All right, let's get going. Good afternoon, everyone. It is my pleasure to introduce the next speaker, John Quisel from Disc Medicine. John, welcome. First time for me to host you at the Goldman Sachs Conference.
Yeah, thank you. Great to be here.
Turn it to you for opening remarks.
Oh, yeah. It's a great time at Disc . For those of you who don't know us, we're a non-malignant hematology company focused on manipulating red blood cell biology. Our lead program is called bitopertin, taking aim at a rare disease called Erythropoietic Protoporphyria, or EPP. We're progressing towards a projected NDA filing in the second half of the year on an accelerated approval pathway that we're discussing with the agency now.
Fantastic. So bitopertin is going after two orphan disease indications. Maybe just a little bit about overview of the two conditions, what is the metric that you guys are trying to address?
Yeah, yeah. I mean, I'd say the substantial amount of patients and investor interests are around the lead indication, Erythropoietic Protoporphyria. That is a genetic disease that arises from mutations in the last step of the heme biosynthetic pathway. The consequence of that mutation is that during red blood cell synthesis, that enzyme can't process the intermediates fast enough. The last compound of heme biosynthesis builds up to vast excess. That's called protoporphyrin-IX, or PPIX. Hence the name of the disease, Erythropoietic Protoporphyria. It's a red blood cell, excessive buildup of protoporphyrin. As PPIX builds up, the really bizarre outcome of that, it turns out to be an absorber of sunlight energy. When exposed to sunlight, it becomes a free radical that damages the surrounding tissue.
These patients, when they go out into light, and it could be, on average, about 20 minutes of light or 30 minutes of light, will trigger an excruciating pain attack where they literally feel like their descriptions are lava beneath the skin. It takes days, once they get a full attack, it takes days to resolve. We actually looked in the claims database. Many of them receive opioid therapy, for example, which is not effective. It is a really tough, life-altering condition because then the reaction to that is patients will no longer go outside ever. Even light, such as through the windows we have here, can trigger pain attacks as well. Meanwhile, protoporphyrin-IX is also eliminated through the liver, can cause damage in the bile ducts and lead to liver failure. Really severe, life-threatening complications as well.
Got it. You guys completed two phase two studies, the Aurora and the Beacon study. Both looked at the reduction of the PPIX. Can you go over why you think that the reduction levels that you guys achieve are clinically meaningful? Also, maybe just a little bit about anything else that you find in that study that you think you should be, that you want to point out?
Yeah, yeah. An open-label study, placebo-controlled study, collectively about 100 patients across the two, which is a pretty good size for a rare disease. Consistently had very nice reduction in PPIX levels, roughly 50%-60% at the 60 mg dose, good safety at that same dose. You'd predict that if you got more than about 30%-40% reduction in PPIX, you get major, if not complete, resolution of the symptomology. What we saw was, in fact, numerically, we improved the amount of time patients were able to spend in light, the number of phototoxic reactions that they have, quality of life. On phototoxic reactions and quality of life, that was actually stat-sig, even in these relatively small studies. What was fascinating on the phototoxic reactions is that you see protoporphyrin-IX coming down. It takes about six weeks to reach the minimum on the drug.
After about month two, there were literally no phototoxic reactions that happened. If we're able to prove that out in the Apollo confirmatory trial that we're studying now, that would be just a remarkable outcome to be able to show that you can take patients who have phototoxic reactions, excruciating pain, and completely eliminate it. That would be a beautiful profile if we can demonstrate that.
Fantastic. You guys already align with the FDA on using PPIX as a surrogate endpoint to support accelerated approval. What is now gating that NDA submission process? Maybe just give an update on your discussion with the FDA?
Yeah. So it all started last fall when we had our end-of-phase two meeting. We shared with the FDA the package of data that we had and suggested perhaps PPIX could be used as a surrogate endpoint. That is where we reached alignment on that concept. We had a Type C meeting to discuss the design of the confirmatory trial. That was in December. That was followed by a CMC meeting to discuss how we can compress our CMC program down to meet the accelerated timelines. That meeting was also quite positive. We are happy to say the FDA was collaborative around finding solutions to condense the CMC program. The next step is we have disclosed that we have on the schedule a pre-NDA meeting, which is a pretty routine step.
Next would be the NDA filing itself as guided to the second half. I think the rate-limiting step on all of it actually is really not the clinical data. The only new piece of clinical data would be a data cut from our long-term extension to look at long-term safety and efficacy in these patients. We committed to share that with the FDA. That will get presented. That data will be presented publicly at the European Hematology Association basically later this week. That is the last clinical piece that is needed to get to the NDA. There are things like stability data from the CMC program, some of the comparability assays that have to be sorted out. Those have been the rate-limiting step.
Got it. The market was generally surprised when you guys first announced the potential for an accelerated approval pathway for bitopertin last November. What does it say about FDA's openness for this pathway and the data that you guys generated regarding the unmet need in EPP?
Yeah, we've found the FDA to be very interested in the unmet need here for these patients. I think a high degree of awareness of this disease. Certainly, the patient advocates have been working with the FDA around this disease for a while. We were really gratified to find the level of interest in finding solutions for these patients. I think coupled with that, there is a recognition that the disease is basically driven by PPIX, right? Not only is it a surrogate endpoint, but it's kind of an end in itself in the sense that if you're reducing that, you're basically reducing the definition of the disease. I mean, it feels like there's been good receptivity to an accelerated path here. If anything, the momentum has just been getting better and better as we go along.
Got it. You mentioned the Apollo trial earlier. This is going to be likely the confirmatory trial to support full approval. Can you walk us through the design of the study and any learnings that you got from phase two that you're incorporating into Apollo?
Yeah. I mean, the phase two trial was incredibly helpful for learning how to design the final confirmatory trial. The key question is around the clinically meaningful endpoint, some measure of time that patients are able to spend in light. We learned a couple of things. Most importantly, though, is that there is a placebo effect, right, that patients, as makes sense, live their lives probably spending less time in light than they could. They're not at the maximum challenging the pain attack. They're holding back. Coming into a study, I think there's naturally a lot of enthusiasm. People want to push themselves. You see both the placebo and treatment arms go up for about a month in the time they spend in light.
The placebo arm declines back to baseline, presumably because of bad experiences, while the treatment arm stays elevated and, in fact, even starts to go up in month five and six. That was a crucial learning that was not apparent from prior studies in this field because those studies have generally been with tanning agents that are functionally unblinded. The learning was you should measure your effect of the drug after the placebo effect has waned. Again, the way we designed the Apollo trial is to look primarily at the last month's worth of time in light as a way of assessing. Looking at the end of the study is a good way to look. The intention here is chronic therapy. You want to show that your effect is durable over time.
I see. So the Apollo study has a co-primary endpoint?
Correct. Yeah. That was actually a really exciting recommendation from the FDA to elevate protoporphyrin-IX, which we had assumed would be a secondary endpoint, up to a co-primary. We need to hit both, which you might say would increase the risk to the endpoint. The PPIX has been exceptionally reliable. I mean, it's very clear the drug mechanistically reduces PPIX. It was exceptionally stat-sig in a patient with 25 patients per arm. Having that as a co-primary and a 75 per arm study feels very comfortable to us. We like the elevation of that endpoint because I think it reflects how the KOLs view this, which is if you can show that you're reducing PPIX, there's a general understanding that you are improving the disease. The other clinical endpoints are just essentially supporting that basic premise.
I see. Going back to the variability that you mentioned regarding sunlight exposure, maybe give us a better sense of how the exposure data will be collected and how it would be evaluated and how you guys are going to mitigate the variability.
Yeah, yeah. I mean, basically, we were very happy with the data we got from the Aurora trial. Very high quality. The patients keep a diary. Compliance is really important, having a rigorous endpoint. We make it easy for them. It's on an iPhone. We do get blinded information on the back end about whether they're filling the diaries. When you see any diaries unfilled, we can contact the sites to alert the patients. We got over 80% diary completion rate in the Aurora trial, which we're happy with. I think we can replicate that. I think the only other real learning we had is to get a rigorous baseline.
That is now part of the Apollo trial, requiring a two-week diary completion effort that both trains the patients to be compliant on the diaries and provides a rigorous quantitative baseline that we can build from. I think putting that all together, we're basically running the trial almost the same as Aurora, but just shifting the way we analyze the endpoint to improve the baseline visibility and move the measurement point outside the placebo effect zone.
I see. Is there any restriction or any guidance in terms of sunlight exposure that the patient gets? Like would you say, "Hey, is it more just live your life regularly?" I think a lot of times these patients are already conditioned to not wanting to be outside.
Right, right. Yeah. In the first, in the Aurora study and in Apollo, we have what's called a sunlight challenge. We can't really require it, but we ask the patients to test themselves and go out into a light exposure that would normally create a reaction and keep track of how much time they have before they get a warning sign that they may be getting a reaction. Now, it's a bit of a tricky endpoint because it is very subjective. We didn't find it to be quantitatively very helpful in the Aurora study. What it does do, and this is why we retained it in the final trial, is it does give the patients an opportunity to experience whether the drug is making a difference.
I think we're quite confident that the patients who are getting a benefit eventually see, "Oh, wait, I can spend a lot more time out here in the light." Therefore, they'll start to potentially adjust their lifestyle. As a result, you get an increase in the diary of time in light. We felt it was important to keep that design feature so that you're not changing the way patients are managing their life between Aurora and Apollo because we want the Aurora data to be predictive of the outcome in Apollo.
I see. Maybe a quick update on the Apollo's enrollment status. When do you think that will be completed? When should we expect data?
Yeah. So look, the history is that this patient population is very enthusiastic about looking for therapies and has made themselves available for clinical trials, both ours and others. We super appreciate that. Typically, you can enroll a study like this in a year. We were able to do that with the Aurora study at 75 patients. Now with 150 patients in the Apollo trial, we're adding more sites, and we expect to be able to enroll that in a year. We disclosed it was open and enrolling early in May. You can assume that we'll complete enrollment by next May.
I see. Okay. Let's shift gears to the commercial opportunity for bitopertin. You guys cited about 14,000 diagnosed patients, and then 6,000 of these are engaged patients based on your claims analysis. What's giving you confidence in the opportunity for EPP? Also, how do you see as the initial addressable population?
Yeah. I mean, we think that full 14,000 patients represents people who could benefit from bitopertin. So that's probably the pretty good statement of the total opportunity. And that's U.S. only. And we've identified the 6,000 based on the recency of their claims or the frequency of their claims. So it gives you some indication of how much medical care or how engaged in their care they are. But I think the confidence here comes from the fact that this is a life-altering disease that the patients experience on a daily basis, right? This is not what you think of as a preventative therapy, right? If you take this drug, you could then go out and spend more time in light, right, and kind of live a more normal life. And then if you stop taking the drug, you will immediately find your life constrained again by the disease.
I think our experience so far with patients interacting both formally through studies, but also informally, is that people are highly motivated to be able to live a more normal life. No surprise, I think everybody aspires to that. The kind of anecdotes we hear about people being able to take trips to the beach for the first time in their life, I mean, these are sort of capstone things that people want. I think it is almost more important we hear again and again, "Hey, I'd like to be able to take my kids to the playground," right? It is like a very human thing that people want. I think our sense is this group of patients is highly motivated. That is the kind of thing that is going to drive, I think, rapid uptake of the drug.
Right. Okay. When I think about commercial opportunity, I also think about some of the barriers that you guys could face. Have you guys talked to payers, reimbursement challenges, and what that could look like? One thing that I, part of payers, is that you look at the health economic, the value of the drug, and what that means to the benefits that you can give to patients and what that means. Have you done any of those health economic values type studies? What does that look like?
Yeah. Right. Naturally, at this stage of development, we have had initial interactions with payers. I'm happy to say that just like the FDA, the payer community appears to be well aware of this as a very severe disease, acknowledge the significant limitations these patients live, as well as the life-threatening risk of liver disease complication, which the drug should also address by reducing PPIX levels. Yeah. There is one approved product already. It's called Scenesse. It works through a tanning mechanism. It has to be surgically implanted every two months. Perhaps for that reason, does not get used by very many patients. Nonetheless, that means the payers have come into contact with the drug for this disease, had the opportunity to assess pricing in that context. That drug is priced at roughly $300,000 a year.
In a related porphyria, there's a drug at Alnylam called Givlaari, which actually works through a similar type mechanism of suppressing heme biosynthesis, but for a liver porphyria. That is priced at about $575,000 a year. We see the payers are familiar with really dramatic unmet need these patients have and the value that can be brought by a good drug.
Okay. Got it. In regards to the drug having accelerated approval initially and not the full approval with the sunlight exposure data, how do you think, I mean, is there any challenges from that from a payer perspective, just looking at the PPIX?
Yeah. We've heard some discussion about that. We haven't really seen any evidence of that. I mean, we were stat-sig on many clinically meaningful endpoints. As I mentioned, phototoxic reaction rate was pre-specified, stat-sig achieved, as was almost 90% of the patients reported being feeling much better on a PGIC PRO. I think these kinds of clinical pieces of information will be taken into account and will provide a sound basis for the value proposition for the drug.
I see. Okay. Maybe just your expectation in terms of the commercial uptake of the drug, how are you guys thinking about or you're expecting the uptake in the next couple of years, maybe initially, and then with the full approval, what does that mean to the commercial uptake?
Yeah, yeah. We're cautious about setting expectations too early here. We're still a little bit ways away. We don't have our final label, for example. Some things that we think are in our favor are we will patients have the opportunity to roll into long-term extension. Right now, we're carrying about 85 patients, which is out of 100 patients, pretty good rollover rate into the long-term extension. Those patients presumably will eventually convert onto marketed therapy. The same is true for the Apollo study. We expect to get over 100 of the patients will be from the U.S. We could have a very nice set of patients just for year one where we're simply rolling people off of clinical trial extension onto just lifetime commercial therapy.
There is really good connectivity with the, call it, 10-15 KOL, world-leading porphyria centers who have a significant number of patients. Obviously, those folks who understand the root cause of the disease find the PPIX mechanism generally very compelling. We think that provides a second kind of layer to any launch scenario. As we have already talked about, we are really designing our field force, call it 25-35 reps plus MSLs, to access that 6,000 highly engaged patient population.
Right. Okay. Fantastic. Let's move on to your second asset, DISC-0 974. This is designed to suppress hepcidin for the treatment of anemia-associated inflammatory diseases, including myelofibrosis. Maybe here, what's the unmet need for myelofibrosis, given that there's other treatments that have already been approved and have been on the market based on symptomatic relief and also benign size improvement?
Right. Yeah. No, the really interesting thing about myelofibrosis is most patients are diagnosed with anemia, right? The starting point is ineffective production of red blood cells driven in part by highly inflamed bone marrow and this kind of bone marrow scarring. That does lead to a symptomology, a kind of inflammatory disease symptomology, as well as terribly enlarged spleens. Most of the therapies that are approved, in fact, all the therapies that are approved for myelofibrosis are targeting that spleen size problem and to some degree the symptoms as well. What's completely missing is any therapy for anemia. There is literally no approved therapy to treat anemia in myelofibrosis. Some agents are used off-label, ESAs, luspatercept, both see use and have some efficacy, but generally kind of limited in nature.
I think our goal is to create a drug that is truly efficacious across all of the anemic patients with myelofibrosis. That would be roughly 80-90% of the 25,000 estimated U.S. MF patients are anemic and have no approved therapy. We would love to fix that. What we are providing is an antibody, very simple, appears so far to be very safe, and once monthly Sub-Q dosing, right? We think that is going to be a great antibody. It is nice because it can basically not interact with any underlying small molecule therapy. We have shown so far that, for example, it seems to remedy anemia very well on top of the standard of care, which is Jakafi, which is kind of the best approved agent for managing spleen and symptom scores.
I think the last point that's really important, and I think because there haven't been drugs approved for anemia, the investor community has been a little bit unaware of the unmet medical need there. The fact is, KOLs will tell you, everybody wants to manage anemia in these patients. In fact, the anemia in these patients is associated with poor disease outcomes. There is a strong desire to rectify that aspect of disease.
I see. You guys have a phase two study ongoing, with initial data coming second half of this year and then full data in 2026. What are you going to share in this initial cut of data compared to the full data, the top line later on next year? What are your expectations?
Yeah. The phase two RALLI MF study is up and running. Yeah, we're happy to say that. Designed to three cohorts to explore the drug effect in three categories of anemia, ranging from the non-transfused, lightly transfused, to heavily transfused. We also have an exploratory cohort to look at therapy on top of some of these newer JAK inhibitors like momelotinib and pacritinib. In terms of what data we'll share as we come into the end of the year, we usually target ASH. We find that to be a good meeting for myelofibrosis therapies. It's going to depend on the enrollment. We haven't guided to anything specific about enrollment, except to say that that exploratory cohort of 10 enrolled extremely rapidly. There was a high enthusiasm for potential anemia therapy to go on top of momelotinib and pacritinib, which is exciting to see.
I mean, that data, we can pretty much plan to have in hand by the end of the year. It is a six-month study. A patient who enrolls today might have data by the time we get to ASH, right? That is the tricky part of taking interim cut.
I see. Okay. What is the bar for success in terms of how you guys are looking at the top line for next year?
Yeah. I mean, broadly speaking, 30% response rate appears to be kind of the benchmark to then assume that you can go on and win in phase three and also be better than the best other agents that have been tested in this disease. That is kind of the rough estimate. Of course, right now, we're sitting at more like a 50-60% response rate. We feel very good about how the drug is performing.
I see. How are you guys thinking about a registration study? Because this is just not, there's no clear precedent in terms of myelofibrosis anemia. Is there any possibility for accelerated approval?
Yeah. I know that latter part you mentioned, that comes up more and more these days. I mean, I think historically, the answer would be not clear, not so clear. We'll see as things develop around. There have been a lot of statements recently from the FDA on accelerated approval in rare diseases. Maybe that kind of favorable energy will trickle over into myelofibrosis. In terms of our base assumption, it is that there will be a phase three trial. We've had discussions around the kinds of endpoints that might be appropriate. As it sits right now, our feedback from regulators is a different kind of endpoint for each of the three categories of anemic patients. Broadly speaking, the goal is to show that you're taking symptomatic anemic patients and treating their anemia and resolving some aspect of the symptomology.
In patients who have transfusions, that can be achieved by just showing a reduction in transfusion burden. That is viewed as a symptom. In patients who are not transfused, there's other ways of measuring patient symptomology. I mean, fatigue is something that is almost always associated with anemia and can be resolved. That's an obvious one. There are other ways of looking at exercise capacity, quality of life, what have you. We're measuring all these in the phase two trial.
Got it. You guys are also developing DISC-0974 for anemia in non-dialysis dependent CKD patients. You guys presented data from a single dose study last year. What's so exciting about that? What should we expect for the multiple dose readout later this year?
Yeah. Anemia associated with chronic kidney disease, obviously, is a huge unmet need. There's probably 6 million anemic patients. You see limited use of ESA-type agents, erythropoietin, and limited use of IV iron. There's a pretty significant unmet need, 6 million patients. Everybody knows that hepcidin is heavily involved in, and iron dysregulation is heavily involved in, this anemia. I think there's a lot of mechanistic rationale. These patients have very high hepcidin levels. By correcting that, as our drug does, we expect to provide an anemia benefit. Our single dose study at 60 mg dose, which is the second from top dose, showed about a third of patients responding well.
I think we're reasonably optimistic that as we go to higher doses and add multiple doses to that, we should see response rates that are in a range that would suggest we should move on and develop this in larger trials.
I see. Got it. How large is this population in terms of patients? Why are patients untreated and undertreated today? What proportion of these are addressable by your approach?
Yeah. I mean, like I said, there are 6 million estimated anemic non-dialysis chronic kidney disease patients. The two modalities used to manage anemia are the erythropoietin-derived agents, the ESA class, and IV irons. They each have applicability in different settings, right? The ESAs are most suitable for patients who have low EPO, no surprise. The IV irons are most suitable for patients who have low iron levels, which is assessed by ferritin. Why are these patients not being well managed with these two agents? I think there are patients who are neither low iron nor low EPO, which would imply a need for hepcidin-based therapy. The other issue is just conveniences and issues. The ESAs all come with black box warnings, require a lot of titration and monitoring, so not readily used in a kind of primary level of care type setting.
IV irons come with the need for an infusion center, all that kind of inconvenience. We think we can also provide something that's just genuinely convenient for these patients, hopefully a simple, safe once every four weeks or once monthly Sub-Q injection.
Got it. Okay. Why don't we move on to one more asset, DISC-3405? This is your Sub-Q monoclonal antibody therapy for PV. There's already a lot going on in this space. We saw Protagonist, really good data that came out recently. Silence has a program, siRNA. And I think Ionis or Ono has something going on there too. How do you see this space? And how do you plan to differentiate?
Yeah. Hats off to Protagonist and the rusfertide compound, which is now partnered at Takeda. They just presented the data from the phase three trial showing achieving 75% phlebotomy-free, good maintenance of target hematocrit levels in these patients, which is kind of the first therapeutic intent of this iron restriction approach. Also, I think one of the remarkable stories here is that those patients felt much better, right? I think people coming into this thought, "Well, polycythemia vera, kind of precancerous disease of overproliferating red blood cells. If you iron restrict them, is that really going to provide a meaningful benefit?" It turns out, yeah, the patients feel a lot better. You can manage the cardiovascular risk by maintaining hematocrit. I think this iron restriction approach is going to become a major kind of mainstay therapy for PV patients, which is very exciting.
The question is just whether rusfertide with once weekly injection certainly has some record of injection site reactions, whether that's the best way to do this or whether there's some yet better agent to come along. The class of drugs competing to be that better agent is the TMPRSS6 inhibitors. Here, rather than putting hepcidin in the body, which is essentially the Protagonist approach, hepcidin-mimetic, the TMPRSS6 approach is to actually trigger your body to make more of its own hepcidin. We think that that approach will at least allow us to get to something like once monthly dosing. We'll see with clinical experience whether we're able to deliver either higher efficacy or better safety or just a better patient experience. You mentioned there is a crowd of companies chasing TMPRSS6 antagonists.
We think we will be the first antibody in this space. We think an antibody is going to give a really nice safety profile as well as a high degree of titratability, right? One thing you do not want to do with these patients is restrict their iron too much and drive them into anemia. I think we will see the other advanced competitors are working with nucleic acid-type modalities, which may be a little trickier to titrate. We will see over time.
I see. I believe Takeda guided about $1 billion-$2 billion peak sales for this indication. Just looking at that and looking at how many drugs are already in development, how do you think about sort of the coming in later on and behind a lot of these other competitors?
Yeah. I think our goal is to be best in class. If you take the class to be iron restriction, our goal is to be best in class. I think we have a good rationale for that. I guess we will see where Takeda prices this drug. To me, you have a disease with 150,000 patients in the U.S., something that could become a mainstay therapy. I would view their estimates as pretty conservative.
I see. Got it. One last question before I turn it to you for final remarks. Looking at your company and the pipeline, you guys have been pretty active with business development and have licensed a lot of these products. Are you still looking to build that pipeline to do business development? How are you thinking about sort of the pipeline going forward?
Yeah, yeah. Look, we've always been really capital efficient as a company. That's something I take a lot of pride in. I think we've developed three molecules now, one to the cusp of approval or NDA filing, two of them in phase two. We've done it on a really lean budget. My goal is, as we commercialize bitopertin, to start to wean ourselves off the need for dilutive financing events, really focus on building the company off of revenues. That's going to be the guiding light. Adding new things to the portfolio with three agents, we've got a lot going on. They all have some breadth to them. We want to explore that breadth. If we find something really exciting that fits well and we feel like we are going to be really good at based on our experience, we are always looking.
It could happen, but we'd have to fit it into a framework where we're continuing to be capital efficient and start to really focus on how to create good investor returns.
Fantastic, John. It's been a pleasure hosting you at the Goldman Sachs Conference today. I'll turn it to you for one final comment or concluding remark.
Thank you. Yeah. No, it's been a pleasure. Listen, this is going to be an exciting year as we wrap up. Hopefully, we get our NDA filing data from the 0974 program, get the phase two started with the third program, and then next year, really big news events all around. Exciting future.
Great. Thank you, everyone.