Good morning. Welcome to Synlogic's First Quarter 2020 Conference Call and webcast. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end of this call. Please be advised that this call is being recorded. I would now like to turn the call over to Dr. Elizabeth Wolffe, Head of Investor Relations and Corporate Communications. Please proceed.

Thank you, Carlo. Good morning, and thanks for joining us on today's conference call. Earlier this morning, we issued a press release, which outlines our first quarter 2020 financial results and several other topics that we plan to discuss today. The release is available on the Investors section of our website at www.synlogictx.com. Joining me on this call are several members of Synlogic senior management, including Aoife Brennan, President and Chief Executive Officer; Gregg Beloff, Interim Chief Financial Officer; and Richard Riese, Chief Medical Officer. After Aoife's introductory remarks, Gregg will briefly summarize our financial results for the quarter and Aoife will outline our progress for the quarter and our expected activities for the rest of the year. Following our prepared remarks, we'll open up the call for questions. As we begin, I'd like to remind everyone that comments today may include forward-looking statements made under the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, without limitation, statements other than statements of historical facts, regarding the potential of Synlogic's platform to develop therapeutics to address a wide range of diseases, including cancer, metabolic disease, and inflammatory and immune disorders; the future development of synthetic biotic medicines and the approach Synlogic is taking to discover and develop novel therapies using our synthetic biology technology; and the expected timing of Synlogic's clinical trials and availability of clinical trial data. 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-Q, which was also filed today. Synlogic cautions you not to place undue reliance on any forward-looking statements. Now, I'd like to turn the call over to Aoife.

Thank you, Liz. Good morning everyone and thank you for joining us on our quarterly update call to discuss our financial results for the first quarter of 2020 and provide an update on our programs and upcoming milestones. We hope you and your families are healthy and coping with the unprecedented circumstances we find ourselves in. As we navigate a new way of working in the face of the COVID-19 pandemic, I think it's fair to say that the recent weeks have challenged us all. At Synlogic, we're working to continue to keep both employees and patients who participate in our clinical trials safe while we operate against our strategy and advance our programs. These difficult circumstances have challenged the usual format of site visits, ad boards, clinical trials, and investor meetings. We're devising new ways to successfully conduct many of these activities virtually, including our upcoming R&D event on May 27, which I will tell you more about later in the call. Under the heading 'That You Don't Know How Strongly You Are Until You're Tested', I believe that as a company we have responded by becoming more innovative and resilient. Despite the disruptions of COVID, we've made good progress in 2020 as we continue to develop our Synthetic Biotic platform and pipeline. Innovation is part of our culture. We're developing a novel class of medicines based on engineered microbes, Synthetic Biotic medicines that have the potential to address unmet medical need in a variety of therapeutic areas. In designing our Synthetic Biotic medicines, we use synthetic biology to engineer different elements into bacteria. These include factors that can provide therapeutic benefits as well as elements that enhance the safety of the medicine. The beauty of this platform is that it allows us to use and reuse some of the same synthetic biology parts in different medicines. With every strain we build, we gain information and understanding of the utility of these reusable parts and the potential of the platform. The experience we're gaining with these components in different Synthetic Biotic medicines is enabling us to advance subsequent programs more efficiently. As an illustration, all of our Synthetic Biotic medicines thus far are based on a single strain or chassis, a nonpathogenic strain of E. coli called E. coli Nissle, which has a long history of safe use as a probiotic. Using the same chassis strain repeatedly means that we've become experts in its engineering and manufacturing. We are leaders in developing this new class of medicine and are building the capabilities and skills required across all stages of development of these novel drugs. In early March, Nature Communications published a perspective, authored by several of our scientists that provides a great introduction to the design and development of engineered microbes as therapeutics. You can access a copy of the published article on the Presentations and Publications page of the Investors and Media section of our website. Our current pipeline is focused on a couple of areas that exploit the natural properties of bacteria. E. coli are among the many types of bacteria that are able to live and function in the human GI tract. Our core focus is on metabolic diseases including phenylketonuria or PKU and enteric hyperoxaluria, in which a metabolite that is present in the gut can build up to toxic levels in the blood and other tissues. We can engineer bacteria to enable them to consume the metabolite in the gut with the potential to lower systemic levels. These disorders have relatively simple and well-understood biology and affect relatively small numbers of patients. In addition, dietary intervention in these disorders provides support for a GI-based approach. In addition to our rare metabolic programs, an important part of our strategy is to explore the breadth of our platform and evaluate the potential of Synthetic Biotic medicines in modulating the immune system. We are currently focused on leveraging the ability of bacteria to interact with the immune system in two areas; oncology and inflammatory bowel disease. We see these broader indications as areas that could be developed with a partner or collaborator. We have an ongoing collaboration with AbbVie to develop Synthetic Biotic medicines for the potential treatment of IBD. These Synthetic Biotic medicines are engineered to produce factors that down-regulate the disease-associated immune response. Bacteria can also stimulate the immune system in certain settings, and we're exploiting these properties in our immuno-oncology program with SYNB1891. SYNB1891 is a Synthetic Biotic medicine that we have engineered to express an immunostimulatory effector called a STING agonist that augments the natural properties of the bacteria. SYNB1891 is administered directly into solid tumors to stimulate the immune system to fight and potentially clear the cancer. In addition, we believe that the immunostimulatory properties of our engineered bacteria could also be used as a vaccine and have initiated an early initiative to evaluate this approach as a potential COVID vaccine working with our collaborators at Ginkgo. Work with Ginkgo has moved into high gear with the initiation of several other projects for strain improvement and optimization. We will share more details of these promising uses of Synthetic Biotic medicines at our R&D event on May 27. Before I tell you more about what we've planned for the event, let me hand over to Gregg to cover the financials for the quarter. Gregg?

Thank you, Aoife, and good morning, everyone. Earlier today, we filed a Form 10-Q that describes our financial results for the first quarter of 2020, and we issued a press release that also summarizes that data. I'm pleased to review now the highlights of those results with you. Research and development expenses were $12.7 million for the three months ended March 31, 2020, compared to $10.4 million for the corresponding period in 2019. This increase was primarily due to the use of synthetic biology services provided under Synlogic's collaboration with Ginkgo and increased clinical study activities associated with our SYNB1618 bridging study and our SYNB1891 Phase 1 clinical study. General and administrative expenses were $3.8 million in the first quarter of 2020, compared to $3.7 million for the same period in 2019. For the first quarter of 2020, the company reported a consolidated net loss of $15.8 million or $0.46 per share compared to a net loss of $12.9 million or $0.51 per share for the corresponding period in 2019. Revenues in the first quarter of 2020 were $0.1 million as compared to $0.3 million for the same period in 2019. Revenue is associated with the services performed under Synlogic's collaboration agreement with AbbVie to develop a Synthetic Biotic medicine for the treatment of IBD. Now turning to the balance sheet. Synlogic ended the first quarter of 2020 with $114.2 million in cash, cash equivalents, and other investments. As we outlined in the press release at the end of March, as a result of the COVID pandemic, we have experienced some delays in recruitment of subjects into our SYNB1891 clinical trial, as well as a potential delay in the initiation of our Phase 2 clinical trial of SYNB1618 in PKU patients. These delays are expected to push out some of our projected expenses. We are currently evaluating the effect of these delays as part of our customary long-range planning process. We iterate that under our current operating plan, we expect that our cash will take us into 2022 and enable us to advance our clinical programs through important data readouts over the next 12 to 24 months. Now before I hand the call back to Aoife, I want to introduce a new member of the finance team, Dan Rosan, who has joined us as our VP of Finance. Dan brings broad expertise in strategy, long-range planning, valuation, corporate development, capital allocation, and portfolio management. He previously spent six years at Biogen in roles of increasing responsibility in the finance and research and development departments. Now, Dan joined Synlogic just before the stay-at-home orders went into place here in Massachusetts. In the midst of a busy reporting season, he had a mere 48 hours in the office to meet the team. So it's been a baptism by fire, but he's done a great job so far. Thank you for your attention, and we look forward to keeping you updated on future calls. I will now turn the call back to Aoife.

Thank you, Gregg. As mentioned, when stay-at-home orders were implemented, our immuno-oncology Phase 1 clinical trial of SYNB1891 was in progress, with patients being screened and dosed who had advanced tumors or lymphoma. In the following weeks, patients already enrolled in the trial have continued their treatment. Although many sites have remained operational, enrollment has slowed down. While we expect to have data from the monotherapy arm of the study this year, it may not be as thorough as we initially hoped. We are exploring ways to enhance patient participation as sites become safer, and we will keep you updated on when we anticipate sharing data. With the bridging study data for SYNB1618 available, we also planned to start a Phase 2 study of a solid formulation of SYNB1618 in PKU patients to assess its potential to reduce systemic phenylalanine levels. We're progressing with the necessary paperwork to initiate this trial. Additionally, we are adjusting our plans to incorporate flexibility with virtual visits to reduce risks of future disruptions to clinical trials once this initial phase of the outbreak concludes. Transitioning to more home-based trials is under consideration for all our programs, supported by our platform and the successful formulation of SYNB1618 as a lyophilized preparation. We have made significant strides in this plan and look forward to sharing more details about the design during our upcoming R&D event later this month and in future calls. During the R&D event, alongside detailing our clinical programs in immuno-oncology and PKU, we will also provide further insights into the engine we've developed and the concept of reusable parts that supports our Synthetic Biotic platform. These foundational capabilities enable us to efficiently advance additional programs, particularly in our metabolic disease pipeline aimed at creating strains that can consume harmful metabolites in the GI tract. In this regard, we will present preclinical data from our enteric hyperoxaluria program. We will be joined by Dr. David Goldfarb, an expert in the field, who is a Professor of Medicine and Physiology and Clinical Chief of the Division of Nephrology at NYU School of Medicine, and also serves as Chief of Nephrology at the VA Medical Center. Dr. Goldfarb will provide an overview of enteric hyperoxaluria and contribute a patient perspective based on his personal experience with kidney stones. Our virtual R&D event is scheduled from 12:30 to 3:30 p.m. ET on Wednesday, May 27. More detailed registration information can be found on the Events calendar in the Investor and Media section of our website, and we hope you can join us. The past weeks have tested the nation and introduced new operational methods for all of us. Throughout this period, our aim has been to keep our employees safe. Many have been able to work from home, which, as we are discovering, presents challenges but is manageable in this era of video conferencing. However, due to our ongoing laboratory work, we have also had to establish a work schedule that allows these activities to continue while maintaining social distancing. I want to commend all my colleagues for their resilience and remarkable dedication during this time to keep our operations flowing smoothly so that we can pursue our strategy and mission of developing Synthetic Biotic medicines to help patients with unmet medical needs. In summary, we have a clear mission to develop Synthetic Biotic medicine for patients with unmet medical needs. Our strategy leverages the platform engine we have built to cultivate an internal pipeline of metabolic programs, where our engineered bacteria are designed to eliminate metabolic toxins from the GI tract, alongside broader immunology indications expected to be developed through collaborations and partnerships. Importantly, we are well-prepared to meet this challenge with a solid cash position that will support us through key milestones for our platform. Thank you all for joining us this morning. We will now open the call for questions.

Thank you. Our first question is from Mark Breidenbach of Oppenheimer. Please go ahead with your question.

Hey, good morning and thanks for taking the question. Aoife, I was just wondering if you can give us a sense of where we are in the SYNB1891 dose escalation process? And how many cohorts you would want to complete before feeling comfortable with presenting interim data from the trial?

Sure. So we announced with our press release around the beginning of the cohort that we were dosing patients in the second cohort of that dose escalation. The aim of that trial is to see target engagement at a relatively well-tolerated dose. And it's difficult right now to project how many cohorts that's going to be. And you know certainly, we'd like to continue to escalate. And so far the safety and tolerability profile appears to be amenable to continue to escalate. But as with every Phase I study we're kind of feeling our way along with regard to kind of safety and tolerability early on. So it's really very difficult Mark to say whether we'll be achieving maximum tolerated dose at the fourth or the fifth or the sixth cohort right now, just given where we are. And so I think it's going to be one of these issues of kind of feeling our way through the dose escalation and looking at the biomarkers as we go along. And certainly, if we feel that there's something meaningful to discuss we'll do just that.

Okay. That makes sense. And a quick follow-up, I'm just wondering if it would make sense to activate any new trial sites in the SYNB1618 study to maybe focus in geographies that are relatively less affected by COVID? Any plans to expand the number of trial sites there?

Yes, it's difficult. We're obviously watching very closely. The biggest lever for us in the PKU program is going to be bringing the trial to the patient's home so that you're not bringing patients into a medical center or clinical trial center. We recently received some feedback from the Patient Advocacy Organization around patients with PKU and their appetite for coming into a center versus having maybe a study nurse visit them at home. And I think the response to that survey has been overwhelming. Patients are very amenable to having the study come to them in their homes with maybe a single nurse visit and a telehealth visit from the investigator to take any of the medical information. And my personal belief is that I think that's the way trials are going anyway. So if we can get ahead of the curve and invest in some of those capabilities now, I think it will stand us in good stead for the long term. We have looked geographically, and it's as you know a moving target. And early on it seems like we may be going to regions that appear to have good control and have seen very low numbers of cases that might be a good way. But even there some of those regions of the world have seen an uptick in cases now that they started to loosen up and open up their economy. So it's difficult to predict where in the world. And as you know, it can take about six months to open up the trial sites in some of these new regions. So it's almost like looking through your crystal ball at six months in the future. But I think diversification is definitely the name of the game. Flexibility and being agile is definitely the name of the game. And I think as I said earlier, allowing more things to occur virtually I think is the way that clinical trials are going to get done over the next year or so. So we've been moving in that direction.

Thank you. Our next question is from Raghuram Selvaraju of H.C. Wainwright.

This is Blair Cohen on for Ram. Just a couple of questions for you. How is the enrollment proceeding for SYNB1891? Can you give us a little bit more detail there? And when might the second arm of the trial begin enrollment? Could this still happen before the end of the year?

In terms of enrollment, we have observed that patients already participating in the study can come in for dosing. However, most of the academic medical centers involved in the U.S. study have slowed down the intake of new patients for ongoing studies, leading to a noticeable decline in enrollment. Despite this, we anticipate that many of these studies and centers will resume operations over the summer, especially for oncology trials. There is a growing understanding that these patients will continue to progress, and often, participating in the trial might be their only option. Among the studies affected by COVID, oncology trials are likely to be among the first to restart once it is safe to admit patients. Regarding your second question, the study design stipulates that we need to reach the maximum tolerated dose in the monotherapy arm before we can initiate the combination therapy segment of the trial. This means the timeline is contingent on how many cohorts we must dose to achieve that maximum tolerated dose. As I mentioned earlier when responding to Mark's question, it is still early in the study to predict whether we will reach the maximum tolerated dose after the fourth or sixth cohort, so this remains uncertain. We are making every effort to accelerate enrollment in the latter half of the year by opening additional sites, and we will keep the investment community updated as we progress through the study and gather more information on the safety and efficacy of the agent. At this moment, it is challenging to make any predictions.

Okay. Perfect. And last question for me. Do you think sepiapterin is a competitive threat in PKU?

I'm not familiar with the product you're referring to.

The molecule – the molecule, I may be pronouncing it wrong. Sepiapterin.

It's that product that's the analog of Kuvan?

Yes.

Okay. So the issue with Kuvan is an analog of BH4, which is a cofactor for the PAH enzyme. That's the endogenous way that those of us who don't have PKU metabolize phenylalanine to tyrosine. A small subset of patients with PKU respond, whether it's Kuvan or a Kuvan-like agent. The subsets of patients who actually respond to Kuvan is about 20% to 30%. So we see that, certainly, if patients are responding to Kuvan and doing well, they're not going to be a candidate for our product. But there is still a large proportion of patients with PKU who either don't respond to Kuvan or a Kuvan-like product or who have a suboptimal response, meaning they see some decrease in their blood Phe levels, but they don't actually achieve the therapeutic target. And so we were aware, Kuvan has been approved for some time now. So there's a good idea of how many patients are candidates for that product. We don't see it as a threat necessarily. We actually see that there could be some complementarity at some point down the road if we can achieve blood Phe lowering.

Perfect. Thank you very much.

You're welcome.

Our next question is from Ted Tenthoff of Piper Sandler. Your line is open.

Good morning. Happy Friday.

Hey, Ted. How are you?

I'm glad to hear everyone is doing well, and I'm looking forward to the R&D data. That's steal your thunder, but maybe to kind of ask a question a little bit on a higher level. I'm wondering sort of, where you are in terms of for the platform in general ratcheting up potency on primary mechanism? But also in terms of looking at introducing secondary mechanisms into the chassis, I'm really just trying to think at a high level where this technology can start to show meaningful differentiation versus other modality? Thanks so much.

Thank you, Ted, for the great question. I'll address this in two parts, as it's aligned with our strategic thinking. First, regarding our internal pipeline in rare metabolic programs, we believe that success hinges on selecting targets that are feasible based on our learnings from PKU. We will choose targets where the required metabolite consumption aligns with what we've established from our initial PKU insights, which is why we are pursuing the enteric hyperoxaluria program. We think that the necessary metabolite consumption for clinical benefit is manageable with our current capabilities. The second key to our success is enhancing the ceiling of metabolic activity to improve potency and handle higher metabolic loads. Over the past year, we've gained significant insights through collaborations with Ginkgo and other technology partners, which have helped us optimize bacterial strains for specific functions. This insight is beneficial across various biomedical applications, including increasing the metabolite consumption by bacteria. You might have observed that Ginkgo is also collaborating with others like Moderna to optimize manufacturing steps for their vaccines. Thus, the application of synthetic biology to enhance activity—whether in manufacturing or in vivo metabolic processes—is an exciting area of ongoing research for us. Now, moving to our external pipeline, we're focusing on complex diseases that often require multiple effectors. The ability to combine elements within our platform was one of the factors that initially attracted AbbVie to collaborate with us. This capability allows us to integrate various factors that can perform different functions in vivo, which is crucial. For example, with SYNB1891, our preclinical data indicates that we can activate various aspects of the innate immune response simultaneously, a feat that is difficult with other approaches. While we will take a measured approach as we explore this space, it presents a medium to long-term opportunity for us, and we're excited about our potential to disrupt the field. This realization has been incredibly energizing for us over the last few months.

Sure. That's excellent. That's helpful. And I can imagine that Ginkgo is helping out with those capabilities. I think that's a great partnership. Thanks so much. Looking forward to the R&D Day.

Thanks.

Thank you. Our next question is from Yigal Nochomovitz of Citi. Go ahead. Your line is open.

Hi. This is Samantha on for Yigal. Thanks very much for taking my question. So maybe building on the prior question and specifically for maple syrup urine disease. I noticed that you're still working on maybe further optimizing that but you have some initial data that you've included in your corporate deck pretty striking trend in your base molecule and then how Ginkgo is able to allow you to optimize? I wonder can you just tell us a little bit more about what further optimization needs to be done for that? And then just maybe a broader question in general, how do you know when your optimization process is complete? I imagine you could continue to go through many iterations here. Just curious on your thought process there.

Yes. So it's a perennial issue in drug development when it's good enough to move forward into the clinic. What we've been able to build based on our lead programs is to establish a set of go/no-go criteria for a clinical candidate. So once we start on the program, we'll be able to set a set of criteria around how does that program need to look before we move forward into the clinic. I'll just give you kind of an illustrative example if you will. In enteric hyperoxaluria, we know that we all eat about 150 to 200 milligrams of oxalate in our diet every day. We know that in patients with enteric hyperoxaluria, it's very, very difficult to get rid of oxalate from your diet because it's in vegetables and fruits and lots of different things. But if you can, you know when the enteric hyperoxaluria that's there the oxalate will go down. So that gives us some benchmarks in terms of how potent a strain needs to be to move forward into IND-enabling studies. So we'll use that understanding of saying, okay we need to engineer a bacteria that can consume 150 to 200 milligrams of oxalate at a dose based on what we've learned from PKU that's well tolerated and that will have good manufacturing characteristics. We always want to have the ability to get this into one capsule or one pill. So we're able to make some calculations based on those learnings. Then we can calculate back how much oxalate does 10^9 cells need to be able to consume per hour in order to be good enough to move forward. We continue to do our iterative optimization until we hit that target. Programs that hit that target get to move forward into the next year. You get to take two steps forward on your snakes and ladders game. Programs that don't reach that target continue to be optimized. Programs that move forward, de facto, have kind of achieved what we think we need from a potency perspective. In the case of maple syrup urine disease, we have made tremendous progress with Ginkgo, but it hasn't achieved the bar that we believe is needed from the potency perspective to meet our minimum product profile based on our calculations. So that one continues in optimization, how we've made great progress. There's still some things that we think could continue to improve that strain and that continues to be a work in progress. Others where we've achieved that goal, we're moving forward into development. That's kind of how we think about our drug development framework. We're learning all the time and continuing to tweak those criteria, but the idea is that hopefully if we're doing a good job, every program we take forward has a higher probability of success based on learnings from programs that went before. This process has been worked out for protein biologics and small molecules. We've had to work it out for Synthetic Biotic medicines. I think we've made some good progress there and will continue to learn as we go along. Does that make sense?

Yes, that was very helpful and fair. Regarding the enteric hyperoxaluria program, could you provide a preview of the mechanism of action? How many synthetic circuits have you incorporated into that asset? Do they produce a biomarker, similar to how 1618 produces hippuric acid that can be measured, or is that unnecessary for this particular disease since measuring plasma oxalate levels is straightforward?

Yes. So the biomarker there would be oxalate lowering. Certainly, prior companies who have been working in this space have demonstrated that it's possible to increase urinary oxalate in healthy volunteers by putting them on a high oxalate diet, and that could be a useful way to demonstrate proof of mechanism in vivo. I can't spill too many beans. Otherwise, people won't come to our R&D event, but we'll certainly show the full engineering and all the preclinical data that we've developed to date and some more of the work and future plans at that event later this month.

Our next question is from Joe Schwartz of SVB Leerink. Please go ahead with your question.

Thank you. Good morning. I hope you're faring well. I was wondering if you could give us some more insight into how you stand in terms of the rate-limiting steps to starting the next trial for SYNB1618? And what you see as the biggest challenges in this environment for the next phase of clinical development? It seems like we're tentatively entering a period of somewhat more relaxed public behavior. But obviously, there are IRBs that need to be maintained, perhaps amended, things like that. So I was just wondering if you could give us some more insight into how you feel well-positioned with enough sites given this environment? And how intensive this trial needs to be?

Yes. We'll provide all the details regarding the study design at the end of the month. One positive aspect we've noticed during the COVID pandemic is that many busy metabolic physicians are now available for more interaction with us. They have been more accessible for phone calls and virtual discussions than they were six months ago, allowing us to engage with them and understand the local situations at each site. Some IRBs are still operating and providing feedback on protocols virtually, while others are focusing on emergency INDs and adjusting according to their specific circumstances. Just as different states are reacting in various ways here in the U.S., we see many local variations in how each site is functioning. It’s important to recognize the unique challenges at each site when developing a protocol that can be implemented in a way that accommodates each site's specific needs. We believe that this time has strengthened our relationships with advocacy organizations and sites, and has refined our approach to executing these studies, especially as we shift towards more home-based trials for the PKU program and future initiatives. Our goal is not just to survive this period, but to use these challenges as opportunities for operational growth. We are confident that all visits for the upcoming study could potentially occur virtually in patients' homes if necessary, and we’re working on a home-based virtual setup. While there are logistical considerations such as shipping medication directly to patients rather than to sites, these are manageable. We have been surveying vendors and organizing logistics to offer maximum flexibility. Richard has been overseeing this effort, and I invite him to add anything he might want to share about our progress.

Yes, I think you've covered it, Aoife. We've taken the opportunity to reach out to investigators, patients, and home health care providers to plan our next steps. It's clear that investigators are excited about our upcoming study and that patients are interested in their involvement. There is a general shift towards telemedicine, whether you call it virtual or at-home visits, for both clinical trials and clinical services. We continue to push forward with the necessary paperwork. Recently, the National PKU Association contacted us, allowing us to conduct a patient survey for PKU patients regarding their responses to coronavirus and their interest in study participation. We found that many patients are still interested in participating in studies, with 86% indicating they would consider involvement in a fully virtual trial. This aligns with our previous statements. We've also been reaching out to home health care providers to ensure flexibility in our next study, whether that means a traditional clinic visit or conducting everything at home, including the tracer study we typically do for PKU. We are preparing to take the next steps and conduct these studies.

That's really helpful. Thanks for the added information.

Thank you. Our next question is from Julian Harrison of BTIG. Go ahead with your question please.

Hi, good morning. Thank you for taking my questions. For MSUD and enteric hyperoxaluria, just wondering if you plan to start clinical development with the liquid formulation like you did for SYNB1618 or is a solid form from the beginning in the realm of possibilities here? And on enteric hyperoxaluria specifically, kidney function seems like a very important aspect of the natural history here. So just curious how you plan to consider the spectrum of CKD in future development?

Yes. Our preference would be to move forward with the lyophilized form from the get-go, and that's certainly what we're planning to do right now. Unless there's some reason not to do that, that's how we plan to proceed. The nice thing about having our own manufacturing infrastructure means that we're not relying on supply chains or vendors that may be in parts of the world that are more or less affected by COVID. So as of now, I don't see any reason why we wouldn't move forward with the lyophilized product straight from the get-go. Sometimes things happen where you feel like, okay maybe we should learn something with liquids rather than wait for lyophilized. But as of today, our plans are that we would start clinical development straight away with the lyophilized product based on what we've learned from PKU and just implement it. In terms of kidney function, I might hand that over to Richard. He has a lot of experience with oxalate disorders from his time in Alnylam. I think he's probably best positioned to answer that particular question.

Yes, I think for our initial studies will be done for PH1 and also for enteric hyperoxaluria aim at doing a proof-of-concept in patients without severe kidney disease and look at urinary oxalate excretion models. Does that answer your question?

It does.

Next one is from Chris Howerton of Jefferies. Please go ahead with your question.

Thank you. Good morning everyone. I have two questions. For the virtual or home-oriented clinical trials, I would like to know what kind of capital expenditures you're allocating to enhance those capabilities. Additionally, I’m curious about the implications for the number of clinical trial sites that may be needed for each trial. Lastly, have you thought about moving away from E. coli due to some tolerability issues possibly related to the presence of LPS in the patient's gastrointestinal tract? Thank you.

Yes. I'll take a stab at both parts of your question, Chris. The first one in terms of the capabilities to do virtual clinical trials has been around for a while. Each component that's required to do a successful virtual trial has been established. Some of the challenging components are just setting it up and getting it going in real-life kind of thing. In terms of how that impacts the number of sites, generally what happens is there's kind of a central site that provides oversight of a number of virtual groups. As Richard mentioned, for our initial PKU study, we're going to have a hybrid, so the protocol will be written flexibly such that patients can come to and have a traditional center, they can do some visits at home, or the entire study can be conducted virtually. We're still at kind of the early days of working out what the implications of that are on the number of centers that we would have in the U.S. We'll certainly learn as we go here and learn from others who have gone down this path. But I think doing more remotely is definitely the way of the future. So whatever time and effort we invest now I think will pay off. In terms of the capital expenditure, some costs increase obviously, but other costs decrease when you're doing these kinds of studies. Our initial assessment is that the distribution of costs will change as we look at the study plan, but the overall ballpark of how much it will cost us to execute the study will stay relatively flat compared to a type of traditional setup. In terms of the chassis organism that we're engineering in, listen, there's no perfect chassis, right? There are certainly advantages of using E. coli Nissle, and then there's the potential that other chassis organisms may have lower LPS and maybe have better tolerability. Certainly, for now, we're committed to E. coli Nissle. We think that there may be trade-offs where you move to a different chassis, but you actually have to dose much higher because it's more vulnerable to digestive enzymes and low pH compared to E. coli Nissle. There are constantly pros and cons, and no matter what chassis organism you choose to base your engineering on. We know E. coli Nissle now. We know it and love it for all its faults. We think that we have a lot of experience engineering it. Certainly, as we go forward, we're constantly evaluating bringing a second chassis on board, as I talk about this shelf of reusable parts. Once we get to a point where we really think that we know and we've gotten our arms around engineering and manufacturing E. coli Nissle, we may add another chassis organism to that shelf of reusable parts. Our assessment now is that that will be based on capabilities, maybe a chassis that is better at secretion, and a chassis that is better at colonization as opposed to something based on tolerability. That's how we think long term. But in the short term, we're pretty committed to Nissle.

Okay, great. I have another question regarding the enteric hyperoxaluria program. I would like to clarify if you plan to target patients with chronic kidney disease and what you believe the approvable endpoint will be in this context.

Yes. As Richard mentioned earlier, we'll initially be focusing on patients with good renal function. This is because we have a strong understanding of urinary oxalate as a biomarker, which becomes difficult to interpret in patients with very low kidney function and chronic kidney disease. Our primary population will consist of those with decent renal function. However, we see significant potential in patients with chronic kidney disease. These patients often experience systemic oxalosis due to being unable to excrete oxalate through urine, leading to its accumulation in the heart and other tissues, which can result in multisystem oxalosis. There is a substantial unmet need in this group. After establishing proof-of-concept in patients with adequate renal function, we will explore this secondary population. We still need to determine what the approvable endpoints might be, such as evaluating cardiac function through echocardiograms or measuring plasma oxalate levels. We're in the early stages of our planning and haven't had any regulatory discussions regarding the path forward for this second population or indication. Nevertheless, we believe that, based on the underlying biology, this represents a great opportunity. If urine production is absent, the only way to eliminate oxalate is through feces. This is where we see our potential. Based on fundamental principles, we view this as an excellent opportunity. Does that make sense?

Yes. Okay. Very good. Yes, that definitely does. Okay. Well, thanks so much for taking the questions and look forward to the event in, I guess, just a few weeks.

Great. Thanks, Chris. Talk to you soon.

Okay. That concludes the Q&A session. I would now like to turn the call back to Aoife Brennan.

Great. Well, thank you so much everyone for joining us today, and we look forward to seeing many of you at the end of the month at our R&D event. We'll be available later today if there are any follow-up questions. Thank you, operator.

This concludes today's webcast. Thank you all for attending. You may now disconnect.