Good morning. Thank you for joining us today. My name's Elizabeth Webster. I'm on the Biotechnology Equity Research team here at Goldman Sachs. 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 Maze stands today with your lead assets, MZE829 in AMKD and MZE782 in PKU and CKD?
Yeah. Well, thanks for having me today. Yeah, 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's a four-year waiting list for-
if you will, a transplant. Unfortunately, there hasn't been a lot of innovation in kidney disease, and that's exactly where we fit in. We develop small molecules, really focused on being able to provide precision for those patients. Starting with 829, which is for APOL1-mediated kidney disease. There's about a million people in the U.S. alone who suffer from the disease. Our second program, MZE782, which is being developed for two particular indications, one for a rare metabolic disease called PKU, and also equally excited about what we can do in kidney disease.
Awesome. You relatively recently presented data from Maze MZE829 in the broad AMKD population. Can you just go through that data and summarize what the learnings were there?
Yeah. It's 829.
Oh, sorry, 829, yes.
That's okay.
829.
Yeah, no. What we did earlier this year is we presented 829 data from our HORIZON study, which is a global phase II open label study. A couple of things that were accomplished there. One is that we show that it continued 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 in FSGS patients. 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. We plan to start our pivotal study using MZE829 next year.
Great. Walking through the different subgroups, can you talk about the signal in the diabetic patients versus the non-diabetic patients, and then how you think about the data in FSGS versus the non-FSGS patients, and just walk us through those subgroup?
Yeah. 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 literature before. Despite being heavily pre-medicated with other forms of kidney disease agents, we showed a 62% reduction in UACR, which had really exceeded anything that had been described previously. 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. When we think about the change in UACR, I think you've mentioned this 30 mL bar. Talk about what's clinically meaningful in these populations from change from baseline.
Yeah. If you take a look at the overall clinical development of other approved agents in kidney disease, 30% reduction in proteinuria translates well to overall, if you will, benefit in looking at other measurements, including what's called eGFR.
This is the filtration rate of the kidneys, which is one of the approvable endpoints for some of the indications in kidney disease. The fact that you can see a 30% reduction has demonstrated in previous studies to be, if you will, translatable to other endpoints. The other thing to keep in mind is that it really is used in the KDIGO 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. 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's not getting to that 30% reduction.
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. Unfortunately, despite all the going through multiple treatments, including things like ACE/ARBs, immunosuppressants, SGLT2s, they're not seeing that 30% reduction straight away. An agent like 829 shows that real promise because we're able to do that across a number of different patients, and different types of patients, including FSGS and non-FSGS patients.
Mm-hmm. Great. You're kind of targeting some near-term updates on the development path here, where do you see clinical development for 829 proceeding, and what's your plan there?
Yeah. 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, number one, identify whether or not we had an active compound, which I think we did. The second thing we were able to do is really describe, are there any particular cohorts that we think about accelerating and move into 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. With that in hand, we're pushing forward, in particular in the non-diabetic patient population, to advance into pivotal studies. We accomplished that. 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 the way that they might potentially treat their patients that have diabetes and have APOL1 kidney disease. They find it incredibly encouraging. Primarily because they're not responding necessarily to other agents like GLP-1s or SGLT2s.
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.
To better understand the signal, right? If you look at the literature, in DKD, 40%-50% response rates are typical in DKD patients. You can see in the literature, even the last approved product for kidney disease, which was Kerendia, in their phase II study, they had about 20%-25% reduction in UACR. That now is an approved product.
Right, for kidney disease.
If we can take that type of learning and better understand, one, can we see UACR reduction in diabetic patients as well as, number two, figure out are there particular markers that might help us enrich. That'll allow us to think about the development plan for, I would say, the diabetic patient population.
Okay, great. If you could put a timeline on those, would you say?
We'll have the full readout for HORIZON the end of 2026 and 2027.
Okay.
We will have the three cohorts of FSGS, non-diabetic patients as well as diabetic patients. 10 to 15 patients per cohort. That'll 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. Just thinking about the competitive landscape, there are other kind of assets in AMKD in development. Where do you think MZE829 is most differentiated, and how do you think about the competitive landscape here?
Yeah. Fortunately, there are new therapies in development. There are no approved therapies for APOL1 kidney disease today, the current standard of care, unfortunately, is not proven to really improve the patients' lives. Many of them unfortunately transition not only to end-stage renal disease, but unfortunately to dialysis. As you know, their outcomes are horrible when you think about if they have to shift into dialysis.
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 pre-clinical 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 one could think about in terms of apples to apples if you wanted to compare
across trials. Always dangerous to do so, that is the closest one could do. You can see even when our patients were treated with many co-meds, 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. 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 one of the, hopefully, cornerstones for these patients. I think the other thing to think about too is also in cardio-renal, I think we've all seen this, first is not always best
in the sense of commercialization. Order of entry is important. I think what we can learn from others in front of us is important. We can see that in other areas, smaller ATTR-CM and in more in terms of cardio-renal, where companies that are coming behind with differentiated medicines, given the unmet need and the size of the population, will have a role.
Mm-hmm. Great. Just mechanistically, in the pre-clinical data, I believe you show kind of a dual mechanism for blocking the channel here. Can you speak to that? I think that's an important aspect of driving the potency.
Oh, yeah. Of course. Yeah. 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 or what are called kidney cells, really under certain conditions, you get this overexpression of APOL1, usually an inflammatory response. That overexpression cause it to be expressed in the, if you will, in the cell membranes of the podocytes, basically punching holes in them. These are ungated channels, and then you have an influx of particular, if you will, bad actors that ultimately cause nephrotoxicity. You have this overexpression, this ungated channel, and basically having this nephrotoxicity. The idea with an APOL1 inhibitor is minimally you want to block the pore from allowing the particular agents entering into the cell.
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 from forming to begin with. We think that's important for a few reasons, but one is that APOL1 highly turns over in the podocyte every hour, sometimes as quick as 42 minutes in the literature.
The idea that you want to not only think about blocking the pore but working upstream such that the pore is never formed to begin with, makes sense that you would be able to, if you will, change the proteinuria levels in these patients. Compared to other molecules that have been described, they're only able to block the pore.
They're not able to disrupt the assembly. All right. That's why it helped, I think, for us, partially explain the potency. If you're translating into the clinic, again, looking at the FSGS, saw a 62% reduction in that UACR. Previously, in terms of UACR, that was in the high 30s. Our patients were treated on a background of multiple meds, including SGLT2, versus what's been described in the literature that the high 30s, the patients were not treated on SGLT2.
Got it. Thinking about what a phase III trial could look like here, walk through how Maze is thinking about that, and then your point about the background therapies, is that similar to how you would think about patient enrollment in such a study?
Yeah, I think what's nice, there's an academic working group called Parasol that was started at the University of Michigan, that was really helpful for other companies working at FSGS. There was a recent approval.
which was great for FSGS patients. That particular academic working group, at that time, they were working with the FDA. They're now working on APOL1 kidney disease. The good thing is we now know for FSGS patients alone from the previous Parasol study is that proteinuria reduction is the approvable endpoint, not a surrogate or accelerated approval. That is the full approval endpoint. 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? It may be the same guidance, or it may be different. We'll have to see what the working group comes up with. 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, where they're combining both proteinuria reduction as well as eGFR slope as a basis for accelerated approval. That would be highly informative if that's going to be possible, I guess end of this year or early next, as that will help clarify, at least for our program as well, the ability to think about the non-FSGS patients.
I think in summary, I think FSGS, 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. Just double-clicking on FSGS, could you speak to how that population is diagnosed and just the term of FSGS, what that means clinically, and how those patients might be different, if they are, than the non-FSGS population?
Yeah, I think there's been a lot of education, as you're
inferring about what FSGS is, it's not a clinical diagnosis, it's a histological diagnosis
by looking at a biopsy. Historically, kidney patients weren't biopsied that often. It wasn't something that nephrologists had done. I think to the credit of other companies in front of us, and now approved therapies for those patients, we're learning that 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?
I think that's important to note. Typically, APOL1 kidney disease patients, they are disproportionately affected in the Black community. 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 a physician saw that type of blood pressure. They'll look at their liver, their kidneys, and if they come back, they'll see, even if in trace amounts, proteinuria. They'll ideally refer them to a nephrologist. 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 genotyped, but that's being worked on to date with additional efforts in terms of, I would just say, advocacy in the community. We're seeing more and more people being genotyped, and then more importantly, getting biopsied. That's allowing them
to direct them to the right care.
Okay, great. Maybe we can move to PKU.
Yeah
MZE782, I think it'd be helpful just framing the data that you've shared to date and contextualizing it for us in this disease.
Yeah. Last fall, we described MZE782 and published the phase I data, which was over 100 healthy volunteers. What we were able to do there, again, show that it was safe, tolerable, PK was linear and predicted well, and a half-life of about 11 hours that allows us to think about either once or twice a day dosing. More importantly, what we're able to do is show 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 left untreated, unfortunately, you have this toxic accumulation of an amino acid phenylalanine in the blood. What that does is, unfortunately, some of it makes its way to the brain, causing some neurodevelopmental neuropsychiatric impact.
Right now, the standard of care is to either take what's called a BH4 cofactor or an enzyme substitution therapy, which basically tries to break down that phenylalanine accumulating in the blood.
Unfortunately, not everyone can tolerate these, or it's not efficacious enough to really be able to reduce. The magic number that you hear right now is that you would want to try to reduce phenylalanine levels below 360 micromolars in the blood, maybe even 120 micromolars in the blood. Okay, clinically, that's what you're trying to do. 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. What I mean by that is, most of them can have maybe up to 10 grams of protein a day. That's basically two eggs. You and I will probably have eight, 10 times that much in a given day. 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. A new therapy like MZE782 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 who have to stay on this medical diet and ultimately try to get them off that. As we talk to patients, parents of those patients, they just want to get off this diet.
If they can do that will transform the way that they live, because they don't have to be restricted so much, and live hopefully more healthier lives.
Got it.
The data that we published, there was another company who had demonstrated proof of concept of inhibiting SLC6A19. SLC6A19 is a solute transporter expressed in the gut and the kidney. What we're doing is basically hitting the target, getting rid of that toxic accumulation of phenylalanine in the blood by excreting it out in the urine. It's that simple of a mechanism. The good thing about that is you can measure, even in healthy volunteers, how much phenylalanine is excreted out into the urine. We know that that translates very well to the plasma Phe reduction eventually in patients. There was another group that had published a few years ago that they had, in healthy volunteers, shown a tenfold increase in urinary Phe relative to baseline at one of their doses. Right.
Showing that proof of mechanism, eventually in PKU patients, they showed a 40% reduction in plasma Phe. The good thing about plasma Phe reduction, that's the approvable endpoint.
That's not a surrogate or accelerate. That's the approvable endpoint. We knew what the bar was. If in healthy volunteers we can beat a tenfold increase of urinary Phe, relative to baseline, we would have evidence that we could be best in class.
What we did last September is we showed at many doses we're able to beat that up to 40 times. Over four times greater urinary Phe excretion than what has been described in the literature to date, which should translate into best-in-class plasma Phe reduction in patients when we run that study, which we're running right now.
Great. In terms of the mechanism and the structure of MZE782, 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?
Yeah, that's an important point. At the end of the day, people want to just get off this medical diet.
That means getting their plasma Phe as low as possible, ideally below 360, even below 120. If we can do that, we can get them off the medical diet in the long term. Pre-clinically, we showed that we were three to four times more potent.
We had talked about that before. Then in the clinic, even in the healthy volunteer study, we reinforced that. They showed at one of their doses a tenfold increase of urinary Phe relative to baseline. We showed over 40 times increase of urinary Phe excretion. Reinforcing that three to four times potency relative to anything that's been described in the literature to date. What that should translate into is better plasma Phe 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.
What we know about the agent that you described earlier in their phase II study, what we know is that at their low dose, they had about a 40% reduction of plasma Phe. At their high dose, they had a 60% reduction of plasma Phe. We have a good mapping of where they are and what the bar is set. They also had, of the 19 patients that they reported, they had three that went below 360, and they only had one that went below 120. Clearly proof of concept was demonstrated, but there's room to go there.
If you think about those numbers, most patients that have PKU are called severe or classical.
What that means is that they have a greater than 1,200 micromolar of plasma Phe. If you want to reduce that down to 360, if you just do the math, that's 70%. I said at their top dose they were 60, so they won't be able to serve all of the patients that way. With our potency, our early clinical data, we have reasons to believe that we can beat those numbers.
Great, could you talk about the prevalence numbers and the addressable population sizing? When you speak to that 60% of patients that are on that medical diet, how big is that population in terms of numbers?
Yeah. 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% are on an enzyme substitution therapy. 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.
Most patients in that 20%-30% are using what's called the BH4 co-factor, which is basically just a co-factor to allow the enzyme that's there, that breaks down the phenylalanine, to work better. That's what was recently approved with another molecule in phase III. That's what Kuvan is. Our agent works in a different type of mechanism, which should, in theory, work across the entire spectrum of disease-
because we don't rely on the enzyme that's present to be efficacious, because we just get rid of the toxic substrate to begin with.
If we can do that safely, we should be able to serve the entire spectrum of the 60,000 patients.
Great. Before moving to chronic kidney, maybe just finishing up on PKU, remind us of your next data catalysts and potential trial initiation timelines.
We're starting a trial that's a phase II proof of concept study. We have a couple doses that we're doing, plus placebo. This is not an open label study.
This will be placebo controlled. 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 with a BH4, 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 120. 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 the 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, the high dose, and combo, we potentially can work across the entire spectrum of disease.
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 Phe, which again, at the low dose was about 40% reduction of plasma Phe. We're running that study right now. The data will be in 2027. We have a few catalysts coming up, as you pointed out, 829 end of the year, early next, where we'll have the full HORIZON readout across the three different cohorts, FSGS, diabetic, non-diabetic.
Then we'll also have the PKU data in 2027 as well.
Great. Maybe switching over to chronic kidney disease. You've talked about a potential protective mechanism here, and maybe to start, what does this mean exactly clinically, and mechanistically, what could be driving that?
Yeah. SLC6A19, 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 phenocopy what we call the genetics here, with a small molecule such that by inhibiting the target, people that have kidney disease might also have that protection.
We had not only been able to look at that from the genetics and published, we showed in vivo proof of concept in an animal model. We were the first group to do that. Contextualizing that with one of the current cornerstones of standard of care, SGLT2.
What we showed was that not only were we able to reduce proteinuria, to demonstrate that proof of concept, we actually, in that model, did it better than the SGLT2. Importantly in combination, we basically got the levels back to normal. We published that, and that was encouraging. We had the genetics; we had the preclinical data. Last year, what we did, in terms of the clinical data, now we knew that all approved kidney disease agents had this phenomenon where they showed what's called an initial eGFR dip, which is a little bit counterintuitive because you actually want your eGFR to improve over time.
All agents that have been approved for kidney disease, including ACE-ARBs, SGLT2, even Kerendia, 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.
That was interesting, and it was in the literature that you could see this even in healthy volunteers. We knew that, and if we had this hypothesis of genetics as well as some of the preclinical data, we said let's look for that eGFR dip in the healthy volunteers. We saw that. 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, their eGFR bounced back, inferring that the effect is due to the treatment, not just by chance. 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 published.
That all was very notable and interesting to us. That helped us better understand we could have a hemodynamic effect. Our current understanding of the mechanism of, I would say, SLC in the context of-
kidney disease, one is that 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 solute transporter and not just of neutral amino acids like phenylalanine, which we talked about for PKU, but it also manages these toxic metabolites, which in excess can be damaging in the kidney. 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. Not only could you have the benefit of an SGLT2-like mechanism with the 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.
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 ARB or maybe an SGLT2. If we see, again, a 30% reduction in UACR, that would be proof of concept.
Not only now do we have, one, the genetics, the in 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.
Yeah.
In the last few minutes here, just on the financial aspect, just remind us of your cash position and your cash runway.
Yeah, we just reported with a recent raise, we had a little over $528 million.
That funds multiple catalysts that have been described today. Not only does it complete the HORIZON study, which we'll have the data later this year or 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.
Well, great. Just in CKD, when can we expect that next data set timeline?
We said we would start the study first half of 2027.
Yep.
We haven't announced when the catalysts-
Okay
Would come from that. You can see multiple catalysts, again, from our APOL1 program, as well as our PKU program. The cash runway guidance that we have through that I just gave you, is into 2029.
Okay, great. Well, thank you so much-
Yeah, thanks for having me
Jason, for being with us.
Yeah.
Really appreciate it.