Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference. For our next session, very excited to have a hybrid presentation and fireside with Maze Therapeutics, and it's my pleasure to introduce Jason Coloma, the CEO of Maze. Jason, it's a privilege to have you here. Thank you for joining me. I'll hand it over to you for the presentation.
Thank you, Tyler. Hi, I'm Jason Coloma, and good morning, and thank you for joining us for today's presentation. At Maze, our mission is simple yet ambitious: to harness the power of human genetics to really transform the lives of patients. I gotta say thank you to Tyler and the TD Cowen team in general for all the support they've had through the years. They were with us even earlier in the process. We just celebrated our one-year anniversary as a publicly traded company, and I know that the team has been working even longer and harder to help make that happen. Thank you for the TD team, TD Cowen team for all the support over the years. I'd like to acknowledge our forward-looking statements slide.
As I mentioned, our vision is very simple, which is really to be able to harness the power of human genetics to transform the lives of patients. What we do is we apply cutting-edge genetics techniques to diseases like kidney disease as well as meta-metabolic diseases. We focus on small molecule drug developments. We are a mid-stage clinical development company, and we've been able to, through multiple finances, be able to have the cash runway to get through multiple catalysts as we go be having the funding through and into 2028. I'm very proud of the slide that you see here, as it represents all the hard work that our scientists have been able to accomplish over the years, starting with MZE-829, a small molecule approach for APOL1-mediated kidney disease.
Six million individuals in the U.S. alone have the variants that cause the disease. About one million individuals of that six million have some form of chronic disease, and at least 250,000 individuals could benefit from a therapeutic approach based off of our partner cutoff that we're utilizing in our phase 2 global study of HORIZON.
We also have a program that we published data, in late I would say September last year, MZE-782, also a small molecule approach that we're developing for two indications, one in a rare metabolic disease called PKU, where we showed, the ability to have the potential to be best in class, as well as we were the first group to describe proof of mechanism in chronic kidney disease, where we might be able to show, if you will, proof of concept, in patients especially that are not responding to the current standard of care, including, what has become an important anchor of kidney disease, treatment today, SGLT2 inhibitors.
We have additional small molecules in development, but that's not the focus today, and we have the capital based off of our recent financings to be able to fund multiple data catalysts for both of these programs over the coming years. MZE-829 is what could be a best-in-class approach for APOL1-mediated kidney disease. There are no approved therapies to date for these patients, and unfortunately, standard of care is ineffective in being able to improve their kidney health in the long run. Unfortunately, these patients don't have a lot of options in terms of therapies. Over the years, we've learned a lot more about who the patients are and their patient journey.
When you think about chronic kidney disease, typically that's associated with an elderly population, and what we know about APOL1-mediated kidney disease, that it ends up manifesting much earlier in age, usually before the age of 50. We also know that people that have this form of kidney disease, it's more accelerated in progression, and what that means is that they actually transition to end-stage renal disease and potentially even to dialysis, where they have horrible outcomes, about 10 years earlier than those that do not have APOL1-mediated kidney disease. We know current standard of care, including things like ACE/ARBs, which are the classic, first-line treatment or how patients are treated with some form of kidney disease, is ineffective at really being able to improve kidney health for these patients.
Given all this, us and other sponsors have taken on the challenge of being able to try to develop the first disease-modifying therapy that ultimately can benefit the patients. There are at least 250,000 individuals that could benefit from a therapeutic approach. To contextualize this number, people might be more familiar with other indications, including IgAN, if you will, a kidney disease that affects around this many people, multiple approved products there now. ATTR-CM, which is another disease where around this particular size of addressable market, also with multiple approved products. What we understand about sort of how this breaks down is about 60% of the individuals don't have diabetes, and about 40% do.
We've confirmed that type of work with some of the data that we published at the seminal kidney conference called the American Society of Nephrology late last year and reinforced by a number of different epidemiological studies from others. Really sets us apart in better understanding how H&I could really have an effect and be truly disease-modifying. We have to understand how APOL1 itself is actually causing disease. The genetics were known about APOL1 for over 10, 15 years. Unfortunately, no one really understood the function by which APOL1 was causing disease. Our group, in collaboration with an academic were the first to help resolve that, and what we realized is that under certain conditions, APOL1 overexpresses, and that what you see here on the right panel.
You have an overexpression of APOL1 ultimately inserting itself into membranes and pores of the podocytes, which are kidney cells. That causes cellular damage, as you will, even cellular death on its own, but also these pores and these channels are ungated. Ultimately resulting in a, if you will, an influx of cations resulting in cellular damage, cellular death, and this nephrotoxicity. At minimum, you wanna be able to block the pores from being ungated. We learned over time that we have a truly differentiated molecule in a sense that we are not only able to block the pore, but this relative to other compounds that have been described in the literature, we were significantly more potent.
We really wanted to try to understand why we were more potent, so we did additional work, and what we realized here is on the left, is not only we're not able to block the pore, but we're also just able to disrupt the assembly of the pore, and that's important because not only do you have fewer holes that eventually form in the podocytes or these pores forming in the podocytes, you have the ability to be able to block the pore as well. Other compounds that have been described in the literature, they're only able to block the pore, they're not able to disrupt the assembly of those pores from forming to begin with.
We think that's important as we understand the biology of the pore itself, because they rapidly turn over in the podocyte, some in the literature report under an hour. Even though if you're blocking the pore, you may not be able to, if you will, avoid the ability for it to continue to form and assemble and insert itself into the membrane. We think this matters, and it gives us the highest probability of being able to show an impact on even more moderate forms of APOL1-mediated kidney disease. We reported our phase 1 at the seminal kidney conference a couple years ago at ASN, and what we showed is a favorable safety profile. We're also be able to show predictable PK in terms of linear dose proportionality in terms of the doses that we use.
We have a half-life of about 15 hours, so this will be a once a day therapy. We also were able to select the dose, and what you see here across this, across the SAD and MAD, but more importantly, what you see on the last panel in terms of what we did in terms of overlaying our clinical data onto a preclinical BAC transgenic mouse model, we're able to identify a dose of at least 240 that gets us above an EC90, being able to maximally, if you will, inhibit the target and be able to give us the highest probability of showing some type of efficacy, in particular in more moderate forms of disease. With this data in hand, we were able to start our phase 2. Our phase 2 is called the Horizon Study.
It is a global study. What we're able to do in the top right panel is we are selecting for the variants. There's only two variants that cause the disease. They're called G1 or G2, so you're either homozygous G1 or homozygous G2, or you could be compound heterozygote, meaning G1G2. We treat for three months, and we follow for a month. What we're trying to do in terms of efficacy is look at urinary albumin to creatinine ratio, which is called UACR. It's the clinical measurement of looking at protein in your urine. If you were to take a laboratory test today to look at your kidney function, your physician would be looking at this. Our cutoff point is 300 mgs per gram in terms of the proteinuria.
That gets us to about that 250,000 individuals who can benefit from a therapy. The other thing that we're trying to do in addition to this is to show, not collect just the UACR, but what we wanna show in terms of efficacy is at least a 30% reduction of proteinuria or UACR relative to baseline. Now why did we pick that number? Not only is it, would be clinically meaningful as we've talked to investigators, as well as nephrologists who are working and treating these particular patients, but if you can see here on the right, you know, there's many reasons why we would think about 30% as the right cutoff and to declare that this could be clinically significant and clinically meaningful.
In terms of what we know today, in terms of all clinical development for kidney disease, UACR and the reduction at that magnitude tends to correlate very well to eGFR, which is the true filtration rate of the kidney, which is a measurement of how well your kidney is working. The other thing is that this is actually used in the clinical guidelines. They're called KDOQI in the U.S., and it's really important to understand, the fact that this is how physicians treat the patients today in the sense that they are looking for, you know, particular response of about 30% reduction in UACR to really see that there's benefit from a therapeutic intervention.
The other thing is that all clinical development programs, whether they be ACE, ARBs, SGLT2s, even the MRAs that were previously approved, they all looked at this 30% reduction in UACR as an early indication that they can have a path to approval. Then finally, the 30% reduction number that we're referencing here has been cited by other groups. There's an academic working group called PARASOL, which has worked, you know, even with the agency to look at potential surrogate endpoints for diseases like APOL1-mediated kidney disease to look at different ways that they might be able to accelerate paths to approval for certain agents being developed, and they have cited this number of 30% reduction in UACR. Now in terms of the data that we hope to show later this quarter, again, what we wanna be.
aspire to be is the first company to show clinical proof of concept in broad AMKD with or without diabetes. We think that 30% is the bar in the sense of showing something that would be clinically significant, show clinical proof of concept. This would be the first time anyone has publicly shown clinical proof of concept in broad AMKD with or without diabetes. If we're able to show that type of data, we believe that we would be able to start with the planning for a phase 2b/3 registrational study. There are other sponsors that have started a similar type of approach. The size and order to, I would say the magnitude of that study would look similar to other sponsors ahead of us. Now that said, you know, we're very excited about what's possible this year.
We have multiple catalysts on top of the way that we think about 829. We've worked very hard over the years to develop programs using our genetics as well as our small molecule approach to really be able to put us in a position to have multiple programs that can have impact for patients. We've been able to recruit and retain a really great team that really has been able to execute on time and be able to deliver the data, including 829, as well as other data that's coming in the future.
Through capital that we've been able to secure, both through partnerships as well as equity financing, we're well-capitalized in the sense that all of the catalysts, including, the phase 2s for our second program, MZE-782, fully funded, as well as should we be fortunate enough to see the data we hope to see, even the 2B portion of a 2B 3 study is fully funded. I think for us, you know, well-positioned as we go into this particular readout, we do have additional programs that we are developing, use our genetics approach, as well as our thinking about applying that to small molecules.
A lot to come as our vision of really being able to be the next generation precision medicines company is fully coming into focus this year and going into what we're reading out, even subsequent readouts with our other programs. Before I conclude, I'd like to acknowledge our team back in South San Francisco, working really hard for our patients, you know, really being able to get us to this point. Do want to recognize them and all the hard work that they're doing, as we're really excited about what's to come and looking forward to sharing the data as we get there, later this quarter. Thank you.
Great. Thanks very much for that presentation, Jason. It's again, a privilege to have you and the Maze team here just ahead of the data coming, I guess, by the end of this month, right? You know, I guess maybe we could just on that readout from the phase 2 HORIZON Study, can you start with a broad overview of how many patients we should expect to get, what type of patients, and I guess the UACR data are quite obvious in safety, but is there anything else we should expect from that readout from an endpoint clinical efficacy perspective or endpoint perspective?
Yeah. First off, Tyler, we're still blinded to the data, so I can't describe exactly the numbers here. In order of magnitude, we've described that to be similar to what Vertex had reported in their first readout in terms of number of patients. You know, our goal is to try to do that across both with or without diabetes. Again, I think our focus right now is the 30% cutoff in terms of 30% reduction showing clinical proof of concept. I think we. You know, as you pointed out, we're focused on the measurement of UACR as the measurement of, you know, as a way really to be able to measure that in terms of success.
I think if we're able to do that, you know, I think the idea would be that we can think about planning for a 2b/3 study. I think that would look in order of magnitude of what other sponsors have done before.
Great. Can you elaborate on the significance of UACR versus UPCR?
Yeah. I think there's, you know, clinicians, as we were kinda designing HORIZON, had been able to kind of focus us on saying this. You know, UACR, which is specifically albumin, versus UPCR, which is an array of different proteins, is really what they use. They use UACR in clinical practice. It's really what's been get demonstrated. If you were to go get a lab test today, you're gonna see that measurement. Looking at kidney function, you would see that measurement on your lab test. It really helps in terms of sort of normalizing how even a clinician would look at this. Now, previous sponsors have reported on UPCR, but I think the other thing to kinda note is that they actually did report also their UACR values in that particular study.
I mean, people can also look at that and understand the order of magnitude that they're, you know, sort of in decrease of UACR. I think the other thing to kinda think about is, not only are we using UACR for Horizon, and we would going forward, but, you know, other sponsors are gravitating to UACR as well. You know, Vertex for their phase 2 amplified studies using UACR, AstraZeneca, which is also developing, but an antisense for APOL1-mediated kidney disease. In their phase 2, they're using UACR as the endpoint.
Before I get to a couple follow-ups on the UACR reductions or just expectations for that, can you talk about the baseline proteinuria that's expected from the patients enrolled here? You obviously touched on it briefly on the slide, but maybe you could elaborate on what we might expect at baseline here relative to what was reported with the inaxaplin data?
Yeah. For those not as familiar, I mean, they reported data in the New England Journal of Medicine showing clinical proof of concept in highly proteinuria, FSGS patients, which are a subset of broad AMKD, a rare form and a subset. We're focused on trying to be the first company to show clinical proof of concept in broad AMKD, both with or without diabetes. That's more moderate disease. We put the cutoff at 300 milligrams per gram in terms of the UACR. Again, we're blinded to the data, we can't describe exactly, where, you know, people are gonna do. We're gonna report on that, of course, as we report out the data. You would expect more, probably more moderate forms of disease, we'll have to see when we look at the data, Tyler.
Understood. We hosted a renal panel yesterday, so it was very encouraging to see that they agreed that's a 30-plus % reduction is kinda the minimum kinda efficacy threshold, which obviously, as you noted, is validated by multiple sources. As we think about proteinuria reduction in general, should we expect it to be similar in non-diabetic versus diabetic AMKD patients?
I think there's a lot of discussion about this in particular, because I think, you know, people look at diabetes, there are many different reasons why people can kinda think about should we expect to see something different given the fact that you have these comorbidities. For us, you know, there really isn't anything to point to in terms of data to support this, right? When we did the original analysis in terms of the population genetics, we looked at that and reaffirmed some of the previous work that had been described in the literature that showed progression of disease, whether or not you had diabetes is about the same.
Moreover, you know, some of the work that we did to identify a protective variant, not one causing disease, but one that actually protected people from disease, seemed to be protective whether or not they had diabetes or not. I think for us it would be a little bit arbitrary to say it should be lower at this point because there's no data that really supports that. We would be the first group to help try to elucidate that. I think for now that's why we've said 30%, and been consistent on this, 30% across about these populations would show clinical proof of concept, and then we'll have to look at the data plus other sponsors to better understand should there be some type of heterogeneity in response.
Okay, that's helpful. On the safety front, how are you all thinking about on-target or off-target safety? Is there any particular adverse events that you all are focused on going into this readout?
Yeah, we had a very favorable safety profile, as you know. We had more detail, of course, at our ASN presentation in terms of the safety profile and a lot of margin between where we predicted EC90 and above. So I think for us, you know, when you look at and go back to the genetics, which is another reason why we use genetics as our core anchor, there are individuals that are out there that don't have APOL1, so the true human experiment of knockout. For those that are less familiar with the genetic story, and I know Tyler knows this very well, but I'll just repeat it. You know, it was evolutionarily conserved, primarily to protect people of West African descent from African sleeping sickness.
Unfortunately, the negative consequence, if you live long enough, if you ended up developing, some form of kidney disease. So they found individuals in the literature that actually had no APOL1, and they only, other than having, I would guess, increased susceptibility to African sleeping sickness, they were clinically normal, right? That gives us some level of confidence that, you know, knocking out, even a full knockout, doesn't seem to have any negative consequences on target. Then, of course, anything related otherwise would then be to the molecules themselves.
Great to hear. With the HORIZON data coming by the end of the month, if it's successful like we hope it will be, how quickly can you start a pivotal trial and get to the market?
Yeah, we haven't provided any guidance on that yet, 'cause, you know, first we gotta look at the data. We have to make sense of it, then I think, you know, if we're fortunate enough to see the data we hope to see, one should expect a end of phase 2 type meeting. This would be a global study, we'd have other, you know, groups that we'd have to interact with other than just the FDA. We would provide more guidance once we have some resolution on that.
In general, given everything that's gone on in the renal space, is it fair to say that there might be the potential for an accelerated approval on proteinuria reduction?
I think it's a little early to say that. I think it's nice. What's gonna be informative to us as we think about should we see the data we hope to see and be able to start that planning for a 2b/3 , I think there's a couple, you know, pieces of information that will be useful. One is the other sponsors' interactions with the agency and sort of a pathway for accelerated approval. For those less familiar with sort of the progress there, a accelerated approval could be based off of a combination of proteinuria and eGFR slope with full approval based off of outcome. That would be sort of conservatively to kinda think about that as a pathway.
There is an academic working group that I mentioned called PARASOL, which has worked on other kidney indications, including FSGS, that has taken on a couple other indications, including APOL1-mediated kidney disease. If they were to find, you know, sort of evidence that you could look at a surrogate endpoint like proteinuria alone, as an accelerated approval pathway, that would be an upside to us, right? 'Cause I think for us right now, we're thinking let's plan around what we're, you know, sort of other sponsors are doing, and then we'll get feedback from the agency as well as have the input from an initiative like PARASOL to inform our work going forward.
Okay, that's helpful. You showed the number of patients in this broader AMKD population that you all are testing in diabetic and non-diabetic, and you multiply that times some of the more recent pricing updates from other drugs in the renal space.
Oh.
You get to many, many billions, if not tens of billions. You know, the KOLs on our panel yesterday said that, you know, if your drug is successful and this class of drug is successful and gets across the finish line, they're gonna use it in the vast majority of their patients, which I guess is fairly straightforward. I guess what's the latest on patient diagnoses? Where do you believe the diagnosis rate is? How about testing, and how do you expect that to progress moving forward?
I think a lot of progress has been made in particular in the past year to think about what needs to be set up to allow for, you know, the proper diagnosis rates. For those that are not as familiar, I think part of that is just having testing available. Now this is part of, you know, sort of a genetic kidney panel that's available on LabCorp, Quest, Natera. I would say that testing is available.
There was an ICD-10 code, based off of the work of academics as well as some other sponsors to help, you know, advocate for an ICD-10 code, which has been used really to, I think, for other indications in particular in rare disease, to think about being able to help identify the true diagnosis rates, at least, looking at claims databases, in the U.S. I think that was incredibly helpful. There's also just an increased awareness, based off of the work of some of the nonprofit groups, some of the public-private partnerships like the Kidney Health Initiative. There's not only patient advocacy groups for kidney, but we're aware that they are starting to form APOL1-mediated kidney disease specific, patient advocacy groups, which will be important.
That'll be important particularly to think about awareness of testing for nephrologists and the patients themselves. I think all of that will be helpful, but we're still early, Tyler. I think what we want to be able to do, like they do in other diseases like ATTR-CM, is start to pull those claims databases over time to see how that's tracking, and to think about the proper diagnosis rates as opposed to just looking at the epidemiology, which is where all the sponsors are estimating right now.
Yep. Makes sense. We got to spend some time on MZE-782, which is just as exciting as MZE-829. You all reported some data in the fall. You know, what's nice about the setup for Maze going into this Horizon readout is, you know, the floor valuation is not just cash, right? You've got a real meaningful opportunity here with MZE-782 and PKU and potentially CKD. Can you elaborate on that early data that you showed in PKU, why you're excited by it, and what your next steps with that program are, and what you think the opportunity is?
Yeah, no, it's I think, really encouraging to really think about, you know, the application of our second program, really could be applied to multiple indications. I think what's nice about the rare metabolic disease of PKU, it's clear as we've been interacting with patients' parents, the advocacy groups, I think there was this misunderstanding that, you know, PKU had been solved by, you know, other therapies, and that's not the case at all. I think even, the recent launch of SUFIANCE has shown that, you know, really patients and their parents of those patients are really looking for new therapies that really give them the opportunity to get off of this really horrible medical diet. For those that are unfamiliar, you know, those that are...
You know, most people that have PKU are defined as having severe or classical form of disease. What really happens in the disease is that you get really this inability to break down phenylalanine, a neutral amino acid, and it really just starts accumulating in the blood up to the point that it starts to get into the brain, ultimately causing some of the neurocognitive effects that, including seizures. It's horrible, and you have to stay on this really horrible medical diet. For some of those patients, they can only have up to like 10 grams of protein a day. Like Tyler, you and me, we're probably having over 100, you know. To put that into context, that's like two eggs, right?
You think about that, what the patients have to do to live their sort of a normal life and sort of just looking for new therapies, right? You know, the data that we showed, you know, all preexisting approaches has been, let's either substitute the enzyme that can break down phenylalanine or let's actually introduce a cofactor that allows for that enzyme that's present to work better, right? That's essentially what has been developed, including SUFIANCE. SLC offers a different type of mechanism that doesn't rely on the residual enzyme to be present. We go after the toxic substrate itself by simply just urinating it out.
I think it was nice that another company, called Nanna Therapeutics that was acquired by Astellas, had shown clinical proof of concept that if you can hit this target, you can actually reduce plasma phenylalanine levels. They also showed the value of a non-invasive biomarker urinary Phe excretion that maps very well to that plasma Phe reduction. We knew of course in their phase 1 and phase 2 what they had shown. We knew preclinically, 'cause they did disclose their structure. We did know that we had some attributes that showed that we had a better compound at least preclinically. That data we showed in September was the first time to give a reason to believe that we definitely have a better molecule.
What Jeana had previously shown in healthy volunteers at a 75 mg BID dose, they showed a 10-fold increase of urinary Phe relative to baseline. They took that dose into PKU patients. They eventually showed a 24-fold increase of urinary Phe and a 40% reduction in plasma Phe. For why that's important is because that's not a surrogate endpoint. That plasma Phe reduction is the approvable endpoint for PKU drugs, right? Very clear in terms of, you know, sort of the regulatory approval path. What did we show in our phase 1 in addition to, you know, a strong profile in PK and safety? We showed not a 10-fold increase.
We showed multiple doses that got well above that tenfold bar some even getting to that forty-fold bar in terms of urinary Phe excretion demonstrating for the first time that there's clearly room to go as well as the ability to show best in class sort of properties. Now we can carry that forward, as you kinda pointed out. We guided early this year that we plan to initiate a phase 2 in PKU by the middle of this year. You know, our goal is to try to show in that study that we could be again differentiated relative to the compound in front of us. If we look at their data in terms of their phase 1/2, as I mentioned at that 75 mg BID dose, they showed that 40% reduction in plasma Phe.
More importantly, what you wanna show, Tyler, is this ability to get, you know, patients below this number of 360 micromolars of plasma Phe or even ideally 120 micromolars, 'cause then you can really get them off of that medical diet. If you look at, you know, what they did at that 75 mg BID dose at least, they only showed one patient out of the, you know, 19 that they had enrolled below that 360 number. Nice to show clinical proof of concept. That's great. We think that we have the ability to, you know, do better than that, and we have early data to help demonstrate that. The other thing we did is we showed, you know, the proof of mechanism in a new approach in chronic kidney disease.
you know, SGLT2s have become an important anchor, but not everyone can stay on drug for various reasons because as we know about SGLT2s, they really are about glucose reuptake, and one of the on target issues is that if you hit the target too hard, you end up developing hypoglycemia, and some patients even get urinary tract infections, which for elderly patients, they end up developing what's called a brain fog, and ultimately, you know, they need to be pulled off the drug. you know, we showed some early data in terms of genetics, preclinical data that said that we can complement or maybe even be better than SGLT2.
What we also knew going into the phase 1 study is that all kidney disease programs that had been approved, whether they be an ARB, a SGLT2, or, you know, even MRAs like Kerendia, they showed what was called this initial eGFR dip, which is a little bit counterintuitive 'cause you actually wanna increase your eGFR over time. They showed this initial dip. Relative to placebo, what they showed is that the curve ended up flattening such that you had a better outcome than those that were on placebo. SGLT2 showed it in healthy volunteers and other agents as well.
We knew that going into the study, so we said if we collected serum creatinine, calculated eGFR, and if we could look for that dip, that might would be the first evidence of, you know, proof of mechanism, in particular, being able to show this potential renal protective effect, and we saw that. You know, I think what we showed in September, which I think got people's attention, especially in the nephrology community, is that we were able to show that. It was related to the dose 'cause we knew that when we took them off the dose, the eGFR bounced back up. We saw, you know, that it was dose dependent. We showed it. We showed that data at ASN.
I think the other thing that we showed, which was, encouraging to the nephrologists we talked to, is that it was in the same range as what's been reported in the literature of SGLT2 in healthy volunteers. All of that just reinforces what we previously had in genetics, preclinical data, and now there's proof of mechanism, and we'll be able to start that study, later this year.
Great. The market opportunity there is pretty self-explanatory. You can look to the billions of SGLT2 sales, very interesting. We're up on time, we'll go ahead and wrap up. Jason, thank you very much.
Yeah, thanks for having me, Tyler. Appreciate it.