Great. Welcome back, everyone, to another session here at Oppenheimer's 35th Annual Life Sciences Healthcare Conference. I'm Leland Gershell, one of the biotech equity research analysts on the Oppenheimer team, and really pleased to have with us as our next company, Quince Therapeutics. The company is public, ticker is QNCX, and the company has a technology platform that it is using to develop, first and foremost, an innovative candidate for ataxia-telangiectasia. I'm glad I could pronounce that okay. Not sure if I can spell it. With the company, we have the company's CEO and CMO, Dr. Dirk Thye. Welcome, Dirk.
Thank you, Leland. Nice to be here.
Absolutely. He has a technology platform that it is using to develop, first and foremost, an innovative candidate for ataxia-telangiectasia. I'm glad I could pronounce that okay. Not sure if I can. Thank you for bearing with us. Had some technical difficulties. Often crops up in these webcast sessions. Again, we just want to mention that we do have the opportunity for you to lobby in questions, so please do so. We'll work those into our discussion. I think maybe to set the stage, Dirk, if you could tell us about Quince's opportunity in AT, what that disorder is. Most people are maybe familiar with it, and kind of what your general approach is to improving upon the current treatment condition for these patients.
Sure. Yeah. AT, you're right that there's not a lot known about AT in the general investment community, and that's because there's nothing approved for AT. AT, from an epidemiological perspective, is a lot like Friedreich's. There are about 10,000 patients in the U.S. and Europe with this disease. This particular disease is actually worse than Friedreich's ataxia. It is a form of inherited genetic ataxia, but it's an autosomal recessive genetic disease affecting the ATM gene. The ATM gene, there are about 450 or so different genetic mutation combinations that lead to this phenotype, and it's a terrible disease. Children at a very young age, on the order of two or three years old, start to get rapid neurological deterioration, and that continues until they're about 10 or 12 years old, where they're typically in a wheelchair by that point in time.
As teenagers, they start to get an increasing number of infections and cancers, and their lifespan is usually in their mid-20s. To date, there is nothing approved, as I mentioned, and they basically just get supportive care. They get occupational therapy, physical therapy for their neurological deterioration, and they get treatments for infections and cancers. We have a therapy. We have a machine that encapsulates drugs inside the patient's own red blood cells, and we're encapsulating dexamethasone, which I'm sure we'll talk about, that dramatically changes the pharmacokinetics and pharmacodynamics and biodistribution of dexamethasone in a manner that you can give it safely over time.
We believe that that will slow the rate of progression of neurologic deterioration that these patients see without having the safety liabilities, which is important for this population because, as I mentioned, they get infections. One of the features of the disease is that they have chronic immunosuppression, and they're very vulnerable to different types of infections.
Is AT well diagnosed? Is there a bit of a patient journey there? What does that look like?
Yeah. There's a very significant and very harrowing patient journey, both for the—well, the kids are so young at the time they get diagnosed. They're not really aware of the journey, but it's very difficult for the families because unless you know you're a carrier of AT, you're not going to select any prenatal testing for this, and it's not part of any standard genetic testing panels prenatally. Typically, what happens is the child will just—the parents will notice the child isn't developing normally at a young age. It's not immediately noticeable. It's usually around the age of one or two or three where the patients really notice, and it has to do with rolling over, crawling, learning to walk, and they start to stagger. They're slow in development, and they also have slow growth later on.
Because there's no standard testing for this, sometimes kids get picked up with SCID testing for T- cell deficiencies. The genetics testing company, if they're negative for SCID, has to notify the physician to then do further genetic testing. Sometimes they get picked up that way, but generally, what happens is they bounce around from specialist to specialist until they get this specific genetic testing required. Often, they're not diagnosed until four, five, six years of age, at which point they've already had a few years of problems.
Got it. Nothing approved, but steroids have utility. Are these patients, do they tend to be on an oral corticosteroid? To what extent?
Yeah. No, I mean, we think steroids have a role to play here, and the historical data for that comes from originally, there was a case report of a child that had an asthma exacerbation or chronic bronchitis, one of those problems, an AT child, and was treated with a short course of corticosteroids. This was like 15 years ago, and there was a case report written about the child because the physician noticed that the child had a dramatic increase in their neurological functioning during that short course of steroids. That led a couple of academic investigators to do a couple of small studies, one in Japan, and I think there were two studies out of Italy. These involved small numbers of patients on the order of 6- 12 patients and a variety of low-dose steroid regimens.
They designed steroid regimens in an effort to avoid the toxicity, so they did low doses, and they did a variety of things like two weeks on, two weeks off, or skipping days, things like that. There were some mixed signals of efficacy even at the low doses. There were hints that it was helping the children neurologically, but in every study, they had toxicity problems. As I mentioned, the toxicity is particularly problematic in this population because they're so vulnerable to infection. Steroids never really caught on as a standard of care. Occasionally, you'll run across a physician that has attempted them, but invariably, they run into toxicity problems. You'll see that very commonly in the DMD, the Duchenne muscular dystrophy population as well. That steroid toxicity is a very common feature of that disease where steroids are the standard of care.
It hasn't really caught on, but because of its potential promise to delay neurological degeneration, it seems like a very good opportunity to test our technology. We have a lot of safety data in patients that have been taking it for up to 13 years without adrenal suppression or steroid toxicity. It looks like we have a pretty good data set that suggests that this is a safe way to give steroids. Testing it in AT, I think, is a good scientific test of whether it's efficacious when given this way.
Right. The problem seems to be kind of the up and down of giving steroid, let's say, in the daily format. Obviously, steroids are much more challenging given chronically than, let's say, acutely. These patients obviously have a chronic disease, as you mentioned, DMD as well. With EryDex, with your platform, it looks like you're able to really solve for that. If you could just review what you've shown from a kind of a PK, maybe PD perspective. Also, I know you have data from a prior potential registration study. If you wouldn't mind reviewing those.
Sure. This will be a little hard to follow without slides, but let me mention a couple of mechanistic things that are important to understand with respect to steroids so that you have sort of a mental framework for why this is safe. I'll preface it by saying it's been given in 6,000 different doses to about 384 patients, three of whom have been taking it monthly for 13 years. About 68 kids have been taking it for an average of about three years, all with no steroid toxicity. It's pretty clear that when given this way, it's safe. What we're trying to prove is that it's also efficacious, and we'll get the answer to that at the end of this year.
The reason why we think it's both safe and efficacious is because all corticosteroids have pretty short half-lives, regardless of their formulation, even if it's pegylated or liposomal. You have to give them pretty frequently. You have to give them frequently because in order to be efficacious, you have to have a Cmax that achieves a concentration of around 100 nanograms per mL. That's important for establishing the non-genomic benefits of corticosteroid therapy. There are also really important genomic benefits that you want, and you get those by having long-term receptor occupation. If you need both a Cmax and receptor occupation and you're using a short half-life drug, you have to give it frequently.
Regardless of the formulation of steroid, that's what happens is you give it once a day or you give it even more than once a day in order to achieve those two important things: Cmax, long-term receptor occupation. When you do that with standard corticosteroids, you have this up-and-down effect, and you end up, just by virtue of having that much dosing, triggering these different plasma threshold concentrations that typically lead to corticosteroid toxicity. It's the stuff that all people familiar with medicine know about: hyperglycemia, leading to diabetes, immunosuppression, and then everything related to adrenal suppression, bone problems, behavioral issues, growth problems, delay in puberty, all that stuff. With corticosteroids, conventionally, you can't get around that due to those things I mentioned.
What our technology does is it satisfies that Cmax and the receptor occupation because by encapsulating dexamethasone into a patient's red blood cells, the release characteristics mean that you get an initial Cmax within a couple of hours of the administration. I should have mentioned it's given once a month. You take a little bit of blood, you process it, you give it back to the patient. It's done once a month. You get this Cmax within a couple of hours, and then you get this long, slow decline over one month. That long, slow decline has enough corticosteroid exposure to maintain receptor occupancy over that period of time, which leads to the genomic effects.
You get the Cmax for the non-genomic effects, the long, slow tail for the genomic effects, thus hopefully satisfying the requirements of efficacy, which we'll prove or not prove by the end of the year here. Clearly, it's safe as supported by that safety database that I just described.
There were data of the ATTeST study, which was a Phase 3 study, and the results, I believe, were published in Lancet Neurology. Obviously, there was support there. This is the primary endpoint, but there may have been some issues. Subgroup analyses kind of took Quince in the direction of doing what it is now in the NEAT study. Maybe just elaborate a bit on kind of what may have, sort of, in hindsight and ATTeST, what maybe happened there.
Yeah. This is a little complicated. It's easier to show with slides as well, but let me explain that study. That study was the largest study ever done in AT, and they studied—it was double-blind, double-dummy—they studied placebo, low dose, and high dose of encapsulated dexamethasone. In the overall population—I'll just talk about high dose because high dose did a little better than low dose—in the overall population for the primary endpoint, which primarily measures lower limb function, the ability to stand and walk is basically what it measures. When looking at that outcome measure, the high dose was better than placebo, but the p-value for the difference was 0.07. They just missed statistical significance in that study. When you look at the design of that study, they enrolled patients six years old and above.
I described the natural history of the disease where at a young age, you deteriorate rapidly, and then you're often in a wheelchair by the age of 10 or 12. In that ATTeST study, about half of the children enrolled were between the ages of 6 and 9, and about half of the children were 10 and above. If you're using a primary endpoint that looks primarily at gait and standing, gait and posture, then if you're looking at the 10 and above population, you really wouldn't expect to see much because they've already had most of their deterioration, and their neurological deterioration has plateaued out at that point. In the 6- 9 year-olds, you would expect to see a larger difference.
That's exactly what happened. When you divided up—and this is pre-specified by them—when you divided up between the younger kids and the older kids, in the older kids, you saw very little difference. There was a small difference, but it wasn't statistically significant at all. When you looked at the younger population, it was highly statistically significant, and the change there was very meaningful. We looked at that data very carefully in a lot of different ways and looked at all the secondaries and the additional endpoints and sliced and diced it many different ways. We came away with the conviction that the signal in that younger population is real. We embarked upon a new study, what we call the NEAT study, just in that younger age group, using that same outcome measure, looking primarily at posture and gait. It is a valid endpoint because this study is under a special protocol assessment with the FDA. They have agreed that it can serve as a single pivotal if it is positive.
Yep. No, absolutely. It's good to always have the spine in place. Let's talk a bit about the NEAT study. Is that fully enrolled at this point?
Not fully enrolled. We're in phase three right now. I think we enrolled our first patient last June. We just announced enrollment update a few days ago. I think it was 47. And we had about two-thirds of our sites up at that point in time. This month and next month, we'll get the remainder of our sites up. I expect things—screening has already really accelerated over the past month or so, and I expect with the remainder of the sites going up, we'll be able to speed up significantly. We're anticipating completing enrollment by the second quarter and getting data by the end of the year.
Got it. Okay. Obviously, it'd be a big event for Quince. Once beyond that, presumably, if the data are positive, you'd be in position to file. How do we think about kind of the U.S. revenue opportunity based on what we know about the numbers of patients with AT? Maybe talk a little bit about maybe ex-U.S. opportunities as well.
Okay. Sure. So we've done some patient finding in the U.S. If you look at the literature, you'll come up with about 5,000 patients in the U.S. In our patient finding exercises, where we used an outside vendor to look at ICD-10 codes, we identified 4,600 in the U.S. with the AT diagnosis. It's pretty consistent. We don't yet have granular data on age, but we expect that probably somewhere between 600 and 1,000 of those are between the ages of 6 and 9. Although I don't anticipate that we'll have an age-restricted label. I don't think we'll be labeled for below the age of 6 years old. The FDA and the SPA did ask us to include 20 patients in our phase three study, 10 years between ages 10 and 18. They're not included in the primary analysis population.
We're collecting efficacy and safety on them, but I think it's primarily to look at safety. In the absence of a safety signal in that cohort, I think we'll get labeling for 6 and above. That opportunity, based on traditional rare disease pricing, somewhere on the order of $475,000-$600,000 or so gets you to a market opportunity close to $1 billion in the U.S. That would be less due to the pricing paradigm in Europe. It'd be a little less than that. The epidemiology and the big five in Europe is about the same, about 5,000 kids.
Right. Would the NEAT trial presumably be sufficient then for approval in Europe? Would you expect to need to do some more work there?
I think it'll be sufficient, although in Europe, we also have the pediatric investigational plan requirement that also comes with timelines. We are in the process of working on initiating that study. We anticipate doing that before the end of the year. That's actually a really interesting study because it includes patients as young as one year of age, up to six. If we can get data in that study more quickly, I'd like to include it actually in the NDA, which would allow us to get a label as young as one. I don't know if we'll be able to finish the study in time. For Europe, that'll be one of our requirements. I do think the single pivotal for this disease, there's nothing approved in Europe for this disease either, in addition to the U.S. I think it would be sufficient.
Yeah. That would make sense. In terms of presumptive launch, obviously, there's a device technology involved. Maybe just kind of walk us through what that would look like from the perspective of scaling EryDex and the platform.
Yeah. I think this is one of the advantages of working in rare disease for this platform and building the distribution of the sites and the machines slowly because if you were to—you could use steroids for rheumatoid arthritis or systemic lupus, but the commercial approach would be totally different. I think the advantage we have in rare disease is that we can target about 50 centers of excellence throughout the United States for our initial launch. We can build that over time, maybe starting with 20 and building up to 50 over a short period of time. We will have to place the machine at the site, and the patients will have to come in once monthly for therapy. There are some precedents for this.
I mean, it's a little bit similar to a dialysis unit, but the machine can be placed in an outpatient treatment facility or an IV clinic or even a hospital. We will have to work on the details of exactly which sites get these. The IV infusion center, the outpatient IV infusion center is an attractive model that we're investigating right now.
Great. Yeah, let's talk about other indication opportunities. Again, Duchenne, that seems like a prime place to go. What are the activities in that direction for Quince?
Yeah. Duchenne is extremely attractive to us. Essentially, despite ASOs and gene therapies, almost every patient with DMD is on steroids, and they all have toxicity issues. As I mentioned a couple of times, the safety database for this looks really, really good. If this is efficacious in AT, that'll be, I think, even though the pathophysiology of DMD is different, steroids are known to have efficacy in DMD, and this is a corticosteroid. The mechanism might be different, but I think it would also work in DMD. If you could have equivalent potency or efficacy in DMD without the safety liabilities, that would just be a huge opportunity. I think it's a little different treatment paradigm because it's harder than taking a pill. You have to come in and get some blood drawn and get it reinfused.
We assume that you'd have to step through those other therapies and fail those therapies before you got onto ours. If we really have a chronic steroid with no safety liabilities, it would be a huge advantage to that patient population. That is next. We are designing a Phase 2 study in that indication. Right now, we do not have enough money to run it. We are basically just making plans, plans that we could launch quickly in the event of a financing. We will be opportunistic about doing one when the chance arises. After that, there are about a dozen diseases. Only in rare disease, there are about a dozen diseases that are of great interest, things like pemphigus vulgaris, dermatomyositis, autoimmune hepatitis, juvenile systemic lupus. We will try and pursue some investigator-initiated trials in a couple of these things.
Ultimately, we'd like to pursue a lot of different indications in rare disease. Then in non-rare disease, we'd like to take an alternative steroid like betamethasone and basically pursue the same strategy, same technology, same monthly therapy, but for non-rare diseases since it'll require a different commercial model and different pricing.
Yeah. Absolutely. Outside of steroids, any other API thoughts that you have for delivery through the red blood cell technology?
Yeah. I think just this lead product alone is enough to keep me busy for the rest of my life, for sure. The people that invented the technology have encapsulated lots of different molecules. You can encapsulate chemotherapies. You can even encapsulate enzymes. The idea there is the opposite of instead of the drug leaking out of the cell, the substrate leaks in and gets metabolized. They have done that for enzyme deficiencies. It is a very versatile technology that can encapsulate a variety of sizes of molecules. We would like to, for those programs, we would look to partner those out.
Great. That's really a broad potential. Maybe just the last question or two here, just as we think about, I don't know, going from a test to the NEAT study. So you have the SPA. And the primary endpoint, it's based on this metric called, I think it's called the.
ICARS.
The Rescored Modified ICARS.
Rescored Modified ICARS.
Yeah. Is there any difference in that between what was used previously and in the current study?
Yeah. It's a little bit of a complicated story. The ICARS is one of these neurological scoring tools that are common to a lot of these diseases, SARA and MFARS and ADAS-COG. It's basically this panel of neurological tests that you run the patient through. Each item, the ability to walk or finger to nose, heel to shin, things like that, has a score associated with it. The score adds up to 100. This tool was developed in the mid-1990s and validated in the early 2000s for ataxias in general. It was used historically in these AT trials by the company we acquired. It's lived with the program all along. That's what we do in the study. We do the full 100-point test.
Now, the FDA, over previous years, changed their mind a couple of times on which subset of those 100 points was of most interest to them. Ultimately, they selected 29 points out of the 100. The vast majority of those points are in the gait and posture domain. The 100 points has four domains, and gait and posture is the largest domain. It's like the ability to walk, the ability to stand. The FDA decided that they believed that that domain best reflected how a patient feels and functions. They came up with this Rescored Modified ICARS, which is 29 out of the 100 points, primarily from that domain. That's the ultimate primary endpoint in our study. We handle it programmatically. We do the whole 100 points, and then we just report out on the 29 of most interest to them.
Got it. Okay. Good. Obviously, we look forward to hearing on the completion of enrollment and on the primary endpoint top-line readout coming toward the end of the year. I think we're at our time here. I'll conclude there. Thanks very much, Dirk, for joining us. Great discussion. Thanks to all of you who zoomed in for this session with Quince Therapeutics. Wish everybody a terrific rest of the conference.
Great. Thanks a lot, Leland. Bye, everyone.