Morning, everyone. I'm Tara Bancroft, one of the senior analysts here at TD Cowen. Thank you for joining us for TD Cowen's 45th Annual Healthcare Conference. For this next session, we have Disc Medicine here, and from the team, we have John Quisel, the CEO, Jean Franchi, the CFO, and Pamela Stephenson, the CCO. We're starting with a presentation that John Quisel will be giving, and we'll do some Q&A after. John, you can take it away.
Great. Thanks, Tara. Great to be here. Really enjoying the conference, and so I think, you know, many folks are quite familiar with the story. We've been public. I think this will be our third year as a public company, trading under the ticker symbol IRON, market cap, you know, hovering around $1.9 billion, but there are also folks who are new to the story, so I'll give a quick overview, touch on some of the things that are current, and then we'll go to the questions. All right, so there will be forward-looking statements. These should be taken in context with our securities filings and things on our website. We'll talk about our three pipeline programs: bitopertin, DISC-0974, and DISC-3405. None of these are approved in any jurisdiction, so Disc Medicine, we are a company focused on red blood cell biology.
Our approach is to use mechanisms that are highly validated in humans, either through genetics or extensive clinical experience, to control red blood cell biology, and we're doing this with molecules that regulate heme and iron metabolism. These are the fundamental building blocks of red blood cells. And we believe, and we're starting to show in the clinic, that we can manipulate red blood cell biology across a wide range of diseases, so you'll see that our pipeline, and it's kind of shown along the bottom, we're able to take aim at, you know, in our lead program, rare diseases on the left-hand side, like erythropoietic protoporphyria, and then we have pipeline products that go all the way up to very common large markets, like the anemia of chronic kidney disease.
The unifying theme is that all of these can be addressed by controlling red blood cell form and function through the control of iron and heme metabolism. That's the overall theme of the company. This is our pipeline chart. The lead program, bitopertin, is a small molecule. It's taken once daily, very convenient. It was developed at Roche. We licensed it after they had done 4,000 patients' worth of clinical research. We have an enormous safety database for this program. It's well established in humans that it controls heme biosynthesis. We took that over under our own IP, directing this molecule to treat a disease called erythropoietic protoporphyria. There, as you'll hear in a moment, we're starting up what we believe will be a confirmatory trial called the APOLLO trial, as we're heading down an accelerated approval pathway.
We also have a small IIT and a rare anemia called Diamond-Blackfan. I'm not going to talk about that today. Our second pipeline program is an antibody. We license it from AbbVie. We're in now a phase II trial to treat the anemia of myelofibrosis. The overall objective here is to treat what's called the anemia of inflammation, which is a very broad indication space, essentially anemia caused by the inflammatory disease taking place in many different kinds of patients. Myelofibrosis is our starting point. We're seeing very nice activity in our initial trial data and looking to expand that success in phase II now. And then meanwhile, we're in earlier stages with very large indication of the anemia of chronic kidney disease, looking at the non-dialysis population. So that's the second program in our pipeline. We also have a long-acting antibody as well called DISC-0998.
That's in the pre-development stage. I think that's going to create an opportunity to pick apart this very large market space that we have in front of us and also provide some lifecycle management. And then the third program, which actually we're super excited about, DISC-3405, it's an antibody against a target called TMPRSS6. The goal here is to create iron restriction. We've seen just recently very positive data in polycythemia vera from a molecule called rusfertide. It's Protagonist now and Takeda. So it, you know, looks like it has the attributes to be a really important therapy for polycythemia vera, which is a fairly large Heme-Onc indication, actually pairs nicely with myelofibrosis. And we think this antibody is going to provide essentially a best possible presentation for those patients.
So we've completed a successful healthy volunteer study there, and we're looking to start up our trial in polycythemia vera patients this year. So that's the pipeline, you know, kind of late stage and the lead rare disease program, and then substantially larger Heme-Onc and anemia of inflammation type indications, you know, hanging around phase II. And all this, you know, accomplished from a Series A that was five years ago, so where we were entirely preclinical. So I think we've got a great track record of execution and operation as a company. In terms of just detailed catalysts for this year, first half, right? So for bitopertin, a lot of the catalysts are about progressing through the regulatory process, less about data this year. We've already had positive feedback from our Type C meeting with the FDA. That was actually the springboard to a financing we did.
We're actually now in great financial shape. We have runway into 2028 to execute across this whole portfolio. So we've already checked the box on that first catalyst of the year. We're looking to get our confirmatory APOLLO trial started in the first half and then get our NDA submitted in the second half of the year. I think there's substantial value creation to be had just from that lead program if we're able to hit all of that. Then the second program, anemia of myelofibrosis and chronic kidney disease, you know, broadly speaking, we're running those trials. It's an operational year, and we'll have a data cut from both programs as we come into the second half of the year. And then 3405, as I said, we'll be starting up the phase II study in polycythemia vera. Strong cash position.
And I guess one other thing to highlight is all of these have broader indication applications at ASH. Just last December, we had some preclinical data showing very nice effects of DISC-0974 in anemia of inflammatory bowel disease and DISC-3405 in patients in a mouse model of sickle cell disease, where iron restriction, I think, is an exciting emerging approach. So we're also looking to start thinking about placing bets on additional clinical areas based on that preclinical data. So, you know, a lot going on this year, essentially regulatory progress on the lead program in the porphyria, clinical progress on DISC-0974, the second program with data coming second half, and, you know, getting started phase II studies going on the third program. So that's the menu for the year. How are we doing on time?
Okay, so I'll touch briefly on the science and market for the lead program, bitopertin. As I mentioned, this is a heme synthesis modulator that we licensed from Roche. It comes with a huge safety database, excellent safety profile, by the way. So erythropoietic protoporphyria, EPP, a rare disease hasn't drawn a lot of attention in the biotech space yet. There is one approved product, but it is really a severe disease, very high unmet medical need. And I think a lot of patients actually who really need therapy. So it's lifelong, presents early in childhood, derives from a genetic defect in the last step of heme biosynthesis, which causes the buildup of a toxic molecule called protoporphyrin IX, or PPIX, as we call it. And that toxic metabolite, it's toxic because it does two things. One, it absorbs sunlight energy and causes intense burning inside the bodies, right?
This stuff is in the blood. When the blood is exposed to light, it becomes active, causes nerve damage, extensive pain. Really, that causes patients to live their entire lives out of the sunlight. It changes patients' entire life trajectory on a daily basis. Then also quite severe is that it builds up in the liver, causes damage to the hepatobiliary system. About a third of patients have evidence of liver disease, gallbladder removal, things like that. All of those patients are at risk of converting into liver failure. It's a rare complication, 2%-5% of patients, but extremely dangerous, obviously potentially fatal complication of the disease and essentially a risk for about a third of the patients every day. Quite a severe disease, and this has been recognized by regulators and, frankly, by payers as well, at least in early testing.
There's no cure or disease-modifying treatment for these patients. There's one approved drug called Scenesse. It's implanted through a surgical procedure that has to be done every two months, and it works by causing tanning. So we are coming in with bitopertin to try to reduce the levels of protoporphyrin IX, right? So we're going right to the root cause of the disease. And the way this works, this is the heme biosynthetic pathway. I'm not going to go through it in detail, but basically, it all starts with glycine. Glycine comes into a newly forming red blood cell. It's processed into protoporphyrin IX, you see in the middle of the slide, and that ultimately turns into heme. When you jam that last enzyme, ferrochelatase, because of a genetic mutation, PPIX builds up and becomes toxic, causing the sunlight sensitivity and the liver damage that I already talked about.
So what bitopertin does is actually block the flow of glycine into newly forming red cells with the intention of reducing PPIX levels. And at this point now, we've shown that in cellular models, in mouse models, and now quite convincingly in both open-label and randomized controlled clinical trials. So the mechanism is trying to reduce the level of PPIX, which is the chemical that causes this disease, and we've proven in the clinic that our drug does that. So it's a great place to be, and with a, you know, really no major safety findings at all. And like I said, it's a meaningful rare disease market. And so we're very fortunate here because this patient population is quite organized. There is one approved product that is really used very lightly, I think, because of that surgical implantation.
But nonetheless, it has allowed this established kind of medical framework here. So there is an ICD-10 code for this disease. It means that we can look back at claims data for the past seven or eight years. And that claims data comes with each patient linked to the physician that made the diagnosis and the treatment. So we have a very good view of how many patients there are and where they're located. And what we see is that there's a total of 14,000 patients. This is not too far off of the genetic estimate of 20,000. And of those, you know, the main challenge then for us is simply figuring out which of these patients are going to come forward and want therapy. And we think, you know, in the end, given the severity of disease, everybody's going to want therapy.
Based on either the recency or the multiplicity of which patients are seeking care, that there's about 6,000 patients that form the foundation for a very significant rare disease launch. We're super excited about that. Pamela, who's sitting here today, is, you know, working hard on building that team and fundamentally really just trying to access all of the treating physicians and activate those, you know, find those patients to provide them the care that we think we'll be able to offer. Okay, the clinical package, we've run two phase II trials, BEACON, which was open label in Australia, AURORA placebo-controlled in the U.S., total of about 100 patients, of which about 80%-90% rolled on to a long-term extension called HELIOS. This is the package today that we brought to the FDA for our end of phase II meeting.
We'll form the foundation of this accelerated approval process that we're on after a successful end of phase II meeting. And, you know, in that context, we'd be using the change in blood protoporphyrin IX as the surrogate endpoint. And that was associated with a whole suite of clinical endpoints. So to give you a quick taste of the data, this chart summarizes it very nicely at our top dose, which was safe and is the dose we'll take forward, 60 mg once a day. We showed meaningful reduction in protoporphyrin IX levels, which is the dark blue line. And really important here is that as you see protoporphyrin IX levels come down, you can see in the light blue line, patients are spending more time in sunlight, right? So that's one of the key endpoints here is having patients keep track of how much time they are spending in light.
And you see that that jumps up as soon as the PPIX levels go down and essentially just keeps going up. This is a placebo-corrected curve, so you see increasing gap relative to placebo across this four-month study, and then super significant down at the bottom is the reported phototoxic reactions. This is just raw data. Patients on the placebo group, you can see a scatter of phototoxic reactions across the study. Patients on the 60 mg bitopertin, you can see that you get to about week eight, PPIX levels come down to their new minimum, and there were no new phototoxic reactions, zero. We'll see if that holds up in our larger trial, but that kind of reduction, if we're able to eliminate phototoxic reactions for these patients, that will be a very significant improvement.
Okay, so we're targeting the underlying physiology, significant improvement in sunlight tolerance, functional benefit by reducing phototoxic reactions, and we also significantly improved how patients feel. So great package of data pushing forward on this accelerated path. I've already gone over the events, and I think I won't summarize anymore. The deck is on our website if you want to look into the confirmatory trial design. So with that, I'll touch just real quickly on the pipeline programs. These are both antibodies. Looking at the fundamental genetic control points for iron metabolism in the body, all validated by human knockouts. Our targets are known as human knockouts where the phenotype is really only changes in iron metabolism. So we think we have a strong reason to believe these approaches are going to be safe and active in mobilizing iron.
The lead indication of myelofibrosis, we presented data showing about a 60% response rate, would be the best anemia therapy going if we're able to prove that out in a larger phase II trial. So at this point, we're in 35 patients of data, moving now to about a 100-patient phase II trial. Trial design is here. And, you know, bottom line, consuming this data, you can see the goal is to reduce hepcidin, which is the control point that leads to mobilization of iron, and then that leads to hemoglobin benefits. This is data from our chronic kidney disease trial, early days here, but generally seeing good activity, and we'll have more data as we come into the end of the year. So that's that third program, trying to actually restrict iron. It's the, you know, kind of the off switch to the other also genetically validated.
We've done our healthy volunteer trials, hit all of our targets. We're moving into polycythemia vera. I think that pretty much summarizes it, and I'll stop there to make some room for questions.
Great. Yeah, thanks, John. So I think, you know, you guys have had a lot of really great regulatory updates over the last two quarters, which have been great to see. So I'm curious, what else is left to do to file the NDA? And what's your level of confidence that you will receive accelerated approval for bitopertin?
Yeah, sure. So we have, you know, we feel confident our data package is good. We have alignment that PPIX can be used as a surrogate endpoint. We had our Type C meeting creating alignment around the design of the confirmatory trial. So those two elements are aligned with the FDA.
You know, I mean, in the end, there's going to be an NDA filing and there's going to be review of the data, et cetera. And that, you know, will be what it is. But between here and there, I think the next meaningful step is an end of phase II meeting around our CMC program. Nothing out of the ordinary here. It's a very routine small molecule, but we've had to compress our, you know, manufacturing timeline from the conventional timeline by about a year or so to meet these accelerated timelines. And we just need to touch base with the FDA, ensure that that's all aligned. So I think, you know, we want to get through that. I think that will allow us to tighten up the guidance on exactly when we'll get the NDA filed. So that's the path we're on.
Okay, great.
And then I guess, yeah, yeah.
Have you agreement on what the primary endpoint will be for the confirmatory trial?
We do, yeah. So that was the Type C meeting that we had in December, came out with the press release in January. So the primary endpoint will be a combination. It's a co-primary endpoints, protoporphyrin IX reduction, which is essentially fundamental to the drug activity. We hit that with very high statistical significance. We have essentially certainty that we'll hit that endpoint. And if we don't, we don't have a drug. And then we will have also, as a co-primary, the time in light, the time the patients are spending in light during the last month interval of the six-month study.
And is that either or?
We have to hit both. So there's no powering hit. There's no statistical hit associated with that.
We feel very good about hitting the PPIX one. Obviously, the sunlight one is a more variable endpoint, and that is really the foundation of the powering calculations.
Yeah, no problem.
Yeah, yeah.
One more question on bitopertin. You'll have the APOLLO trial up and running upon, you know, by the time you expect to be launching this drug. I'm curious how you're going to be balancing enrollment versus commercial uptake, how you're going to split those patients and try and boost demand for both aspects.
I'll say first, we're going to get the APOLLO trial running by the middle of the year. That's our guidance. We don't anticipate enrollment being an issue for the, you know, eventual PDUFA date. But Pamela, why don't you address some thoughts around that?
Yes, absolutely.
So we'll have, you know, as John says, most of the patients in the U.S. and APOLLO will be up and well into the, you know, the open label portion and then easily rolled over to commercial product upon launch. And then, you know, really that's 150 patients potentially in the U.S.. I mean, our target patient population, as you heard from John, is 14,000 diagnosed patients who are already identified and then the 6,000 sort of hyper-focus at launch. So pretty confident in that.
Okay, so maybe now we can move on to MF. So I know you have the data that are coming in the second half. So how should we think about expectations for that?
Yeah, so right now, you know, we've presented 35 patients' worth of data from our dose escalation process, six-month duration, patients rolled onto or had the opportunity to roll onto an extension study. That data showed about a 50%-60% response rate across essentially every subset of MF patients, right? So the anemia there can be looked at as segmented into three buckets. And this is really what, you know, what the regulators are telling us to do is to look at the non-transfused patients, the lightly transfused and heavily transfused. And then it's also important to look at the other standard of care therapies these patients are on, typically a JAK inhibitor, ruxolitinib, Jakafi being the mainstay therapy for these patients. So we're kind of looking across three different kinds of anemia status and then whether on or off ruxolitinib.
If you look across all those categories, our response rate is pretty consistent, actually, in that same kind of 50%-60% zone. That's super exciting. The goal probably to get, you know, kind of justify a phase III trial is a response rate around 30%. We have, I mean, if we can prove out the 50%-60%, it's phenomenal. There's a lot of room to give as we go into a larger trial. We've already seen a fairly diverse population. I think, you know, we have every reason to think that response rate will hold up. The goal would be to see that continue to be broadly applicable across all these patients.
And then you design a pivotal program, really, to try to bring in anemia therapy that can be just what physicians reach for for any anemic myelofibrosis patient, which is, you know, something like 80%-90% of them are in need of anemia therapy.
I know this might be thinking ahead a little bit too much, but what would you guys like to see, you know, later on for a registrational trial? Like what would be the ideal design, you think, for this?
I mean, the design we'd love to get, probably. I mean, again, give us a chance to get our phase II data and then we'll really tell you what we think.
But based on the data we have today, I think what would be great is to be able to just pull all comers and simply measure their transfusion, collective transfusion burden at baseline and show stat-sig improvement in that on drug. That would be, I think, an excellent trial design. We know the FDA is aligned with that kind of design for any patient who has baseline transfusions. I think the question mark is patients who have no baseline transfusions. There, we know regulators are supportive of an endpoint that shows a hemoglobin benefit plus some type of symptomatic improvement, commonly fatigue. The drug is performing really well on fatigue scores in these patients so far. So that also could be, in the end, a pivotal endpoint if you want to start breaking it up by patient subpopulation.
So, you know, either one of these designs would probably work based on the data we have today, but let us get through phase II and then we can really be sophisticated about how we design this.
Okay, yeah, thanks. So next data set, anemia of CKD. So you have the MAD update also in the second half of the year. Very busy data time for you guys. But what are you hoping to see there to have confidence in moving a dose level forward?
Yeah, so I mean, it's a huge number of patients, right? Estimated six million anemic non-dialysis CKD patients in the U.S. alone, and right now, you know, in our single ascending dose cohort at the top dose we reported out, 60 mg, the study is designed to go higher, in fact.
With one dose, we saw two out of six patients responding, like getting more than a gram per deciliter of hemoglobin. So I think what we'd like to see as we come into a more, now we go to a higher dose, multiple doses, would be to see, you know, on average, the overall, the mean hemoglobin increase across all patients treated in the ballpark of 0.7 g-1 g per deciliter increase. That would tell us we have something that can be taken forward for the whole population. Or alternatively, if it's, you know, just a smaller number of patients responding well, some ability to look at baseline conditions that define those patients in the end. Either way, it's a great development program with an enormous patient population.
Yeah, definitely agree. Okay, now last question on programs is for PV.
So where do you see 3405 fitting in in the treatment paradigm, especially if, let's say, that Protagonist rusfertide is approved and maybe even a reaction to the phase III data that came out just a few days ago on Monday?
Yeah, yes.
All of that together.
Super exciting moment. And really hats off to Protagonist and now Takeda is taking that over through partnership. You know, I think the goal here with these patients was understood to be get hematocrit to 45% or below. That's the guideline to avoid the risk of thromboembolic disease, which is kind of the way you want to manage these patients, at least in the initial phases of the disease. You know, most of the patients are kind of early stage.
And so, you know, everybody pretty well, I think, knew that this iron restriction approach that the Protagonist molecule is going after and that our antibody is trying to do as well should be able to achieve that kind of hematocrit control. And in fact, they hit that perfectly well as their primary endpoint in phase III. The question was, you know, are they going to be able to make patients feel better? Because physicians are going to have a choice. Hey, I can use this phlebotomy. It's cheap. It, you know, if done right and with sufficient discipline, can achieve hematocrit control. In reality, I think it doesn't, and hence the desire for a drug. But nonetheless, you do have this choice about, well, what do I use? Do I use this phlebotomy thing? Do I use this drug?
Either way, I can probably get hematocrit under control and achieve guideline care. But what we see now is that I think what was great about the phase III data from Protagonist is that the patients actually performed really well on PRO scores, feeling better. And this now, I think, confirms a hypothesis that rebalancing iron in the body of these patients would make them feel much better versus phlebotomy, which is basically just sucking iron out of the body and leaving the patient's iron deprived, which does not feel good. This is the learning, I think, that a lot of the symptomology in this disease, which has been attributed to inflammation, disease progression, might just be the result of making people iron deprived, which isn't great, right?
So if that's, you know, now we know that, I think there's going to be a lot of interest in using this product for these patients because your choice is going to be, well, I'll make them iron deprived by phlebotomy and they will feel bad, or I can use a drug and achieve the same therapeutic objective, but have patients feel better. I think that's going to be a straightforward choice. So super exciting. I think that's going to be an important product for this pretty significant, you know, large number of patients who need therapy. And I think the TMPRSS6 approach that we're taking, and admittedly, it's a competitive space.
There are several people, you know, several companies going after that, is going to be super exciting because I think it offers probably a, you know, what may be a better profile for patients who will be able to do, you know, hopefully once monthly dosing. I think, you know, there's been some issues around injection site reactions, et cetera. All that hopefully will be cleaned up in the kind of profile that we're able to get to with our antibody. So I think it's going to be established as an important therapy in the management of this disease, iron restriction. And I think TMPRSS6 as a target is going to offer kind of the best approach to doing that.
Great. Thank you so much for that. All right. So one more minute. What do you think is the most underappreciated aspect of Disc Medicine by investors?
Interesting.
I think it's the enormous market potential and unmet need for the second program, actually, the anemia of inflammation. ESAs, EPO used to be used broadly, right? And then they found that there were cardiovascular side effects. This is, you know, decades old news, right? But kind of the big picture of anemia therapy was EPO was used everywhere. In certain patients, it required very high doses that led to cardiovascular events, had to retreat to a smaller subset of patients who had basically low EPO at baseline. And that's where it's restricted to now. And there has been no satisfactory replacement for that therapy ever, right? And so these patients basically went from having a treatment to having no treatment.
And I think there's general understanding that hepcidin is elevated in a lot of those patients and that being able to mobilize iron may, you know, provide an appropriate therapy that could kind of address that problem that went from treated to untreated because of the retreat on ESA usage. So I think there's just huge potential there with the second program.
Yes, definitely agree. All right. Well, thank you, John. Thank you to the rest of the Disc team. And thanks, everyone, for listening.