Synlogic Inc (SYBX) 2021 Q3 法說會逐字稿

Good morning. Welcome to Synlogic's third Quarter 2021 conference call. (Operator Instructions) Please be advised this call is being recorded.

I would now like to hand the call over to Daniel Rosan, 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 third quarter 2021 financial results and additional business updates. The release is available on the Investors 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. Aoife 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 and uncertainties, which may change over time. Actual results could differ materially from those contained in any forward-looking statements 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.

And 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 updates on our recent progress as well as our financial results for 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 SynPheny 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 Phe 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 locally in the GI tract has had an impact on systemic Phe levels. Furthermore, we believe our evolved Synthetic Biotic strain in SYNB1934 may demonstrate even more Phe 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 are 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 SYNB8802 has demonstrated robust consumption of oxalate in the GI tract, as measured by both urinary and fecal oxalate reduction. SYMB8802 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 SYNB8802 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 SYNB1353. SYNB1353 degrades methionine in the GI tract for the treatment of homocystinuria, or HCU. HCU is an inboard era 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 the Phase I all-comers immuno-oncology study of SYNB1891 with anti-PD-1 L1. We look forward to sharing data on that study at (inaudible) later this week. In order to focus our resources on our oral programs, however, we will not be continuing further studies of SYNB1891 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.

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 their 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 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 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 dietitian specialists who are clinical as well as research experts and who are passionate about taking care of and advancing research of 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 impaired trial periods to determine response. And yet. 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 eightfold greater risk of intellectual disabilities or a different study, which is focused on patient populations who are connected to specialized clinics and still show that 70% has 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 was 70% of adults living with PKU were disconnected and despite these drug approvals are not receiving treatment through the establishment of all 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.

So [pattern's] utility is generally limited to people living with "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 Phe reduction for all comers that is relatively modest at just a negative 10% decrease. With this, the version of approximately 10 pills a day on top of required dietary restrictions and needed supplement. The treatment experience can be conducive to intermittent compliance and risk discontinuation.

So as 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 1 calendar year, daily injections and those who are both the capacity and the vigilance to manage the risk of anaphylaxis at any moment, which is as it's characterized in this box 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 Phe 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 inherited 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 provides significant reduction in plasma Phe 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 Phe, which enters predominantly via dietary protein.

Synlogic designed a biotherapeutic with the potential to metabolize dietary Phe in the GI truck. 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 today.

Thank you, Molly. Earlier this quarter, we presented 2 data sets, which gives us confidence in advancing our PKU program. Firstly, in SynPheny, a Phase II study in patients with PKU, we achieved our target reduction in blood Phe levels in an interim analysis of 8 patients with available data. And secondly, in a head-to-head comparison of SYNB1618 and SYNB1934, our optimized strain for PKU in healthy volunteers, we found that the Phe consuming activity of SYNB1934 is approximately twofold that of SYNB1618. This suggests SYNB1934 may provide an even more attractive clinical profile.

Based on these highly encouraging data, we will be adding SYNB1934 to the Phase II SynPheny study and preparing to advance our PKU program into a pivotal Phase III study. As you recall, our ongoing Phase II SynPheny is a single-arm study in patients with classic PKU. This population has Phe 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 8 patients to complete the study, which remains open to enrollment. An important design element of this study is that each patient functioned as their own control. Subjects were placed on a strict diet that was designed to match their usual protein and Phe intake and had a diet run in followed by baseline assessments. They then received increasing doses of SYNB1618 over 2 weeks, which repeats on treatment assessments followed by a washout period. The diet management was maintained throughout the trial out to the day 29 assessment.

There were 2 critical endpoints in this study. First, a meal challenge test, which were performed with a standardized breakfast containing label Phe, here called D5 Phe, at the beginning and end of the dosing period to determine if SYNB1618 prevents dietary Phe absorption. Second, we evaluated fasting plasma Phe. This was measured prior to dosing after 7 days, again on day 14 and at the end of the [watched] period on day 29.

Let's begin with the meal challenge results. In these tests, the subjects received a standard breakfast containing B5 Phe. They received their first meal challenge on day minus 1 and then underwent the same test on day 15 after a dose of 2e12 live cells, which is the highest dose study. The purpose of this test was to look at whether SYNB1618 was metabolically active and metabolizing Phe in the GI track and preventing it from being absorbed and increasing blood Phe levels.

On the left-hand panel is shown the increase in blood TCA, our biomarker of strain activity, because it's a byproduct of Phe 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 B5 Phe. Compared to baseline, we observed a reduction of 40% in the amount of B5 Phe absorbed from that meal. The combined production of TCA and lowering of blood Phe indicates that SYNB1618 is actively metabolizing Phe in the GI tract before it can be absorbed by the gut.

The next key question was whether treatment with SYNB1618 over 2 weeks would impact fasting Phe levels in patients. Fasting blood Phe is a critical endpoint in PKU and with 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 used to assess whether or not they're in Phe controls. When we compared levels on treatment to those at baseline, we observed a dose-dependent reduction in blood Phe 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 interval. The second blue bar on this graph represents the 1e12 dose where we observed a lean 20% blood Phe reduction compared to baseline. Importantly, the confidence intervals here do not cross 0, indicating that this decrease was statistically significant. Finally, on this slide, you will see what happens when patients stopped taking SYNB1618, represented by the pink bar, despite continuing study procedures, including diet management, blood Phe levels increased, indicating that the observed decline in blood Phe on treatment is likely a response to SYNB1618.

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 chemical research in the field.

In an all-comers analysis of the Kuvan Phase III trial, the mean blood Phe lowering was 10%, with approximately 30% of patients showing a reduction in blood Phe levels sufficient to be defined as responded to Kuvan. In our interim data set of SynPheny, the all-comers analysis demonstrated a mean 20% reduction, with half of the patients achieving a 30% blood Phe lowering. What does this mean? It means that for the first time an intervention in PKU, which is acting from the gut lumen to breakdown Phe has been shown to have an impact on systemic plasma Phe 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. SYNB1618 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 potent Phe consuming product candidate, which we called SYNB1934. SYNB1934 was developed using advanced Synthetic biology techniques, which we recently published in major communications. Through the first 3 dose cohorts in healthy volunteers in the Phase I study of SYNB1934, we have demonstrated 2 things. First, that SYNB1934 metabolites Phe in dose dependent manner. And secondly, that it does so at approximately twice the rate of activity at SYNB1618. 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 D5 Phe production between SYNB1934 and SYNB1618, we find that SYNB1934 activity was approximately twofold greater than that of SYNB1618. 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 SYNB1934 activity translate to Phe lowering in PKU patients. One way to assess its potential is to compare the activity in healthy volunteers based on the controlled meal challenge to inform activity in patients.

With SYNB1618, we previously observed a 7% reduction in labels Phe in healthy volunteer, which has translated to a 20% lowering and fasting Phe in PKU patients. Of note, the post meal assessment between SYNB1618 and SYNB1934 is a cross-study comparison with the usual caveats. Nonetheless, after seeing a 27% reduction in B5 Phe post meal with SYNB1934, we expect an improved clinical profile in PKU patients, which is why we rapidly advanced SYNB1934 into a new arm of the SynPheny study to confirm its efficacy.

Upon conclusion of the SynPheny study, we intend to select the strain, which will advance into pivotal development. Because SYNB1618 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 HOX, is a devastating condition with no treatment option in which dangerously high levels of urine oxalate lead to progressive kidney damage. It often occurs as a result of a primary infill 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 early oxalate caused 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 their overall care. There are approximately 75,000 to 90,000 patients with enteric hyperoxaluria and chronic recurring 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 convert it into [formase], 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 SYNB8802 proof of mechanism in a dietary hyperoxaluria study earlier this year. We previously showed that in the efficacy analysis part of the Phase I/Phase A of the 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 oscillation Firm D findings.

This is significant because consistent reduction of oxalate excretion in both urine and feces demonstrates that SYNB8802 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. SYMB8802 has demonstrated the potential to do great 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?

Thank you, Aoife, and good morning, everyone. This morning, we released our financial results for the third quarter ended September 30, 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 3 months ended September 30, '21, compared to $10.5 million for the corresponding period in 2020. R&D expense consisted primarily of clinical study activities associated with SYNB1618 and SYNB8802 as well as the SYNB1891 Phase I study and the initiation of the SYNB1934 Phase I 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 $0.29 per share compared to a net loss of $13.2 million or $0.36 per share for the corresponding period in 2020.

Revenue was $0.9 million for the third quarter of '21 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 costs. I will now turn the call over to Aoife to wrap up.

Thank you, Dan. Our team has made tremendous progress across all our programs, both in and outside the clinic. We're executing effectively with the 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.

(Operator Instructions) Our first question comes from the line of Keay Nakae with Chardan.

Yes. 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?

Yes. Thanks, Keay. I'm going to turn you over to Dave to talk about just the compound and the work that we've 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 couple of comments on the size of the market opportunity. Obviously, 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.

Yes. 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 SYNB1353 is a strain that is engineered to consume a finding 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 SYNB1353.

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, putting that into our kind of base chassis and kind of the base organism that we've developed. So we're looking forward to advancing that into IND-enabling studies and then into the clinic, and 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.

Yes, sure. And I think building on Dave's comments about synergies from the technical side or the -- our therapeutic development side. It's similar on the -- 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. So I think first point to consider from our perspective is that as a market is, the synergies and the opportunities for a company that's already in PKU are really attractive. It's the exact same call point, the exact same prescribed over based some very similar challenges in terms of lifestyle and current burden and, in some cases, even greater due to the admin ed 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 in homocystinuria is really a very dynamic situation right now, and it's particularly interesting that the historic assumptions in terms of market size are 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 a therapy that could be efficacious, safe, convenient, and orally administrated is something we're tremendously excited about and very much looking forward to. So we're really thinking about it that way in terms of there is the market size and potentially 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.

And just to clarify, this is Aoife here. Just to clarify what Molly said because it may not -- for those familiar with PKU, may not be familiar with this element of HCU in that 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, early 20. So for that reason, there is 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 that's just for those not familiar with the disease, just wanted to provide that additional clarity. Keay you had a follow-up question as well?

Yes. Just wondering with respect to the Roche collaboration, 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.

Yes. So this is a discovery phase collaboration with the single target in inflammatory bowel disease. Similar to other similar collaborations. There are a number of milestones followed by an option – and option exercise Phe that has been disclosed in our filings. What happened subsequently is still very much open to negotiation as we progress. But 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 initiated the collaboration earlier this year, I think, has been a real positive, and we're getting some excitement there as we think about using our platform in inflammatory bowel disease. So 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.

And our next question comes from the line of Joseph Schwartz with SVB Leerink.

I'm Joori dialing in for Joe. The first one is on the PKU program. As you mentioned in your prepared remarks, the PKU market appears to be underpenetrated. 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 commercial -- potential commercial strategies you could employ to penetrate the PKU market that's currently dominated by one sponsor.

Awesome. Yes, that sounds like a perfect question for Molly. So Joori, I'm just going to pass the call to Molly to provide additional color around some of the commercial strategies. Obviously, Molly is a perfect person with her extensive experience in rare disease. She will likely meet this challenge. And I'll ask her to provide some color around her plans and how she sees the opportunity.

Sure. Thanks, Aoife. So yes, [it 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, as Aoife described earlier, very strong and consistent in the United States and most countries, diagnosed this way. 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 -- and what you picked up on is really interesting, is this very low treatment rate, right. So -- and why is that? And given how long the treatments have been available. And really, what we hear consistently, and it makes a lot of sense is that while there are 2 approved therapies as we described, they're inherently -- the first short [term] 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 mechanisms of their underlying disease that therapy will work out for. But it's important to note that basically every person diagnosed with PKU is universally tries sepiapterin around H2 or so. So it's not for lack of awareness, testing and 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 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, why is this low treatment rate? 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.

Okay. Great. And then my second question is on your collaboration with Ginkgo. How many more programs can we expect from your collaboration? And then maybe more broadly, how different is 1353 different from your other programs in the clinic? Does it mean that the time in the preclinical development stage gets set up? Or do you think that through the Ginkgo platform, you could develop more potent drug at the first try?

Great. Yes, Joori, 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?

Yes, for sure. Yes. So in terms of the similarity between the 1353 program and some of the PKU programs and the HOX program, we're leveraging a lot of understanding and a lot of the molecular tools and parts that we've built as part of our platform, right. So we're using the same chassis organism. We're using the same types of promoters and molecular switches, the same types of genetic manipulations that we're making for regulatory purposes. So that registered everything we're doing, and that's a core part of our platform and the pipeline that we're building out behind 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, right. 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 translate, right, 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 of breakdown phenylalanine. And so this is where the collaboration with Ginkgo has been very fruitful for SYNB1353, and we think will continue to be. So the real way that we're working effectively with them is they have the capabilities to both screen and deep databases to find components that might allow us to improve the activity of strains, right. Different transporters, different enzymes, enzymes with better activity as some examples. And so with 1353, they were able to, through a screening approach, identify some of those components, transfer those components to us for engineering into our strains and ultimately building the clinical candidate. So 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 the mechanisms that we're going after.

So it's been a really great collaboration to date, and we're working on with them on a number of other 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 SYNB1353 program.

And our next question comes from the line of Raghuram Selvaraju of H.C. Wainwright.

This is [Muz] on for Ram. I have 3 quick ones, if I may. So you previously observed this kind of dose-dependent effect of SYNB1618 on Phe reduction. So we've seen data of 20% versus 40% reduction with the 1e12 dose compared to the 2e12. 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?

Yes. 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 in that we've really achieved what we set out to achieve was making this bacterial based platform like a traditional drug development platform with pharmacology and predictable dose response. So I think that's a really strong attribute of our underlying platform. In terms of -- 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 get 2x the amount of activity that we see for 1618. 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 Phe levels after 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 maintained the same number of cells.

I think the second comment I would make is in terms of our strategy around kind of making sure we're optimizing the clinical profile of the product. Will -- the likelihood is that our Phase III study will look at allow patients to individualize based on both their tolerability and their response to the treatment. So it's likely that there will not be a single dose, but there'll be a starting dose and then a dose range where physicians and patients can adjust the dose based on their chemical 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 so that -- there's likely to be some flexibility there in terms of getting patients on to 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 III program. Does that make sense?

Yes, absolutely. That's great. Shifting gears to SYNB1353, the candidate generated in collaboration with Ginkgo. I was interested in the 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.

Yes. Great question for Dave.

Yes. 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 enzymes and proteins and other components of interest is really valuable. 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, the construction of the clinical candidates 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.

Yes. 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.

I think you already know the answer to that question. If we had in the partnership, we absolutely would disclose that and we wouldn't disclose anything that wasn't final. So the answer to that is no. But we are -- 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. Some of the recent publications, exploring other opportunities for our platform and high-profile journals exemplifies that strategy. So strategy hasn't changed. Our ability to execute hasn't changed, and we'll continue to pursue opportunities that make sense.

(Operator Instructions) And our next question comes from the line of [Jacqueline Lu] with Oppenheimer.

This is [Jacqueline Lu] for Mark from Oppenheimer. We just have a few questions. The first one is regard the 1618 in the out PKU, I know you've been able to demonstrate safety. Are you considering pediatric trials to run in parallel with your plant pivotal study next year.

Yes, that's a great question. I think as Molly nightly outlined earlier in her prepared remarks, there really is a big opportunity here for an oral product in the pediatric population, who, 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.

Okay. And also, assuming you can demonstrate clinical proof-of-concept for 8802 in the HOX 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.

Yes. So I think the key question we have there for the HOX program would be expanding into -- 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. I think whether we proceed to a Phase II or go directly to a Phase II III. It's 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 business 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.

Right. Sounds good. And also our last question with regards to the 1934. I think the answer is no, but can you remind us if the 1934 [fall centers] umbrella of your collaboration with Ginkgo? And if so, is there any milestone or royalty obligations to Ginkgo is 1934 makes to the market and eventually get commercialized.

Yes. So 1934 was not, it was developed with technology that it actually restarted a collaboration with enEvolv who subsequently become 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 we -- that's the kind of providence of that strain. I just to remind you, our collaboration with Ginkgo does not involve any milestone or royalties, it's really a -- 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 we have full rights, there's no further commercial obligation downstream to Ginkgo as part of that collaboration.

And we have a follow-up question from Keay Nakae with Chardan.

Just a question about the oral presentation coming up at ICIEM. Is that just going to include perhaps more detail, but not any new patient data per se.

Correct. Yes, it will be the [end of 8] that we presented in the press release a part the interim, but there will be, 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 be more detail and color. But key conclusions remain the same, and the number of patients that are included is consistent with our press release earlier this year.

And I'm showing no further questions at this time. And I would like to turn the conference back over to Aoife for any closing remarks.

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.

This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.