Maze Therapeutics, Inc. (MAZE) Earnings Call Transcript & Summary

Welcome to Day 2 of Citi's Back to School Summit Biopharma Conference. I'm Eric Joseph, Senior Biotech Analyst with the firm. And our session now is with Maze Therapeutics. It's my pleasure to have with us CFO Misbah Tahir to talk to us about the company. Misbah, thanks for joining us today. Maybe just for those less familiar with the company and the webcast, it would be useful to have you to kind of provide us with a brief snapshot of the company and what some of Maze's key objectives are over the next 12 to 18 months?

Eric, it's great to see you again, and I'm excited to represent Maze this afternoon. Some background on Maze Therapeutics. We're a clinical stage biopharmaceutical company focused on developing precision medicines for kidney and metabolic diseases. We have 3 programs in clinical development. Our lead program is MZE829. That's an APOL1 inhibitor for the treatment of patients who suffer from APOL1-mediated kidney disease or AMKD. We're currently in a Phase II trial, testing MZE829 in AMKD patients. And we've guided to data from this study, which we refer to as HORIZON, by the end of this year or early next year. We've also committed to initiating a pivotal program with MZE829 8 in the first half of 2027. Our second program is MZE782. That's an inhibitor SLC6A19, a transporter of neutral amino acids. I just announced last month that we initiated our Phase II study of MZE782 for the treatment of patients with PKU. And we've guided to top line data from that program in 2027. Our third program is also MZE782, the same drug. We're also testing that drug in patients who suffer from chronic kidney disease, or CKD. We've guided to initiating a Phase II study in CKD in the first half of next year. All 3 of those programs -- those drugs are small molecules. They're all wholly owned by Maze. And they're all built with the support of our Compass platform, our discovery platform in which we are a discovery engine in which we harness the power of human genetics to develop precision medicines.

Okay. Great. So let's start with MZE829 for APOL1-mediated kidney disease, or AMKD. And I want to start by just thinking about the market opportunity here. The epidemiology studies give us a good understanding of who's at risk for developing AMKD and suggest that patients who have -- who are homozygous for the 2 varying alleles, right, or have 2 of the variant allele, are up substantially higher risk for progression to [ NH ] kidney disease. That said, how routinely is AMKD-diagnosed today? And what stage of kidney dysfunction are patients typically identified?

Yes, I think the short answer to your question is there's a lot more work to be done here. Let's start with the genetics as you were starting to do. If you have 2 copies of the APOL1 high-risk variants, you're at risk of developing a more aggressive, a more accelerated form of chronic kidney disease. You're potentially going to develop CKD at an earlier age, a younger age, potentially before you turn 50, and you're likely or you're at risk of reaching dialysis earlier, potentially as much as 10 years earlier. So the more aggressive, more accelerated form of CKD. Now the APOL1 high-risk variance were first described in literature and only just back in 2010, and there are no approved treatments today for AMKD. And I also want to add that this is a disease that predominantly impacts people of West African descent. So we're starting from a very low base of awareness, and that's a key lever for testing, for enrollment in trials, et cetera, but that's starting to change with sponsors like Maze in the field. There's certainly growing awareness of the disease. There's growing awareness of the need for testing. And with us and other sponsors, we're helping to drive that awareness. So I suspect that over the next several years, the next several years of drug development and enrollment and testing will look very different than the last several years because the need is certainly there. And I think the clinical data that we all collectively are generating in this field and the potential for new treatments to treat AMKD is going to drive further testing.

Has the understanding of the pathophysiology evolved a little bit over the past couple of years, particularly as it relates to other risk factors or other known contributors for kidney disfunctions with folks you have 2 copies of the variant alleles? I'm kind of thinking about this double-hit hypothesis that comes up a little bit and thinking about the indication.

Eric, I think this is an area of active exploration in the field. We estimate that there are roughly 6 million Americans who have 2 copies of APOL1 and high-risk variants. Roughly 15% to 20% of that 6 million will actually develop CKD and eventually AMKD. And so it suggests that you need a second hit in order to redevelop or read AMKD. And so there's a lot of work going on and what factors may represent that second hit, so to speak, whether it's genetic or more environmental, some of the work we've seen and doing suggest it might be more environmental. But there's a lot more work that needs to be done. But we estimate, currently, of the 6 million, roughly 1 million or so have CKD. And of that number, roughly 250,000 patients in the U.S. could benefit from an APOL1 inhibitor drug such as MZE829. So that, to us, is the current addressable patient opportunity.

Excellent. Excellent. All right. So you're running a Phase II HORIZON in patients with different subtypes of AMKD. Can you maybe be -- from a high-level standpoint, it would be good to have you walk us through the clinical activity that you're observing to date and sort of what -- there's a target product profile you're striving for here as the Phase II program evolves and you think about advancing the candidate into pivotal development.

Sure. Let me start with some background on HORIZON. HORIZON is our Phase II open-label basket study in which we're testing MZE829 in proteinuric CKD patients, adults who have 2 copies of the APOL1 high-risk variants. And we're focusing on 3 segments within AMKD. The first is patients with FSGS, second patients with diabetes and then we have a third segment of patients without diabetes and without FSGS. So we're testing across all 3 of those segments, a broad spectrum of AMKD patients. And in March of this past year, March of 2026, we released some initial data from that HORIZON study, which is still ongoing. And the results were really encouraging and positive to us at Maze. We had 12 evaluable patients. We saw responses, responses defined as achieving a 30% or greater uACR reduction. We saw responses in each of those 3 subtypes. And across all 12 evaluable patients, we saw a 36% average uACR reduction. Half of those patients received -- achieved a response of 30% or more. Within FSGS patients specifically, we had 4, we saw average uACR reduction of 62% with 3 out of those 4 patients achieving a response. So these were highly encouraging results for us. And since we released that data in March, we've been focused on 2 priorities related to 829, first is completing enrollment in HORIZON, and we've guided to releasing 10 to 15 patients worth of data in each of those 3 segments by the end of this year, early next year. That 10 to 15 patient, figure that I cited, is inclusive of the patients we've already shown. The second priority coming out of data release is to get a pivotal trial with 829 up and running as quickly as possible, and we've guided to initiating a pivotal study in the first half of 2027. The design and scope of that study is a topic of active discussion within the company. It's certainly going to be informed by our final HORIZON results as well as our discussions with the FDA. So a lot more to come on that.

Okay. You're not alone in the space, of course, right? We know Vertex's Nexplanon, right, another APOL1 inhibitor, and they're expecting some data readouts there over the next 2 to 3 quarters. What comparison should investors drop between Vertex's Nexplanon and your compound?

Well, I'll sort of leave it to Vertex to speak to their drug. I think with respect to MZE829, this is a drug that could be potent given the dual-mechanism nature of the drug. What APOL1 does is it punches holes in -- when you have the high-risk variance, it punches holes in the podocytes of the kidney. An MZE829 not only blocks those pores or holes that form, it also disrupts the assemblies of those ports in the first place. So in that way, prevents the leakage of protein. And so you have this dual MOA that preclinically, we think could certainly be potent. And then in the initial data release from HORIZON, we saw in our FSGS patients, the potential potency of the drug in that segment and across all the evaluable patients. So we think there's a potential differentiation there, and we're looking forward to the final results from HORIZON.

Just coming back to sort of efficacy expectation in HORIZON and the different -- given that you're looking at distinct cohorts, right, you've got non-FSGS, nondiabetic MKD patients in 1 cohort, a second in diabetic AMKD and another with FSGS patients. Like, is there perhaps are there differing thresholds of activity that you want to see perhaps? I guess, is the threshold for what you think would be a profile that you'd want to bring forward into clinical development the same across each of the 3 buckets?

Yes. It's a question that comes up often in our discussions. 30% is the threshold that we can point to that comes up consistently in discussions with KOLs, practitioners. In the literature, there's a linkage between achieving a 30% [indiscernible] reduction, an improved long-term renal outcomes in adjacent kidney area. So it's the one hard number we can point to and seems to resonate with the nephrologist community. But certainly, it's been suggested to us that in segments such as diabetes, which is arguably much more complex set of patients, unclear what may be driving the CKD in a particular patient, that a lower threshold might be more appropriate. And if we were, for example, to achieve a 20% uACR reduction, that could still be clinically meaningful to nephrologists to patients because these patients have no other treatment options. And in the absence of a new treatment, they're going to continue to progress in an accelerated fashion with their AMKD. In our HORIZON and initial HORIZON data in diabetes, we saw 2 out of 5 patients achieve responses, one with a 35% protonary uACR reduction and another with a 47% uACR reduction. And that was incredibly encouraging to the KOLs to whom we showed the data because these were patients who are already on a number of background meds, such as GLP-1, such as SGLT2s, and the effect that they saw with 829 was on top of those treatments. And so that could be really important for the treatment landscape going forward. But it also suggests, just sticking with diabetes for a moment, that if we continue to see a pattern where there are responders within clear non-responders, perhaps we need to think about how we identify potential resonders better going forward and enrich for that in future studies. So that's something that certainly on our minds. We're going to wait and see what the final HORIZON data look like before we make any decisions, but we're actively exploring that whole concept.

And I suspect there might be something to learn from Vertex's programs here as well, right? And I think we're expecting a readout from the Phase II AMPLIFIED study with Nexplanon in fourth quarter or probably in [indiscernible], right? I guess how are you -- what insights are you sort of anticipating perhaps from the readout of the data? What are you looking for, perhaps investors should be -- how should investors kind of prepare themselves when thinking about potential readthroughs?

Yes. We're going to design our pivotal program and think about our next steps for 829, mostly using what we learned from our Horizon study and feedback from regulatory authorities. There's also an important initiative called the PARASOL initiative that may have some recommendations in the coming months, and that's a public-private initiative with a focus on accelerating drug development, clinical advancement and approvals in kidney diseases, and they have a project specifically in AMKD, and they're looking to potentially define surrogate endpoints that could accelerate drug development and approvals in AMKD. So HORIZON and our discussions with the FDA and potential recommendations coming out of PARASOL, that's what we're really lean on in terms of developing our next steps for 829. But for sure, data releases from other sponsors, it's going to be informative to us, informative to the whole field. Over the last 4.5 years, we've probably seen 25 patients' worth of clinical data come out from ourselves and other sponsors, and that's going to change dramatically in the next 12 to 16 months as we read out, as other sponsors read out. So it's an exciting time to be following AMKD, and we're going to learn quite a bit in the coming months.

Great. Great. Maybe we can shift gears a little bit to the our second pipeline program, MZE782, in particular, the program in PKU. This is, I think, an indication that investors are becoming much more familiar with, specifically with a new market entrant we saw to come to market last year. Maybe talk a little bit about how 782, its mechanism and how it controls toxic piloting accumulation in a different manner relative to the existing treatment landscape?

Yes. We're excited to move forward with MZE782 in PKU. As I mentioned at the outset, we announced last month the initiation of our Phase II study in patients with PKU, and we guided to top line data from that in 2027. MZE782 represents a novel MOA, mechanism of action, in the treatment of PKU. And currently, when you look across the landscape, we estimate there are roughly 60,000 PKU patients in key geographies. Roughly 2/3 of the patients are on an onerous medical diet or are receiving no treatment for their PKU. And that plus some of the excitement we've seen around the new entrants, suggests there's definitely a desire for new treatment options for PKU and a novel -- a drug with a novel MLA could be really helpful to the field. MZE782 works in some different ways. It's an inhibitor of SLC6A19, which is a transporter of neutral amino acids. And recall that PKU really results from the toxic accumulation of phenylalanine in the bloodstream. And normal individuals have a functioning enzyme called PAH, which helps to break down and clear that phenylalanine, but when that enzyme is deficient, defective or not present, you see that toxic accumulation of phenylalanine, or Phe. What MZE782 does is, by targeting the transporter of Phe, it reduces the amount of Phe being absorbed or reabsorbed back into the bloodstream, it also helps to clear that phenylalanine, or Phe, through the urine. So it works in a way that is independent of existing treatments, it doesn't require the presence of PAA, and it's not looking to interact or boost the PAH enzyme. It works independently of those. So that could be a really important tool in the arsenal to treat PKU going forward.

Yes. Let's -- so just kind of digging into -- before we kind of dig a little bit into the Phase II CIPheR study now underway. Maybe let's just talk about the learning -- the Phase I experience in healthy volunteers and what was learned there and sort of how the finding is informed, go-forward dose selection and activity? Or I guess, how those data sort of derisk activity in the PKU population going forward? Can you just sort of speak to what data points actually kind of drove -- have you arrived at the dose -- the set of doses that you're evaluating in Phase II? And just generally, how predictive looking at Phe reduction in healthy volunteers in plasma -- or sorry, in the urine relates to -- translates to expected Phe reduction in the plasma in PKU patients?

Great. So about a year ago, in September of 2025, we disclosed results from our Phase I study of 782 in healthy volunteers. And this was a randomized double-blind placebo-controlled study of roughly over 100 healthy volunteers, a SAD/MAD study, testing a range of doses. And in addition to safety and tolerability, we were also looking to see what level of urinary Phe excretion we could achieve with 782, and the threshold or benchmark we set was informed by another sponsor who's developing an inhibitor of SLC6A19. And in their Phase I study, they had achieved a roughly 10-fold increase in urinary Phe excretion in healthy volunteers. So with our results, what we disclosed is that not only was 782 well-tolerated, but we were able to achieve an up to or over 40-fold increase in urinary Phe excretion. At our 240 BID dose, we actually achieved a 42-fold increase in urinary Phe excretion. So those results exceeded our expectations and certainly resulted in us moving as quickly as possible to get 782 into a Phase II study, which we've since initiated.

What do you think is driving that sort of high level of Phe excretions? Is it just kind of tighter affinity for the transporter, or is it a function of pharmacokinetics? Maybe you can just kind of speak to the difference in either -- the pharmacokinetic profile, I guess, both PK and PD profile of 782 perhaps versus the other sponsor compound.