All right, good afternoon, and thank you for joining Guggenheim's 2026 Emerging Biotech or Emerging Outlook Biotech Summit. I'm Debjit, one of the therapeutic analysts, and my privilege to welcome our next presenting company, Maze Therapeutics. And from Maze, we have Jason Coloma, the CEO. Thank you so much for your time, Jason.
Yeah, thanks for having me, Debjit.
Before we sort of delve into the Q&A, there's a lot going on at Maze, maybe a very quick intro from your side?
Yeah. So we apply advanced human genetic analyses to really identify, you know, variants of particular genes in the context of disease, that allow us to really direct our small molecule efforts, primarily for kidney and metabolic diseases. So we have multiple programs now in the clinic. MZE829, which is for APOL1-mediated kidney disease. I know we'll spend some time on that, and we also had another program that we described some data in September last year, called MZE782, which targets SLC6A19, which we're taking forward, based off the strength of that data, into two phase 2s, later this year: one in a rare metabolic disease, PKU, and another program that we're taking forward in terms of CKD, second half of the year. So a lot going on this year.
We have data for MZE829 later this quarter, with additional studies starting later this year for our MZE782 program.
Awesome. So let's start with the MZE829 program, given that we'll have data sometime in the first quarter. You're going off—the initial data is going to be in APOL1 AMKD and the diabetic AMKD cohorts. Do you expect these cohorts to behave very differently compared to, say, FSGS?
Yeah, I think, you know, what we know today is that, based off the literature, we know that the progression of disease, whether you have diabetes or not, is roughly the same. We actually had some data that built off of some earlier work, a New England paper that Parsa wrote a few years ago. We actually had additional work that we published on at ASN, which is the large, seminal, kidney conference, that reinforced that you see this progression whether or not you have diabetes. And then previously, we've also published, Debjit, you know, looking at protective variants of APOL1 kidney disease, and we saw that that protection happened whether or not you have diabetes, right?
So we'll have to see, of course, with our data that's coming up, but there's no reason to believe that we shouldn't see, at least based off of the genetic analysis, some type of impact, clinically for those with or without diabetes.
Got it. And, to get my numbers correct, we are expecting about 20 patients of data?
Yeah, we've guided in terms of the overall, sort of the similar size of what Vertex reported on in what their New England paper, so size and order of magnitude in that range. We're blinded to the data, so we'll be able to, you know, give more specific number, patient numbers when we have that, you know, and we do the readout.
Is it gonna be roughly equal between diabetic AMKD and AMKD... or just in a primary AMKD?
That would be ideal, but again, we'll have to be able to publish that, once we were able to look at the data and talk about specifically the splits.
Given that you're not doing a biopsy, could some of the APOL1 AMKD patients also happen to be FSGS? We just don't know.
Oh, yeah, we've previously described that, we have the three cohorts, one with diabetes, one without. There could be FSGS patients in those that don't have diabetes, but in terms of comparing that to previous studies, they're not going to be biopsy-confirmed, or nor are they gonna probably be in the higher range of, if you will, proteinuria, which is what previous sponsors had reported, you know, very high nephrotic disease, you know, in those particular FSGS patients.
Got it. So, I believe that from your expectations are roughly 30%-ish kind of UACR reduction?
Yeah, I mean, so what we're planning to, you know, what we hope to be is the first company to show clinical proof of concept in broad, what we call broad AMKD, with or without diabetes. The idea would be, in terms of what we call clinically meaningful or clinical significance, to show that proof of concept would be at least a 30% reduction of UACR, or the measurement of protein in the urine, relative to baseline. And then if we see that type of data, just as previous sponsors have done, if we see that type of signal in a significant number of patients, we could initiate planning for what could be a, a registrational study going forward.
I believe you're also collecting, UPCR data?
Yes.
Do you plan to share both, or would you just focus on UACR?
Yeah, I think for the guidance that we've been given by our investigators, and through the study, has been, and especially in more moderate forms of disease, including the patients that we're studying, to use UACR as the measurement for efficacy. Now, we will report on UPCR because we know other sponsors have as well. But, you know, with specifically for this type of disease, you know, the feedback we've gotten from investigators and nephrologists themselves is to really be able to use UACR as the measurement. And now we're actually seeing that in other sponsor studies, using UACR as the efficacy measurement for proteinuria.
Got it. Any challenges in recruiting patients, whether it's APOL1 or diabetic AMKD?
Yeah, I mean, the good thing is that we haven't changed our guidance from the very beginning, and to be able to deliver the data by the end of the quarter. So what's nice to say is that I think, you know, and I think, granted, and giving all credit to other sponsors, I think there's more increased awareness about the disease. I think there's been a lot of work by patient advocacy groups to make people aware. There's been a lot of work in terms of, I would just say, the academic community. So what's nice is we're being able to draft off of that, just to increase awareness.
You've probably seen a couple things: One, that the test itself, because you do have to genotype patients to actually have these variants that cause disease, that is now on the standard panels LabCorp and Quest, which physicians can request. And the other thing that happened last year, based off of some work that other sponsors have done, an ICD-10 code, which is important because now, that could be billable for physicians to order the test, and I think that'll give us a good sense for, you know, overall, how many patients are being diagnosed with the disease once that is being used more prevalently, in the industry.
When you do have the data, are you thinking of like a waterfall chart with individual patients? Is it gonna be a mean number, or how should we think about what to expect?
Yeah, I think for us, we would, you know, I think it's similarly to what other sponsors have done. You know, I think we wanna look at an average, but we do also wanna be able to, you know, provide information on a patient-by-patient basis and looking at, you know, do we see a significant number of them getting at least that 30% reduction, such that we have further confidence in, you know, reinforcing the hypothesis? And then that helps us to think about which patients we would think about, you know, pushing forward in terms of a potential registrational study.
Mechanistically, 8-9 does a couple of things, which is whereas your peer company does one thing. How do you think it's gonna manifest in efficacy?
Yeah, I think what's really nice to see, I guess, you know, because the genetics of APOL1 in terms of kidney disease has been known for a very long time, Debjit. The problem was that no one really understood the function by which these variants could be causing disease. The work that we published a couple of years ago indicated that, you know, what ends up happening when you have these variants is you have a toxic gain-of-function such that you have overexpression of a pore that forms in the podocyte or the kidney cell. They eventually embed themselves into the cell membrane and ultimately create... basically punching holes in terms of the kidney. That results in, if you will, influx of cations that cause the toxicity.
So what's nice is that all the sponsors, including us, that is, the prevalent hypothesis that has emerged, you know, how it's causing disease. So minimally, you wanna be able to block the pore, right? I think, you know what? We all can say that that's important to be able to see the cations not being able to flux into the cell. But what we learned over time are a few things relative to other compounds that have been described in the literature. One is that we're not only blocking the pore, but we have a better understanding mechanistically in terms of we have a different biology, which you're alluding to, which is that we're disrupting the assembly of the pore.
To us, that's important because if you think about it, if you have this overexpression happening, and we know that APOL1 highly turns over in the podocyte. If you look through the literature, it's happening every hour, sometimes even reported every 40 minutes. So it doesn't matter really if you're blocking all of them. Just imagine they keep reforming and inserting themselves into the pore, so ideally, you would have an compound that can do both. Now, what we know is other sponsors are only able to block the pore, not to disrupt the assembly, and we think that matters now that we have a better understanding of the biology and ultimately the pathophysiology of how APOL1 is causing disease.
Got it. So something that you mentioned beginning of our conversation here, the baselines could be different from in terms of nephrotic or non-nephrotic.
Yeah.
How much of that is being driven by the underlying alleles, whether it's the two aggressive alleles versus G1, G2, you know?
Yeah, I think-
I-
... I mean, the literature is not so clear on that. So I think, you know, I think we're gonna learn a lot more about, you know, sort of the impact of that and what that does in terms of a potential intervention, including ours, you know, I think with additional data that's gonna be published not only by us, but other sponsors as well.
And then sort of you mentioned, you know, potential registration study. The current program in registration study is using GFR and proteinuria as a co-primary-ish endpoint.
Mm.
Is that the-
Yeah
... route you're thinking about, or is there a different way of getting to market or closing the gap?
Yeah, I think for us, I mean, what we've been talking about with investors and investigators is to kind of think about looking at that, you know, study that's out there, looking at a potential 2b pathway, which looks at proteinuria reduction in combination with eGFR slope as a potential pathway to accelerated approval. And if we're able to see that, I think what's good for us, I think, is that, you know, that registrational pathway will be better, I would say, elucidated by other sponsors, as well as some of the work that's being done by different academic groups that can help guide.
So, if we're fortunate enough to see the data that we hope to see later this quarter, I think what's nice is that we'll be able to draft off of some of the registrational work that's done by other sponsors, as well as some of the academic work that's being analyzed to inform how we would think about a pathway to approval.
We're now gonna get the FSGS, a subset, with the upcoming data. How are you guys thinking about that, or that disease by itself?
Yeah, I think for us, I mean, it's nice that, you know, other sponsors have shown clinical proof of concept already in FSGS patients. I think for us, what we wanted to do from the onset of HORIZON was try to be the first company to show a clinical proof of concept in the broad AMKD patient population, given some of the genetics work and some of the preclinical work that we've done. And I think if we can show that, that increases the opportunity here, 'cause we know that most of the patients don't have FSGS, and we know that at least 250,000 individuals in the U.S. alone could benefit from this therapy, and this could be one step closer. 'Cause we know now a lot about the patients in the sense that, you know, they're not responding to current standard of care.
You know, physicians are trying, and nephrologists specifically, are trying different therapies, not seeing improvements in both, you know, proteinuria reduction or eGFR improvement or increases. And so this potentially could be a way to have a truly disease-modifying therapy for patients 'cause we know that they end up being younger, they have more progressive disease, and as I mentioned, they're not responding to current standard of care.
... there's a lot of discussion regarding the thallium flux assay, given the sort of dual mechanistic,
Oh, okay.
Do you think thallium flux assay is the end-all be-all for this, or there is something beyond that?
Yeah, so for those that are not as familiar, I mean, different ways to kind of think about dose selection, and we know that other sponsors have used an in vitro assay to basically decide on what dose to select, which I think is one way to do it. We decided to combine that with also an in vivo assay, which is looking at the BAC transgenic mouse to be able to better predict, you know, reductions in proteinuria, and pick the dose that we think is going to have the best chance or so in effect in this broader patient population. Now, I think that gives us a level of confidence that allows us to do that. I think it better represents what we better now understand more about the biology.
As I mentioned earlier, you don't want to just block the pore, you want to disrupt the assembly of the pore to begin with. An in vitro assay that's looking at thallium flux that you mentioned is only really looking at blocking. It doesn't really look at, you know, the ability to kind of think about, are you really having a disruption of the pore solely to begin with? So we think the in vivo model is a better representation of that, and it's how we've selected our dose, you know, in combination with our Phase I data, to give us again that the highest, you know, probability of success, we should see activity in a broader set of patients.
Right. We're looking forward to the upcoming update. Let's switch over to the 782 program.
Sure.
I believe the plan is to get the PKU study up and running first-
Mm-hmm
... in the second quarter, if I'm not mistaken. How quickly do you think we could get a clean signal in patients? And, you know, how do you expect that to play out, given the precedents to date?
Yeah, I mean, I think what's really nice in this case, as well as what we have in the APOL1 program, there was another sponsor who had shown clinical proof of concept of an inhibiting SLC6A19 in the context of PKU, which is a rare metabolic disease. And what they showed, not only the ability to lower plasma Phe, which is great, because that is for PKU. For those not as familiar, PKU, that is the approvable endpoint. But they also showed the value of a non-invasive biomarker, urinary Phe excretion, that we now know maps very well to plasma Phe reduction.
So based off of, you know, what the data that we showed in September, we showed, you know, reason to believe that we have best-in-class properties relative to the other sponsors', therapy, because we maximally inhibit the target such that we have over 40-fold increase, whereas what they showed in their healthy volunteer at a certain dose, they only showed a 10-fold increase of the urinary Phe biomarker. So based off of that, you know, we now know, what might be possible in showing a maximal effect in PKU patients. So as you're alluding to, what they showed in their clinical study in PKU patients, they showed, at their highest dose, a 60% reduction in plasma Phe, which is great.
But they only showed, in a smaller subset, you know, 3 of the 19 patients that were able to get below 360 micromolars of plasma Phe. And why is that number important? Well, that ends up being the threshold where physicians that treat PKU patients end up starting to believe that they can remove patients off of this onerous medical diet. And as we talk to patient advocacy groups, physicians and patients, as well as parents of those patients, we all know that they just want to get off this diet, right? And even if, you know, they're on current therapies, we know that they're not satisfied with that and the ability to move off the diet.
'Cause what ends up happening is, if they're not monitoring their diet very well, Debjit, you get this issue where the Phe that's in the plasma ends up going into the brain, and ultimately, that's what's causing some of the issues, including seizures in these patients. And so what ends up happening, unfortunately, is that these patients end up having to really monitor what they're taking in terms of protein. You know, what we've used in the past is that, you know, someone like you or I are probably typically on a Western diet where you're having at least over 100 grams of protein a day. A PKU patient, on the other hand, can only have about 10, right? That's basically two eggs. So, you know, imagine trying to monitor and try to deal with that on a daily basis.
Then, you know, at the end of the day, if we can provide a therapy that removes the need for them to monitor and really be able to get them off that medical diet, that would be transformative for the PKU patients.
So how are you thinking about this program? Do you start with classical PKU patients with 1600 or above Phe levels, or do you do a very broad program? Do you want a, you know, normalization of diet as the endpoint, or ... I'm just trying because it could be a pretty broad program, and-
Yeah, I think, you know, we'll have more details after the 829 readout, more specifically as we get ready. You know, we said by the middle of the year, we'll have started that study. So after this 829 readout, we'll come back with, you know, what doses, the study, the patient population that we'll be looking at. But roughly what you're looking at for the first study is being able to reduce plasma Phe. That would be the most logical endpoint, and to think about the number of patients that you might be able to get below that 360 number.
Got it. So beyond PKU, obviously, CKD is a pretty large opportunity. How are you guys thinking about—because where do you take that program? Because there's so many iterations that we can think of.
Yeah. Yeah, I mean, I think what's really nice for those that are not as familiar, you know, we're also really excited about the ability to take this target to chronic kidney disease. We were the first group to identify the genetic relationship of this target and chronic kidney disease. We were the first group to show in vivo proof of concept in a preclinical model and showing it in comparison to SGLT2, which is an important anchor now in kidney treatment for patients. And what we showed in that study is that even at an EC50 relative to the clinical dose from an exposure standpoint for SGLT2, we showed, you know, proteinuria reduction that was better, and also additional markers that we published at the ASN conference last fall.
Then what we did is we were the first group to show proof of mechanism of this target in healthy volunteers. 'Cause what we knew, Debjit, is that all agents that have been approved for chronic kidney disease had shown what's called this eGFR dip, even in healthy volunteers. We know SGLT2 has done that. And so we saw that if we were able to collect that type of data, show what was that eGFR dip, we know that that's, you know, indicative of long-term renal protection. And if we could see that even in healthy volunteers, that gives us, you know, the first demonstration of proof of mechanism. And so, you know, we showed that data last September. That gives us the ability to pursue it, and I think what's important as we think about these two indication, one, sequence is important.
I think the ability to go into the rare disease first, that will have the ability to kind of think about what's the, you know, with PKU and being able to see that. The second thing, I think, as you kind of think about two indications is, at the end of the day, you know, I think what you want to be able to do, if we are using the same molecule for both of these applications, is to think about, you know, what's called two SKU, like, different SKUs or different, you know, sort of product. And that can come in the form of, you know, thinking about different doses, different formulations.
I think if we're fortunate enough to see data that we hope to see in the proof of concept study, we can then use that kind of information to kind of guide how we think about development going forward.
So that's a good segue to my next question in terms of, given the focus on MZE829, have you thought of the dose that you want to take forward in PKU versus CKD, whether it's once daily, BID? Because obviously, there is-
Yeah
... ramifications with pricing, and PKU is different than-
Yeah, absolutely
CKD.
Again, sequence matters, so I think going first, and we've seen that commercially in other areas. And so we'll, you know, I think that's important to make sure that we have the PKU study going first, and then the CKD study. But there'll be more details. You know, again, what we've given guidance publicly is that after the MZE829 readout, we'll talk about these studies in more detail, which doses, which patient populations, and we'll be able to describe the study, and what, you know, timing for potential readouts.
The eGFR dip that you talked about, what are you hearing from experts with respect to, say, the hemodynamic versus the tubular detox contributions?
Yeah, I mean, I think, you know, so for those not as familiar, what's interesting about, you know, SLC6A19 inhibition is that you do have this potential hemodynamic effect, which is similar to SGLT2s. But we also have. You know, we've been exploring that you have this orthogonal mechanism, which is that SLC6A19 inhibition ends up, if you will, reducing the amount of toxic metabolites that accumulate in that region of the kidney called the proximal tubule. So what's nice is you could have the benefits of that you see of an SGLT2, but it could potentially be different and potentially even better than SGLT2 for certain patients, and we saw that at least in the preclinical models.
So I think for us, you know, we'll have to - we're gonna explore more of that, in terms of the biology. We'll be able to kind of talk about that and publish more, you know, in upcoming conferences, but more to come on that, 'cause it is something that's interesting for investigators to kind of think about. Because, you know, as they kind of think about new mechanisms for CKD, this potentially has the ability to work in patients that may not be responding to the current battery of options that they have, including the SGLT2s.
Well, awesome. We have a long day ahead of you, so I'm gonna give you an extra two minutes to hydrate.
Thank you.
Um-
I'll take both of them.
Looking forward to hosting you at the dinner.
All right. Thank you, Debjit.
I appreciate the time.
Appreciate it. Yeah.
Thank you so much.
Thank you.