Great. Good afternoon, everyone. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name's Tom Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to welcome our next company to the stage, Disc MediScenesse. I'm happy to be joined by CEO John Quisel, CMO Will Savage, and CFO Jean Franchi. Thank you all for joining us. John, for those who are maybe a little bit less familiar with the Disc story, maybe you could just kick us off with some introductory remarks and kind of like a state of the state of where Disc is today.
Sure. Great. Yeah. For those who don't know us, we're a company focused on controlling red blood cell biology by controlling heme and iron metabolism, those heme and iron being the fundamental building blocks of a red blood cell. It turns out you can manipulate a lot of how red blood cells form and function in the human body and in disease using these tools. We have a portfolio of three clinical stage programs. The lead program called bitopertin is a small molecule designed to control heme biosynthesis. We're taking aim at a rare disease called erythropoietic protoporphyria, or EPP. With this program, we've completed a phase 2 program. We're now in an accelerated approval pathway with the FDA, guiding generally to an NDA filing in the second half of the year. A very exciting year for that program as we move through the regulatory process.
Behind that, we have a pipeline of programs that control iron metabolism. There, DISC-0974 is in a phase 2 trial in patients with anemia of myelofibrosis. We're generally looking to treat a very large area of anemia of inflammation. We have an initial study running now in patients with anemia of chronic kidney disease as well. Finally, the third program is looking at iron restriction. First and foremost, as a way of managing polycythemia vera, this is an area that's been validated, for example, by recent positive data from a program called rusfertide, coming out of Protagonist and partnered with Takeda. We think that the approach we're taking may provide a really nice both therapeutic benefit, but a very favorable profile for patients as well. That program has completed phase 1.
Essentially, we have a portfolio with a rare disease lead, heme-onc, second and third assets, and then a giant indication space in the anemia of inflammation and chronic kidney disease.
That's great. I want to start by double-clicking into bitopertin and received some important regulatory feedback in the second half of last year that kind of opened the door to this accelerated approval pathway. Maybe you could just discuss some of the regulatory dialogue and how FDA has become comfortable with PP IX, the biomarker PP IX, as a surrogate endpoint potentially for approval in this patient population.
Sure. Yeah. As I'd mentioned, we completed our phase 2 program in EPP last year. Primary endpoint was looking at the reduction of protoporphyrin IX, which is the chemical that builds up in the body of these patients and causes all of the sequelae of the disease. Phototoxicity being the day-to-day problem these patients face. Long term, there is a buildup in the liver that can lead to liver failure. All of that is caused by protoporphyrin IX or PP IX. As our primary endpoint, we hit very clear reductions in the ballpark of somewhere between 40% and 60% reduction, which is a level that should lead to major clinical improvement.
In fact, if you look through all of our clinical endpoints in the phase 2 program, we were numerically favorable on all of them and prospectively stat-sig on several of them, including the rate of phototoxic reactions, which is very important for these patients, and then also PRO, quality of life type metrics. That package, being able to share that with the FDA, showing them that not only are we improving on all clinical endpoints and reducing protoporphyrin IX, but in fact, the PP IX level reduction is associated with improvement on those clinical endpoints. That is the touchstone for getting into an accelerated approval pathway. We presented that data. The FDA said, yes, this is interesting. Protoporphyrin IX could serve as a surrogate endpoint to support an accelerated pathway.
Importantly, they aligned with us on all the basic attributes of the next trial, which we thought was going to be a phase 3. Now it is turning into a confirmatory trial under the accelerated pathway. They said, please come back for a Type C meeting to talk about the feasibility and design, statistical design of your confirmatory trial. We had that meeting in December, came out with the results after we got the minutes in January. Again, complete alignment. Trial design is solid. The FDA is very concerned nowadays with sponsors' ability to actually complete their confirmatory trial. They wanted to probe that with us. Our projection is that we can enroll this trial readily. There are a lot of patients waiting for access to this therapy. We were able to present all that information and reach alignment on the confirmatory design.
Next steps for us are getting that confirmatory trial up and running. We call it the Apollo trial, guiding that that should happen before the middle of the year. We aim to get the NDA filed in the second half. That's kind of the arc of the story.
That's great. I guess, are there any outstanding data items with respect to the NDA filing or what's kind of the gating steps to filing the NDA?
Yeah. The data components will be the phase 2 program. That data is already in hand. We also had about 85% of patients roll onto a long-term extension study that we call HELIOS. The request there was that we would take a safety data cut from that long-term study to provide as big a window of safety information to the FDA as we can. That would be one new piece of information that goes into the NDA filing. The other gating factors are having an end of phase 2 CMC discussion with the FDA to ensure that they're aligned with how we're conducting the last stages of our commercial preparedness on the CMC side, which has had to be accelerated to some degree in order to capture this opportunity. The next step after that would be the NDA.
Got it. On that CMC front, is there anything, I guess, that is, I mean, this is a small molecule manufacturing, just like anything that is particularly different or complex than how we would think about, I don't know, any other sort of CMC activities preparing for an NDA?
No, there's nothing complex. The synthesis is simple. The molecule is quite stable. The tablet formation is also routine and quite stable as well.
Got it. OK. You mentioned patients from the phase 2 studies, BEACON and AURORA, rolling into open label extension HELIOS study. Are there, I guess, plans for presenting a look at that long-term extension data to the street?
Yeah. We haven't guided to that specifically, but it should become available at some point to present over this year. Yeah.
OK. Yeah. I guess, what would you kind of envision presenting from that? I imagine it is very different following these patients long term versus the placebo-controlled or even the open label experience, having them fill out kind of like daily diaries.
Right. I mean, that's the thing. So protoporphyrin IX, very important clinical data output. That's objective, derived from laboratory blood test. That we can continue to monitor in the long-term extension. We'd be able to provide that information to investors and at a scientific conference. Safety also, of course, you monitor that. Those two pieces we can get from long-term extension. Other endpoints like tracking how much time these patients are spending in light, their kind of quality of life, these things come from kind of diary keeping where it's hard to maintain that compliance in the setting of a long-term extension study. We wouldn't really expect to have that kind of data coming out of that. PP IX, safety, that would be what we get.
Understood. OK. Let's talk about the, you receive feedback this year regarding Apollo, basically locking in the Apollo phase 3 design. Maybe just talk about the patients that you're targeting, I guess your enrollment strategy to drive patient enrollment into that study, number of sites, and I guess how you think about the timeline for that study and data set relative to NDA filing, potential approval, commercialization.
Right. Right. Sure. Will, do you want to take that one?
Sure. The Apollo study is going to look a lot like our AURORA study, same patient population. We have a lot of enthusiasm. The word about bitopertin has gotten out in the community. I think enrollment is going to, we project is going to go well. Studies in EPP generally take about 12 months to enroll. We do not anticipate any issues there. We are going to make Apollo a global study. We are going to have 20-30 sites. It is still being finalized now, but it will be U.S. and Europe, Australia, where we ran BEACON.
Great. I guess let's talk about market opportunity.
Sure.
There is one approved therapy for EPP today, Scenesse. Does not appear to be getting a lot of uptake, obviously, like a lot of product, feels like product-specific considerations with that drug. Could you talk about, I guess, some of the market sizing work that you have done and how you are thinking about initial targeting of prescribers and patient population?
Yeah, sure. Right. Genetic evidence would suggest about 20,000 patients in the U.S. Diagnosis is routine, right? A simple blood test for PP IX. One thing that was really revolutionary for our commercial approach is discovering that there's an ICD-10 code for EPP. It allows tracking of claims, health care claims for treatment of this disease. We're able to go to claims databases and find that there are about 14,000 patients in the U.S. who have made claims where there have been claims made for health care of EPP. That probably defines the window of patients. This code's been there for seven years. It's a look back of about seven years, about 14,000 patients who've received care for EPP. That's fantastic. That comes linked to the physician who made that claim, which essentially gives us a roadmap.
Looking with more detail into that roadmap, we see about 6,000 of those patients who either because of the recency of their care or the multiplicity of claims, we consider to be quite engaged in their health care for their EPP disease, right? I mean, I think one of the issues that's fairly intuitive here is while this sunlight tolerance is something that patients have to deal with every day, so there's potentially a great drive to get therapy, it also forces patients to adjust their lives, right? Because they really have no therapeutic remedy right now. Most of them have found ways to adjust their lifestyle to avoid the consequences of the disease as much as possible. Some patients have kind of taken themselves largely out of the health care system.
We see these 6,000 who are clearly engaged, clearly looking for treatments, visiting the receiving narcotic prescriptions. Clearly having a rough time of it. We think they're going to represent a really great launch population. That is where we're really focusing our launch, trying to identify all the physicians who are providing this kind of care. We're obviously already aware of the top 20 or so centers, and we're trying to move out from there. We think that can make a very nice launch. We're really dedicated to try to bring this drug to as many patients as possible.
That makes sense. I guess within this sort of initial target, 6,000 patients, do you have a sense of how many of them exist within these 10-20 centers of excellence in the U.S.? I guess how easy do you think it might be to target these patients, get access to these patients? Maybe building on that, if you could just talk about how you're thinking about resourcing commercial infrastructure, how many sales reps do we need?
Yeah, yeah. We're assembling the numbers of the centers and kind of the centers that feed into those, right? Because we can start to map out those relationships. I think importantly right now, we can say that about 25-35 field-facing representatives that combine sales reps and MSLs. We believe that will provide us easy coverage of those initial 6,000 or so patients.
OK. It's a very modestly sized sales force. Seems very doable for a biotech with your resources. That's great. I guess lastly on bitopertin, just the competitive landscape. Alluded to Scenesse, don't really see as much of a competitor. We have dersimelagon. Maybe you could just speak to, I guess, the latest on dersimelagon and how you think about kind of where you are in development relative to that compound and the profile, obviously, of your compound versus dersimelagon.
Right, right. Like you say, there's one approved product, Scenesse, works by a tanning mechanism, requires a surgical implant, sees relatively light use in the community because I think access problems, et cetera. Following that concept, Mitsubishi Tanabe has developed dersimelagon as an oral tanning agent. They ran a phase 3 trial, which did not meet its endpoints. They've gone back to try again with a second phase 3 trial. That's in process now. We don't have any information about when they'll get to final data readout.
Understood. All right. Let's shift gears and talk about DISC-0974. You presented some, I think, really nice data at ASH in myelofibrosis. Previously at ASN, you had presented some data in NDD CKD. Maybe just remind us of the mechanism, like what you're looking to do here. Within the myelofibrosis study, we've launched into a phase 2 dose expansion portion of that. I guess building off of the dose escalation data, like what are you expecting to see in the dose expansion portion of the myelofibrosis study?
Yeah. In broad strokes here, we're kind of picking up where the ESA EPO class of drugs had to retreat from a broad swath of patients because it required higher and higher doses, right? That eventually led to cardiovascular adverse outcomes. Now you see EPO use restricted to patients who are probably EPO deficient, which makes some sense. I think the learning from that was that a lot of patients are anemic because of problems with their iron dynamics, right? You can't make a red blood cell unless there's an adequate flow of iron in the bloodstream to the bone marrow. That's measured by looking at serum iron levels.
I think what we know now is a lot of patients who don't respond well to EPO have something called anemia of inflammation, which is they have a chronic disease that causes sequestering of iron in the body. What was discovered is a central hormone called hepcidin that controls the availability of iron inside the body. People have tried then, it's become a very interesting target, to manipulate hepcidin. In our case, what we're looking to do is decrease it as a way of releasing iron from internal stores to address anemia in patients who have chronic inflammatory diseases. That's the core premise of the program. Others have tried before, generally failed for lack of efficacy. Our target was genetically defined from humans who have a loss of function as being probably the most powerful target for controlling hepcidin.
That is what we have seen in the clinic now. For the first time, we saw in healthy volunteers, actually, you could mobilize iron and increase hemoglobin levels. That is kind of the therapeutic target for an anemia drug, to increase hemoglobin. Seeing it in healthy volunteers, that was remarkable. We moved into myelofibrosis, a severe hem-onc type indication where you have really significant anemia. It is known to be a highly inflamed disease state. Relatively recently, it was discovered by the Mayo Clinic that these patients have very high hepcidin levels, probably driven by that inflammation. The theory was maybe we could use this as a kind of starting point in the journey of finding a treatment for the broad anemia of inflammation field. Let us start in myelofibrosis.
There's probably about 25,000 patients in the U.S. with this disease, of whom around 90% or 80% are anemic and in need of therapy. It is a pretty good rare disease market. There is no approved drug at this point for the anemia in these patients and well recognized by clinicians as an important unmet medical need. We did a ran a phase 1 B trial, did some dose escalation, enrolled about 35 patients in active dose groups, and showed a response rate that was really quite remarkable, around, call it a 50% response rate. Importantly, we saw that response rate across all patient populations here. Whether you're not yet receiving transfusions, receiving a few transfusions, or heavily transfused patients, and whether you're on or off the mainstay therapy called Jakafi, which has some hematologic effects and therefore is of interest.
Anyway, with our drug, we see basically the same response rate regardless of which segment of patients you're looking at. That now sets up for us an objective of creating just a generally available, readily combinable, we're talking about a subQ antibody delivered once per month at a pretty low dose, hopefully with a great safety profile that can be combined with anything. Regardless of what therapy you're on to treat other aspects of the disease, like spleen size and symptom score, you can add our drug on to try to ameliorate the anemia. That's the goal. We have set a phase 2 program in place to essentially reinforce the data we've seen in our first 35 patients, now in a body of 100 patients, and just prove out that the effect size is roughly the same and set up a pivotal trial.
Understood. You have guided to initial look at the phase 2 data towards the end of this year. I guess what can we expect in terms of patient numbers? I guess what are you seeing in terms of early enrollment into that study? Are we enrolling? Does it skew more towards high transfusion burden, low transfusion, non-transfused? Just help us kind of frame expectations for what to look out for in the second half of the year.
Yeah. Will, do you want to speak to that?
Sure. I mean, anybody is eligible, of course, to come into the study. We're not guiding specifically to what patients are coming in at this early point. This phase 2 just opened in December. What we're going to present in the second half is, since it's an open label study, an interim look at the endpoints that we've been talking about, hemoglobin and transfusion burden. The trial is six months once you're on it. We will have some patients who will have completed six months, but a larger number of patients who will be somewhere in the middle of their treatment. It'll just be wherever we are at that data cut.
Are we still dosing patients from the phase 1 B experience? Will there be, I guess, additional learnings from that patient population with respect to durability?
Yeah. We have, in fact, a majority of patients who continued on the continuation phase in the study in the 1B. We have not planned a specific data cut on those continuation. It is a different part. We will have to think about whether that is possible for the second half of the year.
Got it. I guess on the radar for a lot of investors this year, there's a phase 3 study for luspatercept in transfusion-dependent myelofibrosis. I know you're quite familiar with that compound from your Acceleron days. Maybe just what are you guys expecting to see out of that study, I guess, on the basis of the phase 2 data? The data that you've generated to date, you're seeing consistent efficacy outside of that transfusion-dependent population. I guess where do you think luspatercept kind of fits in relative to 974?
Yeah, right. Luspatercept is our primary competition here. I guess the important thing to frame right at the outset is while we're seeing good efficacy across all subsets of myelofibrosis patients, the Luspatercept phase 2 trial showed good efficacy really only in one category of patients. That's patients who are heavily transfused and on Jakafi for reasons not really understood, the drug. These patients don't seem to work unless it's also paired with Jakafi. That subset is the subject of the phase 3 trial that should read out sometime this year. We'll see. The phase 2 response rate was a little bit north of 30%. I guess the best prediction would be they'll see a response rate of about 30% on active therapy. That conventionally would be viewed as a response rate that should distinguish itself from placebo.
Probably we'll see some decent data there. Who knows? I don't have any special information about that. I think the important thing is our response rates look broadly, maybe numerically higher than that at this point, although admittedly on less data. We think we're going to have a great therapy, and importantly, for all patients versus just this one subgroup of patients.
That makes sense. If we move over to CKD, where we've seen some SAD data, you've guided towards MAD data in the back part of the year. I guess what's your expectation for the evolution of the product profile in CKD as we move into multidose data?
Yeah. The goal here in the very long run is probably to get to a place where you have an average response of about 0.721 g/dL increase in hemoglobin in response to our drug. CKD is known to be a disease with very high levels of hepcidin. The non-dialysis population is no different. It represents about 6 million anemic patients in the U.S., so a huge market. What we've done so far is single ascending dose work. One dose at doses of 28, 40, and 60 mg, fixed dose, subQ. At the 60 mg dose, we saw about 1/3 of the patients responding, getting about 1.5 g/dL . It's very nice as an individual response. As a mean for that group of six patients, for what it's worth, it was around what, 0.6 g/dL ?
Hanging just below what you'd say is your target. I think we feel a pretty high degree of confidence that as we go to a higher dose and then start to add multiple doses, we'll see that response rate get up into the range of what you'd be looking for to have a drug that could potentially be developed to treat anemia in all of these non-dialysis CKD patients.
Got it. Assuming that the MAD data shows you a signal in the ballpark of what you just outlined, what can we think of as next steps for that program? Eventually, how are we thinking about potential registrational programs in a massive market opportunity like CKD?
Yeah. We haven't given a lot of guidance to what the phase 2 program looks like. That would be what comes next. I think in our minds, it would be a study in the ballpark of 50-100 patients to try to prove out in a very thorough way the hemoglobin benefit for these patients and kind of set up late stage development.
Got it. Maybe just lastly on 974, you presented some very nice preclinical data at Ash from an IBD model. I think on the mind of a lot of investors is where else can we take 974? Maybe just walk through how you're thinking about indication selection and when we could have greater visibility into sort of next steps outside of myelofibrosis and CKD.
Yeah. Like you said, the mouse model for IBD performed exceptionally well with this drug. We saw a 6 grams per deciliter increase in hemoglobin and even saw some amelioration of the underlying disease, which is something we're digging into. There are some interesting connections between iron and inflammatory states and hepcidin as well. We're pretty excited about that. I think it represents an area of significant unmet need. I think if you talk to these patients, they are experiencing fatigue. They're aware of the anemia that they have and would welcome a therapy like that. We haven't committed to exactly when or the design of a trial in IBD anemia. We're also thinking about other inflammatory diseases. I mean, essentially, any autoimmune disease is going to come with anemia of inflammation as well.
In general, it's not being managed anyway because EPO is no longer used in these populations. We think there's a lot of expansion possibility. We're trying to think about what's the most efficient way to kind of bring as many patients as possible the benefits of this therapy.
Got it. That makes sense. Shift gears and talk about 3405. You alluded to the rusfertide data. I guess just want to come back to that, maybe double-click on that. You called it validating, but I guess specifically, what were the most impressive parts of that data set from your perspective? How does that read through to 3405 and the mechanism and what you guys are working on?
Right. I think the general category here, rusfertide is a hepcidin mimetic. If you deliver that to a patient, it will cause a decrease in iron availability. The premise here is in polycythemia vera, you're trying to decrease the overproduction of red blood cells. The standard of care right now to accomplish that, it's framed in terms of achieving your hematocrit goal. You want hematocrit of 45% or less to avoid the risk of cardiovascular adverse events. Phlebotomy is the standard of care right now, where you just literally draw off iron by taking away red cells and eventually drive the patients into a state of iron deprivation. When you reach that state, you can in fact control the hematocrit. That's the standard of care.
I think what's fascinating about what the team at Protagonist has shown is that with a hepcidin mimetic, what you're doing there is you're not taking iron out of the body. You're simply reallocating it within the body out of the red blood cell compartment. When you do that, what they've shown in this phase 3 that just read out is you are able to achieve ideal hematocrit levels therapeutically without phlebotomy. In doing so, the patients are spared the experience of iron deprivation. They hit on two. We don't know the numbers yet, but they hit on two quality of life scores showing that there's really some measurable benefit to allowing patients to keep the iron in their body and control their hematocrit by reallocating that iron. That program requires roughly once weekly subQ injections.
Our approach with a standard type antibody against a target called TMPRSS6, we believe can achieve the same kind of iron restriction, but now with something like a once monthly subQ injection that we think will be beneficial for patients.
That's great. We've seen some initial data there. You're getting ready to start a phase 2 in PD patients. Yeah, just remind us, I guess, of what you saw in the phase 1 and what gives you confidence in the target and the mechanism and what you're doing there and what you expect out of the phase 2.
Yeah, Will, you want to speak to that?
Sure. We saw dose-dependent increases in hepcidin and reduction in serum iron. That led to evidence of restriction of red cell production in healthy volunteers, which is exactly the PD you want to see before you bring it into PD patients.
Understood. You have also presented some preclinical data in sickle cell.
Yeah.
How are you thinking about that particular opportunity and I guess other indications that you could tackle with 3405?
Yeah, there's a fascinating story they're developing in sickle cell disease. It sounds like coming from left field. I think for people who've been thinking about sickle cell disease, fetal hemoglobin is the kind of mechanism of choice, some of these gene therapies we've seen. Behind the scenes, there's been this growing experience first in Europe and now in the U.S. that phlebotomizing these patients can lead to clinical benefit. The mechanism by which we think that's working is, again, achieving this state of iron deprivation. You actually diminish the hemoglobinization of red cells. It's that concentration of hemoglobin S that drives the sickling reaction with very high order kinetics. The thinking is that there's now all this clinical experience showing that phlebotomy and iron deprivation can lead to clinical benefit in sickle cell patients. We're very interested.
We saw good results actually in a mouse model in seeing whether this kind of approach can work with an iron-restricting type drug rather than phlebotomy. Stay tuned. We haven't yet committed to when that'll happen, but I think it's one of many intriguing next indications for this iron restriction mechanism.
Yeah, very interesting. I know we're up against time, but we just talked about sort of like pipeline and a product opportunity across each one of these assets. I guess just remind us capital resource-wise, like where are we with cash now? Are we thinking about resourcing each one of these programs?
Yeah, great, Jean.
Yeah, the company is well capitalized. We have cash into 2028. That's on the back of ending the year at $490 million. We also did an offering in January bringing in a gross of $259 million. That funds us well past bitopertin commercialization in the U.S., but we're not including inflows from that in any of our runway. Most importantly, of all the programs John and Will discussed, we're funding all of them to the next level and beyond for proof of concept. We got a lot going on, but we're well funded to deliver it.
That's great. Certainly a lot going on. Yeah, unfortunately, we're a few minutes over, but we will certainly stay tuned to the Disc story. Thank you, Disc team.
Thanks, Tom.
Thanks, Tom.