the recent gastroenterology collaboration with Roche, has this triggered any interest and momentum for further partnership opportunities?

Yeah, so the Roche agreement is very exciting for us. We're absolutely thrilled. It's exactly the kind of deal that we want to do in inflammation and immunomodulation generally. As we've disclosed, the Roche collaboration was around a single specific target that that organization are interested in based on their research in immunology. Obviously, we will continue to advance our own programs that Dave's group are working on and continue to have discussions with potential partners around the same kind of area broadly. Dave, anything you want to say about the immunology strategy, just more broadly to add to my comments there?

Yeah, sure. I mean, I think you've summarized it well. I mean, I think we still believe there's a lot of biology that we can unlock using the platform. We have a number of internal programs that we're working on at the preclinical stage, and those will be opportunities to explore either additional partnerships or to advance our own pipeline as those mature. So, I think it's all pretty consistent with the strategy we've been following, and we're excited about the Roche agreement and that as a highlight of kind of that strategy going forward.

All right. Thanks very much for taking our questions, and congrats on the exciting developments in the pipeline.

Thank you.

Our next question comes from Joseph Schwartz with SVB Lyric. Your line is open.

Hi, I'm Jury dialing in for Jill. Thank you for taking our questions. My first question is on CINDI 8802. I was wondering if it could help frame how we should be thinking about the Phase 1 Part B data in patients with EHOCs resulting from gastric bypass surgery when it becomes available. How representative is this group from other manifestations of EHOC, such as inflammatory bowel disease and celiac disease? You know, are there any biological considerations we should be taking into consideration about this group, or is this a fairly good representative of the overall EHOC population?

Yeah, thanks for that question, Jory. Number one, I would say that our goal is to develop a product for patients with severe enteric hyperoxyluria, regardless of their underlying GI disease or condition. So that's, you know, our target is that segment of patients with enteric hyperoxaluria, recurrent stones that are really having a very high burden of disease for whom there's currently no treatment. Based on the precedents and others who have done work in this area, we don't believe that there's going to be a difference based on the underlying GI insult that has occurred. You know, when we've looked at prior studies that have been done in this indication, what we see is very similar and consistent treatment effects across all of the underlying GI kind of conditions. We made a decision to focus in on a kind of relatively homogeneous group to get proof of concept. I think that was kind of a development tactic. It doesn't necessarily indicate that we'd be pursuing a very, you know, a narrow group or a narrow underlying GI etiology as we move forward in development. In fact, I think The next step in the development program would be for us to evaluate efficacy in a much broader population, including patients with some of the diseases you just mentioned there, like inflammatory bowel disease or bowel syndrome, chronic pancreatitis. I think there's a lot of diseases that can result in enteric hyperoxyuria, and we plan to pursue all of them.

Okay, great. Thank you. That's super helpful. And then my second question is kind of building on our earlier one. So wondering if you had any color in the order in which we will see your HOCS program relative to your PKU program.

Yes, unfortunately we get asked that frequently and we don't have sufficient line of sight to be able to provide guidance around the specific order. Both are on track for results in the second half of this year. in terms of which way they'll fall from a sequence perspective, we just don't know.

Okay, great. Thank you for taking our questions. Thanks, Geri.

Thank you. Our next question comes from Mark Bridenbach with Oppenheimer. Your line is open.

Hey, good morning, and thanks for taking the questions. Just looking at the Symphony protocol, I'm remembering that you ramp up to dose levels that are about an order of magnitude higher than the previously established MTD for 1618. And I'm just wondering if you can remind us what's giving you confidence that you can safely dose up to those levels in Symphony. And with respect to the upcoming 1934 data later this year, will that be inclusive of both healthy volunteers and PKU patients or healthy volunteers only? Thanks for taking the question.

Yeah, great, Mark. Thanks so much for giving me the opportunity to clarify the first point. So I think you'll remember that we did an early study with the liquid formulation of 1618 where we studied a small cohort of patients with PKU patients. The doses that we're currently using in the symphony study are a log higher than the doses that we previously used, approximately, with the liquid formulation in patients with PKUs. I think that's where the log piece comes. But they're not a log higher than the maximum tolerated dose. In fact, when we did the bridging study with the Lyo formulation in healthy volunteers, the maximum tolerated dose there was 2E12. So they're absolutely still within the tolerated dose range that we established in Healthy Volunteers with the Lyo formulation. They're just a log higher than the dose we used in the prior PKU cohort with the liquid formulation. So that's just a clarification there in terms of the safety and the dose that we're using in Symphony. In terms of the second part of your question around 1934, No, the current study is designed to evaluate 1934 head to head with 1618 and healthy volunteers. And we look at the production of the strain specific biomarkers to make a determination around whether 1934 is actually more active in humans compared to 1618. It will not include any data in patients with PKU.

Super helpful. Thanks for taking the questions.

You're welcome. Thank you. Our next question comes from Ted Tenthoff with Piper Sandler. Your line is open.

Great, thanks. Good morning, everybody. Thanks for the update. I really appreciate you guys laying out sort of the efficacy bar for Symphony in terms of what you're seeing as sort of a win.

And I'm wondering, you know, what would next steps be assuming positive data? Thanks.

Yeah, so I think... In the second half this year, we have data from Symphony as well as from 1934. I think the first step is going to be determining which strain of those two that we're going to take forward into the next phase of development. And I think then the next step from there will be planning and getting regulatory alignment around our phase three plan, as you would with any program. So starting that conversation with regulators in the regions globally that we would intend to commercialize the product and starting to plan for that kind of confirmatory phase of development as we move forward with the program. So that's the kind of the two steps, obviously a lot of work going into that second step, you know, preparing to move to phase three is not for the faint of heart, but in kind of the logical flow would be making a decision on which strain and then starting to kind of lay out the phase three plan and get engagement with the various stakeholders. Does that make sense, Ted?

Our next question comes from Kia Nikkei with Chardin. Your line is open.

Hi, yes, Kia Nikkei from Chardin. So, Eva, my question is for EH. You know, recently we saw another company who's developing a drug for primary hyperoxyluria show a failed result in the type 2 patients. And you guys have done a great job in prior presentations in explaining the differences in pathology and metabolic pathways for EH versus PH. But I guess the takeaway from that failed study in PH is, you know, just a lack of understanding of what they thought the pathway was prior to or versus prior knowledge. So how confident are you that you understand the pathway for EH and just building on that prior question in the different patients with different underlying insults?

Yeah, yeah. So I'm assuming you're referring to the diurena results, which showed nice activity in the type 1, but not the expected activity in the type 2, 3. So number one thing I'll say is we don't believe that that has any bearing on our program. You know, I think the primary is, as you mentioned, you know, very different disease due to a genetic liver defect, overproduction of oxalate. a number of different mutations that result in that kind of overproduction there. But, you know, we think it's a very, very different disease, a very different etiology, a very different underlying pathophysiology. What I will say about enteric hyperoxaluria is, you know, we have a pretty good understanding that it's due to overabsorption of oxalate. We know that these patients have fat malabsorption that results in a lot of free oxalate being available in the GI tract that then continues to be absorbed at a much higher rate than individuals who have a normal GI pathophysiology would be. So across all of the diseases, what they all have in common, pancreatitis, IBD, short bowel syndrome, is that they have this linking kind of underlying pathophysiology of having a lot of free fatty acids in the GI tract lumen. And based on our understanding of the pathophysiology of enteric hyperoxaluria, that appears to be the kind of unifying component of driving the elevated urin reoxalate levels. So I think that gives us confidence that we'll be able to kind of address that broader population regardless of underlying GI insults, but obviously the proof of the pudding is going to be in the clinical study once we, you know, assuming that we get nice results in Part B of the current study. Our next step would be to broaden to include, you know, some of those other GI diseases and to start to evaluate whether we get similar efficacy in that broader patient population, but As I said, based on what we know today about the pathophysiology and the precedence from prior studies in the enteric hyproxyurea population, we believe that there's a substantial chance we'll be able to address that broader group of patients.

Okay, great. And then just in terms of the homogeneousness of the bypass patients is something specific about that population that makes them more consistent versus some of the others, you know, within disease state?

Yeah, so the bariatric patients have all had similar surgery, right? So that's, you know, a nice component in that they'll be quite, you know, you try in early development, you're trying to do a smaller study and get as much information as you can out of you know, limited treatment numbers so that the more homogeneous they are, often the cleaner the signal is. You know, if you go out into different groups of patients, you're, you know, for instance, you're going into IBD, you know, could some of those patients have, you know, active inflammation within their GI tract? You know, could there be other, you know, con meds that you worry about? You know, so there's different things that you need to take into consideration as you look across broader patient populations. So it was really around you know, keeping it homogeneous as well as being able to, you know, execute a relatively straightforward study that led to that decision. But, you know, I think the next step, as I've mentioned, would be to broaden out and to look at different patient types as we move forward in development.

Okay. Well, thanks for the color on both those questions.

Pleasure.

Our next question comes from Tom Schrader with BTIG. Your line is open.

Hello, good morning. This is Sung Darling in for Tom. Just one question regarding the PKU program. So I know you have power for 20% reduction in phenylalanine. So regarding, like, patients, like, what does that mean for patients? Is a 20% reduction based on the low phenylalanine meals that a patient ingests? Thank you.

Yeah, so thanks for the opportunity to clarify that. Our current study is being done with patients who have blood fee levels that are greater than 600 millimolar. So they're patients who are not on a controlled diet or maybe they're semi-controlled but have elevated blood fee levels at baseline. We believe in those patients being able to reduce blood fee levels by 20% is meaningful. It may bring some of them down. into the less than 600 range. But really importantly for us, we think that this is a gateway to moving into other patient segments, including patients who are maybe on diet but not achieving their goal, or patients who are on a very strict diet but would really like to be able to eat additional protein. That's a particularly important consideration in the pediatric patients. We consistently hear from parents that in the pediatric group managing protein intake such that kids are getting enough so that they feel full, they're satiated, and they're growing normally is a real challenge with the very, very restricted diet that these kids have to be on. And when we kind of extrapolate what 20% fee lowering in adults who's uncontrolled could mean for pediatric patients in control, we estimate that that could mean being able to double the amount of natural protein that that kid is able to eat on a given day. which I think would be a huge boost to that kid from both a clinical and a quality of life perspective. So we really do see being able to demonstrate 20% fee lowering in the current population as kind of a step to further evaluation across patients with different clinical scenarios. and we'll continue to build that value story as we move forward in development and execute additional studies.

Thank you. That's very helpful.

Thank you, and there are no further questions in the queue. I'd like to turn the call back to Aoife Brennan for closing remarks.

Great. Thank you, Operator, and thank you, everyone, for joining us today. A very exciting year for us at Synlogic, and we look forward to keeping you up to date.

This concludes today's conference call. Thank you for participating. You may now disconnect.