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spk02: Good morning. Welcome to Synlogic's second quarter 2022 conference call. At this time, all participants are in a listen-only 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 Andrew Funderburg of Kendall Investor Relations.
spk00: Please proceed. Thank you, Operator.
spk01: Good morning and thank you for joining us on today's conference call. This morning we issued a press release which outlines our second quarter 2022 financial results and additional business updates. The release is available on the investor section of our website at www.synlogictx.com. Joining me on this call are Dr. Aoife Brennan, President and Chief Executive Officer, Molly Harper, Chief Business Officer, Dave Hava, Chief Scientific Officer, and Michael Jensen, Chief Financial Officer. Other members of the management team will be available during the Q&A. During the call, IFA will provide a review of this quarter's highlights. Molly will provide additional detail for the clinical programs. Dave will discuss our earlier stage programs and collaborations. And Michael will provide a financial overview. Following our prepared remarks, we will open the call for 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.
spk03: Thanks, Andrew. Good morning, everyone, and thank you for joining us. I'm happy to share updates today on our recent progress, the financial results for the second quarter of 2022, and upcoming milestones. This is an exciting time for Synlogic and the synthetic biotic platform. For our most advanced program in PKU, in the second quarter we announced that we received a positive opinion on orphan drug designation from the European Medicines Agency, or EMA, for CINB 1618 for the treatment of PKU. This is an important step for our program as the EMA's opinion reflects the recognized need for new treatments of PKU. In the remainder of 2022, we expect three clinical data readouts from three different programs. These include, for the PKU program, the phase two data readout and phase three cancer confirmation. For SYNB1353, a synthetic biotic designed to consume methionine as a potential treatment for homocysteineuria or HCU, findings from the recently initiated phase one healthy volunteer study. And finally, For CINB-8802, a potential treatment for enterocryperoxaluria, we also expect to share proof of concept data. We recently recognized CINB-1353 as our third program to enter the clinic in less than two years, reflecting the advantages of synthetic biotics. CINB-1353, built on technical as well as regulatory synergies, and the promise of this platform of biotherapeutics based on synthetic biology. CINB 1353 entered the clinic within just a year of being named as a candidate. As was done for CINB 8802 and CINB 1934, the FDA waived the traditional preclinical toxicology package for CINB 1353, recognizing the transferable findings of using the E. coli NISL chassis. Moving beyond the clinical pipeline, I'm excited to announce the newest addition to the SynLogic pipeline, SynB 2081 for gout. Gout is a well-known and often debilitating form of inflammatory arthritis, causing intense joint pain and limited range of motion due to excessive levels of uric acid. Patients remain underserved, especially those who are intolerant of or refractory to available therapies. We are excited to advance SYNB 2081, our second synthetic biotic developed through our partnership with Ginkgo Bioworks. And finally, it was a pleasure to share earlier that Brendan St. Amant has been appointed Synlogix General Counsel and Corporate Secretary. As discussed on our last call, trial readiness activities are underway for the start of our phase three study for the PKU program in the first half of 2023. This builds on phase two interim analysis and proof of concept data shared last fall, demonstrating in PKU patients, SYNB1618 strong activity and reduction in plasma C, the amino acid PKU patients are unable to metabolize and becomes neurotoxic at high levels. In parallel with the proof of concept readout, we confirmed even greater potency with next generation CINB 1934 while establishing the safety bridge at a phase one head-to-head study. Since then, we've progressed CINB 1934 such that it is now the presumed phase three candidate. However, that will be confirmed after assessing the SYNB 1934 experience in PKU patients from the Phase 2 study to be shared later this year. Looking ahead to the Phase 2 data, we have an opportunity to remind this audience of the endpoints we use to confirm drug activity. For all of our programs, we look for multiple endpoints that are specific to the synthetic biotic to assess if they are working as intended. For PKU, our synthetic biotic is designed to metabolize C in the GI tract. To measure this effect in a more precise and controlled way, we provide labeled C, or DeFi C, as part of a test meal at baseline and then again after treatment in the study. This is the primary endpoint for the Phase II Symphony trial. We are also assessing the impact of our synthetic biotic on fasting plasma C levels, as well as TCA in plasma and HA in urine, two metabolic byproducts, which can only be produced if our strain is effectively consuming C. We also look forward to sharing data from evaluation as a monotherapy, but also as an adjunct to saproterin or CUVAM. With that, I'll pass the call over to Molly to provide a bit more perspective on the significance of this positioning and our differentiation in PKU, as well as some further color on our HCU program. Molly.
spk10: Thank you, Aoife. Aoife has described how our phase two design reflects our positioning in PKU, targeting the more severe patients who in the case of PKU are also a large majority of the patient population. This includes both monotherapy and adjunctive patients. The more mild patients with PKU are often described in terms of BH4 or CUVAN responsiveness. However, even these patients, in spite of responding to and benefiting from CUVAN, often have B levels far above desired levels. these patients present an opportunity for adjunctive treatment. The large majority of PKU patients in the U.S. and Northern Europe are considered to have classical PKU. These are the patients with higher fee levels who did not respond to KUVAN and for whom Palantzic is not an option. We find tremendous appreciation for the potential of an oral, non-systemic approach like Synlogix. This is the currently untreated patient population who present an opportunity for our approach as monotherapy. Synlogix program positioning, which you see shown here in the middle, is for these more severe patients who are currently untreated or in need of additional fee lowering as an adjunct. Turning now to CINDI 1353. which, as Aoife noted, recently entered the clinic in healthy volunteers. We shared that this program builds on disease state synergies, since as an inborn error of metabolism, there is a direct overlap between HCU and PKU in terms of PIs, KOLs, and connected patient communities. In terms of the current disease management, patients with HCU also must live with restrictive diets that are considered even more onerous and challenging than those for PKU, and to reduce the risk of impaired cognitive function or developmental disabilities. In addition, however, elevated homocysteine levels in HCU presents significant risk of devastating and acute systemic complications, including thromboembolism and stroke, skeletal weakness and associated fracture, as well as lens dislocation. But like PKU, the current standard of care for HCU leaves a need for a new approach, an approach that is orally administered without systemic absorption and associated risks, and also conducive to both monotherapy or an adjunctive or combination treatment approach. Today's standard of care is the generic betaine, known as the brand name Cystidine, which has been generic for decades, does not alleviate dietary restrictions, and often leaves further need for homocysteine reduction. Current options in development are injectable enzyme replacement therapies. From speaking with KOLs, clinicians, and patients, we have heard consistently the excitement for an oral option, particularly one with the profile of an engineered probiotic, and we are excited about moving this program forward. At this point, I'd like to turn the discussion over to Dave to provide a bit more context regarding our upcoming data readouts as well as our newest drug candidate.
spk08: Thanks, Molly. It is a pleasure to review this exciting time for our pipeline as it both advances and has added a new drug candidate. Molly and Aoife have both touched upon our upcoming data readouts in PKU and HCU. We are also looking forward to proof of concept data in support of CINB 8802 designed to consume oxalate in the GI tract and reduce risk of recurrent kidney stones and related renal complications in patients with enteric hyperoxaluria. SYNB 8802 is being evaluated in two studies, one in patients with Roux-en-Y gastric bypass surgery who have elevated absorption of oxalate, to evaluate whether SYNB 8802 can lower urinary oxalate in those patients. There is a second ongoing phase one study to the CINB 8802 program to continue to build our clinical data set in patients with Roux-en-Y gastric bypass. This is an inpatient setting study where we can collect diet data as well as high quality 24 hour urine and fecal samples. We believe that the combination of parameters assessed will support proof of concept for this patient population. It is also my pleasure to share that we've named an additional program in our metabolic pipeline, SYNB 2081, a synthetic biotic designed to consume uric acid in the GI tract with the goal of lowering systemic uric acid levels for the treatment of gout. As Aoife mentioned, this is our second drug candidate through our partnership with Ginkgo Bioworks. We are tremendously excited about the opportunity to add another much needed option to the gout treatment repertoire, which remains quite limited today by current treatments, which are limited in terms of safety, efficacy, or the patient experience. I'll now turn things over to Michael to review our financial results.
spk04: Thanks, Dave, and good morning, everyone. Earlier this morning, we released our financial results for the second quarter ending June 30th, 2022. And I'm pleased to review the highlights of those results with you now. Revenue was 0.2 million for the second quarter of 2022, consistent with the same period in 2021. Revenue was from our collaboration with Roche for the discovery of a novel synthetic biotic for treatment of inflammatory bowel disease. For the second quarter of 2022, the company reported a consolidated net loss of 15.7 million compared to a consolidated net loss of 15 million for the corresponding period in 2021. Turning to the balance sheet, Synlogic ended the second quarter of 2022 with 106.8 million in cash equivalent and marketable securities compared to $120.5 million as of March 31, 2022. Under our current operating plan, we expect that our cash will take us into 2024 and enable Finlanti to advance a clinical program through multiple important data readouts across the metabolic portfolio. Thank you for your attention, and we look forward to keeping you updated on future calls. I will now turn the call back over to Issa to wrap things up.
spk03: Thank you, Michael. This is an exciting period for Synlogic as we advance to three anticipated data readouts in the coming months and a phase three initiation in the first half of 2023. We're well positioned with a strong balance sheet to advance these important programs and are in the fortunate position of having funds available to support us well into 2024. I'm very pleased with all of our progress and the commitment of our entire team to advance promising therapies to patients in need of new treatment options. We will now open the call for questions.
spk02: As a reminder, to ask a question, you will need to press star 11 on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from the line of Joseph Schwartz from SVB Securities.
spk11: Thank you for taking our questions. The first one is on your PKU franchise. So another company recently lowered their sales guidance for their PKU franchise, citing that PKU treatment centers have not bounced back from the pandemic. And I know you mentioned labor shortages on your earnings call last quarter. So I'm wondering if you're still detecting some challenges in Rolling Symphony and if internal expectations on the market opportunity have been adjusted based on the recovery rate observed from the other company.
spk03: Thanks, Jury. This is Aoife. I can say that our guidance for the RM2 data is unchanged. We plan to have data later this year. Regarding the market dynamics in PKU, maybe I'll pass the call over to Molly to make some comments. We've obviously been observing other products and learning from them, and she can provide you with a little bit more color there.
spk10: Hi there. Thanks for the question. So in terms of the other products, what we've generally heard from the clinicians there is that the interest in new therapies and alternate therapies that provide a different profile is extremely strong. And in every single patient appointment they're having, they're talking about not just what's available, but also options in development. So, you know, while, you know, clinicians across categories and different treatment categories are seeing different paces of return to, you know, quote, unquote, the normal, including seasonality considerations, what's guiding the excitement and the opportunity that's the foundation of our program really hasn't changed. And if anything, as we engage with the community, it's just getting stronger and stronger.
spk11: Okay, that's helpful. Thank you. And then maybe continuing on the enrollment theme, I know it's very early, but are you anticipating major differences in your Phase 3 enrollment versus Phase 2 that could affect the enrollment rate? I'm wondering if you're just expecting it to be faster, slower, or about the same based on your experience in Phase 2.
spk03: Yeah, great question. I think there are a couple of things that are going to be very different, Jury, for the Phase 3 program compared to the Phase 2 program. Number one thing is that we'll have a lot more sites. So we anticipate going to multiple countries and regions and having a full difference in terms of the number of sites. that we'll be using to enroll. The trial will obviously be bigger, but I think spreading a broader geographic net will certainly help us in terms of achieving the required enrollment rates. I think the second component is that there are going to be big differences in terms of the study design. So these patients with PKU are very interested in having access to therapy, you know, beyond just two weeks of a phase two study. And that's some of the feedback that we've received as we've been enrolling phase two is that these patients are interested in maybe phase three where they have the opportunity to participate in an open label extension study and have that opportunity if they benefit from treatment to be able to continue until the product is approved. That's very similar to lots of rare diseases. That's always a key concern for patients in enrolling. They don't want to have potential benefits and then have to discontinue the product. And I think the third thing that's going to be very different between the phase two and the phase three is that the phase three will obviously be a lot less intensive in terms of the commitment and work required for patients and sites. Our phase two study is very data rich. There's lots of endpoints. Patients have multiple visits to the clinic for meal tests and other things. And that's obviously a big burden for patients. It pays off because you get these nice biomarker endpoints. And while we're learning about the program, that makes perfect sense. But as we move to phase three, I think the burden for sites and for patients will be a lot lower because we'll really be focusing in on the plasma fee lowering as the primary endpoint with less frequent visits, with, you know, much more less intensive visits in terms of blood draws and other assessments. So I think those are the kind of key factors. And the good news is we have other, you know, studies, other phase three trials to base our enrollment projections on. So when we come to that point and are providing guidance around, you know, phase three enrollment rates and things like that, we have some precedent to go by for those kinds of data points.
spk11: Okay, great. That's very helpful. And then maybe finally, if I could just squeeze one more in. How should we think about age playing a role in fee reduction? My understanding is KUVAN's phase three trial included children and adults. On the other hand, your phase two trial is enrolling 18 and up. And I know that the platforms are different. But, you know, I guess the question is, are you anticipating or expecting a difference in fee lowering based on age? Thank you very much.
spk03: Yeah. Yeah. So, I think that's a great question. I think number one thing in terms of pediatric product development, you know, Kuvan was a little bit of an outlier because it had been used clinically in Japan when it, you know, when Biomarin filed the initial IND. So, it did have some clinical data and safety and efficacy and exposure. But in general, the agency like you to demonstrate safety and some probability that patients will benefit before you start enrolling those who are below the age of consent, essentially. Our plan would be to continue to work with the FDA to be able to broaden and enroll those younger patients in a step-wise manner based on the data that we're gathering in the phase two study, because we do recognize that the pediatric patients are key segments for us with big unmet need and obviously lifelong consequences. So we'll be moving as quickly and as aggressively as possible to get those patients on study. I think in terms of the end point with the pediatric patients, there's no reason from a biology perspective why pediatric patients will respond differently to adults in terms of fee lowering. One thing that is different in the pediatric patients is maybe the endpoint needs to be different. You know, often particularly the young kids who are under very tight parental control will often have baseline lower C levels. And in those patients, maybe the endpoint needs to be protein liberalization as in how much additional natural protein can be added to their diet rather than just looking at C lowering because some of these parents with kids who have PK are very obsessive. monitoring sea levels very frequently and really keeping the diet very tightly controlled. So there may be differences just in terms of the right end points in the various populations as we've marked down the age groups. But we're absolutely thinking about pediatric development as part of our overall clinical development plan and see that there's a tremendous opportunity in that particular segment for our candidates.
spk00: Thank you.
spk02: Our next question comes from the line of Mark Bredenbach from Oppenheimer.
spk09: And thanks for taking our questions. Just a few from us. First of all, when can we expect you to announce the finalized phase three protocol details? Are we going to have to kind of wait until next year for that? Can we assume the trial is being designed with the intention to support registration in more than one geography, maybe both U.S. and Europe? Second question on PKU is whether or not you're going to be relying on your in-house manufacturing capabilities to support the study. And if you have clearly spelled out the list of CMC requirements from the FDA for drug products that's going to be used in Phase III and beyond, So, those two questions on PKU, and then maybe one on the new program in Gallup. I guess I'm just wondering if you would expect 2081 to have any impact on uric acid production from endogenous sources, or maybe even on renal excretion of uric acid, or would this product only reduce uric acid derived from dietary sources? Thanks so much for taking the questions.
spk03: Great. Yeah, thanks so much, Mark, for your questions. For the first one, in terms of the phase three design, we plan to have an end of phase two meeting with the FDA where we'll get final alignment on the specific design before we disclose that externally. I think that's the prudent thing to do. Ditto the manufacturing requirements. We've had a lot of good discussions with them as we've been going through development around our CMC and particularly our analytics for our products and have very good alignment and a good collaborative approach. discussion with them. We don't foresee any major showstoppers there based on the back and forth that we've had to date. But obviously, the final agreement comes with the end of phase two meeting minutes. And as soon as we have those in hand, we'll be sharing the overall study design, as well as the overall feedback from FDA with the investment community. I think the other component of your question is about global regulatory. We do see a lot of opportunity for this product. You know, there are about 55,000 patients with PKU globally, about 17,000 of those are in the U.S. So there is clearly a big unmet medical need, a large PKU population, and I think some interesting commercial opportunity ex-U.S. in some of those geographies. So we are, as you've seen with our announcements of our EMA orphaned designation. We're actively pursuing XUS regulatory alignment. Having said that, the most important thing for us is speed to BLA in the US. So we are engaging, but also maintaining focus on initiating our phase three study as quickly as possible and don't want to compromise our speed or success with FDA in trying to get global alignment for PKU. And then On the final PKU question about manufacturing, I think we have Tony on the line. Maybe I'll ask him to explain in more detail what our plans are for manufacturing the phase three material for the trial. Tony?
spk06: Yeah, thank you, Gisela. No, I think the first point you mentioned in terms of regulatory correspondence with the FDA, we've had positive support of CMC regulatory correspondence. We constantly are going back and forth, and that's on good path. To the question, I think, on manufacturing and supporting the Phase 3, we've made concrete progress in executing the plan, so we have product to supply for the Phase 3. And that comes from what I've described as maybe three different pieces. The first piece is we optimize our process, both to allow for higher yields by improving our cell densities, but we also have scaled up. The second piece is that we have completed expansion and renovation of the suite or our manufacturing facility to allow us to support this next level scale-up or the scaled-up process. And we've also completed a tech transfer into the suite, and we're really getting ready now for the future GMP activities to support the Phase 3. So the combination of the scale, the improved process cell densities that allow for high yield, the fact that we've expanded our suite, All of these pieces come together to allow us to support the Phase III, and we will provide material and support production of material for the Phase III from our current suite. Does that answer your question?
spk09: It does. Thank you. And I'm not forgetting that.
spk03: Yeah, yeah, yeah. I wasn't forgetting that, Mark. I think we have Dave Hava on the line who can maybe explain some of the biology. We've done some really elegant work in research to elucidate the role of gut And we look forward to sharing that at a future academic meeting, but maybe Dave can give you some of the high points today.
spk08: Yeah, I'd be happy to do that. Yeah, as Aoife just said, you know, I think understanding the biology and uric acid kind of metabolism and distribution has been a big component of advancing this program forward. I think for many of the metabolites we're interested in, there are multiple pools to draw on, right? There's the obvious diet component. That's true for the amino acids, oxalate. I think we think that's also true for uric acid. There are also pools of many of these metabolites that recirculate from the systemic compartment into the gut and then back out as kind of a recirculation pathway. And we've described that for phenylalanine and methionine as a potential pool to also access. We also think that happens with uric acid. And so that comes from some literature, some older literature that's really highlighted a gut component in the metabolism of just endogenous uric acid and clearance from that compartment. And so we do think that there'll be the ability of the bug to access some of that pool as well. And we have some of our own data in both rodents and non-human primates that support that. So it's likely to be both compartments. is kind of the short answer to your question.
spk09: All right. Thanks so much for that clarification, and good luck with everything. Take care. Thanks.
spk02: Thank you. As a reminder, to ask a question, you will need to press star 1-1 on your telephone. As a reminder, please hit star 1-1 on your telephone. Our next question comes from the line of Rag Huram. Selva Raju from HC Wainwright.
spk05: Hi, everyone. This is Mitchell on for ROM. Thank you for taking our questions. Hi, everyone. This is Mitchell on for ROM. Thank you for taking our questions.
spk07: I wanted to ask, you were talking about on the enrollment rate for PKU for phase three versus phase two, it could be a little less intensive. because in phase two you're collecting a lot of data, it's going to be very data rich. Could you talk about any differences that you could expect, anything you would leave out on this being a lot of data, it's going to be very data rich. Could you talk about any differences that you could expect, anything you would leave out on the phase three design versus phase two in terms of that data? In terms of biomarker collection and others, what might we see more of in the phase two that we potentially wouldn't get to see in the phase three?
spk03: Yeah, so good question, Mitchell. This is Aoife. So in the phase two study, we really wanted to do the most efficient design possible that helped us understand whether this product could be effective in lowering fee in PKU patients. We think based on the data we announced last year, that we were successful in that. I think the data is very internally consistent. We had multiple biomarkers, all arrows pointing the same way. So we know based on those data and are hoping to kind of further confirm that later this year, that the product can work. I think the phase three study is now going to evaluate and kind of sharpen up the clinical profile for this product. And there's going to be multiple learnings from the phase two that we'll take forward into the phase three design. The two most important components, I think, from my perspective as a drug developer are the proportion of patients who are going to respond, the proportion of the PT patients who are going to have a response, and then what's going to be the fee lowering in that responder population. I think those are the real critical endpoints, and that's a much easier endpoint. It's a blood sample that can be taken every couple of weeks for plasma. There's no need for meal tests, overnight fasting, intensive fasting. you know, multiple time point daily curves like we're doing in phase two. I think the second component is just making sure that we optimize the tolerability profile of the product. You know, as you've mentioned before, we have GI AEs. We've learned a tremendous amount from all of our programs in terms of, you know, how to best manage and mitigate. What we've seen is that those AEs are very individual. And I think allowing people to titrate up to the right dose and find the right dose for them is going to be a really important component of our Phase 3 study design. So I think there's both efficacy components as well as tolerability components, and I think overall we see tremendous promise based on the learning from Phase 2 that we can really optimize that Phase 3 design to be as informative as possible and also have a good enrollment rate by having it low burden for patients and for sites.
spk00: Thank you.
spk02: I would now like to turn the conference back to Ito Brennan for closing remarks.
spk03: I'd just like to close by thanking everyone for joining us today for the call. We look forward to a busy second half of this year, and thank you so much for your attention.
spk02: This concludes today's conference call. Thank you for participating. You may now disconnect.
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