Yeah. Welcome to Day 2 of Citi's Biopharma Back to School 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 on the webcast, it would be useful to have you provide us with a brief snapshot of the company and what some of Maze's key objectives are over the next 12 - 18 months.
Eric, it's great to see you again, and I'm excited to represent Maze this afternoon. Just some background on Maze Therapeutics. We're a clinical -stage biopharmaceutical company focused on developing precision medicines for kidney metabolic diseases. We have three 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 in the first half of 2027. Our second program is MZE782. That's an inhibitor of SLC6A19, a transporter of neutral amino acids.
We 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 been guided to initiate a phase II study in CKD in the first half of next year. All three 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, our 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. 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 are homozygous for the two variant alleles or have two of the variant alleles are at substantially higher risk for progression to end-stage kidney disease. How routinely is AMKD diagnosed today, and at what stage of kidney dysfunction are patients typically identified?
Yeah, 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 two copies of the APOL1 high-risk variants, you are at risk of developing a more aggressive, a more accelerated form of chronic kidney disease. You are potentially going to develop CKD at an earlier age, a younger age, potentially before you turn 50. You are likely, or you are at risk of reaching dialysis earlier, potentially as much as 10 years earlier. So it is a more aggressive, more accelerated form of CKD. The APOL1 high-risk variants were first described in literature only just back in 2010, and there are no approved treatments today for AMKD. I also want to add that this is a disease that predominantly impacts people of West African descent.
We are starting from a very low base of awareness, and that is a key lever for testing, for enrollment in trials, et cetera. That is starting to change with sponsors like Maze in the field. There is certainly growing awareness of the disease. There is growing awareness of the need for testing, and with us and other sponsors, we are helping to drive that awareness. 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. I think the clinical data that we all collectively are generating in this field and the potential for new treatments to treat AMKD are only 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 dysfunction with folks who have two copies of the variant alleles? I am thinking about this double- hit hypothesis that comes up a little bit in 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 two copies of the APOL1 high-risk variants. Roughly 15%-20% of that 6 million will actually develop CKD and eventually AMKD. It suggests that you need a second hit in order to develop or reach AMKD. There is a lot of work going on on what factors may represent that second hit, so to speak, whether it is genetic or more environmental. Some of the work we have seen or are doing suggests it might be more environmental, but there is a lot more work that needs to be done. We estimate currently that 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.
That to us is the current addressable patient opportunity.
Excellent. All right. You are running a phase II study now, HORIZON, in patients with different subtypes of AMKD. Can you maybe, from a high-level standpoint, walk us through the clinical activity that you are observing to date and what, if there is a target product profile you are 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 are testing MZE829 in proteinuria CKD patients, adults who have two copies of the APOL1 high-risk variants. We are focusing on three segments within AMKD. The first is patients with FSGS, second, patients with diabetes, and then we have a third segment, patients without diabetes and without FSGS. We are testing across all three of those segments, a broad spectrum of AMKD patients. In March of this past year, March of 2026, we released some initial data from that HORIZON study, which is still ongoing. The results were really encouraging and positive to us at Maze. We had 12 evaluable patients. We saw responses defined as achieving a 30% or greater UACR reduction.
We saw responses in each of those three subtypes, and across all 12 evaluable patients, we saw a 36% average UACR reduction. Half of those patients achieved a response of 30% or more. Within FSGS patients specifically, we had four. We saw an average UACR reduction of 62%, with three out of those four patients achieving a response. These were highly encouraging results for us. Since we released that data in March, we have been focused on two priorities related to MZE829. The first is completing enrollment in HORIZON, and we have guided to releasing 10 to 15 patients' worth of data in each of those three 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 have already shown.
Sure.
The second priority coming out of the data release is to get a pivotal trial with MZE829 up and running as quickly as possible, and we have 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 is certainly going to be informed by our final HORIZON results, as well as our discussions with the FDA. A lot more to come on that.
Okay. You are not alone in this space, of course, right? We know of Vertex's inaxaplin, another APOL1 inhibitor. We are expecting some data readouts there over the next two - three quarters. What comparisons should investors draw between Vertex's inaxaplin and your compound?
Well, I will certainly 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, when you have the high-risk variants, it punches holes in the podocytes of the kidney. MZE829 not only blocks those pores or holes that form, it also disrupts the assemblies of those pores in the first place. In that way, prevents the leakage of protein. 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. We think there is potential differentiation there, and we are looking forward to the final results from HORIZON.
Just coming back to efficacy expectations in HORIZON and the different. Given that you are looking at distinct cohorts, right? You have non-FSGS, non-diabetic AMKD patients in one cohort, a second in diabetic AMKD, and another with FSGS patients. 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 would want to bring forward into clinical development the same across each of the three buckets?
Yeah. 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% proteinuria reduction and improved long-term renal outcomes in adjacent kidney areas. It's the one hard number we can point to and seems to resonate with the nephrologist community. Certainly, it's been suggested to us that in a segment such as diabetes, which is arguably a 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.
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. In the absence of a new treatment, they're going to continue to progress in an accelerated fashion with their AMKD. In our initial HORIZON data in diabetes, we saw two out of five patients achieve responses, one with a 35% proteinuria UACR reduction, another with a 47% UACR reduction. That was incredibly encouraging to the KOLs to whom we showed the data, because these were patients who were already on a number of background meds such as GLP-1s, such as SGLT2s, and the effect that they saw with MZE829 was on top of those treatments, and so that could be really important for the treatment landscape going forward.
It also suggests, just sticking with diabetes for a moment, that if we continue to see a pattern where there are responders but then clear non-responders, perhaps we need to think about how we identify potential responders better going forward and enrich for that in future studies. That's something that's 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.
I suspect there might be something to learn from Vertex's programs here as well, right? I think we're expecting a readout from the phase II AMPLITUDE study with inaxaplin in fourth quarter, or probably in time for ASN, right?
Yeah.
What insights are you anticipating, perhaps, from the readout of those data? Or what are you looking for, perhaps, investors should be. How should investors kind of prepare themselves when thinking about potential read-throughs?
Yeah. We're going to design our pivotal program and think about our next steps for MZE829, 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. 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. HORIZON, our discussions with the FDA, and potential recommendations coming out of PARASOL—that's what we'll really lean on in terms of developing our next steps for MZE829. But for sure, data releases from other sponsors, it's going to be informative to us, informative to the whole field.
Over the last four and a half 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 - 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. Maybe we can shift gears a little bit to your 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 MZE782, its mechanism, and how it controls toxic phenylalanine accumulation in a different manner relative to the existing treatment landscape.
Yeah. We're excited to move forward with MZE782 and PKU. As I mentioned at the outset, we announced last month the initiation of our phase II study in patients with PKU, and we've guided to top-line data from that in 2027. MZE782 represents a novel MOA, a mechanism of action, in the treatment of PKU. 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. 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 drug with a novel MOA 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.
Recall that PKU really results from the toxic accumulation of phenylalanine in the bloodstream. 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 PAH, 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.
Yeah. So just before we dig a little bit into the phase II CIPheR study now underway, maybe let's just talk about the phase I experience in healthy volunteers and what was learned there, and how the finding has informed go-forward dose selection and activity, or I guess how those data sort of de-risk activity in the PKU population going forward. Can you just speak to what data points actually drove how you arrived at the set of doses that you're evaluating in phase II, and just generally, how predictive looking at Phe reduction in healthy volunteers in the urine translates to expected Phe reduction in the plasma in PKU patients?
Okay, great. So about a year ago, in September of 2025, we disclosed results from our phase I study of MZE782 in healthy volunteers, and this was a randomized, double-blind, placebo-controlled study of roughly over 100 healthy volunteers, an SAD/MAD study testing a range of doses. In addition to safety and tolerability, we were also looking to see what level of urinary Phe excretion we could achieve with MZE782. 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 tenfold increase in urinary Phe excretion in healthy volunteers. So with our results, what we disclosed is that not only was MZE782 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. Those results exceeded our expectations and certainly resulted in us moving as quickly as possible to get MZE782 into a phase II study, which we've since initiated.
What do you think is driving that high level of Phe excretion? Is it just tighter affinity for the transporter, or is it a function of pharmacokinetics? Maybe you can just speak to the difference in the pharmacokinetic profile, I guess, both PK and PD profile of MZE782 perhaps versus the other sponsor's compound.
Yeah. So, I think rather than getting specifics, I'll give you the generic CFO answers. We have a better -designed molecule, and I think at 240 BID, we achieve that result regardless of being fed or fasted, so no food effect. That certainly informed bringing that dose forward into the phase II. I think what we're looking to see in the phase II now is how well does that urinary Phe excretion translate into actual plasma Phe reduction. You were starting to get at this with one of your other questions, but the nice thing of having another sponsor go ahead of us with a similar MOA is that we could see how their results in phase I, their urinary Phe excretion, translated into plasma Phe reduction. We saw a nice translation with their molecule. We exceeded their urinary Phe excretion in phase I.
We'll see what we achieve in phase II with plasma Phe reduction. But that, in addition to safety and tolerability, is what we'll be primarily looking at in the phase II.
Right. Okay. Yeah. I think probably until your data readout, it is still going to be a bit of a question as to whether that relationship going from urinary Phe change in healthy volunteers is at a linear relationship to plasma Phe change in patients, because we are talking about different reservoirs that we are looking at, number one. Secondly, it's not probably mark very different starting Phe levels, right? I guess we understand what it looks like from one compound here, and I guess we will learn whether that relationship is linear or is it asymptotic, perhaps with MZE782. It should be pretty interesting.
I guess the other thing to think about here, in thinking about 782 and the indication is on tolerability. So far tolerability in healthy volunteers is excellent. You do have a seemingly higher clearance of Phe, but along with that, you probably also have a higher clearance of other neutral amino acids. I think it begs the question whether there are potentially any downsides to increased elevated excretion of neutral amino acids via this mechanism. I guess, how does the phase I experience perhaps, or data elsewhere, sort of de-risk any potential consequences from that potential phenomenon, right? Seeing depletion of other neutral amino acids. I guess, in other words is there a concern around a drug or drug-related Hartnup-like syndrome emerging from an approach like this?
Yeah. The short answer is that no concerns have emerged so far. As I mentioned in the phase I study with healthy volunteers, the drug was well-tolerated. We did not observe any issues or adverse events related to the excretion of neutral amino acids. In the other sponsor with a similar mechanism of action, as best as we can tell from the publicly disclosed data, no such concerns have emerged from their phase I or phase II studies. Taking the case of Hartnup syndrome patients, that is where a patient has a complete loss in SLC6A19 function, and those patients seem to be managed very well with assuming a normal standard Western diet.
Sure.
No real concerns have emerged from that patient group that could impact our program at this point. Nothing that we have seen so far in our clinical studies.
Excellent. All right. Just on thinking about the mechanics of the CIPheR trial, this is also going to proceed through a dose escalation scheme. Maybe just walk through operationally how you are proceeding from one cohort to the next and the extent to which I do not know if you actually. Have you disclosed the doses that you are. The dosing regimen?
We have.
You have?
Yeah.
Maybe just speak to those and whether any of the cohorts that you are looking at are also evaluating a once -daily dose regimen.
Yeah, no, happy to. We are testing three cohorts. We have the first cohort is 120 milligrams BID, the second cohort is 240 milligrams BID, and the third cohort is 240 milligrams BID in combination with any BH4 agent. We certainly think there is potential for MZE782 to be potent as a monotherapy. But there may be patients when we start thinking about treatment in the context of diet liberalization, and that will become more important with the phase III. There may be some patients who need that extra potency in order to get below the Phe thresholds that really allow one to liberalize their diets. Those are the three cohorts we are testing, and we will start with 120 BID and then move forward accordingly.
Okay. All right. In the BH4 combination cohort, any concern regarding drug-drug interactions there? Is this the first time that you will be interrogating that?
Yeah, no, it is something we do what we can pre-clinically and whatnot to de-risk and remove concerns, and so we feel comfortable moving forward.
Okay. Great. This is all very forward-looking question, I suppose, but I wonder whether co-formulation of MZE782 with a BH4 is something that you would be interested in pursuing down the road.
Yeah. I don't want to take that off the table, but it's not an area of focus for us currently. We're really focused on testing MZE782 as a monotherapy, and then as I mentioned, we have this one cohort in combination, and we'll see what we get there. But once we get through the phase II, we'll look at what makes sense going forward to further develop the drug.
In that combination cohort, I presume patients are going to be coming in on a steady experience of BH4 treatment, right? They probably have lower Phe levels than in the other monotherapy cohorts. Having said that, what would be considered a meaningful reduction in Phe levels in that patient population, do you think?
Yeah. The eligibility threshold for cohorts 1 and 2 as monotherapy is 600, and then for the combination therapy, it comes down to 360. I think the question that we're looking to answer is just, how far below 360 can we get? Because that's really a key delineation in terms of starting to liberalize diet. We haven't talked a lot about that, but it is fairly onerous for these PKU patients.
Yeah.
They have to cap the amount of Phe intake they have in any given day. It's the equivalent of about two eggs. It's really tough for folks, and we were certainly hearing a desire to get off of that diet with an available therapy. If folks have an oral therapy with a relatively benign safety profile, that could certainly be an attractive option for them.
Okay. All right, great. I know the study is still in its early phases, and there's also a stepwise fashion in terms of dose escalating. But I guess, is there a sense of timeframe within 2027 you think you might be reading out from that study?
Yeah, I think our official guidance is 2027. We'll have more to add as we get further into the study and see how enrollment is going. But so far, we're off to a great start.
Excellent. All right, awesome. I'm going to throw in a thematic question here at the end. Our colleagues covering tech also ran a conference this week, and so I'm partially asking this on their behalf, right? But the topic of AI and the impact of AI tools is something that comes up a lot, affecting all of our line of work and all of our lines of work. So to you, can you tell us a little bit about how Maze currently is using AI-enabled tools across the organization and how their impact is measured?
Yeah. No, we're getting that question a lot from a range of different folks and audiences. It's early days for us, to be sure, but an area of increasing focus for us. We're starting to look at how we can increase adoption within the company of AI tools. We're starting to look at how we can deploy AI in various forms to improve productivity and ultimately to look at how we can shorten the drug development cycle, which would be the holy grail for us. So a lot more to come, but I would basically characterize it as early days but an area of increasingly high focus for the company.
Excellent. All right, great. Well, thanks so much for your time this afternoon, Misbah. We really appreciate it. Thanks for tuning in.
Thank you, Eric.