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spk08: Good morning. Welcome to Synlogic's third quarter 2021 conference call. At this time, all participants are in a listen-only mode. There will be a question and answer section at the end of this call. Please be advised this call is being recorded. I would now like to hand the call over to Daniel Roseanne, Head of Finance and Investor Relations. Please proceed.
spk09: 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 third quarter 2021 financial results and additional business updates. The release is available on the investor section of our website at SynlogicTX.com. Joining me this morning are Dr. Aoife Brennan, President and Chief Executive Officer, and Molly Harper, our newly appointed Chief Business Officer. Other members of the management team will be available during the Q&A. During the call, Aoife will provide a review of third quarter highlights and recent progress, including an update on our program in phenylketonuria, and Molly will share her perspective on the unmet need in PKU and the opportunity to impact patients. IFO will then return to provide an update on our metabolic portfolio. 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, uncertainties, which may 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. So, logic cautions you not to place undue reliance on any forward-looking statement. And now, I'd like to turn the call over to Eva.
spk05: Thanks, Dan. Good morning, everyone, and thank you for joining us. I'm thrilled to share with you today updates on our recent progress as well as our financial results from the third quarter of 2021. When we began 2021, we set out to prove the clinical potential of our synthetic biotic platform. We had the opportunity to demonstrate proof of concept in phenylketonuria in our Phase II symphony study, and we're thrilled to report that we've done just that. Our lead asset, SynB1618, demonstrated a robust and statistically significant reduction in plasma C-levels and clear alignment across a multitude of study endpoints. This is the first time in the history of PKU drug development that a therapeutic that is delivered and acts locally in the GI tract has had an impact on systemic fee levels. Furthermore, we believe our evolved synthetic biotic strain, SYNB1934, may demonstrate even more fee lowering activity. This is also the first example of a biotherapeutic generated by the synthetic biotic platform demonstrating robust proof of concept in a disease population. But we do not intend to stop at PKU. We're building a robust portfolio with significant progress over the past quarter in multiple metabolic indications. In enteric hyperoxaluria, as we shared at the American Society of Nephrology Kidney Week, our product candidate, SYNB 8802, has demonstrated robust consumption of oxalate in the GI tract, as measured by both urinary and fecal oxalate reduction. SYNB 8802 has the potential to be a meaningful therapy for patients suffering from enteric hyperoxaluria who face as we also reported at Kidney Week, a substantially increased risk of incident chronic kidney disease as a result of the insidious damage oxalate does to renal function over time. We continue to prosecute the proof of concept study of CINB 8802 in patients and will report on that data in 2022. We're also proud to have unveiled this week with our partners at Ginkgo Bioworks, our third oral metabolic program, which we call CINB1353. CINB1353 degrades methionine in the GI tract for the treatment of homocystinuria, or HCU. HCU is an inborn error of metabolism and a natural extension of our work in PKU, We'll be speaking more about this program as we prepare for and file an IND and advance into the clinic next year. Our immunology pipeline, while more nascent, also continues to advance. We're excited that our collaboration with Roche is to develop a synthetic biotic medicine for the treatment of IBD is off to a fast start with the first milestone already achieved. And we have also completed enrollment in the combination arm of a Phase I all-comers immuno-oncology study of CINB1891 with anti-PD1L1. We look forward to sharing data on that study at CICCI later this week. In order to focus our resources on our oral programs, however, we will not be continuing further studies of CINB1891 at this time. Synlogic today is well positioned to deliver on the promise of our platform and bring a meaningful new therapeutic approach to patients. We are executing on our strategy, focusing on rare and niche metabolic diseases where a targeted approach restricted to the GI tract can treat patients in ways other modalities cannot. Now, let me welcome Molly Harper to the team and give her a few moments to share her thoughts on the unmet need in PKU. Molly comes to us with a wealth of pre-commercial launch experience in both broad and rare diseases in the United States and globally. And we are thrilled to have her build our capabilities as we look to pivotal development in PKU. Molly, over to you.
spk03: Thank you, Aoife. It's incredibly exciting to join the Synlogic team, particularly at this momentous time. I'm delighted to share some initial observations regarding the remarkable opportunity that Synlogic has before us as we advance a program with the potential to transform the lives of those living with and those affected by PKU. As a disease and for the community affected by the disease, PKU presents something of a paradox. So on the one hand, PKU is a well-characterized disease with a community that has seen tremendous progress. It is a sizable population for a rare disease, and it has been extensively researched. The diagnosis is straightforward, and it is universally implemented via newborn screening in many countries. In the United States, every person born since the 1960s who has PKU has been diagnosed at some point in their lives. There have been ICD-9 and ICD-10 codes. There are dedicated clinics. There is a vibrant and well-networked advocacy community who provide clear links to those specialists and clinics. There are both well-defined medical subspecialists as well as dietician specialists who are clinical as well as research experts and who are passionate about taking care of and advancing research for this population. On the therapeutic side, multiple drugs have been approved. There is regulatory precedent. There are clear protocols for reimbursement. One of these therapies is now generic, facilitating empiric trial periods to determine response. What we perhaps have not heard enough about is that despite these attributes, PKU is a disease that continues to be devastating for those affected and for their caregivers. The burden of living with PKU is often extraordinary on every level, medically, psychologically, socially, economically. Much of this burden is well documented, such as a large claims-based analysis that showed that even among those diagnosed and well-insured, there remains an eight-fold greater risk of intellectual disabilities. Or a different study, which was focused on patient populations who are connected to specialized clinics, and still showed that 70% had significant neuropsychiatric comorbidities, with 50% of those with multiple comorbidities. Reflecting these disease complications and the limitations of truly transformative treatment for most patients, one study found that 70% of adults living with PKU are disconnected, and despite these drug approvals, are not receiving treatment through the established metabolic clinics. So, with multiple FDA-approved drugs, it's hard to understand why this would be the case. Looking closer, these advances, while important, have unfortunately left a majority of those living with PKU in need of additional options. Subprocteran's utility is generally limited to people living with quote-unquote mild PKU. who maintain some PAH enzyme functionality that does respond to that mechanism of action. This mild group represents a minority, about 30% of patients. This renders fee reduction for all comers that is relatively modest at just a negative 10% decrease. With this, the burden of approximately 10 pills a day on top of required dietary restrictions and needed supplements, the treatment experience can be conducive to intermittent compliance and risk of discontinuation. So it is the classic or the more severe PKU population, which makes up the majority of people living with PKU, and the population who have been most significantly underserved by options today. Pegvaliase injection does offer efficacy for those adults, but those adults who can persist through the titration, which can extend over one calendar year, daily injections, and those who have both the capacity and the vigilance to manage the risk of anaphylaxis at any moment, which is as it's characterized in this boxed warning. It is important to note that even for those who adhere to both dietary requirements and drug therapy, there is a great desire for a treatment that can provide additional fee lowering. or something closer to what most of us take for granted as a normal eating and social life. So looking to the split on the right side of the screen, the well-controlled segment represent those with more mild underlying disease who are able to respond and inherit a treatment, as well as those children whose diets are closely managed by their caregivers. The larger part of this population outlined here includes people living with PKU who are in need of a novel treatment. that provide significant reduction of plasmacy regardless of their treatment status. So for several years now, the Synlogic team has been actively listening to and learning from the PKU community who have been consistent in sharing their wish list for a new treatment option. That would be one that would be orally administered, convenient, safe, and efficacious. Designed with these exact needs in mind, The synthetic biotic approach to PKU has the potential to address these needs. The mechanism could not be more intuitive. People with PKU cannot metabolize dietary C, which enters predominantly via dietary protein. Synlogy designed a biotherapeutic with the potential to metabolize dietary C in the GI tract. The synthetic biotic is orally administered. conveniently packaged with a locally delivered mechanism without systemic absorption and the associated potential AE risk. And we recently were able to share an early view of how this has worked in those with the greatest need. So now let me ask Aoife to take you through the clinical data that we've been able to share to date.
spk05: Thank you, Molly. Earlier this quarter we presented two datasets which gives us confidence in advancing our PKU program. Firstly, in Symphony, a phase two study in patients with PKU, we achieved our target reduction in blood fee levels in an interim analysis of eight patients with available data. And secondly, in a head-to-head comparison of CINB 1618 and CINB 1934, our optimized strain for PKU in healthy volunteers, we found that the fee-consuming activity of CINB 1934 is approximately twofold that of CINB 1618. This suggests CINB 1934 may provide an even more attractive clinical profile. Based on these highly encouraging data, we will be adding CINB 1934 to the phase two symphony study and preparing to advance our PKU program into a pivotal phase three study. As you recall, our ongoing phase two symphony is a single arm study in patients with classic PKU. This population has fee levels above 600 micromoles per liter at screening and is not served by available therapies. It's a more severe population than the BH4 responsive population in which Kuvan has been studied. The interim data we shared from the first eight patients to complete the study, which remains open to enrollment, An important design element of this study is that each patient functioned at their own control. Subjects were placed on a strict diet that was designed to match their usual protein and feed intake, and had a diet run in, followed by baseline assessments. They then received increasing doses of CINB 1618 over two weeks, with repeat untreatment assessments, followed by a washout period. The diet management was maintained throughout the trial out to the day 29 assessment. There were two critical endpoints in this study. First, a meal challenge test, which were performed with a standardized breakfast containing labeled fee, here called D5 fee, at the beginning and end of the dosing period to determine if CINB 1618 prevents dietary fee absorption. Second, we evaluated fasting plasma fee. This was measured prior to dosing, after seven days, again on day 14, and at the end of the washout period on day 29. Let's begin with the meal challenge results. In these tests, the subjects received a standard breakfast containing DeFi fee. They received their first meal challenge on day minus one, and then underwent the same test on day 15. after a dose of two E12 live cells, which is the highest dose studied. The purpose of this test was to look at whether CINB1618 was metabolically active and metabolizing fee in the GI tract and preventing it from being absorbed and increasing blood fee levels. On the left-hand panel is shown the increase in blood TCA, our biomarker of strain activity, because it's a byproduct of feed breakdown by the strain. As expected, we can observe that it increases significantly with dosing. On the right-hand panel is the area under the curve of blood D5C. Compared to baseline, we observe a reduction of 40% in the amount of D5C absorbed from that meal. The combined production of TCA and lowering of blood C indicates that CINB1618 is actively metabolizing phi in the GI tract before it can be absorbed by the gut. The next key question was whether treatment with CINB1618 over two weeks would impact fasting phi levels in patients. Fasting blood phi is a critical endpoint in PKU and was the basis of FDA approval of the product previously approved in this indication. It's also the measure which physicians and patients think about the most as they manage this disease and use to assess whether or not they're in fee control. When we compared levels on treatment to those at baseline, we observed a dose-dependent reduction in blood fee levels. The mean percent change from baseline was 14% after the dose titration period, which went up to 3E11 live cells. This is represented in the graph by the first blue bar with 95% confidence intervals. The second blue bar on this graph represents the 1E12 dose, where we observed a mean 20% blood-free reduction compared to baseline. Importantly, the confidence intervals here do not cross zero, indicating that this decrease was statistically significant. Finally, on the slide, you will see what happens when patients stopped taking CINB1618, represented by the pink bar. Despite continuing study procedures, including diet management, blood fee levels increased, indicating that the observed decline in blood fee on treatment is likely a response to CINB1618. One thing that's particularly exciting to me is that this data matches very well our prospective biomarker-driven modeling, which increases our confidence that our synthetic biotic therapy is doing what we expect it to do and that we can predict its effect in patients. Also, critically, it compares favorably to prior clinical research in the field. In an all-comers analysis of the CUVAN Phase III trial, the mean blood fee lowering was 10%, with approximately 30% of patients showing a reduction in blood fee levels sufficient to be defined as responded to CUVAM. In our interim data set of symphony, the all-comers analysis demonstrated a mean 20% reduction, with half of the patients achieving a 30% blood fee lowering. What does this mean? It means that for the first time, an intervention in PKU, which is acting from the gut lumen to break down fee, has been shown to have an impact on systemic plasma fee levels, a clinically relevant endpoint in a disease population. In short, it means this approach could be therapeutically relevant for the treatment of PKU. Finally, and importantly, safety. CINB1618 acted in a gut-restricted manner. There were no serious adverse events and no treatment-related discontinuations. The adverse events we did observe were predominantly GI-related and mild to moderate in severity and consistent with the gut-restricted action of our strain and our prior experience in healthy volunteers. Now, as you know, we've also been developing an evolved, more potency-consuming product candidate, which we've called SYNB1934. SYNB1934 was developed using advanced synthetic biology techniques, which we recently published in Nature Communications. Through the first three dose cohorts and healthy volunteers in the phase one study of CINB-1934, we have demonstrated two things. First, that CINB-1934 metabolizes fee in dose dependent manner. And secondly, that it does so at approximately twice the rate of activity as CINB-1618. We think this has an exciting implication for both the PKU program and the broader metabolic portfolio at Synlogic. When we calculated the ratio of D5P production between CINB 1934 and CINB 1618, we find that CINB 1934 activity was approximately two-fold greater than that of CINB 1618. This was consistent across both biomarkers, TCA in plasma and HA in urine, and also consistent with findings in preclinical studies. With these data in hand, the important question becomes, How will the improved CINB 1934 activity translate to fee lowering in PKU patients? One way to assess this potential is to compare the activity in healthy volunteers based on the controlled meal challenge to inform activity in patients. With CINB 1618, we previously observed a 7% reduction in labelled fee in healthy volunteers, which has translated to a 20% lowering in fasting fee in PKU patients. Of note, the post-meal assessments between CINB 1618 and CINB 1934 is a cross-study comparison with the usual caveats. Nonetheless, after seeing a 27% reduction in D5C post-meal with CINB 1934, we expect an improved clinical profile in PKU patients, which is why we rapidly advanced CINB 1934 into a new arm of the symphony study to confirm its efficacy. Upon conclusion of the Symphony study, we intend to select the strain which will advance into pivotal development. Because CINB1618 meets our minimum product profile, we are in the enviable position of having potentially multiple viable assets, but we will advance only the asset with the greatest potential for a differentiated profile based on the clinical data. Validation of our platform from this groundbreaking data set in PKU has exciting implications for our other metabolic diseases. Let me briefly provide an update on our efforts in enteric hyperoxaluria. Enteric hyperoxaluria, which we often call HAAS, 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 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, This means that patients are at risk for serious kidney complications. For most patients, enteric hyperoxaluria isn't a standalone problem because the pathologic 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, or IBD, who also 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 our overall care. There are approximately 75,000 to 90,000 patients with enteric hyperoxaluria and chronic recurrent kidney stones and 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. Our approach is simple and intuitive, an oral synthetic biotic medicine which metabolizes the toxic substance oxalate in the GI tract and converts it into formate, which is harmlessly excreted. This approach is able to consume oxalate throughout the GI tract, the only one currently in development which can do so. As you may recall, we demonstrated CINB-8802 proof of mechanism in a dietary hyperoxaluria study earlier this year. We previously showed that in the efficacy analysis part of the phase A of this study, the percent change from baseline urinary oxalate level was 28.6% compared to placebo at the 3E11 live cell dose with a robust dose-response relationship. We reported at ASN Kidney Week earlier this month that other measures of oxalate reduction, including fecal oxalate, confirmed these findings. This is significant because consistent reduction of oxalate excretion in both urine and feces demonstrates that CINB 8802 is metabolizing oxalate in the GI tract in a dose-responsive manner at levels consistent with our translational modeling. The amount of oxalate consumption is significant with greater than 60% lowering of fecal oxalate concentration at the 3E11 dose. Lowering dangerously high levels of oxalate is the only way to reduce the risk of disease progression and reduce or eliminate oxalate nephropathy. CINB 8802 has demonstrated the potential to degrade oxalate at clinically meaningful rates, and as we progress the program in patients with enteric hyperoxaluria, we are looking forward to providing additional data in 2022. Now, let me hand the call over to Dan to briefly run through our financial results. Dan?
spk09: Thank you, Aoife, and good morning, everyone. This morning, we released our financial results for the third quarter ended September 30th, 2021, and I'd like to review the highlights of those results with you now. Research and development expenses were $13.4 million for the three months ended September 30th, 2021, compared to $10.5 million for the corresponding period in 2020. R&D expense consisted primarily of clinical study activities associated with CINB 1618 and CINB 8802, as well as the CINB 1891 Phase 1 study and the initiation of the CINB 1934 Phase 1 study, as well as other costs related to our collaboration with Ginkgo Bioworks for the optimization of synthetic biotic medicines. General and administrative expenses were $3.6 million in the third quarter of 2021. compared to $3 million for the same period in 2020. For the third quarter of 2021, the company reported a consolidated net loss of $16 million, or 29 cents per share, compared to a net loss of $13.2 million, or 36 cents per share, for the corresponding period in 2020. Revenue was $0.9 million for the third quarter of 2021, compared to no revenue 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 inflammatory bowel disease. Now, turning to the balance sheet. Synlogic ended the third quarter of 2021 with $150.1 million in cash, cash equivalents, and short-term investments, compared to $100.4 million as of December 31, 2020. This was buttressed by our recent financing. Under our current operating plan, we expect our cash and cash equivalents will be sufficient to fund the company into 2024. This will enable Synlogic to advance our clinical programs through important data readouts across the metabolic portfolio. Thank you for your attention. We look forward to keeping you updated on future calls. I will now turn the call over to Aoife to wrap up.
spk05: Thank you, Dan. Our team has made tremendous progress across all our programs, both in and outside the clinic. We're executing effectively with a sense of urgency. We look forward to continuing to advance meaningful new therapies for patients with PKU and other serious metabolic diseases. We will now open the call for questions.
spk08: Thank you. If you have a question at this time, please press star then 1 on your touch-tone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key. And our first question comes from the line of Kay Nakai with Chardon. Your line is open. Please go ahead.
spk01: Yes. Thank you. Just wondering if you could comment a little bit further on your newest compound, 1353, for HCU. And specifically, can you characterize the size of the market opportunity here?
spk05: Yeah. Thanks, Kay. You know, I'm going to – turn you over to Dave to talk about just the compound and the work that was done in research to get us to this point, because I think it exemplifies how we are leveraging our collaboration with Ginkgo to rapidly advance high-quality programs to the stage of being ready to move into an IND. So I think that's a very exciting element of that program. And then I'll ask Molly to make a early days there in terms of mapping that out. But we do believe there's a substantial unmet need and a sizable population of patients in need of treatment. So I'll ask Molly to make some comments on that. So first over to you, Dave, just to give a couple of the highlights on the research side.
spk10: Yeah, sure. Happy to do that. So HCU is a disease where patients have elevated homocysteine levels systemically that drives a lot of pathology that we think we can address with a gut-based approach. So homocysteine is generated from methionine. So what we have in CINB1353 is a strain that's engineered to consume methionine in the gut. as a way to prevent the absorption of methionine and its ultimate conversion to homocysteine. So that probably sounds familiar. It's very similar to the approach that we're taking with PKU and phenylalanine, and we've certainly been able to leverage a lot of our understanding and the advancement of a platform from the PKU program towards the development of CIMBY1353. As Aoife mentioned, this is also a program where Ginkgo and we have collaborated to ultimately land on the clinical candidate. And so Ginkgo was involved in kind of discovering and identifying some of the molecular components that went into that strain, namely transporter and the enzyme components that we're using to transport methionine into the bacterium and then break it down. you know, putting that into our kind of base chassis and kind of the base organism that we've developed. So, you know, we're looking forward to advancing that into IMD enabling studies and then into the clinic. And, you know, we think it's a really nice kind of extension of what we've been doing in PKU and kind of building upon that story. So, Molly, you can speak a little bit more to the market and the disease.
spk03: Yeah, sure thing. And I think building on Dave's comments about synergies from the technical side or the therapeutic development side, it's similar in terms of the commercial opportunity. So we think it's really interesting in terms of both synergies and comparisons as well as distinctions from the PKU market in some ways. I think the first point to consider from our perspective is that as a market, it is the synergies and the opportunities for a company that's already in PKU are really attractive. It's the exact same call points, the exact same prescribed or base as very similar challenges in terms of lifestyle and current burden, and in some cases even greater due to the need of current therapies. But in contrast, it's interesting, as opposed to PKU where the market has been fairly defined in terms of diagnosis, the underlying prevalence and diagnosis rate is area is really in a very dynamic situation right now. And it's particularly interesting that the, you know, the historic assumptions in terms of market size are, you know, increasingly we're learning are quite different. But the other opportunity, too, comes down to just the therapeutic potential. And so similarly to PKU, we are also hearing very clearly from this community that the opportunity for therapy that could be efficacious, safe, convenient, and orally administrated is something they're tremendously excited about and, you know, very much looking forward to. So we're really thinking about it that way in terms of the market size and potential is a very dynamic situation driven by diagnosis and awareness, but at the same time there's a lot of opportunity for us, or rather there's very attractive synergies from us given our current investment and development in the PKU system.
spk05: Yeah, just to clarify, this is Aoife here, just to clarify, you know, what Molly said, because it may not, for those familiar with PKU, may not be familiar with this element of HCU in that, you know, a proportion of patients are diagnosed at birth, but newborn screening for HCU is not 100%. So there are actually a substantial proportion of patients with homocystinuria who are diagnosed when they have their first stroke in their teens or early 20s. So for that reason, there is, you know, a little bit of variance around the PKU prevalence estimate and epidemiology is very precise because all patients are diagnosed at birth based on the heel prick test. HCU, there's a little more variance in terms of the prevalence because of those kind of later diagnosed patients because the newborn screening test is not 100% at catching those patients. So, yeah. That's just for those not familiar with the disease, just wanted to provide that additional clarity. Sorry, Kay, you had a follow-up question as well?
spk01: Yeah, just wondering with respect to the Roche collaboration, you know, you mentioned you achieved the first research milestone. So for that program or others under the collaboration, what is the next step once you reach this first milestone? Essentially, how far do you take it before you hand it over to Roche to pursue further clinical development?
spk05: Yeah. So this is a discovery phase collaboration with a single target in inflammatory bowel disease. Similar to other similar collaborations, there are a number of milestones followed by an option exercise fee that has been disclosed in our filings. And what happens subsequently is still very much open to negotiation as, as we progress. But, you know, I think both sides, both ourselves and Roche are very pleased with how things are going, the achievement of the first milestone. So quickly having, you know, initiated the collaboration earlier this year, I think has been a real positive and, uh, we're, uh, we're getting some excitement there as, as we think about, uh, using our platform in inflammatory bowel disease. So, uh, I think a great testament to the work Dave and his team have done, and I think a great relationship being established between both companies.
spk01: Okay. Well, let me jump back in queue. Thanks.
spk08: Thank you. And our next question comes from the line of Joseph Swartz with SBB Lyric. Your line is open. Please go ahead.
spk07: Hi. I'm Julie Daly in for Joe. Thank you for taking our questions. And the first one is on the PKU program. As you mentioned in your prepared remarks, the PKU market appears to be underpenetrated. You know, there are many patients who are diagnosed but are not treated. So in your opinion, what do you believe are the key drivers for adoption? Maybe you could talk a little bit more about potential commercial strategies you could employ to penetrate the PKU market that's currently dominated by one sponsor.
spk05: Awesome. Yeah, that sounds like a perfect question for Molly. So, Jury, I'm just going to pass the call to Molly to answer. provide additional color around some of the commercial strategies. Obviously, Molly's a perfect person with her extensive experience in rare disease to, I think, meet this challenge. And I'll ask her to provide some color around her plans and how she sees the opportunity.
spk03: Sure. Thanks, Deepa. So, yes, PQ is really interesting compared to a lot of other recent launches in rare diseases in the sense that there's a really high degree of awareness and There's also, you know, as Eva described earlier, very strong and consistent in the United States and most countries diagnosis rate. So it's actually, unlike a lot of other situations, not an area where there needs to be, of course, tremendous efforts in terms of disease awareness lift and things like that. So what you picked up on is really interesting. There's this very low treatment rate, right? So, you know, and why is that? And given, you know, how long the treatments have been available, And really what we hear consistently and, you know, it makes, you know, a lot of sense is that, you know, while there are two approved therapies as we described, they're inherently, you know, the first is inherently limited basically due to the mechanism. So there's a minority, there's a finite minority group of patients that based on the mechanism of their underlying disease that therapy will work out for. But it's important to know that Basically, every person diagnosed with PKU is universally triage, around age two or so. So it's not for lack of awareness, testing, inclusion awareness in the market, but really the availability of a viable treatment option that can work for a wide range of patients, but also can be safe, convenient, orally administrated, all of those points. And it's really remarkable how consistent both the clinicians and the patient community have been in describing exactly what you point out. You know, why is this low treatment rate? And it's really just fundamentally about the options that have been available to date and where that's left the community in terms of remaining medical need for a new option.
spk07: Okay, great. Thank you. And then my second question is on your collaboration with Ginkgo. How many more programs could we expect from your collaboration? And then maybe more broadly, you know, how different, you know, is 1353 different from your other programs in the clinic? You know, does it mean that the time in the preclinical development stage gets set up? Or do you think that, you know, through the Ginkgo platform, you could develop more potent drugs at the first try. Thank you very much.
spk05: Great. Yeah, Jury, that sounds like a perfect question for Dave, because I think he's the person most closely involved in the research and the Ginkgo collaboration. So, Dave, do you want to kind of comment on this?
spk10: Yeah, for sure. Yeah, so in terms of the similarity between the 1353 program and some of the, you know, the PKU programs and the HOCS program, you know, we're leveraging, you know, a lot of understanding and a lot of the molecular tools and parts, you know, that we've built as part of our platform. Right. So, you know, we're using the same chassis organism. We're using the same types of promoters and molecular switches, the same types of, uh, you know, genetic manipulations that we're making, you know, for regulatory purposes. Um, so that, that threads through everything we're doing and that's a core part of our platform and the, and the pipeline that, that we're building out behind, um, the clinical stage programs. A lot of that learning also helps us speed up how we study the organisms or how we predict their potential activity in humans. So all of the translational capabilities that we've built to predict strain activity, to model that activity in humans and therefore predict the types of impact we might have translates and is applicable. So that does allow us to go at a slightly faster pace than we might have with some earlier stage programs. The thing that is really different across the programs are the molecular components that drive the biology that we're interested in, right? So the types of specific transporters for phenylalanine, for example, and the enzymes that break down phenylalanine. And so this is where the collaboration with Ginkgo, you know, has been very fruitful for CINDI 1353, and we think will continue to be so. the real way that we're working effectively with them is, you know, they have the capabilities to both screen and, you know, deep databases to find components that might allow us to improve the activity of strains, right? Different transporters, different enzymes, enzymes with better activity, you know, as some examples. And so with 1353, they were able to, through a screening approach, identify some of those components, you know, transfer those components to us for engineering into our strains and, and ultimately building the clinical candidate. So, you know, it's a great thing for us in that we don't need to build that out internally, right? We can leverage their expertise and kind of what they built. We can focus on constructing the clinical candidates, translating the activity of those candidates into the clinic, and then really focus on the biology underlying, you know, the mechanisms that we're going after. So, you know, it's been a really great collaboration to date, and we're working with them on a number of other projects earlier stage programs, and we would look forward to updating you all on that as those emerge and get to a similar level of maturity at the CINB 1353 program.
spk07: Okay, great. Thank you very much.
spk08: Thank you, and our next question comes from the line of Ram Seville. Are you with HC Ringwright? Your line is open. Please go ahead.
spk02: Hi, morning. This is Maz on for ROM. Thanks for taking our questions. I have three quick ones, if I may. So you previously observed this kind of dose-dependent effect of SINB 1618 on fee reduction. So we've seen data 20% versus 40% reduction with the 1E12 dose compared to the 2E12 dose. As you continue to analyze data, are you able to provide any color on perhaps widening this dose range towards higher doses when you go into your pivotal study?
spk05: Yeah, thanks. That's a great question. You're absolutely correct. We have a nice dose-response relationship across all of our programs, in fact, that we've taken into the clinic, which really gives us confidence that we're hitting the right biology and that we're seeing consistent effects and that we've really achieved what we set out to achieve was making this bacterial-based platform, you know, like a traditional drug development platform with pharmacology and predictable dose response. So, you know, I think that's a really strong attribute of our underlying platform. In terms of, you know, I think you're absolutely right. We're constantly looking, how can we do better for patients? And what we've focused on for the PKU program is actually to work with a strain that has more enzyme activity per cell, rather than continuing to increase the dose of cells. So that's what we've done with 1934. So dose by apples to apples, 1934 actually gets 2x the amount of activity that we see for 16-18. I think in healthy volunteers, that behaves exactly as we predicted. We see about 2x in terms of the amount of biomarkers developed. And in healthy volunteers, we're able to see this really nice, reduction in blood fee levels after a meal, after that meal challenge. So we believe that that will also translate into PKU patients. So while it's kind of increasing the dose from a potency perspective, it's maintaining the same number of cells. You know, I think the second comment I would make is in terms of our strategy around kind of making sure we're optimizing the chemical profile of the product. The likelihood is that our phase three study will look at, you know, allow patients to individualize based on both their tolerability and their response to the treatment. So it's likely that there'll not be a single dose, but there'll be a starting dose and then a dose range where physicians and patients can adjust their dose based on their clinical response. And we believe that that's the best way that we can achieve the optimal outcome for each individual patient, recognizing that each patient will have different needs and And so there's likely to be some flexibility there in terms of getting patients onto the right dose for them. So we think both 1934 as well as this flexibility and individualization around dosing will both achieve a really interesting profile at the end of our Phase 3 program. Does that make sense? Does that make sense?
spk02: Yeah, absolutely. That's great. Shifting gears to CINB 1353, the candidate generated in collaboration with Ginkgo. I was interested in their high throughput testing code base. They were able to advance the candidate really relatively quickly. Will you be using this code base for all future lead candidate selection? Or are you going to look to develop similar capability yourself?
spk05: Yeah, great question for Dave.
spk10: Yeah, I mean, we're happy with what has come out for 1353, and we would look to replicate that for as many programs as we can into the future. I mean, I think there is no need for us to do it internally. I mean, I think the capabilities that Ginkgo has built, both with the code base and that kind of database of genetic material with which we can search for and identify, you know, enzymes and proteins and other components of interest is really valuable. You know, other approaches like specific protein engineering and building libraries and databases around that is also something that we've employed with them. And so the expectation would be we would continue to operate in that fashion and, again, really focus our internal efforts on the underlying biology, you know, the construction of the clinical candidates, you know, and really the translational aspects of, translating these strains and their activity into early clinical development. So I think we would expect it to be very similar going forward.
spk02: Great, thank you. And just finally, are you able to reveal news of any further partnerships, any opportunities in the near term in addition to the Roche and Ginkgo partnerships?
spk05: I think you already know the answer to that question.
spk04: But if we had another partnership, we absolutely would disclose it. And we wouldn't disclose anything that wasn't final. So the answer to that is no.
spk05: But our strategy, we've been very consistent and overt about our strategy, which is we're pursuing these metabolic programs internally. We continue to advance really interesting candidates that build on our experience in PKU. And then the second component of our strategy is to leverage our platform to pursue opportunities outside of that core focus in metabolic diseases. I think the progress we've made with Roche exemplifies that. You know, some of the recent publications exploring other opportunities for our platform in high-profile journals exemplifies that strategy. So, you know, strategy hasn't changed. Our ability to execute hasn't changed. and we'll continue to pursue opportunities that make sense.
spk02: Okay, brilliant. Thanks for the comprehensive update.
spk08: Thank you. And again, ladies and gentlemen, if you have a question at this time, please press star, then 1. And our next question comes from the line of Jacqueline Liu with Oppenheimer. Your line is open. Please go ahead.
spk06: Hi, this is Jacqueline Lu for Mark from Oppenheimer. We just have a few questions. The first one is regarding the 1618 in the doubt PKU. I know you've been able to demonstrate safety. Are you considering pediatric trials run in parallel with our plant pivotal study next year?
spk05: Yeah, that's a great question. I think as Molly Knightley outlined earlier in her prepared remarks, there really is a big opportunity here for an oral product in the pediatric population who, you know, if you don't respond to KUVAN, you have no opportunity for therapeutic intervention. So we see that as a key market for us, and we'll be pursuing pediatric development just as soon as we get regulatory alignment on that. And so you'll be hearing more about our plans there as those regulatory discussions progress.
spk06: Okay, thank you. And also... Assuming you can demonstrate clinical proof of concept for 8802 in the HOCS next year, what would be the most likely next steps for the program? Would you want to go right into a pivotal study in the gastric bypass population?
spk05: Yeah, so I think the key question we have there for the HOCS program would be expanding into, you know, we've chosen the bariatric surgery population for proof of concept opportunity, but we do plan to expand into other underlying etiologies. So I think making sure that the product is similarly efficacious across a range of underlying etiologies is something that we will pursue. I mean, our goal is to have as broad as possible an indication statement at launch. You know, I think whether we proceed to a phase two or go directly to a phase two three is still kind of under discussion internally and will of course depend on how clear the data is coming out of the proof of concept study. We also have some work going on with kind of generating real world evidence that I think will inform the clinical development plan. We had a really nice presentation at the ASN Kidney Week meeting last week that kind of demonstrates how we're using real-world evidence to make sure we're making the best possible decision for the program going forward. So I think both the data from the proof-of-concept readout as well as our continued understanding of the natural history of the disease and the opportunity in the patient segmentation will really inform the next step on the program, but we'll absolutely keep the investment community apprised as we make some of those key decisions.
spk06: Okay, sounds good. And also, our last question is in regards to 1934. I think the answer is no, but can you remind us if the 1934 falls under the umbrella of your collaboration with JNCO? And if so, is there any milestone or royalty obligations to JNCO if 1934 makes it to the market and eventually gets commercialized?
spk05: Yeah, so 1934 was not. It was developed with technology that actually we started a collaboration with Enevolve, who subsequently becomes Zymergen, before we had signed the Ginkgo collaboration. And the enzyme, the PAL enzyme that's inside 1934, it was actually developed by Zymergen. And so that's the kind of provenance of that strain. And just to remind you, our collaboration with Ginkgo does not involve any milestone or royalties. It's really a, you know, they have an equity stake in the company and I think are very incentivized to make sure we're getting the best possible candidates through their ownership stake in Synlogic. But, you know, we have full rights. There's no, you know, further commercial obligation downstream to Ginkgo as part of that collaboration.
spk06: Okay. That's all the questions from us. Thank you for taking our questions.
spk08: Thank you, and we have a follow-up question from Kay Nakai with Chardon. Your line is open. Please go ahead.
spk01: Yeah, just a question about the oral presentation coming up at ICIM. Is that just going to include perhaps more detail but not any new patient data per se?
spk05: Correct. Yeah, it will be the N of 8 that we presented in the press release as part of the interim, but there will be, you know, I think more data. Obviously, it's an academic presentation. It's being presented by Jerry Vockley, one of our principal investigators on the trial, and then we'll just see more detail and color. But, you know, key conclusions remain the same, and the number of patients that are included is consistent with our press release earlier this year.
spk01: Got it. Thanks.
spk08: Thank you, and I'm showing no further questions at this time, and I would like to turn the conference back over to Eva for any closing remarks.
spk05: Great. Well, thanks, everyone, for joining us this morning. It's been a pleasure to share the updates that we've had across all our programs, and we look forward to keeping you informed as we go into next year.
spk08: This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.
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