Synlogic, Inc.
Q4 2020 Earnings Call Transcript

Published: 25 Mar 2021

[Operator:]

Good morning. Welcome to Synlogic's Fourth Quarter 2020 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end of this call. Please be advised that this call is being recorded. I would now like to turn the call over to Daniel Rosan, Head of 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 fourth quarter and full year 2020 financial results and additional business updates. The release is available on the Investors section of our website at synlogictx.com.

[Aoife Brennan:]

Thanks, Dan. Good morning, everyone, and thank you for joining us. I'm thrilled to share with you today our financial results from 2020, as well as recent progress across our portfolio, including the initial clinical results from our Enteric Hyperoxaluria program, SYNB8802, which we announced yesterday. Across our programs and platform, the groundwork of the last year has catapulted us into a data rich 2021, with anticipated clinical readout in three programs. An increasing momentum in our research engine focused on advancing additional clinical candidates. As we emerge from the winter months, Synlogic hasn't missed a beat. We've done anything but hibernate. We are rapidly progressing our metabolic disease pipeline, which leverages the ability of our platform to engineer synthetic biotic medicines, and deliver them safely into the human GI tract to consume a toxic metabolite. We believe that there are wide variety of disease states, where this approach could transform patients’ lives. Based on the initial readout from SYNB8802, which we will discuss in more detail in a moment, we now have two metabolic programs that have demonstrated the ability to consume and metabolites within the human gastrointestinal tract.

[Richard Riese:]

Thank you, Aoife. I would like to now walk you through the progress across our metabolic portfolio. As Aoife said, we now have demonstrated proof-of-mechanism in humans, for both our lead metabolic programs, PKU and Enteric Hyperoxaluria, and have the potential to demonstrate proof-of-concept in both programs later this year.

[Gregg Beloff:]

Thanks, Richard, and good morning, everyone. This morning, we released our financial results for the fourth quarter and full year ended December 31, 2020. And I'm pleased to review these highlights of those results with you now. Research and development expenses were $11.4 million for the three months ended December 31, 2020, as compared to $11.3 million for the corresponding period in 2019. These costs were driven by Synlogic’s collaboration with Ginkgo Bioworks for the optimization of synthetic biotech medicines, as well as clinical study startup activities associated with SYNB1618 and SYNB8802, and the ongoing SYNBY1891 Phase study. General and administrative expenses were $3.3 million in the fourth quarter of 2020, compared to $3.5 million for the same period in 2019. For the fourth quarter of 2020, the company reported a consolidated net loss of $14.6 million or $0.39 per share, compared to a net loss of $12.8 million or $0.37 per share for the corresponding period in 2019. We had no revenues in the fourth quarter of 2020, as compared to $1.2 million of revenue for the same period in 2019. Revenue was associated with the services provided under Synlogic’s collaboration with AbbVie to develop synthetic biotic medicines for the treatment of inflammatory bowel disease, an agreement which has since been terminated. Now, turning to the balance sheet, Synlogic ended the fourth quarter of 2020 with $100.4 million in cash, cash equivalents and long-term investments. Under our current operating plan, we expect that our cash will take us into 2023, and enable us to advance our clinical programs through important data readouts over the coming months. Thank you for your attention, and we look forward to keeping you updated on future calls. I will now turn the call over to, Aoife, to wrap up.

[Aoife Brennan:]

Thank you, Gregg. Our team has made tremendous progress across all of our programs, both in and outside the clinic. We now have demonstrated proof-of-mechanism in humans from both of our lead metabolic programs, PKU and Enteric Hyperoxaluria, laying the groundwork to demonstrate proof-of-concept in both programs later this year. I want to end once again, thanking the Synlogic team, employees and their families for their work and dedication in driving those programs forward. We will now open the call for questions.

[Operator:]

Our first question comes from Lina Kaminski with Jones Trading. Your line is open.

[Lina Kaminski:]

8802. Maybe start off, can you remind us kind of how that disease, how is Enteric Hyperoxaluria currently managed? And where is really the high unmet need? And where would 8802 fit in the treatment regimen. And then kind of along the line. Hello, can you hear me?

[Aoife Brennan:]

Yes, I can hear you, Lina. I think, I'm catching all of your questions.

[Lina Kaminski:]

Yes. And I guess along the line, maybe also, can you kind of remind us how is your approach differentiated from other approaches in development? And help us maybe quantify how much more oxalate you anticipate 8802 will be able to consume and inflate as compared to other approaches? And how should that increase translate into more or -- well into decreased urinary oxalate excretion and to clinical benefit? Thank you for taking the questions.

[Aoife Brennan:]

Thanks. I'm just going to recap, because I think there were about four questions in there. And I'm sure there are questions others on the call have as well. So, I think the first thing you were asking was about the current landscape, where are the unmet needs and what are the segments within the Enteric Hyperoxaluria population. The second component was differentiation versus other mechanisms of action. And then the third one was about trying to get some feel for quantifying how much oxalate the strain can consume and how that could be relevant in patients with disease, correct?

[Lina Kaminski:]

Yes. I guess how much more you would anticipate to consume the data in those two, as compared to other programs in developments in the field?

[Aoife Brennan:]

Yes. So maybe I'll hand that over to Richard, I think he's our expert on all things Hyperoxaluria. So, Richard, do you want to start off addressing Lina's question, maybe starting with our understanding of the disease based on the feedback that we've collected from KOLs and physicians and patient groups?

[Richard Riese:]

Yes, sure. I'd be happy to. Enteric Hyperoxaluria can result into irreversible and progressive kidney damage. But, one of the interesting aspects about this disease is it arises from patients with a primary insult from their GI tract leading to hyper absorption of oxalate from the gut. And a variety of -- as we mentioned, a variety of GI diseases which can lead to this, patients who have Roux-en-Y gastric bypass surgery, patients with Crohn's disease, short bowel syndrome, celiac disease, pancreatitis. There are no approved treatments for Enteric Hyperoxaluria. So in some ways, it's kind of a wide open field. But of course, our interest is to go after the patients with more severity in their disease spectrum. And these are patients maybe with recurrent kidney stones, maybe patients with chronic renal insufficiency or renal damage to the EH, Enteric Hyperoxaluria or maybe a patient with combination of both, where the recurrent kidney stones and kidney damage to really direct our response to the more severe spectrum of the patient population. And we are undergoing -- we are now conducting some really good research, epi research in that sort of thing to identify those patients. I think your next question is how does 8802 fit and differentiate from other approaches. I think there are a couple of things on approaches such as enzyme to degrade oxalate. We believe our effective integrating oxalate in the upper GI tract as is 8802. But when we feel there's benefit is first of all our enzyme system is protected by the E. coli bacteria the nasal bacteria. So, we believe that that gives us advantage right off of that. And secondly, we believe that we're going to be able to reach a colonic colon better than other products in development. And that's in patient with the EH where a lot of the action takes place, where a lot of hyper absorption of oxalate takes place. So, I think that's sort of a differentiation in where we think we may have benefit, particularly in patients with EH over healthy volunteers. Now, let me turn to translating how much oxalate we expect to consume. In normal diet, humans, people consume about 200 to 250-milligrams of oxalate a day, and that's similar between healthy volunteers and patients with Enteric Hyperoxaluria. In our dietary model for Hyperoxaluria in healthy volunteers, we ramped up the oxalate to 400, and then to 600-milligrams of dietary oxalate a day. And even at those higher levels, we're able to show what we think is a meaningful decrease in urinary oxalate levels. And in evidence, we're able to consume a meaningful amount of oxalate even in patients taking more oxalate than expected. So, if anything, patients taking lower amounts of oxalate, we would expect that our SYNB8802 would be able to consume very effectively those levels of oxalate in the diet, including patients with EH. So that fair to get at your questions, Lina.

[Lina Kaminski:]

Yes, thank you. It's really clear. And, again, congrats on the new data and all your progress. I'll jump into the queue. Thanks.

[Richard Riese:]

Thank you.

[Operator:]

Thank you. Our next question comes from Joseph Schwartz with SVB Leerink. Your line is open.

[Unidentified Analyst:]

First is on your 8802 program. So given the fact that healthy volunteers on a high oxalate diet was used to mimic conditions of the Enteric Hyperoxaluria state, and was able to blunt the rise of urinary oxalate. I'm curious to know how this relates to Enteric Hyperoxaluria patients, because the absolute effect of the drug on was modest at just minus 4.7 mgs per 24-hours.

[Richard Riese:]

Yes, sure. Thank you for that. There are a couple things we look for, in sort of a Phase 1 data set. And we think the most the best comparison is what happens to placebo compared with patients on 8802. And what we can say is patients on placebo didn't decrease, whereas patients on 8802 did decrease. And when you look at the difference, at the end of treatment between the placebo patients and the 8802 patients, it was quite marked there, 28.6% in 14-milligrams absolute. So, we would argue that we did see really good absolute differences from placebo, which is our marker for really understand the results and moving forward. And the other thing we look for absolute difference is one marker. We look for consistency across doses, consistency across cohorts and oxalate intake levels, check there for both, consistency across sensitivity analysis, check, dose response, check, no decrease in placebo check, decrease in 8802 groups, check, and a meaningful differences between 8802 and placebo, check. And these ideas and this consistency of the data which really excite us moving forward to Enteric Hyperoxaluria patients, which the proof is in pudding there, right. But, we're really excited with this data package and excited to moving into patients.

[Unidentified Analyst:]

Okay. Thank you. That's helpful. And then I know you announced the new strain for your PKU program. So I was just wondering, do you plan to introduce the new strain for your Enteric Hyperoxaluria program as well? Or do you envision this being your final formulation?

[Aoife Brennan:]

Yes. So, I think as with -- Julie I can take that question. As, with all programs, we moved in a lyophilized formulation, we think as Richard just really nicely outlined, we still that we have a really strong data set. We still have some work to do in terms of scaling that up to a Phase 3 scale, but we think that that's all incredibly possible. So, there will be tweaks to the formulation, tweaks to the final presentation, whether it be capsules or tablets that we'll need to do as we go through development, as you would with any development program. And certainly, we will be updating the external community as we go through that process. But today, we're just really thrilled with the data, as Richard outlined, and looking forward to seeing data in the patient population later this year.

[Unidentified Analyst:]

Okay, great. Thank you. And then finally, I'm wondering if you could talk about the site of oxalate consumption in healthy volunteers with 8802? I don't know if you are able to see this in your study, but I'm wondering if the primary site of activity was in the upper GI tract, as you had expected. And how that translates to potential efficacy in Enteric Hyperoxaluria patients?

[Aoife Brennan:]

Great. I'll maybe ask Richard to address that question, Julie.

[Richard Riese:]

Yes, sure. Thank you for that. We didn't do a study to actually identify where -- it's a great question where the oxalate is consumed in healthy volunteers versus patients with EH. But based on prior knowledge and based on prior studies, we are expecting that majority of the oxalate consumption in healthy volunteers occurs in the upper GI tract, presumably in the stomach and proximal small intestine. Whereas, in patients with EH, it's likely that a lot of the oxalate absorption and consumption will be done further down in the colon. And that's kind of what makes us very excited because, as we said previously, that's one of the areas where we think we can differentiate with a strain, whether an actual bacteria that gets into the colon that we may have good activity there. So, we're excited on seeing if that happens in patients with EH.

[Unidentified Analyst:]

Okay, great. Thank you so much. Congrats on the data.

[Richard Riese:]

Thank you.

[Operator:]

Thank you. Our next question comes from Ted Tenthoff with Piper Sandler. Your line is open.

[Ted Tenthoff:]

Great. Thank you. Good morning, everyone, and congrats on the data update. I have got a couple of questions, if I may. So firstly, would you ever envision evaluating 8802 in primary Hyperoxaluria? And secondly, and probably I am asking is a little out of order, so I apologize. What do you see as the potential and that might be required? I know this is a little further out for a pivotal study of 8802 in Enteric Hyperoxaluria. And then I have a quick question on PKU. Thanks.

[Aoife Brennan:]

Yes. So, I think you have the exact right person here on the line with Richard to answer your question about the primary Hyperoxaluria. Obviously, there are great products, close to or already available commercially for that indication, one of which Richard was involved in developing. So, I think he's absolutely the right person to answer that. And so maybe I'll hand over to him and then we can come back to some of the other kind of forward-looking questions around regulatory requirements, if that works, Ted.

[Ted Tenthoff:]

Of course. Thank you.

[Richard Riese:]

Yes. Thank you for that. Yes, I was fortunate enough to be part of that very talented team and enjoyed it. We've given a lot of thought about this, is there a role for GI removal of oxalate in patients with other causes of Hyperoxaluria, including primary of Hyperoxaluria. As you know primary Hyperoxaluria is due to over production of oxalate in the liver, due to a genetic defect. So, GI approach doesn't have direct access to that, but they have access to that, that would be a systemic circulation, and if oxalate recirculates into the GI tract, which it may, exactly. I think in patients with in tract renal functions, the treatment that is out there now and the treatments that are coming are pretty effective. So, it's hard to see to envision whether it's possible, but hard to see how a GI-related entity could impact that. But on the other hand, and we're playing around this idea in patients with renal failure, which they can't excrete oxalate in the urine, which is a major way oxalate treat it from your body. And dialysis only works when the patients are on dialysis, it doesn't work in between the dialysis sessions. So, would there be a role in GI removal of oxalate via 8802 like a mechanism between the dialysis sessions and sort of GI dialysis. That's something we're all playing around with anybody with high oxalate levels.

[Ted Tenthoff:]

That’s interesting. Thank you.

[Richard Riese:]

Yes. And in terms of the potential and for the pivotal study, we're not going to give out. We're still in the process of designing our Phase 2 and Phase 3 study. At a high level, certainly, we will make sure the N is big enough to test our hypotheses that we're interested in testing to get approval. And, I think there are some good examples on what kind of Ns that we'll take out there. So, I guess you know, it doesn't exactly enter --

[Ted Tenthoff:]

Yes, it does. No, no, that's fine. Well, I mean, again, let's see what we get from Part B too, in patients, and I think that'll help as well. And then just a quick question, if I may, on PKU. It seems that data is in the second-half. Again, really looking forward to that result. Two questions. Firstly, would 1934 ultimately replace 1618 in the clinic or would have more be a situational follow-on? And do you think -- kind of a similar question here, do you think that ultimately, you would be able to evaluate this in combination therapy with Kuvan or enzyme replacement therapy? Thanks.

[Aoife Brennan:]

Yes. Thanks, Ted. That's a great question. I think one of the key attributes of our platform that I think is really exciting is this ability to think about these products is kind of synthetic biotic, right. And one of the key components of this issue is with development. So, you design, you build and you test, and then you can continue to kind of optimize and tweak. Now that's different from the traditional drug development kind of framework and model. So, we're really excited by the fact that we can move quickly, we can develop additional strains, using tools that we have. We can move them very quickly into the clinic, because of the experience that we've accumulated, and kind of the regulatory path to opening an IND and initiating clinical studies is very rapid. I think as the timeline that we've achieved for 8802 has demonstrated. So, right now we're moving 1934 into IND enabling studies. But as we get kind of more clarity on the timeline, and what that looks like from a performance perspective, we will provide more guidance in terms of how the programs might play together. But as you can imagine, there are a number of interesting scenarios that could play out, including kind of the lifecycle management initiative with a strain that allows maybe lower dosing levels at similar activity, or a situation where one replaces the other for Phase 3 development. So, I think that's all dependent on the data, obviously, the data from at the SynPheny study, as well as the data from 1934, as it continues to advance in development. But, as always, we'll make sound database decisions when we have the right amount of data in hand.

[Ted Tenthoff:]

Great. Excellent. Thanks so much for the update, and congrats on all the good progress.

[Aoife Brennan:]

Thanks, Ted.

[Operator:]

Thank you. Our next question comes from Chris Howerton with Jefferies. Your line is open.

[Chris Howerton:]

Thanks for taking our questions. So, I just have two on 8802. So first, I was wondering if you can go into any more detail on the safety and tolerability. Was there a max tolerated dose? And were nausea in GI symptoms dose limiting? Maybe you could give us a little more information on potentially rates? And the second question was on whether what the trends are for a Roux-en-Y surgery? And whether you expect the market opportunity to change, if this procedure were to fall out of favor?

[Aoife Brennan:]

Great. I think maybe I'll hand over to Richard to provide the update on 8802. And just to say, we will disclose the entire data set at some point down the road later this year at an appropriate academic meeting, as we generally do. So, obviously, there'll be a lot more color behind all of the endpoints at that time. But Richard, do you want to answer the question about safety, and even, the Roux-en-Y question as well, I think both are pertinent to you?

[Richard Riese:]

Sure. We saw safety profile I think pretty similar to other strains across our platform, as we went up and dose. We did see GI symptoms, including nausea and vomiting. And that's sort of the limiting part of our doses. And we saw there was more at a 6e11 than we did at the 3e11. One thing that was interesting from our viewpoint, is that when we titrated up the dose, when we gave patients one dose for one day, instead of getting overwhelmed them, immediately gave them two doses for one day, and gave them three doses, means did the three dose TID dosing. We found that was much better tolerated, I think to give their GI tract a little time to be accustomed. And in the 3e11 dose, we did see a tolerable safety profile in terms of GI symptoms. It was similar to what you see with a probiotic. And because of that, we decided to move forward with that dose, in addition to the fact that we saw good efficacy of that dose, and manufacturer ability thoughts and things of that nature. So, that's why we decided to move forward with that dose. In terms of the Roux-en-Y, it is true that the gastric bypass surgeries are moving away from there. And it may be less, although it's not zero. Enteric Hyperoxaluria area after other type of GI surgeries, and we will certainly be following that closely as we develop 8802. There are plenty of other causes of Enteric Hyperoxaluria, which including Crohn's, short bowel, celiac hepatitis, which won't be affected by this change in surgery. So, those are the things, it goes on, what we'll be considering as we move on with clinical and even commercial evaluation in 8802. Does that answer your questions?

[Chris Howerton:]

Yes. Perfect. Thanks so much.

[Operator:]

Thank you. Our next question comes from Tom Shrader with BTIG. Your line is open.

[Julian Harrison:]

Hi, good morning. This is Julian on for Tom. Congrats on all the recent progress. And thank you for taking my question. I'm wondering just given how much urinary oxalate levels can be affected by diet. Do you have a good sense for how the placebo group will respond it over time, and Roux-en-Y and Hyperoxaluria patients, maybe beyond five days? Are you able to maybe walk us through your assumptions here?

[Richard Riese:]

Yes, that's a great question. Right now, we're going to enroll patients with Roux-en-Y on stable oxalate diet. And in fact, we have dietitians dedicated to study to work with Roux-en-Y patients, and they're recording their diet in a pretty extensive way. Certainly, recording their diet every time they take . And we're going to be have those diets analyzed by dedicated dieticians, to look for changes in diet and advise on what they can do to manage their diet in maintaining a stable, as much as possible oxalate diet throughout the study. So, we are taking precautions. Obviously, there's going to be some variability in diet. And there's some ways you can handle that on the analytic back end. But certainly, from my viewpoint as a clinical person, I prefer diet be as steady and as steady in oxalate as possible, so we'll get the clear signal.

[Julian Harrison:]

Got it. Thank you.

[Operator:]

Thank you. Our next question comes from . Your line is open.

[Unidentified Analyst:]

Apologies if this is a little bit repetitive, because I think you touched on this earlier. Going back to the absolute reduction in urine oxalate that you saw with SYNB8802.Could you comment a little bit on whether you think the effect size might differ in the actual Enteric Hyperoxaluria patients versus in the dietary model, for example, due to higher baseline urine oxalate levels? Or do you think that the effect sizes will be roughly the same?

[Richard Riese:]

Yes. It's hard to predict what the effect size is going to be. Obviously, as a company out there, we hope they're higher. And there's some theoretical and biological reasons why that may be the case. But of course, we can't say that now. I think the baseline assessment is we expect the change in oxalate in Enteric Hyperoxaluria patient to be at least as much as what we saw in healthy volunteers. And this gets to your point, one of your points Bola is that we will be enrolling patients with higher baseline urinary oxalate levels and greater than 70-milligrams per day. And I think it's been pretty well-established by data both in Enteric Hyperoxaluria and primary Hyperoxaluria. When you start with higher oxalate levels in the urine, you tend to get larger decreases in percent than when you start with a lower oxalate levels. And this is one of the things we're really excited about that we're able to drive up oxalate levels to the upper limit of normal and slightly over the upper limit of normal, at the end of the treatment, ensure a pretty good effect in healthy volunteers. And I'm really interested to see now when we get Enteric Hyperoxaluria patient on even higher oxalate levels, what that'll show and if it's going to be able to show in terms of percent decrease. So, we're really excited about doing that.

[Unidentified Analyst:]

Thank you, I appreciate the clarity. And one unrelated question, you've made the argument before that the various components that you use are modular or reusable. I was wondering, given that you now have proof-of-concept data for two assets that use the same chassis and one of the same promoters. I guess, to what extent does concordance between those two data sets? I'm thinking of PKU with Enteric Hyperoxaluria. To what extent do those two datasets support this modularity argument? And, I guess to what extent does this modularity or lack thereof read through to your earlier stage metabolic pipeline?

[Aoife Brennan:]

Yes, that's a great question. I think the real advantage for us from the modularity perspective is just the speed at which we can move with subsequent programs. I think, when we started to speak about this, it was unproven that we could really move quicker by having this reusable parts, as we call them. I think now that we've seen how quickly we've been able to move with 8802, because we're using those kind of components that we've used before that the regulators have seen before, that we have a lot of experience with from an engineering perspective, we were able to move that program forward really quickly, both in terms of just the building of the strain, but the preclinical work and the manufacturing work and the assay development work, and all the critical components that go into initiating and executing a clinical study, with things that we already had available to us. I think the other key difference is that we were able to move with 8802 to directly to a lyophilized formulation, which I think was another big advantage that will play out even into the future, as the 8802 program moves forward. You'll remember with PKU, we started with the liquid and subsequently had to move to a solid oral. So, I think we're starting to see the kind of realization or the manifestation of the advantages of using the synthetic biology based approach in drug development. And certainly, we would expect that we would leverage those kind of same speed quality and attributes as we go forward and develop additional candidates.

[Unidentified Analyst:]

Great, thank you very much.

[Operator:]

Thank you. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is open.

[Mark Breidenbach:]

Hey, guys, thanks for taking the question. So, just thinking back to the approval of lumasiran in primary Hyperoxaluria So, I think they saw a pretty dramatic reduction in urinary oxalate, it was like 65%. I guess my question is, why or do you see in secondary Hyperoxaluria a reason why you could get away with a lower reduction in urinary oxalate? Would it's something in the order of 30% reduction be enough to move the needle in secondary Hyperoxaluria? Thanks for taking the question.

[Aoife Brennan:]

Thanks, Mark. Maybe I’ll -- before handing it over to Richard, I'll kind of frame it in two different ways that I think might be helpful. I think there's a component of a urinary oxalate going to be sufficient for full approval in Enteric Hyperoxaluria, the same way that it was in primary Hyperoxaluria. I think that's kind of one regulatory component of the question, you're asking. And then the second question, I think the component of the question is what clinically meaningful in Enteric Hyperoxaluria, in terms of percent lowering of urinary oxalate. I think both are key questions for the program, obviously, and are interrelated. But I think there is a slightly different approach to both. And I think, Richard is exactly the right person to answer both of those questions. So, Richard, do you want to answer Mark’s question on both fronts there?

[Richard Riese:]

Yes, sure. Absolutely. And, let me just take a little step back and tell you about my thinking. For both primary Hyperoxaluria area is the of Hyperoxaluria. The damage comes from too much oxalate in urine. In primary Hyperoxaluria the damage comes because of a genetic defect in the liver. And in Enteric Hyperoxaluria -- or the high levels -- I'm sorry the high levels of oxalate occur because of a genetic defect in the liver. And Enteric Hyperoxaluria oxalate urine or the high oxalates in the urine occur because of hyper absorption of oxalate from the GI tract. Now, once you get to those levels of oxalate in the urine, whether it be from primary or Entreric, the downstream consequences should be essentially similar, that you get kidney stone formation, recurrent kidney stone formation, you get calcium oxalate deposition in the kidney tissue, which in itself is inflammatory. You get nephrocalcinosis. You get chronic renal insufficiency. In some cases, you can even get at least to end stage renal disease in dialysis and renal transplant. So, to me the crux of the argument, biological argument is that toxic metabolite, urinary oxalate in there. And that's the arguments we're going to make to the regulators. Even if our overall effect is 30%, 40% or in the case that a lot of them got a 53% change from placebo, which is really impressive, as you said. Any change we believe is really good for patients. And that's sort of the crux of the regulatory argument we're going to make. And see if we can make a good enough argument and get full approval straight up. That's going to be our approach. And the second part of your question about clinically meaningful, the best we can determine and this the input from KOLs and then also really nice recent epidemiological article, where most people say that a 20% change in urinary oxalate, we believe this is interpreted as a 20% change from placebo in urinary oxalate levels, what is the bar for clinically meaningful to us. And I think recently, this has been backed up by a nice epidemiology study out of the Mayo Clinic, where they looked at patients with Hyperoxaluria, and determined that if patients had about a 20% decrease in urinary oxalate levels, this translated into about 25% decrease in the risk of kidney stones. So, yes, that's where we're starting from. Obviously, the more with better, but we think, when you get into 20% or 30%, any of that is good for the patient.

[Mark Breidenbach:]

Okay. Thanks so much for taking the question.

[Operator:]

Thank you. And I'm currently showing no further questions at this time. I'll turn the call back over to, Aoife Brennan, for any closing remarks.

[Aoife Brennan:]

Great. Thanks, Shannon. And thank you so much for everyone for joining us today. Enjoy the rest of your day.

[Operator:]

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