Synlogic, Inc.
Q4 2019 Earnings Call Transcript

Published: 13 Mar 2020

[Operator:]

Good afternoon. Welcome to Synlogic's Fourth Quarter 2019 Conference Call and Webcast. [Operator Instructions] Please be advised that today's conference 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.

[Elizabeth Wolffe:]

Thank you, Ian. Good afternoon and thanks for joining us on today's conference call. Earlier this afternoon, we issued a press release, which outlines our fourth quarter and full year 2019 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 the call are several members of Synlogic senior management, including Aoife Brennan, President and Chief Executive Officer; Gregg Beloff, Interim Chief Financial Officer; and Dr. Richard Riese, Chief Medical Officer. After Aoife's introductory remarks, Gregg will briefly summarize our financial results for the quarter, and Richard will provide more detail about our new program enteric hyperoxaluria. Following the 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 clinic development of Synthetic Biotic medicines; the approach Synlogic is taking to discover and develop novel therapeutics using synthetic biology; 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 statement as a result of various factors, including those described under the heading Forward-Looking Statements in Synlogic's press release from earlier today or under the heading Risk Factors in Synlogic's most recent Form 10-K which is also filed this morning. Synlogic cautions you not to place undue reliance on any forward-looking statements.Now, I'd like to turn the call over to Aoife. Aoife?

[Aoife Brennan:]

Hi, good afternoon. Thanks, Liz. Good afternoon, everyone, and thank you for joining us on our quarterly update call to discuss our financial results for the fourth quarter and full year for 2019, and provide an update on our programs and upcoming milestones. I have to defend is to develop a novel class of living medicines called Synthetic Biotic medicines, using synthetic biology to engineer non-carrier to perform therapeutic functions. We believe that Synthetic Biotic medicines have the potential to provide new solutions for patients who are currently underserved by conventional medicines.We're pleased to be able to begin 2020 with notable progress in our Synthetic Biotic pipeline. In December, we announced data from our lead program for PKU, demonstrating that a solid oral form of SYNB1618 could achieve a higher maximum tolerated dose compared to liquid, and is metabolically active, consuming phenylalanine of Phe in the GI tract. Based upon learning's from this program, we have advanced two new programs in metabolic disease, a second rare heritage metabolic.Hello, could you hear me?

[Elizabeth Wolffe:]

Yes. Hello?

[Aoife Brennan:]

Hello?

[Elizabeth Wolffe:]

We can hear you, Aoife.

[Aoife Brennan:]

Operator?

[Elizabeth Wolffe:]

Aoife, we can hear you.

[Aoife Brennan:]

We began 2020 with notable progress in our Synthetic Biotic pipeline. In December, we announced data from our lead program for PKU, demonstrating there is a solid all form of SYNB1618, could achieve higher maximum tolerated dose compared to liquid, and is metabolically active, consuming phenylalanine or Phe in the GI tract. Based upon learning's from this program, we've advanced two new programs in metabolic disease, a second rare inherited metabolic disease, maple syrup urine disease or MSUD, and an acquired disease enteric hyperoxaluria. Both of these programs will be built with parts we've established previously, our sheffy [ph], E.coli Nissle, promoters we use to turn genes on and auxotrophies [ph] that we know behave well in the fermenter and in vivo. We've asked Richard to provide an overview of hyperoxaluria program later in the call, and to explain why it's a great application for Synthetic Biotic medicines.In addition to our rare metabolic programs, an important part of our strategy is to explore the breadth of our platform by evaluating the potential of Synthetic Biotic medicines in broader indications, including immune-based diseases such as inflammatory bowel disease, or IBD, and oncology. We have a collaboration with AbbVie to develop Synthetic Biotic medicines for IBD, and are progressing our IO program. In January, we announced that we had treated the first subject in our open label Phase I clinical trial of inter-tumorlian [ph] administered SYNB1891 in patients with advanced solid tumors or lymphoma.Our collaboration with Ginkgo Bioworks enables the rapid optimization of Synthetic Biotic candidates and complements our in-house experience in strain design and engineering. Ginkgo has developed it's code base, which is an extensive library of microbial sequence data, and uses software and automation to assemble and test new strains to enable an optimization of candidate. Their technology provides us with access to a cutting-edge synthetic biology base self-programming platform. The collaboration is going very well with multiple projects underway. These projects have the potential to continue to feed an exciting pipeline of programs.On the corporate side, we announced earlier this year the appointment of a new member to our Board of Directors, Dr. Mike Burgess, who is President of R&D at Turnstone Biologics, a clinical stage viral immunotherapy cancer company. Mike is a physician scientists with over 20 years of drug research and development experience, and a track record of success in translational development, including roles at Roche, Bristol Myers Squibb and Lilly; we're delighted to have him join the Board and have already appreciated his engagement and input as we develop our novel Synthetic Biotic medicines.Our strategy from the start of the company was to move initial programs quickly into the clinic to gain clinical and regulatory experience, and an understanding of where our Synthetic Biotic medicines will be best deployed while continuing to invest and build the driving engine of this platform. We've learned a tremendous amount, particularly from our lead PKU program, which has provided not only practical experience in engineering, manufacturing, and regulatory interactions, but in the value of pharmacodynamics, in vitro and preclinical modeling. This program has also served as a guide for our strategic decisions for pipeline development, and the levels of potency that we will need to achieve before advancing programs into clinical studies. I'll summarize these lessons later in the call.However, first let me hand over to Greg to cover the financials for the quarter and full year 2019.

[Gregg Beloff:]

Great, thank you, Liz. Good afternoon, everyone. Earlier today we filed the Form 10-K that describes our financial results for the full year 2019, and a corresponding press release that summarizes both, the quarter and year. And I'm pleased to review the highlights of both of those with you now.Research and development expenses were $11.3 million in the fourth quarter of 2019, compared to $8.9 million for the fourth quarter of 2018. This increase was primarily due to the use of synthetic biology services provided understand Synlogic's collaboration with Ginkgo, and increased clinical study activities including SYNB1618 bridging study, and the initiation of our SYNB1891 Phase I clinical study. General and administrative expenses were $3.5 million in the fourth quarter of 2019, compared to $4 million for that same period in 2018. For the fourth quarter of 2019, the company reported a consolidated net loss of $12.8 million or $0.37 per share, as compared to a net loss of $11.9 million, or $0.47 per share for the fourth quarter of 2018.Revenues in the fourth quarter of 2019 were $1.2 million as compared $0.1 million for the same period in 2018. Fourth quarter 2019 revenues were associated with the services performed under the Synlogic collaboration agreement with AbbVie to develop a Synthetic Biotic meta-treatment of inflammatory bowel disease. The increase in revenue for the fourth quarter of 2019 compared to the same period in 2018 was as a result of revised estimates of time and effort required to reach certain milestones in this collaboration.For the full year 2019, total operating expenses were $56.6 million in 2019, compared to $53.8 million in 2018. The consolidated net loss for the full year 2019 was $51.4 million or $1.70 per share, as compared to a net loss of $48.4 million or $2.03 per share for 2018. Revenues were $2.2 million as compared to $2.5 million in 2018, and again, were associated with our collaboration with AbbVie.Turning to the balance sheet; Synlogic ended the fourth quarter of 2019 with $127.1 million in cash and equivalents. And under our current operating plan, we expected this cash will allow us to continue operations into 2022.In summary, we have the balance sheet strength to advance our ongoing clinical programs through important data readouts over the next 12 months, and to accomplish our near and mid-term goals as we continue to develop our platform and pipeline. We look forward to keeping you updated on our busy year ahead.Thank you. And I'll now turn the call back to Aoife.

[Aoife Brennan:]

Thanks, Greg, and apologies for the technical difficulties earlier with my line everybody. As you heard, our solid cash position enables us to advance in SYNB1618, our lead program in PKU through the upcoming Phase II clinical trials of our solid formulation in patients with PKU, and SYNB1891, our oncology program through Phase I study in patients with advanced solid tumors or lymphoma. Importantly, we also expect to advance several of our early stage programs in our core area of focus, rare metabolic disease.As I mentioned earlier in the call, our PKU program provides us with valuable information on the potential of our Synthetic Biotic platform. The data we've obtained has reinforced our conviction around the next set of therapeutic targets that we're pursuing in rare metabolic diseases. In each of these indications as with SYNB1618 for the treatment of PKU, our Synthetic Biotic medicine is designed to consume toxic metabolites from the GI tract with the goal of lowering the levels of the metabolites in the systemic circulation. Our clinical data from the SYNB1618 program has given us confidence that this approach is safe, and that our engineered bacteria accomplished what they were programmed to do in the human body. We know definitively from our studies in both, healthy volunteers and patients with PKU, that SYNB1618 is consuming Phe in the GI tract.The bridging study in which we evaluated the activity of a solid oral formulation of SYNB1618 has demonstrated that we can produce a solid oral form of our Synthetic Biotic medicines that retain good viability, activity, and stability under refrigeration and at room temperature. In addition, due to manufacturing process improvements, it's better tolerated compared to the liquid formulation. The next step for this program will be to advance the solid oral material into a Phe-lowering trial in patients with PKU, which we are on-track to initiate in the first half of this year. As I've mentioned earlier, we've demonstrated that the strain is consuming Phe in the GI tract. The next question we would like to answer is whether the strain is consuming sufficient Phe to change systemic levels in patients.We continue to learn about the predictive value of in vitro, preclinical and pharmacodynamic modeling. The upcoming Phe-lowering trial will allow us to evaluate if SYNB1618 is performing as predicted based on our modeling. The feedback loop between the clinic and preclinical assays and modeling is a key component of our research and development strategy. For example, our experience in PKU is helping us to set potency criteria for advancement of new candidates Synthetic Biotic medicines into clinical development.We've also gained useful experience in the clinical and regulatory development of Synthetic Biotic medicines through our interactions with regulatory agencies, in not just the US but in Canada and Europe also. To date, regulators have been receptive to our approach and have provided useful feedback. Based on this experience, we're moving quickly to advance our new programs in enteric hyperoxaluria and MSUD. Similar to PKU, MSUD is another inherited amino acid apathy. Although in the case of this disease the defect is in the metabolism of branched chain amino acids

[Richard Riese:]

Thank you, and good afternoon, everyone. I-fuild [ph] is a compound commonly found in plants that humans are unable to metabolize. We primarily depend on excretion via urine and feces to eliminate oxalate from the body. Hyperoxaluria are caused when there are significantly elevated oxalate levels in the urine due to either production/overproduction of oxalate by the liver, as a result of a genetic defect; this is known as primary hyperoxaluria or from over absorption of oxalates from the diet, which is classified as secondary hyperoxaluria.Secondary hyperoxaluria can be further characterized into different types. One form is enteric hyperoxaluria, which is a consequence of certain intestinal disease, including Crohn's disease, and short bowel syndrome, as well as surgical procedures such as bariatric weight loss surgery. So disorder can lead to a range of conditions of increasing severity from recurrent kidney stones, and urinary tract infections to chronic kidney disease, and potentially the need for a kidney transplant. There are an estimated 80,000 patients with severe enteric hyperoxaluria in the US. These are patients who experienced recurrent kidney stones, and are at risk for kidney failure due to this disorder. This is a patient group that we will target first with our therapy.There is no approved pharmacologic therapy for the reduction of urinary oxalate excretion in patients with hyperoxaluria, either primary or secondary. Existing treatment options are non-specific and include high fluid intake to increase urine output to more than two or three liters per day, a low diet -- a diet low in salt and oxalate, and oral citrate and calcium or magnesium supplementation. Despite these strategies, many patients continue to experience hyperoxaluria with painful recurrent kidney stones, and are at continued risk for long-term kidney damage.We have engineered Synthetic Biotic medicines that are designed to degrade oxalate in the gut to prevent it's absorption by the body. We have demonstrated efficient oxalate degradation in vitro in our simulated gut system. In preliminary studies in mice, the oral delivery of a prototype Synthetic Biotic strain led to reduction of oxalate in the urine of treated animals. While it's difficult to eliminate normal oxalate from the diet, as it is present in so many natural foods, we do know that if patients fed a synthetic low-oxalate diet for a period of time, blood and urinary oxalate levels fall, and levels of urinary oxalate are closely correlated with disease severity over the long-term.We also know that the average diet contains roughly 100 to 200 milligrams of oxalate a day. So this gives us a range of levels of oxalate that our engineered bacterial strains need to consume, and allows us to mark the potency that we will need to achieve to potentially have an effect on urinary oxalate levels. Based on modeling and the in vivo therapeutic effects we have observed, we intend to optimize and select a Synthetic Biotic lead candidate and advancing it into IND enabling studies this year as a potential therapy for patients with enteric hyperoxaluria. We look forward to updating you on our progress later this year.I'll be happy to take questions at the end of the call. But now, let me hand you back to Eva.

[Aoife Brennan:]

Thanks, Richard. Enteric hyperoxaluria is a program that we're very excited about. As Richard mentioned, this is an acquired metabolic disorder that has significant unmet medical needs, and our Synthetic Biotic approach could provide a meaningful therapeutic option for patients. Working from our experience developing SYNB1618, we've been able to move pretty quickly in the early development phases of our hyperoxaluria program, as there are many similarities with PKU.Similarly, we are engineering bacteria to consume a toxic metabolite that's available in the GI tract. We can also model the average daily intake of the metabolite to aid us in defining a therapeutic profile, and the levels of oxalate consumption that our bacteria have to achieve. Unlike PKU, the levels of oxalate that needs to be consumed are significantly lower than the levels of Phe. In addition, the metabolite is present throughout the GI tract, not just in the small intestine, which provides a greater exposure time to our bacteria and a longer window for them to work. We had expected to be able to share more information with you about our platform and pipeline later this month and to provide a KOL and patient point-of-view with an invited speaker as an R&D event that we had scheduled for March 24. However, given the COVID-19 outbreak, as you would expect, and after discussion with our advisors, we've made the difficult decision to postpone this meeting until later this spring when we expect to have a clearer picture of the [indiscernible] progress.Aside from delaying our R&D day plans, we're hopeful that the outbreak will have minimal effect on the progress of our programs. Clinical trial materials for both, our ongoing Phase I study in 1891 in patients with advanced solid tumors or lymphoma, and our upcoming Phase II trial of SYNB1618 is already manufactured. We're able to manufacture adequate material for preclinical studies in our hyperoxaluria and MSUD programs as our manufacturing is in-house, and we have taken appropriate measures to secure supplies of our raw materials earlier this year, when it looked as if there may be shortages. For the clinical sites involved in Phase I study of our IO program SYNB1891 have all instituted plans in the face of the outbreak to limit exposure of patients to the coronavirus, such as limiting in-person visits by clinical trial monitoring. As of this time all sides continue to screen and enroll subjects, and we remain on-track to share data from the monotherapy arm of the study in 2020.Thus far we also remain on-track to initiate a Phase II efficacy study of our solid oral formulation in patients with PKU in the first half of this year. The study is designed to evaluate the potential of SYNB1618 to lower systemic Phe levels in patients, and will provide important additional information about the validity of our pharmacodynamics, and preclinical and in vitro modeling. With the new stable formulation, patients will be able to go back to their normal lives during the study, which will include a dose ramp and stomach acid buffering with PPI. While this study is in progress, we will also continue to further evaluate different presentation of the solid SYNB1618 material, such as enteric-coated capsules and press pills [ph]. I look forward to providing more details on the study, and the data that we plan to collect at our R&D event and on future calls this year.While we don't yet have a firm date for the rescheduled R&D day, our goal is to host this event in the first half of the year. Coming up, we have a strong cash position that will carry us in data in both, clinical programs and are making good progress as we build a pipeline of Synthetic Biotic medicine in metabolic diseases.I'd like to thank all of you for joining us this afternoon. We will now open the call for questions.

[Operator:]

[Operator Instructions] Your first question is from Joseph Schwartz from SVB Leerink.

[Joori Park:]

Hi, I'm Joori Park dialing in for Joseph Schwartz. Thank you for taking our questions. Our first question has to do with SYNB1618. Could you just remind us what you're hoping to see in the Phase II bridging study? And with multiple PKU drug candidates development, are you anticipating some difficulty enrolling PKU patients? And what are you doing to ensure you enroll in a timely manner?

[Aoife Brennan:]

Yes, thanks so much Joori for that question. I'm going to start off a little bit maybe, and then hand it over to Richard, who is the Chief Medical Officer, and will be really leading the last of the both, strategic, but also the operational components of the study. And as you can imagine, with COVID-19 and other changes to programs in development at other companies, it's an evolving landscape. And -- but first off, I think just to clarify, you know, I think you were asking a question about the Phase II Phe-lowering trial and not necessarily the bridging study. And is that correct, Joori?

[Joori Park:]

Yes, that's correct. Thank you. I think I missed the Phe-lowering.

[Aoife Brennan:]

The Phe-lowering, yes, exactly. Yes, so that's the big thing that we want to achieve from that study. As I mentioned in the script, we've demonstrated that the strain is consuming phenylalanine; we're able to measure the product of the biomarkers. We've made some estimate that will translate to from a Phe-lowering perspective. I think the big question now for this program is, how accurate is our modeling and how well are we able to predict based on those biomarkers, the level of Phe-lowering that we get in patients with PKU? And that's really the overarching goal of that study. Of course, we'll be collecting biomarker data and we'll continue to collect information about safety and tolerability in PKU patients, but we really are looking to address and validate some of the modeling that we showed late last year from the program.Richard and his team have been doing a great job to design the trial. And hopefully we'll be able to share kind of more information about specifically the design later this year. But really, the overarching goal is to evaluate how well our modeling can predict Phe-lowering in PKU patients. I hand it now over to Richard to discuss getting the study done.Richard, if you'd like to take that part of the question, that would be great.

[Richard Riese:]

Sure, absolutely. You know, I think you brought up some -- certainly some salient points that we're not the only company doing studies in PKU, and I think it's also speaks to the unmet medical need and the need out there for alternative therapeutic options. I think Synlogic, and certainly, leadership at Synlogic has quite a bit of experience doing studies in rare diseases. And you know, one of the big points is to do your homework in terms of feasibility assessments where you go with the competition law, and where we think we can recruit patients and we're working hard on all those aspects.I think one good thing for Synlogic is we do have some experience from our 001 study and recruiting PKU patients, we recruited 11 PKU patients, for one arm and the 001 study. So we have some experience of where to go in terms of academic, and in other sites in finding these patients, and we're going to continue to work hard at -- as I said, feasibility finding sites and finding patients and making easy -- yes, the other aspect is making it easy for patients to participate in the study, make it easy and convenient and making the study visits -- that's limiting the number of in-house study visits, and the complexity of the trial, we're taking all that into consideration now as we move aggressively to start this round.

[Joori Park:]

Okay, thank you. And then, if I could just ask one more question. So you've been thoughtfully executing studies in an iterative manner to systematically build your platform. And you briefly talked about this in your opening remarks, but I was just wondering if you could just kind of expand on your learning so far, and new lessons that you plan to integrate, whether it be manufacturing or strain optimization techniques into your new enteric hyperoxaluria program?

[Aoife Brennan:]

Yes. So, I think you're spot on in terms of your characterization Joori about how we're really building this platform, hopefully in a thoughtful and iterative manner where things that we've learned from a lead program can be rapidly applied to programs that are going behind. I think that was a big driver in terms of the kind of focus around these rare metabolic diseases where you there is a lot of similarities in terms of the biology, in terms of the formulation and delivery. And as you know, you followed the company carefully for some time now, and you know, our ability to manufacture and deliver a product that was stable at room temperature and refrigeration, that was well tolerated and really could be scaled up in manufacturing was a key challenge for us that we've been kind of able to make a lot of progress on. We're certainly not done yet, and we'll continue to work on that because it's such a key success factor for us and for our platform.In terms of how we've been thinking about applying those earnings to the next set of programs, one thing for sure is that we'll be applying a lot of the assays and the manufacturing methodology that we've established with PKU to those next programs. I think the second component that we're able to do is, really know if that's kind of what dose and that calculates how much potency you need per cell as a given dose in order to achieve our target product profile. So, it really does allow us now to start to push a framework around go, no go criteria for preclinical programs, and to know when good is good enough for a program to move forward into clinical development.So I think we've learned a tremendous amount in the last year and 18 months, and have built a lot of foundational capabilities that we're hoping to leverage with this next wave of programs that we'll advance.

[Joori Park:]

Okay, great, thank you. That's very helpful. That's it from me.

[Operator:]

The next question is from Mark Breidenbach from Oppenheimer.

[Mark Breidenbach:]

Good afternoon and glad to have you back Aoife.

[Aoife Brennan:]

I know, I'm doing some social distancing, and it's not working so well so far, but we'll get used to it.

[Mark Breidenbach:]

Let me start with maybe two very quick ones on 1618, and then one follow-up on 1891. So maybe this is related to the first question; I'm wondering, is it reasonable to expect that enrollment criteria in the Phe-lowering trial will be very similar to the patients who are enrolled in your previous study? Or are you going to be targeting any specific levels of serum Phe for picking the right patients for this trial? And another question on 1618 is on the enteric-coated capsules. I'm wondering if any of these will make it into cohorts in the Phe-lowering trial or if those would have to be tested in healthy volunteers first?

[Aoife Brennan:]

Yes. So I think to answer your first question, Mark, I think it's a fair assumption. We do think that this -- the project, if we can achieve our project profile has brought clickability [ph] across multiple different patient types and patient segments. But we think that the best place to start is in the adult population with elevated baseline sea levels. And once we demonstrate that, we can predict Phe-lowering based on our modeling and that we're kind of moving the needle there in terms of Phe levels we're seeing. Then we can start to think about expanding and looking at other efficacy endpoints in different populations, for instance, in patients who may be partially controlled with [indiscernible] and can we bring those patients into the target range. But for now, we're very much starting and sticking with the adult population who have elevated Phe levels. So, I think your assumption around the patient population being broadly similar to the patients that we enrolled in the Phase I study is absolutely correct. And I think that's the right way to think about this.In terms of the formulation work and the second part of your question; you know, it's always challenging to keep guess studies done versus wait to be able to enroll, add-on cohorts with different formulations. Our assessments and what we're hoping to show is if we can show this, the biomarkers and the healthy volunteers in the modeling we've done really does predict well, what happens in patients with PKU, the huge advantage that gives us from a development perspective is that we can actually do a lot of development work in healthy volunteers, and move a lot more quickly and with the program compared to having to do a lot of evaluation of different formulations in patients with PKU. So that's really an advantage of this program that we're hoping to leverage in order to be maximally efficient as we go through kind of some of these cycles of iteration and different formulations. I would anticipate that that was -- that's what we'll do with enteric-coated capsules, when we have the development work done. But we haven't formalized that plan yet but it's a good advantage for us being able to do some work in healthy volunteers, particularly if we show that we can accurately predict what's going to happen from a Phe-lowering perspective in PKU patients.Does that make sense?

[Mark Breidenbach:]

Yes, got it. That is very helpful. And let me do a quick one on 1891, given that we have some data coming in the not too distant future. I was wondering if we could get your thoughts on what would be the earliest indicators of differentiated activity for 1891 versus the naked cyclic-dinucleotide class of compounds. Is there something more granular than Type-1 interferon response to look for that would be an early indicator that your product is behaving differently in tumors than other things we've seen in the clinic?

[Aoife Brennan:]

Yes. So, I think as you know from the program, there is three different ways that we think are fundamentally different from the small molecule STING agonist. Number one is that we stimulate multiple different pathways in the immune response, and certainly based on our preclinical models, and some work we've done with human white blood cells in vitro; what we see there is, we simulated Type-1 interferon response, that's greater in magnitude compared to the doses that have been or the comparable doses of the naked STING agonist. But we also stimulate other immune pathways, and so one of the endpoints that we'll be looking at from a PG perspective in this Phase I study is not just the Type-1 interferon pathway, but some of those other additional pathways as well. And we'll be hoping to see that we are able to induce a robust Type-1 interferon response as well tolerated dose. With that we're also seeing evidence of some of those other pathways that could be really important in terms of an immune response. So that's the first thing.I think the second two ways that we're different are; the second one is, that we have this longer profile as the naked STING agonists that are given into tumorly have a very short half-life, our bacteria are designed to be able to survive for upto a week in the tumor microenvironment. So, we'll be also looking at that.And then, the third one is this T-cell apoptosis. So it's going to be difficult for me to think about how we can measure that in vivo, in humans and the human clinical trial. But certainly ex vivo, we've looked at that with and shown that the STING agonist is actually intracellularly in the bacteria, and only gets to leave when those bacterial cells are engulfed by APCs. But you know, how that correlates in the clinic, I think it is going to be challenging until we get to an efficacy study.And then in efficacy study, we're going to want to see that higher doses are more efficacious, and that we've avoided this kind of inverted U-shaped dose response curve that seems to impact some of the other STING agonist-based approaches.

[Mark Breidenbach:]

Okay, thank you for that. And congrats on the progress.

[Operator:]

The next question is from Giga Nakamovich [ph] from City.

[Samantha Semenkow:]

Hi, this is Samantha on for Giga [ph]. Thanks very much for taking the question. I appreciate all the detail in the prepared remarks, you mentioned that the hyperoxaluria biotic, it's able to be used all throughout the gut, that's where it's able to consume oxalate. I wonder if you could maybe expand upon that and how you're using your earnings in 1618 and 1022 to sort of investigate? Is there a specific part of the gut that maybe works best or is it truly active throughout the whole gut? And maybe you could -- maybe give us some information as well about the Maple Syrup Disease biotic along the same lines?

[Aoife Brennan:]

Yes. So I think the -- one of the reasons that we're very excited about that enteric hyperoxaluria is that as you mentioned, Samantha, that it works throughout the GI tract. And we know that this approach is validated, others have done studies with oral enzyme based approach showing that working in the gut that you can reduce your oxalate levels. Our approach involves the bacteria being able to consume that all the way along the GI tract. We know that there's available oxalates in the GI tract in both, the small intestine and the colon; but we know as of today, based on the preclinical work that we've done is that the bacteria are active, both in a simulated upper GI environment as well as the simulated lower GI environment, that's anaerobic. We know that it works in vivo in a preclinical mouse models, we haven't yet done any larger animal models but would intend to do that later on this year.So I think based on the data that we've seen and what we know about the physiology of oxalate, we think that there is a nice opportunity for a bacterial-based approach that will work both, in the small intestine like the PKU program, but that also will have some activity in the colonic environment in the large intestine, as well.And I think you referred to the 1618 and 1020 programs, and some of the learning's there. And of course, those learning's have absolutely been integrated into this program. You know, we're using a lot of the modeling that we've developed for PKU program to conservatively model the activity of the strain, assuming that it's only active in the small intestine based on what we know around kind of duration of activity from the PKU program; so that's absolutely been informative. And then, from the 1020 perspective, as we were designing the stream, realizing that, you know, the -- not to get too technical but the bacteria when they switch into the large intestine, they switch to anaerobic metabolism. So you need to have circuits that don't require ATP, and the circuit that we engineered for the prototype stream of the Hawks [ph] program doesn't actually require quite ATP.So, we're learning as we're going along and finding out where at best to apply this platform. And based on the data that we have today, you know, hyperoxaluria seems like it could be a really nice opportunity for us.

[Richard Riese:]

Eva, this is Richard. Just [indiscernible] that we believe in, in Derek Cooper [ph], actually. Yes, colon is a very important place clinically for these patients; so getting to the colon and consuming oxalate; we believe will be a real benefit to our platform in treating these patients with really high unmet medical need.

[Samantha Semenkow:]

Great, thank you for all that additional detail. And maybe sort of sticking to the theme? Let's say you know, you're just starting to face Phe-lowering study but if I could maybe look forward and make some assumptions and assume that you know everything comes up positive and your modeling is validated. And it sounds like, you said that earlier in your prepared remarks that oxalate -- you don't need to necessarily consume as much as you do for Phe for 1618. Is it fair to say that there is maybe a lower bar for oxalate potentially? And then if you're modeling is validated for Phe that can have a positive reason to your oxalate program, that's potentially even other programs in your pipeline?

[Aoife Brennan:]

Yes, I think you know, Samantha, what we're really trying to build this is credibility for the platform. So I think anything that we can do to show clinical meaningfulness, particularly in these rare metabolic diseases; I think makes us feel more confident in programs that are coming along behind. And so we certainly interpret it that way, and there are -- I'm kind of moving logically with the platform and trying to develop similar types of programs so that there is that maximum learning's that can be applied to the programs that are going before. But I think your assumption around the levels of substrate that needs to be consumed with oxalates are correct. And as Richard mentioned in his scripts, our daily -- the average daily intake of oxalate is about 200 milligrams, your average daily intake of Phe is about five grams. So, just from the sure math perspective, there is a lot less oxalate in the diet and lot less oxalate in the GI tract that needs to be consumed.

[Samantha Semenkow:]

Great, that's helpful. Thanks very much for taking our question.

[Operator:]

The next question is from Ed Tenthoff from Piper Jaffray.

[Edward Tenthoff:]

Great. Thank you very much and thank you for all of the updates, and I'm glad to hear you guys are staying safe. Two questions, if I may. Firstly with 1618 in PKU, how can the FDA view existing therapies? Is this something where you would have to go on top of [indiscernible] or other agents out there? Or because they're not ubiquitously used; is there still the opportunity to demonstrate monotherapy activity and even potentially get monotherapy activity? And I guess a quick follow on to that is, would you ultimately -- because of the mechanism-of-action, see synergy with other approved agents out there? So those are the two questions, and then I have a quick housekeeping if I may.

[Aoife Brennan:]

Yes. Hey Ted, how are you? I'm good to actually ask Richard to address the question around the clinical development plan. So far what we've been proposing is a monotherapy indication, and we've had a lot of regulatory interactions around the program. And that certainly is the path that we continue to pursue, and I think it's kind of a first-line indication. Richard has been in a lot of those meetings since joining the company, so I'll pass you on to him to maybe add some additional color there in terms of the feedback and guidance that we've received.

[Richard Riese:]

Yes, thank you Aoife. Yes, so when we've had discussions with a variety of regulatory authorities, both in the US and in ex-US, and most of the discussions have been around -- at least getting the initial approval as a monotherapy. And it's as you said, that -- Kuvan [ph] is efficacious in approximately 30% of patients, so it's not efficacious in all patients and PacBell [ph] is not for everybody. You know, it's only for adults with immuno-genetic issues with that. So, most of our regulatory interactions have been around as a monotherapy. You bring up some interesting questions, like could it be used as combination therapy? There is no scientific reason why that wouldn't happen, they are totally different mechanisms-of-action. And yet, although I wouldn't use the word synergy, I certainly would expect that the advocacy will be additive to other mechanisms-of-action such as Kuvan that are currently available in the US and other markets. And I think I had at other parts of the world where we wanted to talk with regulators, they don't have access to Kuvan, they can -- so are very interested in any alternative therapies that come along with that. I think very productive discussions there.

[Edward Tenthoff:]

Great. Excellent, thank you. I appreciate that perspective. Greg, if I may, just a quick question on the revenue side. With the early recognition of $1.2 million in the quarter, does that kind of exhaust the amortization? Was that a separate upfront? Does this sort of zero out the revenues going forward from the AbbVie line? Thanks very much.

[Gregg Beloff:]

Sure. So generally, what we don't do is comment on how revenues will be coming in in the future. But the way to look at this is just typical of our own proprietary research, just as in collaborations, there are periods of intensity, and then, there are laws and periods of intensity. So, as you know, as part of the collaboration we're -- our efforts are underwritten; and so that's really where you see the spike in revenue in the quarter.

[Edward Tenthoff:]

Okay, thank you very much.

[Operator:]

Thank you. The next question is from Raghuram [ph] from H.C. Wainwright.

[Unidentified Analyst:]

Good afternoon. This is Edward on for Ram, I appreciate you guys taking our questions. For the 1618 study, just wondering real quick what the timeline is to deliver top line data?

[Aoife Brennan:]

Liz, do you want to address that question?

[Elizabeth Wolffe:]

I'm sorry, I missed it. Could you say it again, Ed?

[Aoife Brennan:]

The guidance on top line data from the Phe-lowering study.

[Elizabeth Wolffe:]

We've not given guidance on the -- we've given guidance on the initiation of the study. And at this point, until we get things up and running, particularly with the current situation we're not giving guidance on when we expect to have data, we're moving as quickly as we can and we have experience with some of the centers, they're in academic centers, so they take a little while to get going. And as we said, the situation as it is, is a little hard to know but once we get things up and running and start enrollment, we will certainly be trying to give you as close an estimate as we can.

[Unidentified Analyst:]

Excellent. And what is the likelihood that future development in PKU would be pursued with a different strain? And if this will be the case, how much more bridging work do you think you'd have to do?

[Aoife Brennan:]

Yes, I think -- that's certainly a great question. As we've discussed on previous calls, we are working on -- since we initiated the Ginkgo collaboration, we're working on strain optimization, and one of the first projects that they worked on with us was optimizing the PKU strain. We're in new territory with our platform and in terms of how regulators think about sameness versus differentness, if you will. The really important thing from a timeline perspective is how much of our preclinical work can be cross-referenced in any future interaction if we were to make changes, for instance, that involved the sequence of the strain. I think at that point, when we think we have something that's an interesting and viable, we would need to go back to regulators and make the case that our preclinical work was applicable, depending on what that strain looked like, and would obviously look to move as aggressively as possible.But I will say to date, regulators have been very flexible with us, we've taken a very science-based approach that they have appreciated and have given us a lot of flexibility. And obviously, because this is a rare disease, we also get a lot of opportunity to interact with the agency. And -- so, I'm afraid for now the best advice is as much as we can say, we think we'll be able to move efficiently but until we kind of get into it with regulators, it's going to be hard to say exactly what that data package needs to look like.

[Unidentified Analyst:]

Okay, that makes sense. And just two more quick ones. Just wondering if you intend to assess 1891 in additional regimens beyond that double-combo with eccentric [ph] or this is all as planned?

[Aoife Brennan:]

Yes, that said. Do you want to speak to this one, Richard and given that you're leading the clinical program for 1891 and have had some thoughts about specific indications?

[Richard Riese:]

So the question was around different indications or different combinations, sorry? I hope that also broke out. Did you get that, Liz?

[Elizabeth Wolffe:]

No. Different combinations?

[Unidentified Analyst:]

Yes. In additional regimens beyond the double-combo with eccentric [ph]?

[Richard Riese:]

Yes, so right now we are conducting a Phase I study with -- and first time as a monotherapy, which really determining the MTD, the maximum tolerated dose of -- for monotherapy. And the second arm, once we get the MTD it will be in combination with [indiscernible].

[Aoife Brennan:]

We have no plans to do anything.

[Richard Riese:]

Right. Right now that's the extent of our plans for checkpoint-inhibitor combination. But, you know, I think that one of the questions we have is, if we show efficacy in combination, can they be used in other combinations in the future? Definitely, yes. That's always the math. I got it.

[Unidentified Analyst:]

And finally, you mentioned a lot on this call about enteric hyperoxaluria, but I'm wondering when you might select a candidate for maple syrup urine disease? And how might this program compete against -- I guess, sodium phenobarbitate or butyrate, sorry?

[Aoife Brennan:]

So, you know, for both programs we have set potency criteria in terms of how good they need to be, to be ready for kind of primetime who will declare candidate and start trying to enabling work. And, you know, we'll make significant progress towards that goal this year, whether we'll get the potency that's required during or not, we're still working on it, we're hopeful that we can at least for one of them, achieve the required potency and move forward. And MSUD, we think both are great indications, MSUD is obviously very similar to PKU, in terms of being an amino acid oppresee. And then as we mentioned earlier, enteric hyperoxaluria is similar to PKU but also having a slightly different opportunity set. We think that the MSUD program can be very competitive, the phenylbutyrate data that that's is a little module to us. So, we think that this could be -- if we can achieve our product profile, a really interesting approach for that disease. And a disease that has had no therapy other than liver transplantation and strict dietary controls; so we think both are real programs and very interesting programs with promising data from prototype strains. It's really just a measure of achieving the potency that we've pre-specified for each and declaring a candidate and moving forward into the IND enabling phase.

[Unidentified Analyst:]

Okay, perfect. I appreciate all details. Thank you.

[Operator:]

Thank you. The next question is from Chris Howerton from Jefferies.

[Chris Howerton:]

Hey, everyone, thanks for taking the questions, and addressing a lot of -- I think most of the key questions. For the top line one, I think one thing that I -- that just stands out to me is the relatively strong balance sheet that you have currently. And obviously, in these tumultuous times, getting capital on your balance sheet could be challenging. So kind of given that perspective, what are kind of the key value creating milestones or catalysts that you think can be transformative to your company over the next 12 months or so that we as outsiders should pay attention to?

[Aoife Brennan:]

Yes. We're -- you're right, we're in an enviable position, particularly given some of the uncertainty that we're seeing right now, and that we can really knuckle down and execute, and that's really what we've been focused on doing and what we'll continue to do. I think what we're guiding to and what we're excited about is showing in the Phe-lowering study that we can lower Phe, and that we can do that based on our prediction. And in line with our prediction, I think will give us and the outside world confidence that our biomarkers are actually predictive, that we can do something that has potential clinical meaningfulness. So I think that's going to be an important one milestone for us. I think advancing additional programs into the pipeline and being able to demonstrate that we're able to move quicker with higher quality strains and better clinical candidates based off of our kind of foundational capabilities, and the learning from PKU I think is also going to be really important.And then I think the oncology program, where we have monotherapy data this year, and then combination therapy, thereafter; it will really demonstrate that we can engineer these bacteria, administer them into the tumor microenvironment, and that they behaved -- behave as designed. That this approach is feasible, that there is a regulatory path forward that we're engaging the mechanisms that we've designed into the bacteria. And I think for me that's going to really open up and it's kind of an alternative orthogonal [ph] opportunity for the platform. And, you know, we ultimately see oncology and immunomodulation as partnership opportunities. But given the novelty of the platform, we really felt it was worth us making the investment to take some of that regulatory safety and kind of feasibility with costs per table [ph], and then potentially get the right kind of partnership that's really going to allow us to develop our platform and potentially an interesting additional opportunity on top of our focus on rare metabolic diseases.So, you know, we think all of that is within grasp based on our current resources and our execution plan, and that we're going to have an exciting 12 months ahead.

[Chris Howerton:]

Sure, okay. That makes sense. And then, I guess shifting gears to enteric hyperoxaluria, perhaps just because I'm familiar with this. What is kind of your regulatory path that you're envisioning? Because one of your competitors had spent fair amount of time negotiating with the FDA on a clinical registration path which they've kept largely to themselves. So just kind of what are your thoughts with respect to the registrational path moving forward? And particularly, as it relates to any kind of clinical endpoint that may or may not be required?

[Aoife Brennan:]

Yes. You're right, Chris, you have a lot of experience obviously in this indication. And sometimes it's nice to be second, and obviously, we're learning everything from Alina [ph], I think they've done a great job of kind of thinking through the development path. You know, there is a consortium effort right now in enteric hyperoxaluria that we're part of; it's a academic FDA industry consortium that's specifically designed around understanding the epidemiology of the disease, understand the physiology of the disease, and then working on registrational endpoints in the indication. The reason we love the indication is, I think there is a lot of strong evidence that urinary oxalate really does predict subsequent amorbidity from recurrent stones at unprogressive and kidney failure. So I think it's one of these diseases and indication that on the cusp of having a really nice approvable endpoint if we can build the package or act to support urinary oxalate lowering an important surrogate endpoints.But you know, there is this consortium effort now to really define clinical endpoints in this indication, and certainly based on what we've learned from the public disclosures of Alina [ph] and others; it seems that you know, even if a clinical endpoint over and above urinary oxalate lowering is required, that can be done pretty expeditiously with a modest trial size. So we think it's a nice indication for a company of our size and resources. And that, you know, the kind of evidence base supporting urinary oxalate will move quickly now that there's good kind of stakeholder engagement and the depreciation of the unmet needs in this indication. But, you know, I'd be open to hearing your thoughts also given your background and expertise in the area.

[Chris Howerton:]

Sure. I mean, I'd happy to have that discussion. I think, maybe that's something that we should have offline, but I know the -- in particular, the clinical endpoint has been a sticking point I think for Alina [ph], so I certainly very much look forward to how these discussions evolve overtime with the regulators and yourself.

[Aoife Brennan:]

Yes, we are too.

[Chris Howerton:]

Okay, so that's all for me. So, thank you so much.

[Operator:]

Your last question is from Tom [ph] from BITG.

[Julian Harrison:]

Hi there, this is Julian on for Tom. Thanks for taking my questions and hope you're all doing well. First, just on 1891, I know the primary objective for the monotherapy trial is safety. But do you think a STING agonist and a bacterial chassis could be enough to generate a profound immune response and by extension, maybe early efficacy signals without a checkpoint inhibitor? Thanks.

[Aoife Brennan:]

Yes, so -- you know, I think the -- we're -- this is to be a Phase I population, so it's important to kind of set expectations that these early oncology trials. So it's going to be Phase I, heavily treated population with advanced malignancy. We're going to be looking at biomarkers, we'll obviously be measuring clinical response, and we'll be doing staging and imaging during the study, but you know, we're really designed study to optimize for the biomarkers and the safety learning's and to move quickly into the combination arm. So certainly, internally at the company, there's no expectation that we would see, , complete responses are a partial responses in the monotherapy arm of the study, but we are looking for us. And, of course, we'd be delighted to report that we're seeing something but that's not our expectations.

[Julian Harrison:]

Okay, thanks. That's helpful. And just to piggyback on the last analyst question, and I know this is far down the road, but I'm just curious if you have a good sense for what the registration URL endpoint or endpoints might be for MSUD? Is there a surrogate measurement, like leucine in the realm of possibilities or something more functional, like cognition is likely needed?

[Aoife Brennan:]

Yes. So, I think it's going to be subject to negotiation with regulators. And we haven't had any of those discussions with regulators yet. You know, obviously, we would be much more favorably inclined to you, do you see it lowering as an endpoint for the study. And I think based on kind of analogies and parallels to PKU for a fee lowering is the approvable endpoint. And in addition to the fact that it's a pretty rare disease, and I think likely to be kind of subjected to flexibility and to pragmatism, in terms of what it's really going to take to develop the treatments for the disease. We would be certainly making a strong case for leucine and leucine and this being the endpoint. But we're lifting away from having that conversation, yes, but as soon as we have clarity, we'll update you. And anything else Richard that you'd like to add or that I left out there?

[Richard Riese:]

Yes, no; I think -- I think you get the salient points. And I do want to start reinforce, it is a rare disease and talking between 1000 and 4500 patients in the US. And in the past when we've approached regulators with a pragmatic sort of solution and point out that a clinical endpoint, such as neurological function, how long would take to measure -- to assess? As well as it's just a number of patients depending on the variability of [indiscernible] which is quite high in neurological. So it's not really feasible, so our expectations is we would be going in with the losing related endpoint, either lowering or stabilization. In the past when we presented those type of arguments two regulators has been -- they've been receptive and it's very rare disease arena.

[Julian Harrison:]

Okay, great. Thanks. That's very helpful.

[Operator:]

I am showing no further questions at this time. I would like to turn the comments back to Dr. Brennan for closing.

[Aoife Brennan:]

Thank you so much, operator. We'd like to thank you for joining us on today's call. We look forward to updating you on progress across our developing pipeline in the coming months. And we'll be available later today, if there are any follow-on questions. Hope everyone stays healthy. Bye, bye.

[Operator:]

Ladies and gentlemen, this concludes today's conference call and webcast. Thank you for your participation. You can have a wonderful day. You may all disconnect.