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

Good afternoon, everyone, and welcome to TD Cowen's I&I Summit. My name is Tyler Van Buren, senior biotech analyst at TD Cowen. For this next session, we are very excited to have a fireside chat with Maze Therapeutics. And from Maze, we have Jason Coloma, the Chief Executive Officer. Jason, thank you very much for joining me. It's a pleasure to have you.

Yes. Thanks, Tyler. Thanks for having me.

And for those of you in the audience, if you have questions, you can submit them through the web portal, and we'll do our best to get them asked. But we'll go ahead and get right into it since we have 20-plus minutes. Jason, I thought it would be good with ASN just passing, maybe discussing some brief highlights or takeaways from the conference or observations that you guys noted?

Yes, absolutely. So for those not familiar with our story, we develop small molecule precision medicines, primarily focused on kidney disease. And so last week was the American Society of Nephrology, which is the largest conference dedicated to kidney therapies as well as for overall kidney research. And so we had 7 abstracts, Tyler, they are accepted, which was great, a great showing for our team and our scientists and had presentations as well. But probably 3 things to highlight in terms of what we were able to kind of highlight, especially for APOL1-mediated kidney disease. The first thing is that we had published on a genotyping study. And one of the key takeaways there was it really did reinforce what we were seeing in terms of the literature on the percentage of people that had the variants. And so what we reported was the previous literature had described in a general population, around 13% of the individuals that had been genotype had the pathogenic variants that caused APOL1 kidney disease. In our study, because it was enriched for kidney disease patients, we had about 18%. So a little bit higher than the literature, but mainly explained by the fact that we had enriched for kidney disease. So I think suffice to say, 13% to 18% in that range having the variants that end up causing disease, just reinforcing the literature. The other thing that was important from that study is that sort of the breakdown. We've always talked about 1 million individuals in the U.S. have the variants, at least 250,000 individuals could benefit from a therapy and the split between those that have diabetes and don't have diabetes. We reinforced the literature in the sense that about 40% of the individuals do have diabetes. So it's about nondiabetes, 60%; diabetics, 40% so also reinforcing the literature. The second thing that we did is there's been some discussion, I think, in the sense that should we -- in a broad AMKD patient population with or without diabetes, should there be an effect in diabetes because there's been some previous literature talking about the, let's say, decreased incidence of disease with those with diabetes. But we and other sponsors as well have been starting to educate the field and investors is it's not about incidents. It's about progression to disease. And what we published on was the fact that those that have progressive disease, it is aggressive and progresses at about the same rate with or without diabetes. So conceptually, if a therapy should have an impact whether or not an individual has diabetes or not. And then the other thing that we had previously published on related to that was we had found a protective variant, N264K. And just to remind folks, that protective variant protected individuals whether they had diabetes or not, sort of illustrating if we truly are, us as well as some of the other sponsors, mimicking the protective variant, which is the hypothesis, we should see an effect in either population. So what's nice to see at ASN last week was another group, Natera, reinforced that finding in terms of N264K, which really demonstrated, again, this concept that it should work in both patient populations. And then the last thing that's probably important is, I think prevailing sort of mechanistic understanding of the hypothesis of how APOL1 causes disease. So just to first off say, the genetics were known for a very long time. No one really understood function, us and other sponsors worked really hard to better understand that the pathogenic variants that cause disease cause an aberrant, if you will, function of this poor channel in the podocyte, ultimately leading to nephrotoxicity. And we want to be able to, if you will, block that pore, if not, if you will, disrupt the assembly of that pore ever to be formed to begin with. And we published some additional data to demonstrate and reinforce that the mechanism by which APOL1 is causing disease is truly that it is acting as a poring channel. And so that an inhibitor of that function should continue to see benefit in terms of the clinic. And that's important because there were dozens of different hypotheses on how APOL1 could end up deciding disease. But now we have a better understanding of that. So it's just really nice to see everyone that's working in APOL1, not just us, sort of the common understanding about at least 250,000 individuals could benefit. You should expect to see a signal whether you have diabetes or not. And then the prevailing hypothesis that it's acting as an aberrant pore channel seems to be sort of coalescing around that overall scientific hypothesis. So it's really great to see. And obviously, we're really happy to see all of those sort of get reinforced and accepted and being able to talk about the larger community at ASN.

That's great. Very interesting. Thank you very much for recapping that for us. Maybe we'll get straight into the MZE829 program, your APOL1 inhibitor in development for AMKD. Can you just give a high-level overview of that compound and how it compares to others, obviously, in particular, inaxaplin in terms of its properties?

Yes. So we are developing a small molecule. We have a dual mechanism, APOL1 inhibitor, and we're advancing it for the potential treatment for what's called APOL1-mediated kidney disease. Again, the idea is not only the fact that you might be able to inhibit the pore itself, but also what we call a dual mechanism is that we also have, if you will, differentiated biology relative to other compounds in the literature and the fact that we not only block the pore, but we also disrupt the assembly of that pore to begin with. And that ultimately, in terms of differentiation, leads us to at least in in vivo proof-of-concept models in kidney models, we showed that we had a significant potency advantage relative to any molecule that had been described in the literature before and then further reinforced by other work that we had done. So the idea, of course, is that previous compounds have showed clinical proof of concept in FSGS patients previously. That's great because we know that the mechanism can demonstrate clinical benefit. Our goal with the Q1 '26 readout, Tyler, is, number one, what we want to be able to do is be one of the first companies or if not the first company to demonstrate clinical proof of concept in broad AMKD with or without diabetes. We've set that minimum threshold in terms of seeing a signal at least 30% reduction of proteinuria relative to baseline. Happy to describe how we landed on that number. And then third, what we've been communicating to folks at ASN and this week as well is if we see, if you will, a signal and show clinical proof of concept in that patient population in Q1 '26, we could be in a position to potentially start planning for a Phase IIb/III study, much similar to obviously, what Vertex had done with their data a couple of years ago.

That's great. And just to be clear, with the Q1 update, so we're going to get data from both the diabetes and the nondiabetes AKD (sic) [ AMKD ] cohorts?

Yes. When we set up on HORIZON, our goal was because it had shown clinical proof of concept in a rare population, we'd like to show for the first time and hopefully, broad AMKD with or without diabetes. So that was the intent. And if we see that signal at 30% reduction, to us, that signifies that we have demonstrated clinical proof of concept as we've talked about that with nephrologists. And I think based off of the strength of that data, should we get there, the idea is then we can start initiating planning for what a, if you will, IIb/III design could look like.

Got it. And have you said approximately how many patients we should expect per cohort?

Yes. I think for us, in terms of the readout, people should expect an order of magnitude of what Vertex described in the first study. So that's why we describe it as an initial set of data that should allow us to -- if we see that signal in that percentage of patients, we would hope to, again, think about that 30% number, look at the totality of the data. And if we see that signal, then we can ideally push as fast as possible to something that could look more like a registrational study.

Got it. Is it possible that we see FSGS patients in Q1? Or do you think we need to wait for a pure FSGS update later?

Yes. I think our goal for HORIZON in the first readout is to show clinical PoC in that broad AMKD patient population. We are enrolling patients that have FSGS. And of course, if we have that. But just to set expectations, our goal is to focus really the investors on we could be the first company to show PoC in that broad patient population. And if we do, that gets us from a rare population of FSGS to a broader set of patients who can benefit.

Got it. And when you were recapping some of the ASN highlights, you talked about the variant being protective both in diabetes and in the broader AKD (sic) [ AMKD ] population. So just as we think about proteinuria reductions, is that variant equally protective in diabetes versus nondiabetic patients? Or is there still somewhat of a difference that might manifest in the proteinuria reductions?

Yes. I think what's interesting from the genetics, it progresses at the same rate and equally as aggressive. So that's interesting that whether you have diabetes or not. So conceptually, again, if you could intervene with a medicine, you should see an effect in both. And then the N264K, specifically the protective the variant that you just mentioned, yes, it does at the same rate, protect those with or without diabetes. So we know that's nice that we have the natural, if you will, genetic experiment showing that. And that's why we -- for all of our programs, Tyler, we do look at not just pathogenic variants, we look for protective variants as it might allow us to better understand function and mechanism. And then as we design our small molecules as we did with this program as well as for SLC6A19, if we can mimic that protective effect, that should allow us to reap that benefit you see clinically. And so that is the goal here. And I think what's nice is we'll hopefully try to demonstrate that in Q1 '26.

Okay. And can you just elaborate on how you picked that 30% threshold, especially with the 48% with inaxaplin out there in that very small FSGS data set and your confidence in potentially being able to achieve significant proteinuria reductions?

Yes. So the previous literature described a rare patient population. This is broad AMKD, so more heterogeneous in disease, both with or without diabetes. And the 30%, probably 4 things to highlight for investors. 30% is a number that if you look at some of the analyses, it correlates very well to eGFR slope, which is most likely, just like in IgAN, the approvable pathway for particular proteinuric diseases. The second is in the guidelines, so KDIGO, 30% is being clinical significance. uACR specifically is highlighted as what you should be measuring for this more moderate disease. The third is if you just look historically, things like other classes like SGLT2, they had 30% as their bar eventually sort of translating to, if you will, outcome data and eGFR benefit. And the last is, which I'm not sure if you saw this, Tyler, but PARASOL, which is a group that -- at a University of Michigan, which was instrumental in working with the agency to help define for FSGS, that rare patient population that proteinuria alone should be the approvable endpoint. The PARASOL group has taken on 2 kidney indications, one of them PMN and the other APOL1-mediated kidney disease. And in that press release, they did describe a couple of papers that they even referenced uACRs the proteinuric measurement that people should be using and the 30% number as a good minimal threshold to see clinical benefit for patients. So those are the 4 things we highlight as the rationale for 30%. And I think that allows us to at least see where the bar should be. And if we exceed that, of course, that would be great.

Great. And preclinically, what have you seen with 829 that gives you confidence that you could have significant reductions in proteinuria in patients?

Yes. So we previously published, especially in particular, the BAC transgenic mouse model, which has high levels of proteinuria. We've done that both in the chronic setting as well as preventive and shown that we can get to doses that get to in the [indiscernible] that effectively can get into that range of at least a 30% reduction. So I think in terms of translation, we've seen that in in vitro models. We've seen that in multiple models. But more importantly, we saw that in the BAC transgenic mouse data. And we know why that might be translatable is because we did -- we were able to synthesize inaxaplin, bring that into that model based off exposure of where their clinical dose was, and we saw a proteinuria reduction. So we already know that they showed clinical proof of concept in patients. So very good confidence in the sense of this being a translatable model where we should see at least some level of proteinuria reduction as you move into the clinical trial.

That's great. As we see this initial data and as we think about the development plan moving forward, how do you think about baseline proteinuria? In other words, does baseline proteinuria have a significant impact on the percent reduction that you can achieve in patients? If people have higher baseline proteinuria, do you have a greater potential to have a more significant reduction? Or is it independent of baseline proteinuria? Curious to get your latest thoughts there.