Thank you, everybody. I know we're getting towards the end of the day. I'm Doug Tsao, Senior Analyst at H.C. Wainwright. We're thrilled to have Disc Medicine with us, represented by the company CEO, John Quisel. It has been a very eventful last 18 months for the company, call it. You know, I think why don't we start with bitopertin. You recently completed an enrollment in the APOLLO confirmatory study. You actually went above the targeted 150 patients. I think you ended up with 183. What do you think this implies for underlying demand for the drug and the unmet need in EPP?
Yeah. Thanks, Doug . Great to be here. Right. With most trials that enroll faster than projected and where the demand is very high, I think it's a great indicator, right? In this case, in particular, we had very high demand at the U.S. sites. We actually stopped enrollment earlier than expected there, because of the whole accelerated path we were working towards to try to avoid any sense that a U.S. approval would somehow disrupt the trial dynamics. Meanwhile, we opened up the European sites in November, and, you know, by the middle of the winter, we had already hit our 150 and technically could have shut down enrollment. But that would have been extremely frustrating for a number of the sites where they had never had access to bitopertin before.
They had a lot of patients who were very eager, a lot of physicians eager to try it out for their, for their patients. We made the decision to allow additional enrollment, and essentially decided and we, you know, regret, but we had to close the doors on the study. Honestly, we would have enrolled more people because of the high level of interest. I think it tells us that both the U.S. and Europe, which are probably the major markets, or the major locations of this disease, there's just tremendous demand and enthusiasm for the product.
Do you think it tells you anything about the market opportunity beyond just sort of the enthusiasm on the part of patients, but just how many EPP patients are out there? Because that's certainly something that a question I've gotten from investors over the years—
Sure, sure.
—a little bit. you know, 'cause I think there's some sort of epidemiology work. You've done some claims data work. When you think about what you started to hear on the ground in terms of enrollment, does that sort of align with sort of some of the claims-based work that you've done versus some of the traditional epidemiology studies, which I think have sort of suggested a smaller population than you've thought about?
Right. Yeah, it's always been a little tricky to know exactly how many patients there are. I think that's fairly common for a rare disease where there's really not much in the way of therapeutic options, right? These patients don't have a huge incentive to actually seek out care and become part of the recognizable medical system. The estimates range, yeah, the kind of academic papers put it somewhere between 1 in 100,000, 1 in 50,000, that would put the U.S. at, you know, 3,000 to 6,000. There was a genetic analysis done based on UK Biobank data that came out of MGH that pegged the U.S. population at likely closer to 20,000.
We went into the claims databases and found 14,000 patients who've received care under the dedicated ICD-10 code for EPP in the U.S. Now some of those patients had only one claim in the time that this code has been in existence, which is about eight years. Some of the patients had multiple claims and, you know, we kinda drew a somewhat arbitrary distinction between the 14,000 as kind of the whole group and then an inner core of about 6,000 who seem to be pretty engaged in their medical care. You know, interestingly, that 6,000 matches up not too far off of these academic epidemiologic estimates. I think, you know, interestingly, the experience of running trials here is that the patients are out there, right?
We know there's one approved drug called SCENESSE. We don't know exactly how many patients, but we know that on a yearly basis, not very many people, you know, measured in 200 might be receiving that drug in the U.S. You look at there's another program called dersimelagon that has been recruiting trials, has run, you know, multiple phase III trials and enrolling hundreds of patients. We've simultaneously enrolled hundreds of patients into our programs, and all of these are happening rapidly. These patients are showing up, right? I think there's it's a sign that there are probably more patients than people think. They're probably, you know, near the upper end of these estimates, and that there really is a high unmet medical need.
These people are, you know, really eager to find some kind of therapy because, you know, they're living, you know, all of them very bravely and self-sufficiently with their disease, but they're living basically in the dark, right? They're all very eager to have these experiences where they can go out and kind of have the freedom that we all just take for granted.
I'm curious, when you mentioned some patients who had only one claim, have you been able to get a sense from clinicians what sort of happens with that patient? Is that typically a pediatric patient, and there are no real options besides wearing some protective clothing, staying inside, et cetera, and they're just sort of resigned to sort of their fate, so to speak, with EPP?
I think that's probably the typical story, yes, that someone has, they're aware of a long-standing issue of, you know, pain on sunlight exposure. They work their way through some kind of diagnostic journey, which is always very challenging because no one thinks about this disease, which is an important part of our mission, trying to make people aware and just to have doctors remember to do a very straightforward test. Then, you get the diagnosis and you're told, "Well, you can either show up for a surgical implant every two months, it will tan you and have, you know, some proven benefit, or we got nothing for you." Right? At that point, I think a lot of the patients just simply go back to living their lives in the dark, basically.
You know, going to the complete response letter that you received from the FDA for your application for accelerated approval under the Commissioner's National Priority Voucher.
Yeah.
It was a real sort of mad dash process, if you will. The agency sort of said that they had, there wasn't a strong correlation between PPIX levels and sort of the symptoms of the disease. They sort of acknowledged that this question would be addressed in the APOLLO study. I know you have spoken about having or were going to have a Type A meeting, I guess the question I've gotten from some investors is it feels like the wheels are in motion for us to get the data. You've talked about completion of enrollment. What are you looking to clarify? Are there any operational changes to APOLLO that could be implemented based on any feedback that you get from the agency?
Right. The main, I think, utility for the Type A meeting is really to discuss how the ultimate phase III APOLLO data, which we expect to get in Q4 this year, should be analyzed and kind of packaged up for, a response to the CRL or resubmission of the NDA. Either way, you know, then it sets up a six-month review period, and that's why our guidance is to think about middle of next year is when we might get to, approval. I mean, that's really the objective of the Type A meeting. Obviously, it is a moment to kind of debrief about, you know, what the heck happened with this, accelerated approval process.
What was the, you know, what was the issue around the perceived, quote, "lack of correlation"? I think, you know, the data now from the definitive phase III study is so close that it's our assumption that that's the path we're on to get to approval of the drug.
John, is it fair to say that it is more about sort of maybe understanding what happened during the review and maybe less focused on APOLLO per se, as much as just thinking about the resubmission and what they're looking for so that you can maybe get that done and filed again as expeditiously as possible, just given that understanding?
I think that's correct. Yeah. Yeah.
Okay. I guess, you know, you were moving at sort of this incredibly fast pace as a company from sort of initially after AURORA, sort of anticipating needing to do a traditional phase III to the agency, signaling its receptiveness to doing an accelerated approval, then sort of being granted CNPV, that you sort of went at breakneck speed to get your organization prepared for a potential launch, you know, two to three months ago, right? Quite frankly. Now that you're back to sort of a normal timescale in terms of a launch, what does that allow you to do this time that you weren't able to do? You had built some infrastructure, you'd sort of had pulled back on some of that. You did a restructuring. You know, how disruptive was that to your organization?
Yeah. Well, look, there's I think two real tragedies from the kind of process we went through with the FDA. One is that we weren't able to deliver the drug to the patients now who desperately want it. The second is that we did have to we hired this group of folks to help support the launch and then, you know, found ourselves with a gap where there was really no reason to keep that full team around and had to let them go. That's, you know, really upsetting to have to deal with that.
You know, we did retain about a third of the team, the purpose for that is to continue to understand this market. You know, the claims data gives us a call list of physicians who have, at least on digital traces, you know, treated these patients.
We have set up a system where our, you know, residual sales team and medical affairs teams can now go out and contact these physicians and understand their disease awareness, their, you know, the patients that they have, build those relationships, so that as we come to an actual launch, you know, this market, which otherwise is, I would say, you know, almost as underdeveloped as if there were no drugs approved, that we have, you know, a really good sense of the landscape, really good relationships, and, you know, a bunch of physicians who we know are aware of and excited to provide a new therapy to their patients should it become available.
Just one other final question on bitopertin, because I want to touch on 0974 and 3405. I think I have the right number.
DISC-3405, yeah.
Yeah, DISC-3405. Is pediatrics, right? This is a market where there's—
Yeah.
—a large opportunity for pediatrics, right? Especially for young kids. Obviously, if you think about it from, in some ways, they might be the most impacted by it.
Yeah.
You are pursuing development initially with adults, which is not uncommon. You sort of talked about pursuing pediatrics eventually. Given the delay that we're seeing, you know, we've seen with the FDA process, has your timing or your thought in terms of that opportunity changed?
Yeah. The adolescent population has no approved therapy right now, neither does the true pediatric population. In our phase II program of about 100 patients across U.S. and Australia, we were able to incorporate four adolescents. In our phase III trial, the APOLLO trial, we have essentially open enrollment for adolescents. You know, we'll see soon, like, the total, but I think what it will give us is now a really good data set for the adolescent population in addition to the adults. There's no mechanistic reason the disease is the same.
Yeah.
There's no reason why it wouldn't be the same, but we'll have, I think, a really meaningful data set. The idea of being able to get a label out of the gate that covers at least down to the, you know, age 12 or so, is really good. You know, that seems like a very straightforward process. As you say, we also have a plan for getting to even younger patients that we are executing against, and I don't think anything really delays that.
Okay. You know, turning to DISC-0974, we've seen some initial data from RALLY-MF. I think one of the striking things to me was the efficacy we saw across all patients receiving JAK inhibitors, including momelotinib and pacritinib. How do you think that positions the drug? I think there was a sense that the introduction of those agents sort of relieved the need for an anemia treatment, although obviously that does not seem to be the case. I'm curious what your takeaway on that data was, so that initial data.
Yeah, I think it was fascinating to see just how many momelotinib patients enrolled in the RALLY-MF phase II trial, right? A drug that's ostensibly there to, you know, ameliorate anemia, really we got a lot of anemic patients and you can only get into our study if you're anemic, right? There were a lot of patients who'd been given momelotinib. It clearly did not resolve their anemia, and we had the same response rate among those patients as we did with other JAK inhibitors, as well as patients who were not taking JAK inhibitors.
I think that was very meaningful to us to understand that while there is a pool of patients who are so anemic they cannot tolerate Jakafi, and yet they do have the enlarged spleen and the symptoms that they need a JAK inhibitor, those patients who are receiving, you know, momelotinib, which is a great thing that they can tolerate it better, but actually the anemia that they have is not going away, right? The estimate of 80%+ of these patients have anemia, really, I don't think it's changing over time as these new JAK inhibitors come onto the market. I think we're even seeing now a newer wave where the vogue is to kind of get more selective onto JAK2, which, you know, is the transducer of the EPO signaling pathway.
While those drugs may have a great, you know, effect on spleen and symptoms, et cetera, they clearly are gonna come with a very powerful anemic side effect. I think managing anemia in these patients as an intrinsic part of the disease is very important, but also managing anemia in these patients to allow the optimal use of various, you know, JAK inhibitors and other therapies aimed at the underlying driver mutations is gonna be really important. I think we're very excited about having this kind of broad spectrum agent that looks right now as if it can basically treat any anemic myelofibrosis patient regardless of the co-therapy.
I think we're gonna get data for 0974 at both EHA as well as ASCO. I think it might be helpful to just understand or help us understand, you know, what we should see then and how that maybe sets us up into the readouts at the end of the year. I think RALLY-MF —
Yeah, yeah.
—is expected to read complete by year-end.
Right. We shared some interim data at ASH last year. I think it pretty convincingly showed the efficacy of the drug in the non-transfused population. It also showed, I think, eye-popping data in the lightly, you know, the low transfusion burden population, but with a small n of patients. In the high transfusion burden, we had a lot of questions. Are we, you know, formally we were at zero out of three responders. We were just on the cusp of being three out of six. Our press release that kind of foreshadows the ASCO and EHA presentations coming up, we're sitting at three out of six response in the high transfusion burden.
That's pretty consistent then across all three groups is you know, roughly 50%-60% major responders, which is the best that's been seen with any therapy for these patients. Very exciting. As we come into these conferences, we'll have yet more data. We'll have more patients than that. I think the goal is to strengthen the signal, the kind of the depth of the signal across all treatment groups. Probably the greatest interest is in that high transfusion burden group where we haven't really proved it out yet, right? Where the efficacy is still quite volatile because the n is small.
Okay. You know, DISC-0974, you stopped development in chronic kidney disease, but you have an ongoing trial in IBD. I'm just curious sort of how you're thinking about that or sort of what led to that decision. Was it sort of a greater confidence in the commercial opportunity, or was it just a mechanistic decision for the drug in terms of thinking this will be more relevant in the IBD patients?
Right. Right. The non-dialysis CKD patient population, it's a huge opportunity, desperate need for a better anemia therapy than what they have now. Our data were mixed. Some patients responded well, others not so much. It looks like it has a lot to do with endogenous EPO levels, right? In CKD, EPO is produced in the kidney, and as the kidney fails, you have less EPO being produced. That's the positive driver for red blood cell formation. What our drug does is provide the iron that you need, but it doesn't provide the positive pressure. It looked to us like in the absence of a positive driving signal, the response to the drug was muted. Sorry, non-dialysis patients cover a spectrum. There were responders, but it felt challenging to pick that apart.
It's not a field where people are checking endogenous EPO levels, choosing therapeutic options based on that. It takes some work to kind of probe that. Meanwhile, we have fantastic data from our mouse models of IBD, profound improvements in anemia, even signs of improvements in inflammatory disease. I'm not sitting here claiming that I understand how or whether that will translate into humans, the anemia potential looks great. I mean IBD is a highly inflamed disease. The anemia is significant for a lot of these patients, really a lot of complaints about fatigue. Essentially uniformly, these patients have very high EPO, which is normal. If you are anemic, your body is supposed to make a lot of EPO. You're supposed to be sending the signal, "Hey, let's make red blood cells." Right?
You see that in MF, extremely high EPO levels. These patients respond really well to our drug. By the way, they don't really respond very well to piling on more EPO.
Yeah.
Right. It doesn't make any sense. MF, we have that kind of signals being a really powerful responding group. IBD is a much larger indication where all the hallmarks would suggest that the drug should work well, and there's even a chance that we'll, in some way, contribute to an anti-inflammatory effect, which would be fantastic if we're able to see that.
Okay. I know we're almost out of time, but I did wanna touch on 3405 in polycythemia vera. You know, we've obviously seen, you know, a lot of success with Protagonist, with rusfertide. I'm just curious how you see the opportunity and your differentiation—
Right, right.
—in that set, in that indication.
I think it's well established now that iron restriction can provide a favorable effect for polycythemia vera patients. That's what rusfertide has proven out. Our goal is to provide a simple monoclonal antibody solution that can be given, you know, relatively infrequently, whether it's a couple times a month, once a month, hopefully provide just a much cleaner safety profile for the patients, be much more tolerable. That's the goal.
You know, you are starting a study for DISC-3405 in sickle cell disease.
Correct.
I'm just curious how you see that fitting into the landscape. There's obviously been a lot of activity there. You know, I know Protagonist looked at sickle cell but have decided not to pursue it. I'm curious how you see your opportunity.
Yeah. I think the theory of iron restriction in sickle cell disease has a lot of interest. People are using phlebotomy in these patients now clinically, and I think there's a lot of reports of good effects there. The objective of phlebotomy is this kind of crude way of achieving iron restriction. We think we can do that with the drug, produce the benefit. If we're able to achieve that, it should combine with any mechanism that's out there, right? Because it's just distinct and iron restriction has proven out again and again to be fairly safe, right? We think that will be a good potential option for these patients.
Okay. Well, with that, I think we're out of time, so we'll wrap it.
All right. Thanks so much.
Thank you so much, John, and thanks for the update. Look forward to seeing more.