Good morning, everybody. I'm Doug Tsao, senior analyst at H.C. Wainwright. We're thrilled to have us with us today, Disc Medicine, represented by the company's CEO, John Quisel, and the CFO, Jean Franchi . Thanks for being with us today. It's been a very eventful time for the company over the last, you know, call it 18 months, with the advancement of bitopertin. One of the things that was sort of interesting to me, and obviously with bitopertin, you certainly had favorable interactions with FDA, who has sort of given you the green light to pursue an accelerated approval pathway for bitopertin in EPP. I'm just curious, how much convincing did it take to get the agency to agree that PPIX levels were an acceptable endpoint for you, and that, you know, sort of almost they encouraged you to pursue this pathway?
Yeah. It's a great question, and it's great to be here today. Yeah. So we're on this accelerated approval path, and it really all came about at the end of phase II meeting, which happened last fall. I think it wasn't a case of extensive convincing. We did lay out the arguments. I think the scientific rationale is quite strong. Our surrogate endpoint, protoporphyrin IX, is in fact the chemical that drives all the symptomology of the disease. There's no real debate in the scientific community that reducing PPIX is gonna be good for these patients, since without it, you don't have the disease. I think that was a very strong argument. You know, the rest of the data package we've provided, I think is largely available publicly.
As you march through all of our secondary and so-called clinically meaningful endpoints, we were numerically positive on, I believe it was every single one of them, and we were stat-sig on many of them. Of course, there was this total time of light endpoint that caused some stock dislocation because it was not stat-sig on its initial readout, but it was nonetheless numerically positive. We know now that there was kind of an early wave of placebo effect that disrupted that endpoint. Altogether, the package of showing clear PPIX reduction plus clear outperformance of the placebo group across any number of endpoints in a relatively small study, I think was very persuasive. It really required only one meeting to get the, you know, the green light from the FDA that PPIX could serve as a surrogate endpoint to support accelerated approval.
What do you think it says about the unmet need in EPP, right? There is an approved therapy, but obviously, you know, the agency felt like you represented such a significant breakthrough to afford that.
Right. Yes. The existence of an approved therapy is one of the factors that is considered in an accelerated pathway. I think the factors pushing in the other direction are, A, we know that a lot of patients do not actually utilize Scenesse, and it is probably a mixed, you know, there is probably an access issue there since it is administered by a surgical implant and requires patients to travel to one of a handful of surgical centers to receive it. Either way, no matter how you slice it, we know there are a lot of patients who are not receiving therapy. I think the very fact that Scenesse does require a surgical procedure every two months means there is a real need for something that is just an oral, simple therapy like, like bitopertin can offer.
Maybe just sort of helpful to orient people just in terms of the overall patient population with EPP and as well as sort of what you see as the target population for bitopertin.
Yeah. The target population for bitopertin is really anybody who has EPP and symptoms. Sorry, what was the first part of your question?
Just sort of the overall magnitude in terms of patients.
Yeah, right.
10% now are being treated with, with Scenesse and.
Right, right.
What that leaves, you know, and obviously I think we would acknowledge bitopertin represents much more clinically meaningful benefit. Just in terms of the numbers for people to get their arms around.
Yeah. So it's, it's always a challenge to figure out exactly what the patient population is. If you look at the genetics, by extrapolating from the UK Biobank, this was a paper published from MGH, you would expect about 20,000 people with the genotype that would drive EPP in the U.S. And then when you look in the claims database, we've used the Komodo database, and we've put a lot of effort into trying to clean that up. We have an ICD-10 code. It does look back seven or eight years, from when the code was created. In that time, we can see 14,000 patients, of ages 12 and up, who have received therapy under a code for EPP. And then if you look at, you know, the recency of that engagement or multiple engagements, you come up with a number of about 6,000.
We're, you know, we view it as a launch into those more recently or more frequently treated patients in a group of 6,000, and then a kind of a social media patient advocacy campaign to reach the full 14,000 patient population. The numbers that are on Scenesse are never, it's never crystal clear. But, you know, I think in the security filings from that company, there have been statements like, you know, a total of maybe somewhere close to 2,000 patients are in their safety database, implying that number of patients. That's, you know, U.S. plus Europe have ever received the drug. That's not necessarily saying regularly received the drug, but ever received the drug. I think you can, you know, split that up between U.S. and Europe however you want, and then, recognize that, you know, relatively few of these patients are receiving that therapy.
You know, I think when the AURORA dataset first came out, I think you characterized it as a complex dataset. It, you know, I think over time, the data sort of simplified as you sort of underwent more analysis. I think you alluded to that a little bit in terms of your interactions with FDA. Maybe walk through exactly, you know, as you untangled it, what you saw and how that contributed to the ultimate design of the APOLLO confirmatory study.
Yeah. You know, AURORA and BEACON, these two trials, one open label, one placebo-controlled, these were phase II trials, and they ended up functioning exactly how phase II is supposed to function, which is you learn about your endpoints and how to measure what's clinically meaningful in these patients. What was complex is that while we hit our primary endpoint, protoporphyrin IX reduction, very cleanly, stat-sig in both studies, the clinical endpoints were a mixed bag. Some we hit stat-sig and some we did not. You know, in the top line data, we didn't have access to the temporal information, meaning what we got were sort of no numbers representing, for example, the total time in light the patient spent over the trial.
What we learned is when we got the time course, we could see that the placebo groups had this wave of increased time in light that then trickled back towards baseline, whereas patients on therapy had this tendency to just keep going up or at least stabilizing and performing very well over time in, you know, being able to spend more time in light. This, of course, is one of the key readouts that is viewed as clinically meaningful by the FDA. I think, you know, that was the key learning, that there is an important placebo effect in these patients. It perhaps should not have been a surprise because it is essentially a lifestyle and pain-driven endpoint, which placebo effects are known to occur in these types.
You know, to be fair to us, the main class of drugs that's been studied before in these patients is one that works by tanning. It's been published that those patients are well aware of whether they're on drug or not, and therefore, you know, placebo effects don't really happen when patients know whether they're on drug or not. We were kind of the first ones doing a real blinded, placebo-controlled type study. I think the key learning from that was, well, if you look after about the first two months on study, the placebo patients are tending back towards their baseline, whereas, and that's when the gap really opens up between those on therapy, on active therapy, and those on placebo.
We designed our pivotal endpoint to be really using the last month interval of the six-month study as the place in which to, or the time point in which to measure, the difference from placebo patients to assess that key endpoint.
Basically, to some extent, much of the study sort of runs as sort of like a run-in, if you will, right, to sort of get through essentially an offset that placebo effect that you did see in AURORA.
Yeah, that's right. That's exactly right. Speaking of run-ins, we're also, you know, the other learning was that baseline really matters. We're doing a more rigorous baselining. We had very good diary compliance. We have a lot of ways of managing that, both in phase II that worked well. We're also including some efforts in the baselining process to ensure the patients are well trained on how to use the diary. I think we're well prepared. I think the other feature of the study that we're pretty excited about actually came from the regulators, to promote PPIX to a co-primary part of that endpoint.
It's now, you know, in that APOLLO confirmatory trial, we will wanna hit both PPIX, which, you know, is kind of fundamental to the mechanism, would be very surprising if we don't hit that, and then, this time in light endpoint. You put those together, and I think we have a really, you know, feel very good about our likelihood of success in this trial.
And to your point, John, I think in both the AURORA as well as the BEACON, the earlier open-label study, the PPIX reductions were quite dramatic, right?
Quite dramatic. Yeah, yeah.
And almost, you know, pretty much every patient had a response on that. And, you know, you had been pursuing development in Diamond-Blackfan anemia.
Yeah.
It was another rare indication. I'm just curious, does the accelerated approval pathway change how you're thinking about that indication as well?
It doesn't. You know, that indication, it's quite, quite rare, you know, rarer than EPP. We really approached that, well, we were approached by KOLs from that field, including some at the NIH who have a pool of prevalent patients that have been willing to, you know, enter into clinical trials sponsored by the NIH. They approached us with a mechanistic rationale, did some preclinical work. It seemed to work there. We allowed the NIH to open up that study on an IST or IIT type basis. You know, whenever you arrange that design for a trial, the company gives up control over the timing, basically. I don't think there's any center that's better suited to do this than the NIH because of their experience in this patient population.
At the same time, you know, we're not really privy to exactly how things are progressing. We think we have a great partner. We know they're working very hard on this, but it's always been kind of a side project for us that's, you know, relatively low expense and would be a great outcome if we see success in the end. I don't think anything's really changed. If we're successful with that, we will then run, I think, a small sponsored study that would drive approval. If it's not successful, we'll just simply shut that, shut that approach down. At this point, I think our focus, we're able to focus entirely on the EPP, you know, regulatory process and launch preparation.
You know, John and Jean, one thing is that you've taken, you know, your planned launch timing was probably like in 2028, and now we're thinking about it taking place next year. Maybe how does that change things operationally for the company? Maybe some thoughts or an update in terms of where you are in terms of building out your commercial infrastructure.
Yeah. Jean, do you wanna take that one?
Yeah, it's a great question. It is, it's fantastic to be accelerated, but it comes with a good set of problems, and I think we're navigating those quite well. We hired our Chief Commercial Officer over a year ago, so she's been at work and planning for this launch. We have our marketing team basically on the ground now also building, for the launch. We are, you know, we're not getting ahead of our skis. We're putting in investment, to be phased with our interactions with the agency. We are continuing to be ready to build the field, field force in later when we understand our PDUFA date. I would say right now we are just deep into the market details, connections with KOLs. Our MSLs are in place, so we are ready to launch.
The area where we've really accelerated work, which is the natural thing to do in these cases, is CMC. We put a lot of investment there and we've de-risked and really aligning with the agency on an accelerated plan that matches what we can achieve in this timeline. We feel pretty confident. Right now the goal is to get into our pre-NDA meetings and get the NDA on file in the second half, and we are planning to launch in the U.S.
Okay. And you may be now turning to some of your other pipeline assets. You recently hosted a KOL event on, on DISC-0974, which is a monoclonal antibody, which is intended to reduce hepcidin levels and, and treat anemia in, in patients with myelofibrosis. You know, what gap do you see it filling in the MF space? And how do you expect it to potentially sort of match up with luspatercept, which is a drug you're very familiar with?
Yeah, we're really excited about DISC-0974 and its potential in myelofibrosis and also chronic kidney disease. We ran a 35-patient dose escalating study, really showed great data across essentially all range of anemic patients. And, you know, I think part of the point of that KOL day was to help people understand that anemia is an important and direct consequence of myelofibrosis. It is associated with mortality, and addressing anemia is an important therapeutic objective in these patients, right? I think a lot of the investor community has been trained on programs like momelotinib, pacritinib, pelabresib, all focusing on addressing spleen size and symptoms in these patients, which are also very important therapeutic objectives. I think lost in the noise is that there is actually no approved therapy to manage anemia in myelofibrosis patients, and it is an important objective for these clinicians.
When you ask how do we anticipate our drug fitting in, our goal is to have this be the drug of choice that people turn to when they have a patient who's anemic with MF. By the way, it's close to 90% of patients with myelofibrosis are anemic. It is often the symptomology that gets them, you know, drives to the diagnosis. We think our safety profile has been great. In fact, you know, we know that human knockouts of this target are generally benign. We think this is the kind of thing that we would hope, you know, we see good data in the earliest stage patients. We would hope that as soon as a patient is diagnosed with this disease and has anemia, physicians would reach for this therapy once we've proven it out.
That would be something they would stay on, and that would allow them also, I think, improve their ability to tolerate some of the drugs that are used for managing spleen symptoms.
And so what you mean by that is sort of a lot of MF patients are ultimately sort of suboptimally managed, right?
Correct.
Currently they're treating, especially with their treatment with a JAK inhibitor. This would perhaps, you know, allow them to, to sort of undergo, not only do you treat the anemia, but you, you sort of allow better treatment of their underlying disease.
Correct. You asked about luspatercept, right? Of course, the drug I know well. It is now being studied in a phase III trial that I think we understand is likely to read out this year. I think with that drug, the phase II program showed that it really only worked in the latest stage patients and only in combination with Jakafi. They are going after a relatively narrow subset of the late stage patients. Our objective is, you know, wish them luck. Hopefully it proves out in these patients. I think our objective is to provide a drug that can be used basically day one from diagnosis and then allow just management of anemia, all of its symptomatology, while, as you said, allowing optimal therapy with other agents as well.
One of the things that you've shown early on is sort of responses across all types of patients of MF.
Correct. Correct. You know, the weight of our data is actually from those earlier stage patients. The current trial we're running is designed to kind of get, expand enrollment across the three kind of identified categories of patients: the non-transfused, the lightly transfused, and the heavily transfused.
I did also wanna touch on sort of your development plans in treating anemia in CKD patients, non-dialysis dependent patients largely. You know, what was, and that program's in much earlier stages of development, but I'm just curious, what was most exciting to you from the data that you've released so far?
Yeah. So that program, like you say, about a year behind the myelofibrosis program, we shared the first three or four cohorts from our single ascending dose at the ASN Kidney Week conference last fall. We did not share the top dose, 'cause we did not have that data yet. At the 40 mg and 60 mg doses, you know, we are seeing about 1/3 of patients showing a meaningful response, which would be meaningful in a single dose study. You are talking about just looking for something in the ballpark of 0.8-1 g per deciliter increase in hemoglobin. So seeing about 1/3 of patients responding with one dose, that is not a bad starting point.
I think the objective in the end is to see, either all patients, you know, the average of all patients arriving at that 0.8-1 g per deciliter range, or identifying a subgroup of patients, 'cause this is an enormous patient population. Subgroup is perfectly acceptable and may even be more efficient. You know, either seeing all patients or a subgroup, identifiable subgroup achieving that type of hemoglobin increase and, you know, seeing we're at 1/3 with one dose with some room to go up higher, knowing multiple doses, you know, in MF, we typically see responses after about two months on therapy. You know, I think puts us in a good position as we run this multiple dosing study.
One of the things that struck me was that we saw very robust improvement in reticulating hemoglobin levels.
Right.
Doesn't that bode well as you go into multiple doses and longer duration of treatment?
It does. Yeah. I mean, that shows you the mechanism is engaged. That's the primary way, you know, this works by mobilizing iron. When you mobilize iron, you make that more available to form heme and hemoglobin. The primary way, you know, if you look at something like EPO, it typically works by increasing the numerosity of red blood cells. The primary way that our drug works is by increasing actually the hemoglobin that's in each cell so that each cell can carry more oxygen around the body and resolve the anemia symptoms. Yeah, seeing that engaged in those precursor cells, the reticulocytes, is a great sign, bodes well for future data.
Okay. I think we're pretty much out of time, but I did wanna ask you to just review quickly maybe some of the timelines for 0974 over the next 12 to 18 months.
Twelve to eighteen months. Sure. So coming into the end of this year, we expect to have MAD data from our CKD trial. We expect to have a cut in time, a slice in time from the phase II myelofibrosis study. Then, you know, if all goes well, we'll be starting phase II in CKD. And next year we'll have what should be top line data from the phase II myelofibrosis study. If that goes well, then we progress into a pivotal trial, which we would ballpark the precedent here would be about 200-300 patients trial size.
Great. With that, I think we'll have to wrap up, but thank you so much. It's great hearing the update and congrats on all the progress.
Yeah, thank you. Great to be here.