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

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-temperv ] 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 media responses across all patient subgroups, regardless of baseline transfusion status and independent of [ combinant ] 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 a 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 fast 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, 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 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 that's how 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 [ zalitinib ]. 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 [ IVD ] 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 [ IVD ], continuing to explore ideas around next indications. And in the background, we're progressing a long-acting anti [ hematotolin ] 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-temporast ] 6 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 [ thermonic ] events, among other debilitating symptoms. And many patients are not achieving optimal hematocrit control with current treatments. The upside in [ mimetic rustin ] 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 FC 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 Leering Partners.

Just starting a bit of [indiscernible], 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 is a bit different 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 million 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.

SP-5 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 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 space that he had, especially from [indiscernible], 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 [indiscernible] the parts.

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 [ ilitercept ], 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 [ Callar ], 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 as effects in the platelet apartment. 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 basket 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 [ acetate ] 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 Basset 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 II 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 ] ad hoc analysis of the Phase III [ VERIFI ] study so an elevation of platelet counts when the dose of [ cytoreductive ] therapy, [ hydroxyurea ] is reduced in the patients who are we accessing [indiscernible], what are you seeing the implication for drugs impacting Hepcidin 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 [ respitide ] 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 sale 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 [indiscernible] 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 trade [indiscernible] trial?

Will, you want to take that?

Sure. Yes. So the [ Madewell ] 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 MS 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 or align that as you restate it, have you seen sort of an increase in silo populations? And I'm just curious of patients in terms of JAK inhibitors continue strong demand provisional 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 notion pico 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 [ cerufficient ] numbers of certain types of patients just giving their interest and have a broad label of top and sort of how you're thinking about what to see.

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 trials, [ Aurora and Beacon ] to 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 [ Callar ] and [ NPL ] 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 [ Callar ] 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 [Callar ] 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.