Gemini Therapeutics Inc Aktie

Good day, and thank you for standing by. Welcome to the Disc Medicine Corporate Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, John Quisel. Sir, please go ahead.

Thank you. Good morning, and welcome, everyone. This is John Quisel speaking, CEO of Disc Medicine. And I'll be joined today by Will Savage, our Chief Medical Officer, and Pamela Stephenson, our Chief Commercial Officer.

And we're here to review the topline results for the APOLLO Phase 3 trial of bitopertin in erythropoietic protoporphyria or EPP.

Before we get started, a few preliminaries, I'd like to remind everyone that we will be making forward-looking statements, and these should be taken in context with respect to materials that we have filed with the SEC and have posted on our website.

Additionally, bitopertin, selcodebart and DISC-3405 are investigational agents and are not approved for use as therapies in any jurisdiction worldwide.

Okay. Well, as indicated in the press release earlier this morning, the topline APOLLO data are very positive, achieving all primary and secondary endpoints with remarkably robust p-values. And we will provide additional data on this call in a few minutes.

But first, I just want to step back and take a look at the big picture. These results mark a significant scientific advancement in EPP, demonstrating for the first time in the clinic that by targeting the production of the toxic metabolite protoporphyrin IX or PPIX, that causes this debilitating disease, it is possible to achieve unprecedented improvements in important metrics of disease status. I expect these results will permanently change the focus of drug development in this field.

Moreover, this combination of data and the numerous publicly documented patient stories suggest that bitopertin has the potential to fundamentally change the care and life experience of EPP patients. So very exciting results altogether. I want to express gratitude to everyone who helped make this possible. The patients deserve the greatest thanks for entrusting us with their health and participating in our trials, but also much gratitude goes to the advocacy groups and the doctors who worked closely with us and to the academic scientists who described the molecular basis of this disease over decades of research.

I also should say that we're grateful to those who stepped up with the capital to support these R&D efforts. We couldn't do this without any of you. And I want to thank the team here at Disc that designed and executed a beautiful series of trials, taking the experiences that we learned in Phase 2 and using those experiences to design a winning Phase 3 trial. There was a lot of anxiety headed into this readout. And fair enough, these endpoints are extremely challenging ones, but our team showed up and delivered both operationally and statistically.

This was our first multinational Phase 3 trial as a company, and I believe it won't be our last. We can now progress with great confidence as we begin to design and plan to execute on Phase 3 trials for our pipeline programs in other severe blood disorders. We have a great team of drug developers here at Disc and the future is exciting.

Okay. So now turning to the topline data. APOLLO met both co-primary endpoints and all secondary endpoints. We showed again that bitopertin targets the underlying pathophysiology of EPP, reducing whole blood PPIX, which is the biochemical driver of light intolerance and other complications of the disease.

For the first time, we also showed unequivocally that bitopertin increased the amount of time patients on the trial were able to spend in light without pain while significantly decreasing the number of phototoxic reactions they experienced. We also saw significant improvements in the time to prodrome and in patient-reported quality of life measures.

Bitopertin has now been studied in over 4,000 clinical trial participants across its development history, and we saw a generally favorable safety and tolerability profile in APOLLO that was consistent with prior EPP studies.

It is also worth noting that APOLLO was completed on a remarkably fast timeline and nearly every patient elected to continue receiving treatment in the open-label extension portion. Collectively, these data provide compelling evidence of the clinical benefit of bitopertin for EPP patients. We look forward to resubmitting an NDA to the FDA by the end of this year, and that would set up a timeline where we would anticipate an FDA decision by mid-2027.

Now we recognize that some of the attendees on today's call may be less familiar with EPP and XLP.

So I'll turn it over to Will to provide a brief overview of the disease before he reviews the APOLLO trial design and topline results in greater detail.

Thanks, John. I want to take a moment to talk about EPP and why new treatments for this patient population are needed so much. This is a serious, rare, debilitating lifelong disease that is driven by a genetic mutation, which causes the toxic accumulation of the heme metabolic precursor, PPIX. X-linked protoporphyria is a genetic variant of EPP that similarly results in the accumulation of PPIX. The main clinical manifestation is extreme photosensitivity with severe disabling pain attacks called phototoxic reactions when patients are exposed to light.

PPIX is a photoreactive molecule and patients essentially get a chemical burn from the inside out when overexposed to sunlight. The photosensitivity to accumulated PPIX means patients can typically spend about 30 minutes and sometimes as few as a couple of minutes in the sun before experiencing symptoms, including excruciating pain, swelling and burning, all of which can last continuously for days. The fear associated with the sun and the psychosocial impact of a lifestyle of sunlight avoidance mean many patients experience anxiety and depression.

The consequences of PPIX accumulation are systemic. For example, about 1/3 of patients develop hepatobiliary complications, which can advance to liver failure and be life-threatening. There is no cure or disease-modifying treatment for EPP, so patients typically manage the disease by avoiding light, wearing head-to-toe protective clothing or sometimes using tanning agents. Our aspiration here is to provide an oral treatment option that targets the cause of the disease and allows patients to be relieved of the debilitating impact of EPP, to be relieved from the multifaceted burden of light intolerance, to be free from the need to plan every day around sun exposure, to be free from the pain of phototoxic reactions and to just be able to live their lives.

We designed APOLLO, our global Phase 3 study to specifically capture these aspects of the disease. APOLLO is a randomized, double-blind, placebo-controlled trial of 60 mg bitopertin versus placebo for 6 months. APOLLO enrolled adults and adolescents aged 12 and over with EPP or XLP. Randomization was stratified by baseline light tolerance and geographic region. The study had 2 co-primary endpoints: average total monthly time in sunlight without pain between 10:00 a.m. and 6:00 p.m. during month 6 and percent change from baseline in whole blood metal-free PPIX at 6 months. Today, we will share the topline results of APOLLO.

Here's a look at the baseline characteristics for the 183 APOLLO participants. You can see that the treatment arms were generally well balanced across key demographic and disease characteristics. The study exceeded its original enrollment target of 150 participants, ultimately randomizing 183 participants in just 10 months, reflecting strong patient and physician enthusiasm. Notably, we have meaningful adolescent representation with 34 of the participants being aged 12 to 17, and there is substantial unmet need in this younger group. 7% of participants had XLP.

Geographically, we had good global representation with a roughly even split between patients coming from the U.S. and ex-U.S. We also had even distribution of the season in which patients completed the APOLLO study with half of the patients completing their last month in the spring/summer and the other half completing their last month in the fall/winter months.

Overall, these demographic and baseline characteristics are typical of the EPP patient population and are similar to those in our Phase 2 studies. Before I review the topline data, I need to remark how compelling these results are. All primary and secondary endpoints were not only met but met with clinically meaningful magnitude and strong statistical significance.

Looking at our co-primary endpoints, bitopertin met both of them, demonstrating statistically significant reduction in PPIX and increase in total time in light without pain in month 6 of the trial. Bitopertin-treated participants had a 45.8% reduction in whole blood metal-free PPIX at month 6 compared to baseline and a 41.4% greater reduction in PPIX relative to placebo with a p-value of less than 0.0001. Consistent with the AURORA and BEACON clinical trials, these results continue to support bitopertin's potential to modify EPP and XLP through reducing production of the disease-causing metabolite in the body.

With this PPIX reduction, we observed a statistically significant 12.2-hour improvement in average total time in light without pain during month 6 of treatment relative to placebo with a p-value of 0.001. You can see that the y-axis starts at 20, which is intended to roughly indicate an extrapolated baseline monthly light tolerance from the 2-week baseline assessment. The average baseline time in light over the 14-day screening period was 11.4 hours for the bitopertin group and 10.7 hours for the placebo group. It's important to note that this endpoint is not a measure of maximum light tolerance. It is a measure of how much time patients were able to choose to spend in light on the study.

The secondary endpoints give more insight on the light tolerance improvements with bitopertin. Looking at the first secondary endpoint, bitopertin dramatically decreased the incidence rate of the severe painful phototoxic reactions experienced by patients by 71% relative to placebo with a p-value less than 0.0001. To help put this reduction into perspective, we've also provided on the right, the total number of phototoxic reactions observed in each treatment arm over the 6-month treatment period, 231 for patients on placebo and 71 for patients on bitopertin. Notably, this marked reduction in phototoxic reactions occurred while patients were spending more time in the sun.

Along with the co-primary endpoints, this paints a clear picture of the potential therapeutic profile of bitopertin. This is the first time a potential treatment for EPP has shown robust evidence of whole blood PPIX reduction alongside unequivocal improvement in time in light and substantial reduction in phototoxic reactions, which builds on what we saw in the Phase 2 AURORA trial.

Bitopertin also achieved statistical significance on cumulative total time in light without pain over the entire 6-month treatment period relative to placebo. Patients on bitopertin achieved 58 more hours in sunlight with a p-value less than 0.0001. This is an endpoint precedented by the regulatory approval of afamelanotide.

Time to prodrome is another way of evaluating light tolerance, and this endpoint captures the weekly sunlight exposure challenges where patients are asked to expose themselves to sunlight until they feel that they cannot tolerate anymore. This analysis was prespecified for adult patients only as the sunlight challenges were optional for adolescents, which is why the N is a bit lower than the other analyses. At month 6, bitopertin significantly increased change from baseline in the average daily sunlight exposure time to prodrome over a 2-week interval by 56 minutes relative to placebo, p equals 0.0077.

This is a meaningful outcome as delaying the onset of prodromal symptoms extends the period patients can tolerate light exposure before experiencing the earliest signs of a phototoxic reaction. Again, this increase in sunlight exposure is achieved with markedly fewer phototoxic reactions. We are also encouraged by the favorable safety profile observed with bitopertin with no new safety signals identified in APOLLO. There were no study discontinuations in the bitopertin group. There were a total of 3 SAEs occurring in the trial, 2 in the placebo group and 1 in the bitopertin group, none of which was considered related.

Consistent with our Phase 2 studies, dizziness was the most commonly reported treatment-emergent adverse event, 50% in the bitopertin group, 11% in placebo. All events were mild to moderate in severity, generally occurring within a day of treatment initiation and generally transient. These findings further strengthen the robust and growing body of evidence supporting bitopertin safety and tolerability profile, which now has been evaluated in over 4,000 clinical trial participants over the course of its development history and studied for up to 2.5 years in EPP patients, which we believe demonstrates a favorable long-term safety profile.

Taken together, the APOLLO topline results highlight why we have confidence in the therapeutic potential of bitopertin in EPP and XLP. The data demonstrate a clear impact across multiple dimensions that matter to patients.

First and foremost, we have demonstrated consistent, clinically meaningful reductions in the disease-causing metabolite PPIX. This translates into clear evidence that bitopertin treatment increased the amount of total monthly time EPP and XLP patients were able to spend in light, not only as measured during the course of their day-to-day lives, but also in sunlight challenges testing sunlight tolerance.

Importantly, this greater time in light is coupled with a substantial reduction in the incidence rate of severe painful phototoxic reactions. To be able to spend more time in light without incurring pain while reducing risks of phototoxic reactions is a fundamental change to how patients experience their disease.

Lastly, we know that these effects are not only measurable but palpable to patients as those receiving bitopertin reported clear quality of life benefits compared with placebo, including highly statistically significant improvement in Patient Global Impression of Change score and Patient Global Impression of Severity scores with more bitopertin-treated patients describing their change in EPP as much better and their severity as not at all severe, respectively, at the end of the study, both with p-values of less than 0.0001.

Combined with its well-characterized safety and tolerability profile and patient-friendly once-daily oral presentation, we believe bitopertin has the potential to offer a differentiated and highly attractive therapeutic profile and hope to establish a new standard of care that aligns with the needs and priorities of both patients and physicians.

We are excited by these results and what they potentially mean to adolescents and adults with EPP and those who care for them. We are encouraged by the strong interest and enthusiasm we have continued to see from the patient and physician communities in participating in our clinical trials and now our Expanded Access Program.

Now I'll hand it off to Pamela to speak more about the EPP market opportunity and launch readiness efforts.

Thanks, Will. We wanted to spend a few minutes discussing how we think about the EPP market opportunity and the work we've done to refine our understanding ahead of launch. We generally anchor to 3 patient population estimates. At the broadest level, estimates of genetic prevalence suggest there is an upper bound of 20,000 people living with EPP in the U.S. Based on our analysis of claims data, we estimate that roughly 14,000 patients aged 12 and older, have been diagnosed. And of these 6,000 are what we would call engaged, meaning they have multiple or recent EPP-related claims.

These 6,000 patients represent what we believe to be the most proximal patient population to activate at launch. In parallel, our field teams, including our key account specialists and our field medical team have been actively engaging with healthcare providers to better understand current diagnostic and management practices and to support patient validation. This work has helped to validate our market assumptions at the top accounts across the U.S. Over the past 6 months, we've remained focused on 3 key priorities: raising awareness, sharpening our understanding of the market and addressing critical unmet needs for EPP.

First, we are actively addressing disease awareness through targeted educational initiatives and the identification of regional opinion leaders who can help organically enhance disease recognition in their communities. At the same time, we continue to deepen our understanding of the EPP landscape through account profiling and patient validation efforts.

This work has strengthened our confidence in the opportunity across centers of excellence and high-volume academic institutions while also helping us to identify and prioritize key community accounts for targeted outreach.

Finally, we are excited to announce the upcoming launch of a new PPIX testing program in November of this year. This initiative is designed to provide quick, accurate and accessible PPIX testing for EPP and XLP helping to reduce diagnostic barriers. Collectively, these initiatives are building the foundation for a successful launch and will enable us to identify, reach and support patients more effectively from Day 1.

Now I'll hand it back to John to provide some closing remarks.

Thanks, Pamela. The positive APOLLO topline results represent an important milestone for the program. And based on these results, we plan to resubmit an NDA to the FDA by the end of the year with an FDA decision then anticipated by mid-2027. We look forward to engaging with the agency with the goal of bringing an important innovative medicine to the EPP and XLP community as efficiently as possible. We also plan to present more detailed data with additional insights from APOLLO during a future medical conference.

In the meantime, we remain committed to supporting eligible patients through both our ongoing open-label extension study, HELIOS and our Expanded Access Program, which is active in the U.S. and other select countries.

In parallel, we are continuing to advance our commercial readiness efforts, as Pamela discussed. So we are one step closer in our mission to deliver meaningful new medicines to patients with serious hematologic diseases and significant unmet needs. APOLLO marks our first Phase 3 win as a company, and we look forward to bringing that same level of rigor across our rapidly advancing portfolio of new medicines, each with commercial potential.

Selcodebart, an investigational antibody designed to suppress hepcidin is being evaluated in anemia of Myelofibrosis.

DISC-3405, an investigational antibody designed to induce hepcidin is being evaluated in Polycythemia vera and Sickle cell disease. Both of these programs have shown positive Phase 2 readouts earlier this year, and both assets are on track and expected to begin Phase 3 studies in 2027. And we expect to present additional data for both of these programs by the end of this year, 2026.

So a lot of exciting things to come. And before we open it up to Q&A, I want to just reiterate that none of this work would be possible without the patients and families, investigators and advocates who have continued to support the advancement of the bitopertin program. We are deeply grateful for their partnership and trust.

And with that, thank you for joining, and I'll hand it back to the operator for Q&A.

[Operator Instructions] Our first question is going to come from the line of Roger Song with Jefferies.

Great. Team, congrats for this impressive result. Two from us. One is with those 2 co-primary endpoints clearly support the regulatory approval. The secondary endpoints seem to be very clinically meaningful. Can you just comment on the magnitude of the benefit do physicians, patients want to see to potentially drive the real-world adoption, particularly for the phototoxic reaction reduction and the time to prodrome with the sunlight challenge?

And then regarding the safety, the only thing to stick out is the dizziness, but I understand this is mild and transient. And then I just want to confirm, do those events occur if bitopertin restarts after a temporary pause upon the AE? And how do you believe bitopertin will be used in the real world with this dizziness profile?

Thanks, Roger. Will, I'll pass that to you.

Sure. So I think that the profile that we see with reduction in the disease-causing protoporphyrin IX, coupled with large reductions in phototoxic reactions and meaningful improvements in light tolerance is a profile that is going to be extremely appealing to physicians and patients.

I think that regarding the dizziness, it does tend to occur very early on in the study or early on upon initiation of treatment and is short-lived. We don't have data on stopping and restarting drug at this time. I will say that this dizziness has not led to any discontinuations.

And so I think a potential real-world use case in the future is not going to have a meaningful impact on the way people live their lives.

Got it.

[Operator Instructions] Our next question comes from the line of Thomas Smith with Leerink Partners.

Congrats on these truly stellar data and this really huge milestone for the company. Now that you have the results in hand, just wondering if you can expand on the plans for NDA resubmission. What are the gating factors? And what are your expectations for the label now that you're pursuing full approval rather than accelerated approval?

And then as a follow-up, I was wondering if you could provide an update on the long-term extension and Expanded Access Programs for bitopertin, specifically wondering how many patients are in these respective programs that could become eligible for commercial drug if approved? And are there any plans to further expand the EAP, maybe adding some additional centers now that we have these definitive and frankly, compelling results?

Yes. Thanks for the question, Tom. Right. We are obviously excited to go and engage with the regulators as quickly as we can with this kind of data set. And to that point, we're on track with our prior guidance to move towards the NDA resubmission by the end of the year, which obviously feels long to all of us, but it really is as fast as you can manage this kind of thing. So we're moving with all urgency on that front.

Yes. And then meanwhile, these ongoing -- the HELIOS trial and as well as the EAP, we feel like these are really important to allow continuity in therapy for patients who've been in our study as well as an opportunity for those who have need, but were not able to get into our study.

So in the U.S., across the HELIOS trial, it's roughly 150 patients present in the HELIOS trial. And then in the EAP, we haven't disclosed specific numbers yet, but I can say the demand has been very high.

We are enrolling patients there as quickly as we can. And to your point, we actually are bringing on new sites also as quickly as we can. And I think the rate-limiting step has simply been operational to allow people to get access here through that EAP mechanism.

So yes, really excited to see that kind of group of patients with access to therapy continue growing as we move through the regulatory process. And hopefully, that will all come to a resolution by the middle of next year.

Great. Congrats again on the data.

[Operator Instructions] Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

Let me also add my congratulations on these unprecedented data. So 2 questions for me. The first is just on the prevalence of patients. It seems like there's more than double that are diagnosed that are not engaged in the system. How much of this do you believe is attributed to the fact that these patients either are interested or haven't been able to tolerate or are effective on standard of care and thus might reenter the system if there are new options out there for them, including bitopertin?

And then just on the efficacy, recognizing that you are just seeing the topline now, can you give us a sense of any trends you see over time for -- as I know, for example, the drug takes a couple of weeks for those PPIX reductions to get in the Goldilocks zone. So do you start to see even more benefits as patients progress further on therapy?

Yes. Thanks, Kristen. Maybe I'll just hit your second question first. I think we can expect to see the same kind of trend in the APOLLO data that we've seen in Phase 2, where patients tend to experience or take advantage of the opportunity to spend more time in light over time. We've seen that just be kind of a continuous increase as you move from the AURORA main trial into the Phase 2 trial into the long-term extension.

So we don't have a formal analysis from Phase 3 yet, but I imagine those trends will be the same. And while it does take about 6 weeks to reach a maximum reduction in PPIX, we often have seen and heard patients with improvements in their symptoms or reporting improvements as early as the first week or so of therapy. So I think a pretty exciting package there.

Meanwhile, to your first part of your question, we have had -- we were able to retain a significant portion of our sales force as well as our MSL team. Those folks have been out working to engage with the physician community, discuss disease state education and awareness. And we've learned a tremendous amount from that group.

But maybe for more detail, I'll hand it over to Pamela.

Sure. Thanks, John. Kristen, the question that you raised about the patients who are sort of outside of the engaged patients, your hypothesis is right on in terms of those patients once they are just not being currently managed by EPP specialists.

And I do believe, based on what we've learned out in the field that a fair number of them will come back into the system once there is a product that's available to them. And also once there is more awareness of the EPP and new products at the community level.

So we've learned this through our disease state education efforts, as John mentioned, we're out there in the field talking to both the academic centers and identifying the community specialists who are sort of knowledgeable and willing to treat EPP. So we do anticipate that there'll be more patients coming back into the system once there are options for them.

[Operator Instructions] Our next question comes from the line of Sean Laaman with Morgan Stanley.

Congrats again. Given that the EPP treatment could potentially be lifelong, what have APOLLO plus HELIOS taught you about longer-term persistence and tolerability that might not be obvious from the 6-month pivotal data set?

Yes. Thanks, Sean. Great question. And just to reiterate, what we did see in 6 months is that zero study discontinuations from the treatment arm. I think that speaks volumes already to the need and demand here for bitopertin, and the long-term extension has shown similar levels of persistence. Will, do you have any additional comments?

Sure. I think what -- the data from our HELIOS long-term extension study has shown us that the PPIX reductions as would be predicted, persist for years. And time in light actually continues to improve as patients continue on bitopertin past 6 months.

[Operator Instructions] Our next question is going to come from the line of Tara Bancroft with TD Cowen.

I also want to offer a very sincere congratulations. So I want to ask a little bit more. It was helpful to hear all the thoughts on how you'll reach all the different segments that make up the TAM Pamela. So thanks for that. But I was wondering if you could also maybe talk about your thoughts on how you actually envision like peak potential estimates of bitopertin. Like what level of use do you think you'll get in the highly engaged patients in terms of penetration of that population?

And then how do you envision use to grow in the other segment, the larger segment, especially with all the efforts that you're implementing like the testing and everything, that would be really helpful.

Yes. Thanks, Tara. Yes, we're certainly excited about the potential here, this kind of clear data set, I think, will as Pamela mentioned on the last question, kind of make it easier to engage with physicians around this.

But Pamela, do you want to talk about some of these attributes?

Sure. So absolutely in this engaged patient population, what we see is a lot of patients and families who are really ready and wanting to engage and are looking for an option. So I think there, with the sort of concentration of these patients in the top centers, I think that speaks to a relatively quick adoption.

In the broader community, it's more of a question of ensuring that the patients are aware of where they can go seek care with knowledgeable providers and that they're getting the appropriate PPIX testing, which is one of the reasons that we're launching this new PPIX testing program and that they're able to gain access to the product.

So I think there, as we always see, it may take a little bit longer for these patients to get into the system. But once they're in the system, I think they'll be ready to go.

[Operator Instructions] Our next question is going to come from the line of Evan Seigerman with BMO Capital Markets.

Three for me. First off, in terms of the NDA resubmission, aside from this data set, what else do you need to put together for the agency?

Number 2, I know you previously submitted under the Commissioner's priority review program, but would you be eligible for a pediatric rare disease priority review voucher upon approval?

And 3, for Jean, I know that you had folks on board that were going to be there to commercialize. How quickly can you reengage the prior commercial folks to make sure that you're set up for success?

Yes. Thanks, Evan. So in terms of the NDA resubmission, I think everyone saw the CRL, the gap or the requested evidence from the FDA was really pointing at the APOLLO trial data. And given how clean the data are, we think that's really the substance of the resubmission. There's always -- you're supposed to kind of integrate your safety database and your efficacy information across the multiple trials. But that's about it. Nonclinical CMC, these modules are all previously aligned to the process we've already been to. So we don't anticipate any additional submission data on those fronts. So really focused on the APOLLO data.

Yes, we were delighted to have a shot at this through the [ CNPV ]. That program is now kind of utilized for us, and we're just going through a regular resubmission process under the standard Phase 3 traditional approval pathway. We did include a substantial number of adolescents now in this trial. We don't yet have a specific subgroup analysis of that group, although broadly speaking, we expect all subgroups here to show the same trends given the p-values that we're seeing. So we feel optimistic that, that group is going to show nice results as they did in Phase 2, but in much smaller numbers.

So we will be seeking a label that covers both adolescents and adults. And we do have a rare pediatric disease designation. So if we're successful, it would make us eligible for a PRV. So that's something we're keeping an eye on.

Lastly, the question of how we rebuild and ramp up to commercialize. And yes, our CFO, Jean Franchi, is here as well. And Pamela, so Jean, do you want to just comment quickly on that?

Evan, thank you. Yes. And keep in mind, remember, baseline here, we do have half of our sales team in place already. And as Pamela already highlighted, they have been incredibly active in the field, along with our medical affairs team. On top of that, remember, we were in a race to get to market under the voucher prior. So we were able to ramp within 2 months.

So I'm quite confident with this data being incredibly attractive, Pamela and the team will be able to ramp back up very quickly because we've kept all our activities ongoing. So we're in a very good place for a traditional approval.

[Operator Instructions] Our next question comes from the line of Derek Archila with Wells Fargo.

Let me add my congrats on the data this morning. So maybe first off, can you just discuss the prior Scenesse versus naive split in the trial? What was kind of the enrollment mix and did efficacy really differ between those 2 groups?

And then just in terms of the label, obviously, the co-primaries getting on the label, but would you specifically look to include those phototoxic reaction reductions and time to prodrome data on the label?

Yes. Thanks, Derek. For sure. I mean, with our -- all of our secondaries, we think, are quite meaningful, and we will look to get them on to the label. I think that would be extremely helpful as we look to launch the product. In terms of Scenesse, I guess, baseline characteristics, I'm not sure -- I can't really speak to that. But Will, do you have anything to say?

Sure. I think we enrolled a general EPP population that had inclusion/exclusion criteria that really didn't limit to a meaningful degree who could enter. And that's in EPP clinical trials, that's a similar case across the board.

[Operator Instructions] Our next question will come from the line of Douglas Tsao with H.C. Wainwright.

Congrats on the data. John, you just talked about the data and the sort of hope to get approval in adolescents. We know that a fairly significant part of the opportunity here is with children under 12. You'd always sort of talked about sort of eventually getting to that. And I know it's still early, but given the sort of compelling nature of this data, I'm just curious if some additional thoughts on how quickly you'd be able to initiate a study to go into younger patients?

And if you have any thoughts, I mean, because obviously, you noted there is a difference in terms of how you looked at the adolescent patients in terms of time to prodrome. Would this be a study sort of largely replicating APOLLO? Or would there be some other considerations needed looking at younger patients?

Yes, it's a great question. I mean I think the youngest patients with EPP is definitely a group that we want to try to help out here. And as usual, you approach it carefully getting -- walking through adults and adolescents first and then moving on to the youngest pediatric population. And so that is certainly part of our plans. We have a PIP that's been largely aligned with the European regulators, and we plan to go down that path.

The other thing we're going to be focusing a lot, as Pamela already alluded to, is trying to improve the diagnostic journey here.

The number of patients under 12 diagnosed with the disease is actually quite small today. And part of that is because it takes so long to get diagnosed. And one of our missions is to really try to help the physician and patient community reach diagnosis much faster so we can deliver appropriate care much sooner and hopefully help people adjust to the disease and get better care as quickly as possible.

So I think the focus on the pediatric population is important to us. It's a small group of patients right now, but we're looking to kind of improve awareness and access. And as I mentioned, we'll be progressing with, I think, typically in this situation, a pretty small study is all that's required. That's something we'll talk more about in the future.

Great. That's very helpful. And I'm just curious, maybe Pamela can talk about this. Just you've obviously been in the field doing work. I'm just curious what the most striking learning you've had over the last 6 months now that you've had reps sort of engaged sort of on the ground talking to clinicians.

I think one of the most striking insights is how this disease when you're really out in the community and you go into a physician's office that may not be aware of EPP, consistently, what we see is they are interested and eager to learn more. There's a real human interest element to this where people -- providers in the community, they want to help identify and diagnose and manage and help these patients.

So I think that's been a really nice thing to see. You don't always see that. So that would be #1. And then the other thing I would just say is among the top centers, just a real high -- on the other hand, like a very high awareness and readiness. Obviously, based on the clinical trials, the EAP, there's a lot of awareness now there in the top accounts, and they're just -- everyone is really eager to have this product approved.

Okay. Great. Congrats on the data.

And our next question is going to come from the line of Rami Katkhuda with LifeSci Capital.

I wanted to pass on my congrats on the data as well. I guess the reduction in phototoxic reactions is particularly compelling. Can you provide any additional color on whether bitopertin reduced the severity and duration of these reactions as well and whether the benefit was driven by fewer patients experiencing reactions or a lower frequency of events per patient?

And then I guess, more broadly, could the treatment effect with bitopertin be even larger when accounting for the increased time outdoors for many patients?

Yes. Thanks for those questions. We certainly agree that those reduction in phototoxic reactions is an important endpoint here, an important indicator of benefit to patients. The specifics of your question, we may not have it in our topline, but Will to you.

Yes. Suffice it to say, there are going to be a lot of exciting and interesting analyses that come from this data set that we don't have right now as part of topline data. But to your first question, that is something that we will be able to look to.

Regarding the second question, I guess, I mean, we have the data that we have in our trial. I think an individual patient experience can be -- the data might not capture every individual's experience. It might be a lot more time in light for a number of individuals on bitopertin. But at the end of the day, right now, we're talking about the trial output and what we see when we look at the population enrolled.

Makes sense, and congrats again.

[Operator Instructions] Our next question comes from the line of David Nierengarten with Wedbush Securities.

I just had a quick one. Most of mine have been asked. And in the market research, just how many of the patients are paying patients versus Medicare, Medicaid in your research?

David, I can answer that. So for EPP, what we see is about 60% of patients are covered through commercial insurance, 25% Medicare and 15% through Medicaid. So really, really strong...

[Operator Instructions] Our next question is going to come from the line of Martin Auster with Raymond James.

Congrats to the team on a really well-executed trial. So congrats to everyone there. A couple of questions, I guess. One would be on your ex-U.S. regulatory strategy. Curious if there's any kind of updates about your thought there?

And then maybe just really high-level comments about sort of what does that commercial opportunity look like relative to the U.S. opportunity in your mind at this time?

Yes. Thanks. Great question. We are vigorously pursuing approval in European countries as well. And our guidance is that we will get a submission -- we expect to get a submission into the EMA in 2027. So that's the kind of timeline we're on there. I think it is a meaningful commercial opportunity. There are actually quite a lot of patients in Europe, probably roughly the same frequency of occurrence demographically in European countries as in the U.S.

Of course, it takes some time to kind of access all the different countries there. There's more territorial complexity. But we think it's quite meaningful. And obviously, we're super appreciative that European sites participated in this trial for the first time. And we saw really vigorous enrollment there. So we think there's a high degree of patient unmet need that we want to try to meet in the European countries.

[Operator Instructions] Our next question is going to come from the line of Stephen Willey with Stifel.

Congratulations on the data, really well-run study. Most of my questions have been asked, but we've received a few questions this morning just regarding the comparison of APOLLO data to the dersimelagon INSPIRE data. And I know the endpoints are -- they're nuanced in a way that don't provide a direct apples-to-apples comparison and dersimelagon obviously is addressing the underlying pathology of the disease. But just curious if you could kind of speak to how you're thinking about any high-level comparisons here relative to the INSPIRE data.

Yes. Thanks. It's a great question. I think one of the features of our data that has been the most exciting to us is the consistency that we've seen in the reduction in pain in these patients. The phototoxic reactions -- if you recall, in the AURORA study, underpowered or really not powered for this endpoint. But nonetheless, nominally stat sig, prespecified endpoint, stat sig showing about a 75% reduction in the rate of phototoxic reactions. And there was definitely a diminishment in the number of people who were having reactions. That was very clear in that Phase 2 data set.

And what we're seeing now in a properly powered Phase 3 trial is p-value less than 0.0001 on that reduction in pain reactions. We've shown you here, it's based on the number -- well, we've seen -- we've shared with you the number of reactions across the study. And it's a 71% reduction, right? So incredibly consistent data across these 2 trials. I think that's striking and distinctive about this product.

And I think it probably is, in a sense, capturing what happens when you get to the root cause of this disease and reduce the whole blood PPIX and the production of PPIX that we think is driving the disease state.

[Operator Instructions] Our next question comes from the line of Danielle Brill with Truist Securities.

I'll extend my congrats as well on the data excellent outcome here. So one on the robustness of the result, I recognize that we're not going to see detailed subgroup analyses until you present them at a meeting as they're being worked through. But I was wondering if you could provide any qualitative color on whether the treatment effect was consistent across geographies?

And then a commercial question. Of the roughly 6,000 engaged patients that you view for the proximal launch opportunity, how much of that population have you actually validated at the account level versus remaining a claim-derived estimate?

Yes, great question. Thank you. Will, why don't you speak to the clinical side? And then Pamela, you can touch on the commercial side.

Sure. Regarding the subgroup, I think with the magnitude and the statistical significance that we're seeing, there's not going to be meaningful differences across subgroups that are important. So while it's something that we may look at in the future, I don't think it's going to change any of the conclusions of this study.

And then on your commercial question, as I mentioned, we really have spent the last 6 months digging into validating patients in the sort of the top 100 and 120 accounts across the U.S. And I would say everything that we've seen to date has been consistent with what we've seen in the claims data. We've been able to validate a significant number of patients and are very confident in the claims data analysis that we've already shared for these top-level accounts.

One clarification. I'm sorry. So of those 6,000, would you -- like are you saying the majority of them you would assume are concentrated across those top 120 accounts?

I would say that we have -- I wouldn't what I would say for this is that we have identified a fair number of them in these top accounts. I think what we will see as we go out and the product becomes available is that more patients will funnel into those accounts.

And I'm showing no further questions at this time. And I would like to hand the conference back over to John Quisel for closing remarks.

Okay. Yes. So obviously, we're delighted with the data and the progress we've made, and thank you all for your attention today.

This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone, have a great day.

Good morning, everyone. My name is Sean Laaman. I'm the Head of SMID-Cap Biotech Equity Research here at Morgan Stanley, and welcome to our Global Healthcare Conference. Before we begin, just to make you aware of some important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you do have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have the pleasure of welcoming from Disc Medicine, their CEO, John Quisel. Thank you for your time today. John, a pleasure to host you.

Great to be here. Thank you.

Thank you. Maybe just some macro considerations to start with, and we're doing this for all our covered companies. But how is the rise of China origin innovation, if at all, changing your competitive positioning and your R&D and business development playbook, if at all?

It's a great question. I think we are fortunately unaffected so far. We don't see anyone else developing GlyT1 inhibitors for a lead indication in porphyria. And similarly, that's true in the second indication in myelofibrosis anemia. We haven't really identified any competition from that sphere at this point. And as you know, these are all now -- our pipeline programs are all transitioning towards Phase III and the lead program has Phase III readout and hopefully a commercial transition shortly. So I think we've managed to kind of get beyond that competitive wave, at least at this.

Okay. And what about AI and its adoption? Are you adopting AI within your business? And what sort of impact do you think it can have?

Yes, we are working on that. It's still early days. I think it runs from the menial to the really -- well, even the menial is quite important actually. And -- but as you know, in a rare disease setting, one of the most important factors in driving towards peak revenue is literally, if you have a good therapy, being able to identify where the patients and their treating physicians are located. And I think that's an area where there's a lot of interesting new tools being developed.

Sure. And last question before we dig into the meat of disc, but maybe it is quite high on your agenda. Which policy variables, is it FDA, Medicare negotiations, MFN tariffs, global pricing, which policy variable you think will have the most impact?

I mean we do think a lot about MFN pricing. It impacts the perceived value of overseas markets, which itself impacts ideas about whether you might partner or develop on your own an asset, such as bitopertin, right? We are clearly committed to building in the U.S. market on our own. But strategy is still evolving in terms of overseas markets and MFN has an impact on that.

Sure. Right. Now to get into this specifically, thank you for doing that. But bitopertin in EPP and looking -- I've got a couple of questions here in the APOLLO readout and the regulatory path. But I guess sort of following the June Type A meeting, can you share any more detail about the feedback you received during that meeting in terms of what the FDA is looking for?

Yes. I mean I think broadly speaking, we and they are both focused on the APOLLO Phase III trial and I think broad alignment around the endpoints. That's really about all there is to it. I think we're just in a position now where we need to deliver what's hopefully fantastic data from the Phase III trial.

And on the powering, we understand that APOLLO is designed to detect roughly an 11-hour time in sunlight difference. Can you walk us through how you arrived at that powering assumption? What gives you confidence that the placebo-adjusted delta holds up in a larger, more geographically diverse study?

Yes. I mean the objective of the drug is to reduce the protoporphyrin IX and give these patients the freedom to spend time in light if they choose to do that. And that endpoint is designed to detect the time that they choose to spend. And I'm using the word choose to emphasize that it's a voluntary endpoint, right? And what we saw in Phase II is that, by and large, over time, patients who are on the active arm tend to choose to spend more time in light. And we see that trending upward. The placebo-controlled trial in the U.S., the AURORA trial was 4 months. In the last month of that, you see an upward trend. When you look at the 6-month open-label trial in Australia, you see that continues.

And when we look now at snapshots of data from the long-term extension trial, where, to be honest, the data quality starts to erode a little bit on these diaries. But nonetheless, what you see is patients with just spending vastly more time in light. So it appears -- it's kind of what you would expect. The drug gives people the biochemical ability to spend time in light within a matter of weeks. But then for patients who spent their entire life avoiding sunlight and often design their entire lifestyle around that, having that newfound freedom takes a while to adjust to. So back to which month do we -- so we're using the last month, this month 6 because we think it's a good place where you get beyond the placebo effect, but also you give patients time to adjust their behavior to detect a difference of the drug therapy. But what we chose to use for our projected effect size, we didn't use the last month of the Phase II trial.

What we did is we basically took months 2, 3 and 4, where you're still just starting to separate from the placebo group and use that as our projected effect size. So essentially, as long as the patients behave like any of months 2 through 4 or at least an average of months 2 through 4 from Phase II, then our powering calculation should be robust to that. And if they're doing what we expect was actually spending more time separating further from placebo when you get out to month 6, then we should be in an advantageous situation.

Sure. Thank you, John. On seasonality, U.S. patients exited all times of the year. But the majority of ex U.S. patients are expected to complete in spring and summer. And you noted roughly half the geographies that weren't in AURORA now synced up. Given more patients completing the higher daylight, how are you thinking about the seasonality impact?

Yes. We think it's well represented in the Phase II data. So that placebo-controlled trial conducted in the U.S., 75 patients running from Seattle, Boston down to Miami and Texas. So I think representing a lot of different seasons, a lot of different geographies, a lot of different light intensities. So all of that, I think, is already represented in the Phase II data that we used. We also know that the seasons didn't have a dramatic effect. We can detect a difference from -- with the drug both in the winter and in the summer. I think our intuition is that -- and the data bears this out is that the delta is larger in the summer. And so I think it's -- what we see here in the way the enrollment played out is that the U.S. patients are a pretty broad smear across the seasons. And like you mentioned, through the accident of a very rapid enrollment, the European patients ended up concentrated as completers across the summer. And I think we don't know for sure, but our guess is that should be favorable to detecting a drug effect.

Sure. Thank you, John. And on the clinical meaningfulness language that we observed in the CRL, can you share about what this means for the APOLLO readout? And would it be achieving stat sig on the time in sunlight endpoint?

Yes. I mean the key here is that exactly. The co-primary endpoints are PP9, which would be shocking if we missed that and then the sunlight endpoint, which is where we really powered the study and in doing so, of course, overpower the PPIX, hitting those 2 co-primary endpoints, p-value less than 0.05, that's the key.

Sure. And I guess given the work essentially every patient felt better. How much does the patient experience in real-world advocacy that builds up after the CRL reinforce the case regardless of how the primary endpoint reads?

Well, right. I mean, so with the CRL, I think that really activated the patient groups deep frustration around that result and so you see a lot of media reports now with patients coming forward and telling their story about the disease. I think they're trying to make sure that the seriousness of what they're living with is made more public perhaps than it has been before. And then many of them are choosing to talk about their experiences on Bitopertin, and those have been remarkably positive stories. And I guess what we take in from all of that is that there is a meaningful impact here with the drug. And the challenge we have really is just detecting it with our endpoints, right? That's converting that patient experience into clinical output. But I would argue that's a vastly better place to be than if you don't really know what your drug is really doing, right? I feel like we have very good insight into what it's doing for many of these patients and gives us a lot of confidence that the math we've put into designing the Phase III trial will work out correctly.

Sure. And thinking about the HELIOS-B study, the extension study. How much is there a way to think about that in terms of derisking some of the data that we might observe from APOLLO?

Yes. Well, it's certainly helpful to see, for example, the protoporphyrin IX suppression continues essentially uninterrupted for apparently years on end. And that, as I mentioned before, people tend to increase the time they spend in light, the more time they're on therapy, which I think is evidence of perhaps people adjusting their lifestyles in a way that is very meaningful. So those things are all very encouraging. And simply the rate at which people choose to go into that long-term extension. We've talked about in Phase II, we had about 86 out of 100 patients choose to roll over under the long-term extension. We've talked about the enthusiasm there was in the rapid enrollment in the Phase III trial such that now we're -- we know the last patient last visit is in this month. And so at this point we start to have insight into the rate at which patients have chosen to roll into the long-term extension out of Phase 3. And it's literally only 2 patients have chosen not to, which out of 180 plus eligible patients, its -- I think, shows an astonishing level of enthusiasm and interest in receiving this therapy.

Okay, thank you, John. I've got a couple of questions here on the commercial opportunity for Bitopertin and the competition. But assuming approval, how do you think about sizing the U.S. EPP opportunity and the number of patients you'd realistically target at launch? And is it patients on Scenesse or treatment-naive patients?

Well, the patients on Scenesse is, in our view, a pretty small number. It's not easy to estimate, but I would say on a year-to-year basis, it's probably no more than we have already in our clinical trial numbers. And then, so obviously that is a group that will want to offer Bitopertin to you in a launch situation. But I think what's more interesting is the patients that we see, at centers of excellence. I think we reported something like 600 patients at the top 10, 15 centers, and that's been validated by our field force. So validated on the ground, not purely based on claims data. That's an excellent place to think about launch potential. That doesn't get you, of course, to the kind of peak sales that we're hoping to achieve here, but it certainly gives you a place to start from and then we're continuing to kind of engage with accounts using the claims data as our guide, right, going to the physicians who are reported to have a decent number of patients and working down that list.

And we see a decent correlation between the two. It's not perfect. The claims data is never exact to the current real world situation but I think. Directionally, it looks like it's going in a good direction.

Sure, thank you. And what does the cost structure of the launch look like? Should we expect a ramp ahead of the approval?

Should we expect them, sorry, what?

Sorry, the cost structure of the launch as you're thinking...

Oh yes, yes.

about the infrastructure etc, etc.

Oh yes. I mean, you know, our cash runway is into 2029. We assume no revenues in that model, but we have fully loaded in commercial expenses. And some of those commercial expenses are going on right now as we speak, you know, around disease education, engagement and then as we get across the data assuming everything looks good, then those activities will continue to ramp as we head towards launch.

Wonderful. And how do you think about scaling that if, you know, the PV and MF opportunities, how do you think about scaling that infrastructure?

Well, I think some of the home office infrastructure scales very well. I'd say the field force infrastructure will probably be different. We'll, you know, as originally planned, 24 reps to focus on the porphyria population. I think when we get to myelofibrosis and polycythemia vera, those two indications are directly overlapping in terms of physicians. So that's one sales force to address those two patient groups, but that's probably a different sales force specialized in the HemOnc space versus the porphyria space.

Sure. Sure, thank you. And just on the competitive dynamic, just in emerging competition in EPP space, how do you frame that for investors?

Yes, so we all know about Scenesse, the surgically implanted drug, the only approved product today. There's dersimelagon, which works by a similar mechanism, essentially an oral version of Scenesse. It failed in initial Phase III, had a successful second Phase III, was acquired by a company this summer called LEO Pharma. And, you know, that's, we're probably on roughly the same timeframe of getting to launch sometime in the first half of next year. We think we're unique in the sense that we reduce protoporphyrin 9. We think it gets to the root cause of the disease. And then behind us there's one additional product that's targeting, I guess a novel theory of targeting the plasma compartment of protoporphyrin IX versus the whole blood, which is what we go after.

Thank you, John, and maybe moving on to 0974 in MF anemia. Can you remind us what the most recent cut of data that you've shown to date has shown?

Yes, it's been a remarkable developing data set. We designed a Phase III trial with telemetry 3, 4 cohorts initially to just look across the whole survey of anemic myelofibrosis patients. And these patients range in profile from newly diagnosed patient who's never received any therapy, just simply had an anemia, which turned out to be myelofibrosis, all the way through to patients who are getting as many as 6 units of blood on a 12-week basis, so very intensely transfused patients. And what we see across that spectrum is generally the same overall response rate of around, if you look at what's called the major response, which is what the FDA is going to key in on, it's around 50% to 60%.

And then if you look at what's called the minor response rate, which is probably what the clinicians look at, you're up to, you know, 70%, 80%. So remarkable response rate, but even more remarkable is the way that this, you know, fairly heterogeneous disease population, we get roughly the same degree of response across all of them. And that kind of common response is probably driven by just like a common mechanism, which is we're stimulating hemoglobin formation, and that fundamentally gets to whether you're a responder for hemoglobin or a responder for transfusion.

Okay. On competition with that one, your momelotinib establishes a mechanism anemia sparing and mutant CALR targeting antibodies emerging. How do you see 0974 fitting?

Yes, well, what we've learned about momelotinib, to your point. It's anemia sparing, but it doesn't, we saw at least as a trial experience, we created a special cohort to allow some of these new JAK inhibitors to come in, and we saw quite a few momelotinib patients, and in fact, many of them, you couldn't get into a trial unless you were anemic already. So patients who were receiving momelotinib remained anemic and responded very well to our therapy. So I think momelotinib, I view, is just part of the background therapy for us, right? There's Jakafi, there's momelotinib, there's pacritinib, there may be some new agents coming even, pelabresib, who knows what. And our expectation is, you know, our mechanism by mobilizing iron is just kind of orthogonal to all of those and should prove to be effective on top of really any background therapy. So I don't view that really as a competitive dynamic there.

Sure, thank you. And what signposts, whether it's the data or what signposts can we expect from 0974 over the next sort of 6, 12, 18 months and just your general alignment with the FDA on clinical endpoints.

Right, well that is the big signpost. So we've seen enough from an efficacy safety point of view, we believe this drug should progress to Phase III. We will share one more data cut from that later in this year, and that will be the same data cut that we use as the basis for end of Phase II meeting with the FDA. So before the end of the year, we hope to provide the public community with insight into that last data cut, which probably will be about the same as data we've seen before. But also now a kind of what we hope will be an aligned Phase III trial design with the U.S. regulators. And, of course, we'll talk to European regulators as well.

Sure, and on other indications for 0974s, the RALLY-IBD trial started early this year, and how do you compare the opportunities in MF and IBD?

Well, yes, Rally IBD, we're excited about the, we remain excited about this kind of broad anemia of inflammation concept. So that'll be a trial probing that specific question in the setting of IBD patients. There are a lot more IBD patients in this country than MF patients. And even if you take the anemic subset of IBD patients, it's measured in hundreds of thousands. So by target population, it's a very large -- or it's a large indication. And you know, to that point, while we're using 974 as our signal-seeking study agent, we may well choose to use our second-generation product with the longer serum half-life, which may be better for those patients who see their doctors less frequently. That may be where we actually continue that development once we find, you know, validate a signal in the anemia of inflammation population.

Sure. Thank you, John. Maybe moving on to DISC-3405. So you presented the RESTORE-PV data at SOHO last week. Can you give us a recap of the data and how you believe the antibody performed?

Sure. Really, you know, overwhelmed by the enthusiasm for our Phase II program. And so we were able to move our first data release up into SOHO rather than conference later in the year although we probably still will have yet an additional data cut before the end of the year. So we took our first cohort, right? There's two cohorts here. The first one cohort A, which involves a little bit of dose escalation and then the settling in at a Q2 weeks 300 milligram dose level, and then cohort B is a steady 300 milligrams Q4 weeks dose level. So very similar dose ranges and the data were great. Really pleased with what we saw. You know, the measures of efficacy where you're looking at reduction in phlebotomy, a stable hematocrit at around 45%. Those look really good and pretty much right on with, as we know, it's a competitive field with other agents in the field.

So on efficacy, I think we're meeting the standard and I think one of the places we're hoping to distinguish in the long run is the by having a product that's more tolerable to patients. So we're keeping an eye on some safety and tolerability aspects like, whether patients become anemic on therapy, whether patients have injection site reactions, and so far, early days still, but both the rates of those events appear to be quite low. And possibly, you know, we'll see, but maybe allowing us to in the long run claim to have one of the better product profiles in the space.

So it seems in the data so far you're seeing what you need to see on phlebotomy and hematocrit control. When do you get to a level of confidence to bring it forward into Phase III?

Oh, I think if we replicate that same data in cohort B, we'll be able to choose a dose and progress. So that's kind of slated for next year is our end of Phase II meeting on that program as well as the presumed Phase III trial start, which time-wise puts us right in the mix with the other TMPRSS6 targeted agents.

Okay. Yes, so maybe give us your view on the comparative dynamic when we think about what we've observed so far from Silence and also the recent launch of rusfertide. What should we really be looking at? Phlebotomy, hematocrit, injection site reactions?

Right, right. Yeah, well, like I said, I think you see all these agents collecting around the same degree of phlebotomy free rate, which has emerged, I guess, as kind of the, it's the endpoint that Ruxolitinib used to support approval as primary. So you see rusfertide, you see divesiran, you see our program, you see Ono, and safrablursin all performing in the same range. Everyone has different mass of data, right? Obviously, rusfertide has the largest, most rigorous data set, and then those of us in Phase II have smaller data sets, but assuming that all proves out, on that front, everyone will be pretty similar. And then the differentiation probably comes from tolerability, safety, convenience, ease of use, all of that.

Sure. And still on 3405, so we've got the Phase 1b data coming up in sickle cell disease. So what should investors expect there?

Yes, yes. So by the end of the year, I think we will have a little bit of data from that trial. It's a novel approach to sickle cell and we're taking it slowly because safety is paramount in that population and so I think we'll have, think of it as single digit patient information, so essentially almost case reports. And we're able to look in a very detailed way at the way the mechanism works. And the goal would be to see restriction of iron manifested in reduced concentration of hemoglobin inside the red cells and then if things are going great that could convert into a reduction in evidence of cellular damage, sickling, which can all be measured through a variety of different biomarkers. The big question in the end is can you reduce important clinical adverse events like vaso-occlusive crises, retinal damage, kidney damage. That is something we're not going to see for quite a while in this study, but really just trying to look at the physiological and scientific underpinnings that predict whether those clinical endpoints might be worth pursuing in a larger trial.

Sure. I've got this financial question, here's on one of my last questions, you've kind of already answered it, but seeing I get so much inbound on it, I'll ask it again, but before I do that, a lot of the inbound I get is on bitopertin, so I don't get so much on PV and so much on MF, but just your view on how you think investors maybe underappreciating those assets relative to bitopertin. How would you sequence them in terms of value?

Yes, well, interestingly, bitopertin is, of course, a totally novel financial proposition, right? It's the first potentially disease-modifying therapy in this rare disease where there's not a lot of experience. So we're building that story with various pieces of evidence and the value proposition around that. The other two indications, there's tremendous numbers of peer case studies that provide value indexes. There have been numerous companies with Phase III myelofibrosis programs, and I would argue our program may have the broadest applicability many of these molecules across these patients.

And so I think you can look at other, there's been a whole series of Phase III myelofibrosis programs that have been acquired at value points and a quick AI search would give you a sense of what the value ought to be for that product. The same could be said now for polycythemia vera. Now, we have several different peer companies, some of whom are essentially single asset TMPRSS6 agent valuation and that gives a very good kind of basis for thinking of a value for our TMPRSS6 program. And I would say if you put those things together with our cash, which as of last quarter sitting above $700 million, it would tell you that if you wanted, this is not how the market's viewing it, but I would argue, you know, you could almost see the entire value of the company embedded in its pipeline plus cash.

Sure, sure. Last question, but you have kind of answered it, or we have answered it already, but just to double down, the $718 million cash on balance at the end of Q2. There is a lot going on at the company, and just sort of, you're confident that we're going to get to your long-term trajectory. We're not going to see, you know, a blowout on costs either way?

Oh no, I mean our cost, our guidance is cash into 2029. It's quite conservative in the sense that it does not include any potential revenue from bitopertin. And so, you know, you can kind of straight line the projected burn if you want, but and I would imagine that that'll be the trajectory.

Awesome. And is there anything that I didn't ask that I should have today?

No, no, no, I don't think so. I think we're just super excited to be coming in to the end of the year. First evidence that our TMPRSS6 program is looking good, looking like it's on a path to Phase III. We'll have our APOLLO trial data in Q4, which will answer the question about where bitopertin's headed. And then we'll have, hopefully, the end of Phase II readout from myelofibrosis, which will show the path for that to Phase III. So I think incredible transitional moment here for the company at the end of this year.

For sure. I agree, pretty exciting. But thanks for your time today, John.

Yes. Thank you.

We'll call it closed, but thank everyone for listening.

Ladies and gentlemen, thank you for standing by, and welcome to the Disc Medicine Corporate call at EHA 2026. [Operator Instructions] Please be advised that today's conference is being recorded. I would like now to turn the conference over to John Quisel, Chief Executive Officer. Please go ahead.

Good morning, and welcome to the Disc Medicine Management call. This is John Quisel speaking, CEO here at Disc, and I will be joined by Will Savage, our Chief Medical Officer; and Jonathan Yu, our Chief Operating Officer, to review the data presented at the European Hematology Association conference in Stockholm this past weekend, as well as data from our oral presentation at ASCO earlier in the month.

Before we get started, I'll cover a few preliminaries. We will be making forward-looking statements, and they should be taken in context with respect to materials that we have filed with the SEC and are posted on our website. Additionally, Bitopertin, DISC-0974 and DISC-3405 are investigational agents and are not approved for therapeutic use in any jurisdiction worldwide.

Turning to the agenda. I will give a brief introduction and provide a status update on Bitopertin, reviewing the results of our Type A meeting with the FDA. Then we will get into the EHA updates. Will will present updated data from HELIOS, the open-label extension study for Bitopertin and EPP as well as an updated data cut from our Phase II RALLY-MF study of DISC-0974, which now has an approved nonproprietary name, Selcodebart. And this trial is in patients with anemia of myelofibrosis. We're very excited about these data because as you'll see, the results continue to indicate that Selcodebart is a potentially transformative treatment for patients with anemia of MF. Then Jonathan will provide some commercial perspectives on the MF anemia market. And finally, Will will discuss our third program, DISC-3405, providing an overview of our vision in iron restriction and study designs for the first two inpatient studies in polycythemia vera and single cell disease, for which we'll present data later this year. I will close with a review of the company's catalysts for the rest of 2026.

Here is a quick reminder of our pipeline, which most of you are familiar with. We have Bitopertin, which is in a Phase III study for patients with EPP. Our second program, Selcodebart, or DISC-0974, is targeting anemia of inflammation generally. And we have ongoing studies in anemia of myelofibrosis and anemia of inflammatory bowel disease. Our third program, DISC-3405 is an Anti-TMPRSS6 antibody which we are currently studying in polycythemia vera and single cell disease.

So here are some of the key messages for today's call. For Bitopertin, as we shared a few days ago, we successfully completed our Type A meeting with the FDA to review the CRL, and we're happy to say that the FDA is aligned that the results of the Phase III APOLLO study can serve as the basis for our CRL resubmission, which we expect to happen by the end of this year.

We also shared an update at EHA from the HELIOS open-label extension study Bitopertin, which continued to show sustained reductions in protoporphyrin IX for over 1 year, which translated to sustained and significant improvements in light tolerance measures, all with a favorable safety profile.

For Selcodebart, we shared updated data from our Phase II RALLY-MF study, showing meaningful durable overall anemia responses across all patient subgroups, regardless of baseline transfusion status and independent of concomitant JAK inhibitor use. We also saw evidence of symptom improvement on several PROs, including FACIT-Fatigue and TSS 50. We find this very encouraging and feel it supports the potential of Selcodebart to treat a broad range of anemic MF patients.

Finally, for DISC-3405, our clinical trials in PV and sickle cell are ongoing, with initial data to be shared in Q4.

Now I'll go into details around these updates, starting with Bitopertin. As I mentioned, we are happy to share that we had a productive Type A meeting with the FDA. In this meeting, we confirmed alignment that APOLLO can serve as the basis for our CRL response. If all goes well, we would now be looking at a traditional approval rather than an accelerated approval. And as a reminder, we completed enrollment of APOLLO in March and expect to share the top line data from the study in Q4, and then we will use that data to support our CRL resubmission by the end of the year.

In the meantime, we have also launched an expanded access program for Bitopertin and are continuing our commercial preparations to be ready for a potential launch in the middle of next year.

I'll now hand it over to Will to walk through the HELIOS data presented at EHA.

Thanks, John. As a reminder, HELIOS is our open-label extension study for Bitopertin, and we will be sharing data here from the 86 patients who rolled over into HELIOS from the Phase II BEACON and AURORA studies.

Looking at the PPIX data, we see that PPIX reduction seen with Bitopertin treatment are sustained for the duration of HELIOS, including patients who now have over 1 year of follow-up. As a reminder, the start of the HELIOS study includes patients on a mix of 20 and 60-milligram doses. And then ultimately, patients transition to 60 milligrams, which is the reason there's a slower decrease in PPIX compared to those who are on 60 milligrams for the full study. What is notable here across all patients is the durability of the PPIX reduction, which we are now showing is maintained for over a year.

We also, for the first time, shared light tolerance data for the HELIOS study. The frame of reference for light tolerance is the first day of HELIOS and note that some placebo patients had already started Bitopertin in an in-built extension in AURORA. Importantly, all patients continue to experience significant improvements in light tolerance. Those previously on Bitopertin and those previously on placebo. This shows that the sustained reductions in PPIX with Bitopertin continue to translate into improvements in EPP symptoms over the long term.

We are also encouraged that the safety profile of Bitopertin continues to be favorable with over 2.5 years of drug exposure in some patients. All SAEs and TEAEs were reported as unrelated to study drug and all other TEAEs were mild or moderate in severity. We also saw the rate of dizziness decrease in HELIOS as compared to AURORA, adding to the evidence that any dizziness side effect tends to be transient.

So overall, a great data set coming out of HELIOS on long-term use of Bitopertin with sustained reductions in PPIX and improvements in light tolerance, all with a favorable safety profile.

As John mentioned, we are also currently conducting our Phase III APOLLO study, which we expect to serve as the basis for our CRL resubmission. As a reminder, this study is being conducted in the U.S., Canada, U.K., Europe and Australia, with primary endpoints with PPIX reduction in average total monthly time and light at the end of study. We designed the study with an initial sample size of 150 patients, providing 80% power with conservative assumptions. And now that we have expanded the sample to 183 patients it has even greater power, so it is really a robust study. We completed enrollment for the study in March of this year and expect top line data in Q4 this year.

Now that the study is fully enrolled, we also wanted to share the baseline characteristics for patients in our APOLLO study. You can see we have strong adolescent representation with 34 of our 183 patients being under the age of 18, which we think emphasizes the level of unmet need in these younger EPP patients.

In terms of baseline light tolerance, measured as time to program, the patients are split evenly between those with the baseline time to program of above or below 30 minutes. Geographically, we have good global representation with 45% of patients coming from the U.S. and 55% ex U.S. with 72% located in northern sites and 28% at Southern ones.

We also had fairly even distribution of seasons in which patients entered the APOLLO study, with the greatest number of patients randomized in the winter and spring. Overall, these baseline characteristics are typical of the EPP patient population and are similar to those in our Phase II studies. And now I'll hand it back to John to talk about Selcodebart.

Thanks, Will. We're excited to share these updates on Bitopertin, and we know this program is on a lot of folks' minds. And so we'll have the APOLLO data in a few short months in Q4. But I think our biggest update today is actually in our RALLY-MF trial with Selcodebart. Selcodebart is our monoclonal antibody that suppresses Hepcidin, which as a reminder, is a master regulator of iron. We are exploring this drug across a broad range of anemias, leading with the RALLY-MF Phase II trial in anemia of myelofibrosis. We presented initial data from RALLY-MF at ASCO last year, which showed anemia response rates that are unprecedented in this population.

Anemia and myelofibrosis is a severe consequence of the disease that has no approved therapy and has been resistant to treatment despite decades of research. The emerging profile of Selcodebart in the RALLY-MF trial suggests that we may finally have a meaningful impact on this form of anemia. The trial is progressing well. And as we presented at ASCO a couple of weeks ago and at EHA this past weekend, we are encouraged to share that the anemia response signal has been strengthened and solidified with additional enrollment and longer follow-up. I'll hand it over to Will to go through the details.

In this update, we are looking at data through April on 61 patients across the non-transfusion-dependent or nTD, TD low and TD high cohorts. I'll call out, in particular, the TD high cohort which had only three evaluable patients at the last data cut. So today's update is a meaningful update for that group.

Looking at the pharmacodynamics, as expected and consistent with prior results we see significant decreases in Hepcidin and increases in serum iron. This translates into a remarkable hematologic response across all cohorts, with 56% of all patients achieving a major response and 72% achieving an overall response.

Going cohort by cohort, I'll start with non-transfused patients. On the right-hand panel, you can see there were early, meaningful and durable hemoglobin increases. This translated into major response rate of 55%, defined as a 1.5 gram per deciliter increase in hemoglobin maintained for 12 weeks and an overall response rate of 68% and defined as a 1 gram per deciliter hemoglobin increase over 12 weeks.

For TD low patients who tended to have a lower baseline hemoglobin, the hemoglobin increases were strong and durable across the board. 64% of patients achieved a major response of transfusion independence over a period of 16 weeks and 73% reduced their transfusion burden by 50% or more.

Finally, for the most heavily transfused patients, 50% achieved transfusion independence over 12 weeks and 88% achieved a transfusion burden reduction of 50% or greater.

We also looked at several patient-reported outcomes to further characterize the clinical benefit of anemia improvement. We saw marked improvement in the FACIT-fatigue score in the nTD and TD low groups which was correlated with hemoglobin change. An increase of 3 points on FACIT-Fatigue is considered the threshold for clinical significance.

Among nTD and TD low major responders, 50% of patients achieved a 50% decrease in the MPN-SAF total symptom score. Hemoglobin improvement was also tightly correlated with improvement in patient global impression of severity.

Importantly, we permitted patients to enroll who are not taking a JAK inhibitor or who were on a stable dose of any JAK inhibitor. The pharmacodynamics and hematological response remained consistent across all background therapies, positioning Selcodebart for broad potential use in any patient with MF in anemia. Note that the pacritinib line in yellow represents one patient who held drug due to normalization of hemoglobin, and that's why the curves are variable.

Finally, looking at safety, Selcodebart continues to be generally well tolerated with no serious treatment-related AEs. Overall, we are very excited about this data set where Selcodebart continues to shed strong responses across a broad range of patient types within anemia of MF. And now I'll hand it over to Jonathan to review the MF anemia market.

Thanks, Will. Based on the strength of this data update and the significant need for treatments for anemia of MF, we believe Selcodebart represents a blockbuster opportunity in this indication.

To give you a sense of the magnitude of today's market, current sales of JAK inhibitors in the U.S. for myelofibrosis comprise around $2 billion annually and continue to grow. This reflects patients who are presently receiving treatment with these agents.

It's important to remember that while JAK inhibitors are a mainstay of treatment to control symptoms and reduce spleen size and MF patients. They do not treat the anemia. And in fact, this class of drugs is often associated with worsening anemia.

And beyond these patients is a large prevalent segment of MF patients who are also anemic, but not receiving JAK inhibitors. And this can be due to a variety of reasons, but often, it is because their anemia precludes them from treatment with these agents.

Our data suggests that Selcodebart has the potential to address both these groups, anemic patients on or off JAK inhibitors, which combined represent about 22,000 addressable anemic MF patients in the U.S. alone. When you consider the severity and difficulty of treating anemia in MF, we believe this implies a total addressable market potential greater than $4 billion for just the U.S.

So this is a very meaningful commercial opportunity and we believe the Selcodebart could become a preferred option for these patients. And if we move to the next slide, we believe that is because our emerging product profile continues to check all the boxes for meeting the key needs in anemia therapy. And we think of this along three critical dimensions.

First is the Selcodebart's potential utility across patients independent of whether they are non-transfused, lightly transfused or heavily transfused. And this update shows that we are seeing strong similar rates of hematologic responses across each of these different groups.

Second is its potential utility across patients independent of background therapy. And again, we are seeing strong similar rates for Selcodebart as both monotherapy and in combination with JAK inhibitors. And because JAK inhibitors can worsen anemia to the point of requiring dose reduction or even discontinuation and addressing the anemia with Selcodebart could enable optimal treatment with JAK inhibitor therapy. This breadth of activity is a differentiating attribute of Selcodebart, and we believe will enable its use across the spectrum of MF patients with anemia, including in the frontline setting, together with the current standard of care of Ruxolitinib.

And finally, even with a larger data set and longer treatment duration, we continue to see very high hematologic response rates. Major responses of 50% to 68% and overall responses of 64% to 88%. The magnitude and quality of the responses, together with the fact that this improvement is palpable for patients is extremely encouraging, and we think we'll set the bar for efficacy in treating anemia in these patients.

And now I'll turn it back over to John to discuss how we are thinking about applications beyond MF.

There is a lot to be excited for on the MF front as this data set evolves. But I want to remind everyone that we view this mechanism as potentially broadly applicable across a range of anemias of inflammation driven by high upside in a mouse model of inflammatory bowel disease, we saw that Selcodebart suppresses Hepcidin and increased iron and hemoglobin, and we even saw signs of disease modification and anti-inflammatory activity in this model.

So based on this data, we initiated a Phase II trial in anemia IBD earlier this year. We started dosing patients, and we expect to present some initial results next year, which will be an exciting indicator of the broader Selcodebart opportunity.

So to recap, we expect to bring the RALLY-MF to the FDA by the end of this year, in preparation for pivotal trial initiation in the first half of 2027. Meanwhile, we are advancing in the clinic in IBD, continuing to explore ideas around next indications. And in the background, we're progressing a long-acting anti-hemoglobalin antibody towards IND.

Lastly, I want to touch on our third program, DISC-3405, which will have some exciting updates as we come into the end of the year. As a reminder, DISC-3405 is an Anti-TMPRSS6 antibody, which increases Hepcidin and limits iron availability. This has therapeutic applications and diseases associated with excess red blood cell production, like polycythemia vera and also potentially in the treatment of sickle cell disease as well as other indications where iron overload may be an issue for patients.

We presented healthy volunteer data at ASH last year, which showed this mechanism is working as expected, and we have now advanced into two inpatient studies in PV and sickle cell disease. We have also explored DISC-3405's potential role in treating conditions of iron overload, as shown in our iron pulse study presented last year, and we are continuing preclinical work in some of these indications.

This slide is a brief reminder of our healthy volunteer data for DISC-3405 which demonstrated the drug's ability to significantly increase Hepcidin and decrease iron availability. This led to decreases in hemoglobin and hematocrit, which are expected to be beneficial in conditions like PV. DISC-3405 is an exciting growth driver for Disc, offering a differentiated product profile starting in PV, which has been derisked to a certain extent and represents an attractive market opportunity. PV is a larger orphan indication with around 150,000 U.S. patients, half of which are treated today with plenty of room to grow.

This is a serious disease with uncontrolled hematocrit leading to significant risk of potentially life-threatening thrombotic events, among other debilitating symptoms. And many patients are not achieving optimal hematocrit control with current treatments.

The Hepcidin mimetic rusfertide has shown great results in PV achieving significant phlebotomy-free hematocrit control and improving negative symptoms associated both with the disease itself and with the iron deprivation that is caused by frequent phlebotomy. If this product is approved, it should open up the market for upside and pathway targeting agents in PV and then we believe we can improve on that profile with a monoclonal antibody that is dosed less frequently and has shown favorable safety and tolerability and a low rate of injection site reactions to date.

Importantly, there is also a significant synergy here with our MF program. And this synergy has already benefited both programs in terms of clinical development efficiency. So these two programs together form the start of a strong MPN or hem/onc franchise. And so here, I'll hand it back to Will to discuss our initial Phase II PV trial.

Here is a look at our Phase II PV trial, which we are calling RESTORE-PV. This is an update from what we have shown previously. In the early days of the trial, we saw such strong interest in enrollment that we amended the protocol to increase the size to 40 and from 20, with 20 patients in cohort A in 20 patients in cohort B. Cohort A has a dose escalation period before moving into maintenance periods, dosing DISC-3405 at 300 milligrams every 2 weeks. Cohort B will receive dosing of 300 milligrams every 4 weeks for the entire study period.

We'll be focusing on safety, PK, Hepcidin, iron, hematocrit and phlebotomy rate and expect to present initial data in Q4 this year. Enrollment is well underway and baseline characteristics of the trial population, which you can see on our EHA poster, are generally consistent with comparable PV trials.

In addition to PV, we have been investigating other indications in which DISC-3405 could be beneficial. One such indication is sickle cell disease, where there is a growing body of literature supporting the potentially disease-modifying effects of iron restriction either through phlebotomy or dietary changes. We conducted a preclinical study in talent mice to test whether iron restriction through weekly doses of DISC-3405 could have a beneficial effect. In our study, we saw that treatment with DISC-3405 led to reductions in red cell hemoglobin S concentration, improvements in markers of inflammation and improved hemolysis markers. These data are encouraging and open up the possibility of sickle cell disease as an interesting indication for DISC-3405.

And here is our Phase Ib sickle cell trial design. The main cohort of 12 participants will include patients with hemoglobin SS and hemoglobin SC genotypes. There will be 20 weeks of dose escalation from 75 milligrams to 300 milligrams followed by an optional maintenance period. We're measuring safety, PK, Hepcidin, iron hematologic parameters and hemolysis markers and we'll explore additional efficacy endpoints, including PROs and clinical endpoints. We expect to present data in Q4 as well. And now I'll hand it back to John to wrap up.

Thanks, Will. So overall, this represents another exciting set of updates at these midyear conferences of ASCO and EHA for our programs and with more catalysts to come in the second half of the year. We continue to execute across all three programs and expect a steady cadence of value-driving milestones through the remainder of the year.

For Bitopertin, we have aligned with the FDA on our CRL response strategy and continue to generate encouraging long-term clinical data. We expect APOLLO top line results in the fourth quarter ahead of a planned NDA resubmission by year-end.

Selcodebart continues to demonstrate strong activity in myelofibrosis with additional data and regulatory interactions anticipated later this year.

While DISC-3405 advances in both PV and single cell disease, with initial patient data expected in the fourth quarter with approximately $730 million in cash and runway into 2029 and we are well positioned to advance our portfolio and deliver on these upcoming milestones.

To summarize, we feel we have three strong programs here, each of which has blockbuster potential in the initial indications alone.

For Bitopertin, we have been pushing forward with our regulatory and commercial activities as we covered today, and we look forward to delivering this potentially transformative therapy to EPP patients soon.

For Selcodebart, we are continuing to build on our foundation of strong data and progress the program quickly in myelofibrosis, which is we expect an over $4 billion opportunity on its own. While also building towards the broader opportunities in other anemias of inflammation.

And from DISC-3405, we are excited about the opportunities in PV and sickle cell disease and we look forward to seeing our first inpatient data later this year.

So a lot of excitement to come as we head into the end of the year. And with that, thank you for joining, and I'll hand it back to the operator for Q&A.

[Operator Instructions] The first question comes from Thomas Smith with Leerink Partners.

Just starting with Bitopertin, any additional color you can share from the Type A meeting with FDA on APOLLO? And what was discussed there? Specifically with respect to alignment on the trial size and co-primary endpoint and how you're defining that time and daylight co-primary endpoint? And was there any discussion on the potential to resubmit prior to the APOLLO top line data? .

Tom, yes, thanks for the questions. I'll start at the back end of what you asked. I mean, as we've been saying for months now, really since the CRL. We're delighted that the APOLLO trial has enrolled as quickly as it did. That means the data is coming pretty soon. And I think that creates a situation where getting regulators to agree to approve the drug without the benefit of seeing that data, it's just impossible.

And so we've been guiding everyone all along. Don't count on that and nothing coming from that type of meeting would suggest that we'll get approval based on Phase II data, essentially reversing the CRL. So the path here is really crystal clear, deliver the APOLLO data and then follow the traditional approval path.

In terms of the discussion around the trial design, et cetera, I mean we had thorough discussions with the FDA back when we set that trial up on the end of Phase II process and -- there's nothing -- we're just looking to deliver that data essentially as designed in the fourth quarter.

Great. That makes sense. And if I could just sneak in a quick follow-up here. With respect to the Bitopertin expanded access program, just talk about the rationale there? Was the decision to initiate that program driven by patient and clinician inbound interest? Or is there anything you can share from the early experience here perhaps in terms of patient numbers and how you think this could play into the broader commercialization strategy?

Yes, yes. We're really excited about the expanded access program. I think like if you're on social media, the frustration from the patient community around the lack of availability of Bitopertin now as was expected. It was really disappointing. And so we wanted to try to find a way to make the drug available to as many people as we can for compassionate use.

And so -- and glad to see the regulators also appreciated the importance of that. So I mean, it's pretty straightforward to set that up and kind of obvious that we should. Just as a bit of a warning, we are also keeping the enrollment criteria for that consistent with the clinical trial just to kind of make sure we maximize our chances of approval with a clean data set for APOLLO.

So it's not going to be wide open to everyone, unfortunately, that's going to have to wait until after a formal approval. But at least we're able to get it to as many people as we can who would otherwise have qualified for the trial.

And the next question is going to come from Kristen Kluska with Cantor Fitzgerald.

First, on MF anemia, I'm curious about the commercialization aspect, do you expect that one or a few of the subpopulations is going to lead to the most initial uptake where that experience could then make physicians more comfortable to expand into others? Or do you think from the get-go, there's going to be a little bit of uptake everywhere? .

Yes. Thanks, Kristen. I mean based on our clinical trial enrollment, if that's a kind of crude measure of demand and patient need, we're going to see it across the board. It seems to be something that physicians and patients are looking for, regardless of their status.

I think people gravitate to the obvious use case where someone is going to go on to ruxolitinib or another JAK inhibitor that's expected to exacerbate anemia. Any idea of either in advance of that or ...

Okay. then for Bitopertin, can you talk a little bit more about the seasonality? We've been getting questions on this particularly the patients enrolled in regions where it's winter. What do you expect the impact of the sun is in that season? And then also, will this mitigate the amount of time spent in sunlight. .

Yes, thanks Kristen. Sorry, I think I accidentally hit the mute button there while I was talking. But Will, do you want to handle this question?

Yes, sure. So I think the most important thing to note is that the AURORA trial had patients exiting throughout the year at all seasons, including fall/winter and starting in fall and winter. And so the result from there is showed no effect on the time and light end point in terms of a bit of Bitopertin always being superior to placebo. So it is true that there are fewer daylight hours in winter and the time and light does go down in winter, but it remains greater in the Bitopertin group.

So when we look at APOLLO, we have people in the U.S. exiting at all times of the year. And when you look at ex U.S., those sites got started later. So essentially, they all started in the fall and winter, meaning that they are all exiting in spring and summer. So essentially, half of the study in the geographies where we did not have experience in AURORA are essentially synced up.

And the next question will come from Roger Song with Jefferies.

This is ChaCha on for Roger. Just one question from us on the RALLY-MF data. Just wondering if any of this new data influences anything about your future trials? Is that for inclusion, especially for TD high patients as you go forward?

Absolutely, it does. I mean I think now we have real indication that the drug works across the full spectrum of patients. So we're pretty motivated to design a Phase III program that will capture and include all of those patients with the goal of getting the broadest possible label and making this drug available to as many patients as possible in this disease.

And our next question is going to come from Tara Bancroft with TD Cowen.

So I know it's been a pretty busy EHA across the board. So curious if you have any updated thoughts on competitive positioning or even plans for expansion of combination cohorts in MS, perhaps even with other investigational drugs because there were other updates in MS space at EHA, especially from CALR, which it does look like it rated a bit, but still looks better than momelotinib. But just curious to hear what you think happened there and how this changes, if at all, the utility of Selcodebart.

I mean, broadly speaking, I think, no. Obviously, there is a lot of action. I think we see the what I'll call the active and ligand trap class of drugs, luspatercept and elritercept, both reporting data and leaning into efforts to get approval in MF patients.

I think there the key points are that there's almost very little overlap between the type of patients they're trying to treat. They're generally taking aim at the very high transfusion burden patients who are also on ruxolitinib that represents some pretty small fraction of the patients that we're either studying or they even exist in this population. So we see those as kind of a sequester set of drugs. And obviously, we'll have to see how it all comes together from the safety efficacy profile given the miss primary on luspatercept. So that's that class.

And then CALR, yes, I mean, this is super exciting for patients. It's great to see these antibodies targeting a driver mutation. Here, we're talking about 1/4 to maybe 30% of MF patients overall, who, by the way, are sort of underrepresented in the anemia population because that driver mutation tends to be kind of focused its effects in the platelet compartment.

So not clear how much that's really going to affect who needs anemia therapy. And I mean, we see effects on hemoglobin with those drugs in those patients. But again, kind of need to wait and see how it all settles out when you look at response rates, et cetera.

Like my guess is a large number of those patients will still be looking for, for example, a combination with Selcodebart to manage their anemia which I guess comes back to where you started about would we run combination trials.

Yes, we'll see. We'll see. That is entirely possible that we could do some additional sort of small trial work while we're running our Phase III program. But yes, let's get through our end of Phase II meeting and then we'll be able to update on those things.

And the next question will come from Evan Seigerman with BMO.

Malcolm Hoffman on for Evan. You touch again on the importance of the change you saw in that FACIT-Fatigue score for Selcodebart. I know you've mentioned a 3-point change could be clinically significant here. And given the results we saw here for the Phase II, how do you think about the importance of FACIT-Fatigue for potential approval if included in the Phase III.

Yes, thanks. It's certainly a precedented endpoint for anemia studies. But Will, do you want to comment further on that? .

Sure. So FACIT-Fatigue is one of the many PROs that we're administering in the Phase II. The past experience with FACIT-Fatigue in a number of different settings has shown that an increase in three is kind of a consensus clinically important difference. It's -- there's a spectrum there, like the higher the greater the change, the clear the benefit.

I mean, people have gotten demonstrated benefit with less than 3. So we just -- but we just picked 3 as the dotted line on the figure to just pick the most commonly cited thresholds in the literature. So I think at all levels, there's -- it's clear that there's a benefit on the PRO. And yes, for the Phase III that I think this is more applicable to the nTD and perhaps TD low groups because the change in or the improvement in the FACIT-Fatigue is related to the delta and the improvement in hemoglobin. And those with higher transfusion burdens, it's more about reducing transfusion burden than then increasing hemoglobin.

And the next question will come from Stephen Willey with Stifel.

Hello. This is Carolina [ Evanson ] for Steve. Related to DISC-3405 post-hoc analysis of the Phase III VERIFY study show an elevation of platelet counts when the dose of cytoreductive therapy, hydroxyurea is reduced in the patients who are we accessing Rusfertide, what are you seeing the implication for drugs impacting Hepcidin are in clinical practice? Do you think that they can be dosed without hydroxyurea?

Yes. Thanks for the question. So regarding kind of the effects of Rusfertide on platelets, particularly in relationship hydroxyurea use. Will, do you want to comment on that?

Sure. So many patients in PV are managed with their TD without hydroxyurea. I mean it is described that iron restriction can increase platelet count. I think the question is what is an important increase in platelet count. And I think what you see with iron restriction approaches that for the vast majority of patients, the increase in platelet count is not considered clinically meaningful. I mean it's measurable, but it doesn't meet a threshold of clinical significance. So I think that when you look at the population in all of the PV trials that are going on, I don't think there's a need to change the additional therapies interferon, hydroxyurea or phlebotomy alone. I don't think the platelet count changes themselves would change the landscape of PV treatment.

And then if I may ask another question on this program. There was also initial data presented in a set of Chinese Polycythemia vera by your lessor of DISC-3405. Can you confirm the molecule that use is similar or a very close iteration of DISC-3405? And how do you think -- if it is the case, how do you think this Chinese data set can be extrapolated to the ongoing Phase II RESTORE trial?

Will, you want to take that?

Sure. Yes. So the Mabwell poster is the -- that was presented is related molecule. It's the source of the in-license for DISC-3405. The management -- so we are not co-developed. They're doing their own development path and their management of PV in China is very different than it is in the U.S. and the endpoints are different. And so we don't really know how those data reflect on management of TD in this country in potential efficacy signals. So I think it's -- what's most important is waiting for us to present our data later in the year.

And the next question will come from Martin Auster with Raymond James. .

This is Jon Shawn for Marty. On RALLY-MF, we just -- I was just curious if you could provide some color around major responses for these different TV as patients on JAK inhibitors. Or are these details like do you think will be reserved for a future update?

And then I think the second part of my question is just more so on. Could you at least educate us on like the distribution of TD status of these patients when they start on these JAK inhibitors.

Yes, sure. I mean -- so just to refresh, broadly speaking, what we see is that about somewhere between 50% and 60% of these patients would classify as non-transfusion-dependent in our study, meaning they have no transfusions in the 12-week run-in period. We probably see another 25% or so, 30% in the low transfusion burden, meaning 1 to 2 units in that 12-week run in. And then for our study, the high transfusion burden would be the last 15 percentage or so of patients who are getting 3 units or more in the 12-week run in. So that's how we've broken it down and how that kind of relates to the way we estimate the population of patients in the U.S., at least in these categories.

Now you're asking about the subset of people who are receiving transfusions at baseline, who might also be on JAK inhibitors. I think that breakdown, Will, maybe you want to speak to that. I think it's around 50% or so or a little higher.

Yes, it's generally. It follows the overall trend. I mean, the subset of the subset question, we haven't explicitly presented, because the trends are basically the same. You do get over the course in general in MF treatment, you get people with more advanced disease tend to be on more JAK inhibitors. So I think there's a slight increase in the proportion of TD high, for example, that are on a JAK inhibitor. But we see responses both on and off JAK inhibitors in all transfusion cohorts.

And the next question will come from Douglas Tsao with H.C. Wainwright.

In terms of interest sort of I guess, as we've seen reflected enrollments in RALLY-MF as you have research data, have you seen sort of an increase in any particular populations? And I'm just curious in particular what you're seeing in terms of interest, in terms of patients on JAK inhibitors continue to see strong demand [indiscernible] alot than I would note.

Good question. So I think if I heard you right, just looking at the enrollment in the RALLY-MF trial, have we seen trends of certain kinds of patients who seem particularly in need of anemia therapy?

Yes. Especially if we see more names coming out, I mean, again, sort of a momelotinib patient policy just what you're seeing today, just given updates that you give it over the last few months.

Right, right, right. I mean one thing we've definitely said is we've been surprised, and I guess, interested by the number of people who have been on momelotinib who have come into our study. that data, we've continued to present. We presented some of that at ASH. And clearly, a lot of patients who are getting momelotinib well, it may be anemia sparing we see a lot of people still in need of actually improving their hemoglobin and that -- and the DISC-0974, Selcodebart seems to deliver that effect very well in combination with momelotinib.

And it's also pretty clear that at least those patients coming into our study, the Hepcidin has not been managed on that therapy. There -- in fact, their baseline upside is about the same. So that's been kind of an interesting little subgroup for us to be looking at and confirms the overall view that regardless of the underlying MF therapy people might be on there's still any need to manage anemia and DISC-O974 can manage that.

The other point I'll make, just so as enrollment continues here, hopefully closing out pretty quickly now. We have actually stopped enrollment on nTD patients. So you won't see any more accumulation of those patients in the study. It's going to be focused entirely on the somewhat harder to find transfusion-dependent patients. So as you see those numbers increase while the nTD doesn't increase, it doesn't mean that there's a different demand or unmet need. It's simply the dynamics of how we're enrolling the study.

Maybe I'll pause and Will, if there's any further commentary on these points?

No, I think that I think that covers it. I mean, I guess the only thing to note is that we that's -- the answer I got for you.

And just a quick follow-up, just when we think about redesign, do you anticipate just given what you've seen enriching for certain populations in particular?

Sorry, can you say that again, the design of the Phase III trial?

We're you plan to sort of having sort of enrichment to just ruxolitinib numbers of certain types of patients just giving their interest and have a broad label as possible and sort of how you're thinking about what those might be?

Right, right. Well, it's very clear ruxolitinib is the backbone therapy for these patients. and it will continue and maybe even become more so as it trends towards potentially becoming generic. So we'll definitely want to make sure that our Phase III program has adequate experience in that group of patients, which, by the way, we're getting a lot of experience down the data looks great.

Other groups, they're going to be smaller fractions of patients and I would expect -- I'd be surprised if we're going to have sort of enrollment criteria for those, whereas we might for ruxolitinib to ensure that there's a minimum number of patients. But we're going to have in interaction with the FDA in Q4, at least that's the plan. And we'll be able to provide more details after that.

And the next question will come from Rami Katkhuda with LifeSci Capital.

I guess for patients who switched from placebo to Bitopertin and HELIOS, can you just remind us, do the kinetics and magnitude of clinical benefit ultimately mirror what was seen in earlier studies? And why was there so much variability in light tolerance at the week 12 and 16 time points?

Yes, thanks. And I know it's a little confusing. So big picture, the way to look at this data is really kind of patients who've been on Bitopertin for a long time, how are they doing? And by and large, how they're doing is their PPIX has come down and in a sustained way. There's no sign of tachyphylaxis there.

And what we see is that people are increasingly taking advantage of their ability to spend time in light. And that's true whether you were a crossover patients or just continuing on Bitopertin. That's the best way to kind of really look at the data we presented at EHA. To get into the weeds a little bit, the way the studies were designed and there was a lot of operational complexity to this, we designed both the Phase II , AURORA and BEACON trial's, have what are called in-built extensions. I mean people -- patients would go through their either 6- or 4-month treatment period in study.

And then they would -- actually, many of them first rolled on to crossover or extension study inside that study. And then a little bit later, we got the HELIOS extension study formally open, and we're able to cross people on to that. So when you look at people starting the HELIOS study, some of them had already crossed over into extension and some of them have not. And that creates -- when you use that as your cut point, it creates a lot of variability in the baseline conditions because some of them have already started on Bitopertin where they may have been on placebo before.

And the other complexity is here in the U.S. initially, we needed to get permission from the FDA to put people on the 60-milligram dose after the first 4 months. So some people crossed on to 20. And then we're able to bounce back up to 60 later, once we've done the necessary regulatory rigor role.

So anyway, so the transition point between the BEACON and AURORA studies and then on to HELIOS, was a little bit choppy, right? It really wasn't designed to be a clean crossover type study design. And that's why you get some noise in the baseline data when you look at the HELIOS start.

So that's kind of how I started the conversation is really just look at this data as a snapshot of patients who've been on drug a long time and take it as a view of how patients on Bitopertin are performing after a long time. And they're really performing great. I mean we would love to see this kind of effect for any patient with this disease. That's the right way to look at the data.

Got it. And how are you guys thinking about the regulatory and commercial path forward in Europe? Do you think the EPP light results there will help with Ultimate access?

Yes, I think so. I mean we're doing a lot of work to look at the -- some of the pharmacoeconomic pieces that perhaps have a greater significance in the European system. We're certainly all signals go on driving towards approval in the European region. That, of course, will require the APOLLO data. So our cadence is probably first to get our response to the CRL in push for availability in the U.S. as quickly as possible.

But then our team can also work simultaneously on getting those European regulatory filings done as well. And you'll notice the AP is also opening up in various European countries. So we're doing our best to make the drug available to people there as well.

And the next question is going to come from Derek Archila with Wells Fargo.

This is Jacob on for Derik. So just a quick one from us on RALLY-MF. Just in terms of the mutational status, could you speak to what responses look like across JAK CALR and MPL driver mutations? And is there any expectation that there would be any differences?

There's no reason why it would be different. And we didn't design the study to meticulously sort out driver mutations and attach to that by response rate.

As I mentioned earlier, the CALR population tends to be less anemic. So when we say 80% of MF patients are anemic. I think the number is more like 60% for that in CALR group. So -- but Will, are you on to able to answer now?

Yes. I don't know if you can hear me, John.

I can now, yes.

Yes. We are doing that sequencing. It's being done in batch at the end of the study because we did not have a reason to think it would make a difference both in terms of the biology of the anemia and the interaction with Selcodebart. So we will look at it formally, but I think the responses we're seeing even just in a casual way looking at people's past history, not from their mutational status is not our own record, but we're seeing responses across the board.

And there are no more questions in the queue at this time. This will conclude today's Q&A session and today's conference call. Thank you for your participation, and you may now disconnect.

Good day, and thank you for standing by. Welcome to the Disc Medicine Corporate Call. [Operator Instructions] Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, John Quisel, Chief Executive Officer. Please go ahead.

Great. Good morning, everyone. Thank you for joining. We're here today to discuss the regulatory update for bitopertin.

But before we get started, I'll mention that we will be making forward-looking statements, and they should be taken in context with respect to materials that we filed with the SEC and is posted on our website.

So I'll start by saying, I wish we were here today discussing better news. As you all saw last Friday, we received a complete response letter from the FDA noting that while in their view, there's sufficient evidence that bitopertin significantly lowers protoporphyrin IX or PPIX there was uncertainty in the regulators' minds about whether the reductions in PPIX were reasonably likely to predict clinical benefit. And as we'll talk about in a minute, that's the standard for an accelerated approval, to meet those 2 prongs.

So Disc has been committed to bringing bitopertin to patients as quickly as possible. because we believe in the potential of this program and the importance of a potential disease-modifying therapy for the EPP community. We are deeply disappointed that this is happening today. But our commitment to bringing this program forward and pursuing an approval has not wavered.

We believe the issue raised in this complete response letter or CRL is readily addressable with the results of the ongoing Phase III APOLLO study. And as you'll hear more today, we're delighted with the progress and rigor of that study. We expect data from APOLLO in Q4 this year. So we look forward to working closely with the FDA to support their review, and we're pursuing all avenues to support approval.

So on this slide, we've summarized the details of the CRL. The full letter has also been published by the FDA on their website and by Disc in a Form 8-K. And it's remarkable actually to see this level of transparency. I think it's a new standard in the availability of these complete response letters to the public, and we're actually proud to be part of that.

So I'm not going to rehash all the details here since it's all available to be read, a pretty brief letter. It's clear, and we believe readily addressable by completing and submitting the results of the Phase III APOLLO trial, which, as I mentioned, is well underway and progressing very nicely.

This next slide is data from our Phase II AURORA study. This was central to the regulatory review -- this data has been presented extensively at scientific conferences and is now published in the Journal of the American Academy of Dermatology. This slide provides a brief summary, I'm not going to go through it all again in detail, except for a few highlights.

I do want to note that we hit our primary endpoint of protoporphyrin IX reduction with high degree of statistical significance. And as shown on this slide, there was evidence of improvement in several endpoints that were designed to measure clinical benefit. There's a light blue line that shows an increase in placebo-corrected time and light. And below that on the same time line as shown with red hashes the phototoxic events.

And I think that phototoxic events bar is probably the most remarkable data showing the reduction of phototoxic reactions in the 60-milligram dose group, the complete elimination of those attacks during the second half of the study. And there's a clear temporal relationship between the reductions of PPIX and the improvements in these clinical endpoints. I guess this was our view of the data.

However, this study was powered to look at the protoporphyrin IX reduction, and these other endpoints, the so-called clinically meaningful endpoints. Some of them were statistically significant and some of them were not. And this is what probably created the room for debate and whether we'd satisfy the standard for accelerated approval.

So let's talk about that standard for a moment. There are the 2 prongs. You have a surrogate endpoint in our case in protoporphyrin IX, which has been noted as being mechanistically compelling and the obligation is to achieve a clear statistical reduction in that biomarker, which we did, and that was acknowledged.

The second prong of the analysis is whether that reduction in the biomarker is thought to be reasonably likely to predict clinical benefit. Now this is a very broad standard subject to a lot of different interpretations. And I guess, I think it's also remarkable to note as I've gone through the data, the stories in the media from patients about real changes in their lives, people going on beach vacations with family, spending time on boats for the first time in their lives, really very moving stories of recovery from a devastating disease.

We know now from the complete response letter that the FDA did not ultimately feel that these lines of evidence met the current standard of reasonably likely to predict clinical benefit for the purposes of the second prong in achieving accelerated approval.

I guess the policy debate about accelerated approval has been going on for years both in prior administrations and the current administration. And I think it is fair to say that recent decisions have indicated an increasingly stringent approach to this question of when an accelerated approval is appropriate.

We, as a single biotech company, we can't set or meaningfully influence this policy. It's our job to do our best to bring promising therapies to patients as quickly and safely as possible. And we will continue that mission now by focusing on the Phase III APOLLO trial, which we hope will deliver inarguable evidence of the safety and efficacy of bitopertin for the EPP patients.

And if we're successful in this, we'll be seeking approval through the traditional route rather than this accelerated route. So looking forward then, this slide shows the APOLLO trial overview. I think that is the next big question and what to expect from this important trial.

We are happy to say that enrollment enthusiasm has been high, very high, in fact, and the trial will be fully enrolled in March, which is several months sooner than we'd expected. This means that we will be able to have or we expect to have top line data in Q4 this year.

As a reminder, this trial is a randomized double-blind trial designed to measure both PPIX reduction and improvement in Sunlight tolerance as co-primary efficacy end points. And we reviewed and aligned with FDA on this trial design at our -- both our end of Phase II meeting and Type C meetings that were held in 2024.

We're confident in this trial design for several reasons. The primary endpoints are robust and clinically meaningful. We have demonstrated statistical significance on protoporphyrin IX reduction in 2 studies now, both BEACON and AURORA in Phase II. And our light tolerance co-primary end points was designed by taking into account all of the learnings from our Phase II program as well as did a protoporphyrin IX mechanism of action and the behavioral dynamics that were noted in the AURORA study.

We also have a very strong study design, which includes rigorous assessments of baseline like tolerance during screening, which we learned were -- was an important feature. And we've also introduced now stratification by geography. And these are both set up to minimize confounding factors in our analysis.

The APOLLO study is also well powered, and we're happy to share that we have completed a blinded sample size recalculation of time and sunlight data that showed no increase -- no need to increase sample size. So that's a lot of jargon that means essentially the variability in our endpoints that we used to design and power the study appears to be sustained so far in the first 50 completers for the study so far. So actually, really good news there in terms of the way this study has come together in terms of rigor and our ability to capture reliable data sets.

So we're very excited about the study. We have a lot of confidence in the design and chosen endpoint, and we'll look forward to sharing the data from it in Q4 this year.

So on this next slide, to spend a little more time on the APOLLO endpoints. We have 2 co-primary efficacy endpoints. The first looks at the amount of time that patients can spend in light on a longitudinal basis, letting us evaluate improvements over time on therapy. The graph shows how bitopertin performed on this endpoint in the AURORA trial.

And you can see that there is, and this is important to note, this is a post-hoc analysis. But had we designed the study this way, there would have been a significant difference between -- versus placebo, when you look at the time points after we know that PPIX has reached its new low point. And after the placebo effect, which is marked in the first couple of months of the study has waned.

This endpoint showed statistical significance in the AURORA trial, despite only having 25 patients per arm, and it accounts for the amount of time it takes for the PPIX lowering effects of bitopertin burden to occur.

So this endpoint has a greater than 80% power over a wide range of data scenarios in our 150-patient 2-arm study, APOLLO. So a very well-powered trial using these endpoints. Our other co-primary endpoint is reduction in protoporphyrin IX, which we have shown with a high degree of statistical significance in both the BEACON and AURORA trials 40% if you look at it versus baseline, actually closer to 50% if you look at it with respect to the placebo group.

So really important reduction here in the disease-causative metabolite PPIX and a high degree of confidence that we will hit that part of the co-primary endpoint as well.

So all in all, we feel we have two very strong endpoints here that we expect to successfully demonstrate the clinical benefit of bitopertin and its potential to be a transformational drug for EPP patients.

So what does this mean for timing and next steps. We plan to request a Type A meeting to review our approach for resubmission and response to CRL, APOLLO is designed to demonstrate the clinical benefit of bitopertin in EPP patients. As mentioned, we are on track to complete enrollment of APOLLO in March and present top line data in Q4 this year. We'll then plan to prepare the package and resubmit.

Typically, for a CRL response, the FDA has a goal date of 6 months for the review, which would put us roughly in the middle of 2027 in terms of when we could expect a decision on a traditional approval basis.

So to reiterate, we are confident in this program. We believe that it can set a new standard of care for EPP. This is a debilitating disease that touches patients' lives every day. And so we've made every effort and pursued multiple avenues to expedite the process of making bitopertin available to the EPP community.

This decision from the FDA is an unfortunate setback, but we remain committed to advancing the program and working with the FDA to support their review. We've heard stories through patient advocates, the investigators and in the media about how certain patients' lives have been transformed by bitopertin. We want to make it clear that helping those patients is our mission. And those who are currently on bitopertin through a clinical trial will continue to receive access to treatment while we respond to the CRL.

And we want to thank really with deep gratitude all the people who've made this work possible, most notably the patients, the clinical trial participants who put their time and their health into this research effort. Their families who have to facilitate this, the broader advocacy community and the clinical investigators, all of whom have given so much of their time and energy to support this program over the past several years and continue to do so. In fact, without their support, we wouldn't be making this great progress on the APOLLO trial.

Okay. So backing up to the overall corporate outlook, I feel that as a company, we are in great shape here to deliver across a wide range of programs. This is the so-called catalyst slide that we've shared before. with a few changes now responsive to this update. As I've noted previously, we are expecting top line data now from APOLLO in Q4 of this year, after which we plan to submit a response to the CRL by the end of the year. And with a 6-month review period, we would then expect an updated FDA decision in mid-2027.

We are also very excited about the other catalysts we have coming this year for our other programs. For DISC-0974, we expect to have additional data from our Phase II myelofibrosis study in the second half of this year, followed by our objective is to have an end of Phase II meeting where we expect to align on digital trial endpoints with the agencies.

And then we're super excited about the third program, DISC-3405. We expect to be able to share initial data from our Phase II study in polycythemia vera and we've talked about how the excitement for this mechanism has led to a very rapid trial enrollment there. And we've opened up our Phase Ib study in sickle cell disease patients, and we hope to have some data from that trial by the second half of the year as well.

And all of this comes with being in a great financial condition. We have been and we will continue to be highly capital efficient. We do ensure that we're investing in activities that will we think create a great potential for creating value. And delighted to say that we'll be able to maintain our runway guidance of having cash into 2029. So really well funded to pursue all of the R&D programs that we have here.

So that's everything I wanted to run through today. Thank you all for joining the call. We wish we had a better update today. But as I said, we are committed to getting bitopertin to patients and we are confident that we have a strong path forward to do so.

With that, I will turn it back to the moderator to open up the Q&A. Thank you.

Our first question comes from the line of Roger Song with Jefferies.

Great. And thanks for providing confidence despite the surprising CRL. So maybe 2 questions from us. The first one is, can you just confirm this pain-free sunlight exposure in the PPIX co-primary endpoint will be likely to support the approval any indication during the review process, FDA has any different view?

And then specifically, given this is a core primary endpoint, is that p-value 0.05 hitting both of them will be supporting the approval.

Yes. This trial design and the endpoints that were used here has been discussed with the FDA and are aligned with them. And I think, in fact, what we see in the CRL with specific references to the APOLLO trial would suggest that we have continued alignment there. So we're not aware of any change in FDA position on that. And yes, the 2 co-primaries, the protoporphyrin IX and the time in sunlight during month 6. These are independent. And so both need to hit p-value 0.05.

Got it. Just one quick one, if I may, is the -- in the CRL, they talk about the association between the PPIX and the clinical benefit. Is FDA looking for strategical significance, association between the 2 endpoints or they just looking at the clinical endpoint or some of the clinical endpoints are reaching the specific, so they think you lack of the association.

Yes. So the language that's there in the CRL is also all we know about the basis for this nonapproval event. So we're speculating in the same way you are. But it does appear that they were in the end if not in the beginning, looking for some kind of statistically significant, I guess, relationship between protoporphyrin IX and one of the various clinical endpoints. I'm not sure which one, to be honest. So it's something we'll try to understand better as we continue our interactions.

Although to be honest, it's not -- I mean that's a feature of the accelerated approval path, which at this point is probably irrelevant now, we'll just be looking to get stats on our 2 coprimaries in the APOLLO trial. So it's more of a backward-looking exercise to understand what happened here. But right now, really, the CRL is the only information we have.

Got it. Exactly.

Our next question comes from the line of Tom Smith with Leerink Partners.

This is Pujan Patel on for Tom Smith. Could you please provide additional color on the powering assumptions for the APOLLO trial, specifically for the assumed treatment effect and the placebo response for the primary endpoint, the time and daylight endpoint?

Yes. Let me hand it over to Will to speak to that.

Sure. So we -- as John mentioned, we have in a variety of both variability and effect size scenarios have over 80% power that gives us a lot of confidence in the success of APOLLO. We haven't discussed the exact numbers that went into specific power calculations.

Got you. That's helpful. And then a follow-up on that. Do you plan to propose any changes to APOLLO during the upcoming Type A meeting as it currently stands?

Well, we're still trying to figure out. I mean, this news is really only effectively a business stable for us. So we're trying to figure out exactly how we want to approach that meeting. We don't have our final plan in mind. Modifying the APOLLO trial is not on the menu at least as we're thinking about it right now.

But I don't want to -- yes, I mean, actually, it's just simply not on the menu right now. We feel like it's a robust trial. It's done very well. So I can't see why that would be part of the discussion. But to say generally, we haven't actually sorted out our final approach on that meeting.

Our next question comes from the line of Sean Laaman with Morgan Stanley.

Maybe just to double-click on the last question, John. What specifically will you seek to lock down in the upcoming Type A meeting regarding APOLLO's endpoint hierarchy analysis populations and success criteria, especially since you said the diary data can be analyzed in any way the FDA wants.

Yes. So I do think that's probably the primary purpose of the meeting is to just make sure that there's not some kind of misalignment around the data package that we'll plan to bring upon successful completion of the APOLLO trial.

And to your point, I mean, I guess, on the off-chance there is some additional or different data analysis that the FDA has in mind. We believe we're really capturing through our diaries, et cetera, essentially all the information you would want to look at for this patient population.

And if there's a different approach that's desired, then we should be well positioned to address that as well with what we think is a pretty the evidence so far suggests rigorously done and well captured data set. Again, I think that, that's an outside probability. We haven't had any sense of a difference opening up around the APOLLO trial design. But yes, that is probably the primary thing we think about.

Maybe just one other quick one, I hope. So the FDA called the 40% PPIX reduction at 60 mg is relatively modest and question whether that magnitude is predictive, what magnitude or threshold or distributional shift, you believe is clinically meaningful and how you demonstrate that prospectively, APOLLO and/or by bridging analyses from AURORA/BEACON?

Yes, there was a surprising comment. I think there's a lot of good evidence for why our reduction is quite meaningful. But Will, why don't you speak to that?

Sure. I think we look to the data to determine what is a reduction that is meaningful. And we've provided before evidence in the literature of women with EPP who would come pregnant and go into remission with about a 40% relative reduction of PPIX, experiment in Denmark with kind of mechanical extracorporeal reduction of PPIX of 30%, leading to very large increases in time and light.

We have our animal model data, and we've shared the results of what happened in BEACON and AURORA showing light tolerance improvement. So I think our position as the data are telling us that bitopertin is achieving a level of reduction that has clinical benefits.

Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

Sorry about the news, but I appreciate the positive attitude you have here today. I wanted to ask just on your confidence for the co-primary endpoint on time and light without pain, whether or not the FDA will maintain looking just at that final month.

And then I think with the AURORA trial, people were probably really excited by the data in Beacon. And out of the gate, we're trying to test whether or not the drug works. So that we know the onset does take a couple of weeks here for the drug arm. Are physicians and KOLs kind of working with patients more to mitigate that high risk initially just given that -- it does take some time for the PPIX levels to go down?

Yes. So on the first point, and maybe I just need to be a little clearer because I hear everyone asking like, oh was there, is there an issue? Is the FDA going to change their view on the APOLLO trial? I mean I feel like I can lean in pretty hard on that and say there's just absolutely no evidence of that right now.

But of course, we will have the Type A meeting and report back if there is something that's opened up there. But truly, I don't see any evidence of that. And I don't even really in the CRL see evidence of that. In fact, to the opposite, I feel like the CRL is essentially pointing to the APOLLO trial as designed as being the path to getting the data set that they would view as appropriate for supporting approval.

So just kind of on that general lean, really, we feel good about the way the APOLLO trial is designed and the true to which it's embedded with the FDA.

Your second question, a very interesting question, right? We know it takes a couple of weeks for protoporphyrin IX levels to reach meaningful reductions. And so, Will, maybe you can speak to this question of how investigators managing that, et cetera.

Sure. So one of the approaches to success in APOLLO that we took was doing things in a similar way to AURORA as much as possible. Of course, our analysis approach is different, given the placebo effect and looking at a time after that initial month or so of placebo effect time.

But other than that, we have the same diaries and the same instructions. And so we think that's the best path to success is getting the same type of data that we did in AURORA and analyzing it in the way that we feel at month 6 is going to give the best chance to hit that.

Our next question comes from the line of Tara Bancroft with TD Securities.

This is Frances on for Tara. Can you just tell us a little bit more about the nature of the alignment you reached before the CRL. What -- given the recent events, what's your level of confidence in the current along with the FDA on the co-primary endpoint, specifically looking at those last 4 weeks. Kind of how important is total pain-free time in light given this was the approval precedent for SAS?

Yes. Like I said, in response to the prior question, we feel that it's fully aligned, both in the -- I guess, kind of 3 meetings on the topic, the end of Phase II in the fall of 2024, and then we had a Type C meeting that was dedicated solely to the topic of the APOLLO trial design and reached alignment there. In fact, that was kind of where the final alignment was reached.

And then there was opportunity in the pre-NDA meeting over the summer, where there was no issue identified with that as well as throughout the NDA review, where I think the questions around the APOLLO trial have really just focused on this inquiry into whether it's well underway and how rapidly we expect to get the data on that -- from that trial.

So really seeing no basis for a difference to have opened up there. But I guess I understand the sense of unpredictability here given the result that we have in the CRL.

In terms of the SNES precedent, I mean, we haven't really talked about that since end of Phase II meeting. I think the FDA showed a lot of flexibility around endpoints here. We've seen that with other drug programs in this space. So I think it's to their credit they're clearly allowing sponsors to design endpoints that capture the appropriate biology for the drug in question. And that seems to have been applied to us as well.

Our next question comes from the line of Evan Seigerman with BMO Capital Markets.

I actually wanted to go back to some language you used back of November 2024 around the end of Phase II meeting. You noted that the FDA, you described the alignment for accelerated approval as potentially or is potential. Can you just expand kind of what led to the alignment between FDA and this medicine back in November of 2024. And might, what could have potentially have changed?

Yes, sure. So actually, it's pretty much the exact data set that I shared in the earlier slide in this presentation, that was available and presented to the FDA in the end of Phase II meeting, which if you'll recall, we went into that meeting offering of 2 alternatives. We provided a justification for why accelerated approval might be appropriate using protoporphyrin IX served end point. We also just offered up that we would pursue a traditional approval using the APOLLO trial as a Phase III trial.

And the FDA at that time indicated interest in moving down the accelerated path, invited us to have a Type C meeting to discuss the APOLLO trial design as a confirmatory trial, which, of course, is an indicator of an accelerated path. After that, we had a meeting around the CMC package, and then a pre-NDA meeting where it was clearly asked and answered that we'll be filing an NDA -- I'm sorry, submitting an NDA on the premise of an accelerated approval.

And then subsequent to that, we -- the NDA was accepted granted priority review again on an accelerated basis. So a rich record of the FDA aligning with us on this as the appropriate path for review. But I guess the important thing to say is that they -- none of that obviates the need for a review, right? And they have conducted that review and reached a different conclusion than expected, which certainly creates a lot of whiplash for everyone.

I think that the general nature of NDA review is that you go from small sub team at the FDA focused on the package and forming an opinion about the appropriateness of the pathway that you're on and the likelihood of approval and then you get into a broader and broader set of people in the agency who engage and bring different perspectives and different standards.

And I guess what we see here is a different standard that arose and ends up controlling the outcome. So I mean, I think that's how we see the arc of what went on here although, to be honest, we don't actually have a tremendous amount of information from the review process at this point.

And just as a follow-up there. In your kind of interaction with the regulators following the submission and the announcement of the commissioners prior to review voucher, could you give any indication that there was skepticism around the accelerated approval pathway, or did it seem that they were on board or just ask some questions. Just trying to get a sense as to where this changed?

Yes. So I don't think -- so there is an intense review process, a lot of information requests, essentially an entire NDA review packed into a relatively short period of time and actually a huge appreciation to the reviewers at the FDA for putting in that work and moving along quickly.

There was no obvious skepticism of parent in the information request as we went along. And I think the first indication of potential challenges may have come, frankly, from some of the leads that we saw in the media, which was news to us. And I guess, in the end, spoke to the direction that things were going.

Our next question comes from the line of Danielle Brill with Trusit Securities.

This is Alex on for Danielle. You mentioned previously that you've been slowing down U.S. enrollment to satisfy FDA concern about patients potentially dropping out with the commercially available bitopertin. I guess now with the plan is changing, will you have the ability to enroll a sufficient number of U.S. patients to satisfy any potential regulatory concerns for full approval?

Yes. I mean we have -- we certainly have enough U.S. patients to satisfy any kind of regulatory requirement around that. I mean probably roughly 2/3 of the study is going to be U.S.-based. And we shifted enrollment over to Europe, which was kind of the plan. Anyway, those sites in Europe come online slower. So there was kind of a natural progression to the study towards greater European enrollment.

And what we've seen is just this kind of overwhelming enthusiasm and eagerness from the various European sites to get patients on to study, and so there's not going to be any need to come back and reopen U.S. sites or whatnot, we're going to frankly struggling to manage the enrollment demand as it is just based on the European sites that are still enrolling.

Our next question comes from the line of Douglas Tsao with H.C. Wainwright.

John, I guess I'm just curious, during the review process, which was obviously very compressed, could you get a sense in terms of the issue of correlation between PPIX reduction and some tolerance that they were focused on the analysis of AURORA that you presented showing that sort of temporal relationship? Or were they just sort of looking at the data sort of at the study sort of as it was initially presented, which obviously sort of mask the underlying effect and sort of was ultimately a very complex data set.

I guess the general sense is that they were looking at everything and proving all aspects of the data and I guess behind the scenes forming their own opinion.

And John, just as a follow-up also, in terms of the commercial organization, obviously, as a company, you've been going at we see sort of preparing for a launch. Obviously, that's now going to likely be delayed some amount of time. Can you just talk about sort of what is going to happen with some of the infrastructure?

And just does that -- or was the sort of spend sort of not material and not necessarily something that you're going to keep the sales team sort of in place for the MSLs because obviously there are other things for them to do.

Yes. No, it's a great question, very much where I think our heads are internally at the company is figuring out how to ensure that we continue to be capital efficient, that we do the things that we should do to ensure that when we do launch this drug is successful, but only do things that are clearly going to be value-creating in the long run.

So that's the process we're working through, essentially reestablishing the business plan around the commercial push and I think there'll be some greater clarity on that soon.

Our next question comes from the line of Stephen Willey with Stifel.

Maybe just to build on the prior question. I guess, is there anything that you can say regarding just the prelaunch activities you're going to be prioritizing ahead of a potential approval in mid-'27, and how you might be looking to leverage this additional time to potentially improve the trajectory of initial uptake? And then I just have a follow-up.

Yes, it's a great question. And I think to give a little taste right, I think we have had some teams out in the field essentially using the claims database information as a call point list, right, to kind of go through each physician account that's listed in those claims data and check in to see and confirm whether there are patients actually being seen by that physician.

And I think that kind of activity is unbelievably valuable for this kind of rare disease launch. I mean I think that our ability to get the word out to patients or, I guess, really to physicians who can then get the word out to patients. That's the way that we make this drug work, right, that we make -- give patients the opportunity to get it, they won't find out unless we're able to work through the physician community to get the word to them.

So really continuing the work of validating those accounts which has progressed well, but it's still in the early days relative to the 14,000 patients that are in that claims database. If we can use this time to kind of solidify that and then launch with just a crystal clear account -- validated account list for our sales team, that would be, I think, incredibly value creating. So I think that's one activity that we would assume that we'll plan to execute on.

And then other kind of related activities, that's something we'll have to think through and again, balance while I'm delighted that we are well funded. We also want to make sure that we're using those funds in a way that's just clearly value created. So figuring out the other activities we want to engage in how to staff those. That remains an internal question that we're working on.

Okay. That's helpful. And then is there anything more you can say just about the inputs that were used to conduct the sample size for calculation within the first 50 completers. Was this a blinded assessment of either co-primary? Was it just an initial look at endpoint, variability, patient dropouts, et cetera. I think just any color you can provide would be helpful.

Yes. Let me just first emphasize, it's absolutely blinded. We have no information about efficacy from that analysis. But to give you a little bit more color, I'll hand it over to Will.

Sure. So the analysis was prespecified to look at the time and sunlight diary data and looking at the variability. That variability is -- there was an assumption that goes into the power calculation if the design of the trial. And then this analysis tests that assumption of that variability in that time in sunlight diary data.

And it said that we're -- the study is on track with the initial assumption of variability. So we did not have to increase the sample size from a statistical perspective. So the protoporphyrin IX is not part of -- not part of that assessment. We have high confidence in the ability to demonstrate a stat reduction there.

Our next question comes from the line of Derek Archila with Wells Fargo.

I just wanted to know how quickly you'll be able to request that Type A meeting, and I guess whether you'll wait for minutes before communicating the outcome?

Yes. So I think we'll move reasonably quickly, although actually we just -- we're -- as I mentioned before, we really just putting together our plan right now. And yes, we have typically wanted to get the minutes from meetings before we share anything with the public. So I assume we'll follow the same process. So of course, it can depend on what the outcome of the meeting is.

But in this case, I would assume it's something we'd wait for the minutes on, which, as you probably know, typically is about a 30-day delay.

Our next question comes from the line of Rami Katkhuda with LifeSci Capital.

Okay. Just a couple of quick ones for me. I guess, first, has the FDA ever pointed to a minimum threshold of improvement in light tolerance that must be met for approval? And then secondly, can you also provide an update on the status of other NDA modules, including CMC and whether the FDA has commented on those aspects of the application?

Yes. Yes, good question. So no, no threshold for light tolerance was ever identified. And in terms of the other modules, yes, I mean, actually, we're really pleased with the way the CRL looks in that regard. It's intended to be a listing of items that are causing the FDA to be unable to approve the drug. And therefore, items that we should be addressing as a company.

And there's no CMC or other issues raised on that CRL. So we interpret that as meaning that the interactions that we had around during the NDA review on those topics were satisfactory and that they're closed off.

I guess just one thing I will say about CMC, while we had reached a line with the FDA on drug supply that would go along with the February launch time line, there are still some trailing PPQ activities with the commercial supply that will continue over the next few months. All indications is that those are going well and we'll be concluded successfully.

But now that will become additional material that will probably, at some point, amended into the NDA filing. So I guess to summarize, everything appears to be aligned. All processes agreed upon with the FDA, all CMC aspects of review complete, except that there are some final activities that we have to close out. And those, of course, will get reviewed in the final version.

And I'm currently showing no further questions at this time. I would now like to turn the call back over to John Quisel for closing remarks.

Okay. Thank you, everyone. We appreciate your time today. Again, sorry, we couldn't achieve a better result. We're going to keep working on this. And hopefully, we have great data as we come in towards the end of the year. Thanks a lot, everyone.

This concludes today's conference. Thank you for your participation. You may now disconnect.

Good afternoon, everybody. Thank you so much for joining us on day 3 of the J.P. Morgan Healthcare Conference. My name is [ Pavna Balakrishnan ], and I'm an associate from the health care investment banking team. We are here today for the presentation of Disc Medicine, and we're joined by John Quisel, Chief Executive Officer. And I'll turn it over to you, John.

Great. Thank you. All right. Great to be here. Thanks, everyone, for taking some time today. I guess Wednesday afternoon, we've reached maybe the exhaustion stage of the conference. But thanks to the JPMorgan team for providing a speaking slide for us here.

Okay. So it's -- we're about the 3 years public listed here at Disc. It's been an exciting run, highly productive. We look forward to next year being a really exciting year. We're on the cusp of approval of our lead program, and then we have a whole pipeline behind that progressing well. So we'll walk through all that today.

First, a few disclaimers. We'll be making forward-looking statements. Everything should taken in context with what we filed on our website and with the SEC. And 3 clinical programs, we'll be talking about, [indiscernible] sorry, bitopertin, DISC-0974 and DISC-3405. These are investigational agents, and they're not approved as therapies anywhere in the world.

So a quick rundown. I'll -- for those less familiar with the story, I'll give a brief intro of who we are here at Disc. And then we'll run through our lead program, some of the background, the progress towards approval and then some launch strategy and launch dynamics to talk about. Then we'll go through the pipeline and wrap up with the overview for the year.

Okay. So who we are at Disc. We're focused on red blood cell biology. Our programs all manipulate heme and iron metabolism. The theory is that by manipulating those components, you can control a lot about red blood cell biology, how red blood cells form, how they function. Many of the targets are genetically validated. At this point, of course, we've proven most of them out in the clinic as well. And our goal was always to go broad, right? If we can control red blood cell biology, we should be able to deploy that against a wide range of diseases, and so we've had for years now, the bottom of this slide, is a list of diseases running from the left-hand side, very rare, like Diamond Black fan anemia, up to very common diseases like anemia of chronic kidney disease.

And we set out to address each of these with one of the molecules in our pipeline. And happy to say, we've almost knocked off the whole list at this point with a lot of exciting data to go with that along the way.

But actually now, for the first time, this is going to be the least science you'll ever hear out of a Disc presentation. We're transitioning now to a commercial company. So we're going to talk a lot about the market opportunity that we're looking at. And so what this slide shows is that we are progressing from our launching our lead program, assuming approval into this erythropoietic porphyria disease, or EPP, which we estimated about 14,000 patients in the U.S. and then our pipeline of 2 hematology oncology programs, taking aim at a pool of about 175,000 patients. And then from there, there are expansion opportunities into various anemias of inflammation and other disorders where we hope in the end to address more than 1 million.

So we've designed this company to progress through this focus on hematology, iron and heme biology from a rare disease focus initially into hem/onc and from there into broader markets. And we think this build can all be achieved as a stand-alone company. This can be viewed as a pipeline chart, of course. So this is not our full pipeline chart. You can find that on our website.

I would view do this as a pipeline chart that shows what we view as the major opportunities or the places that we're really deploying the most capital. So our lead program called bitopertin in EPP is now -- the NDA is submitted. We're under review on an accelerated basis under this Commissioner's National Priority Voucher program, looking forward to getting to target approval date, hopefully, end of this month, early next -- early in February.

And then the second program, DISC-0974, targeting something called hemojuvelin. Here, we're in late stages of Phase I development, looking present additional data later this year and move to Phase III next year. There's a second-generation antibody with an extended half life that gives us some optionality, some life cycle management.

And then we have DISC-3405 an antibody against the target called TMPRSS6 designed to restrict iron and address disorders like polycythemia vera and sickle cell disease. So these are where we're active right now, and I'm going to move into bitopertin.

so first, let me talk about the patients, the disease we're trying to treat, erythropoietic protoporphyria, really a rare debilitating lifelong disease, arises from a genetic mutation in the last enzyme, typically in the last enzyme of the heme biosynthetic pathway. And it leads to a buildup of a toxin called [indiscernible] and that toxin in then wreaks havoc throughout the body. First and foremost, it absorbs sunlight energy. So as it's flowing through the blood, that blood flows through the skin, light excites this molecule and gives patients the sense of excruciating pain as if they describe variously is like you have boiling oil flowing through your veins. And on average, that -- patients can only tolerate maybe even less than 30 minutes of sunlight exposure, can even be through a window before they experience these excruciating pain attacks.

This metabolite also builds up in the liver with devastating consequences leading in 1% to 5% of patients to over liver failure, which can be a fatal complication of the disease. And the visuals are just striking. We have on the slide here, just an image of what a healthy liver looks like and then what a liver of an EPP patient looks like. And you can see this horrific purple color that builds up over time as this compound crystallizes in the hepatobiliary system, ultimately driving severe liver damage in many patients.

And so that's the basic description. The other consequences patients can't live -- by not going outside, can't live a normal life, a lot of psychosocial complications, and there's no disease-modifying therapy. Generally, the treatment is recommended to just stay indoors, come get your liver monitored on a yearly basis and design your entire life, your career choices, sports, whatever, all around just never being outside.

There's one FDA-approved agent called afamelanotide, surgically implanted, works like tanning. So we're hoping to bring now the first molecule that has the potential to reduce the level of that toxin.

So our clinical data have -- we've studied this in 2 Phase II programs. We actually in-licensed the molecule from Roche, who had tested in over 4,000 patients pursuing other indications before we picked it up. And our trial data have been fantastic, right? We've shown our primary endpoints in both was reducing [ Protopor9 ]. We reduced that by between 50% and 60%. The 2 trials here that are -- we just kind of quick hits on the data. Aurora was placebo-controlled with about 75 patients in the U.S. Beacon was an open-label study in Australia with about 20, 25 patients. So either way, we saw this highly statistically significant reduction of PP9, that toxin that drives the disease. So if you're reducing that meaningfully, probably more than 30% is meaningful. You would predict to see major improvements in the disease pathology.

And that is what we see, can measure various ways, light tolerance, sunlight tolerance, and we saw a two- to threefold improvements to those, slightly different numbers depending on whether you compared to baseline, compared to placebo. We saw -- if you look at these phototoxic reactions, right, these pain events that are probably the central feature for these patients' lives, we saw a 75% reduction of that against placebo in the AURORA study, 92% reduction from baseline in the open-label study in the placebo-controlled trial actually at the top dose, 60 milligrams once a day. We saw after 4 weeks on drug -- sorry, after 8 weeks on drug, reduction of PP9 is complete. And at that point, there were actually 0 phototoxic reactions. So a remarkable effect.

And then if you just ask patients how they felt, did they experience their disease state, that was statistically significant, and nearly everyone reported seeing major improvements. We also had almost everyone, over 80% rolled over into our [ Helios ] long-term extension study. We've reported data from that, where people go on to maintain that reduced PP9 level and continue to report, I think it's like more than 90% of patients saying they feel better.

So we seem to have a drug that's long term. The safety has been excellent. It's well characterized in the safety database of over 4,000 patients. And this once-daily oral actually is a big deal for the patients who otherwise the only therapy requires a surgical implantation every 2 months at a specified center that they have to travel to and travel is not easy if you can't go out in the sunlight.

So a really exciting set of data. We've reported it extensively in the past. So that's probably all, talk about it today. Today, we're going to talk about our anticipated approval and launch plans. So we filed that NDA at the end of September. The NDA was accepted at the end of November. If you think of this through a regular way PDUFA, we were given priority review. PDUFA date would late May. But in the meantime, we were awarded one of the first Commissioner's National Priority Vouchers, something we're very proud of, sets up the time line now where we anticipate an action and approval, we hope, at the end of January or early February.

And then meanwhile, the premise for approval here is an accelerated approval using the PP9 reduction as the surrogate endpoint. So as part of that, we have a confirmatory trial running as well. This is called the APOLLO trial. That's been received with a lot of enthusiasm, 150 patients to enroll here in the U.S., Europe, Australia. And we expect to have the top line data from that by late this year or early next year. So all progressing well.

I'm going to just touch on the CNPV, the Commissioner's National Priority Voucher for a moment. I think this has become, I would acknowledge a politically hot issue. We've seen a lot of critiques of that coming from folks, ex-FDAers, folks in the industry. I think from our point of view, it's been a fantastic program. We're just so delighted and pleased to have been chosen for this. And I would highlight that the day that announcement came out, the patient groups that represent EPP patients just were overjoyed to have that kind of recognition for a rare but severe disease that is often overlooked and ignored.

So as an effort here by the FDA to bring drugs to patients more rapidly, we think it's been fantastic and rigorous and really hope that this becomes something that's ultimately viewed as very positive for the industry as another path to get more rapid approval of drugs and also as a way for patients to get access to drugs more quickly than they would have otherwise.

So back to our launch. One of the things, the consequence of all of this acceleration is that our launch time lines moved in substantially. And when we first got the award, there was a moment of absolute celebration and then a moment of sheer terror. Well, we're going to have to launch this drug about 4 or 5 months quicker than we thought we would. So what are going to be the stumbling blocks? Can we meet those events? First thought was CMC. Can we -- will we have a drug supply available if we're launching this drug at the end of January. And we're now happy to say we've worked through all that and received alignment with the FDA that, yes, the supply we have on hand is qualified for launch. We're ready to go.

The other area is, of course, building the access and reimbursement team. That team is seated. They're working with payers. So that's all going very well. We do anticipate that, that will phase in a little slower than it would have otherwise. A lot of payers we typically would have had 4 to 6 months of conversations to establish reimbursement policies. Those won't be established at launch. So we anticipate there may be some larger-than-usual lag between when patients get access to the drug, which we're going to prioritize, versus when they become or start to see the reimbursement roll properly.

Sales team, we've accelerated that by about a month, and we will have that team seated. They've been hired. We'll talk a little bit about that in a minute, 24 reps ready to go the day of launch. We're again missing about 4 months of disease state education that would have happened, but I think overall, a lot of folks at the top accounts understand our drug, its mechanism very well and are very excited. So we think that sales team, the deployment is going to go smoothly and drive a smooth launch process.

And then lastly, our marketing materials, there's typical and accelerated approval process. We'll be using just the label itself as the marketing material initially, while the FDA prospectively reviews the other marketing materials and then everything will be fully available by the middle of the year.

So overall, we'll be well prepared to launch the drug and then essentially all of the full launch capabilities will kind of blossom by the middle of the year.

So moving to the launch dynamics in this disease. So what's the opportunity here? So the genetics would say there's about 20,000 patients. We went to the claims data databases and we found there 14,000 patients with a look back of about 8 years. There is an ICD-10 code for EPP. And it looks back about 8 years. And in that time, we saw a 14,000 patients hitting that diagnosis code. And of those, we see about 6,000 that have had care in the last 3 years around their EPPs. We view those as the engaged patients.

And I'm happy to say now we've have an MSL team that's been out in the field for about 6 months. One of their jobs is to go to the top accounts and start validating the claims data. Are these patients not just digital signatures in the claims but actually acknowledged by the doctors in the field? And so we've been working through that. And we've also been using a variety of digital tools to help assess the quality of this claims data and corroborate independently. And by and large, it really does seem to be checking out as we through those.

So again, our team is going to be 24 reps, going to be 6 MSLs, 6 field-based access team members to help break through barriers of access for the patients, will have full patient services, both internally and externally. We're going to be working with one of the top exclusive rare disease-focused specialty pharma partners. So all of these components are now in place and ready to go. And we'll obviously be focusing first on the top 15 centers of excellence. I think that's going to drive the initial phase of the launch. But this 24 reps is sized to call on essentially 1,500 key accounts.

So if we break that down, and this is now at least the top 2 boxes based on work done by our MSL team, we can now validate that the 15 centers of excellence for this disease have about 600 EPP patients. And that includes also the clinical trial patients who are going to presumably roll over onto commercial product. And we have 105 additional high-volume accounts. These are typically large academic institutions, where we've identified another 1,000 patients. So that total of 1,600 patients I identified at the top 120 sites, that's more or less would have been predicted from the claims data as well. So we're delighted to see that correlation or relationship between what we see in the claims data and what we see from the boots on the ground, the MSLs going to the physicians.

And that gives us a lot of confidence that the rest of this data is true as well. So there'll be 1,500 community specialists. These are dermatologists and hematologists who also are seeing a total of an additional 4,000 patients. So that will be the focus of the launch, will be the top 120 accounts for this year. We will -- we did size the sales team 24 reps to call on this total of almost 6,000 accounts that see these 6,000 patients. And there's the final about 8,000 patients where we will do -- these are GPs, 1 patient, 1 doctor. We're taking a variety of tactics to activate those patients as well. And that's already started and actually already yielding identified patients and prescribers.

So very exciting. We think this sets up a stage for a rare disease launch that will be consistent with a lot of other successful launches in our industry.

Last piece of information. We now have some insight into payer mix that we'll be dealing with. I think it's very favorable. About 16% will be commercial payers, 25%, Medicare, 15% Medicaid. So those are the launch dynamics we're looking at. Again, we're designing this program to aim at an anticipated action date from the FDA coming late in January, early in February, consistent with the original time line guidance from the FDA around this program. And if all goes well, we get through that and looking forward to what should be an exciting launch later this year.

So I'll move to the pipeline. Our ticker symbol is IRON, so you might be saying, where is the iron. It's in the pipeline. The 2 targets here are well-known, genetically validated targets that control the fundamental regulator of iron in the body. So this is hepcidin. We have DISC-0974, anti-hemojuvelin antibody on the left side of the slide. This suppresses hepcidin, makes iron more available, and this is useful to treat anemia of inflammation. So myelofibrosis has been our lead indication, and we're looking at a variety of large indications that we can also expand into.

Then I'll talk about the third program in the pipeline, DISC-3405 against called TMPRSS6. What this does is actually increase hepcidin, restricting iron. When you restrict iron, actually it inhibits red cell formation. This has been demonstrated as an effective way of managing polycythemia vera, and we're also probing its efficacy in sickle cell disease.

So DISC-0974, anti-hemojuvelin antibody reduces hepcidin, increases iron. And with the flush with iron, that enables red blood cell production, right, because iron is, of course, one of the critical nutrients that's necessary to make heme, which is a building block of red blood cells.

So we've been focusing in a disease called myelofibrosis. This is a sort of precancerous myeloproliferative disease. They're a driver mutations. It leads to -- it can start with production of cells with -- polycythemia vera, for example, can be a lead in. But also can just arise directly in the bone marrow where you get the scarring and fibrosis, ultimately leading to what can be a very severe anemic state as well as in large spleen and other symptoms of inflammatory disease.

So we think this is a very significant unmet need. There's actually no therapy approved to treat anemia of myelofibrosis. There have been, unfortunately, a variety of failures recently. So there's actually almost nothing in the pipeline even to try to treat this. We are essentially the only product now that I'm aware of in clinical development to manage anemia in these patients.

So if you look at kind of a treatment algorithm and patient distribution, we see that there's probably about 25,000 myelofibrosis patients in the U.S., a substantial number of them are being treated with a JAK inhibitor. Jakafi is kind of the standard of care. It's designed to manage spleen size and symptoms but actually exacerbates the anemia. So we see that about 87% of these patients are anemic, meaning there's 22,000 addressable patients. If you figure in some kind of estimated oncology pricing, you could look at luspatercept, a program proved to manage anemia in a different precancerous disease called myelodysplastic syndrome. That price is in the ballpark of $200,000 to $300,000 per year. So it implies altogether, roll that up a $4 billion-plus total opportunity here.

And as I mentioned, really essentially no competition. And when we say no competition, meaning no good solution for these patients coming on the horizon. So we've seen a lot of excitement around the data that I showed you. We presented data at ASH. We're in Phase II. We call it the RALLY-MF Phase II trial. The drug is designed to reduce hepcidin. The left panel shows profound hepcidin reduction. This is elevated in essentially all patients, and our drug, as you would predict from the genetics, is just very powerful at reducing that. We've seen it in healthy volunteers, chronic kidney disease patients and myelofibrosis patients as well.

So the consequence of suppressing hepcidin is you mobilize iron, and that's the middle panel. You see extraordinary increases in the serum iron levels. That means that ensures that the red cell compartment is flush with iron to help support erythropoiesis, and that ultimately translates to a hematologic response, which, depending on the patient type, is calculated differently, but if we have a major response that's using the criteria that are defined by KOLs and guidelines, we see that we get to about 50% major response rate. That's a response rate that's never been seen in this disease with anemia therapy.

So we're truly excited about that and really looking to progress fast as we can.

To dive in a little bit more deeply, I can share, if you break these down into the non-transfused patients, right, anemic patients run the gamut from non-transfused all the way to heavily transfused. Our most numerous patients, which match the market expectations are the non-transfused. That's about 60% to 70% of the market. The low transfusion patients represent probably 25%. You can see in the NTD group, very nice hemoglobin increases. We show the red line is the major responders. The blue is the average.

And then interestingly, we see great improvements in fatigue. So this is -- it's important when you're developing anemia product to show that there's a clinical benefit, like a real patient can feel type benefit. And we see great fatigue improvements, and it seems to be associated with the level of hemoglobin improvement.

We also see in the TV low populations really spectacular effects. These patients, their hemoglobin typically starts around 7 or 8. So they're getting occasionally transfused 1 or 2 units every 12 weeks. And we see, on average, about 3.5, somewhere between 3 and 4 grams per deciliter increase in hemoglobin, which is a very marked response. And with that larger hemoglobin response, we see a larger increase in the fatigue scores, so again, confirming that these hemoglobin increases are translating into benefit for the patient's overall health, as would be predicted because by the way, I'll note that anemia is well documented to correlate with poor disease outcome and a worsening disease state.

And then for those myelofibrosis aficionados, JAK inhibitors, like I mentioned, ruxolitinib, Jakafi as well as momelotinib, [ jar ], these are used to manage spleen size and symptoms in these patients. They also have effects on erythropoiesis. So there's a common question about how well does our drug work on top of this. Jakafi, in particular, exacerbates anemia, so there's a very strong need to manage anemia in those patients to help them reach their optimal Jakafi dose and just generally live higher quality life. Ruxolitinib is what we would call anemia sparing. So it's more benign on that front, but we've seen a lot of patients in our trial actually who are on momelotinib needing anemia therapy. So we are curious to see how well the drug would work in combination.

And the answer, it works very, very well. It's the same dynamics that play these patients come in with elevated hepcidin levels as is typical in myelofibrosis. Our drug reduces that. It mobilizes iron. And then you can see the different hematologic responses depending on patients who are not on JAK, on ruxolitinib on momelotinib. It's basically the same across the board, circling around a 50% major response rate.

So really robust working across a broad range of patients, appears to be active all the way from the non-transfused patients down to the heavily transfused patients. And so with this kind of data set, we're just pushing as fast as we can to get this into a pivotal trial. So we'll continue to run the RALLY-MF trial. It was designed to enroll about 90 patients. As of last October, about 45 have been enrolled, including essentially the entire nontransfused cohort.

So we'll have another data cut as we come into the end of the year. I don't think it's going to really change much about the data. The end is already pretty substantial, but nonetheless, for completeness and actually, that extra data does help us when we our proposed pivotal trial. And that was the major goal for the year for this program, is to get to an end of Phase II meeting with the FDA and look to start up a pivotal trial as early next year as we can.

Meanwhile, we're also looking at other anemias of inflammation, right, hepcidin is iron regulator. It's known to be elevated in almost any inflammatory disease. Many of those come with an anemia that can be difficult to manage. Inflammatory bowel disease has been identified as one of those. The patients have attributes that would suggest they should be responsive to our drug. We know now that high EPO levels are a predictor of responders, just like MF patients, have very, very high EPO levels.

So we're excited about getting that trial started. By the way, the mouse data was spectacular, like we saw 6-gram per deciliter increases. So a lot of reasons to believe going to be exciting. We're doing this as a signal-seeking study, planning placebo-controlled, but planning to start off sometime in the first quarter here.

And then we have a second-generation antibody called [ DISC-998 ], extended half-life, could be used for life cycle management, could also be used as the differentiating molecule to approach some of these larger indications like inflammatory bowel disease and chronic kidney disease. So that's the second pipeline program, again, aiming to be into pivotal by next year.

The third program, pushing iron in the other direction, anti-TMPRSS6, another genetically validated target here. With this antibody, we're trying to increase hepcidin, decrease iron availability, and this modulates red blood cell production in a way that has already been proven out by the Protagonist team, fantastic work with a molecule called rustetide, showing that restricting iron in polycythemia vera patients delivers a meaningful therapeutic effect.

So that is where we're going to go first. We think we have what will be a great presentation for patients. This is a simple antibody, subcu injection, projected to be once every 4 weeks, maybe over 2 weeks. We're probing those 2 doses in our Phase II trial. If we think about the market opportunity here, this is actually the exact same prescriber group as myelofibrosis. These are -- all fit into the myeloproliferative disease world, broadly in hematology oncology. There's probably about 75,000 patients who are in this PV population who are treated, most of them with phlebotomy, a way of drawing blood off, to basically crudely create iron deficiency in these patients. And again, we're trying to supplant that with the drug that will just create pharmacologically an iron restriction.

And so we think that among these patients, some are treated with phlebotomy, some with hydroxyurea, ruxolitinib, interferons. These are all used sometimes in combination. This iron-based mechanism, we expect, it doesn't really interact with these, meaning it can be used on top of any of these. So essentially, I think any patient who's being phlebotomized as a way of controlling the excess red blood cell production in this disease would find considerable benefit from going on a therapy like this.

So with that number of patients, it ends up being a very attractive market. The drug is doing what it's supposed to do. It's really not a surprise when you work with a genetically validated target. It does limit the surprises. So we've done and published our healthy volunteer work. Here, the concept is to actually increase hepcidin, not decrease it. That's in the -- I'm sorry, the first 2 slides here are actually the PK/PD, and then, yes, the percent change from baseline in the hepcidin that we see going the left-hand panel.

And then the serum iron trace is in the second panel. You can see it going down below the baseline, so significant reduction in serum iron as expected. And then that leads to decreases in hemoglobin and hematocrit and in polycythemia vera, but the therapeutic objective is to achieve decreased hematocrit.

So the healthy volunteers tells us the drug is doing what it's supposed to do, affecting the hematocrit in the desired way. So I think significant derisking coming from this healthy volunteer study. Based on this, we opened up a Phase II trial in polycythemia vera at the end of 2025. We actually designed it to be an initial cohort of 20 patients, using them to explore a variety of doses. We had an overwhelming response to the trial, and we took advantage of that to double the size, anticipating rapid enrollment and also trying to satisfy demand from the sites.

There's just a lot of excitement about iron restriction for these patients. And so that has allowed us to accelerate all of our time lines for this program. We hope then in 2026, this year, by the end of the year to present a very significant data package, proving out proof of concept in the disease population. And then that should enable an end of Phase II meeting early and progression to pivotal trials early in '27.

So all told, the pipeline situated in hematology, oncology is coming together beautifully. We expect to progress through clinical regulatory activities this year and look to have both kickoff as pivotal programs next year.

So this leads to how this all rolls up into our milestone and catalyst chart. Needless to say, the most important of which is an anticipated FDA action date coming in just a matter of weeks now. That would be followed by launch. You'll start to get the kind of launch characteristics, revenue, patient starts, prescriptions that will run on a quarterly basis. But in terms of clinical catalyst, then we'll also have the top line data from our confirmatory APOLLO study.

And then 2027, we'll start to -- with the successful APOLLO readout, we would start to approach ex U.S. markets and get those regulatory filings in place. On the pipeline, we expect to start up first half of the year, the IBD study I talked about, then get top line RALLY-MF data and progress to that end of Phase II meeting with the FDA and then Phase III initiations penciled in for 2027. And then PV, again, the initial and hopefully pretty substantial set of data from the PV trial, that's our Phase II trial.

And then I didn't even really talk about sickle cell disease, but it's another place where phlebotomy is used clinically, and we expect iron restriction there to be an effective therapy. We started just a pilot study there, but we'll get some data from that this year as well. And that all rolls up into then hopefully, a Phase III start-up for PV in 2027.

So a lot going on, and I'm delighted to say we're well capitalized. We have about $791 million on the books right now or as of year-end. And that provides us runway into 2029. That runway assessment assumes all of these activities are carried out, Phase III myelofibrosis, having the commercial team in place for bitopertin, Phase II for PV as well as these all -- these signal-seeking studies. And that runway does not assume any revenue from bitopertin yet, right? So essentially, it's an all burn, no revenue type model, very conservative, takes us into 2029. Of course, as we start to get revenue off that program, we can reassess that, but I think that runway will reach far into the future at this point.

So bottom line summary. We built this company always wanting a business plan that would allow us to be stand-alone with sustainable growth. We're now so happy to have bitopertin on the cusp of a potential approval through the CNPV program, launch ready, strong product profile. We think we see a lot of potential benefit for these patients. And we think the overall addressable market is actually $2 billion plus, right? If all 14,000 of those patients can be found, we think this could be a really big rare disease program. We have now DISC-0974, DISC-3405. We've established proof of concept in the clinic, in the patients with in myelofibrosis, mechanistically in healthy volunteers with the third program. And these are also very large hem/onc-type opportunities. So we assess $4 billion plus in myelofibrosis anemia and even in larger in polycythemia vera market.

So that's everything I wanted to run through today. I really appreciate your attention. I think it's going to be an exciting year at Disc.

We have time to take questions from the audience if any. Maybe one question from me. You talked about the funnel a little earlier about for EPP. And we said there were about 20,000 patients who are predicted with genetic prevalence and then 14,000 who are diagnosed and addressable, and then 6,000 were engaged. What could we do to bring more patients down the funnel and how is your launch accounting for that?

Yes, it's a great question. Yes, we're going to try to make sure those 8,000 patients have access to what we think is going to be an important therapy. So some things are happening organically. The patient advocacy groups are just really excited and engaged on this program. And maybe as a result of that work, we've actually seen a number of media articles coming out, patients kind of stepping up and saying, "Hey, this has been a really rough disease for me, and I got into a trial with bitopertin and they're talking about how exciting the results have been for them." And that kind of publicity actually has caused some patients to come out of the woodwork that we had another identified.

So I think there's kind of an organic thing going on, which is super exciting. We're also using a variety of digital tools to try to help identify where there might be doctors that we can go call on. The claims data as part of that as well. And then we also are just setting up basically call centers to try to just reach out to the 8,000 prescribing physicians who are identified through the claims as having those patients. And we'll just try to make sure we call them all.

And that process has started as well and already yielding some physicians who are the call, first of all, that's the hard part, but then saying, "Oh, yes, in fact, I do have a patient and would be interested to learn more about this disease," right? So I think there's a lot of efforts we're going to make to try to ensure at least the word gets out and patients have a choice across that full set of 14,000 diagnosed patients.

We have time for maybe one question. Maybe very briefly if you could tell us more about your ex U.S. strategy and how we should think about that.

Yes, yes. So ex U.S., it's going to be a traditional approval path, meaning we have the APOLLO trial, which is confirmed for U.S. purposes. It is actually a Phase III for ex U.S. markets. There are a lot of EPP patients in Europe. That's actually a very concentrated market. Those patients all come to single centers. For example, there's a KOL at the Parisian center, who will tell us he has 400 patients at this 1 center. So a very concentrated market. Our intention is once we get that APOLLO trial data, then we'll use that to file the MAA and then move ahead from there. Japan also represents a country with a lot of patients with this disease as well. So those are probably the first 2 regions we'll look at, and we're projecting that those filings will start to roll in 2027.

Well, thank you so much for your time, John. Thank you.

Thank you.

Good day, and thank you for standing by. Welcome to Disc Management Conference Call.

[Operator Instructions]

Please be advised that today's conference is being recorded.

I would now like to hand the conference over to your speaker today, John Quisel, CEO. Please go ahead.

Good morning, and welcome to the Disc Medicine Management Call. This is John Quisel speaking, CEO here at Disc, and I'll be joined by Will Savage, our Chief Medical Officer; and Jonathan Yu, our Chief Operating Officer. We are presenting from Orlando, where the 67th Annual Meeting of the American Society of Hematology is underway. We presented an exciting first look at data from the RALLY-MF trial at the ASH Conference yesterday, which will be the focus of today's call, along with a couple of broader corporate updates on the progress of our portfolio.

Before we get started, I'll cover a few preliminaries. We will be making forward-looking statements, and these should be taken in context with respect to materials that we have filed with the SEC and have posted on our website. Additionally, Bitopertin, DISC-0974 and DISC-3405 are investigational agents and are not approved for therapeutic use in any jurisdiction worldwide.

Turning to the agenda. I will give a brief introduction and provide a status update on Bitopertin, which is currently under FDA review for accelerated approval for treatment of erythropoietic protoporphyria, or EPP, under the new Commissioner's National Priority Voucher Program. Then we'll get into the ASH updates. Will is going to present the first interim data cut from our Phase II RALLY-MF study of DISC-0974 in patients with anemia of myelofibrosis. We first showed our proof-of-concept data for this program at ASH last year. And as you'll see, the results continue to point to this being a potentially transformative treatment for anemia of MF. And then Jonathan will discuss how these data position DISC-0974 in MF care and our view of the commercial opportunity.

Finally, Will and Jonathan will discuss our third program, DISC-3405, providing an overview of our vision in iron restriction and study designs for the first 2 inpatient studies that we've initiated this year in polycythemia vera and sickle cell disease. I will close with a preview of where the company is headed in 2027.

So on this slide are some of the key messages for today's call. With respect to Bitopertin, I'm delighted to announce that the NDA has officially been accepted for review. We were notified of this over the Thanksgiving holiday precisely on schedule. This has been a rigorous and intense review process to date, and we are planning for an approval decision and potential launch by the end of January 2026. This is consistent with the 1 to 2 months review period that is expected under the CNPV following NDA acceptance. However, to be clear, there is no statutory obligation for this time line, and I expect that the regulators will take whatever time is necessary to ensure a thorough review. Our commercialization efforts have been accelerated significantly, and we are well on our way to launch readiness.

On DISC-0974, the highlight today is the RALLY-MF data. Like in the Phase Ib study, this initial data cut shows consistent and substantial decreases in hepcidin, leading to iron mobilization, and these translate to durable benefits on clinical meaningful measures of anemia, including hemoglobin, transfusion burden and symptoms like fatigue. Importantly, we will show that these results are consistent regardless of whether patients are on an underlying MF-directed therapy and regardless of which therapy they're on, including ruxolitinib, momelotinib and other JAK inhibitors. This is the lead indication for our second program and is shaping up to be a strong beachhead for Disc's second act in the myeloproliferative neoplasm hem/onc space.

Then we have our third program, DISC-3405, which entered its first proof-of-concept study this year. We started the Phase II polycythemia vera trial around midyear and saw immediate interest and rapid enrollment from the community, prompting us to expand the study. These physicians are many of the same treaters who have been involved in our MF trials. So there's a great synergy between these programs from a development and commercial perspective. More recently, we started a Phase Ib trial in sickle cell disease. We expect initial data from both indications in 2026.

So now let's get into the Bitopertin updates. As a reminder, we submitted our NDA for Bitopertin in EPP on September 29 of this year. And then a couple of weeks later, we were awarded the CNPV as part of the program's first pilot cohort. The CNPV grants a review time of 1 to 2 months from the NDA acceptance as well as increased engagement and enhanced communication from FDA reviewers. We have seen that engagement play out over the last several weeks, and we're actively collaborating with reviewers and responding to information requests. The FDA officially accepted our submission at the 60-day mark, so we anticipate an approval decision by the end of January 2026. We are preparing for a potential launch accordingly. And additionally, I can confirm that we've made great progress in accelerating our CMC readiness for launch, and we now expect to have drug supply available by the end of January 2026, coinciding with our anticipated launch time line. So really great progress across the board on this Bitopertin effort here.

And aside from supporting the FDA's review for our application and preparing for launch, we are also continuing to drive enrollment in the ongoing APOLLO trial, with our focus shifting now to the ex-U.S. sites, which are currently being activated. As a reminder, APOLLO is intended to support full approval in the U.S. as well as a standard MAA application in Europe. We plan to present more detail on our U.S. launch strategy at the JPMorgan Healthcare Conference in January.

And so with that, I'll hand it over to Will to provide ASH updates.

Thanks, John. As a reminder, DISC-0974 is an anti-hemojuvelin or HJV antibody that works to inhibit hepcidin, leading to an increase in iron availability and greater red blood cell production, which is why we are studying it in several anemias of inflammation. The focus today will be the data shared at the ASH Conference from our ongoing Phase II RALLY-MF study of DISC-0974 in anemia of myelofibrosis. In this study, patients received DISC-0974 every 28 days for 6 months and then have the option to roll into a continuation phase. As of the cutoff for ASH, we had enrolled a total of 47 patients in the study, and you can see these patients are spread across transfusion categories as well as a good mix of patients on and off JAK inhibitors, including 13 patients on momelotinib.

Looking at pharmacodynamics, we can see the drug is working exactly as expected with significant decreases in hepcidin, which translated into increases in serum iron, and these impacts were seen consistently across transfusion cohorts. Here, we are looking at the nontransfusion-dependent and transfusion-dependent low cohorts, which represent the majority of patients. We see durable hemoglobin response in the overall population in the blue line in each cohort and even greater response in those patients who qualify as major responders. When looking at FACIT-Fatigue scores, where a 3-point change is seen as the threshold for clinical significance, we're seeing meaningful improvements in nTD and TD Low cohorts, particularly in the major responders. And this is encouraging because it shows us that the improvements in anemia are translating into improvements in anemia symptoms for these patients.

Continuing with the nTD and TD Low cohorts, we are getting great hematologic responses, consistent with what we saw in the Phase Ib study. In the nTD group, we see a 63% overall response and a 50% major response rate. For TD Low, 71% of patients had both an overall response and a major response. As a reminder, historical response rates have been around 30%. So what we're seeing here is very encouraging.

Moving on to the TD High patients, which represent the minority of MF patients and a small portion of the patients enrolled to date, we are seeing a 67% overall response rate in the 3 patients who had been on study for a sufficient duration and no major responses as of yet. On the right, you can see an additional 3 patients who have been on study for slightly less than the cutoff of 85 days for determination of a response. And these patients have excellent responses so far in terms of reduced transfusion and have not received any transfusions while on therapy, with all of them trending towards a major response of transfusion independence for at least 12 weeks. So of course, these are small numbers right now, but it's encouraging data. The data shown so far demonstrate meaningful response across transfusion cohorts. And here, we are also showing a consistently strong response regardless of concomitant use of JAK inhibitors.

On the left, we show that regardless of which JAK inhibitor is used, DISC-0974 significantly lowers hepcidin, including in patients on momelotinib who actually start with the highest baseline hepcidin levels. This hepcidin reduction consistently leads to increases in iron, and then that translates into strong overall hematologic responses of at least 50% across all groups. These data continue to give us confidence that DISC-0974 can improve anemia no matter what other therapies patients are on.

Finally, looking at safety, the profile is consistent with background adverse events typical for the MF population. DISC-0974 continues to be well tolerated with no treatment-related SAEs. So overall, we're very excited about this data set where DISC-0974 continues to show strong responses across a broad range of patient types with anemia of MF.

And now I'll hand it over to Jonathan to review the MF anemia market.

Thanks, Will. As we've discussed previously, anemia is a serious unmet need when it comes to treating MF patients. And when we think about anemia of MF, there are really 5 key treatment objectives. Very important is a treatment that can work across the spectrum of MF patients with anemia. So first, patients need a treatment that works independent of the transfusion burden. Second, patients also need a therapy that can work as a monotherapy or on top of their backbone JAK inhibitor with the potential to optimize their JAK inhibitor regimen.

DISC-0974 has shown similar strong efficacy as a monotherapy and in the combination with a range of JAK inhibitors, including ruxolitinib, the current standard of care as well as newer JAK inhibitors such as momelotinib and pacritinib. And we shared data on the latter for the first time at this conference. And most importantly, patients need a therapy with high response rates, something that DISC-0974 has demonstrated to date with overall response rates of over 60% and have also shown that this activity is durable.

Moving on to the next slide. The implication of this profile is that DISC-0974 has the potential to address a very significant market opportunity. As we noted before, anemia of MF is a serious condition that affects approximately 22,000 patients in the U.S. alone. And these patients suffer from severe symptoms that negatively impact their prognosis, outcomes, optimal treatment and quality of life. This is a very clear and top-of-mind unmet need for both patients and physicians who contend with a lack of good existing or emerging treatment options for this burdensome condition. It's a well-characterized market with established treatment pathways and also that enables us to find -- that makes finding patients and connecting with HCPs fairly straightforward.

So our goal then is to enter this market with a truly differentiated product that maximizes anemia benefit and has the potential to be used across the spectrum of anemia of MF patients and particularly in conjunction with the underlying JAK inhibitor therapy.

Thanks, Jonathan and Will. It's a very exciting data set in a rich market where we think DISC-0974 has real potential to address significant unmet need and reach blockbuster status. In anemia of MF, we will continue to progress this Phase II study with data planned for the second half of 2026. Following this, we are planning for an end of Phase II meeting with the FDA to align on the registrational trial design before proceeding into a pivotal trial, likely in the first half of 2027. We are also continuing to progress efforts around DISC-0974 in other anemias of inflammation with plans to initiate a Phase II study in anemia of IBD early next year. And we also have a long-acting version, which we call DISC-0998, and we are moving that molecule quickly into IND-enabling activities.

I'll now hand it back over to Jonathan to discuss our third program, DISC-3405.

Thanks, John. DISC-3405 works in exactly the opposite direction from DISC-0974. So it works by increasing the endogenous production of hepcidin, thereby limiting iron availability, and it does so by inhibiting a well-validated target called TMPRSS6. We believe this approach to restricting iron has numerous therapeutic applications in diseases associated with erythrocytosis like polycythemia vera, ineffective erythropoiesis like sickle cell disease and other indications where iron overload is an issue. We presented healthy volunteer data at ASH last year, which showed this mechanism is working as expected and have now advanced the program into 2 proof-of-concept studies in polycythemia vera and sickle cell disease.

We have also explored DISC-3405's potential role in treating conditions of iron overload as shown in our iron pulse study at EHA earlier this year and are continuing preclinical work in some of these indications. This program is an exciting growth driver for Disc, offering a differentiated product profile starting in 2 indications, which have been derisked and both represent attractive market opportunities. Starting with PV, this is a larger orphan indication with around 150,000 U.S. patients alone. This is a serious disease with uncontrolled hematocrit leading to significant risk of potentially life-threatening thrombotic events, among other debilitating symptoms, and many patients are not achieving optimal hematocrit control with current treatments.

The role of therapeutic iron restriction in PV has now been well validated based on the clinical trial experience of Rusfertide, an exogenously administered hepcidin mimetic that has achieved significant phlebotomy-free hematocrit control and improved negative symptoms associated both with the disease itself and with frequent phlebotomy. We believe our approach can improve on this by using a monoclonal antibody to induce endogenous hepcidin production and which would allow dosing that is less frequent and has shown favorable safety and tolerability and no injection site reactions to date.

Importantly, there is also significant synergy here with our NMF program, which we have already benefited from in terms of clinical development efficiency. So these 2 programs together form the beginning of a strong MPN hem/onc franchise. On the other side, sickle cell disease is another larger orphan indication, where there has been a lot of advocacy, KOL interest and R&D activity, but still very few effective treatment options. We believe iron restriction is a very promising approach based on clinical evidence, phlebotomy is increasingly being used as a treatment in clinical practice, especially in European countries and has shown evidence of disease modification.

Mechanistically, we anticipate restricting iron to decrease hemoglobin S concentration would decrease the red blood cells propensity to sickle and therefore, may have benefits on hemolysis and VOCs or vaso-occlusive crises. This is a different approach from many mechanisms in development, which aim to increase hemoglobin, but it's fundamentally linked to the mechanism of sickling, which is directly driven by hemoglobin S concentration.

I'll hand it back to Will to talk through our ongoing development program.

Thanks, Jonathan. Here's a look at our Phase II polycythemia vera trial, which we are calling RESTORE-PV. This is an update from what we have shown previously. In the early days of the trial, we saw such strong interest in enrollment that we amended the protocol to increase the sample size to 40 with 20 patients in Cohort A and 20 patients in Cohort B. Cohort A will have an initial dose escalation period before moving into first maintenance period, dosing DISC-3405 at 300 milligrams every 2 weeks, followed by 300 milligrams every 4 weeks. Cohort B will receive dosing of 300 milligrams every 4 weeks for the entire study period. We'll be focusing on safety, PK, hepcidin, iron, hematocrit and phlebotomy rate and expect to present initial data in 2026.

And here's our Phase Ib sickle cell trial design. The main cohort of 12 participants will include people with hemoglobin SS and hemoglobin SC genotypes. There will be 20 weeks of dose escalation from 75 milligrams to 300 milligrams, followed by an optional maintenance period for up to 12 weeks. We will measure safety, PK, hepcidin, iron, hematologic parameters and hemolysis markers as well as explore additional efficacy endpoints, including PROs and changes in frequency of sickle cell complications. We expect to present initial data in 2026.

Now I'll hand it back to John for closing remarks.

Thanks, Will. While the main update today was around the new MF data, I want to step back and acknowledge the transformative year we've had at Disc. A little more than a year ago, we learned that the FDA was open to an accelerated approval path for Bitopertin in EPP using PPIX as a surrogate endpoint. And now we are anticipating a potential approval and launch of Bitopertin before the end of next month. We have also today presented strong initial data from RALLY-MF, which further increases our confidence in the path forward for our second program, DISC-0974. And we expect to engage in discussions with the FDA about the registrational path for that program over the next year.

We have outlined our next phase of development with 3 new trials in PV, sickle cell disease and soon in anemia of inflammatory bowel disease. And we continue to work in a highly focused way on exploratory research that will pave the next wave of pipeline development. We completed 2 follow-on offerings this year, which fund the company into 2029. And importantly, to note, that runway does not include any revenue projections from Bitopertin. So it's a very conservative runway statement. And this should take us through the launch of Bitopertin as well as several key pipeline milestones, all of which position us well to become a self-sustaining commercial stage biotech company with multiple levers for growth in the long term.

And on the next slide, we have all that summarized in a pipeline chart. This chart is focused on what we view as the key value-driving trials. As you all know, there are other smaller exploratory trials going on with each of these molecules and the full pipeline chart is available on our website. But this set of key drivers for the company is going to drive multiple catalysts over the next 18 months. And we will be back presenting at JPMorgan next month. And at that meeting, we plan to give additional detail on our launch plans for Bitopertin as well as a view of key milestones for the company running into 2027.

So with that, thank you all for your attention today, and I will turn it back to our moderator to open the Q&A session.

[Operator Instructions]

Our first question is going to come from the line of Roger Song with Jefferies.

Congrats for the data. I do have 2 questions related to the poster. So the first one is, given the momelotinib anemia sparing effect, what should we expect the incremental anemia response on top of momelotinib? And then can you give us some reasonable benchmark?

And then the second question, interesting. So you have a couple of patients pausing dose because they reached the upper normal range of the 12 gram deciliter for the hemoglobin. So how should we interpret that? And then can you give us some color around the frequency of such incidents and the kinetics of the pausing and resume the therapy?

Yes. Thanks for the question, Roger. As to point number one, yes, the effect of DISC-0974 to manage anemia on top of momelotinib in these patients, that's actually one of the exciting parts of this data. And I think what we see in the hemoglobin results when we break it out by the momelotinib group is great. It just shows essentially the same level of response as we see -- from a hemoglobin perspective as we see in all the rest of the patients. Interestingly, we see the same kind of decrease in hepcidin, and we see the same kind of iron mobilization.

So essentially, patients who are receiving momelotinib, which as you say, it's an anemia-sparing JAK inhibitor, we get basically the same type of anemia response as we do with all other background therapies that we tested so far. So that's great to see. And it's a pretty robust data set at this point. Greater than 10 patients have come through on momelotinib. So we have a high degree of confidence around the robustness of that data.

As to your second question, yes, we're delighted to see some patients reaching targets such that we had to pause the drug, and I'll hand it over to Will to comment further on that.

Sure. So we wrote in the protocol to hold the dose if hemoglobin gets into the near normal range just for common sense reasons. There's no need to continue treatment if they're not anemic. So we hold doses where applicable for hemoglobin and patients are evaluated on a monthly schedule for the protocol, and they just resume their monthly -- their dosing once the hemoglobin goes down below 12.

Our next question is going to come from the line of Thomas Smith with Leerink Partners.

Congrats on the data and all the progress. Just first on Bitopertin. It sounds like really great progress with the agency and ongoing engagement with FDA. But because you're one of the first companies going through this process, I was wondering if you could just comment on the acceptance notification and how it compares versus other typical sort of acceptance notifications. Is there any indication of review types like priority review? Or was there any explicit acknowledgment that the FDA would be proceeding under a more accelerated review process?

And then a second question, if I could, just on 974 and the competitive landscape in myelofibrosis. Like you're clearly seeing consistent activity on top of JAK inhibitors with 974, including momelotinib, could you just comment on the mCALR targeted agents and how you think 974 fits into the treatment paradigm with those agents?

Yes. Thanks for the questions, Tom. Yes, I mean, it's really exciting to be part of this new Commissioner's National Priority Voucher program. And like you say, I think we and the FDA together are carving some new territory and procedures here. So I can tell you, it has been an incredibly rigorous and intense process. I don't know what the count on information request is at this point, but it's nearly daily. And there's an expectation that we will do some pretty complex analyses and respond within 24, 48 hours. So it's been a great process really to see the kind of speed and rigor combined and the sort of resources the FDA is able to bring to bear, all with the goal of bringing this therapy to patients as quickly as we can. So that's fantastic.

In terms of the NDA acceptance, indeed, we did receive written communication around that. As a formal matter, it was designated as priority review. It is still considered under the accelerated approval pathway status, meaning the base plan here is approval based on a surrogate endpoint with indicators of meaningful clinical benefits and the APOLLO confirmatory trial. So that all is the basic premise here. And that's essentially what we know. Otherwise, the expectations around the 1- to 2-month review period are simply consistent with the public guidance that FDA has given around the CNPV program.

And -- but like I said, it's clear that the intention here is to have it be a rigorous review that goes more quickly simply because the FDA is able to put more resources on it. And honestly, it would be great if this becomes a more broad widespread model for drug approvals here.

So yes, then in terms of your second question, DISC-0974 with respect to the emerging mCALR targeted therapies, Will, do you want to speak to that?

Sure. I think 2 things to acknowledge regarding this exciting development in MF therapy. One is that those therapies are going to be potentially useful for a subset of MF patients. And we all hope that patients can benefit in many ways from new therapies, but it's only going to be applicable to those with mutant CALR. The second thing is that our mechanism of action is orthogonal to all MF-directed therapies, including mutant CALR. I think MF development has been trained to think about -- from other sponsors has been -- has trained everybody to think about single agent versus combined with rux.

And there's kind of a legacy there that I don't think really applies to DISC-0974. And so we keep showing data that it doesn't matter what background therapy you're on in terms of a JAK inhibitor and expanding to other therapies as they become available, I anticipate the same response from patients.

Our next question comes from the line of Sean Laaman with Morgan Stanley.

Congratulations on multiple fronts. Just to clarify, the major hematological responses were achieved regardless of concomitant JAK inhibitors. But is there forward plans for specific combination strategies is the first question.

And a similar question, opportunity for combination studies with ESA, luspatercept or other agents to further enhance efficacy or broaden the addressable population?

And just lastly, first things first, of course, but beyond anemia and MF, what sort of other market opportunities might you observe with this mechanism?

Yes. Thanks, Sean. Yes, I mean, broadly speaking, the data again and again, both in the Phase Ib and now in the Phase II RALLY-MF study shows us a broad applicability of this mechanism. It just seems to provide benefit to all categories of patients that we're testing it in, in myelofibrosis. So while we could design trials and we have considered trials that would, for example, pair the drug, pair DISC-0974 directly with ruxolitinib on -- as soon as patients go on to that drug as a way of trying to buffer against the downward pressure that rux is known to put on hemoglobin levels. I have no doubt that, that would be an effective use of the therapy.

But whether that's the exact trial design that brings this drug to the most potential patients, I think that's something that remains to be determined. I think right now, our bias, but let's wait until we get the full Phase II data, our bias is that this appears to be broadly usable in many different contexts in this disease. And we'll probably plan to study it essentially that way in the most generalized and broad way in our eventual pivotal trial. So that was the first question you had.

The second question was going to studying with EPO and luspatercept. Will, do you want to speak to that?

Sure. So I'll say, Sean, despite John's comment about we want to develop this in the core development program for the broad range of anemic MF patients, there are interesting questions that are useful to answer like you bring up, like combination with EPO and luspatercept or upon initiation of rux, these are interesting questions that I think can be answered over time, but they're -- and certainly interesting to answer over time, but are not part of the core development program.

I will note we have presented at prior conferences, preclinical data showing the combination of the iron mobilization mechanism with EPO or luspatercept. And it's clear that these mechanisms do synergize. I think no real surprise there as you push red blood cell production with some of those agents, there becomes a demand for iron and that providing that by mobilizing with our antibody approach does appear to, at least in wild-type animal setting, drive additional erythropoiesis. So I think a lot of rationale why it would work, how we unpack that, we'll see over time. I feel like there was...

Market opportunity.

Right. Okay. Other market opportunities. Yes, I mean, this is something we're exploring. We had the readout from our study showing some activity in patients with a higher EPO level in that disease state. So we're still evaluating that. We have noted that we plan to open a trial in patients with anemia as a consequence of inflammatory bowel disease, and that's slated to start up in the first quarter of 2026. And that's what I would call sort of a pure anemia or -- well, definitely an anemia inflammation type disorder. And I think that remains the primary sort of expansion indication effort is into these anemia inflammation.

Probably the right way to view that with DISC-0974 is that these are signal-seeking pilot studies and then we probably use our second-generation antibody to treat those wider indications. DISC-0974, I think at this point, with the success we're seeing in myelofibrosis, we'll keep it pretty focused there. We are probing MDS patients in a small cohort of this study as well. So that's an interesting neighboring indication that we're looking at, but we don't have any data to report out on that yet. So that's a sampling of where we're going. But yes, I mean, I think hepcidin and iron mobilization, it is a fairly broadly applicable mechanism.

Our next question comes from the line of Kristen Kluska with Cantor Fitzgerald.

This is Rick on the line for Kristen. Congrats on the RALLY-MF data and progress across the pipeline. Just one question from us. On fatigue score, is there anything you can say even anecdotally about the TD High patients and the fatigue that they're experiencing and sort of relate that to the baseline that you see the patients starting at?

Sure. Sorry, the question was about fatigue and what the patients are feeling there.

Yes. Sorry, go ahead.

Yes. So we have only interim data on that. You noticed that we've reported out fatigue throughout the 6-month period for nTD and TD Low because we had data that far. We don't have complete data yet on TD High that's still in progress. But that is something we are evaluating.

Our next question comes from the line of Evan Seigerman with BMO Capital Markets.

So given the level of responses we've seen across both JAK and -- patients with both JAK and non-JAK background treatments, can you talk about what the FDA might need to see beyond this data in a Phase III to support a broad label across JAK usage and across kind of underlying hepcidin at baseline?

And secondarily, for patients that are nonresponders or super responders, can you comment on how they've reacted to dose escalation to the 75 milligram, like how many patients have gotten to that level? And are they getting extra benefit from this escalation?

Yes. Thanks for the question. Will, do you want to go ahead?

Sure. Well, I don't -- from what FDA -- I think the key question is endpoint not so much population. So I think that we need to continue getting data from this study, come up with a Phase III design, engage with FDA and figure that out. But I think it's going to be acceptable to just take patients with -- continue to take patients with a wide variety of background MF therapy into a Phase III. This is precedented in other diseases where you're studying not the -- where they're receiving treatments that are not directed at what your drug is treating. So while other treatments are treating the spleen and symptoms, we're evaluating separately the anemia. So as long as it's balanced across groups, I don't think there's going to be much of a question of what the -- what kind of background therapy they're on.

Regarding the dose escalation, I can say that it's a small number of -- it's a minority of patients who are receiving that dose escalation. We haven't reported out the results of that dose escalation because, of course, this is still an ongoing study. But looking at our Phase Ib portion with dose escalation, you can imagine that there's not a lot of iron benefit from escalating a dose, but we're doing the formal test of seeing what happens with dose escalation.

Our next question will come from the line of Tara Bancroft with TD Cowen.

So I'm curious if you could tell us if baselines, especially absolute hemoglobin levels, if they differed at all between enrolled versus efficacy evaluable patients and also by JAK use, if there's anything notable there at all if they were consistent. And then the clinical relevance of these hemoglobin increases you saw. I know that they experienced less fatigue, which is great, but it would be great to learn what you're hearing on how that impacts patient lives and their enthusiasm to continue or adopt therapy.

Yes. I'll start actually with the latter part. It's -- again, I don't want to put too much weight on anecdotes, but we've recently been hearing a lot of anecdotes about patients just feeling great on DISC-0974. I think the general reporting we hear is that there's not a lot of sense of side effect or anything -- any kind of negative feeling on the products. And we are starting to hear stories from investigators about how great some of the patients feel. But more rigorous, obviously, the data itself.

Will, I'll hand it over to you to talk about the baseline hemoglobin levels and the other questions.

Yes. I'll just add one thing about the clinical meaningfulness of the increases that we're seeing. An important part of hemoglobin level is adding a buffer for patients. So if they get an acute on chronic problem, both physicians and patients feel some level of protection, like they're not on razor's edge with their hemoglobin and transfusion. So there's kind of a peace of mind aspect that's not captured in any endpoints that we're measuring, but it's certainly valuable clinically.

Regarding the baseline hemoglobin difference, they are -- it is a mix across the board when you -- within each transfusion cohort. We're not looking -- there's no trend nor is there any inclusion/exclusion criteria that would bias the population. So it's still small numbers, but that's something that we may present in the future just to address the question.

Our next question will come from the line of David Nierengarten with Wedbush Securities.

I just had one left. When you look at anemia and IBD patients, are there any plans to stratify for baseline hepcidin or EPO levels in those patients, just thinking about the experience with CKD.

Sure. So in IBD, we know from the literature that it is a high EPO anemia like MF. And these have chronic kidney disease. In fact, in both MF and IBD significant in those trials, significant CKD is excluded from the study. The relationship between baseline EPO when you're -- and response is -- there's not a relationship in our study because everybody in the MF study because everybody has a high baseline EPO. And we expect the same in IBD. So it's not something we're planning. I mean we'll certainly evaluate as data come along, but it's not a stratification or enrollment criteria.

Regarding baseline hepcidin, that as you may know it's a highly variable biomarker. It changes by the hour inside of a person. And so it's very sickle and not a good way to stratify patients nor when we look at our MF data, does baseline hepcidin matter for response. It's elevated in essentially everybody. And the key PD effect that we're looking for is increasing in iron, and that has been consistent regardless of what you're starting hepcidin.

Our next question comes from the line of Stephen Willey with Stifel.

Just a couple of quick ones on the Phase II PV trial. So what proportion of patients are you expecting to be on background standard of care therapy? And is there any mechanism in place to make sure you get a representative amount of monotherapy data? And then just based on the TPP [indiscernible], where do you think this best slots into the treatment landscape with respect to hydroxyurea?

Yes, good questions. Yes, we're certainly excited about the PV trial, but you picked up on that. We heard that enrollment was rapid. We've added another cohort. Yes, Will, do you want to speak about the plans for standard of care?

Sure. So there's there is not a protocol-specific way to ensure that we get representation of background therapy, but we do have the option to add a cohort into this study. So we can always add an attribute if we find out that there's some imbalance for an unexpected reason, we could always ensure that we get broader representation. But when you look at other sponsored studies, nobody has had an issue getting representative background therapy. We're not expecting that either.

And regarding the TPP, I think we -- and hydroxyurea, I think people are going to -- one of the features of our TPP is the safety and tolerability profile. And if you're on hydroxyurea for hematocrit control, you have to compare what that looks like versus a once -- potentially once monthly antibody and that tolerability profile. So I think there's -- it's about giving options, and I think it would be an attractive option for patients and physicians.

Our next question comes from the line of Danielle Brill with Truist.

Congrats on the update. First, on the Phase II, I was wondering if you had the breakdown of response rates by background JAK use and baseline transfusion dependency status readily handy. If not, any qualitative comments you can share on whether there were deviations in response rates by the transfusion cohort when you look at background JAK use? And then I guess, looking at the optional continuation phase participation, only 68% of completers continued on. Any thoughts on reasons why others did not?

Sure. So regarding transfusion status and background, the question was on the transfusion responses and their background JAK status in the TD Low and TD High. We didn't present that. There's -- honestly, we haven't done [indiscernible] analysis. We have consistent results with the hemoglobin and overall response rate separated out by JAK inhibitor. As we get more data and particularly enrollment in the TD Low and TD High, looking specifically at transfusions will be more interesting. I think the question is -- it's really getting into finer and finer detail of a small data set. So I think it's something that could be forthcoming.

Regarding those who -- only 68% of completers continuing, I don't know if it's only 68%, I think that's pretty good. But the -- we haven't collected the reasons. I know that one thing that has come up just in the study conduct is because of the appeal of the study, we do have a number of people who are flying to sites. There is a big travel burden for people for a number of participants, but we haven't collected systematically reasons for not continuing.

Our next question comes from the line of Rami Katkhuda with LifeSci Capital.

Congrats on the data. I guess do you think the slight differences in efficacy in the rux arm versus other JAK inhibitors is due to the small sample size? Or could it ultimately reflect a potential ceiling on anemia benefit from targeting this pathway?

And then maybe secondly, on Bitopertin, the CNPV obviously accelerated the potential launch here. Could you provide a quick update on the status of your commercial readiness and sales force?

Yes. I mean I think the variations between the different JAK inhibitors are numerical small number type variations. Really, we're seeing consistent and similar responses across all groups regardless of background therapy. I think that's the take-home message from this data set, and that's how we expect it to evolve even as we get to larger numbers.

I mean one thing to add is that anemia in MF is multifactorial. There's bone marrow fibrosis, there's splenic sequestration, splenomegaly are causes of anemia. With the hepcidin data that we've shown, we're essentially doing the scientific experiment of showing the full extent of anemia in MF that is driven by hepcidin because I think we are essentially completely correcting the hepcidin problem. So I think the ceiling that is really just based on the pathophysiology of MF. I think when it comes to hepcidin, there's no more meat on the bone, and we are completely fixing that problem.

Let's see, your second question was about the commercial preparation for Bitopertin. Yes, great question, huge occupation of the company these days is accelerating all of our launch preparations by roughly 6 months over our initial plan. And I would say, generally, it's going great. We are working on hiring our sales force. We're expecting to hire 24 reps across the country, and that's ongoing. And assuming a late January approval, that field force will be out in the field pretty shortly after that date. So really coming together there. Reimbursement and access conversations are ongoing. That's probably one place where this accelerated process leaves us a little shorter than we might have been otherwise.

And to that end, I think I've been guiding expectation that there may be a higher degree of use of start-up programs initially where we provide -- we may provide some free drug initially out of the gate while we sort through some of the prior auth questions.

And then drug supply, this is a super important, exciting development. I think this is always one of the longest lead time activities of a company. And at this point, we feel pretty good that we're able to meet FDA expectations on a drug supply that we can make available on that kind of late January time line. So really, all the elements are coming together well, and we feel good about that accelerated process from a commercial point of view.

Our next question is going to come from the line of Derek Archila with Wells Fargo.

Congrats on the update. Just a couple of questions. So just a follow-up to a couple of questions ago, but just any differences on the disposition of the patients on momelotinib and pacritinib relative to the Jakafi patients? Just kind of reconciling that slightly lower response rate, but it does sound like it's probably just small end. And also, what was the average Jakafi dose in the patients on Jakafi?

Yes. So I do think it's a small numbers issue right now. I mean we don't have any specific information on different disposition in the study, just they're all doing well. The average Jakafi dose, I mean, that's something ultimately that we will look at. I mean in an interim look, it's less fruitful, I think, to look at that because patients are -- many patients are still in the middle of the study, and it is a manual extraction sort of analysis, but it is a relevant question.

Our next question is going to come from the line of Martin Auster with Raymond James.

Curious if you guys had any observations in MF and the non-JAK inhibitor cohorts. I was just curious if there's any color on whether those patients were those who maybe didn't meet criteria for JAK inhibition or if they've maybe been patients who previously exposed and a discontinued drug?

And then secondly, I know you'll be thinking a lot about the registration path in MF next year. But I was curious for now if you could comment on whether you're thinking about sort of a unified Phase III with multiple cohorts or if you'd be looking to maybe separate out the non-transfusion-dependent and/or low transfusion-dependent population from the high TD population and whether or not that can kind of meaningfully accelerate Phase III enrollment and maybe help get to market a little faster?

Yes, I can start tackling your second question about our pivotal trial design. I think our objective is to run a unified single trial, including whatever patient groups we can unify well under a single trial design and feel confident about enrolling. And I make that last comment because acknowledging that the high transfusion burden cohort, while preliminarily looks like the response rate is going to be pretty good. A small end, it was that way in Phase Ib, just a somewhat difficult to enroll, probably fairly rare patient group.

So whether we're able to logistically incorporate those into the pivotal trial into the end or may pursue those through a separate trial, that remains to be determined. But your point about paying attention to time lines here, that is something we are absolutely going to pay attention to and try to make sure we're running a really efficient trial to get this drug to patients as soon as we can.

Now your first question, I'll hand it back to Will.

Sure. So regarding the non-JAK inhibitor patients, we're not rigorously characterizing in the study why they are not on a JAK inhibitor, but we have surveyed investigators and most of them are -- most of these patients are people who just do not need a JAK inhibitor yet. There's a large population, a large minority of MF patients who don't have spleen or symptoms issues yet and anemia is their primary problem. There are some patients who have been previously exposed to a JAK inhibitor and have stopped, but that's fewer in the nTD cohort.

Thank you. And I would now like to hand the conference back over to John Quisel for closing remarks.

All right. Well, thanks, everyone, for your attention today. Again, really successful ASH Conference for us here. We're really excited about the quality and breadth of data that we're seeing at this interim look in the RALLY-MF trial for DISC-0974 and look forward to more updates next year. And then meanwhile, also excited about just the excitement and the pace of enrollment in our DISC-3405 polycythemia vera trial. So again, I appreciate your attention. Thanks a lot, everyone.

This concludes today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.

Hello, everyone. Welcome to Jefferies London Healthcare Conference 2025. My name is Roger Song, one of the senior analysts who covers mid-cap biotech in the U.S. It is my pleasure to have the fireside chat with our next company, Disc Medicine. Welcome, John.

Yes. Thanks. Great to be here.

Awesome. John I think we have a lot going on for the Disc, which is all towards the very good direction. Maybe you give us 1, 2 minutes overview of the company? what are the key program you are focusing? And then what's the underlying philosophy for the company, and then we can go into each individual programs.

Yes, that's great. Thank you. Yes, it's been a great year Disc. So we're a company focused on controlling red blood cell biology by controlling the metabolism of iron and heme, which are, of course, 2 of the critical building blocks for red blood cells. Our lead program called Bitopertin, is in-licensed from Roche, is a molecule that controls heme biosynthesis in red blood cells. And for using that molecule and studying it in patients with a rare disease called erythropoietic protoporphyria or EPP for short, as we call it. The claims data would tell us there's about 14,000 of these patients diagnosed in the U.S. We've completed a Phase II program. And the big news for this year is we were in an accelerated approval process with the FDA, and it got even more accelerated when we were awarded one of these Commissioner's National Priority Voucher.

And so we're now in the middle of -- we submitted the NDA at the end of September. And if all goes well, it would be just a matter of a few months, like late this year or early next year for when we could potentially be approved and launching. So that's been the big news for the year. We also have a pipeline of 2 Phase II programs that focus on controlling iron metabolism. DISC-0974 is an antibody that we in-licensed preclinically from AbbVie. It's in a Phase II trial called the RALLY-MF trial for addressing anemia in myelofibrosis patients, a rare hem/onc indication. And that program has also gone really well. We reported data at ASH, American Society of Hematology in December last year with about 35 patients worth of data showing unprecedented positive response rates in treating this intractable anemia. And coming up at ASH this year, we expect to have about 40 to 50 patients' worth of data from our Phase II program now. So a lot of excitement around that. And then the third program is in Polycythemia vera, works by restricting iron, and that's just initiated its Phase II. So that's the quick rundown of the 3 clinical programs for the company.

Excellent. Okay. Maybe we can just go one by one in terms of the stage of development. For EPP program, Bito, you got a CNPV, which is one of the -- the first batch of the one of the [indiscernible] right, so first 9. So maybe just -- just out of the curiosity, how you got that? And what's the process look like? And then more important is, how do you think this voucher is going to change your time line and then likely success, if anything changed for the approval?

Right, right. I mean the truth is we don't know a lot about the process. We applied. It was a very succinct application. And it was only a couple of months later, we were notified that we've been awarded. I think we spent a year of meetings after our end of Phase II meeting. The FDA put us on an accelerated approval pathway. Then we had a whole series of additional meetings with the dermatology division, which is the review division for this disease. And I think there was a good interaction. They had good insight into the program and how it was progressing. I think that probably made a difference in our application for that voucher.

And how do you think about the time line and then the success?

So if you look casually at the website, the PR about how this program works, it will say a 1- to 2-month review period. If you look carefully, it will say 1 to 2 months from when the file is complete. And that language, I think the FDA is preserving their process of the submission of an NDA and their review of the quality of the NDA to ensure that the file is, in fact, complete. It has all the materials they need to conduct the review. And that's normally a 2-month process. And then that will be followed by this 1- to 2-month review system. So for us, we submitted our NDA at the very end of September just before the government shutdown. 2-month process would get you to the end of November. And then 1 to 2 months after that would be the intended action date for the FDA.

Got it. Okay. Great. And then that seems to accelerate a little bit about the potential launch as you initially planned. But how prepared is the DI team in terms of the prepare for the launch?

Yes. No, it's a great point. I mean I think we're originally planning the earliest under the accelerated path would have been June of next year. So we're pulling that in by about 6 months. And we have a great team, really seasoned group of executives who have launched drugs before. So everyone knows what they're doing. But that said, it was a longer process than we were anticipating, and now we're accelerating everything. And so we'll have many things in place. The logistic core of providing drug to patients, that will be all set up, no problem. Other aspects, though, will be not as optimal as they would have been on a traditional time line. So the sales force will likely get seeded and be able to go out into the field only after the likely launch date, but by a matter of weeks.

We'll have fewer payer conversations, right? So some of the reimbursement pathways may be less established at the point of launch than they would have in a regular way situation. So there may be increased use of various free drug or starter programs relative to a regular way launch setting. But I think all in all, it's going to be great for patients. There'll be an earlier access point for this therapy that we think is going to be important. But -- and so -- and once we're a quarter or so into this, all the machinery will be in place and things should take off on a regular path.

Yes. Okay. Got it. The investor community, once you have a drug approval and then launch, everyone will be very focused on the initial launch trajectory. So how do you think about this population and how readily those are -- those patients can available for treatment? And then also just remind us how is the open-label extension or the compassionate use program working in this pop because this is a rare disease population that you seems to be knowing where those patients are and then how readily those patients can get on the drug once they get approval on the commercial side?

Yes. So big picture, we're very fortunate to have an ICD-10 code that was set up about 8 years ago. So we're able to use claims data to really map out the patients who've been diagnosed and use that claim. That identifies about 14,000 patients in the U.S. Now the nature of the disease is that there's not much to be done for it. So there's definitely a pattern of some patients who see a doctor, get their diagnosis and then probably disappear from the medical system. So a significant number of those may be somewhat challenging to activate and bring on to a new therapy. But we see about 6,000 patients in that claims data who are highly engaged. They're seeing their physicians. They're getting treatment, both coded for EPP, but also otherwise. For example, you'll see a number of patients who are getting care for an ongoing liver disease, which is a common -- a relatively common complication of the disease. So we see kind of a 6,000 engaged patient population. We've designed our sales force of about 24 to call on the doctors that see those 6,000 patients. And then in the very near-term stages of launch, we'll have patients who are rolling over from our clinical trials.

So we have an ongoing long-term extension study, which will eventually probably capture about 150 patients there who will likely over the first year, mostly convert on to commercial product. And then at the top 15 or so centers where we're highly connected, those KOLs understand our mechanism and the important potential it has for the patients.

They tend to be the top enrollers in our trials as well. And so there's a good number of patients there that we can launch against. And that's part of why I think the sales force timing isn't as critical as it might otherwise be because there's a decent number of patients who are already identified and interested in the therapy and requires a lot less activation to access those patients.

Yes, we want to set the right expectation, right? So it is a rare disease population. The approval seems a little bit earlier than we expected. You don't have the full commercial sales rep team, and field team are ready by the time of approval. On the other side, you just like you said, right, so you have open-label extension, 100, 150 patients already there and then they can convert to the commercial product and then you have the relationship with the top enroller. So how do you think about the launch, kind of initial launch kind of trajectory going to look like? And then if we're thinking about -- you mentioned this patient open-label patient, they can convert within a year. So how quickly they can convert just considering the reimbursement and then everything kind of in place?

Right, right. Yes. Well, so I mean, priority #1 is going to be providing access to the patients to what we think is going to be an important therapy. And we're going to make a significant corporate effort to have that happen regardless of how the reimbursement pathway has been hammered out yet. And then we'll allow over time to get those -- the prior auths resolved and get people who have commercial insurance onto a proper paying system. So the trial patients will, no doubt, convert to commercial product. I mean we will have to shut down the long-term extension study at some point. And that conversion should be pretty rapid. I mean it's not going to be -- it's not instant, right? It does take time. The physicians have to write the script. The patients have to go fill it and get on to product. So it's not an instant process, but it's a process that should play out over about a year.

Got it. And then you are also enrolling your confirmatory study for the -- for your -- for full approval. I think -- I believe you guided the enrollment should be complete within a year. So remind us how you're going to play this clinical trial participation and versus the commercial product participation.

Right. So we're running what we call the APOLLO trial right now. That's the confirmatory trial for U.S. purposes. It would be the registrational study for ex U.S. purposes. So European and Japanese markets are going to depend on that APOLLO readout. Like you said, we initiated enrollment back in May of this year. We expect that to wrap up about 150 patients total by May of next year is our guidance. And everything we've seen, there's a tremendous amount of enthusiasm. Enrollment has gone well. We expect to be able to hit that guidance.

And those patients, probably about 100 will come from the U.S. Those are the first enrollers. Then the latter end of the study, the last 50 or so will enroll out of European sites, which is important because it's the first time actually we're able to treat patients in the European jurisdiction. So it's important for EMA regulatory purposes. And all of those patients will be eligible to roll on to the long-term extension study as well. So those 100 U.S. patients as they transition on to that long-term extension eventually will also then transition on to the commercial product.

Got it. Okay. All right. We've spent a fair amount of time on the EPP, the Bito, and then the potential launch. But also another major part of the value driver is coming from the anemia MF, particularly. So coming into the ASH in a couple of weeks, and then you will have a big presence there. So just give us some preview on what we're supposed to be seeing and then what will be your guidance on the expectation for investors?

Yes. So the big event at ASH for us this year is our myelofibrosis program. This is a rare disease marked by anemia that typically a diagnosis and persists and worsens throughout the course of the disease. There's actually no on-label therapy to manage anemia in these patients. I know the investor community has been conditioned to think about spleen size and symptoms because of the JAK inhibitors that has been a very successful class of drugs for treating these patients.

But those JAK inhibitors typically don't manage the anemia in these patients. In fact, Jakafi, the leading therapy exacerbates anemia, makes it worse. And so our goal with this program was to use this iron mobilizing mechanism to make iron available to support erythropoiesis in these patients. It's well known from work at the Mayo Clinic that that's one of the driving mechanisms for the anemia. And it's been great data. So at ASH last year, we showed 35 patients worth of data at different -- a variety of different doses coming off a Phase Ib study with really great response rates. The FDA has suggested that we look at the patients in 3 categories: the non-transfused, the lightly transfused and the heavily transfused.

And we've seen really leading response rates across all 3 of those categories. And so as we head into ASH, our, I guess, when people ask for guidance, we're running a Phase II trial called the RALLY-MF with 90 patients. We expect to have data from about half of those patients that are evaluable for our ASH presentation. And they will be sprinkled across all 3 categories.

It roughly matches the epidemiology of the disease, meaning most of the patients are in the non-transfused category, then about 1/4 in the lightly transfused and a relatively small subset are in the most heavily transfused category. And I would say, based on past data, we have a lot of confidence that we're going to continue to see great data from the non-transfused and lightly transfused populations. And the heavily transfused, we really only had 5 patients worth of data, 40% response rate 2 out of 5 at ASH last year, which is great, but also such a sparse data set, we don't view it as having much in the way of predictive value for what we'll get this year.

So that will be the set, and then we'll go on to complete that Phase II trial, have an end of Phase II meeting with the FDA, set up the pivotal trial. I think that's something the investor community is very interested in seeing what that final pivotal trial will look like because there hasn't been a kind of broad spectrum anemia therapy pivotal trial in myelofibrosis yet.

We saw luspatercept focused on just the subset of most heavily transfused and on Jakafi patients, a very difficult-to-treat population. They -- that study read out earlier this year with a p-value of 0.067 so failed. And so I think that category of patients remains probably a little bit challenging for any therapy.

Got it. And then the study design is you can use on top of any JAK inhibitor plus, minus, and I understand different population. But just biologically, do you see the different expectation in terms of the hemoglobin increase or the transfusion independence? Do you see any different expectation in terms of you don't have any background therapy or different JAK inhibitor therapy? Any nuance there we should be aware of?

Yes. So the leading therapy for these patients is Jakafi, ruxolitinib. We showed in last year's data set in about 10 to 15 patients who were on background rux, a very good response rate with our drug. So no negative interaction between our therapy managing anemia and the underlying rux therapy. So that was incredibly important because a very significant number of these patients will be on rux. Rux actually exacerbates anemia.

So having something to help patients stay at the optimal dose of rux is a very important medical objective of an anemia therapy. So continuing to see that kind of combination data with ruxolitinib in the Phase II trial will be very important. There's also a new entrant in the JAK inhibitor space, momelotinib, which has an element of addressing anemia, right? It also touches the hepcidin pathway, touching iron in the same way our drug does. So there was some expectation early on that, that might represent a competitive dynamic. But actually, our experience, and we talked about this early in the year, is that we've had tremendous enrollment in our study with patients who are on momelotinib where their anemia was not actually managed. And I think, our experience with those trial patients is to see momelotinib as more of an anemia sparing JAK inhibitor as opposed to really addressing the anemia.

And so we're going to get a good look at the combination effect of our drug on top of momelotinib. And the objective, of course, is to see good data there. We think there's good evidence that our drug has a much more profound iron effect than that drug, which is, first and foremost, a JAK inhibitor and just kind of touches the iron pathway as a secondary effect. So if we're able to show that, then we'll be looking at a data set that demonstrates really the broad applicability of our drug, which has always been the basic thesis.

The iron mechanism that we have is orthogonal to essentially every other mechanism that's used in these patients to manage other aspects of disease. There's no other approved therapy to manage the anemia. If we can just create a simple, safe, broad-spectrum anemia therapy that addresses -- that's useful in a simple way for all of these patients, then that's a U.S. market size of about 22,000 anemic myelofibrosis patients that could benefit from this drug, which is pretty substantial.

Yes, totally. Maybe just those subgroup maybe in -- will become too small to really tell the difference. But just directionally, let's say, 3 dose population without any JAK inhibitor on the background, so using 0974 and then with the Jakafi and then with momelotinib. But do you have a different expectation in terms of the hemoglobin increase or the transfusion independence, which one you're expecting to see even bigger effect size on top using the 0974?

Yes. We really haven't seen much difference. Again, last year's data in about 10 to 15 patients on ruxolitinib the data was basically equivalent to those who are not on ruxolitinib in terms of response rates using all the kind of most rigorous response rates in the field. So that appears -- I mean, that's great data. It appears to have no real interaction. And I guess, broadly speaking, we expect the same to be true of momelotinib. And actually, in the middle of the year, we did do a sort of preliminary assessment of that exact point and said, hey, preliminarily, it looks like it works about the same in combination with momelotinib. Now we'll be able to provide some actual quantitative data around that point.

I think that's a very critical point and particularly for the investors to really dive deep into the space because that's one of the CC says, okay, can you address this patient with momelotinib still having the anemia [indiscernible].

Exactly. Exactly.

You're hitting the similar pathway. Okay. Got it. And then in terms of the -- let's see, the next step into the pivotal. So this is the interim data, you say 40, 50 patients worth of the data, and then that's probably half of the patient. So next year, you're going to give us the full data? And then how the cadence between now and the FDA discussion also all the way to the pivotal design. How should we think about the full data, FDA discussion and then you're going to give us some pivotal pathway?

Right, right. Yes. I mean our basic expectation with a little bit of imprecision around the clinical trial speed. But basic expectation is that we'll finish the trial next year in time to also have an end of Phase II meeting with the FDA. And then once we've had that meeting, hopefully, that puts us in a position to really educate everyone about how the pivotal trial design is going to work.

Our goal is typically in this field, myelofibrosis, the pivotal trials are around 300 patients. We plan to have a very broad enrollment criteria as we've done in the Phase II program. Essentially, it's an all-comers trial. If you're anemic and you have myelofibrosis, there's no reason why you can't come into our study. And we think that's going to be supportive of a pretty brisk enrollment in a pivotal setting. But the FDA does look at this as several different subsets of patients, and our goal would be to present a data set that allows us to coalesce all into one simple roughly 300-patient study. But that's where the dynamics of the data we have and those discussions with the regulators have to play out.

Excellent. Okay. Great. You mentioned earlier that luspatercept, the small portion of the anemia population, they still failed, right? So the Phase II that seems to drop out of the competition. I know they seem still guiding they will file anyway because of the sNDA. So we'll see how FDA is going to react to that. And then how do you think about the emerging competitive landscape? Incyte recently announced they have some early clinical program for the calreticulin, right? So there's a mutant. So they also try to address the myelofibrosis as a whole. So -- and then this modifying kind of a mechanism. How do you think about 0974 as anemia specific adjunct therapy for the MF treatment for the long term?

Yes, yes. I mean I think this is the natural progression of therapies in myelofibrosis. There are known driver mutations that drive proliferative activity in the bone marrow. It eventually progresses to fibrosis and splenomegaly, which ironically leads to cytopenias, right? So you have these driver mutations that are cancerous in nature, myeloproliferative, leading eventually to a disease course where you have marked cytopenias.

And we've seen Jakafi was designed to target one of those driver mutations and actually, it exacerbates. While it's very good for the patients, it's a great drug. It exacerbates some of those cytopenias, notably red blood cell anemia. So now we have this new set of therapies targeting the calreticulin driver mutation. I think that's been pegged at being about 25% of patients who carry that mutation. So we're talking about a subset of patients where there may be some benefit here.

And what the ultimate role of that drug or that mechanism in managing anemia remains to be seen. I think there are some reports in the ASH abstracts of improvements on hemoglobin in some of these patients, while those who are, for example, on Jakafi appear to show essentially no improvement in hemoglobin. I think it's early days, but the past indicator would be that targeting the driver mutations has good benefits for the patients, but typically doesn't necessarily address the cytopenic issue. So we think an anemia therapy for these patients is going to be something that's important for years to come still.

Excellent. Great. Okay. So last minute. What's the balance sheet look like? And then also any other [indiscernible], you mentioned the Polycythemia Vera, PV, that is also into the Phase II next year. So any other earlier pipeline you want to highlight?

Yes. I mean just a quick touch there. Our third program is designed to restrict iron to address the excess red blood cell production in Polycythemia vera, which is a mechanism that's been proven out to be efficacious in these patients, and we're really looking to provide a better patient experience with our product. That Phase II has already started. We expect to get data from that next year and may also be moving to a pivotal trial in, call it, 12 to 18 months or so. So super exciting, potentially 2 pivotal trials coming in the not-too-distant future in the hem/onc space. So yes, was that -- sorry, was there another question there?

Yes, the balance sheet.

The balance sheet, yes, yes, yes. So we have a busy pipeline, hopefully, revenue coming our way. We raised money recently. We now have a balance sheet with, I want to say, about $825 million. If you take no revenue into account, just burn, that would run us all the way until 2029 -- into 2029. And then if you add the revenue on top of that, which we'll eventually be able to forecast that and take account of that, puts us really in a great position to finance the whole pipeline that we're building out.

Excellent. Thank you, John.

Yes. Thank you, Roger.

Thank you, everyone.

So we're going to go ahead and get started. I'm Steve Willey, one of the senior biotech analysts here at Stifel. and glad to have with us from Disc Medicine, Jonathan Yu, who is the Chief Operating Officer. We're going to have a fireside chat. [Operator Instructions] We'll get your question asked and answered. Before we jump into Q&A, Jonathan, any kind of introductory comments you want to make about the company?

Yes. Just thank you very much for having us here again this year, especially at such an exciting time in the company's growth. I feel like every year, we're saying, it's an incredible time for the company. It's a very incredible time for the company right now. And Stifel has been following the story for some time. So hopefully, it's been gratifying for Carolina and other members of the team to sort of see this portfolio come together.

For those who are new to the Disc story, we are a company focused on developing treatments for the -- for serious and debilitating hematologic diseases, name the company is Disc with the shape of the red blood cell. And the way we decided to construct our portfolio has been based on targeting pathways that are fundamental to red blood cell biology. So we have programs designed to affect heme synthesis and programs that regulate how iron is metabolized iron homeostasis by controlling a key hormone called Hepcidin.

So just very briefly, our lead program is called Bitopertin. It's a oral small molecule inhibitor of target called GlyT1. It's designed to be -- to treat a rare debilitating condition called erythropoietic protoporphyria. And that is a program where we recently submitted the NDA at the end of September, and then we were very happily a recipient of the -- one of the first recipients of the FDA's commissioner's National Priority Voucher program. So we're -- that could potentially put us in a position to potentially commercialize at the end of the year, early next, so really tremendous program -- progress on that program.

And then the other programs in the pipeline designed to control iron also have progressed extremely well. They're both in Phase II. The lead program there in the iron portfolio is a drug called DISC-0974. It's an antibody against the target called hemojuvelin. It decreases Hepcidin and increases iron and that's designed to be treated a variety of -- potentially treated variety of anemias. Our lead indication is anemia of Myelofibrosis, and we showed exceptional activity at ASH last year and follow-up activity at EHA. And the first phase from the Phase Ib portion of the study and the first installment of the Phase II data is going to be shown at ASH this year.

And the last program is a drug called DISC-3405. It's an antibody against a target called TMPRSS6. That's also in Phase II, and it does the opposite of 974, it's designed to induce production of Hepcidin and restrict iron. There are a variety of applications for therapeutic iron restriction but we're taking that into Polycythemia Vera initially, and we should have the first data readout sometime next year. So extremely busy time for the company.

All right. Let's talk about all those things. So the CNPV award was a very interesting development. I think certainly recognition of the unmet medical need that exists in EPP. You did not have to initiate the investment of a $5 billion manufacturing facility to get one, it's even better. But so what are the benefits to you as a company now for this CNPV? I know you submitted the NDA in September. You've -- they've talked about how this could be turned around in 1 to 2 months, how does this now set up for you? And I guess, what are the position points that you're going to be disclosing kind of from here on out, right? Do you announce acceptance of the NDA? Do you...

Exactly. Yes. I mean this is a groundbreaking program and like we're very honored to be a part of it. And one of the things that it does, and I think the primary advantage of this is -- and this is what the FDA has said, it's like accelerating the review time. So it cuts down the review time from 10 to 12 months to 1 to 2 months. And the way we sort of think about the cadence and the timing of that is, it's a 1- to 2-month review period from when the filing is accepted. So thinking through the time lines, we submitted the NDA on September 29, give it the standard 60 days for when the FDA would determine whether or not the filing has been accepted. So sometime in the sort of November 29 time frame, that would be -- put you at the 60-day mark.

We'll be able to let folks know whether or not the filing has been accepted. And then from there, it's a 1- to 2-month review time period with -- of course, the FDA always reserves the right to be able to take longer than that. But that's been the projected time that they said they would review the application. So that puts us in a potential approval window either at the tail end of this year, December or in January. So that's sort of how do we think about the time line. And as far as the benefits that come along with it, one is like just greater communication with the FDA, but primarily the acceleration of like resources to be able to focus on the review in that time line.

Okay. I think the outcome of the approval itself, I don't think is necessarily viewed to be a controversial thing amongst investors and certainly not now post the CNPV. But I guess we do have some discussions around labeling. And I know that you guys have the opportunity to maybe secure a pediatric review voucher. You do have some adolescent data. I think it's limited to 4 patients. Do you think this CNPV award somehow now changes the likelihood of you getting a broader label that covers adolescents?

Yes. I think to be sure, I mean, I think the drug certainly has applications in the adolescents, the 12 and up. And our base assumption is that -- and our expectation is that the label would encompass adolescents, the 12 and up and then, of course, adults as well. And we are seeking a broad label to treat EPP and XLP. You do bring up the point that it is just 4 patients. I think that there is a pretty good case here, though, because we've shown that the drug does what it's supposed to do, lowers PPIX in these patients in those 4 patients, the safety is extremely well understood broadly of the drug. But -- so I think we continue to believe that there is a good case to be made for the -- for inclusion of adolescents. So yes, the biology of how Bitopertin works doesn't seem to be any different in adolescent patients.

And it certainly seems like there's some increasing scarcity value around these priority review vouchers just given they're starting to get phased out a little bit.

Yes, yes, remains to be seen where the things land with that. But I think even if it were just focused on the adult patient population, that is where the majority of the patients are. So I think that there's still a very good, certainly a very strong business case. So it doesn't affect the overall thesis too much. But yes, there's no reason to think that adolescents shouldn't benefit from Bitopertin.

Maybe you can talk a little bit about launch readiness and just kind of where you are now in terms of building out your commercial infrastructure? Do you think that your teams that you have in place now are rightsized? Do you have a lot more hiring to do?

We do have some hiring to do. So I think this is -- as you can imagine, originally, we were thinking that a launch would be potentially in kind of the midyear Q3 time frame, and that was our original plan for the launch. This substantially accelerates things. We are also -- we are accelerating internally operationally and getting ready for launch. But the way we're thinking about it is, that, if we are thinking about a commercialization in the December, January time frame, it's very unlikely we'll have the sales force entirely hired and trained and deployed at that time.

That said, we do have the supporting commercial infrastructure largely in place. We'll be focusing primarily on building up our market access capabilities. And we already have an MSL sales force and med affairs team in place. So I think the way to think about this is it will probably be staged and kind of a staged approach where we'll be relying largely on our existing relationships and word of mouth early on, and then there will be a wave 2 once the sales force is trained and deployed, where true awareness and the classic things you think about in the launch, we'll be able to leverage that sometime, call it, midyear.

And another point of leverage I would imagine is the fact that EPP has its own specific diagnostic code.

It does.

So that kind of helps you determine the volume of claims and maybe where those are originating from. Where are you in the process right now of kind of identifying patients and mapping accounts?

Yes, we're right in the middle of that right now. So you bring up a very good point in a -- the nature of the EPP, we're not starting from -- entirely from scratch. There is an ICD-10 code. There is rich claims data that allows us to be able to do more like kind of a surgical focus kind of account targeting launch. So I think what we're doing right now is relying on our MSL team to be able to qualify those accounts and to help us prioritize where to focus initially. But yes, so like that's -- we're in the thick of that right now. Initial read is that our data -- that the data is sound and that we'll be able to be able to have a very bespoke targeted early launch.

And so for those folks that are trying to think about what the trajectory of uptake here might look like over the course of the next 12, 18 months, how are you thinking about this notion of there's obviously a pre-identified pool of patients that could be candidates for therapy right off the bat. I know you have another 150 or so patients in open-label extension trials that could become paying customers as they convert over to commercial products. So how do you frame up what that trajectory will look like over time? Is there going to be a bolus of patients? Would you expect it to be kind of more measured as you build out infrastructure over the course of the first 1, 2, 3 quarters?

Yes. I think if you look at -- there have been any number of recent rare disease launches in the last year or 2, which I've shown. I think if you look at that trajectory, it's very similar to say lots of these conditions and launches, they really were able to rely on patients who are already in clinical trials, they able to leverage folks who are at centers of excellence. And then it's kind of a Steady Eddie kind of growth. So that's kind of how we think about it in that.

There's going to be some word of mouth that's required long term to be able to sustain the long-term growth, but we'll also be able to use, as you say, patients who are in the clinical trial already. We have good relationship with patient advocacy groups and the centers of excellence are important initial source of patients as well. So I think it's -- there's no reason to believe that the launch shouldn't resemble some of these other early rare disease loss.

Okay. And then I know you're trying to complete enrollment in the confirmatory Phase III APOLLO trial. Does the commercial availability of Bitopertin somehow impact that at all, good or bad?

Yes. I -- we don't think it will have a negative impact. I can totally see where that comes from. If you have the drug available and sometimes the patients don't want to be in your trial anymore. But the trial has been open since around May and recruitment is going well. We've basically given guidance before that it takes about a year to enroll the full study. And so we don't think it should be -- should have an adverse impact on the study completion. And just as a reminder, it's a global trial as well. So we also have European sites that will be able to support continued recruitment for the study.

Okay. On the competitive front, we know Synapse has been in the market for a while. There's also a product from Mitsubishi Tanabe that I believe they're guiding to data before the end of this year. Just how do you think about maybe that product? And if that were to procure approval at some point, how do you think the 2 product profiles line up?

Yes. I think the biggest distinction between our drug and some of these standing agents is that we would be the first agent, if approved, that affects the underlying driver of the disease. And so it lowers PPIX which is a photoactive molecule that accumulates in your body, and that's what causes the phototoxic reactions whenever patients go on to sunlight.

And the data that we've seen so far is that our approach of lowering PPIX has this profound impact on photosensitivity, patients are able to spend more time in sunlight, their attacks disappeared at the end of the study and then they felt palpably better. So and so far in our patients who are on Phase II study, there's been -- patients have stayed on the drug. There's been a lot of desire to stay on the drug. So I think all that says that the profile is very strong.

And there is also a reason for patients to want to have a PPIX reducing agent because that has an impact long term, we believe, on the hepatobiliary complications, which these standing agents will not have an impact on at all.

Okay. [ Place ] For Bitopertin outside the U.S. I know you have some legacy economics here that are owed to Roche. Does that incentivize you to maybe try to do this on your own? Do you think that this is something that you guys could do?

Yes. I think that EPP is one of these conditions where, yes, certainly, it's -- and there have been many examples now where like if we wanted to go it alone, we certainly could. The time line for ex U.S. approval is a little bit more delayed from the U.S. approval, particularly now with the CNPV. So the basis of any approval in jurisdictions outside the U.S. will be around the APOLLO -- with the APOLLO data.

But what we understand about the market outside the U.S. is that the structure is very similar to the U.S. and it's also centers of excellence, there are patient advocacy groups, and there's already an infrastructure ex -- outside the U.S. that we think could enable a small company to potentially launch if we so choose.

Okay. I know you flagged other potential opportunities for this drug, one of those being Diamond-Blackfan anemia. I believe there's a study that's been going on there in conjunction with NIH. We're going to see some of that data at ASH. I think we learned the ASH abstract, didn't really look to be much in the way of responses, but also looked like these were really difficult patients to treat. Just kind of what's your general conclusion? I know we're not going to see the data until next month, but just kind of what are your thoughts around that opportunity specifically?

Yes. I think the case in DBA and some of these other indications is the biology is just going to be more complex than EPP. Like EPP, the biology translated very clearly from like PPIX reduction into clinical benefit that we observed in the Phase II study. Yes, it's more complex than some of these other indications. We'll continue to explore, but I think the upshot of this is -- Bitopertin is being -- our focus is going to be on EPP.

Okay. Maybe you can provide a little bit of just an expectation framework for what we should expect from the RALLY-MF data that's going to be presented at ASH. So this is now shifting gears to the anti-hemoglobin 0974. So I know you've guided to an update. We obviously saw the ASH abstracts. But what should we expect to see within the framework of the presentation itself just with respect to patient numbers, duration of follow-up, et cetera?

Yes. Yes. So I mean, so just as context, at ASH last year, we showed data from the Phase Ib portion of the study, which is dose finding for patients with anemia of MF and anemia of MF is an extremely difficult to treat anemia. And we just saw extraordinary efficacy in the dose-finding study. And along the lines of there are a couple of dimensions that we look for in terms of the profile, the magnitude of increase in hemoglobin or reduction in transfusion burden, the durability of that effect and then how broad that effect is and specifically how the drug works in patients who are on JAK inhibitors and those who are not.

And I think it's very important that our -- for us to be able to show that the drug works together with JAK inhibitors because those will continue to be the mainstay of treatment. We were able to show even in the Ib study that the drug was able to hit each of those attributes. And so the goal at ASH, and I think what people are looking for now with -- now that this is the first -- this will be the first data release of the Phase II portion of the study having selected the 50-milligram dose, just seeing those attributes continue to persist.

And I think we haven't given guidance in terms of patient numbers but the study has recruited well. We expect to have a meaningful group of patients that we can report data on. And I think these patients, it will be a variety of how -- it will be a range of how long patients have been on the drug and that we'll have show data on. But what we showed at EHA was that some patients had already been on the drug for almost a year. This is from the Ib patients. So you should be able to have a range of patients from -- who have recently started on the study to who have been on the drug for a very long period of time. And that should give folks a sense for how durable the effect is.

I'll say the last thing that we plan to show -- report on is we said that at EHA that we had completed recruitment of the exploratory cohort of patients who are on momelotinib. And so that means what you can take from that is that we should -- we will have data showing how the drug works not only on top of ruxolitinib but also on top of momelotinib, one of these newer JAK inhibitors.

So the go-forward assumption will be that this will be a drug that can work in a way that's agnostic to JAK inhibitor.

Exactly. I mean 25,000 patients in the U.S. with MF, almost all of those patients are anemic. And the idea is that if you have anemia, we want to -- 974 should be the go-to agent to treat the anemia independent of what your background treatment is.

And maybe last question related to that presentation but how should we think about the attribution of patients we'll see at ASH as a function of baseline anemia status, right? So are we going to see an overrepresentation of patients who are not transfusion dependent, who are high transfusion burden? Just how are those going to break out across those buckets?

Yes. I think what we showed in the Ib is a pretty good representation of that patient set.

And do we know if we're going to be getting independence data at ASH from [indiscernible]

We don't know. I didn't see the abstract.

I didn't see the abstract. I'm not sure if it's going to be popping up somewhere else.

I mean that was the major development this past year that missed its primary endpoint. I think it speaks to a year ago, this was a very, very crowded field. There were approaches targeting oral small molecule inhibitors targeting ALK2, there was luspatercept. And now what we have shown now is that we seem to have a leading profile and the other programs seem to -- the competition seem to have faded away. So that we're very excited about the program.

What do you think registration looks like here? And I know I think there's been some commentary before around potentially being able to incorporate all of these different patients in a variety of different anemia states into a single registrational trial. But just curious as to how that works logistically, right?

And I guess when I look at what Bristol did luspatercept with in INDEPENDENCE, just kind of knowing that, that drug doesn't really work well in patients who have a high transfusion burden at baseline. I don't know if the FDA pushed them to that patient population specifically because they're of the greatest unmet medical need. But just wondering how you're thinking about what a registrational Phase III could look like here?

Yes. Yes. I mean it's hard to say exactly what drove the -- what specifically drove the independence design. I will say that, that segment was the one segment that where luspatercept performed. It was transfusion-dependent patients who are also receiving a JAK inhibitor. That was the best performing segment.

My suspicion is that is what drove that study design. Because if you look at the segments in their Phase II study, luspatercept just didn't perform as well. From where we are, our expectation is that independent of the patient segment, the drug should be -- our drug should be able to have a benefit. So our going proposition is still to have a single study independent of background JAK or transfusion status or anemia status would give us -- enable us to have sort of a broad label in MF.

And I think if you balance the subgroups properly, you should be able to tease out an anemia signal in a single study. So you might need to use different endpoints, whether it's hemoglobin in one subgroup or reduction in transfusion burden in different subgroup, you'll have to sort of design the study that way. But we believe it's feasible. As far as what that endpoint is, that's a discussion to be have once we have completed the Phase II study, but we're collecting all the classic information that you'd be -- all the different -- we're collecting a very rich set of data that will inform that at the end of Phase II.

Okay. And another data point of relevance that we just saw was the nondialysis-dependent CKD data for this drug that was presented at Kidney Week. What would you kind of highlight just as the takeaways there? And when might you be in a position to communicate kind of what the status of this program is going forward?

Yes. I mean we showed a little bit of the same data from the SAD portion of the study at ASN last year. So the upshot of what we showed at ASN is that the drug in a different disease setting, now nondialysis-dependent CKD continues to do what it's supposed to. It lowers Hepcidin, it potentiates iron and that we also saw early markers of erythropoiesis that iron is getting into red blood cells.

The efficacy in terms of hemoglobin readout, however, was a little bit more variable. And what we showed at ASN is we believe that is driven by background levels EPO, which EPO kind of serves as a multiplier for hemoglobin by driving the number of red blood cells. So I think what that tells us is that the efficacy -- the mechanism is -- the mechanism of the biology continues to translate extremely well. There's some patient heterogeneity, particularly with regard to background EPO levels in CKD patients that we need to figure out. And so for the moment, that's what we need to understand, does it make sense to do a study together with EPO, does it make sense that we select patients who are high EPO, that's something we need to sort of define what the next steps forward are.

In the meantime, our plan is to continue to take 974 and explore in other indications just to understand how the biology works in other settings, and we're planning to initiate an IBD anemia study early next year. And so the idea then is to focus 974 on MF and then continue to understand the biology in some of these other indications. And we're also looking to bring online the next-generation anti-HGV antibody, which is a longer-acting form, which might allow us to be able to separate some of these indications.

Okay. Can you share your rationale for going after anemia in IBD?

Yes. In these patients, so anemia is a pervasive issue in patients with IBD. It is kind of a classic presentation of anemia of inflammation. So underlying inflammation that drives Hepcidin production and that restricts iron, so you have functional iron deficiency. Also, these patients experience blood loss. And so that also contributes to anemia. And so supplementing enhancing iron levels should be able to help address the underlying anemia. And these patients have normal to high levels of endogenous EPO production. So we shouldn't run into the same issue that we encounter with CKD.

Okay. Maybe we can switch gears to 3405. So as you said before, this is the TMPRSS6. I know you're looking at this in Polycythemia Vera. You're also looking at this in sickle cell. The PV opportunity for me, I think, is very interesting. We follow Incyte. I've seen the commercial success of a drug that has become $1 billion plus in PV simply because it causes anemia. So I think there's a lot of opportunity here. The biology has been validated, right? You know that iron restriction is key to the pathology here. There does appear to be some room for improvement on the safety and dosage front, just given what we've seen from the protagonist product profile. So high level, I guess, what are your thoughts on 3405, the opportunity in PV specifically? And just what kind of competitive edge you think you may have over Rusfertide?

Yes. Yes. I mean, very well said and exactly, we're very excited about the opportunity in PV. I think it is a significant market opportunity. And it's very clear that iron restriction is a very important and now well-validated way to be able to treat the condition, not only because what Rusfertide has shown is that by iron restriction through Hepcidin that you're able to control hematocrit and avoid [indiscernible] but that patients seem to feel better as well.

And this is -- that's a key element -- there are limitations to Rusfertide with regard to the drug itself as a Hepcidin mimetic, that requires at least once-weekly dosing. It seems to be associated with injection site reactions. And the reason why we went after an antibody and going after TMPRSS6, which promotes -- by doing so, it promotes your body's own production of Hepcidin is that, one, it enables more less frequent dosing.

So anywhere we anticipate we'll be able to get once a month dosing. But it also gave us -- what we also showed at least preclinically and in the healthy volunteer setting is that we had a better quality of what we believe is a better quality of iron restriction. In other words, we're able to see very significant iron restriction levels and that was durable as well as opposed to some of these other approaches, it's a little bit more cyclical and -- and so we feel that being able to have a controllable potentially deep iron restriction that's also durable, that mix of iron restriction is the best way to come up with an agent to be able to restrict iron.

So that's how we view the opportunity in PV. And the antibody has been very well behaved so far that we showed in the healthy volunteer study and looking forward to the Phase II readout sometime next year.

Okay. There's also some oligos, some siRNAs that are in this space going after the same target. I think SILENCE has one, Ionis ONO have one. How do you measure 3405 relative to some of those?

Yes. I mean our antibody, what we showed is we should be able to have durable restriction of iron. I think the other attribute we've always cared a lot about is being able to have controllable iron restriction as well, being able to have as much flexibility and being able to balance durability with depth of iron restriction, are you able to get deeper iron restriction without having last for too long, we've heard from certain treaters that they're a little concerned sometimes about having something that -- is there such thing as having too long of iron restriction and you can't back away that. So finding that sort of Goldilocks kind of balance point was important for us as we were thinking about an agent -- an iron-restricting agent.

Okay. Maybe just a couple more questions. Can you talk about the rationale for this drug in sickle cell disease?

Absolutely. Yes. So you have mentioned that before. Yes. So iron restriction is increasingly weathered by -- is an approach that's been explored in sickle cell. The rationale there is what drives the pathology of sickle cell disease is the tendency for hemoglobin S to polymerize. But there's very good evidence showing that, that tendency to polymerize, which also causes sickling and all the downstream complications is -- occurs at a power of 30 of what the concentration of HBS is within the red blood cell.

And what folks have shown preclinically and even in clinical setting is that if you can restrict iron, that can actually reduce the concentration of hemoglobin S within the red blood cell and reduce the propensity of the cell to sickle. And so the problem is there hasn't really been an effective iron restriction agent. Folks have been reduced to either using iron restricted diets or phlebotomy to be able to get that effect of iron restriction and reducing HBS within the red blood cell. So we're very excited that we have an agent now that is very controllable that can reduce -- that can restrict iron and hopefully, that can reduce the HBS within each red blood cell and reduce the propensity for sickling and also hemolysis. So this is an exploratory study and that we've initiated and hopefully, we'll have some data to share next year.

Okay. And maybe just lastly, the balance sheet and kind of what that allows you to execute on.

Yes. I mean we just completed the financing. So that we fortified our balance sheet. That should be able to power through some really key milestones for the company. Pro forma, we have about $820 million in our balance sheet. That takes us into 2029. So that should support at a minimum, the commercial -- we should be well into the commercialization of Bitopertin, completion of the Phase II MF study, completion of the Phase II PV study as well as some of these exploratory studies.

And that guidance doesn't include Bitopertin revenues, correct?

It does not.

Yes. Nor does it include any PRV voucher sales?

It does not. So it's a very conservative view. Exactly. So it is -- yes, exactly. So we are well capitalized to execute on the next phase of the story.

All right. Jonathan, really appreciate it.

Thanks very much, Steve.

Thanks, everyone.

Good afternoon, everyone. Welcome to Guggenheim Healthcare Innovation Conference. My name is Yatin Suneja, one of the biotech analysts here at Guggenheim. Our next presenting company is Disc Medicine. We have a few executives from the company here in the room, but I'm going to be chatting here with the Chief Executive Officer, John Quisel.

John, why don't you make some opening comments. You and I were just discussing about CNPV, which is also congratulations on that. But just tell us the Disc story. Obviously, you have a few programs, but what are some of the key things that investors should be focusing on, and then we'll do a Q&A.

Yes. Great. Thanks. It's great to be here. So the company, yes, the big excitement at the moment is our lead program, Bitopertin in a disease called erythropoietic protoporphyria or EPP for short, was awarded one of the Commissioner's National Priority Vouchers. So that review time puts us projecting that we'll be able to get to approval, if all goes well, by the end of this year or early next year, which is an amazing place to be given that it was about 5.5, 6 years ago was our Series A. Actually, we were entirely preclinical, actually had not in-licensed Bitopertin as a program at that point in time.

So yes, the history of the company, we were built at that time around looking at controlling iron and heme as fundamental building blocks for red blood cell biology, trying to control the metabolism of iron and heme as a way to manipulate a variety of disorders that arise in the red blood cell compartment. So we started off with heme/onc-type indications, myelofibrosis, polycythemia vera being in target, but all preclinical at that time. And then we became aware of this porphyria disease that arises in the red blood cells and the potential to use Bitopertin as a way of controlling heme biosynthesis to diminish the harmful metabolite that builds up in those patients and try to achieve a major clinical response through that mechanism.

So that's how we built the company. We've been public now for -- since end of '22. So this is our third year of trading publicly under the ticker symbol IRON as you have up there.

Yes. Very good. So given the acceleration in time line for Bitopertin, like what -- number one, just are you seeking for a regular approval or this is an accelerated approval? And then I think you're running a confirmatory study, APOLLO study, right? What are the expectations? What do you have to produce there?

Yes. So we completed a Phase II program in about 100 people and had our end of Phase II meeting about a year ago now. At that time, the FDA aligned with a view of putting us on an accelerated approval pathway, which said they're going to use the toxic metabolite PPIX as the surrogate endpoint. And then we would run a confirmatory trial called the APOLLO trial, which we aligned on with the FDA and got that going.

So it was in that context, progressing through about a year of meetings with the FDA around the CMC program, confirmatory trial design, the pre-NDA meeting, we submitted the NDA itself at the end of September, setting up a time line that would lead to NDA acceptance at the end of November. And in that context, the CNPV came in on top of that and really accelerated the projected review time.

Got it. So what preparation now you have to make given that there is a significant acceleration, right? How are you thinking about the sales force? Where are you on the CMC side, all that stuff?

Yes, exactly, exactly. So key pieces of infrastructure, having drug to launch with, right, the CMC. And we have a lot of commercial and clinical batches that are ready to go. The full validation that you typically do wouldn't wrap up until second quarter of next year. But I think there's room to have a discussion with the agency around using the batches that we have in hand, assuming an approval were to come sooner than that.

So that drug supply foundational piece number one, having a distributor, having a specialty pharma, those things should all be set up on time, having reimbursement discussions, those are being significantly compressed and hiring that team is also compressed. So there may be longer prior auth type discussions that happen with the patients coming on with this kind of accelerated launch.

And then the sales force itself, yes, that team will probably be seeded, but not yet fully trained and so not in the field at the time of launch, which is fine. I think that sets up kind of 2 phases to the launch here, one where it's kind of the early run, taking the material we have available, making it available. We'll work through the finding patients at key centers or clinical trial rollovers. And then we'll come out with kind of what I call the full launch where we have the sales force seeded and the full reimbursement system set up.

Got it. Got it. What will be the size of the sales force?

Yes. So we're -- actually, the job ads are up on our website right now, 24 reps is the team we're looking to see.

Okay. Okay. And then like, let's say, if the approval comes on time, it seems like would you be able to launch ASAP or you need, let's say, until the full validation happens in Q2 for you to launch?

So we expect the base plan is that we'll be able to launch as soon as the FDA gives the green light. But the outside possibility would be Q2 then.

Okay. Then in terms of the patient population, could you maybe help us understand what -- how many patients have been identified? Who are the easier patients to go and target initially?

Yes. So the genetics would say there'll be 20,000 people in the U.S. with the genotype. The claims data that we've looked at shows 14,000 people that have been diagnosed using the ICD-10 code for this disease. And of those, we see about 6,000 that we define as engaged patients, meaning they've had more recent EPP care, more frequent EPP care, et cetera. And the caregivers for those 6,000 patients, that's who we size the sales force again.

So we designed the 24 reps to be able to call on the accounts that service those 6,000 highly engaged patients. Reaching the full 14,000 patients will be come through long-term sales rep engagement plus social media strategies, other more kind of broad outreach type approaches. So the launch is focused on those 6,000 engaged patients.

Yes. There is another drug or another device, right, that is approved for it. Can you maybe talk about how that has done? What are the issues with it and how Bitopertin is a little bit differentiated on that regard?

Sure. Yes. There's only one approved therapy for these patients. It's called Scenesse. It works by causing tanning. So providing a barrier against sunlight exposure, which I failed to mention the main consequence of this disease is extreme sun -- pain on exposure to sunlight. So Scenesse works by tanning. But the big impediment there with Scenesse is it requires a surgical implant. So a patient has to go into a surgery department, receive an implant under the skin and then they have to do that every 2 months to receive that drug.

So probably because of that, it's not widely used. We estimate it's about 3% of patients access that therapy. So call it, 200 to 300 patients in any 1 year might receive that drug.

Got it. And what is -- do you remember the price for that?

Yes. So if you receive all 6 implants across the year, it would come out to about $300,000 on a year.

That is the pricing for that. Okay. So now for the 6,000 patients, all the 6,000 sort of identified patients that you are building the sales around, how should we think about the cadence of launch? Because some of these ultra-orphan drug launches can be sometimes very rapid or could be very slow. In what spectrum do you -- or this disease lie, the EPP?

Yes. Well, I mean, I think when we do our own projections, we're just using other parallel launches in the rare disease space. But I think the components that we see in the launch are patients that are already in our clinical trials, meaning rollover patients from the long-term extension, et cetera. And there, it's probably around -- expected to be 150 or so patients in the trials already. Then we see the top 15 or so centers, essentially our clinical trial sites. There's a substantial number of patients seen by those sites. That is a highly accessible group of patients. And then you get the remaining top centers that round out that 6,000 patient population.

Got it. Have you talked about the pricing?

No, we haven't. And obviously, we won't set a price until we understand what our label, what the whole package looks like. But like you said, if you look at precedents in the porphyria disease space, you have Scenesse priced at $300,000 a year in EPP. And in an adjacent porphyria called hepatic porphyria, Alnylam markets a product called GIVLAARI priced at $575,000 a year. So that gives you a sense of fairly standard rare disease pricing in these indications.

Okay. With regard to the -- actually, first on the label, how should we think about the label? Any particular consideration for the label that we need to focus on?

Yes. I think our preferred label will be a simple one indicated for treating EPP. I think areas where there may be discussion would be the age range. We'll be looking to get a label that goes all the way into the adolescent population. However, that is based on only 4 adolescent patients in our Phase II program. So I would say there's substantial reason for some risk around whether we'll be able to get adolescents onto this label. And then the other question would be, given that this is an approval premised on a surrogate endpoint of PPIX, whether the drug would be labeled for reducing PPIX or be labeled for just generally treating the disease.

Yes. Okay. Then with regard to the confirmatory APOLLO study, what is the -- what are the requirements? When will that study complete and time lines?

Yes. So we started enrolling roughly May of this year. We project about 1 year to enroll the study. It's 150 patients. And we're enrolling in U.S., Europe, Canada, and Australia. We expect about 100 of those patients to come from the U.S. The balance, mostly Europe with the sprinkling in the other territories. And we've projected about a year to enroll the study, 6 months on treatment. So last patient should be out kind of late next year with the data following a month or two after that. That's the basic attributes of the trial. The endpoint is co-primary PPIX reduction, which we've proven kind of inarguably in the Phase II program and then a measure of time and light at the end of the 6-month trial period.

Got it. Got it. Very good. All right. Moving on to the next asset, 974. Can you maybe describe the mechanism for us and the areas that you're going with?

Yes, sure. So it's a monoclonal antibody against a genetically defined target called hemojuvelin, which is a core regulator of iron in the body, right? So they're actually humans who have loss of function mutations in hemojuvelin. And the phenotype is a kind of fluid iron availability in the blood, which in a normal person is not particularly helpful for anything. But in many kinds of anemia, actually, the anemia is caused by restriction of the iron inside the body. So by targeting hemojuvelin, we expect to and have shown now in the clinic that we release that restricted iron situation and release iron from internal stores into the blood where it can be used by the bone marrow to produce new red blood cells.

And I think axiomatic that iron is one of the key building blocks of red blood cells. So that's the way it works. It's a monoclonal antibody delivered once every 4 weeks, 50-milligram fixed dose. We did a healthy volunteer study where we showed very nice pharmacokinetics, pharmacodynamics, suppressing the target called hepcidin, mobilizing iron in the blood. And actually, even the healthy volunteers saw an improved hemoglobin profile. The target is overall anemia of inflammation. It's a set of anemias driven by inflammatory disease, which is what causes the trapping of iron inside the body.

Our lead indication is myelofibrosis, which is a very severe hem/onc kind of anemia marked by very high degree of inflammation. And as a result, there was a hypothesis, I think, first generated at the Mayo Clinic that this inflammation may be leading to iron-restricted red blood cell production and that by releasing that, you may have a productive effect. There's actually no therapy approved to treat anemia in myelofibrosis patients. And if we're successful with this program, and the data have been very good so far, we'd be the first and really only drug approved for these patients.

I think -- so you've done a Phase Ib, right, where you had shown some data also in patients that were on JAK. So can you just reveal those data for us? What exactly you are able to achieve in those patients?

Yes, sure. So we presented Phase Ib data about 35 patients across a variety of different dose levels. That was at ASH last year in December. And we saw very good response rates across the board. So the FDA advised us to look at the patients in 3 groups, those who are not transfused at all, and this is looking at the 12 weeks pre-dosing. Those who are receiving 1 to 2 units of transfusion. So that's the low transfusion burden group and then those with 3-plus units transfused, and that would be the high transfusion burden group.

And across all those groups, we showed a very good response rate, about 50% in the non-transfused patients, about 80% in the low transfusion burden group and about 40% in the high transfusion burden group. All of those being well above the target you'd want to see in order to feel that you have an effective therapy in a program that can progress into a pivotal trial. So what we're doing now is looking in a 90-patient group of study called the RALLY-MF trial, where we've chosen a single dose now, the 50-milligram dose, which appeared to be the best kind of the lowest high efficacy group. And so we'll be reading out an interim look at that at ASH this year. So coming in about a month now, a few weeks.

Yes. So what would be -- so in the RALLY-MF study, are you enrolling patients in all those 3 subtypes?

Yes, exactly.

So what are the benchmarks? What exactly would you like to show in those 3 subtype as an interim readout?

Yes, yes. So I think 30% across the board is the bar. Maybe it's a little higher for that low transfusion burden cohort, but the endpoint seems a bit less stringent. So call it 30, 50, 30 is what we're looking to see. And again, we're sitting looking at Phase Ib data at 50, 80, 40. So we feel like we're in great shape to clear that bar.

Got it. Are there any biomarker at baseline that you could see to identify these patients?

Yes, like to identify the best responders.

Best responders, yes.

No. Yes, we haven't really been able to identify a biomarker. One, we've learned that baseline EPO is very important in predicting responses to our drug. But in myelofibrosis, essentially every patient has very high EPO level. So that hasn't been a distinguishing feature.

Correct. Yes. And then are these patients on JAK?

Yes. Many of them are. So our trial is designed to be all comers. We have patients on Jakafi. We have patients on OJJAARA or momelotinib. And we'll be -- what we showed last year is a very good response rate on people on Jakafi, which is clinically important because one of the side effects of that drug, which is probably the best therapy for MF patients is that it causes anemia. So having a drug that can help manage that anemia in combination is a really attractive profile, and it looks like we're achieving that.

Yes. So if you hit your threshold of 30, 50, 30, let's say, in these 3 subtypes, which subtype you're going to go for in the pivotal? Because I think I assume it's going to be a separate path for NTD versus transfusion dependent.

Well, our goal is to have one single pivotal trial that aggregates all the patients who are likely to respond. I think actually, I would view the non-transfused and the low transfusion burden patients as being one group. Because they're not physiologically very different. Highly transfused, that's a relatively rare group of patients, and they've typically received a lot of transfusion, which actually ends up loading a fair amount of iron into the patients. So they may have a different attribute.

Okay. Okay. So the next step will be just pivotal after this data and time.

Yes. I mean we'll get this data then next year, we haven't guided when exactly we'll have the final data and end of Phase II meeting with the FDA, and then that will progress to a Phase III trial.

Got it. Are there other indications you're pursuing with 974?

There are. We looked in chronic kidney disease, the non-dialysis population. That data actually just came out over this weekend, patchy, not overwhelming success there. But intriguingly, what we saw is the high EPO baseline patients were the responders, which is -- probably helps explain why we've had such great responses in the MF population.

We're also about to start early next year a study in patients who have anemia as a consequence of inflammatory bowel disease, who are also interestingly, probably a high baseline EPO population. So we think this drug will be applicable across this wide range of anemia of inflammation patients. But I think the first effort now that we really have a good signal coming in myelofibrosis is to focus there, drive towards approval in that indication. We have a second-generation antibody with a longer half-life that we will probably use to carry much of the weight of development in some of these larger indications. Yes. CKD.

Okay. What about the third asset?

Yes. Third asset, very exciting polycythemia vera. The premise here is actually to achieve iron restriction. This has been proven out by Rusfertide, a program at Protagonist and Takeda. Really nice data, at least in the top line press release. And our goal here is to provide something that is given a more patient-friendly presentation kind of Q4 weeks, hopefully, with a better safety profile. But we think the biology has already been largely proven out. And we're in Phase II now, hoping to enroll that rapidly, get some data next year and then progress to a pivotal trial as quickly as we can.

Okay. Any particular bar for the Phase II study that you're reading out next year?

Yes. Well, the key readout is to look at achieving target hematocrit of 45% without needing a phlebotomy. Now Rusfertide achieved about 75% on that, which is very good data. And so our goal is to get close to that.

Okay. A lot going on between the commercial prep and the 2 big programs on the heme side.

Yes, it's very busy.

Very busy. Okay. How are the financials?

Yes, the financials are great. We ended quarter 2 -- sorry, quarter 3 with around $610 million on hand, maybe off plus or minus. And then we raised another $211 million net in a stock offering after the CNPV announcement. So we're sitting at around $826 million or so in terms of pro forma cash on hand.

The runway for that is early 2029. And in that runway, we're taking no revenue for Bitopertin. So it's a very conservative runway statement.

Have you articulated in terms of how big Bitopertin could be from a market -- like what is your...

Yes. I mean, look, if you look at the analyst forecast, it's $800 million peak to $1.4 billion or so. And I think there's a huge opportunity here. We're excited about. If you think about 14,000 U.S. patients with rare disease pricing, if we're able to actually fully access that and bring this drug to all those patients, it's a pretty big rare disease market along the lines of what you see in HAE or PNH.

Got it. So very good. I think that's all I had for you. Thank you so much for your time. Appreciate it.

Thank you. Appreciate it.

Thank you.