Synlogic, Inc.
Q2 2020 Earnings Call Transcript

Published: 9 Aug 2020

[Operator:]

Good morning. Welcome to Synlogic's Second Quarter 2020 Conference Call. [Operator Instructions]. Please be advised that this call is being recorded. I would now like to turn the call over to Daniel Rosan, Head of Corporate Finance and Investor Relations. Please proceed.

[Daniel Rosan:]

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 second 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 this morning are Aoife Brennan, President and Chief Executive Officer; Gregg Beloff, Interim Chief Financial Officer; and Richard Riese, Chief Medical Officer. Also joining us today for questions is Tony Awad, our newly appointed Chief Operating Officer. Congratulations, Tony. During the call, Aoife will provide a brief outline of second quarter highlights and recent projects. Gregg will summarize our financial results for the quarter, and Richard will provide an overview and update on our enteric hyperoxaluria program. Following our prepared remarks, we'll open the call for your questions. As we begin, I'd like to remind everyone that comments today may include forward-looking statements made under the Private Securities Litigation Reform Act of 1995. These forward-looking statements are made as of the date hereof and are subject to numerous factors, assumptions, risks and uncertainties, which change over time. Actual results could differ materially from those contained in any forward-looking 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 statements. And now I'd like to turn the call over to Aoife.

[Aoife Brennan:]

Thanks, Dan. Good morning, everyone, and thank you for joining us on our call to discuss our second quarter 2020 financial results, recent progress and upcoming milestones. As I recently recalled during our R&D Day, it's about 4 years since I first heard about Synlogic and the concept of using synthetic biology to engineer bacterial cells to create a new class of therapeutics. The idea that we could treat diseases in a fundamentally new way captured my attention, both in terms of the challenge of working out how but more importantly, the potential I thought offer hope to patients with devastating diseases. I'm pleased to report that the underlying concept of our company excites me just as much today as it did on my first day at Synlogic. We have made great progress in bringing the promise of synthetic biology to drug development and are building the premier synthetic biology platform to engineer bacterial synthetic biotic medicines that benefit patients in new ways. Our momentum is accelerating. And I know we have the team, technology and portfolio to succeed. This, coupled with a strong cash position, ensures that we have the resources to capitalize on our strong foundation and drive our platform development and clinical-stage assets forward in the near term. One key element of the differentiating capabilities we have built at Synlogic is our internal end-to-end manufacturing capability which can take synthetic biotic medicines from the lab to the bedside at pace and with high quality. Over the past 2 years, Tony Awad has led the way in helping us build a capital efficient, best-in-class and resilient manufacturing and operations group. It gives me great pleasure to congratulate Tony today on his promotion to Chief Operating Officer. This expanded role is both a recognition of his impact on Synlogic and the confidence in our manufacturing capabilities necessary to achieve success. Tony, would you like to say a few words?

[Antoine Awad:]

Thanks, Aoife. Let me just say briefly how grateful I am to the team at Synlogic for the trust and partnership we have built over the past few years. For our manufacturing and laboratory teams, COVID has been a real mental and physical test. I'm so impressed at the way the team has risen to the challenge and continues to execute at a high level so we can deliver for our patients while maintaining the highest standards of safety and quality. I'm looking forward to seeing our portfolio advance and continuing to lead such a great organization.

[Aoife Brennan:]

Thanks, Tony. Now let me turn now to an update on our business and portfolio progress over the past quarter. We are rapidly progressing our internal metabolic disease pipeline, which leverages the ability of our platform to safely deliver a synthetic biotic medicine into the human GI tract to consume toxic substance. The metabolic pipeline is entering a clinically exciting time with the Phase II study, which we call Symphony, expected to begin in late 2020 in PKU, and our newest metabolic program SYNB8802 in enteric hyperoxaluria, expected to enter the clinic early next year. Richard will provide more detail in his remarks, but we're encouraged with the preclinical activity of SYNB8802 and the candidate is currently at IND-enabling studies. We are enthusiastic about the potential of this program to help patients with dangerously high urinary oxalate levels. Since oxalate is present in many healthy foods, enteric hyperoxaluria is almost impossible to control with diet alone. This means these patients are at risk for serious kidney complications, nephrocalcinosis, stones and chronic kidney disease. There are currently no available treatments. And so we are moving on this with the sense of urgency. Our immunomodulation portfolio also continues to advance in both immuno-oncology and immunology. We have recently regained the rights to develop synthetic biotic medicines for all effectors targeting IBD, which will allow us to fully leverage our platform to expand our GI-based program portfolio. More on that work to come as the programs mature. Let me update you now on our most advanced program, SYNB1618, for the treatment of PKU. PKU has become a hot bed of innovation for drug developers advancing new modalities. This is a credit to the efforts and bravery of patients, investigators and parents in the PKU community. But as we talk with patients and caregivers, it's clear to us that both current and emerging treatment options will continue to leave too many patients behind and a safe, tolerable, reversible and oral therapy would be welcomed. Our initial program in PKU has shown promising activity. We have demonstrated the ability to consume Phe in the GI tract, most recently in our solid oral bridging study in healthy volunteers. The next step is to understand how the consumption of Phe in the GI tract in PKU patients would impact plasma Phe levels. To answer that question, we expect to initiate the Phase II Symphony study later this year. The goals of this Phase II study are to demonstrate the potential of SYNB1618 to lower blood Phe in adult PKU patients and validate our PD model in order to understand the relationship between the production of strained biomarkers and Phe lowering for SYNB1618. To ensure we can effectively carry out such a study in the midst of the COVID-19 pandemic, we're using a flexible design in which patients can participate in clinic or in their homes. A design directly informed by patients and investigator feedback. We're looking forward to executing this study and sharing results in the middle of 2021. A key advantage of the synthetic biotic platform is the ability to rapidly iterate and improve the activity of our strains. To that end, we are making investments in our PKU strain to further optimize activity and potency. This may allow us to target higher levels of Phe lowering than we have modeled for SYNB1618. We continue to be active in the lab with multiple collaborators, including Ginkgo, our next-generation streams, and we'll be updating you as we move forward. We also continue to build our immunomodulation portfolio, which leverages our synthetic biotic platform to exploit the interaction between bacteria and the immune system in more complex diseases, including immunology and oncology. We're advancing our Phase I clinical trial of SYNB1891 in solid tumors. Despite the COVID-19 pandemic, enrollment in this study continues to tract well. The monotherapy arm of SYNB1891 study is intended to demonstrate feasibility, safety and identify a maximum tolerated dose. SYNB1891 was designed to take advantage of the immunostimulatory properties of our bacterial chassis, and we've also programmed 1891 to produce a STING agonist, cyclic di-AMP. By delivering a STING agonist directly into antigen-presenting cells in the tumor, we hope to avoid the t-cell apoptosis, which reduces the efficacy of traditional small molecules targeting the STING pathway. We highlighted initial data at our recent R&D Day in May, and we continue to see data which supports that injection of SYNB1891 is feasible and the strain generally well tolerated. To date, there are no dose-limiting toxicities or infection seen with SYNB1891 administration. We will share a fuller readout of the SYNB1891 monotherapy data closer to the end of the year. In summary, we feel that we have great potential to bring a new therapeutic approach to patients, have made exciting progress in our pipeline and are in a solid position to execute on our upcoming milestones. As you can see, across our programs, we're executing effectively to accelerate the generation of clinical data. This includes significant catalysts in PKU, enteric hyperoxaluria and immuno-oncology over the next 6 to 12 months. Now let me turn the call over to Gregg to briefly run through the financials and our updated guidance. Gregg?

[Gregg Beloff:]

Thanks, Aoife, and good afternoon, everyone. This morning, we released our financial results for the second quarter ended June 30, 2020, and I'm pleased to review those highlights with you now. Research and development expenses were $12.9 million for 3 months ended June 30, 2020, compared to $9.7 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 I study. Turning to general and administrative expenses. Those expenses were $3.5 million in the second quarter of 2020 as compared to $3.7 million for the same period in 2019. For the second quarter of 2020, the company reported a consolidated net loss of $15.5 million or $0.44 per share compared to a net loss of $12.3 million or $0.45 per share for the corresponding period in 2019. Revenues in the first quarter of 2020 were $445,000 as compared to $350,000 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. This agreement has now been terminated, and we do not anticipate any further revenue from AbbVie. Now turning to the balance sheet. Synlogic ended the second quarter of 2020 with $109 million in cash, cash equivalents and other investments. Under our current operating plan, we expect that this cash will take us into 2022 and enable us to advance our clinical programs through very important data readouts over the next 6 to 18 months. 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.

[Aoife Brennan:]

Thanks, Gregg. Switching gears, I'd like to turn over the call to our Chief Medical Officer, Dr. Richard Riese, who will provide an overview of our newest oral metabolic program for enteric hyperoxaluria. Richard.

[Richard Riese:]

Thanks, Aoife. I am going to provide an overview of our newest oral metabolic program, which has the potential to address a serious unmet need for patients suffering from enteric hyperoxaluria. SYNB8802 is an orally administered synthetic biotic that has been designed to consume oxalate in the GI tract to reduce oxalate absorption and lower oxalate levels in the urine, which has a direct and preventative impact on kidney stone formation, a hallmark of this disease. This program leverages our platform's ability to deliver an engineered bacteria into the human GI tract to consume a toxic substrate. In this case, oxalate. Oxalate is present in many of the healthy foods we enjoy and are supposed to enjoy. So reducing urinary oxalate via dietary intervention just is not feasible for most patients. Oxalate is a byproduct of normal cellular metabolism and is absorbed through the GI tract from a person's diet. Humans cannot digest oxalate, and rely on renal excretion to eliminate it from the body. If oxalate is present in the kidneys in excess, it has known to cause damage in a condition called hyperoxaluria. Hyperoxaluria often accompanies an underlying chronic bowel disease or inflammatory bowel, be it gastric bypass surgery, inflammatory bowel disease, short bowel syndrome or other causes. Stubbornly high urinary oxalate levels then put patients’ kidney health at risk, leading to nephrocalcinosis, stone formation and increasing dramatically the risk of chronic kidney disease. Hyperoxaluria presented 2 primary forms, primary or hereditary and enteric in acquired form. Primary hyperoxaluria is a very serious and rare form of a disease that usually presents in the pediatric population. It's cause of a genetic defect that results in overproduction of oxalate by the liver. Investigational treatments targeting the underlying genetic defect have shown encouraging results in this population. But such treatments would have no impact on enteric hyperoxaluria, which is pathogenic hyperabsorption of dietary oxalate from the GI tract. We are focused on secondary hyperoxaluria or enteric hyperoxaluria, an acquired medical condition, which affects over 200,000 adults in the U.S. alone. The first critical sign of enteric hyperoxaluria is often the development of kidney stones, a painful and serious consequence of the disease, which can cause great suffering and require significant ongoing interventional care for patients. This risk of kidney stones and kidney damage increases with progressively elevated urinary levels of oxalate excretion. And there is currently no approved treatment for enteric hyperoxaluria and prevention of recurrent kidney stone formation in this disease. Dietary sources of oxalate are difficult to avoid, putting patients with pre-existing bowel disease at risk for poor kidney outcomes. SYNB8802 is a synthetic biotic medication engineered to consume oxalate in the GI tract, using the same chassis organism as our PKU strain. SYNB8802 is engineered to convert oxalate to formate. Thus allowing GI absorption of oxalate and levels of oxalate in the urine. We believe this is a differentiated profile because unlike other attempts to reduce urinary oxalate, SYNB8802 exorol the GI tract. It is important to note that formate is an abundant product of normal microbiome activity and is not a quantifiable biomarker for oxalate consumption as formate is rapidly metabolized with the body -- within the body. Therefore, urinate oxalate will be a primary biomarker showing evidence of efficacy. In designing SYNB8802, we're taking advantage of several components that we have successfully used before in humans, including the E. coli nissle bacterial chassis, the F&R promoter to control expression during manufacturing and in the GI tract and assigning auxotrophy to limit replication of the strain in the body. Leveraging these reusable parts from our platform has allowed us to move quickly through preclinical development. The regulatory and clinical pathway in this indication is relatively straightforward with significant precedent by other sponsors for the importance of urinary oxalate is one critical endpoint. We will continue to work closely with regulatory authorities as we develop our clinical strategy. Our initial efficacy assessment will evaluate critically relevant reductions in urinary oxalate levels. And our goal is to reduce these levels by 20% to 50%. In terms of safety, we expect to demonstrate safety and tolerability at an efficacious dose. Our clinical development plan will give us the opportunity for a relatively rapid proof-of-concept readout by focusing after initial healthy volunteered man study on patients with enteric hyperoxaluria after Roux-en-Y gastric bypass surgery. Because the underlying bowel disease for hyperoxaluria patients can be quite heterogeneous, this post gastric bypass population provides an optimal cohort to clearly assess the ability of SYNB8802 to lower urinary oxalate. In conclusion, enteric hyperoxaluria fits with Synlogic's strategy. It is a relatively well understood biology with a high unmet need. Consumption of oxalate within the GI tract has been shown to directly lower urinary oxalate levels. Prototype strains demonstrate oxalate lowering in in vitro and in vivo preclinical studies. And modeling, which translates that activity to the human GI tract, suggest the potential to result in clinically relevant reductions in urinary oxalate. Our next steps are to file the IND with our drug candidate, SYNB8802, confirm safety and tolerability in healthy volunteers and then move to potentially demonstrate urinary oxalate lowering in a focused gastric bypass population. I look forward to providing more detail in the future. But now let me hand you back to Aoife to wrap things up. Aoife?

[Aoife Brennan:]

Thank you, Richard. As I said, it's wonderful to see our clinical portfolio expanding, and I believe, enteric hyperoxaluria is an excellent indication for our platform. I want to end by once again thanking the Synlogic team, employees and their families for the fantastic work and dedication during what has been a difficult few months for everyone. It's energizing to be part of such a dedicated team. We will now open the call for questions.

[Operator:]

[Operator Instructions]. Our first question comes from Gbolahan Amusa of Chardan.

[Gbolahan Amusa:]

Congrats on the progress. I just came off from another call, so I apologize if this was covered. But can you talk a little bit more about the prevalence of enteric hyperoxaluria, a prevalence incidence, whatever you think is relevant for the market potential? And directionally, to the extent you do get it into the clinic next year, where do you feel this sits in terms of the importance of it as a value driver for Synlogic as a company relative to your other programs?

[Aoife Brennan:]

Yes. Yes. Thanks so much for your question. There are two parts. I think I'll pass over to Richard to address the first part, which is around the epidemiology of enteric hyperoxaluria. And then I'll take the ball back for the second part around the importance of this as a program. So Richard, do you want to provide some color around the epidemiology?

[Richard Riese:]

Sure. Thank you, Aoife. Yes. Unlike primary hyperoxaluria, which is pretty rare with 5,000 to 8,000 in the U.S. alone, we believe that Enteric Hyperoxaluria is much more common. We're looking at a prevalence of about 200,000 and 2500,000 patients a year in the U.S. So it's quite a bit more prevalent. Now what -- as we discussed in R&D Day, our target patient profile will be targeting patients with Enteric Hyperoxaluria who also have recurrent kidney stones. And when you take that into account the target population becomes a bit more focused, somewhere of about 80,000 patients a year with Enteric Hyperoxaluria and recurrent kidney stones, consistent with our planned TPP at this point. Does that answer your question?

[Gbolahan Amusa:]

Yes, indeed.

[Aoife Brennan:]

Great. And I think, Gbola, in terms of the kind of general importance of the program, we think that we have 3 really important programs that are either in the clinic or moving rapidly to be in the clinic. And for us, as a company, I think the most important thing is to demonstrate that we can make a real impact for patients across any one of those indications. I think each one has an opportunity to demonstrate that within the kind of current cash window for the company. I think the nice thing about the 8802 program is that we have this nice urinary biomarker of reduced urinary oxalate levels. And our current plan, as Richard can kind of provide a little more color to, either today or later, is to initially look at patient -- healthy volunteers who were on a high -- we placed them on a high oxalate diet. But then in the kind of an expansion cohort to go into patients who have Enteric Hyperoxaluria and be able to measure an impact on their urinary oxalate lowering. And there's a really great relationship between urine oxalate levels and risk for kidney stones and kidney damage. So we think that just there's a nice development path there with a nice read through to that early phase biomarker and later kind of clinical end points. So we think that this is a really compelling opportunity for us. It's also nice from a program perspective, our bacteria have the opportunity to work on oxalate throughout the GI tract, which is, I think, a big advantage of this program and our approach, in particular. And then finally, we think that the levels of oxalate that need to be consumed by the bacteria is within range of what we can achieve. So I think there's -- we're certainly very excited by the program and looking forward to getting into the clinic and generating some data.

[Operator:]

Our next question comes from Ted Tenthoff of Piper Sandler.

[Edward Tenthoff:]

A question on the immuno-oncology program. I'm wondering sort of how that's progressing and whether you would consider partnering that at some point in the future?

[Aoife Brennan:]

Yes. As Richard mentioned in his remarks, we weren't sure earlier in the year when COVID hit how that would impact these each kind of our ongoing clinical programs. And what we've seen so far with the 1891 program is that the cancer centers have been -- patients are still getting cancer want to enroll in some of these early phase oncology studies. So I think have been relatively less impacted in those kinds of settings compared to some of maybe the more chronic disease settings. So as we said, the study is enrolling well, and we're on track to share some data from monotherapy later this year. We would -- certainly, that's a program that we've been very deliberate about in terms of seeing it as an important partnership opportunity for us while we focus on our metabolic programs is kind of our internal pipeline. What we really need to do is generate some data to demonstrate that this approach is viable, that we're not setting up -- that is a regulatory path forward, obviously, which I think we've demonstrated by getting the IND open and into the clinic, that patients are able to tolerate this, that we're not having infections with the engineered bacteria, which I think is -- has been a drawback for prior similar kind of bacterial approaches. And then I think, finally, that the bacteria are behaving as designed in the human body. And I think those are all questions that we'll be able to answer with the monotherapy arm. So I think as we continue to accrue data in the clinic, we'll continue to learn, and we'll continue to have conversations and to keep our options open around the program. So I think that's kind of the current plan, and we're making good progress against this. Does that answer your question, Ted?

[Edward Tenthoff:]

It does. Looking forward to data later this year.

[Aoife Brennan:]

Yes.

[Operator:]

Our next question comes from Ram Selvaraju of H.C. Wainwright.

[Blair Cohen:]

This is Blair Cohen on for Ram. Just a couple of questions for me. Now that the agreement with AbbVie is terminated, will you look for another partner for the IBD program?

[Aoife Brennan:]

Yes. I think IBD is a really interesting application for our platform and our technology, but is a challenging one for us to take on clinically and commercially, just because it's such a competitive space. And so I think that's firmly part of what we call our expand portfolio, which are areas where maybe we'll do some of the early work, some of the preclinical work, but then certainly look to partner if some of the early data is exciting. So that's very much the plan, Blair, there. And we'll generate some data on some of the programs and share those at the appropriate time.

[Blair Cohen:]

Okay. And for 1618, can you talk a little bit more about how you adapted the trial design for the Phase II to accommodate for COVID?

[Aoife Brennan:]

Yes. That's a great point. I'll maybe hand that one over to Richard. He's been leading the charge there from the clinical perspective. So Richard, do you want to expand a little bit on our operational plans for the study?

[Richard Riese:]

Yes, absolutely. I mean I think we've -- one thing that I'm very happy about is our ability to adapt the Phase II study for the ongoing COVID pandemic. And what we've been able to do, and this is the first time in my career is, we've been able to really design the operational aspects of the Phase II Symphony study in PKU, allowing for both home-based and office-based visits. And we've been able to adapt the protocol to operational -- allow this at all the sites. And so the patients will -- some patients, we had the -- we actually got a great -- earlier in the year when COVID was just starting, the national PKU association came to us and said, we're really interested in making sure the patients have access to clinical trials even during the COVID crisis. And we're able to get access through the PKU association for a survey directly to patients and understand their needs, their desires, and things of that nature for clinical trials. And overwhelmingly, patients were for participating in clinical trials and keeping them going. There's also a nice split. More patients preferred to do the clinical trials at home as opposed to going into the clinic, but they were amenable to going into the clinic. So we received a lot of really good feedback off this design, the Symphony Phase II trial. And now we have a trial where patients can either go into the office, if that's the preference of the patients in the sites, to conduct a visit there. And we also have the ability to conduct sites completely at home. We have trained home health care nurses, which are trained in clinical pharmacology to do all the assessments at home. And one thing that I'm really excited about is our ability to adapt quickly and make this trial available to the broadest contingent patients out there who want to participate and continue moving this project forward.

[Blair Cohen:]

Okay. Great. And then just one more on 1891. Where are you in the dose escalation process? And can you talk a little bit about how the first arm of the trial is going to inform the second arm of the trial?

[Aoife Brennan:]

Yes. Sure. Richard, do you want to continue with that one?

[Richard Riese:]

Sure. Yes. Right now, as we said on R&D Day a couple of months ago now that we had -- we're enrolling cohorts 1 and 2, and we'll continue to enroll cohorts in the monotherapy arm of that trial. So we're looking for in terms of monotherapy and specifically how it will address the combo therapy is we're looking, obviously, the primary endpoint is safety. And if it's [indiscernible] we had no dose limiting toxicities to this point, and we'll continue to move forward on that. And what we're looking for in the monotherapy arm is also target engagement which we are continuing to evaluate in terms of our engaging this same pathway and how effectively in the injected lesions. And any other clinical, we have a variety of clinical endpoints [indiscernible] that we're all looking for. These are exploratory endpoints. And we're primarily looking for those endpoints in monotherapy arm in the injected lesions. And then when we do, and I think this will all directly inform us, of how well we expect both safety in these patients when we use the combination arm and additional efficacy markers as we move into the combo arm for the study.

[Aoife Brennan:]

Yes. And so, Blair, we'll be providing a more thorough update later this year, as we've guided to, with all of the data. So you have to hold your horses until then for a more fulsome update.

[Operator:]

Our next question comes from Mark Breidenbach of Oppenheimer.

[Matthew Biegler:]

This is Matt on for Mark. Two-part question on 1618. The first, what do you see as kind of minimum, clinically meaningful reduction in Serum C? Obviously, that -- the 360 micromolar benchmark is kind of the gold standard. But if you weren't to reduce it as -- under that benchmark, what do you kind of see as at least the minimum clinically meaningful amount? And the second part of my question is, if you're also considering measuring protein liberalization in the trial. And how might you go about measuring that?

[Aoife Brennan:]

Yes, great. I'll handle the first one and maybe, Matt, hand off to Richard for the second one around how we're looking at protein. So what I will say is this is a Phase II study. So what we really want to see in the study is that we can move Phe and that our modeling is predictive of what we're seeing in PKU patients. From a product profile perspective, I think Phe lowering programs really depend on where you're starting. So there's a broad kind of phenotype of patients in terms of where they come in at their baseline Phe levels. And so what we've discussed previously is what we want to see is a 30% lowering from baseline for that to be something that we think would achieve our product profile. Obviously, we'd love to get greater amounts of Phe reduction. But that 30% is what we're aiming for minimally for 1618. Obviously, whether that gets you into the current target for the therapeutic guidance, as you rightly point out, if that's 360, that really depends on where patients start and whether they're already on some kind of protein restricted diet. If you're starting off at 500 or 600, it may get you close. And you may need to continue to take some to limit your protein intake in addition. So that's kind of how we've been seeing things in terms of the primary endpoint for a subsequent late phase study. But obviously, the proportion of patients achieving target blood Phe levels would also be an additional endpoint that we would measure in that later study. But for now, we're really just focused on looking at in the Symphony trial at the Phe lowering in patients with PKU. And you're right, diet is going to be a really important component to control. Richard, I'll maybe pass over to you to talk about how we've been thinking about that in terms of the study design. For now, Matt, we've been just aiming to maintain consistent protein intake throughout the study. And then in a subsequent study could look at the impact of 1618 on the ability to liberalize the diet. But in this Symphony study, we're going to try and isolate the effect of 1618, if you will, by maintaining the back line protein consumption pretty consistent. Richard, do you want to discuss briefly how we've been thinking about doing that?

[Richard Riese:]

Sure. One important aspect when you're looking at Phe levels and where we're at right now is to maintain a diet throughout the study, and we have very strict controls. And we think the strictest at hand, the most rigorous diet control for a Phase II study or proof-of-concept study that has been provided in patients with PKU. During the screening period, patients will record their diet for at least 5 days using a daily food intake log. And then the dietitian will interview the patients with the results and create a customized cycle menu for listing food and serving sizes for meals throughout the trial. The menus will be designed to maintain calories, protein and Phe intake. And then the patients will follow these menus and record their dietary intake throughout the Phase II trial as well as the safety as well as a follow-up period. And so in terms of our Phase II trial, where we're looking at rigorous dietary matching our intake, we worked really hard to do that to get a good proof of concept. The other point you brought up, which is very interesting to us and something we're looking at for future studies is enabling increased protein intake. As you know, adults and even pediatric patients with PKU are often times on very restricted diets, limiting their PKU, total PKU intake to approximately 10 grams per day. And this is really, really hard. It's cumbersome. It's hard for the patients, hard for the families. And we're talking with external experts as well with patients and families themselves. We believe that there will be great value in liberalizing this protein consumption limit up to 10 to 15 additional grams of Phe per day and the patients and families would really find is valuable in our future research options as we -- once we get proof of concept. You have to look into this in design study, specifically looking at protein liberalization, both in adults and maybe even more importantly, in the pediatric population liberalizing protein from 10 to up to 25 grams per day for these patients on restricted diets.

[Operator:]

Our next question comes from Yigal Nochomovitz of Citi.

[Unidentified Analyst:]

This is Carly [ph] on for Yigal. Just first on 1618, what are the gating factors for initiating enrollment in the Phase II?

[Aoife Brennan:]

Yes. So thanks for that question, Carly. We were very fortunate with 1618. We were just at a point of getting the study up and running when the COVID pandemic broke. We really had an opportunity to kind of redesign the study, realizing that COVID was not going to be a 1 or 2 months. The likelihood was that this is something that was going to continue to circulate in the community for a period of time. And I think that approach in retrospect was probably the right approach to take because we decided to pause initiation of the study and really take time to redesign. And as Richard outlined in response to an earlier question, really think about our operational strategy based on an assumption that there was going to be ongoing circulation of this virus until a vaccine was found. So we have gotten -- we looked at it from all different angles. We've gotten the plan in line. We have all of the vendors up and running. And so we're now in that kind of setup phase of the study and are on track, as we've previously guided to, initiating the study in the second half of this year. So in retrospect, I think we've been very pleased that we took that time because there's nothing worse than an open study that can't enroll. So I think we're very comfortable with where we landed in terms of the operational plan, and are looking forward to have data from PKU patients next year.

[Unidentified Analyst:]

Okay, great. That's helpful. And then just one on 1891. You’ve guided for initiating the combo arm with atezolizumab in early 2021. Just wondering if it's still your understanding that you'll have reached the MTD in the monotherapy arm by that point in time. And if you haven't, is there a possibility? Or would you consider opening a combo cohort and continuing dose escalation in monotherapy in parallel?

[Aoife Brennan:]

Yes. So we're constantly evaluating that as we see data emerge from the study. Right now, that remains the plan. But so far, as Richard mentioned, we haven't seen any DLTs and the monotherapy arm continues to go well. And so as we continue to evaluate, we'll absolutely keep you and other investors in the loop regarding our plan. But as of today, our prior guidance stands.

[Operator:]

Our next question comes from Chris Howerton of Jefferies.

[Christopher Howerton:]

So I guess maybe just a couple from me. I was intrigued by the commentary around further 1618 optimization. So just curious how you would consider any of those optimizations moving forward and how you'd be able to bridge that to the current formulation if you saw any of those attractive. Secondarily, for 8802, you mentioned one of the advantages, Richard, was that it can act throughout the GI tract. And just wondering if you could put a specific point on the bio geography that you think is most relevant, particularly in gastric bypass patients?

[Aoife Brennan:]

Great. So in terms of the PKU, as we call it internally PKU 2.0, we've really realized over the past 2 years that learning from the clinic, but also continuing to optimize is a really important component of our platform. It's a really foundational component of synthetic biology. This design, test, build kind of cycles that go through. So we've been working on -- working at whether the -- we can do better than 1618 for some time and have made some interesting progress with a number of external partners, which has allowed us to kind of evaluate what technologies can really have an impact when it comes to optimization of some of our strains, but then also can provide us with a more potent strain potentially compared to 1618. So I think for me, there's going to be 2 components around making the kind of decision, which I think is what you're getting at, Chris. Number one is going to be whether our modeling is predictive of Phe lowering in the clinic. And I think we'll learn that from the Symphony trial. As we've discussed previously, an important component of our platform is being able to predict the efficacy that we're likely to see in patients. And I think we've done some interesting metabolic modeling work. And now the rubber is meeting the road with a Phase II Symphony study and looking at how well that predicts the amount of Phe lowering that we see in PKU patients. So I think that's going to be the first kind of important information point. I think the next important information point is how much better we can do with some of these optimization technologies. We shared some data at R&D Day to show that we've made interesting progress based on all of our learnings. And I think looking at both of those, both the Phe lowering data that we see related to what we predicted as well as looking at how some of those next-generation strains are performing in our modeling will help us determine kind of the best of breed, if you will, to take into late phase development. And I know that the follow-up question that's already on your mind is, well, how a regulator is going to think about that in terms of is it one development program versus starting again at the beginning. So we haven't had any regulatory interactions around that yet. But as soon as we do and we understand a little bit more about exactly what that path will look like, we'll be delighted to share what that strategy is. Does that make sense to you?

[Christopher Howerton:]

Yes, yes, totally.

[Aoife Brennan:]

Great. So Richard, do you want to address the 8802 issue and the kind of where in the gut we think is important for the various etiologies of Enteric Hyperoxaluria?

[Richard Riese:]

Sure. I think in the R&D Day, we had Dr. Goldfarb, who's a rolling out expert in Enteric Hyperoxaluria really pointed out in healthy volunteers the importance of oxalate absorption throughout the GI tract, including the stomach, small intestine and colon. And so we wanted to sort of create an ideal product or a product that would consume oxalate in our components of the GI tract. And as you pointed out, this may depend somewhat on the anatomy and the underlying issue with Enteric Hyperoxaluria patients. For example, post bypass or gastric bypass patients who have a much smaller stomach component. The normal and thus their oxalate absorption is likely lower down in the GI tract, including small intestine, and particularly colon for these patients in particular. And what we've done to sort of answer this question as best we can prior to clinic is use our in vivo system where we've created simulated gut fluid in, in vitro model that simulates both stomach and colonic components. And this was, again, part of our presentation in R&D Day, stomach and colon components and oxalate absorption with our lead strain, which is almost identical to SYNB8802. And we're sure that we're able to consume oxalate in both the simulated compartments for stomach and colon, which I think was very important as we move forward. And indeed, we're also able to show that we've been able to get viable SYNB hacks or cells, viable cells recovered in feces in nonhuman primates, and this was done in nonhuman primates after administration of SYNB hacks in nonhuman primates. And so we think we have some pretty good evidence that we do maintain activity and cell viability throughout the GI tract.

[Operator:]

There are no further questions. Please proceed with the closing remarks.

[Aoife Brennan:]

Great. Thanks so much, Michelle. So I'd like to thank everyone for joining us today. It's been a great call, and I look forward to keeping you updated as the year progresses. Thank you.

[Operator:]

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