Synlogic, Inc.

Good morning. Welcome to Synlogic's fourth quarter 2020 conference call. At this time, all participants are in a listening mode. 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 fourth quarter and full year 2020 financial results and additional business updates. The release is available on the investor section of our website at SynlogicTX.com. Joining me on this call are Dr. Aoife Brennan, President and CEO, Greg Beloff, Interim CFO, and Dr. Richard Reese, Chief Medical Officer, Dr. David Hava, Chief Scientific Officer, Tony Awad, Chief Operating Officer, and our newly appointed Chief Development Officer, Dr. Carolyn Kurtz, will also be available during the Q&A. During this call, IFA will provide a review of fourth quarter highlights and recent progress. Richard will provide an update on our metabolic portfolio, including our recent clinical update on SINB 8802 in enteric hyperoxyluria. And Greg will summarize our financial results for the quarter and year. 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. Synlogic cautions you not to place undue reliance on any forward-looking statement. Now, I'd like to turn the call over to Aoife.

Thanks, Dan. Good morning, everyone, and thank you for joining us. I'm thrilled to share with you today our financial results from 2020, as well as recent progress across our portfolio including the initial clinical results from our enteric hyperoxaluria program, SYNB 8802, which we announced yesterday. Across our programs and platforms, the groundwork of the last year has catapulted us into a data-rich 2021, with anticipated clinical readouts in three programs and increasing momentum in our research engine, focused on advancing additional clinical candidates. As we emerge from the winter months, Synlogic hasn't missed a beat. We've done anything but hibernate. We are rapidly progressing our metabolic disease pipeline, which leverages the ability of our platform to engineer synthetic biotic medicines and deliver them safely into the human GI tract to consume a toxic metabolite. We believe that there are a wide variety of disease states where this approach could transform patients' lives. Based on the initial readout from CINB 8802, which we will discuss in more detail in a moment, we now have two metabolic programs that have demonstrated the ability to consume a metabolite within the human gastrointestinal tract. Both programs have done so at levels that have the potential to be clinically meaningful in patients with disease. And in both cases, we have clinical trials ongoing in patients to demonstrate impact on critical endpoints, with readouts anticipated later this year. Spearheading our portfolio strategy and program leadership across Synlogix's portfolio of synthetic biotic medicines is Dr. Caroline Kurtz, our newly promoted Chief Development Officer. Caroline has been an industry leader for decades, and she has developed blockbuster products. More importantly, she is the team mindset which is critical to drug development. As we move into later stages of development, Caroline's ability to harness the best thinking from across all disciplines of drug development will be critical to our success. We're thrilled to recognize her experience and the role she will play in the success of our programs with this promotion. In the clinical metabolic portfolio, we have two exciting programs leading the way, CINB 1618 in PKU and CINB 8802 in enteric hyperoxaluria. Our lead candidate in PKU is CINB 1618. We have previously demonstrated that a lyophilized formulation of CINB1618 was able to consume phenylalanine in the GI tract of healthy volunteers. We are currently evaluating this strain in adult PKU patients in an ongoing Phase II study called Symphony 1. This trial continues to enroll well, and we're delighted to see so much patient-driven interest despite a challenging COVID winter. We continue to hear from patients and caregivers that a safe oral therapy, which reduces plasma fee by consuming fee in the GI tract, would be a welcome addition to the market. While SYNB1618 has been progressing in the clinic, the research team have been evaluating additional synthetic biology tools to optimize the activity of the strains. They have successfully deployed directed evolution to create an evolved version of CINB 1618, which we are now moving into IND-enabling work. We call this strain CINB 1934, so named because 1934 was the year in which PKU was first characterized. CINB 1934 has demonstrated higher activity compared to CINB 1618 in preclinical models of fee consumption. We will provide additional updates as the strain progresses. CYMB-8802 is our other lead metabolic program. It is designed to consume oxalate in the GI tract in patients with enteric hyperoxaluria, a devastating condition resulting from excess absorption of oxalate from the GI tract, for which there is currently no approved therapy. Yesterday, we shared some very exciting top-line data from the Phase Ia portion of the ongoing trial. In this study, we placed healthy volunteers on a high oxalate diet and increased the urine oxalate levels, thereby inducing dietary hyperoxaluria. Subjects were then randomized to either CINB 8802 or placebo. and provided daily 24-hour urine collection throughout the dosing period. The data demonstrate robust and dose-responsive urinary oxalate reduction relative to placebo. Coming only 15 months after we nominated CINB 8802 as a program, these data also demonstrate the speed and power of the synthetic biotic platform. Richard will walk you through the data in a moment, but I want to emphasize that we are moving rapidly towards clinical proof of concept in patients with enteric hyperoxaluria. Part B of the Phase I study has already been initiated. This study gives us an opportunity this year to demonstrate what very well may be the most clinically attractive profile for patients suffering from enteric hyperoxaluria. Our immunomodulation portfolio also continues to advance. STING-B1891 has moved into combination arm dosing with a PD-1L1 checkpoint inhibitor in an ongoing phase one study in patients with advanced solid tumors or lymphoma. Part A of the study has demonstrated target engagement and activation of the STING pathway. An update on the study will be shared at the American Association of Cancer Research meeting in April. Data from both arms will continue to be reported over the course of 2021, with mature combination therapy data expected by the end of the year. Our team has done a tremendous job executing across multiple programs during a challenging time for everyone over the past 12 months. This resilience and teamwork has allowed us to set the stage for multiple meaningful readouts in 2021. Thanks to our careful stewardship, all milestones occur well within our cash window, which has been extended into 2023. In summary, 2021 has already been an incredibly exciting year for the company. We now have demonstrated proof of mechanism in humans from both of our lead metabolic programs, PKU and enterokyproxyurea. We believe that we have the potential to demonstrate proof of concept in both programs later this year. Now, let me turn the call over to Richard to share progress on the metabolic program. Thank you, Aoife.

I would like to now walk you through the progress across our metabolic portfolio. As Aoife said, we now have demonstrated proof of mechanism in humans from both our lead metabolic programs, PKU and enteric hyperoxaluria, and have the potential to demonstrate proof of concept in both programs later this year. Given the exciting data we shared yesterday, let me begin there with enteric hyperoxaluria. Enteric hyperoxaluria, or EH, is a devastating condition with no treatment options, in which dangerously high levels of urinary oxalate lead to progressive kidney damage. It often occurs as a result of primary insults to the bowel, such as inflammatory bowel disease, short bowel syndrome, or as a result of surgical procedures, such as Roux-en-Y bariatric weight loss surgery. If left untreated, the dangerously high levels of urinary oxalate cause ongoing progressive kidney damage, kidney stone formation, and nephrocalcinosis. Since oxalate is present in many healthy foods, EH is almost impossible to control with diet alone. That means these patients are at risk for serious kidney complications. We are pleased to announce that CENV-8802, has achieved proof of mechanism in a dietary hyperoxaluria study in which healthy volunteers on a high oxalate and low calcium diet were treated with multiple ascending doses of a solid oral lyophilized form of CIMD-8802. Let me walk you through that study now. The primary outcome of Part A of the Phase I study was safety and tolerability. with results used to select a dose for further study in patients with EH in Part B of the trial. We have completed dosing of five cohorts in Part A of this study. In the efficacy analysis, the percent change from baseline urinary oxalate levels was 28.6% compared to placebo at the 3E11 live dose, live cell dose. This dose was well-tolerated, and will be used in part B of this study. Now, let me walk you through the study design and data in detail. One benefit of studying metabolic diseases with biochemical endpoints is the ability to learn in healthy volunteer studies. In this case, we're able to induce a form of temporary dietary hyperoxaluria in healthy subjects. This was done with a very carefully controlled high oxalate low-calcium diet. Subjects were housed in an inpatient unit with meals measured out before and after consumption and a diet that remained consistent throughout the study. As you can see, we successfully elevated urinary oxalate levels to the upper limit of the normal range in these subjects. We initially used 400 milligrams of oxalate per day, but after looking at the data from the first two cohorts, we increased the oxalate content in a diet to 600 milligrams per day. Following a diet run-in, subjects were randomized two-to-one to either SYNB 8802 or matching placebo. The primary endpoint of this trial was safety and tolerability. Similar to our prior programs, we did not observe any systemic toxicity, and there were no serious adverse events, at any dose. Adverse events were generally mild to moderate, GI-related, and transient. We found that a dose ramp where patients take a single dose on the first day, two doses on the second day, and three doses on the third day significantly improved the tolerability profile. CINDI-8802 is a non-colonizing, non-reproducing strain and cleared from subjects after cessation of doses. We also examined the ability of CINB 8802 to lower urinary oxalate levels in this dietary hyperoxaluria model in healthy volunteers. Let me spend a moment on this slide because it is an important one. We present here the change in urinary oxalate from baseline relative to placebo within each dosing cohort across both dietary regimens. The 600-milligram dietary oxalate regimen is on the left, and the one in which subjects consumed 400 milligrams of dietary oxalate is on the right. In both cases, subjects were treated with multiple ascending doses of SYNB 8802. We are thrilled to see substantial urinary oxalate lowering at multiple dose levels under both dietary regimens and across multiple dosing cohorts. This consistent result in a dose-responsive manner is very encouraging. The lower bound of the 90% conference interval did not cross zero for the 1E11, 3E11, or 6E11 dose levels. These data indicate to us a robust and reproducible result. I am now going to focus in on the dose level we have chosen to move forward to Part B of this study in patients with enteric hyperoxaluria due to Roux-en-Y gastric bypass surgery. These patients will have elevated urinary oxalate due to their underlying disease. We will enroll patients whose urinary oxalate levels are greater than 70 milligrams per 24 hours at baseline. We have chosen a dose of three E11 live cells for Part B of this trial. At the 311 dose level, we observed a tolerability profile similar to E. coli missile probiotic with only transient GI side effects. This dose resulted in a 28.6 reduction in urinary oxalate relative to the placebo group. At the end of the dosing period, the urinary oxalate level in the placebo group was 58.1 milligram compared with 40.1 milligram in the group who received five days of dosing with 3E11 three times a day. So we achieved mean oxalate levels into the normal range for treated patients. The clinical implications of this finding are very exciting as we move into patients with enteric hyperoxaluria. Now let me turn to our next steps with this fast-moving program. We have now initiated Part B of the study and will assess the urinary oxalate lowering potential of CINB 8802 via crossover study design in patients with impaired hyperoxaluria following Roux-en-Y gastric bypass surgery. Data is expected in the second half of 2021. The regulatory and clinical path in this indication is relatively straightforward with significant precedence by sponsors in related diseases such as primary hyperoxaluria, for the importance of urinary oxalate as one critical endpoint. We will continue to work closely with regulatory authorities as we develop our clinical strategy. Our initial efficacy assessments will evaluate clinically relevant reductions in urinary oxalate levels, and feedback from our key investigators suggests greater than 20 percent lowering in patients would be beneficial and meaningful. Lowering dangerously high levels of urinary oxalate is the only way to reduce the risk of disease progression and irreversible kidney damage. We are pleased that CINB 8802 has demonstrated the potential to lower urinary oxalate levels in healthy volunteers with induced dietary hyperoxaluria. We are looking forward to advancing the program rapidly into patients and providing additional data this year. I would now like to switch gears to speak about an equally exciting ongoing program to develop an oral treatment for patients with PKU. PKU is an inherited metabolic disease in which children are born without the ability to metabolize phenylalanine. 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 for optimal health. Through conversations with our patients, caregivers, and advocates within the PKU community, it is increasingly clear to us that both current and emerging treatment options continue to leave too many patients behind. And a safe, tolerable, reversible, and oral therapy would be welcome. Synlogic's approach to PKU is simple and intuitive. It is well understood that reducing the dietary consumption of phenylalanine reduces plasma feed levels in patients with classical PKU. Our approach is to build on that biology to introduce a synthetic biotic medicine into the GI tract, which is specifically designed to consume feed and produce measurable biomarkers, TCA, and AGEA. CINB 1618 has shown promising activity. We have demonstrated the ability to consume feet in the GI tract, most recently in our solid oral bridging study in healthy volunteers. We are looking forward to sharing full results of the phase one study using the solid oral formulation of CINB 1618 at the American College of Medical Genetics meeting in April. The next step is to understand how the consumption of fee in the GI tract in PKU patients will impact plasma fee levels. To answer that question, we have initiated the Phase 2 Symphony 1 study at multiple sites across the U.S. Inbound patient interest is robust with the option for at home, virtual, or in clinic participation. The goals of the Symphony I Phase II proof of concept study are to demonstrate the potential of CINB 1618 to lower blood fee in adult PKU patients and validate our PD model to better understand the relationship between the production of strain biomarkers and fee lowering for CINB 1618. Remember, the patients in Symphony have no therapeutic options. They are ineligible inappropriate for or unresponsive to cuvan or PEG values. As you know, only approximately 30% of the PKU population is BH4 responsive. These are patients left behind by current therapies. The study is powered to detect 20% reductions in fee. PKU patients and investigators tell us that 20% fee reductions in an oral, tolerable, and reversible therapeutic which is effective for BH4 non-responders would be a welcome new treatment option. 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. As we move forward with both our lead metabolic programs in PKU and enteric hyperoxaluria. I will come back to you with more information as the studies unfold. Now, let me hand the call over to Greg to briefly run through our financial results. Greg?

Thanks, Richard, and good morning, everyone. This morning we released our financial results for the fourth quarter and full year ended December 31, 2020, and I'm pleased to review these highlights of those results with you now. Research and development expenses were $11.4 million for the three months ended December 31, 2020, as compared to $11.3 million for the corresponding period in 2019. These costs were driven by Synlogix's collaboration with Ginkgo Bioworks for the optimization of synthetic biotic medicines, as well as clinical study startup activities associated with SynB 1618 and SynB 8802, and the ongoing CINB 1891 phase study. General and administrative expenses were $3.3 million in the fourth quarter of 2020, compared to $3.5 million for the same period in 2019. For the fourth quarter of 2020, the company reported a consolidated net loss of $14.6 million, or 39 cents per share, compared to a net loss of $12.8 million, or 37 cents per share for the corresponding period in 2019. We had no revenues in the fourth quarter of 2020 as compared to 1.2 million of revenue for the same period in 2019. Revenue was associated with the services provided under Synlogix collaboration with AbbVie to develop synthetic biotic medicines for the treatment of inflammatory bowel disease, an agreement which has since been terminated. Now, turning to the balance sheet. Synlogic ended the fourth quarter of 2020 with $100.4 million in cash, cash equivalents, and long-term investments. Under our current operating plan, we expect that our cash will take us into 2023 and enable us 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 will now turn the call over to Aoife to wrap up.

Thank you, Greg. Our team has made tremendous progress across all of our programs, both in and outside the clinic. We now have demonstrated proof of mechanism in humans from both of our lead metabolic programs, PKU and enteric hyperoxaluria, laying the groundwork to demonstrate proof of concept in both programs later this year. I want to end, once again, thanking the Synlogic team, employees, and their families for their work and dedication in driving those programs forward. We will now open the call for questions.

Thank you. Ladies and gentlemen, to ask a question, you will need to press star 1 on your telephone. To withdraw your question, press the pound key. Please stand by while we compile the Q&A roster. Our first question comes from Lena Kaminsky with Jones Trading. Your line is open.

Maybe, you know, maybe start off, can you remind us kind of how the disease, how is the hyperchloric currency managed? And, you know, where is really the high unmet need and where would 8802 fit in the treatment regimen, and then kind of along the line. Hello, can you hear me?

Yeah, I can hear you, Lina. I think I'm catching all of your questions.

Yeah, okay. Yeah, and I guess along the line, maybe also can you kind of remind us how is your approach differentiated from other approaches in development and help us maybe quantify how much more oxalate you anticipate ADA and O2 will be able to consume and degrade as compared to other approaches? And how should that increase translate into more or, well, into decreased urinary oxalate excretion and to clinical benefits? Thank you for taking the questions.

Thanks. I'm just going to recap because I think there were about four questions in there, and I'm sure there are questions others on the call have as well. So, you know, I think the first thing you were asking was about the current landscape where the unmet needs and what are the segments within the enteric hyperoxyluria population. The second component was differentiation versus other mechanisms of action. And then the third one was about trying to get some feel for quantifying the you know, how much oxalate the strain can consume and how that could be relevant in patients with disease, correct?

Yeah, I guess how much more you would anticipate to consume with 802 as compared to, you know, other programs in development in the field.

Cool, yeah, so maybe I'll hand that over to Richard. I think he's our expert on all things hyperoxaluria. So Richard, do you want to start off addressing Lena's question, maybe starting with our understanding of the disease based on the feedback that we've collected from KOLs and physicians and patient groups?

Yeah, sure. I'd be happy to. You know, enterocryperoxaluria can result in significant irreversible and progressive kidney damage, but one of the interesting aspects about this disease is is it arises from patients with a primary insult from their GI tract leading to hyperabsorption of oxalate from the gut. And there are a variety of, you know, as we mentioned, there are a variety of GI diseases which can lead to this. You know, patients who have had real and wild gastric bypass surgery, patients with Crohn's disease, short bowel syndrome, celiac disease, pancreatitis. You know, there are no approved treatments for enterocarparoxal urea, so in some ways it's kind of a wide-open field. But, of course, our interest is to go after the patients with more severity in their disease spectrum. These are patients maybe with, you know, kidney stones, maybe patients with chronic renal insufficiency or renal damage to the EH, enterocarparoxal urea. Or maybe a patient with a combination of both where the recurrent kidney stones and kidney damage to really direct our response at the more severe spectrum of the patient population. And we are undergoing, we are now conducting some really good research, epi research in that sort of thing to identify those patients. I think your next question is, how does 8802 fit and differentiate it from other approaches? You know, I think there are a couple of things, other approaches, such as enzymes to degrade oxalate. We believe our effect of integrating oxalate in the upper GI tract, as is 8802, but where we feel there's benefit is, first of all, you know, our enzyme system is protected by the E. coli bacteria, the nisal bacteria. We believe that gives us an advantage right off the bat. And secondly, we believe that we're going to be able to reach colonic colon better than other products in development. And that's in patients with EHS where a lot of the action takes place, where a lot of the hyperabsorption of EHS oxalate takes place. So I think, you know, that's sort of our differentiation in where we think we may have benefit, particularly in patients with EH or healthy volunteers. Now let me turn to translating, you know, how much oxalate we expect to consume. You know, in normal diet humans, people consume about 200 to 250 milligrams of oxalate a day. And that's similar between healthy volunteers and patients with enteric hyperoxaluria. You know, in our dietary model for hyperoxaluria in healthy volunteers, we ramped up the oxalate to 400 and then to 600 milligrams of dietary oxalate a day. And even at those higher levels, we're able to show what we think is a meaningful decrease in urea oxalate levels and in evidence that we're able to consume a meaningful amount of oxalate, even in patients taking more oxalate than expected. So, you know, if anything, you know, patients taking lower amounts of oxalate, we would expect that our CINB 8802 would be able to consume very effectively those levels of oxalate in the diet, including patients with EH. Does that sort of get at your questions, Leah? Yeah.

Yeah, thank you. It's really clear. And again, congrats on the new data and all your progress. I'll jump into the queue. Thanks. Thank you.

Thank you. Our next question comes from Joseph Schwartz with SEV LeRink. Your line is open. The first one is on your 885. O2 program. So given the fact that healthy volunteers on a high oxalate diet was used to mimic conditions of the enteric hox disease state and was able to blunt the rise of urinary oxalate, I'm curious to know how this relates to enteric hox patients because the absolute effect of the drug arm was modest at just minus 4.7 mgs per 24 hours.

Yeah, sure. Thank you for that. There are a couple things we look for in sort of a phase one data set. And we think the best comparison is what happens to placebo compared with patients on 8802. And what we can say is patients on placebo didn't decrease, whereas patients on 8802 did decrease. And when you look at the difference at the end of treatment between the placebo patients and the 8802 patients, it was quite marked, 28.6% and 14 milligrams absolute. So we would argue that we did see really good absolute differences from placebo, which is our, you know, a marker for really understanding the results and moving forward. And the other thing we look for, you know, absolute difference is one marker. We look for consistency across doses, consistency across cohorts and oxalate intake levels, check, check, there for both. Consistency across sensitivity analyses, check. Dose response, check. No decrease in placebo, check. decrease in 8802 groups, check, and the meaningful differences between 8802 and placebo, check. And these ideas and this consistency of the data package really, you know, excite us in moving forward to enterocarpal auxilary patients, which, you know, the proof is in the pudding there, right? But, you know, we're really excited with this data package and excited to moving into patients.

Okay, thank you. That's helpful. And then, I know you announced a new strain for your PKU program, so I was just wondering, do you plan to introduce a new strain for your Enteric Hox program as well, or do you envision this being your final formulation?

Yeah, so I think as with Jury, I can take that question. As with all programs, we moved in a lyophilized formulation. We think, as Richard just really nicely outlined, we feel that we have a really strong data set We still have some work to do in terms of scaling that up to a phase three scale, but we think that that's all incredibly possible. So there'll be tweaks to the formulation, tweaks to the final presentation, whether it be capsules or tablets, that we'll need to do as we go through development, as you would with any development program. And certainly we'll be updating the external community as we go through that process. But today we're just really thrilled with the data, as Richard outlined, and looking forward to seeing data in the patient population later this year.

Okay, great. Thank you. And then finally, I'm wondering if you could talk about the site of oxalate consumption in Healthy Volunteers with 8802. I don't know if you were able to see this in your study, but I'm wondering if the primary site of activity was in the upper GI tract, as you had expected, and, you know, how that translates to potential efficacy in EHOC patients.

Grace, I'll maybe ask Richard to address that question, jury.

Yeah, sure.

Thank you for that.

You know, we didn't study, we didn't do the studies to actually identify where It's a great question whether oxalate is consumed in healthy volunteers versus patients with EH. But based on prior knowledge and based on prior studies, we are expecting that the majority of the oxalate consumption in healthy volunteers occurs in the upper GI tract, presumably in the stomach and proximal small intestine, whereas in patients with EH, it's likely that a lot of the oxalate absorption and consumption will be done further down in the colon. And that's kind of what makes us very excited because, you know, as we said previously, that's one of the areas where we think we can differentiate with a strain, with an actual bacteria that gets into the colon, that we may have good activity there. So we're excited on seeing if that happens in patients with EH.

Okay, great. Thank you so much. Congrats on the data. Thank you. Our next question comes from Ted . Your line is open.

Great. Thank you. Good morning, everyone, and congrats on the data update. I've got a couple questions, if I may. So, firstly, would you ever envision evaluating 8802 in primary hyperoxaluria? And secondly, I probably am asking these a little out of order, so I apologize. what do you see as the potential end that might be required, I know this is a little further out, for a pivotal study of 8802 in enteric hyperoxaluria? And then I have a quick question on TKU. Thanks.

Yeah, so I think you have the exact right person here on the line with Richard to answer your question about the primary hyperoxaluria. Obviously, there are great products, you know, close to or already available commercially for that indication, one of which Richard was involved in developing. So I think he's absolutely the right person to answer that. So maybe I'll hand over to him, and then we can come back to some of the other kind of forward-looking questions around regulatory requirements, if that works, Ted.

Of course. Thank you.

Yeah, thank you for that. Yeah, I was... Fortunate enough to be part of that very talented team and enjoyed it. Yeah, you know, we've given a lot of thought about this. You know, is there a role for GI removal of oxalate in patients with other causes of hyperoxaluria, including primary hyperoxaluria? As you know, primary hyperoxaluria is due to overproduction of oxalate. in the liver due to a genetic defect. So a GI approach doesn't have direct access to that, but it may have access to that load via systemic circulation, and if oxalate recirculates into the GI tract, which it may, exactly. I think in patients with intact renal function, the treatment that is out there now and the treatments that are coming are pretty darn effective. So it's hard to see, you know, to envision whether it's possible, but hard to see how a GI-related entity could impact that. But on the other hand, and we've played around with this idea in patients with renal failure, which don't, you know, they can't excrete oxalate in the urine, which is a major way oxalate is excreted from the body, you know, and dialysis only works when the patients are on dialysis. It doesn't work in between the dialysis. sessions, would there be a role in, you know, GI removal of oxalate via an 80-02-like mechanism between the dialysis sessions and sort of a GI dialysis? That's something we're playing around with, with anybody with high oxalate levels.

That's interesting. Thank you.

Yeah, yeah. And in terms of the potential and for the pivotal study, you know, we're not, you know, we're not kind of give out, you know, we're still in the process of designing our phase two and phase three study. You know, at a high level, you know, certainly we will make sure the end is big enough to, you know, test our hypotheses that we're interested in testing to get approval. And, you know, I think there are some good examples on what kind of ends that we'll take out there. Does that So, again, I know it doesn't exactly answer your question.

Yes, it does. No, no, that's fine. Well, I mean, again, you know, let's see what we get from Part B, too, in patients, and I think that will help as well. And then I guess a quick question, if I may, on PKU, seeing that data is in the second half. Again, really looking forward to that result. Two questions. Firstly, would 1934 ultimately replace place 16, 18 in the clinic, or would it more be a situation of a follow-on? And do you think, kind of a similar question here, do you think that ultimately you would be able to evaluate this in combination therapy with KUVAN or enzyme replacement therapy? Thanks.

Yeah, thanks, Ted. That's a great question. You know, I think one of the key attributes of our platform that I think is really exciting is this ability to think about these products as kind of synthetic biotics, right? And one of the key components is this iterative development. So you design, you build, and you test, and then you can continue to kind of optimize and tweak. Now that's different from the traditional drug development kind of framework and model. So we're really excited by the fact that we can move quickly. We can develop additional strains using tools that we have. We can move them very quickly into the clinic and because of the experience that we've accumulated and kind of the regulatory path to opening an IND and initiating clinical studies is very rapid. I think it's the timeline that we've achieved for 8802 has demonstrated. So right now we're moving 1934 into IND enabling studies, but as we get kind of more clarity on the timeline and, you know, what that looks like from a performance perspective, we'll, you know, provide more guidance in terms of how the programs might play together but as you can imagine there are a number of interesting scenarios that could play out including kind of a life cycle management initiative with a strain that allows maybe you know lower dosing levels with similar activity or a situation where one replaces the other for phase three development so I think that's all dependent on the data obviously the data from the symphony study as well as the data from 1934 as it continues to advance in development. But, you know, as always, we'll make sound database decisions when we have the right amount of data in hand.

Great. Excellent. Thanks so much for the update, and congrats on all the good progress.

Thanks, Ted. Thank you. Our next question comes from Chris Howerton with Jefferies. Your line is open.

Thanks for taking our questions. So I just have two on 8802. So first I was wondering if you can go into any more detail on the safety and tolerability. Was there a max tolerated dose and were nausea and GI symptoms dose limiting? Maybe you could give us a little more information on potential AE rates. And the second question was on what the trends are for a Roux-en-Y surgery. and whether you expect the market opportunity to change if this procedure were to fall out of favor.

Yeah, great. I think maybe I'll hand over to Richard to provide the update on 8802. And just to say, you know, we will disclose the entire data set at some point down the road later this year at an appropriate academic meeting, as we generally do. So, you know, obviously there'll be a lot more color behind all of the endpoints at that time. But Richard, do you want to answer the question about safety and even, you know, the rule on why question as well? I think it's both are pertinent to you.

Sure, sure. You know, we saw a safety profile I think pretty similar to other strains across our platform as we went up in dose. We did see GI including nausea and vomiting, and that's sort of the limiting part of our doses, and we saw those more at the 6E11 than we did at the 3E11. One thing that was interesting from our viewpoint is that when we titrated up the dose, when we gave patients one dose for one day and sort of didn't overwhelm them immediately, gave them two doses for one day, and gave them three doses, then did the three-dose TID dosing. We found that was much better tolerated, I think, to give their GI tract a little time to be accustomed. And in the 311 dose, we did see, you know, a tolerable safety profile in terms of GI symptoms that was similar to what you see with a with a probiotic. And because of that, we decided to move forward with that dose, in addition to the fact that we saw good efficacy at that dose and, you know, manufacturability thoughts and things of that nature. So that's why we decided to move forward with that dose. In terms of, you know, the rule and why, it is true that, you know, That's what bypass surgery is. I'm moving away from that. And there may be less, although it's not zero, enteric hyperoxaluria after other type of GI surgeries. And that will certainly, you know, we'll certainly be following that closely as we develop 8802. There are other causes of enteric hyperoxaluria, including, you know, Crohn's, short bowel, celiac disease, pancreatitis, which won't be affected by this change in surgery. So those are what we'll be considering as we move on with clinical and even commercial evaluation of 8802. Does that answer your questions? Yeah.

Perfect. Thanks so much.

Yep.

Thank you. Our next question comes from Tom Schrader with DTIG. Your line is open.

Hi, good morning. This is Julian Alpertam. Congrats on all the recent progress, and thank you for taking my question. I'm wondering, just given how much urinary oxalate levels can be affected by diet, do you have a good sense for how the placebo group will respond over time in Roux-en-Y and hyperoxaluria patients, maybe beyond five days? Are you able to maybe walk us through your assumptions here?

Yeah, that's a great question. You know, right now we're getting rural patients with Roux-en-Y on a stable oxalate diet. And, in fact, we have dieticians dedicated in the study to work with the Roux-en-Y patients. And they're going to be recording their diet in a pretty extensive way, certainly recording their diet every time they take 24-hour urine. And we're going to have those diets analyzed by, you know, dedicated dieticians. to look for changes in diet and to advise on, you know, what they can do to manage their diet in maintaining a stable, as much as possible, oxalate diet throughout the study. So, you know, we are taking precautions. Obviously, there's going to be some variability in diet, and there are some ways you can handle that on the analytic back end. But certainly, from my viewpoint, clinical trials, I prefer the diet be as steady and as steady and oxalate as possible so we get the clear signal.

Got it. Thank you.

Thank you. Our next question comes from Bola Misa with Chardon. Your line is open. Hi.

Apologies if this is a little bit repetitive, because I think you touched on this earlier. Going back to the absolute reduction in urine oxalate that you saw with Cindy earlier, too, could you comment a little bit on whether you think the effect size might differ in the actual enteric hyperoxaluria patients versus in the dietary model, for example, due to higher baseline urine oxalate levels, or do you think that the effect sizes will be roughly the same?

Yeah, you know, it's hard to predict what the effect is going to be. Obviously, as a company, we hope they're higher, and there are some theoretical and biological reasons why that may be the case. But, of course, we can't say that now. I think the baseline assessment is we expect, you know, the change in oxalate in enteric hyperoxaluria patients to be at least as much to be, you know, at least as much as what we expect. saw in healthy volunteers. And this gets to your point, one of your points, Bola, is that we'll be enrolling patients with higher baseline urinary oxalate levels greater than 70 milligrams per day. And I think it's been pretty well established by data both in enteric hyperoxaluria and primary hyperoxaluria that when you start with higher oxalate levels in the urine, you tend to get larger decreases in percent than when you start with lower oxalate levels. And this is one of the things we're really excited about, that we're able to drive up oxalate levels to the upper limit of normal and slightly over the upper limit of normal at the end of the treatment and show pretty good effect in healthy volunteers. And I'm really interested to see now when we get enterocarporexal Europe patients, whether even higher oxalate levels, you know, what that will show and if we're going to be able to show in terms of percent decrease. really excited about doing that.

Thank you. I appreciate the clarity. And one unrelated question. You've made the argument before that the various components that you use are modular or reusable. I was wondering, given that you now have proof of concept data for two assets that use the same chassis and one of the same promoters, I guess to what extent does concordance between those two data sets, I'm thinking of PKU and enteric hyperoxaluria, to what extent do those two data sets support this modularity argument? And I guess to what extent does this modularity or lack thereof read through to your earlier stage metabolic pipeline?

Yeah, that's a great question. I think the real advantage for us from the modularity perspective is just the speed at which we can move with subsequent programs. I think when we started to speak about this, it was unproven that we could really move quicker by having these reusable parts, as we call them. I think now that we've seen how quickly we've been able to move with 8802, because we're using those kind of components that we've used before, that the regulators have seen before, that we have a lot of experience with from an engineering perspective, we were able to move that program forward really quickly, both in terms of just the building of the strain, but the preclinical work and the manufacturing work and the assay development work and all of the critical components that go into initiating and executing a clinical study were things that we already had available to us previously. I think the other key difference is that we were able to move with 8802 directly to a lyophilized formulation, which I think was another big advantage that will play out even into the future as the 8802 program moves forward. You'll remember with PKU, we started with a liquid and subsequently had to move to a solid oral. So, you know, I think we're starting to see the kind of realization or the manifestation of the advantages of kind of using this synthetic biology-based approach in drug development. And certainly we would expect that we would leverage those kind of, you know, those same speed quality attributes as we go forward and develop additional candidates.

Great. Thank you very much.

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

Hey, guys. Thanks for taking the question. So just thinking back to the approval of Lumith's urine in primary HUCs, I think they saw a pretty dramatic reduction in urinary oxalate. I think it was like 65%. I guess my question is why or do you see in secondary HUCs a reason why you could get away with a lower reduction in urinary oxalate? Would something in the order of 30% reduction be enough to move the needle in secondary HUCs? Thanks for taking the question.

Thanks, Mark. Maybe before handing it over to Richard, I'll kind of frame it in two different ways that I think might be helpful. I think there's a component of, is urinary oxalate going to be sufficient for full approval in enteric hyperoxaluria the same way that it was in primary hyperoxaluria? I think that's kind of one regulatory component of the question you're asking. And then the second question, I think the component of the question is, what's clinically meaningful in enteric hyperoxaluria in terms of percent lowering of urinary oxalate? I think both are key questions for the program, obviously, and are interrelated. But I think there is a slightly different approach to both. And I think Richard is exactly the right person to answer both of those questions. So Richard, do you want to answer Mark's question on both fronts there? Yeah, sure.

Absolutely. And let me just take a little step back and tell you about my thinking. For both primary hyperoxaluria and enterocarpal oxaluria, the damage comes from too much oxalate in the urine. In primary hyperoxaluria, the damage comes because of a genetic defect in the liver. And in enteric hyper, or the high levels, I'm sorry, the high levels in oxalate occur because of a genetic defect in the liver. And in enteric hyperoxaluria, the high oxalates in the urine occur because of hyperabsorption of oxalate from the GI tract. Now, once you get to those levels of oxalate in the urine, whether it be from primary or enteric, the downstream consequences should be essentially similar, that you get kidney stone formation, recurrent kidney stone formation. You get calcium oxalate deposition in the kidney tissue, which in itself is inflammatory. You get nephrocalcinosis. You get chronic renal insufficiency. In some cases, you can even lead to end-stage renal disease in dialysis and renal transplant. So, you know, to me, the crux of the argument, the biological argument, is that toxic metabolite of urinary oxalate in the urine. And that's the arguments we're gonna make to the regulators. Even if our overall effect is at 30%, 40%, or in the case that El Nylon got a 53% change from placebo, which is really impressive, as you said, any change, we believe, is really good for patients, okay? And that's sort of the crux of the regulatory argument we're going to make. And see if we can make a good enough argument and get full approval straight up. That's going to be our approach. And the second part of your question about clinically meaningful, the best we can determine, and this is input from KOLs and also a really nice recent epidemiological article, where most people say that a 20% change and urinary oxalate, and we believe this is interpreted as a 20% change from placebo in urinary oxalate levels, what is the bar for clinically meaningfulness? And I think recently this has been backed up by a nice epidemiology study out of the Mayo Clinic where they looked at patients with hyperoxaluria and determined that if patients had about a 20% decrease in urinary oxalate levels, this translated into about a 25% decrease in the risk of kidney stones. So, you know, that's where we're starting from. Obviously, the more the better. But we think, you know, when you get into 20% or 30%, any of that is good for the patient.

Okay. Thanks so much for taking the question.

Thank you. And I'm currently showing no further questions at this time. I'll turn the call back over to Aoife Brennan for any closing remarks.

Great. Thanks, Shannon, and thank you so much to everyone for joining us today. Enjoy the rest of your day.

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