Good morning, and welcome to H.C. Wainwright's 28th Annual Global Investment Conference. Today, we are very pleased to host Misbah Tahir, CFO of Maze Therapeutics for our fireside chat to discuss Maze's pipeline, much-anticipated HORIZON data readout, the landscape in general, and the pipeline with multiple catalysts in the next one year. Misbah, welcome to the conference. Maybe you can start with a brief introduction of the company, where is it right now, and then we'll go through some of the questions we have on the pipelines. Good morning, Ananda. It's great to be here. Thanks for having us. Thank you. Let me give a little bit of background on Maze for folks who might be newer to the story. We are a clinical-stage biopharmaceutical company focused on the development of precision medicines for the treatment of kidney and metabolic diseases. We have three programs in clinical development. The first is MZE829. That's an APOL1 inhibitor for the treatment of APOL1-mediated kidney disease, or AMKD. We're currently testing that drug in a phase II study that we call HORIZON, and we've guided to data from that trial end of this year, early next year. Our second program is MZE782. That's an inhibitor of SLC6A19, a neutral amino acid transporter, and we're developing that for the treatment of PKU. We just announced last month the initiation of our phase II- What that is? ... study in PKU. That's a trial we refer to as CIPheR. The third clinical program is also MZE782. It's the same drug, but we're developing it for the treatment of chronic kidney disease, or CKD, and we've guided to initiating a phase II study in CKD in the first half of next year. All three of the programs I just mentioned are small molecule drugs, and Maze owns all the rights to those drugs. They're all built with the support of our Compass platform, in which we harness the power of human genetics to develop precision medicines. That's a little bit of the background on Maze. Got it. Great. Thanks. It looks like between now and this time next year, you will have the complete HORIZON data set pivotal underway, 782 in patients, as you've mentioned. Arguably a defining moment for the company. Where do you see Maze in 2027? These are exciting times for the company and for the field. I referred to a couple of our programs and our upcoming catalysts. For MZE829, our APOL1 inhibitor drug in AMKD, we've guided to data from our phase II HORIZON study end of this year, early next year. For our phase II MZE782 program in PKU, we just initiated the phase II clinical trial, CIPheR, and we've guided to top-line data in 2027. We're going to learn a lot about the company, our programs over the next 12- 18 months, but there's certainly significant work to do from there. Great. Maybe let's start our discussion on MZE829, given all the interest and major hype in the AMKD space. Earlier this year, HORIZON data not only established that APOL1-mediated disease pathogenesis, but it clearly, given the robust efficacy in FSGS and in the broader AMKD population. Maybe you can start with the most significant takeaways from the HORIZON that told you to take the program to that pivotal development. That's great. Let me give a little bit of background on the program, maybe let's start with the genetics. If you have two copies of the APOL1 high-risk variants, you're at risk for developing a more severe, more aggressive, more accelerated form of CKD. You're likely to develop it at an earlier age, perhaps before you turn 50, and you're likely to progress to dialysis faster, maybe as fast as 10 years earlier than you normally would with CKD. We started this trial, this phase II trial, HORIZON, to test MZE829 in proteinuric CKD adults across all the different patient groups within AMKD. We're testing it and focusing on AMKD patients with FSGS, AMKD patients with diabetes, and AMKD patients without diabetes, hypertensive non-diabetics. In March of this past year, we released initial data from that HORIZON study, and it was highly encouraging and positive to us and supported advancing the drug and continuing to dose patients in HORIZON. What we saw was, we saw responses in each of those three patient groups that I just mentioned, FSGS patients, diabetic patients, hypertensive non-diabetic patients. Across all the patients, we achieved an average uACR reduction of 36% with a response rate of 50%, response rate being defined as patients who achieve a 30% or greater reduction in uACR. Within FSGS patients, that particular subgroup, we had four of those patients. We saw an average uACR reduction of 62%, with three out of the four patients achieving response. Across the board, MZE829 appeared to be well-tolerated. Those results certainly were encouraging and promising to us and supported continuing to dose patients and accelerating the program as quickly as we could. We're continuing to dose patients now. Again, we've guided to releasing the final data from HORIZON end of this year, early next year. Got it. One of our theses has been that the absolute comparison on the uACR, uPCR data across landscape is probably not meaningful given the short trial length. The question is, we think both Vertex's inaxaplin phase II and the HORIZON showed that the blocking APOL1 is effective. Now, if AMPLITUDE converts and inaxaplin reaches the market first with a narrow FSGS-like label or broader, depending on what the AMPLITUDE tells us, it tells us there are two drugs for a considerably large patient population who have no treatment option today. How do you view this thesis? Well, to your point, there's significant unmet need. We estimate that there are 6 million patients in the U.S. who have two copies of the APOL1 high-risk variants. Roughly 1 million of those individuals have CKD, and we think roughly 250,000 patients in the U.S. could benefit from an APOL1 inhibitor. To your point, there are no approved treatments today, so there's significant unmet need. At this time, we're just focused on executing HORIZON and generating that data to support moving forward. I should mention, we'd also have guided to initiating a pivotal program with MZE829 in the first half of next year. The HORIZON data that we're generating now will be incredibly informative to the design of that study along with some other initiatives that are going on. There's a public-private initiative called PARSOL Shield, which is focused on accelerating drug development and clinical development in kidney diseases, and they seem to be focusing on surrogate endpoints. They may release some recommendations in the coming months. HORIZON learnings from the PARSOL Shield initiative certainly will help inform how we develop MZE829 going forward. It comes back to there's significant unmet need. Got it. Maybe a little bit more on the HORIZON. What was the rationale behind the HORIZON trial design from the outset and with respect to the inclusion criteria? How is it different from AMPLITUDE? If you had to redesign HORIZON, how would you have done it? Well, I'll let other sponsors speak to their studies. I think our guiding principle entering the HORIZON study was to test this drug across as broad a spectrum as AMKD as we could. Because again, the unmet need is there, and the biology supports that an APOL1 inhibitor drug such as MZE829 could be a potential treatment across the spectrum of AMKD patients. We know that irrespective of patient phenotype, if you have the two copies of the APOL1 high-risk variants, you're at risk of developing that more aggressive form of CKD, whether you're an FSGS patient, a diabetic patient, or a hypertensive non-diabetic patient. APOL1 high-risk variants impact all those segments. We also know that there's a protective variant that some of those individuals have that confers protection irrespective of which patient group that you're in, diabetic, non-diabetic, et cetera. We've designed MZE829 to phenocopy that protective variant. The biology supports the potential for a drug like MZE829 to be effective across the spectrum of patients. Hence we design our phase II HORIZON study to address that broad spectrum of patients. I think given the initial results in which we saw responses in each of those three subgroups, we feel pretty good about how we've designed it and what our plans are going forward. We'll see what we have with the final data release end of this year, early next year. Got it. A lot of investor focus on HORIZON data revolved around the percentage of FSGS population in the cohorts, and to some extent, we think probably wrongly interpreting the data. From our viewpoint, if you look at AMPLITUDE dataset, around 48% uACR reduction or uPCR reduction came from 100% biopsy-confirmed FSGS population on minimally background therapy. With respect to that, HORIZON's around 36% came from a mixed to largely subnephrotic SGLT2i GLP-1 saturated population. Maybe it will be useful for the audience to understand how to think about the impact of FSGS on the non-diabetic AMKD cohort of patients. When we release our final HORIZON data end of this year or early next, we're intending to disclose 10 to 15 patients' worth of data in each of those three segments: FSGS, diabetic, hypertensive non-diabetics. Those numbers I just cited are inclusive of the data that we disclosed earlier this year. We'll be able to see by segment how the efficacy, the safety stacks up across the board. FSGS perhaps gives you the cleanest diagnosis because it is biopsy-confirmed. Again, the biology supports that a drug like MZE829 could be a potential treatment across the spectrum of patients. The benchmark that we put out for the threshold we put out for success is this 30% uACR reduction, and that's something we hear time and time again from KOLs, practitioners. It's something that's supported in the literature where the 30% proteinuria reduction, uACR reduction is linked to long-term improved renal outcomes in adjacent renal spaces. It's the one hard number that we can point to, that we can keep coming back to as being meaningful for clinical advancement. It certainly has been suggested to us that a number less than that might be more appropriate in diabetes given the complexity of that patient population. We'll see what we have once we disclose all the data and adjust our pivotal trial accordingly going forward. Got it. Based on our discussions with KOLs, the idea that there was a signal in the diabetic cohort, despite low end was very encouraging. Probably not to the appreciation of some of the investors the way they were looking at the data. What are your thoughts on the diabetic cohort, and do you still believe the role of APOL1 in the diabetic AMKD population? I think the data we disclosed in diabetes was promising but early. We had five patients, two out of the five responded. They achieved uACR reductions of greater than 30%. One was at 35%, the other at 47%. That was really encouraging to us because as you noted, they were on a number of background medications. The effect that we saw from MZE829 was on top of SGLT2s, GLP-1s, et cetera. That was very encouraging to us. But we need to dose more patients and get a sense across the 10 to 15 patient target that I spoke to, and see what we have from there. We certainly are looking at the potential for biomarkers or other ways to identify potential responders in future studies. That's an area of active exploration going forward. You certainly touched on an important point, Ananda, and that is across our HORIZON study, these patients, in order to enter the study, they have to be on stable background treatments for at least eight weeks heading into the study. We're trying to isolate the effects and the impacts of MZE829, and that's an important requirement for the study. These patients across the board are on a number of existing background meds, including SGLT2s, which are certainly prevalent for treatment these days. True. One of my favorite thesis in AMKD, unless proven wrong by PARSOL Shield, which is 30% uACR is great, but physicians are happy if they can see even a 22% reduction, especially in the diabetic cohort. Have your views changed since March? The PARSOL Shield data is also most probably expected this month. What are your expectations from PARSOL Shield? How is it going to define the AMKD, the landscape? Yeah. We're looking forward to their recommendations, particularly if they're able to recommend some surrogate endpoints that could accelerate drug development in AMKD. AMKD is a project specifically that they're tackling. We'll have to see what they come up with. As I mentioned, particularly in diabetes, it absolutely has been suggested to us that a uACR reduction less than 30% could still be really meaningful because these patients have no existing treatment options, and they're already on SGLT2s, GLP-1s, but they're still progressing with their CKD. Treatments are needed, and I think that's what got some of these KOLs and practitioners excited. The fact that they saw two out of our five patients respond, where in the absence of a treatment such as MZE829, you just expect them to continue to progress with their AMKD. They saw some significant reductions in uACR for those two patients. That got people really excited and intrigued and wanting to dose more patients and see more data. Do you think the PARSOL group also will comment on the diabetic or the broader non-diabetic committees, or it's just AMKD as such? Is there a way to kind of assess, what's the baseline uACR, or will it be one single number, or will it be different across cohorts? Is there any- I'm not really sure exactly what- Okay ... they're going to be presenting, but hopefully we'll be learning more in the coming weeks and months from PARSOL Shield. One of the things that we have seen historically with AMKD and with CKD or other renal indication is the idea of responders and non-responders patient population, which kind of makes designing kidney trials, I think, a little bit tricky. Now, very similar to other, even obesity trials, where you have this population of responders, non-responders. Now, there has been recent push, mostly from academicians, to develop biomarkers, as you kind of alluded to, that can help enrich respondents. serum, urinary, APOL1, suPAR, TNFR1, TNFR2, and blah. You mentioned in the 2Q earnings release that Maze is also working towards a biomarker-based approach to enrich responders. Can you elaborate on that, and are we going to see any implementation of that approach in future trials? Yeah. I would just say it's an area of active discussion and exploration within the company, and certainly, as you alluded to, there are a number of folks outside the company, groups that are working on this area. Because it may turn out because of the complexity of diabetes patients, in particular, where it might be unclear what's actually driving the CKD. Is it the diabetes? Is it the APOL1 high-risk variance? Where there might be a way to better identify patients who would respond to an APOL1 inhibitor treatment. I think everything's on the table, whether it's biomarkers or other ways to stratify or identify patients, and more to come. We're obviously going to use the data that we're currently generating with HORIZON to help inform that, and we'll certainly bring in outside information as appropriate. Got it. How is the upcoming HORIZON data readouts set up differently? You lowered the uACR floor to 200 mg per gram and then capped FSGS enrollment, which means that you are targeting much milder patients. What is the significance? If you can elaborate on that would be helpful. Sure. I would characterize the changes more as tweaks. Previously, prior to March, our enrollment threshold, uACR threshold for enrollment in HORIZON was 300, and we lowered it down to 200. Recall that the cutoff for what defines normal proteinuria, et cetera, is 30. We are still treating folks who are proteinuria. It may benefit us in terms of enrollment. Maybe we get a few more patients enrolled, but I wouldn't characterize it as a major change in enrollment criteria. Okay. One of our observations from the initial release of HORIZON data back in March was that there didn't appear to be a simple relationship between baseline proteinuria levels and whether we saw a response or overall efficacy. That got us comfortable making that slight adjustment downward in the enrollment threshold. With respect to the FSGS cap, we just want to make sure that we don't over-enroll in one segment to the detriment of the other segments. We are committed to showing 10 to 15 patients' worth of data in each of those three segments that I referenced earlier when we do the HORIZON data release end of this year, early next. Correct. Coming back to some of the KOL feedbacks. Our KOLs we spoke to have commented that for a pivotal trial, the diabetic/non-diabetic split is biologically kind of artificial. Two-thirds of diabetic CKD patients don't seem to have diabetes as the primary driver and recommend an all-comer pivotal approach with pre-specified subgroup interaction, rather than having separate cohorts. Do you get similar kind of feedback as you are thinking about the pivotal design? I agree that you will be waiting for the HORIZON, but have you come across these ideas or thoughts? Well, I think it speaks to the unmet need and the desire from KOLs, nephrologists, and patients to have a treatment that could address the needs of all patients who have AMKD. It's certainly top of mind for us. That was one of the driving forces behind our design of HORIZON, and including as broad of the AMKD population as we could. With respect to the pivotal, more to come on that. Again, that's an area of active analysis right now. We are still generating data with HORIZON, and we'll disclose more as we have more in terms of the trial design. It may be the case that you start a pivotal study in one of the segments or a couple of the segments, and then eventually expand the trial, or maybe you start a new pivotal study in the remaining segments. We certainly think because of the biology that I referenced earlier, and we'll see how the data with HORIZON turns out, we certainly think there's the potential for MZE829 to treat the whole breadth of patients within AMKD. Got it. From the accelerated approval point of view, what are the things that you learn from AMPLITUDE? Vertex strategizes the development path forward. If it hits or misses eGFR, how would you interpret those data, and how might that impact your pivotal development program? Yeah. I think we're going to learn from all the sponsors in this space. In the past four and a half years, there's probably been 25 patients worth of clinical data combined disclosed between ourselves and other sponsor, and that's going to change dramatically in the next 12 - 18 months. There's going to be quite a bit of data being generated Sure from sponsors, including Maze, and we're going to have recommendations, findings from the PARSOL Shield initiative. So this is an exciting time to be following the field, and we're certainly going to look at our own data, but certainly keep an eye on everything else in terms of informing how we design the pivotal trial going forward. Got it. That brings me to AMPLITUDE trial. Given huge interest in understanding AMPLITUDE, again, with respect to Maze's MZE829 program. Just for our understanding, how is AMPLITUDE different from HORIZON? What do you intend to learn from AMPLITUDE trial, given that they're designed differently from HORIZON? Probably best if I let other sponsors speak to their studies. We are certainly going to learn from all the sponsors in AMKD, and as we've talked about, there's large unmet need. There's a need for multiple treatment options with this patient group. We are going to watch and learn from others as they disclose data and go from there. For Maze, we are focused right now on generating that HORIZON data and releasing that end of this year, early next. Got it. For MZE829, is partnership something that you would contemplate before or after the pivotal data, and does a genotype-defined nephrology launch in U.S. actually require a partner? I know you are busy with executing it, but as you are thinking about the next steps, let's say hoping that it's a positive trial across, then is it something that you think that you can take it alone? Or do you think that given the market, you need a partner eventually? Yeah. No, I think go it alone is very much in the cards, and that's how we're building our company. We've got a number of drugs in development. We've got the Compass platform. I think everything's there to support a go it alone approach. Of course, just like any biotech, we'll be opportunistic with respect to discussions on business development, collaborations, et cetera. Got it. Maybe in the last few minutes, let's switch gear to MZE782. With respect to MZE782, what plasma phenylalanine reduction and what proportion achieving less than 360 micromole per liter do you consider unambiguous to go to the phase III? Maybe before that, a little bit of introduction to MZE782, because we didn't touch MZE782 in a much deeper way, in contrast to the landscape. That might be helpful. What did you learn from the landscape and what is the bar set up for MZE782 to give you a go ahead for the pivotal trial? Yeah, just taking a step back on PKU, I think what we've learned in recent months is that there is still unmet need in PKU, and there's a desire for new treatment options. We estimate there are roughly 60,000 PKU patients in key geographies, and roughly two-thirds of those patients are either on a strict onerous medical diet or are under no treatment. That speaks a little bit to the need for new treatments going forward. MZE782 would represent a novel mechanism action in this field that would be very exciting for patients potentially. Last September of 2025, we released phase I healthy volunteer data. It was a randomized, double-blind, placebo-controlled study of roughly over 100 patients, SAD/MAD study, in which we tested MZE782 in healthy volunteers. We were testing for safety tolerability, but also to see what level of urinary Phe excretion we could achieve in healthy volunteers. PKU results from the toxic accumulation of phenylalanine or Phe in blood. We wanted to see in healthy volunteers what level of excretion would we see of Phe in urine. Not only was MZE782 well-tolerated, but we saw a level of urinary Phe excretion that exceeded our internal thresholds. We had set a bar of roughly a tenfold increase in urinary Phe excretion informed by another sponsor with a similar MOA, and we achieved a 42-fold increase in urinary Phe excretion at 240 mg BID, and we saw similar levels at other doses as well. That strongly exceeded our expectations and accelerated our plans to test MZE782 in PKU in a phase II study, which we just initiated and that we refer to as CIPheR. In CIPheR, in this phase II study, what we're looking to see is how well does that urinary Phe excretion in healthy volunteers translate over in terms of plasma Phe reduction in actual patients. From another sponsor who's a little bit ahead of us, we saw that nice translation, and we certainly have the potential to do as good or better based on what we saw with the phase I healthy volunteers. That's the experiment we're running now to see what level of plasma Phe reduction we can achieve. Certainly, as we get more into a phase III study, we will start looking at what are the absolute thresholds that we can go below, and ultimately, the holy grail for PKU patients is to liberalize their diets. It is a fairly onerous medical diet in which you have to really cap the level of the Phe intake on any given day, and it is the equivalent roughly of two eggs. So that is where we need to get to, but in the phase II study, we are going to be looking at plasma Phe reduction. Got it. Two last questions. One is on, there has been a huge interest.