Disc Medicine, Inc. (IRON) Earnings Call Transcript & Summary

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 at 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 top line results for the APOLLO Phase III 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, our investigational agents and are not approved for use of therapies in any jurisdiction worldwide. Okay. Well, as indicated in the press release earlier this morning, the top line APOLLO data are very positive, achieving all primary and secondary endpoints with remarkably robust p-values. And we will provide additional data on -- in 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 PPI 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 BPP 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 describe the molecular basis of this disease over decades of research. I also should say they were 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 design and executed a beautiful series of trials, taking experiences that we learned in Phase II and using those experiences to design a winning Phase III 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 III trial as a company and I believe it won't be our last. We can now progress with great confidence as we into design and plan to execute on Phase III 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 top line data. APOLLO met both co-primary endpoints and all secondary end points. We showed again that bitopertin targets the underlying pathophysiology of EPP, reducing whole blood PPI, 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 time line 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 time line 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 SLP. So I'll turn it over to Will to provide a brief overview of the disease before he reviews the APOLLO trial design and top line 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 photo reactive 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 the liver failure and be life-threatening. There is no cure or disease-modifying treatment for EPP, so patients typically manage the disease by avoiding life, wearing head-to-toe protective clothing or sometimes using canning 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 III study to specifically capture these aspects of the disease. APOLLO is a randomized double-blind placebo-controlled trial of 60 milligrams bitopertin versus placebo for 6 months. APOLLO enrolled adults and adolescents age 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 a.m. and 6 p.m. during month 6 and percent change from baseline in whole blood metal-free PPIX at 6 months. Today, we will share the top line 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 II studies. Before I review the top line 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, an increase in total time and 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 and light and substantial reduction in phototoxic reactions, which builds on what we saw in the Phase II AURORA trial. Bitopertin also achieved statistical significance on cumulative total time and life 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 end is a bit lower than the other analyses. At month 6, bitopertin significantly increased change from baseline and 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 II 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 strengthened the robust and growing body of evidence supporting bitopertins 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 top line 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 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 some light 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 and 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 and 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 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 was 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 or 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 health care 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 opening 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 top line 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 than 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 1 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 III 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 significant 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 II readouts earlier this year. and both assets are on track and expected to begin Phase III 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 endpoint clearly support the regulatory approval, the secondary endpoint seems to be very clinical and 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 [indiscernible] with the Sunlight challenge. And then regarding the safety -- the only thing to take out is the dizziness, but I understand this amount and transient? And then I just want to confirm, do those events occur if we will restart after temporary pause on the -- upon the AE and how do you believe [indiscernible] be used the real world with this business 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, 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 submission? 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. Are there any plans to further expand the EAT 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, in the meanwhile, these ongoing the HELIOS trial and as well as we feel like these are really important to allow continuity in therapy for patients who have been in our study as well as an opportunity for those who have need but we're 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. 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.

Thanks, Tom.

[Operator Instructions] Our next question will come 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 toller 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 top line now you give us a sense of any trend 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 Goldilock 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 trends in the APOLLO data that we've seen in Phase II, where patients tend to experience or take advantage of the opportunity to spend more time in life over time. We've seen that just be kind of a continuous increase as you move from the AURORA main trial into the Phase II trial into the long-term extension. So we don't have a formal analysis from Phase III. 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 were just not being currently managed by EPP specialists, and I do believe based on what we've learned out in the field that there a 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 and plus HELIOS talk to 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 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 PPI reductions as would be predicted, persist for years. And time and light actually continues to improve as patients continue on bitopertin past 6 months.

Wonderful.

[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. These data are absolutely beautiful. 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. But I was wondering if you could also maybe talk about your thoughts on how you actually envision like peak potential estimates a bit? 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 that 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 see 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 two, I know you previously submitted under the commission is priority review program, but would you be eligible for a pediatric rare disease priority review voucher upon approval? And three, for you, 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 GAAP or the request dividends 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 III traditional approval pathway. We did include a substantial number of adolescents now in this trial. We don't yet have 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 II, 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 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, Jean, do you want to just comment quickly on that?

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 [indiscernible] 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 cut all our activities ongoing. So we're in a very good place for a traditional approval.

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 Sines 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-primary is getting on the label, but would you specifically look to include the photo toxic reaction reductions and time to program data on the label?