Good morning, and thank you for joining Guggenheim's 2025 Healthcare Innovations Conference. I am Debjit, one of the therapeutic analysts, and it's my privilege to host our next presenting company, Maze Therapeutics. Joining us from Maze is Jason Coloma, the CEO. I don't think people are completely up to speed with Maze as yet, given your class of 2025 IPO. A couple of minutes on the platform? Yeah, well, first of all, thank you for having us this year, Debjit, and thank you for the Guggenheim team and all their support. At Maze Therapeutics, we are using advanced genetic techniques to develop small molecule precision medicines for both kidney as well as metabolic diseases. We're mid-stage in the sense that we have multiple phase two programs, and we've been working very hard, as you know, to be one of the first companies this year to go public. We had a recent financing in September, which Guggenheim was supportive of, and that's allowing us to develop multiple small molecule approaches as we have even data coming in Q1 2026 on our lead program for APOL1-mediated kidney disease. So let's talk about the MZE829 program. Obviously, there is proof of concept, proof of biology from your competitor. What would be a good outcome in AMKD and diabetic AMKD? Because that's the one segment that we haven't seen. Yeah, so for those that aren't aware, first off, APOL1-mediated kidney disease, there's about a million individuals in the U.S. that have a variant that can cause toxic gain of function or eventually toxicity in the kidney. Unfortunately, there are no approved medicines for this disease. There's about 250,000 individuals who could benefit from a therapy, and us as well as a few other companies are developing what hopefully could be the first disease-modifying therapy for those patients. And so for us, what defines success for Q1 2026, three things that I'd like to highlight. Number one is that we intend or hope to be the first company to describe clinical proof of concept in broad AMKDs for a broader patient population. A previous, if you will, sponsor had proved a clinical proof of concept in a rare form of disease called FSGS in the kidney. What we hope to do is be able to be the first company to describe clinical proof of concept in a broader patient population, which gets closer to that 250,000 number that I mentioned earlier. The second thing in terms of defining success around that particular outcome, that we define that as in terms of clinical significance and clinical proof of concept to be 30% reduction of proteinuria relative to baseline. That would be not only clinically significant, but show for the first time clinical proof of concept in this patient population. And then the third thing to highlight is that if we are successful in the sense of generating that data, that will allow us, if we see the significant number of patients, to allow us to initiate planning what could be a phase II, III registrational study and try to move as aggressively as possible to the patients. So the first quarter data is just going to be AMKD, sorry, APOL1 diabetic AMKD and AMKD, not FSGS. Right. Our goal from the very beginning with Horizon was to clinical proof of concept has been demonstrated in FSGS. Our goal as we designed that study was really to, can we broaden this out to allow for even more patients with or without diabetes, because our genetics, as well as other work that had been done to really support that we should see activity in those particular patients, and we want to be able to try to prove that out in the clinic. Got it. And the FSGS data, would that should be expected sometime middle of the year or later in the year? And are you sort of thinking about any expedited path to market in FSGS given the findings from the PARASOL group? Yeah, we haven't guided specifically on FSGS yet because we want to be able to really focus investors on the Q1 2026 readout. As we be able to generate that data and have plans to, as I said, be able to think about advancing that potentially in a registrational study, we'll give further guidance on FSGS. Got it. Let's talk about the disease. The rate of progression from diagnosis to end-stage renal disease is very, very quick. So is 30% a target which can stop the progression of the disease, 30% reduction in proteinuria, or do you need a deeper reduction? And sort of can you outline how big the two segments are, the diabetic AMKD versus the AMKD? Yeah. So I think one of the things that we were able to last week was the, if you will, the really important kidney conference, American Society of Nephrology, was just last week. We had seven posters and presentations accepted, sort of highlighting what we're trying to do in kidney disease. And one of the posters we had in terms of the genetics, we further sort of described the ability to look at the disease progression with those and without diabetes. And what we found, Deb Chattopadhyay, was that people that end up developing kidney disease that have APOL1 variants as well as start to progress, they progress aggressively and equally whether they have diabetes or not. And why is that important is that a therapy, as you say, could potentially intervene if we can catch it early enough such that it could be truly disease-modifying. That's the goal of us as well as other sponsors working in APOL1 kidney disease. So the idea for us is that we could potentially address patients that are really progressing aggressively, as you say. In terms of the numbers, right, so I mentioned 250,000 individuals could benefit from a therapy. And we also had a poster at ASN that really kind of described and reinforced the epidemiology and the literature. And one of those things that we did is to look at, well, what percentage roughly of people that have kidney disease have the variant? And two, of those people that have it, what percentage of them have diabetes? So the first number is that we reinforced the literature in the sense that it's been previously described 13% of all African Americans have the variants that cause disease. In our study, it was enriched because they had kidney disease and it was about 18% that had the variants that cause the disease, which in that range is probably safe to say 13% to 18% of the population would have the variant. And we also reinforced this number of about 60% of the 250,000 don't have diabetes and about 40% do. Okay, so I think it's really a better understanding. What this highlights is a better understanding of the addressable patient population. Number two, that the split between 60 non-diabetic and 40% diabetic. And then thirdly, you have this ability that we showed that there should be an effect in both diabetic as well as non-diabetic patients. Got it. Now, these patients have to be genotyped. Correct. Have you had challenges enrolling the study or given Vertex has been in the market evangelizing the target, a large number of patients have now been genotyped? I think we're learning a lot in the way that one has to engage with the community, in particular genotyping and serving the community at large. Awareness is increasing, as you said, Debjit, by Vertex in front of us as well as now AstraZeneca. So I think it's becoming more prevalent, sort of the knowledge base, and that's allowing us to at least be able to engage the community. I go back to ASN, right? So I think just awareness since we just had the kidney conference, which was if you went to the kidney conference five years ago, there were like maybe two or three posters or presentations on APOL1-mediated kidney disease. This year, there was 39. So I think the awareness is there, and that's allowing us and other sponsors to be able to engage the community and be able to enroll these studies. So I think that's allowing us to still be on track for the Q1 2026 timeline that we said in order to show clinical proof of concept in this broad AMKD patient population. Got it, and so the driver of the disease is really whether if you carry the risk alleles, G1, G2, G1, G1, and G2, G2, right? Whether you have diabetes or not, the effect size shouldn't be any different. Yeah, so to go back to what causes this. So the genetics, interestingly enough, have been known for a very long time in terms of this relationship of those that had the variants and had kidney disease. So that was understood for over 10-15 years. No one had really in the scientific community really understood how are these genes and these variants actually causing disease. So our work plus other sponsors really elucidated that this toxic gain of function is APOL1 acting as this aberrant channel or pore that's really causing eventually this influx of cations causing the nephrotoxicity. That is the prevailing hypothesis. So all of the molecules being developed are, let's just inhibit the pore. Let's slam the door shut on this pore, and that should result in better kidney health. So that was the idea is generally like that. If we can do that, then we basically can ameliorate disease. Now, further, there was sort of question to your specific question is based off of that. We know now that progression of disease, whether or not you have diabetes, is aggressive and equally progressive. And so in theory, if you do, if this is the underlying mechanism, if you inhibit the pore, then you should in theory see an effect in both diabetic and non-diabetic. And then what we've defined, as I described earlier, is this 30% number allows us to see clinical significance in both of those patient populations. Got it. So let's fast forward to middle of next year, and the first quarter data looks great. How are you thinking about your phase II, III study? Would it mimic what Vertex is doing, trying to have a dual primary endpoint, or is there a different strategy there? Yeah, I think if we see what we want to see in terms of the signal, so if we see it in broad AMKD, 30%, as you mentioned, we would start to think about initiating planning for a phase II, III. I think it's safe to say what we would try to look at is a study that looks very much in that sort of framework, which is maybe a phase II, III type of design that allows us to look at additional doses to do proper dose ranging. Because if we take a little bit of a step back, what we wanted to do in Horizon is pick a dose in our phase II study to pick a dose that we can optimize to look for a signal. It's signal seeking in this broad AMKD, and if we see that signal, we can push forward. And so I think a II, III design looking at multiple doses. And maybe just to highlight one, we'll learn a lot about other sponsors' studies themselves and the regulatory path that allows potentially for accelerated approval. And the second thing that's important, Debjit, to highlight, there's an academic group called PARASOL, which has been out of the University of Michigan, which has been very instrumental in helping define endpoints in kidney disease, in particular for more rare forms like FSGS. Other companies that are working specifically in FSGS are benefiting from that. And APOL1-mediated kidney disease, as well as PMN, has been selected by that group to work with other sponsors as well as other organizations, including the agency, to look at what the appropriate regulatory path and endpoints are for APOL1-mediated kidney disease. So why that's important is not only our involvement with that and seeing pathways for it. I think by the time we get to your midpoint, 2026, a lot of this information from the environment in general will allow us to inform how we think about our particular study. So a much more clearer path of how we think about sort of regulatory and interaction with the agency and other organizations globally. Got it. And there's been a lot of discussion or back and forth on MZE829 as it relates to Inaxaplin. Is MZE829 more potent than Inaxaplin, et cetera? Any thoughts on that? Yeah, I think suffice to say if we go back to, so yes, preclinically, we had the benefit of generating data relative to Inaxaplin because they had disclosure structure. But I think more importantly, if we take a step back, an opportunity like this where there are no approved therapies for the indication, there's over at least 250,000 individuals who could benefit from a therapy. I think that obviously is an area. If we look at comparable markets or analogs like IgAN, if you look at ATTR-CM, if you look at cardio, multiple opportunities will be there because there'll be different ways that you can treat these patients. And so I think the idea that you can have multiple molecules, clearly, I think the unmet needs high enough where this is going to be a scenario just like what you saw with IgAN as well as for ATTR-CM. Got it. So let's switch to the second program, 782. You had some interesting healthy volunteer data in September. Help us understand the path you're likely to take because the program can go either in CKD or in PKU? Yeah. Makes you sort of puts you in a unique bucket there. Yep. Thoughts on that? Yeah, so for those that are not aware, what we did in September is we highlighted data on our program called MZE782, which was designed to target a particular solute transporter that's located in the gut and the kidney called SLC6A19, and what we did is we were able to use some existing data in the literature that had described this target showing clinical proof of concept by a different sponsor in rare metabolic disease, as you pointed out, in PKU. Now, that's great because they had published so much data and information. We were able to benchmark exactly where they were to help us describe what data we might be able to generate in phase one to show that we had best-in-class properties. We had shown that in preclinically relative to them in the sense of being more potent and being able to potentially go to QD dosing, and that played out exactly what we saw in the phase one, so with PKU and the opportunity there, what this opportunity could be is that it is an approach that doesn't rely on the residual enzyme present in order to be able to work in particular patients, so what this means as you take a step back is this approach could work across the entire spectrum of PKU patients and doesn't rely on what has been previously done in terms of relying on enzyme to be present. Now, that can change the way that PKU patients are treated. Because we had other data out there, what we knew is that one of their doses, they had a particular approach that showed clinical proof of concept by being able to demonstrate a reduction in plasma Phe. That is the approvable endpoint for PKU. So that's number one, that's what they did. Number two is what they did is they validated a non-invasive biomarker, urinary Phe excretion, that correlates very well to the approvable endpoint. So it's great that they did that for the field, but we were able to use that and be able to benchmark where we are relative to them. Now, what they showed in their phase 1/2 study was that they had a tenfold increase in urinary Phe that ultimately translated into the patients in the phase 2 at a 44% reduction in plasma Phe. So great they showed it. What we were able to do in our phase one, which I think investors got excited about, as well as us and the PKU physicians and the patients, is that we showed a over 40 times fold increase of urinary Phe where theirs was 10, demonstrating that we have the ability to potentially be best in class, and we had showed a range of different doses, including QD and BID, where we can get this type of effect, so a lot of flexibility combined with the tolerability data that we had really demonstrates for the first time things we saw preclinically, which we were more potent, we could potentially go to QD, and we can more effectively, if you will, have an impact on PKU patients, so that's very clear. The other thing, Deb Chattopadhyay, where we were really excited about is the concept of inhibiting SLC6A19 in chronic kidney disease, so different concept, I know, but we were the first group to identify the genetic relationship of inhibiting this target in the context of chronic kidney disease, which was great. We also had done some additional, if you will, preclinical work to validate this, target validation, knockout data. There had been some in the literature from a group at UC San Diego that we validated. We also were the first group to show in vivo proof of concept on inhibiting the target in a kidney model and compare that to SGLT2, which is an important anchor in kidney treatment today. We did it better than the SGLT2 in that model. So you had genetics, you had target validation, and you had in vivo proof of concept, very encouraging data to say that we might have an impact in kidney health. As we started the phase 1, we were interacting with nephrologists with this data, and they suggested to us, this is very promising, but would further reinforce the hypothesis is what you should do is collect serum creatinine, which is just a biomarker, as a, if you will, exploratory biomarker so that you can calculate eGFR, which is a measurement of kidney function. And if you see what's called an eGFR dip, to us, that would reinforce the entire hypothesis because what we know is that every chronic kidney disease program or therapy that's been approved shows that, this concept of the eGFR dip, whether it be a RAS, an ARB, SGLT2, Bayer's Kerendia, they all show this eGFR dip. So that to us would really reinforce what you're seeing preclinically in the genetics. And if you see that, we would really like to be part of that proof of concept study for the phase two in patients. So we did that. And what was really nice is that we really showed that for the first time on target mechanism of being able to inhibit SLC6A19. We collected that serum creatinine, calculated eGFR, and what you see is that specific phenomenon of eGFR dip that should be indicative of renal protection. And I think this reinforces all the hard work that our scientists were able to do. And then what this means for the program is that what we're able to do in 2026 is be able to have not just only a PKU phase 2 starting, but also a CKD study where we could really be able to think about this approach transforming two different diseases, which we're obviously very excited about. On the CKD program, this is going to be complementary to SGLT2. What does this bring from both hemodynamic and tubular detox to patients? And what's the best way to think about what a phase two could look like? Yeah. So, for those that are not aware about SGLT2, SGLT2s were originally developed for diabetes patients, and then eventually it made its way into chronic kidney disease. It's an important anchor in how kidney disease is being treated today. But unfortunately, there's some liabilities. Not all patients respond. Up to 25% of them don't adequately have better kidney health based off of the treatment with SGLT2s. And in addition to that, there are some complications which force particular patients to be taken off the drug. We pulled some real-world data, and what we can see is that the number of people that have to drop off the drug after one year is up to 30%-40%, which is really high. And then it's partly because of the fact that they have some of these complications, including hypoglycemia and urinary tract infections, which force certain individuals off of the therapy. Now, there lies an opportunity because clearly it has the ability to be effective in patients, but it has some liabilities. So minimally, if you think about what we could do with our therapy, because we are complementary to SGLT2 based off our data, you could think about equivalent efficacy with an SGLT2, but not have the liabilities of the complications of an SGLT2. Minimally, that would be an excellent target product profile. Maximally, if we have even better efficacy with the safety that I described, one could imagine that this could really change fundamentally the way that patients are treated with chronic kidney disease. So the idea that we could potentially be an important anchor starts to sort of get really not only us excited, but the whole nephrology and kidney community. Now, what would a clinical proof of concept study look like, so to us, again, as we think about those that are not responding adequately to standard of care, including SGLT2s, if we see them sort of stabilizing at a certain high level of protein in the urine or proteinuria, one could imagine that we can introduce our agent, and if we see a certain percentage of reduction in proteinuria, say 30%, that would be clinical proof of concept for the very first time on this mechanism, which would be tremendous. So you guys have a lot on your plate right now, right? Yes. You've got potentially a very large market opportunity in CKD. You've got one rare disease program in PKU. You're competing with some big players in AMKD. What would you like to keep yourselves, and what would you like to have a partner help you out with? Yeah. So 2026 is clearly a big year for us. We have a Q1 2026 data in AMKD or APOL1 mediated kidney disease. Again, we'd like to be the first company to show, if you will, clinical proof of concept in that broad AMKD patient population. 30% is our goal in terms of reduction. If we could do that, we'll be in a registrational study. And I think the other concept in terms of what's really important for 782 is we could have two phase twos ongoing next year, which end up starting in both PKU and CKD. Now, to your specific question, our goal is to really be able to show clinical proof of concept next year. I think if we're able to do that, I think we'll be able to have a lot of different kinds of conversations on what's the best way to advance these to patients as fast as possible, and on the heels of that data, we'll kind of consider what makes sense, but right now, we're focused on clinical proof of concept and execution for all of these data sets, and fortunately, with the IPO earlier this year, as well as our recent financing in September, we have the data and we have the capital to be able to get through all of these different milestones by ourselves. Looking forward to your terrific 2026. Thank you so much for your time, Jason, and apologies for the travel hassles. Thanks for having me, Debjit. Hope you guys have fun in London. Yes. Thank you so much for taking the time. Thank you. All right. All right.