Good afternoon, and thank you for joining Guggenheim's 3rd Annual Healthcare Innovation Conference. I'm Debjit, one of the therapeutic analysts at Guggenheim, and it's my pleasure to welcome Jason Coloma, the CEO of Maze Therapeutics, as our next presenting company. Thank you so much, Jason, for making time for us.
Yeah, thanks for having us.
Well, you just put up the quarterly update yesterday. Maybe we can pick it up from there because the study is fully enrolled and maybe over-enrolled. From what we understand, you have a better handle of baselines right now versus last year. Maybe walk us through what kind of patients we'll get to see in 2027.
Yeah, I think it's, for people that are out there that are not familiar with us, we use genetics as our handle to develop small molecule programs for programs like APOL1 kidney disease and for diseases like that. We had our earnings announcement yesterday, and I think a really positive trend in what we saw in enrollment. We had talked about this, that there were a few factors that would be helpful in kind of thinking about enrollment from the administrative analysis that we had published earlier in the year. One is, I think there's just more disease awareness from a lot of the efforts that are happening, not just from the companies that are sponsors in the trials, but also more importantly, the overall community, the nephrology community, the patient advocacy groups.
So, I think there's just a larger awareness around the disease and the importance of testing to at least know the information that might direct you, right now, no approved therapies for APOL1 kidney disease, but at the same time, it might help them direct them to a study and at least have clarity about why they might be suffering from the disease that they have. So, I think that was incredibly helpful. I think the other thing is just in the sense of what we've been able to accomplish operationally, which was to be able to adjust. That's why we did some of the administrative analysis at that interim to really adjust what we were doing operationally, what sites were going to be the most productive, how do we engage better with the community. So, some of the adjustments we've been doing there have obviously been helpful.
I think the third thing, which was incredibly helpful, is we had data. Part of the idea that we took the administrative analysis, it really does help engage the nephrologists as well as the patients on why they might want to consider participating in a study. I think all three of those things really helped us in the sense of being able to think about enrollment. We had talked about and guided previously that we would have, across three different cohorts, 10-15 patients. So, that's 30-45. We've actually exceeded that. Over 50 patients enrolled into the study, and I think that just speaks to a lot of the hard work that our team was able to do over the last few months.
I think when you think about that, Debjit, in the sense of what that means, in terms of the context, other sponsor studies that were also in phase II had around 50 patients. So, I think it was important to have a size of a study that was comparable to those in front of us or aside us in terms of APOL1 kidney disease. I think for our team, it also gives us the confidence that we can enroll this study, the next study, right? In terms of the pivotal, because of some of the things that we can carry forward in terms of tactics and strategies about how to enroll the study. I think that was a question mark for many investors, and I think we were able to make these adjustments.
I think the other thing that we had talked about is we have a second program, SLC6A19 inhibitor called MZE782. Earlier in the year, we had guided that we would be able to start that study by the middle of the year. We did that on time, as we had promised our investors. That's going very well, as we've gotten that study launched. It could be best in class in PKU, which is, we're seeing a lot of resurgence of interest in PKU as a disease. In particular, other launches that have been very successful in the market have really painted a picture of really sort of the unmet need that patients have. We're excited about being able to enroll that study and being able to have that data in 2027.
The last thing is we're also using SLC inhibition in the context of chronic kidney disease, and what we described in our earnings was the ability to start that study in 2027. A lot of things going great for the company in the sense of those studies. I think we also highlighted a few things that we've been able to do operationally, and then our balance sheet's strong. That gets us through all of the different data catalysts that we will be upcoming, including APOL1, SLC, PKU, and SLC CKD. A lot of good things going on at the company.
Well, a lot to unpack there. Let's start with 829. Just refresh us on the differentiated mechanism of action for 829 versus inaxaplin.
Yeah. I think for those that are not as familiar with APOL1 inhibitors, the concept is that under certain conditions, patients have this overexpression of APOL1s that really embed themselves in kidney cells or podocytes, causing eventually this nephrotoxicity. So, at minimum, what you want to be able to do, because they become these ungated pores, if you will, in the kidney cells, is you want to block the pore from sort of allowing for certain things to coming into the cell. The other thing that you may want to do is not only just block the pores, but also disrupt the assembly of those pores from ever happening. What was interesting is we started to generate our molecule, which was informed by not just genetics, but other things that we were able to do pre-clinically.
We knew that we were binding to the pore, which was at a different location than compounds that have been described in the literature. They're both pore inhibitors, but they bind to a different site. We think that confers a different particular mechanism. The other thing that we saw is that we were incredibly more potent, at least in a preclinical model, looking at proteinuria as the readout. To try to help understand that, we were trying to look at systematically what mechanism we might be able to do in terms of a pore inhibitor. It turns out our compound, 829, not only blocks the pore, but it disrupts the assembly of the pore from ever forming, which is different than what's been described in the literature to date of any other compound, which seem to only be able to block the pore. Why is that important?
It's because APOL1 itself, it rapidly forms and reforms in the kidney. There's some description in the literature that it reforms every 42 minutes or every hour. It doesn't really matter to us that you're blocking the pore. If they keep forming and keep embedding themselves in the podocyte, you might be still have the cell damage ultimately causing the issue. The fact that we have this differentiated mechanism gives us at least a reason to believe we could have some improved efficacy. We saw that at least in the preclinical data and hints of that in our early administrative analysis.
Yeah. Let's talk about the data from earlier this year. If you were just to focus on the FSGS patients. The differentiated mechanism did come about with a deeper proteinuria reduction. If you take that forward now that the street seems to believe that the mechanism is going to be broadly applicable to AMKD patients.
Yeah
How should we think about the data that is going to get presented in March, or next year?
Yeah. I think there were two important things that have kind of happened for APOL1 programs in the past month. One was, I think people had this perception that only a small number of patients would benefit from an APOL1 inhibitor, a very subset of what is called FSGS patients. What we have seen, starting with our data and reinforced with some recent data, is that this can work in a broader set of patients, both with or without diabetes. I think in terms of the addressable patient population, this is not an ultra-rare disease. This becomes an opportunity that could be hundreds of thousands of patients that can benefit from an APOL1 inhibitor. I think that is important, that the addressable patient population starts to be larger than what people thought.
I think the other thing that was sort of a commentary from investors was the fact that what is the regulatory framework to really kind of think about accelerated pathways to approval with APOL1 inhibitors? That is not well established like it is in other kidney disease like IgAN or FSGS. The good thing is there has been some additional analyses. There is an academic working group, Debjit, called PARASOL that has been working with the FDA and the sponsors of all these different studies. What they showed, and importantly, is that there could be a pathway to accelerated approval that is a biomarker, in this case proteinuria or protein reduction.
I think that is really important because at least it sets the framework of what might be possible, that accelerated approval, and I think starts to, for investors, clarify that there can be a regulatory pathway for AMKD or APOL1 kidney disease. For us, if you go back to what we are doing, right? If you think about FSGS, I think most investors would say clearly that it has effect. Clearly, this is a drug for those particular patients, albeit small, but at least in those particular patients, we can start to look for differentiation with our molecule versus what has been described, right? I think a couple ways to kind of think about that. One is, and from an efficacy standpoint, are we reducing proteinuria better than what has been described? I think we have.
I think we have previously showed when we have an effect, you do not see patients with uACRs going up. They all tend to go down, which is good. And we are doing that on top of standard of care, including things like SGLT2, which was not really previously described. I think if we are able to maintain, think about going forward, if we are able to maintain that type of competitive profile while still showing you have a very safe and tolerable compound, which we have been able to demonstrate to date, I think that itself lends itself to kind of be able to have further evidence and reinforces that we might have a best-in-class profile.
The recent data that, or the data cut that was presented at ASN it appeared like the uACR reductions were more of a function of exposure as opposed to baselines. The thought process is, are you comfortable with the dose that is going forward, or maybe are you leaving a little bit of efficacy on the table here?
Yeah. We showed two pieces of new data at ASN, which is just additional detail of the patients that we had described at the administrative. One was exposure, and the other was uACR reduction over time. Let me just address the second one first, and I will answer your question. What we noted, and I said this verbally when we had the data, but we did not show it to ASN, was over a 12- 13 week study, what you would want to see is reduction over time, but more importantly, at that 12- 13 week period, that you do not have this leveling off of the effect, but you actually see a deepening response, or at least a slope still going down, because that gives you a reason to believe that with longer duration of treatment, you might even see better proteinuria reduction. And we have seen that before.
Where have you seen that before? Like IgAN. If you look at the old phase II data of the sort of the earlier IgAN programs, they were in sort of the 20s, mid-20s in terms of uACR reduction over 12- 13 weeks. But as you got to 48 weeks or longer, you see even deeper responses, right? 40%, 50% reduction in uACR. So that, when you show a nephrologist 12- 13 week data and you see that slope going down, that is really encouraging for based off what they have seen before. The other piece of data that we showed was uACR exposure, which you kind of pointed out in thinking about what is the right dose. One thing that we did talk about at our phase I is that we did have a positive food effect, which increases exposure with food.
One thing that we did for that first administrative cut is have patients that were fasting, because we wanted to just kind of see what that would do to tolerability. And when we saw that administrative cut, it was one of the reasons we looked at it, was to say, "Oh, we can actually give it with food." Right. One of the things that we did in our protocol amendment that you saw, that we had talked about previously, is that we can actually give it with or without food. That actually increases exposure. So, we will take a totality of the data when we see it, but that alone should think about, that was incredibly informative to kind of adjust what we wanted to do from a trial perspective.
Got it. Let us unpack the upcoming data a little bit. You will have three subsets of patients here, right? FSGS, primary APOL1-AMKD patients, and then the diabetic cohort. How would you sort of measure success across uACR reductions?
Yeah. We have three cohorts. One is FSGS, one is non-diabetic, and then there's diabetes patients. Probably a couple, we have pretty much equal distribution across those from an enrollment standpoint, which is good. Over the 50 patients, pretty evenly distributed. I think for the entire study, we've always talked about at least a 30% reduction across all of those patients to really sort of define that we see this type of effect, especially on top of standard of care, including SGLT2 inhibitors. I think that's how we kind of think about sort of the totality of it.
Then, of course, people can look at subsets of the data, including FSGS. I think if you go back to, okay, if we can maintain that competitive sort of profile where we see uACRs going down, hopefully we don't see any of them going up relative to what other sponsors have showed, and then have the safety tolerability profile that makes us competitive, I think that's what people should look for.
Got it.
I think the other thing for diabetes, which is interesting, because clearly there's a signal between the two sponsors that have published data, albeit more modest, right, and a little bit more nuanced. I think the question will be, can you identify a subset of patients where the effect size might be bigger, right? Whether that be biomarker-driven or maybe something else. What we did notice in the Amplified data, for example, is that they had talked about these are mostly non-FSGS diabetes patients, which you would infer there were some patients that had FSGS in the diabetes cohort.
I think we've arbitrarily created these three cohorts, FSGS, diabetes, non-diabetic. There's clearly patients that have diabetes with an FSGS histology or a result, right? How do we sort of incorporate that into our analysis and thinking? Because there might be a subset of patients where you have a disproportionate, that might be disproportionately seeing efficacy, and could you incorporate that into further studies later down the road?
Got it. Early next year, we should get the accelerated approval cohort from the other sponsor. If that hits on both the co-primary endpoints
Right
does that become the standard for the projected registration study for Maze? Or on the other scenario is it just hits on proteinuria?
Yeah
But GFR you have to wait for a couple of year or two years. Which part do you choose and where does PARASOL fit in there?
Yeah. I mean, obviously, as many people will be looking to see what sort of comes out of that particular data set and the results of that. I think going back to this academic working group analysis, which is PARASOL, they had worked a bit with the FDA. I think there is clear data for non-diabetic patients that proteinuria maps very well to eGFR outcome, which is good and could be the basis for accelerated approval, or it could be eGFR slope, right.
This is just an observational study that could be useful for interaction with the agency. Then I think obviously based off of that data, other sponsors' data, plus our own data, we can engage the agency on what is the right endpoint for our pivotal. Is it eGFR slope? Is it proteinuria? Or is it a combination? I think obviously more to come on that because we are obviously still working through that.
When the other sponsor started the phase III study or the phase II/III study, the way it started off, it has taken them a while to enroll, but now you are saying with your expansion cohort, started to enroll a lot faster. You think this can be carried on into a registration study? That will define how long it is going to take to get 829 to the market?
Yeah, I think if you go back to one, there's just because of the other sponsors plus all the work that's being done by the community, there's more disease awareness, there's more testing, there's more testing infrastructure and availability. On top of that, I think having data to engage the overall community allows for people to say, "Hey, you should think about enrolling in a study, especially if you're not responding to standard of care." I think that's all helpful. I think this is one of those examples, especially in, you see this in some clinical trials where having someone in front of you actually is helpful for that, in the sense of understanding how you might be able to drive enrollment. You can see it just in our own numbers, right?
Where we were during the administrative analysis to where we are now, being able to enroll that many patients in a pretty short amount of time, enrolling about the order of magnitude that both other sponsors have done, but in a shorter amount of time overall, gives us the confidence to say if we implement some of these activities and probably maybe even expand on some of the things we've done operationally, confidence that we can not only just enroll the study, but do it in a shorter timeframe. We've done that in the phase II. I think that gives us at least a reason to believe why we might be able to be successful in shortening the timelines in our pivotal.
Got it. There's this school of thought that APOL1 as a causal marker for AMKD was only discovered about 11 years ago.
Yeah.
FDA, when the other sponsor went to the FDA for a registration study, FDA not knowing the disease very well, went with proteinuria plus GFR slope.
Yeah.
Right?
It was before the PARASOL analysis.
Exactly.
Yeah.
Now we have had approvals in FSGS and IgAN using just proteinuria. Why doesn't that flow into AMKD, where in many ways the disease progresses faster?
Yeah, I think the agency has always, I think, been consistent, just like they have in IgAN and FSGS, that they would take this in a data-driven approach and do this from an indication-by-indication basis. I think they've held true to that. And I think until this data and this type of analysis had been done, I think that was probably the easiest thing to do based off of limited data. I think going forward, I think that's something we would love to engage the agency on, is based off the analysis and our data, is there a possibility to look at proteinuria alone as the basis for accelerated approval? Now, more to come on that, but I think the data, especially for non-diabetic patients, seems to be clear in the correlation between proteinuria and eGFR outcome, not just slope. So I think that's important.
Got it. Given we have limited amount of time here, I want to switch to the SLC6A19 program. The PKU study is enrolling. You should have some very good insights, call it middle of the year, back end of the year, next year. Could you just remind us how substantially different this is from the Jnana program that eventually got acquired?
Yeah. So, in general, there's a couple of approaches in PKU treatment. One is having an enzyme substitution that basically allows for the phenylalanine in the blood to be properly handled. And then there are a couple approved products, Kuvan and Sephience, which are BH4 agonists, which are just cofactors that allow for the residual enzyme to be better at being able to break down the phenylalanine. SLC6A19 inhibition, that was shown proof of concept by Jnana, as you pointed out, doesn't rely on the residual enzyme to work. It basically just gets rid of the plasma Phe, or the phenylalanine in the blood, by just basically urinating it out. And it's a nice, easy sort of biology to understand, and it's shown proof of concept in the ability to lower phenylalanine in the blood.
As we were embarking on this program, obviously the Jnana data was in front of us, and the molecule was sort of apparent. We knew pre-clinically that we had more potency and we had better ADME than the compound. And so that gave us at least a reason to believe that we might be able to show better pharmacodynamic effect that might be even proven in healthy volunteers by looking at a non-invasive biomarker, urinary Phe.
When we did that in our phase I, we were able to demonstrate not only just the safety tolerability, but we were also able to show a pharmacodynamic effect by looking at that biomarker, because we knew in the literature that they had a particular dose, showed a 10-fold increase over baseline of that particular marker. Then we had multiple doses, both QD and BID, that far exceeded that, like 40, 50 times, in terms of relative to baseline. That just reinforced what we saw pre-clinically, that we might have a better molecule, and then a reason to believe that we might be able to be more effective in lowering plasma Phe in patients, PKU patients, in a proof of concept study. That's what we're running now, the proof of concept study, a phase II. It's not open label like our APOL1 HORIZON study.
CIPheR, as we call it, is placebo-controlled. There's a low dose, a high dose, and we're also exploring the possibility with combining with one of those BH4s to think about patients that may have some level of response to those BH4s, but can't get below a certain threshold to eventually become off of a medical diet, which is where most of the patients are actually using as their treatment option. If we can address this both monotherapy in terms of the doses that we can show more effective pharmacodynamic effect, lower the plasma Phe, and also think about the number of patients that can get below a certain threshold. As we kind of look at that, the literature has also kind of put a guide there in terms of the benchmark.
I think in clinic, in PKU patients, the other program that you mentioned, at least at one dose, showed a 40% reduction in plasma Phe. If you look at the 19 patients that they treated in that phase I/II, they had three of the 19 get below 360. 360 is sort of the level of micromolars of plasma Phe that physicians can start to think about transitioning their patients off the medical diet, right? If we know those are the benchmarks, we have reasons to believe based off our preclinical and now our phase I data, and obviously we'll have the data to try to reinforce our best-in-class profile in 2027.
Got it. The renal signal that you saw in the healthy volunteers, that comes up in discussions.
Yeah.
Do you have a better sense of what we should expect in PKU patients?
Oh, you mean CKD patients?
Yeah.
Yeah. In CKD patients, we are running another proof of concept study to complement or even replace patients that are on important therapy, SGLT2 inhibitors. We've described for the first time, at least high level, what that trial can look like, which we are looking at patients that could be on ACE/ARBs and/or SGLT2s, and in particular have diabetes, sort of DKD patients in that study.
What we want to see ideally in that particular study is a certain percentage drop of proteinuria or uACR to show proof of concept, as well as potentially show what we saw in the healthy volunteers, which is called this eGFR dip, to represent that we have this hemodynamic effect, which all renal protective agents that are approved on the market, including ACE/ARBs, SGLT2, even GLP-1s, they all show this initial dip, which then have prolonged benefit. If we can show those two things, I think we'll have shown proof of concept in this mechanism.
Well, unfortunately, we just ran the clock, and looking forward to a very productive 2027.
Thank you, Debjit.
Appreciate the time. Thank you so much.
Thank you for having us.