Perfect. Good morning, everyone. My name is Cory Kasimov, one of the senior biotech analysts here at Evercore, and it's my pleasure to host our next discussion with Maze Therapeutics and the company's CEO, Jason Coloma. Jason, thank you very much for being here today.
Yeah, thanks for having me, Cory.
Yeah, so look, we've been starting all these chats with a similar question, something of a level set. So hard to believe we're already in December. But given that timing, I'd love to begin the discussion by asking you to kind of reflect back on 2025 and talk about what you think the company's biggest accomplishments were, both the obvious ones, but also perhaps maybe some of the more nuanced ones as well.
Oh, thanks for that, Cory. I think, you know, it's been a spectacular year for us, really transformative in the sense that we were one of the first companies to go public early this year. That has allowed us to really be able to, you know, sort of transform as a company and be able to, you know, take our next step in the journey, so to speak. And it was great because the second point was that we were really able to, you know, be able to start our study around MZE829 for APOL1 kidney disease. You know, we're on track to deliver that data by the end of Q1 2026, and we really were able to get that off the ground. And then the other thing that we were able to do in September is we had additional data on our second program, MZE782.
Happy to talk about that as well, that I think was well received by the street. We also did a small PIPE financing off of that. And so, you know, we have basically had a nice setup of having the product candidates advancing, not only having the people being able to operate across all these different studies, and then finally just having, if you will, the capital through these financings to be able to get through multiple data catalysts for us and shareholders.
Great, great. Okay, so let's start with APOL1, and you know, maybe just kind of a little bit of a background here and talk through, like, the standard of care for these patients today and the unmet medical need that exists.
Yeah, for those that aren't, you know, familiar with APOL1-mediated kidney disease, it disproportionately affects the Black community. It's a genetically defined disease where there's two variants, G1 and G2, that cause this toxic gain of function, ultimately resulting in toxicity in the kidney. There are about six million individuals that have these variants in the U.S. About one million have kidney disease. And what we've been describing, as of late, of those that probably could best benefit from a therapy, at least 250,000 individuals in the U.S. can benefit from a therapy. Now, we know a lot more about the patients, Cory, as you were asking. So we know that they're younger than non-APOL1 kidney disease patients. They usually clinically present before the age of 50. Chronic kidney disease, usually people associate that with an elderly population. These are younger patients. They progress much faster.
So they, if you will, progress and transition to dialysis about 10 years earlier than a non-APOL1 kidney disease patient. And unfortunately, and you asked about standard of care, they're not responding to current standard of care, whether that be RAAS, ARBs, even SGLT2s. Unfortunately, they still have high levels of proteinuria, these patients that end up having progressive kidney disease. And so there are no approved therapies for APOL1 kidney disease to date. And us, as well as a couple other sponsors, if you will, are hoping to be trying to develop the very first disease-modifying therapy for these patients by going after the underlying, if you will, the genetics and biology itself, which is target APOL1 directly.
Okay. And so would this be for, like, the broad swath of AMKD patients, or is it more targeted kind of subset of them?
No, absolutely. So I think, you know, what we've been able to publish, as well as other sponsors as well, is that this has effects beyond a rare, if you will, the initial, if you will, clinical proof of concept was demonstrated in a rare form of disease called FSGS. But us and other sponsors have been able to publish on the fact that this could go across the entire spectrum of AMKD patients, both those with and without diabetes. If you look at the breakdown of about that 250,000 number that I cited, about 60% don't have diabetes and 40% do have diabetes, and a small minority of those patients end up having FSGS.
So the possibilities here, if you think about that number and put it into context, you know, that is about either, depending on the epidemiology you look at, either, you know, double the size of the IgAN market, which I think people are more familiar with in terms of kidney disease, or about the same size. So it is a tremendous, if you will, unmet need that unfortunately doesn't have any approved therapies today.
Yeah, it becomes a huge commercial opportunity as well. So from a mechanistic point of view, how does 829 compare to Vertex's inaxaplin? And I guess, are there specific qualities of 829 that you think make it a potential best-in-class molecule?
Yeah, so what's really been interesting over the, I would just say, past 15 years of trying to understand APOL1 kidney disease better is that we always knew and understood the genetics, which are these two variants that seem to cause disease. Unfortunately, no one really understood how APOL1 was causing disease, and us, as well as others, including Vertex, had elucidated, out of all the different hypotheses that were out there, that APOL1, when you had this toxic gain of function, is forming this pore or channel in the podocyte, ultimately overexpressing in that podocyte and, if you will, punching holes into the podocytes, causing this toxicity, so at minimum, what you want to do is be able to block the pore.
What we realized, not only that, that you want to be able to block the pore, but you want to be able to move upstream of that and disrupt the assembly of those pores from forming to begin with. Now, what differentiates us from inaxaplin is what we've been able to understand is that we've been able to see where we're binding to the pore. We're binding to a different part of the pore than they are. We know that we're able to, in multiple models, both in vitro and in vivo, show, if you will, significant potency differentiation relative to inaxaplin. And the third thing that we really wanted to understand is why. Why were we so more potent than they are? So we had run additional studies.
What we realized is that, you know, we have a dual mechanism in the sense that we're able to block the pore as well as disrupt the assembly of those pores from forming to begin with. In those same studies, we know that inaxaplin can only block the pore.
Okay. So you have data coming up, as you alluded to, in the first quarter of next year from the phase 2 basket trial.
Correct.
Can you kind of remind us of the trial design there and the types of patients that you enrolled?
Yeah, so we have our Horizon study ongoing, and what we are doing is you have to be genotyped. So individuals have to have the G1 or the G2, if you will, genotype. We treat them for three months, Cory, and then we follow them for a month. A few dimensions of the study that are important to highlight, you know, so we are trying to, you know, be able to show for the first time clinical proof of concept in what we call broad AMKD, both with and without diabetes. That would be the first time anyone's demonstrated clinical proof of concept. We've demonstrated we want to show at least a 30% reduction in proteinuria relative to baseline. We're measuring that by looking at UACR, not UPCR, which is a more sensitive, if you will, measurement of proteinuria.
And the other thing that we've done, a couple of things that were a little bit different than, you know, other sponsors' studies is we did include the diabetes patients. We did include measurement of the efficacy based off of UACR. And the last, in terms of lead-in time for the treatment, which is how long do you leave them on standard of care prior to introducing our agent, we did at eight weeks relative to other studies had been previously at four weeks.
Okay.
Right, and so those differences are important mainly because we want to be able to see, again, a broad effect in multiple patients with or without diabetes and see at least that 30% reduction relative to baseline, and that eight weeks allows us to really be able to make sure that the effect we see is due to our agent, not the background treatment.
Makes sense. So when we get these results in the first quarter, should we be expecting data from all three subpopulations? And so diabetics, non-diabetics, and FSGS patients?
Yeah, in terms of guidance for investors, you know, what we want to be able to do is be able to show the, you know, be the first company to show publicly an effect in broad AMKD with or without diabetes. We wouldn't be including at this point the highly proteinuric FSGS patients at this point.
Okay.
That would be the first time anyone has shown clinical proof of concept in this patient population. The second thing for investors to understand is that we've set the minimum threshold that allows us to think about, are we seeing enough data to see clinical significance and allow us to progress into what could be a phase two B3 study by looking at that 30% reduction of proteinuria relative to baseline. And the last is this point of that if we do see that signal, Cory, the idea is that we could initiate planning for a phase two B3 study. And that could look very much like other sponsors' studies in the way that we would look for signal and the registration path.
Okay. And then when you think about this product and its attributes, is there a reason that you would expect, maybe it's not the product, maybe it's the disease itself, a reason to expect that the efficacy would be the same or different across the different subpopulations, the diabetics, non-diabetics, and FSGS eventually, where you'd expect it to do better in one versus another?
Yeah, so I think, you know, based off of the data that we know, one thing is that, you know, we've done a lot of work and others have as well. We had the American Society of Nephrology Conference just a few weeks ago that had been highlighting particular work, including ours and other sponsors as well, that, you know, the progression of disease, whether or not you have diabetes, is about the same. You know, I think, you know, so what we know is that if we have a therapeutic, we should be able to intervene whether they have diabetes or not. That was an important feature. And why do we think that? One of the reasons is that we were one of the first groups to identify a protective variant of APOL1.
We had talked about the G1, G2, which are the pathogenic variants, N264K, which was something we published on, protected individuals in the background of even having those pathogenic variants, whether or not you had diabetes. So if we are truly, as we've designed our molecule to phenocopy to protect the variant, we should see an effect in both, right? And that protective variant was nice to see other sponsors, including Natera, had published on this, so reinforcing what we had been previously published. And so we expect, you know, to see, you know, an effect in both of those populations. And we've said and guided consistently that a 30% threshold in proteinuria reduction would allow us to see that clinical significance.
So that's what's looked at, like, when you think about what question investors will always ask, like, what's a win for this readout? Is that 30%? Is that sort of that line in the sand?
Correct.
Okay, and you know, we always, I'm sure you're always asking yourself, like, kind of what could go wrong? Like, what do you see as the biggest risk to this trial, but also more than just this trial, kind of the program overall? Like, what do you need to be careful you avoid?
Yeah, so, you know, I think for us, you know, when we had, if you will, the opportunity to really be able to talk to nephrologists and investigators and learn, of course, by studies in front of us. So I think, you know, we have full confidence in the fact that, you know, we've designed a good study within Horizon. And a couple of the features that I mentioned are important to highlight to minimize the risk. So one of the things we did was not use UPCR, which is a broad spectrum of proteins to measure, if you will, the amount of protein in the urine. We're using UACR, which is specific to albumin, more sensitive and better measurement for more moderate forms of disease. The other thing that we did is we were able to look at, you know, background treatment and the lead-in time.
We included people that had SGLT2s, and we allowed that lead-in time to be eight weeks rather than four weeks, as I previously described, so that we can see for certain that our agent is what's causing the proteinuria reduction, not anything in terms of background and I think the last thing is that we did look at, you know, decreasing, if you will, the proteinuria range, but leaving it where the patients still have, you know, enough of high enough proteinuria, but still had enough kidney function in terms of eGFR measurement such that they are not necessarily have gone too far down the road in the sense of fibrosis of the kidney, which may mitigate or, if you will, introduce some risk.
So I think we've been able to not only think about genetic identification of the patients, but also look at different features within the study that have allowed us to really minimize some of those risks.
Okay, so interesting. A couple of things I want to follow up on. So the eight-week prior treatment and standard of care, is this something that's been done before by other sponsors in this field? Is something that, I mean, to tease out, it's kind of the background noise, it sounds like?
Yeah, I think, you know, as we had talked to, you know, investigators ahead of Horizon, I think what they had talked about is that previous studies had about a four-week lead-in time, and based off of the different array of agents that they may be, these are polypharmacy patients, meaning they're on multiple therapies to begin with, and, you know, to really make sure that the signal that we are seeing to get to that 30% is due to the agent is to leave it at eight weeks. That to them, from a nephrologist perspective, would give them the confidence that it's truly our agent impacting the disease, and then again, moving to the UACR measurement.
Right. And, all right, so that's the other part I wanted to follow up on, UACR. What's been the FDA's, what's FDA discussion around this endpoint? Was it something that you internally chose to use this as an endpoint, or did this come from the investigator community, and how has this been kind of talked about with the FDA to the point is like, do you expect that this would be a registrational endpoint?
Yeah, so I think for, you know, for us, in terms of 30% reduction and looking at UACR, there's a couple of things that are important there. One is that, again, it is more a sensitive measurement of more moderate disease because we want to be able to show an effect size in a broad set of AMKD patients. The second is that, you know, if you look at the literature, there's a good understanding based off of meta-analyses that that 30% number at a UACR translates very well to eGFR improvement, you know, 10-year sort of like survival, like prevention of transition to end-stage kidney disease. The second is that we know from the fact of looking at the guidelines, like KDIGO guidelines talk about 30% showing being able to have clinical significance.
The third is that if you look across different agents, regardless of class, whether they be SGLT2s or some of the newer agents for kidney disease, we know that they talk about 30% being the threshold going back to this translation to eGFR, and the last, which I think you're kind of alluding to, is there's an academic working group called Parasol out of the University of Michigan, which had, you know, worked with the FDA to help describe surrogate endpoints for a more rare form of kidney disease called FSGS, and they talk about 30% and UACR as a measurement, which is helpful, and what they announced a few weeks ago, Cory, is that this same working group, Parasol, has taken on two indications in kidney, one of them being AMKD, APOL1-mediated kidney disease.
So what's nice about that is obviously awareness of the disease as well as being able to work with the Parasol working group to help guide what surrogate endpoints could be.
Okay. All right, so then assuming you have a successful readout, how are you thinking about next steps at this point?
Yeah, I think for us, what we've, you know, guided investors is the fact that, you know, again, think about us as potentially showing an effect in broad AMKD, 30% reduction of UACR. And if we see that in terms of that would be clinically significant and being able to show that clinical proof of concept, we would initiate planning. If we see where we want to see and hope to see, we would initiate planning of a phase 2b/3 study that would look very similar to what Vertex has done in their Amplitude study.
Okay, and when you think about like sort of duration, how long would something like this take, do you envision?
You know, we could probably talk about that more at the end, yes, as we get closer to the readout. But I mean, you could look at obviously how long it took Vertex to run, you know, Amplitude. But things have changed. I think the good thing in terms of why there are reasons to believe it could be even shorter are the fact that there's broader awareness, patient advocacy groups. One of the things that's been highlighted recently is APOL1-mediated kidney disease now has an ICD-10 code, which was just helpful for physicians in the sense of identifying the disease and making it, you know, billable from that standpoint. And then, of course, the Parasol working groups that's allowing it to have even more of a lens on it.
So I think people think, you know, obviously with all the progress that has happened in IgAN for kidney disease as well as FSGS, I mean, it's clear to see that APOL1-mediated kidney disease could be the next disease that gets a lot of people's attention.
Yeah, absolutely. All right, so kind of a multi-part question on a sort of the strategic front. Clearly, a lot of large pharma companies are now interested in this space. So on, I guess, and then there's also, so this landscape is going to evolve and probably evolve pretty rapidly. So I'd love to get your commentary on how you see this landscape evolving. We've talked about Vertex a little bit. You have the AZ, Ionis, SIRNA. You know, how do you see the evolution of this landscape? And then do you, is it your intention to keep this to yourself? Would you be interested in partnering? Kind of how are you thinking big picture about this?
Yeah, I think, you know, if we're in a fortunate situation to see the data we want to see in Q1, you know, we'd be planning for that phase 2b/3. That is our intention. I think the other thing to kind of highlight is, you know, in particular, like as I mentioned, there are no approved therapies for this disease. And we know that they're younger, they progress faster, they're sicker, and they're not responding to standard of care. So multiple opportunities will be there. And that'll be great for patients as well as, you know, the providers that care for them.
I think the analog that we tend to, you know, point, you know, analysts as well as investors is if you look at, you know, ATTR-CM, which is, you know, clearly, you know, has very similar sort of analogies there, genetic testing, about the same size in terms of patient population. Really sort of you had, you know, in that case, Pfizer sort of paving the way, making more people aware, making, you know, sort of like this option for patients. Then subsequently, multiple players came after, including Alnylam, which was third in the market.
Right.
We saw like in a high unmet need area where the therapies truly are disease modifying. I think there'll be plenty of opportunities for multiple people.
Yeah, it'd be great for all of that to mimic that market in any way. All right, so as we wrap up here, just the last 30 seconds or so, I wanted to ask a quick sneak peek into 2026. Obviously, you have a big event coming up earlier in the year, but it can give you an opportunity to talk about what else is happening at Maze and what are the kind of key objectives for next year.
Yeah, so Q1 2026 in general will just be a big year for us. We have, you know, APOL1 kidney disease data by the end of Q1 2026. We had great data in September on our second program, MZE782, a very novel approach on how you can treat not only a rare metabolic disease, but we really showed the ability to show proof of mechanism in chronic kidney disease. We'll be starting both of those studies based off of the data. So we'll have not only the clinical proof of concept data hopefully by the end of Q1 2026, but then we'll be starting two phase 2s off of the great data in September for 782. So it's going to be a big year for us.
Awesome. We'll look forward to following the progress. Wish we had more time to discuss it, and we'll have to follow up again soon. Though, thank you very much, Jason. Appreciate it.
Thanks for having me, Cory. Appreciate it.