Welcome to the Jefferies Healthcare Conference. My name's Nora. I'm on the healthcare team at Jefferies in the banking division. Today we have Jason Coloma, the CEO from Maze Therapeutics. I'll let him take it from here.
Thank you, Nora. Hi, I'm Jason Coloma. I'm the CEO of Maze Therapeutics. First of all, I'd like to thank the Jefferies team for having us at this year's conference. I'd like to also acknowledge our forward-looking statements. Maze Therapeutics is a clinical-stage biopharmaceutical company where we focus our efforts in harnessing the power of human genetics to really transform the lives of patients. We focus on small molecule drug development, primarily in renal as well as metabolic diseases. We also have successfully been able to raise capital over the past couple years that allows us to have runway into 2029, allowing us to fund multiple data catalysts, as you'll see from our pipeline. Focusing on our pipeline, we have our Maze Compass platform, really rooted in genetics, that has allowed us to develop multiple programs into the clinic, starting with MZE829.
We had some data in March, which really demonstrated for the first time the ability of an APOL1 inhibitor to show effect in a broad set of patients beyond just FSGS, a rare form of kidney disease. We continue to enroll HORIZON, have additional data from the full readout from HORIZON towards the end of this year, early next. MZE782, which is also a small molecule inhibiting a target called SLC6A19. It's been demonstrated clinical proof of concept in a rare metabolic disease called PKU. We had data last September, which really demonstrated for the first time that we have the ability to potentially be best in class as an SLC inhibitor. We unveiled today the ability to advance that program into phase II. I'll be able to walk you through the phase II design later on in the presentation.
We're equally excited about the concept of being able to show clinical proof of concept in kidney disease. We are the first group to show the genetic relationship of inhibiting this target, in vivo proof of concept in pre-clinical models. In September, we will also show proof of mechanism in kidney disease, allowing us to advance the program into the phase II. We have additional programs, including one that we've partnered with Shionogi, that has allowed us, in combination with our equity financings, to really have the runway to deliver on multiple catalysts that you see here within our runway. Now I'd like to shift our attention to MZE829 and APOL1-mediated kidney disease. Now, there are at least six million individuals in the U.S. alone who have the variants that cause the disease. Kidney disease is typically associated with an elderly population.
AMKD, on the other hand, tends to affect, not just predominantly affects the Black community, but generally a younger population. Unfortunately, there are no approved therapies for APOL1 kidney disease today. Current standard of care has been shown to be ineffective in particularly those rapidly progressing in disease. The opportunity that 0829 presents itself is the ability to be the first approved therapy for APOL1-mediated kidney disease, as well as be truly disease-modifying, demonstrating benefit and clinical benefit for patients in dire need for new treatments. Now, diving into the mechanism of how APOL1 itself causes disease and how our agent is uniquely differentiated relative to others described in the literature. APOL1 is a genetic form of disease, which really causes this ability that you see here on the left panel. You have this under certain conditions, an overexpression of APOL1 pores that form in the podocytes.
That's what you see here represented. In that overexpression, not only are you creating toxicity by punching holes in, if you will, in those podocytes, these are ungated pores, which under certain conditions allows for this, if you will, influx of cations into the cell, ultimately leading to toxicity and killing and damaging the podocytes. What we've learned over time is that minimally what you want to be able to do is block the pore from allowing from those cations to enter into the cell. MZE829 is differentiated relative to other molecules that have been described in the literature in that it not only reduces the amount of, if you will, the pores allowing those particular cations in, it itself disrupts the assembly of those pores from forming to begin with.
That's important because APOL1 itself rapidly turns over in the podocyte, less than one hour, and so it doesn't help just to block the pore. It would make sense to actually think about being able to disrupt the assembly of the pores forming to begin with. Other compounds in the literature have not been able to demonstrate that they have this effect. Our differentiated approach allows us to think about being not only more potent, but be able to work in a broader set of patients than just in FSGS. Now, there's at least 250,000 individuals in the U.S. alone who can benefit from this type of therapy. It roughly breaks down into the pie chart that you see here, with about 60% of the individuals not having diabetes and about 40% of the patients having diabetes.
Again, there are no approved therapies to date that allow us to really be able to address the unmet need created by this disease. In terms of the data that we were able to show back in March, I'll point to attention a couple things in terms of the key takeaways. Number one, we're the first group to show that this is ability to show efficacy beyond just FSGS patients and a broader set of patients being able to look at that, not just in non-diabetic, but also diabetic patients as well. The data itself, especially in FSGS patients, demonstrates that we can move and transition to a pivotal study. Plans to be able to do that, especially in the non-diabetic patient population, and supports the plans as we're preparing for that to be in pivotal next year.
I think the other aspect of this is that we were the first group to show at least some level of efficacy in a diabetic patient population. That is about 40% of those that have APOL1-mediated kidney disease, and the ability to further warrant development in those particular patients, and think about disease-modifying therapies. At the end of the day, what we know now, of course, is that people are not responding to standard of care. After the ability to do that, this presents itself as being a possible treatment option for patients. Now, just to reorient individuals or people around what we're doing and what's called our phase II HORIZON study with APOL1 kidney disease. It is an open-label basket study, and what we're doing there is screening for people, so they have to have the variants that cause disease. There's only two, G1 and G2.
We treat them for three months, and then we follow them for a month. It's a once-a-day therapy where we're looking at patients without diabetes as well as those with diabetes, and the idea is to enroll additional patients to allow us not to look only at the safety and tolerability, but to use UACR, which is the amount of protein in the urine, as a secondary point for efficacy. Now, what we showed in March was the ability to not only have impact in FSGS patients but in broad AMKD without diabetes. We can see here in terms of the data, not only leads itself to be that you had UACR reductions at a threshold that we had set at 30% reduction of UACR relative to baseline. You can see most of the patients had achieved that.
A mean UACR across both of these patients at 49%. We had over almost a 60% response rate. We also had, within the FSGS patient population, reasons to believe that we could be best in class given the fact that we had a mean UACR reduction of 62%, as well as notably in the background of SGLT2 inhibitors, which has become an important and critical part of the overall treatment paradigm for patients. Beyond that, we were able to show some level of efficacy in APOL1 kidney disease with diabetes. To take a look at that, if you look at the patient on the left, a younger patient not only had notable reduction in proteinuria, the efficacy endpoint. This was on top of a GLP-1, which is becoming an important part of how kidney disease is being treated today.
On the right, an older patient, as you can see here, with a number of different co-meds, including SGLT2, and also another agent that's approved for kidney disease, called an MRA. In addition to adding those particular therapies, you could see that we met the 30% threshold in terms of reduction of UACR relative to baseline. This data really is the first time any group has demonstrated some level of efficacy in a diabetic kidney disease patient population that has the APOL1 variants. We'll continue to enroll patients and see if we can further tease out the signal beyond these patients and look at, are there particular, if you will, biomarkers that might help us to better understand who could be responding versus those that are not.
Now, in terms of our next steps for MZE829, on the left here, you'll see that the goal is to complete the HORIZON study. What we're targeting for is data for the full readout towards the end of the year, early next, which we're looking at three particular subtypes, those without diabetes, those with diabetes, and FSGS. We'll have 10-15 patients per subtype, so 10-15 per each of those types of patients. We've continued to make learnings around what we need to do in order to be able to execute on the study. This is one of the first trials that has been exploring APOL1 kidney disease and the patient populations that we're trying to serve.
We've made some adjustments in terms of the amendments to the protocol, where we've lowered the threshold in terms of the UACR, as well as we've continued to enroll since the administrative analysis that had been done previously that we reported on, satisfying certain levels of patients we need in the study. We've capped the number of FSGS patients as a result of that, allowing us to really be able to focus the enrollment on non-FSGS patients, both with and without diabetes. Given the data that we have generated to date, I think there's a clear path to a pivotal program, and so we are planning for that and the phase II meeting with different regulatory agencies and planning for what can start a pivotal study in the first half of 2027.
The other thing which is notable and important too is that there's an academic working group that's called the PARASOL Initiative. They were very instrumental in other sponsor studies looking at the approvable endpoints for a disease like FSGS, which we saw recently with an approval there. That particular academic working group is now working on APOL1 kidney disease, looking at particular regulatory endpoints to guide what might be, if you will, the regulatory path for approval for APOL1 kidney disease. That's allowing us, in addition to our data, to have a better, and I would say just better clarity on what the regulatory path forward is for pivotal.
For us, towards the, if you will, where we stand at the middle of the year, is really being able to be focusing on clinical execution, both with the completion of HORIZON, as well as planning for our pivotal, and being able to address the concerns of the patients, which is they need new therapies in order to really be able to address their disease. Okay, shifting gears to MZE782, which we're developing for two indications, the first being PKU. We're planning for initiation of phase II by the middle of this year. We're on track to do so and being able to really address the unmet need in PKU patients. For those that aren't familiar with the disease, patients who are left untreated really suffer from neurocognitive deficiencies from the build-up of an amino acid called phenylalanine, which really accumulates in the blood.
Unfortunately, some of that makes their way to the brain, really resulting in that neurocognitive deficit. The idea there is to be able to address the entire spectrum of patients. Not everyone is being able to respond to the current standard of care. Right now, over 60% of the patients are actually on a medical diet as opposed to a therapy. Unfortunately, they're not responding to the therapies on hand. The idea with MZE782 is that this potentially can work across the entire spectrum of disease, and a well-tolerated oral therapy really could address the patients that haven't converted to any therapy, and being able to address their need. The need that they really want to be able to do is what's called liberalizing their diets.
Unfortunately, a PKU patient has to be on a medical diet that really restricts the amount of protein that they can take every day. A typical severe classical PKU patient can have no more than 10 mg of protein. That's essentially two eggs. The idea that you might be able to improve that. A healthy individual that doesn't have PKU, like many people in this room, can have closer to 100 mgs of, if you will, of protein a day. The idea that you can really be able to have a therapy that really addresses this would really fundamentally change their lives. There's at least 60,000 individuals in the U.S. who suffer from PKU. As noted, over 60% of the individuals are not able to be addressed with the current therapies, which are the current oral therapies or enzyme substitution therapies.
They have to go on this very onerous medical diet that really restricts the amount of protein that they can have every day. If you talk to patients and the parents of those patients, a really difficult diet for them to adapt to. Again, really limiting the amount of protein that they can have a day. The opportunity for MZE782 is really the ability to not only address the patients who are on this medical diet, but potentially address the unmet need for patients that are not responding well to the current standard of care. The way that MZE782 works in terms of as a substrate reduction therapy, as noted, what ends up happening with a PKU patient is they have a toxic accumulation of phenylalanine in the blood.
Some of the particular phenylalanine makes its way to the brain, ultimately resulting in some of the deficiencies. A normal individual, which you see here on the panel on the left, they have enough of the enzyme, or they have a cofactor that helps the residual enzyme that's present to be able to break down that phenylalanine in the blood. You can see here that basically the individual doesn't have this toxic accumulation in the red part of that graph, which is the blood. A PKU patient, unfortunately, doesn't have enough enzyme or is not functioning correctly in a point where the green dots that you see here and the red start accumulating in the blood, ultimately making its way to the brain.
The idea with treatment with MZE782 or any SLC6A19 inhibitor is that by inhibiting the target, you're essentially getting rid of that toxic accumulation on the right in the blood by simply urinating it out and allowing that phenylalanine not to accumulate in the blood. The good thing in this particular example is that not only can you look at that in terms of plasma Phe in the red part, you can use the amount of urinary Phe excretion and be using that as a pharmacodynamic marker to look for particular benefit even in healthy volunteers. We were able to demonstrate that in our phase I, and that phase I data supported the advancement into phase II. We had over 100 healthy volunteers in that study, well-tolerated, excellent safety profile. We have a good sense for PK/PD based off the data.
More importantly, we were able to demonstrate that urinary Phe excretion got to a point that really could potentially have benefit in PKU patients down the road. The other thing that we were able to benefit from the fact is that previous sponsors had published a lot of data, and so we knew that going into this particular study. We knew what the benchmark had been described in the literature before in terms of urinary Phe excretion in healthy volunteers. On the left is a graph of our single ascending dose, but on the right is, I'd like you to pay attention in the sense of our multiple ascending dose. The x-axis are all the doses that we explored. The y-axis is basically what we had in terms of urinary Phe excretion.
The gray dotted line across both the graph is where the previous sponsor study had shown, if you will, urinary Phe relative to baseline. They showed a 10-fold increase in urinary Phe relative to baseline, and you can see all of our doses had exceeded the previous benchmark in terms of urinary Phe, as well as in some of the doses, getting to a 40-fold increase in terms of that urinary Phe, which we know translates very well to the plasma Phe reduction in patients, in PKU patients. The good thing about that is that's not a surrogate endpoint. That's an approvable endpoint, which is looking at the plasma Phe reduction. With this data in hand, we started to design our phase II. What you see here is what we call our CIPHER study, which is initiating in terms of our phase II in PKU patients.
What we'll do, this is a placebo-controlled study where we're looking at a couple doses. In single agent, as well as the ability to think about combination, and I'll explain that in a second. What we do is we wash out, we basically then treat for four weeks, and then we have an open label period of nine weeks, and then have a safety follow-up. We're taking two particular doses, 120 mg BID, 240 mg BID. What we're also doing is doing a combination study, because there are a group of patients that have some level of, if you will, response to a BH4 cofactor, but unfortunately, they can't get to the point where they can come off the medical diet. They have some level of response, but they have to stay on the medical diet.
As we interacted with the community and the physicians and the patients, they said, "If you can actually reduce the plasma Phe of those in combination with a, if you will, complementary mechanism, that might enable us to really be able to come off the medical diet." The good thing with this study's design is we'll be able to explore that concept in this study. More to come in the sense of a CIPHER study getting underway. Again, single agent, two different doses plus placebo, as well as the ability to think about that in combination, and we'll have that data in 2027. Shifting our attention to the idea of MZE782, also equally excited about the concept in chronic kidney disease, which we plan to have the study started in the first half of 2027.
The unmet need here is that SGLT2s have really become an anchor in the way that patients are treated today. Unfortunately, not everyone responds to an SGLT2 inhibitor. Unfortunately, some patients have to be removed off of SGLT2 for various reasons, including hypoglycemia and some level of urinary tract infections, which lead to, ultimately, some level of what they call brain fog, ultimately resulting in patients being removed from treatment. The opportunity for 782 is potentially you can work in a monotherapy fashion for those patients that don't necessarily respond well or have to be taken off of an SGLT2, or for certain patients, you can think about in combination where we might be able to more properly impact their proteinuria and eventually their kidney function.
The way that MZE782 works in particular fashion in terms of our current understanding of the mechanism, I think simply to say that there's a part of the understanding of the mechanism of action that's very similar to an SGLT2, which is all about dealing with the pressure inside the glomerulus. We also have the benefit of having an orthogonal or complementary way of looking at this, which is SLC6A19 also has a potential impact in the removal of particular toxins in the proximal tubule, where you might have even additional benefit than an SGLT2. Keep that in mind as we think about that when we show that in the preclinical data. On the left side here, on the left panel, you see UACR.
UACR, again, is a measurement of damage in the kidney, and you want to be able to reduce the amount of UACR in a patient. Preclinically, we did that in vivo, and what you see here on the X-axis is control versus our agent in the green. DAPA is an SGLT2. We also did that in combination. As I mentioned, there might be some benefit in having a complementary mechanism to SGLT2. You can actually see that in the UACR reduction in the sense that our agent actually improved the reduction of UACR relative to SGLT2. In combination, in that panel, you can see it essentially getting back to a normal state. The other thing that we did is looked at kidney injury markers like KIM-1. Both of these targets are expressed in the proximal tubule. KIM-1 is an indicator of that damage.
Similarly, looking at the X-axis, control versus our agent and in combination. We did that again in the same type of trend. Our agent reduced KIM-1, did it slightly better than DAPA, then more notably, you see this in a combination impact, basically getting to a normal state. Not only do you see level of efficacy, but less damage. That allowed us to really think about, after we had this preclinical data, being able to think about, okay, how could we demonstrate potential proof of mechanism even in healthy volunteers? We had the benefit of knowing that all kidney-approved kidney agents, including SGLT2, have what is called this initial eGFR dip. It's a little bit counterintuitive because you do want to reduce UACR. That's the amount of protein in the urine.
You also want to, over time, improve eGFR, which is basically a measurement of filtration rate in your kidney. Ideally, you want that up. What's interesting, and we know this across all approved agents today in kidney disease, is that the investigators noted, and clinicians noted, that you have this initial eGFR dip, which you see here in the graph. Over time, it actually has a slower rate of decline following that initial dip relative to placebo. It was indicative of a renal protective effect, and we see that not just in SGLT2s, but we see that in ACE-ARBs. We also see that in MRA, which is Kerendia.
The idea was, well, maybe if we are truly having this renal protective effect, we might be able to see an eGFR dip even in healthy volunteers, because we know they have seen that and it's been previously reported in some of the healthy volunteer studies for SGLT2. In fact, we did see that in the data that we published last September, which is the panel on the left. Just to look at that from a dose response, we do actually see a dose response relationship, if you will, looking at that eGFR dip. On the right, what we also see at this dose, not only did we see that particular dip, we can attribute that to the treatment.
In particular, when we pull the patients, or in this case, the healthy volunteers, off of the treatment, the eGFR bounces back up, which you can see at that part of the graph there on the right. Not only do you have a dose response, you can see that it's due to the treatment when we pull them off. Thirdly, what's important to see, what you see in this red band here on the right graph, is the fact that it's within the same range as an SGLT2 as well. These three data points give us some level of confidence around the proof of mechanism that you see a dose response, you see it's due to the treatment, and you see it within the same range as an SGLT2 inhibitor.
Overall, a lot to look forward to in terms of our near-term catalyst, what we have in terms of our additional data for HORIZON, which is our APOL1-mediated kidney disease program later this year or early next. We also have data coming from our PKU study. We've been able to generate, if you will, a lot of interest in the sense of being able to raise additional equity dollars. At the end of Q1, we had over $0.5 billion. That allows us to have multiple readouts, everything in the sense of completing the HORIZON study, initiating what could be a pivotal study, both the PKU data as well as the CKD data from 782 are all within the funding that we have within that particular runway.
Overall, we feel great in the sense that not only do we have product candidates that allow us to have multiple data catalysts over the coming year, not only do we have the team that's been executing around being able to generate this data, and then having the balance sheet that allows us to get through multiple data catalysts over the course of the plan. In general, our overall vision as a company, as Maze Therapeutics, is really to be able to be one of the next generation, if you will, precision medicine company that allows us to really be able to take a better understanding of genetics, apply that into what we're doing from a drug discovery and development standpoint, and develop precision medicines and diseases that haven't necessarily seen precision before.
Our goal here, not only for what we think about for 829 as well as for 782, is the ability to develop truly disease-modifying therapies. We feel great in the sense that not only do we have additional programs, but really the team that's been able to execute to deliver multiple programs into the clinic. Before I finish, I do want to recognize our team working very hard back in San Francisco, being able to advance our programs for patients as well as for the investors, and to recognize all the hard work that's gone into being able to develop and deliver on the pipeline that we have today. With that, I'd like to thank you for attending today's presentation, as well as wish you all well in the rest of the conference. Thank you.