Maze Therapeutics, Inc. ($MAZE)

Good morning, and thank you for joining us today. My name is Elizabeth Webster, I'm on the biotechnology equity research team here at Goldman Sachs. And today, we have with us Jason Coloma, the CEO of Maze Therapeutics. Thank you, Jason, for being with us. .

I guess to start, can you provide an introduction to the company and walk us through where May stands today with your lead assets 828 in AKD and 782 in PKD and CKD?

Yes. Well, thanks for having me today. Yes, so we are, if you will, a small molecule precision medicines company, really focused on diseases that really haven't seen precision before like kidney disease. There's over 800 million people in the world that suffer from kidney disease. It's the ninth leading cause of death globally. In some countries, there is a 4-year waiting list for, if you will, transplant. And unfortunately, there hasn't been a lot of innovation in kidney disease. And -- that's exactly where we fit in. We developed small molecules, really focused on being able to provide precision for those patients. Starting with 829, which is for 81 mediated kidney disease. There's about 1 million people in the U.S. alone who has suffered from the disease. And we've taken an approach where we've been able to demonstrate proof of concept in a broad set of patients earlier this year. And our second program, 782, which is being developed for 2 particular indications, 1 for a rare metabolic disease called PKU and also equally excited about what we can do in kidney disease.

Awesome. And you relatively evenly presented data from Maze 828 in the broad AKD population. Can you just kind of go through that data and summarize what the learnings were there?

Yes. So it's 829, but...

Sorry, Yes. 829.

That's a -- yes. No. So what we did earlier this year is we presented 829 data from our HORIZON study, which is a global Phase II open-label study are a couple of things that were accomplished there. One is that we show that continue to build on its safety as well as tolerability profile. The second thing that we're able to do is -- from across the different cohorts, we had FSGS, those without diabetes and those with diabetes. The third is we showed evidence, at least early and promising that we have a competitive profile relative to other molecules that have been described in the literature, in particular at FSGS patients. And the third thing is that we had the ability to show efficacy in more moderate forms of proteinuria, which hadn't been demonstrated before. The totality of that particular data allows us to really accelerate what we're doing in the sense of being able to advance the program into pivotal planning, and we plan to start a pivotal study using A29 next year.

Great. And kind of walking through the different subgroups -- can you kind of talk about the signal in the diabetic patients versus the nondiabetic patients -- and then how you think about the data in FSGS versus the non-FSGS patients? And just kind of walk us through the subgroup?

Yes. FSGS, what we were able to demonstrate for the first time was really a group of patients that have been treated on various medications, including SGLT2, which hasn't been described in the later before -- so despite being heavily premedicated with other forms of kidney disease agents, we showed a 62% reduction in UACR, which had really exceeded anything that had been described previously. So demonstrating our ability to have at least this concept of being best-in-class. We were also able to demonstrate for the first time the ability to show efficacy, albeit early and promising the idea that you can go in more moderate patients, both with or without diabetes. The previous literature had really not described a lot of evidence that they would be able to see efficacy at all in diabetic patients. We saw early promising signal in some of the patients, about 40% of the patients showed efficacy, even despite having been previously treated with GLP-1s as well as SGLT2s.

Great. And when we think about the change in ACR, I think you've mentioned this kind of 30-milliliter bar talk about kind of what's clinically meaningful in these populations from change from baseline.

Yes. If you take a look at sort of the overall clinical development of other approved agents in kidney disease, 30% reduction in proteinuria translates well to overall, if you will benefit. And looking at other measurements, including what's called EGFR or filtration rate of the kidney, which is 1 of the approvable end points for some of the indications in kidney disease. So the fact that you can see a 30% reduction has demonstrated in previous studies to be, if you will, translatable to other end points. The other thing to keep in mind is that it really is used in the KDG clinical guidelines, at least in the U.S. a physician and a nephrologist will look at the ability to try to reduce proteinuria by 30% with existing agents. If they're not able to do that either with dose adjustments or adding other agents, they keep going. So they'll start a patient on, say, what's called an ACE arb. They'll try to then see if they can adjust the dose if the patient is not getting to that 30% reduction. And they'll keep trying to add agents or switch to different agents in order to try to do that. Unfortunately, patients with APOL1 kidney disease, standard of care is not efficacious in these patients. And unfortunately, despite all going through multiple treatments, including things like ASRs, immunosuppressants, SGLT2s. They're not seeing that 30% reduction straightaway. And so an agent like 829 shows that real promise because we were able to do that across a number of different patients and different types of patients, including FSGS and non-FSGS patients.

Great. And you're kind of targeting some near-term dates on the development path here, but where do you -- where do you see clinical development for 829 proceeding? And what's your plan there?

Yes. So -- to take a little bit of a step back, the data that we had in March was an administrative analysis that allowed us to really be able to, #1, identify whether or not we had an active compound, which I think we did. The second thing we're able to do is really describe, are there any particular cohorts that we think about accelerating and moving to a pivotal study faster, which we were able to do. The third thing is to look for initial signal in more moderate patients, including those with diabetes. Now with that in hand, we're pushing forward, in particular, in the nondiabetic patient population to advance into pivotal studies. So we accomplished that. And I think what we want to do in diabetic patients is to continue to collect more data. It's early and promising as we talk about that with nephrologists in the field and this way that they might potentially treat their patients that have diabetes and have 411 kidney disease, they find it incredibly encouraging, primarily because they're not responding necessarily to other agents like GLP-1 or SGLT2. So what we'll continue to do is collect more data, see if we can tease out the signal. We did see response in some patients as I described. What would be interesting as well is to identify are there particular biomarkers that might help us enrich to better understand the signal, right? If you look at the literature in 40% to 50% response rates are typical in DKD patients. And you can see in the literature in the last approved product for kidney disease, which was Cordia in their Phase II study, they had about 20% to 25% reduction in UACR, yet that now is an approved product, right, for kidney disease. And so if we can take that type of learning and better understand, one, can we see UACR reduction in diabetic patients as well as, #2, figure out are there particular markers that might help us enrich that will allow us to think about the development plan for, I would say, the diabetic patient population.

Okay. Great. And -- if you could put a time line on those, would you say?

Okay. So we have -- we'll have the full readout for Horizon, the end of '26 and '27. So we will have the 3 cohorts of FSGS nondiabetic patients as well as diabetic patients, 10 to 15 patients per cohort that will allow us to really understand and tease out the signal -- in parallel, what we're doing is advancing the non-diabetic patient cohort for pivotal planning, which we expect to start in the first half of 2027.

Okay. Great. And then just thinking about the competitive landscape, there are other kind of assets in AMKD in development. Where do you think 829 is most differentiated? And how do you think about the competitive landscape here?

Yes. I think there's -- fortunately, there are new therapies in development. There are no approved therapies for APOL1 kidney disease today and the current standard of care, unfortunately, is not proven to really improve the patient's lives and many of them unfortunately transition not only to end-stage renal disease, but unfortunately, to dialysis. And as you know, their outcomes are horrible when you think about if they have to shift into dialysis. And so the idea is, could you develop a particular more precision approach that allows us to really be able to help these patients. And hopefully, they'll never have to go into dialysis. I think the opportunity here from our preclinical data, we showed that we had differentiation, especially on potency, which should translate into efficacy. We've actually seen that now clinically early and promising in particular in the FSGS patient population, which is probably the closest 1 could think about in terms of apples-to-apples, if you wanted to compare across trials. -- always dangerous to do so, but that is the closest 1 could do. And you can see even when we were -- our patients were treated with many comeds, including SGLT2 inhibitors they still had high levels of proteinuria, and we were able to reduce the proteinuria significantly in the FSGS patients at 62% UACR reduction and the non-diabetic patient population, nearly 50% reduction in UACR. So we think that, that is not only clinically meaningful, it gives us a differentiated profile relative to others out there that will allow us to participate and really be able to be 1 of the, hopefully, cornerstones for these patients. I think the other thing to think about too is also in cardiorenal, I think we've all seen this. First is not always best in the sense of commercialization, order of entry is important. But I think what we can learn from others in front of us important. We can see that in other areas, smaller TTRC and the Board in terms of cardiorenal, where companies that are coming behind with differentiated medicines, given the unmet need and the size of the population, we'll have a role.

Great. And just mechanistically, in the preclinical data, I believe you show kind of a dual mechanism for blocking the channel here. Kind of can you speak to that because I think that's an important aspect of driving the potency.

Yes, of course. Yes. So I think probably just to take a little bit step back in terms of mechanism. What we learned over the years is that APOL1, the way that it causes disease, particularly in the podocytes, with are called kidney cells, really, under certain conditions, you get this overexpression of APOL1, usually an inflammatory response that overexpression caused it to be expressed in the if you will, in the cell membranes of the podocytes, basically punching holes in them because these are ungated channels. And then they have an influx of particular, if you will, bad actors that ultimately cause nephrotoxicity. So you have this overexpression, this ungated channel and basically having this nephrotoxicity. The idea with an APOL1 inhibitor is minimally want to block the pour from allowing particular agents entering into the cell. But what 829 does relative to other molecules described in literature is it not only blocks the pore, but it disrupts the assembly of the pore forming to begin with. We think that's important for a few reasons. But 1 is that APOL1 highly turns over in the podocyte every hour, sometimes as quick as 42 minutes in the literature. So the idea that you want to not only think about blocking the pore working upstream such that the pore's never formed to begin with, it makes sense that you would be able to, if you will, change sort of the proteinuria levels in these patients. And so compared to other molecules that have been described, they're only able to block the poor. They're not able to disrupt the assembly, right? And so that's why it helped, I think, for us, partially explain the potency [indiscernible] into the clinic. Again, looking at the saw a 62% reduction in the UACR Previously, in terms of UACR that was in the high-30s. And our patients were treated on the background of multiple meds, including SGLT2 versus what's been described in literature that the high 30s, the patients were not treated on SGLT2.

Got it. And thinking about what a Phase III trial could look like here, kind of walk through how Maze is thinking about that. And then your point about the background therapy is -- is that kind of similar to how you would think about patient enrollment in such a study?

Yes. I think there's -- I think what's nice there's an academic working group called Parasol that was started at the University of Michigan. That as really helpful for other companies working at FSGS. There was a recent approval which was great for FSGS patients. And that particular academic working group at that time, they were working with the FDA. They're now working on APOL1 kidney disease. So the good thing is we now know for FSGS patients alone from the previous paracel study is that proteinuria reduction is the approvable end point not a surrogate or accelerated approval, that is the full approval endpoint. So I think it's pretty clear in terms of regulatory path for FSGS patients. What we might be able to learn from the Parasol study that's supposed to read out for APOL1 kidney disease this year is how that applies for FSGS patients that have APOL1 variants, right? So it may be the same guidance or it may be different. We'll have to see what the working group comes up with. But I think that will be very important to help clarify the regulatory path. For non-FSGS patients, I think you can look at other studies that are there, whether combining both proteinuria reduction as well as eGFR slope as a basis for accelerated approval. That will be highly informative that that's going to be possible, I guess, end of this year or early next, is that will help clarify at least for our program as well the ability to kind of think about the non-FSGS patients. So I think in summary, I think FSGS is pretty clear regulatory path in terms of proteinuria reduction. And I think we're going to learn a lot from other programs as well as the Parasol initiative that will inform us how do we think about the non-FSGS patients?

Got it. And just kind of double-clicking on FSGS -- could you kind of speak to how that population is kind of diagnosed and just like the term of FSGS kind of what that means clinically and how those patients might be different if they are than the non-FSGS population?

Yes. I think it's -- I think there's been a lot of education as you're inferring about what FSGS is, and it's not a clinical diagnosis. It's a histological diagnosis by looking at a biopsy. And historically, kidney patients weren't biopsy that often. It wasn't something that nephrologists has had done. But I think to the credit of other companies in front of us, and now approved therapies for those patients. We're learning of many more patients are being biopsied once they get referred to the nephrologist. In particular, that's helping them direct them to better care, right? So I think that's important to note. But typically, APOL1 kidney disease patients, they are disproportionately affected in the black community. So a younger individual will go to a primary care physician, they'll have elevated blood pressure typically and for unknown reasons. They get the typical workup that you or I would get if physicians saw that type of blood pressure. They look at their liver, their kidneys. And if they come back, they'll see, even if it in trace amounts proteinuria, they'll ideally refer them to a nephrologist. Now what a nephrologist will do at that point is try to figure out if they are from the African-American community, right now, not everyone's being genotype, but that's being worked on to date with additional efforts in terms of, I would just say, advocacy in the community. But we're seeing more and more people being genotyped. And then more importantly, getting biopsy, that's allowing them to direct them to the right care.

Great. And maybe we can move to PKU and Maze 782. And I think it would be helpful just framing the data that you've shared to date and kind of contextualizing it. for us in this disease?

Yes. So last fall, we described 782 and published the Phase I data, which was over 100 healthy volunteers. And what we were able to do there is, I think, again, showed that it was safe, tolerable, PK was linear and predicted well and what half life of about 11 hours that allows us to kind of think about either once or twice a day dosing. But more importantly, what we're able to do is show a pharmacodynamic effect, in particular biomarkers that translate well to PKU. For people that are not familiar with PKU, it's a rare metabolic disease, which is left untreated. Unfortunately, you have this toxic accumulation of an amino acid penanylani in the blood. And what that does is, unfortunately, some of it makes its way to the brain, causing some neurodevelopmental neuropsychiatric impact. And so right now, the standard of care is to either take what's called a BH4 co-factor or an enzyme substitution therapy, which basically tries to break down the phenylalanine accumulating in the blood. Unfortunately, not everyone can tolerate these or it's not efficacious enough to really be able to reduce. And so the magic number that you hear right now is that you would want to try to reduce phenylalanine levels below 360 micro molders in the blood, maybe even 120 micromolars in the blood. Okay. So clinically, that's what you're trying to do. And so unfortunately, because not everyone is doing well on these therapies, 60% of the people out there have to stay on this really onerous medical diet, where they can have very little protein. And what I mean by that is most of them can have maybe up to 10 grams of protein a day. It's basically 2 ways. You and I will probably have 8, 10x that much in a given day. So unfortunately, people have to be on this onerous medical diet and then they can't come off of it. and they're on it forever. So a new therapy like 782 provides an opportunity to address not only the patients today who don't respond to current standard of care, but also the 60% of people have to stay on this medical diet and ultimately try to get them off that because as we talk to patients, parents of those patients, they just want to get off this diet. And if they can do that, that will transform their way that they live because they don't have to be restricted so much and live hopefully more healthier lives. So the data that we published, there was another company who had demonstrated proof of concept of inhibiting SLC6A19. SLC6A19 as a saw transporter expressed in the gut in the kidney. And while we're doing is basically hitting the target, getting rid of that toxic accumulation of phenoallanine and the blood by excreting it on the urine. It's not simple of a mechanism. And the good thing about that is you can measure even in healthy volunteers, how much alone excreted out to the Europe. And we know that, that translates very well to the plasma fee reduction eventually in patients. So there was another group that had published a few years ago that they had in healthy volunteers show a tenfold increase in urinary fee relative to baseline at 1 of their doses. -- right showing that proof of mechanism. And eventually, in PKU patients, they showed a 40% reduction in plasma fee. And the good thing about plasma fee reduction, that's the approvable endpoint as set a surrogate or accelerate, that's the approvable endpoint. So we knew what the borrower was in healthy volunteers, we can beat a tenfold increase of urinary fee relative to baseline, we would have evidence that we could be best in class. And what we did last September is we showed at many doses, we're able to beat that up to 40 times, so over 4x greater urinary fee excretion that what has been described in literature to date, which should translate into best-in-class plasma fee reduction in patients when we run that study, which we're running right now.

Great. And in terms of kind of the mechanism and the structure of 782 to help us understand points of differentiation. I think there's another oral substrate reducer in development from another company. And so how do you see that kind of biologically and mechanistically differentiated?

Yes, that's an important point. So at the end of the day, people want to just get off this medical diet. That means getting their plasma fee as low as possible. ideally below 360, even below 120. So if we can do that, we can get them off the medical diet in the long term. So preclinically, we showed that we were 3 to 4x more potent, and we had talked about that before. And then in the clinic, even in the healthy volunteer study, we reinforced that. they showed at the -- at 1 of their doses, a tenfold increase of urinary fee relative to baseline. We showed over 40x increase of urinary fee excretion. So reinforcing that 3 to 4x potency relative to anything that's been described in the literature to date. And what that should translate into is better plasma fee reduction in patients ultimately resulting in a number of people who can get below the 360 and the 120 numbers that are important clinically and get them off more importantly, this medical diet. So what we know about the agent that you described earlier, in the Phase II study, what we know is that at their low dose, they had about a 40% reduction of plasma fee. At their high dose, they had a 60% reduction of plasma fee. So we have a good mapping of where they are and what the bar is set. And they also had of the 19 patients that they reported, they had 3 that went below 360 and they only had 1 that went below 120. So clearly, proof-of-concept was demonstrated, but there's room to go there. And if you think about those numbers, most patients that have PKU are called severe or classical. And what that means is that they have a greater than 1,200 micromolar of plasma fee. And so if you want to reduce that down to 360, if you just do the math, that's 70%, right? I said that their top dose, they were 60%. So they don't -- they won't be able to serve all of the patients that way. And so with our potency, our early clinical data, we have reasons to believe that we can beat those numbers.

Great. And could you kind of talk about the prevalence numbers and the addressable population sizing -- and then when you speak to that 60% of patients that are on that medical diet, how big is that population in terms of the...

Yes. So from a global perspective, there's about 60,000 people that have PKU. About 60% of those are still just on a medical diet, less than 10% on an enzyme substitution therapy -- and unfortunately, not everyone responds to that because they develop antibodies over time. It also has some issues in terms of safety. So it has less than 10% usage even though it is the most efficacious for the patients. And so whilst patients in that 20% to 30% are using what's called the BH4 cofactor, which is basically just a cofactor to allow the enzyme that's there, that breaks down the federal alanine to work better. That's what was recently approved with another molecule in Phase III. That's what Kuvan is -- and so our agent works in a different type of mechanism, which should, in theory, work across the entire spectrum of the disease because we don't rely on the enzyme that's present to be efficacious, because we just get rid of the toxic substrate that begin with. And if we can do that safely, we should be able to serve the entire spectrum of the 60,000 patients.

Great. And then before moving to chronic kidney, maybe just finishing up on PKU, remind us of your next data catalyst and potential trial initiation time line?

Yes. So we're starting a trial that's a Phase II proof-of-concept study. We have a couple of doses that we're doing. -- plus placebo. So this is not an open-label study. This will be placebo-controlled. So not only are we testing these in a monotherapy fashion. But we also have a third cohort, which is going to allow us to look at this in combination would it be H4, just given the fact that we have complementary mechanisms. As we talk to investigators and some of the patients, there's a group of patients that do pretty well on the BH4s, but they can't get below 360 and they can't get below 10 -- so the idea that we can do clinically is, well, maybe we can serve those patients in combination, get them below the 120 eventually, and they might be able to get off to medical diet in the long run. A lot of investigators encouraged us to study those patients. Because then if you think about from a development plan, both the low dose to high dose and combo, we potentially can work across the entire spectrum of disease. And based off of our early data, reasons to believe that we can do better than what's been seen before by hitting this target and reducing the plasma fee, which, again, at the low dose was about 40% reduction of plasma fee. So we're running that study right now. The data will be in '27. So we have a few catalysts coming up, as you pointed out, 829, end of the year, early next, we will have the full horizon readout across the 3 different cohorts, FSGS, diabetic, nondiabetic and then we'll also have the PKU data in '27 as well.

Great. And maybe switching over to chronic kidney disease. You've kind of talked about a potential protective mechanism here. And maybe to start kind of what does this mean exactly? Clinically and mechanistically, what could be driving that?

Yes. So SOC 6, we were the first group to describe the genetics that there's individuals out there in a heterozygous fashion who actually were protected or had renal protection or had healthier kidneys than those that didn't have the variant. That encouraged us to think about, well, could we actually in copy what we call the genetics here with a small molecule so that by inhibiting the target people that our kidney disease might also have that protection. So we had not only been able to look at that from the genetics and published. We showed a vivo proof-of-concept in an animal model. We are the first group to do that. and then contextualizing that with 1 of the current cornerstones of standard of care SGLT2 and so what we showed was that not only we were able to reduce proteinuria to demonstrate that proof of concept. We actually in that model, did it better than the SGLT2. And importantly, in combination, we basically got those -- the levels back to normal. So we published that, and that was encouraging. So we had the genetics. We had the preclinical data -- and then last year, what we did in terms of the clinical data. Now we knew that all approved kidney disease agents had this phenomena where they showed an -- what's called an initial EGFR dip, which is a little bit counterintuitive because you actually want your EGFR to improve over time, but all agents that have been approved for kidney disease, including ACR SGLT2, even Cerenia, -- they show this initial EGFR dip but it plateaus and flattens out relative to the placebo such that you actually have renal protection over time. So that was interesting, and it was in the literature that you could see this even in healthy volunteers. So we knew that. And if we had the hypothesis of genetics as well as some of the preclinical data, we said, let's look for that EGFR dip and then the healthy volunteers and we saw that. So we published that last year, which was not only did we see that in a dose-response manner. We also saw that when we pulled off the patients on treatment or EGFR bounce back, inferring that the effect is due to the treatment, not just by chance. And the other thing that we saw is it's in the range of the EGFR dip that's in the same range as SGLT2 that's been previously republished. So that all was very notable and interesting to us. And so that helped us better understand we could have a hemodynamic effect. And so our current understanding of the mechanism of I would say, SLC in the context of kidney disease. One is it could have a hemodynamic effect, which we've seen now in the clinic. The second thing is that we know that it's a sale transporter and not just on nutriminoacids like phenol, which we talked about for PKU, but it also manages these toxic metabolites, which in access can be damaging into kidney. So the fact if you can inhibit it, you might be able to just get rid of these toxic metabolites by just excreting it out into the urine, similar to what we do in PKU. So not only could you have the benefit of an SGLT2 like mechanism with hemodynamic effect, but you might also be able to just have a complementary or second type of mechanism by just getting rid of these toxic metabolites. So the idea here is that in the clinic, what we might be able to do in kidney disease patients who are not necessarily responding to standard of care in a proof-of-concept study, we would just look for UACR reduction in those patients that haven't been responding to things like an ASR or maybe an SGLT2. And if we see, again, a 30% reduction in that would be a proof of concept because not only now do we have on the genetics, the vivo proof of concept, the proof of mechanism in healthy volunteers. But if we can show UACR reduction in patients who haven't been responding to standard of care, that would be the first time anyone has demonstrated this with SLC6A19.

Great. Yes. In the last few minutes here, just on the financial aspect, just remind us of your cash position and your cash runway?

So yes, we just reported with a recent raise, we had a little over $528 million. That funds multiple catalysts that have been described today. So -- not only does it complete the Horizon study, which we'll have the data later this year, early next, the PKU proof-of-concept study, the CKD proof-of-concept study and allows us to even initiate the pivotal study for 829 in kidney disease.

Great. And just in CKD, when can we expect that next data set?

We said we would start to study first half of 2017. We haven't announced 1 of the catalysts it would come from that. But you can see multiple catalysts again, from our APOL1 program as well as our PKU program and the cash runway guidance that we have through that, that I just gave you is into 2029.

Okay. Great. Well, thank you so much. Thanks for being with us. I really appreciate it.