Ladies and gentlemen, thank you for standing by, and welcome to the Disc Medicine corporate call at EHA 2025. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you will need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be advised that today's conference is being recorded. I would now like to turn the conference over to John Quisel, Chief Executive Officer. Please go ahead.
Good morning. 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 Pamela Stephenson, our Chief Commercial Officer. This past weekend was the European Hematology Association's 30th Annual Congress in Milan, Italy, and we shared several data presentations across our portfolio, which will be the focus of today's call. We will also discuss plans and upcoming milestones for the rest of this year, including our progress towards submission of Disc's first NDA for bitopertin in EPP. 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 summary of the data updates from EHA. Then we'll start with the bitopertin program, and I'll provide a reminder of our progress and status toward the planned NDA submission in the second half of the year. Will is going to walk through the first look at data from our Helios long-term extension study with bitopertin in EPP patients, and Pamela will provide an update on our preparations for commercial launch. For DISC-0974, Will will cover updates from EHA, which include new durability data from the continuation phase of our phase 1b study in myelofibrosis anemia patients.
I will recap Disc's view of the commercial opportunity in MF anemia, which we introduced last month in our MF anemia KOL Day event. Finally, Will will discuss new healthy volunteer data for DISC-3405, shared at EHA, and introduce the design of our first inpatient trial of DISC-3405, a phase 2 trial in polycythemia vera patients, which has now been initiated. I'll start with a brief review of our pipeline, which most of you are familiar with by now. Shown here, we have our three clinical stage programs, bitopertin with its lead indication in EPP, which has been advanced into a confirmatory trial called Apollo in parallel to our NDA preparations.
DISC-0974, a monoclonal antibody in development for anemias of inflammation, and DISC-3405, also a monoclonal antibody, which is now our third molecule to go into patients with the initiation of a phase 2 polycythemia vera study. So far, this has been a year of strong operational progress across these three programs, and we're excited about the updates we'll be providing today. What's new at EHA? For bitopertin, we shared the first look at data from Helios, which is an open-label extension trial. This data cut includes 86 patients rolled over from Beacon and Aurora, some on bitopertin for over two years now. The big takeaway is that we are seeing great long-term efficacy, both in terms of protoporphyrin IX reduction and quality of life improvement, and great long-term safety to supplement the substantial safety database that we already have for bitopertin.
We also showed, for the first time in humans, evidence of bitopertin's effect on liver function, improving ALT levels in a sustained manner. Encouragingly, the benefits of bitopertin were greatest in patients who were on the 60 mg dose for the full duration of treatment. As a reminder, this is the dose we brought forward to Apollo. For DISC-0974, we presented two posters. The first was an update on our phase 1b data shared last year at ASH, looking at longer-term data from the continuation phase of the study. Again, we saw durable efficacy with major responders maintaining their anemia response throughout the follow-up period and sustained activity on key biomarkers that show the drug is continuing to work as expected in these patients. As we have shared previously, we started the phase 2 RALI-MF trial, and we plan to share initial data later this year.
One note on enrollment: the exploratory cohort for patients on momelotinib or pacritinib recruited quickly and is now fully enrolled, underscoring the continued need for anemia treatment among these patients. Given that the responses so far in this cohort are generally similar to the responses seen with patients in other cohorts, either on or off a JAK inhibitor, we will be opening the main cohorts of the trial to allow patients on momelotinib and pacritinib. Not shown here, the other DISC-0974-related poster was from a mouse study of DISC-0974 in combination with ESA and luspatercept, which Will will cover in more detail shortly. These results suggest potential synergistic anemia benefit when combining DISC-0974 with other anemia-targeted agents.
Finally, for DISC-3405, we again shared the healthy volunteer data from ASH 2024, which provided proof of mechanism for this drug in suppressing iron and driving related hematologic changes. These data supported advancing the program into polycythemia vera patients. Based on these results, we have now initiated a phase 2 trial in PV, and Will will cover the details of that trial design. We also published data from a second healthy volunteer study of DISC-3405 that looked specifically at dietary iron absorption. In this trial, we were able to both confirm the pharmacology observed in our phase 1 trial and to show evidence of inhibition of dietary iron uptake, which supports the potential of this compound in indications associated with iron overload, and more to come there in the future.
Moving now into bitopertin, I'm pleased to report that we continue to progress well toward our planned NDA submission, which is still on track for the second half of the year. As we noted in our earnings report, we achieved two critical milestones in Q1. We had a successful manufacturing-focused end-of-phase 2 meeting where we achieved alignment on the proposed CMC components of the NDA package, and we also initiated the confirmatory Apollo study. Looking forward, we have a pre-NDA meeting scheduled with the FDA, which we'll use to align on the format and content of the NDA package. Running in parallel with all this, we are continuing to make progress on our commercial readiness activities, which Pamela will speak to shortly. I'll now hand it over to Will to review the bitopertin clinical data, including newly presented data from our Helios long-term extension study.
Thanks, John. As a reminder, here's an overview of the clinical development program for bitopertin in EPP. We completed the phase 2 Beacon and Aurora trials and subsequently saw over 80% of patients roll into the Helios open-label extension, which is the focus of our update today. As a reminder, we also recently initiated Apollo, which is designed to serve as a confirmatory trial and support the conversion of an accelerated approval, if granted, into full approval. We have seen a lot of investigator and patient enthusiasm for that trial, and we expect the enrollment of 150 patients to be well underway at the time of a potential approval. Here's a quick summary of what we saw in phase 2 as context for the Helios data.
We saw significant reductions in PP9, indicating that bitopertin targets the underlying pathophysiology of EPP, and we saw that PP9 reduction translated into improved outcomes, including sunlight tolerance, phototoxic reactions, and patient global impression of change. Here's a summary of the Helios trial design. Patients rolling over from Beacon were on a 20 mg or 60 mg dose of bitopertin, and patients from Aurora were on 20 or 60 mg dose or on placebo. In Helios, everyone transitioned to a 60 mg dose. A total of 86 patients rolled into Helios, including three adolescent patients and one XLP patient. You can see their baseline characteristics in the table. As John mentioned, we saw impressive durability of PP9 reduction. In these charts, the gray line represents patients that were on placebo in Aurora and then transitioned to bitopertin at the end of Aurora, where you see the vertical dotted line.
The purple line is patients who were on bitopertin from day one, and the teal line is the subset of those patients who were on the 60 milligram dose of bitopertin for the entire duration of treatment. The graph on the left shows the mean PP9 level, and the graph on the right shows the % change in PP9 from baseline. Patients who were on bitopertin from day one, regardless of dose, reached about a 40% reduction in PP9 and stayed there throughout the extension period. The PP9 decrease was even deeper for patients who stayed on 60 milligrams continuously. The patients who were initially randomized to placebo in Aurora, if you look at the absolute PP9, showed a very similar curve in terms of PP9 decreasing and reaching a nadir a few weeks after starting on bitopertin in Helios.
On the relative decrease side, this group may appear to have a smaller % decrease in PP9, but you can see that their PP9 actually increased around 10-15% from baseline during the placebo period in Aurora. The relative reduction from when they started on treatment in Helios is similar to the other groups. In Helios, patients who were already on bitopertin were able to sustain PP9 reduction, and patients who were new to bitopertin were able to achieve PP9 reduction at levels similar to what we've seen in other studies. We know that in EPP patients, in addition to building up in the bloodstream and skin, PP9 can build up in the liver, and this is associated with a range of potentially serious hepatobiliary complications. Here we saw some evidence of improvement on liver biomarkers with bitopertin.
The chart shows how ALT was reduced in patients on a continuous 60 mg bitopertin dose, and we also saw a numerical decrease in primary serum bile acids. There has been a lot of interest from physicians in the potential for bitopertin to improve liver health in EPP patients based on its mechanism, so it's encouraging to see these initial signs of activity. Importantly, we are seeing the sustained PP9 reduction in Helios leading to real patient impact. On three key patient-reported outcomes, the patient global impression of change, patient global impression of severity, and EPP impact questionnaire, we saw near-universal positive responses. At 24 weeks in Helios, almost every patient said their disease was much better compared to the start of the study, and most said their EPP was not at all severe and did not at all impact their quality of life in the previous seven days.
That is important in a disease like EPP that not only has serious systemic health consequences but also impacts many facets of daily life. Here is a look at safety. We continue to see a favorable safety profile in EPP patients, with some patients now being on treatment for over two years. The safety profile was consistent across adult and adolescent patients. We already have a robust safety database of over 4,000 participants from Roche, but it is great to see the continued validation of the profile in EPP patients long-term. An unrelated SAE was reported in one patient, and there was one additional grade 3 TEAE that was also unrelated. All other TEAEs were mild and moderate in severity. Dizziness was reported in less than 5% of participants, which was actually favorable to the dizziness rate we saw in placebo in Aurora, which was around 17%.
Overall, we are encouraged by the long-term safety profile. Now I'll hand it over to Pamela to describe the EPP opportunity in more detail.
Thanks, Will. As we've said before, we feel that EPP is a robust opportunity given the engaged, well-defined patient population and the focused HCP network of EPP experts who are easily addressed by a company of our size. On the left-hand side of the slide, we show the results of the claims data we have presented before, showing there are 6,000 engaged EPP patients in the U.S. These are patients who are actively using the healthcare system and seeing a doctor for their EPP on a consistent basis and are the core focus of our launch. This same analysis showed an overall total of 14,000 diagnosed EPP patients in the U.S., many of whom have been less engaged in the healthcare system, likely due to the lack of treatment options, which represents a growth opportunity with the launch of bitopertin.
EPP is a very strong rare disease market, and we really benefit from knowing where these patients are being treated. This allows us to have an efficient commercial model using a targeted field team focused on key treatment centers. As John noted at the start of this call, we are making great progress with our commercialization efforts in preparation for launching bitopertin for EPP. We are continuing to further refine our patient identification and account mapping and have been building our story with payers and supporting that story with HEOR work, including a study on the healthcare resource utilization that was recently presented at EHA. We are also progressing with operational readiness, including now having MSLs in the field who are helping with both educational and account mapping efforts.
One tangible example of the work we are doing towards commercialization is our disease state education campaign, which we are happy to announce was launched last week. This campaign aims to further reinforce the important role PP9 plays in EPP for both patients and physicians and will be rolled out across a number of channels, including websites, social media, and congresses. I'll now hand it back to Will to review the updated data for DISC-0974 in anemia of myelofibrosis.
Thanks, Pamela. Turning over to DISC-0974. As a reminder, this is a monoclonal antibody that works by inhibiting the hemojuvelin co-receptor, which suppresses hepcidin, thus mobilizing iron stores in the blood. This increases iron availability for red blood cell production, giving DISC-0974 the potential to treat a wide range of anemias. Our overall development approach for DISC-0974 was to establish proof of mechanism in healthy volunteers and then move into a first wave of proof of concept trials in myelofibrosis anemia and chronic kidney disease anemia before expanding into other forms of anemia of inflammation. The data from our myelofibrosis phase 1b presented at ASH last year represent initial proof of concept in that indication, and we will be looking at continuation data from that trial today. For context, here is the hematological response data we shared at ASH.
We were pleased to see strong responses across all three categories of anemia patients, including those non-transfused, lightly transfused, and heavily transfused. In this new data presentation, we are tracking maintenance of biomarker activity and hematologic response over the continuation phase as of the time of the ASH data cut, which is up to around 280 days on treatment for some patients. We show these data for major responders in the dark purple bars and non-major responders. Here you see the long-term biomarker activity. Across the board, we see continued hepcidin suppression and iron mobilization consistent with 0974's mechanism and consistent with previous results. On the rightmost panel, we show percentage change in zinc protoporphyrin 9.
This is a measure of iron-restricted hemoglobin production, so the pronounced decrease in this measure for major responders is further evidence that 0974 is working by freeing up iron for healthy hemoglobin and red cell production. Here you see that the anemia response was durable throughout the continuation phase for major responders. These charts show hemoglobin change from baseline for major responders in red and non-major responders in blue. The non-transfusion dependent group, or NTD group, is on the left, and the TD low group is on the right. You can see the number of patients who have reached each follow-up time point in the tables below the graphs. In both groups, major responders maintained the average hemoglobin increase over 1.5 grams per deciliter throughout the continuation period. No NTD or TD low major responders received a transfusion during this period.
For TD high patients, there were two major responders and one who entered the continuation phase and remained transfusion independent at day 225 with follow-up ongoing. Overall, we're encouraged by the level of durability of response we are seeing in patients who have had long-term follow-up to date. As we advance this program in the clinic, we're continuing to explore the biology and mechanism of 0974 in a preclinical setting. In the past, we have shared mouse models showing 0974's ability to reverse ruxolitinib-induced anemia in wild-type mice. Here we tested combinations of DBIO-100, which is a mouse analog of DISC-0974, in combination with different anemia-targeted agents to see if there is a synergistic effect. We looked at 0974 plus ESA and 0974 plus luspatercept.
In both cases, in wild-type mice, single agents, ESA and luspatercept, or DISC-0974, led to slight increases in hemoglobin, with a combination of 0974 plus an additional agent driving significant increases. ESA or luspatercept alone did not decrease hepcidin or increase serum iron, but 0974 did, both alone and in combination. This shows that 0974's mechanism is distinct from these other anemia agents and has a synergistic impact on anemia. Lastly, an update on the progress of the RALI-MF phase 2 trial. As you know, we designed this trial to amplify the sample size across our three cohorts: non-transfusion dependent, transfusion dependent low, and transfusion dependent high, and initially allowed for patients to be on ruxolitinib or fedratinib or no JAK inhibitor in these main cohorts. We had an exploratory cohort to start to understand the combination of 0974 with the cytopenia-sparing JAK inhibitors, momelotinib and pacritinib.
As John mentioned earlier, we have seen high demand for enrollment in this exploratory cohort, and due to the success of this cohort and the clear patient need, we are amending the protocol to include momelotinib and pacritinib patients in the main cohorts. As a nod to what's to come later in the year, patients on momelotinib or pacritinib seem to be responding similarly to what we saw in the phase 1b. This change in the study is in line with our messaging of the potential of 0974 as an agent that could address the needs of any MF patient with anemia, regardless of their transfusion burden or MF-directed therapy. This bundling of all patients, regardless of MF-directed therapy, reflects how we would expect a pivotal trial to look, inclusive of all comers.
I'll now hand it over to John to speak more about our view of this opportunity.
Thanks, Will, and thanks for the exciting updates. We're looking forward to sharing the initial look at the RALI-MF data later this year. Before I get into the MF anemia opportunity, I wanted to remind everyone that last month we hosted an MF anemia KOL day with Dr. Aaron Gerds from the Cleveland Clinic and Dr. Prithvi Bose from MD Anderson. Doctors Gerds and Bose gave a comprehensive view of why treating anemia is so important in these patients, as well as the current and emerging treatment landscape. A replay of that event can be viewed on the IR page of the Disc Medicine website. The main message from us coming out of that event is that there is a clear demand for better anemia treatments, and we are aiming to solve for the specific unmet needs of this population with the DISC-0974 program.
We estimate that there are 22,000 addressable myelofibrosis anemia patients in the US. As highlighted in the quote on the bottom left of this slide, anemia is a prevalent manifestation of myelofibrosis. Over time, it develops in basically every MF patient. This anemia is severe and highly burdensome on patient quality of life, and it is prognostic of patient outcomes and survival. Treating anemia in these patients is a key therapeutic objective. Right now, while the JAK inhibitors do a good job of controlling other manifestations of MF, like spleen enlargement and constitutional symptoms, there is no approved therapy for anemia. From a commercial perspective, while MF anemia is an emerging space, the overall MF treatment pathway is well established, and this disease is managed by a defined set of experts. We are aspiring to enter in with a truly differentiated product.
Again, as the KOL quote on the right highlights, we are trying to maximize anemia benefit and potentially also support optimal JAK inhibitor therapy across every patient who needs it. Here we lay out the five critical treatment objectives for anemia of MF. First, patients need a treatment that works across anemia severity levels, which DISC-0974 is designed to address as it is being studied across all levels of transfusion dependence and in non-transfusion dependent patients. These patients also need a therapy that can work as a monotherapy or on top of their backbone JAK inhibitor, with the potential to optimize JAK inhibitor dosing regimens. DISC-0974 has shown similar strong efficacy as a monotherapy and in combination with Jakafi, and as we noted on this call today, preliminarily appears to work well on top of momelotinib and pacritinib as well.
We will be continuing to study DISC-0974 on top of all of these myelofibrosis therapies, including patients both on and off JAK inhibitors. Finally, patients need a therapy with high response rates, something that DISC-0974 has demonstrated to date with major response rates of 40-80%, and we aim to solidify our understanding of response with the greater end size in the RALI-MF trial. With that, I'll hand it back to Will to discuss our third program.
Thanks, John. A quick reminder that DISC-3405 is an anti-TMPRSS6 monoclonal antibody that works to lower iron levels by increasing hepcidin. This approach is expected to allow us to address a wide range of hematologic disorders in which excessive iron or excessive red blood cell production is an issue. We completed a phase 1 SAD/MAD study in healthy volunteers, and I'll be reviewing the EHA data from that study in the next couple of slides. Our initial indication of interest is polycythemia vera, or PV, and I'm pleased to announce that the phase 2 study is now initiated. Looking ahead, we also have plans to expand into other indications, such as sickle cell disease. This slide shows the design of our phase 1 study, which involved a SAD dose escalation phase followed by a MAD phase that tested 75 and 150 milligrams dosed once monthly.
In healthy volunteers, we see the 3405 mechanism working exactly as expected, leading to dose-related increases in hepcidin and reductions in serum iron. We see deep reductions ranging to a 50-80% decrease from baseline that were sustained, supporting once-monthly dosing. We were pleased to see these PD markers translate into a hematologic response as well. Here we show two dose groups, the 150 milligram MAD and 300 milligram SAD. For both, you can see that 3405 resulted in meaningful reductions in reticulocyte hemoglobin, hemoglobin, and hematocrit. We also conducted an iron pulse study in healthy volunteers, which was designed to assess the ability of 3405 to inhibit uptake of dietary iron. In this study, participants were first given two occasions of placebo, followed by oral iron. They were given 3405, followed by oral iron two days and 15 days after 3405 was administered.
Serum iron was collected pre-dose and every hour for six hours post-dose. We were very pleased with the results of this study, which showed an average 94% reduction in iron absorption two days after 3405 was administered and a 68% reduction at day 15. These data confirm the mechanism of DISC-3405, giving us greater confidence heading into a PV study and support the ability to block dietary iron absorption, which speaks to the potential of DISC-3405 in iron overload disorders. Taking all this evidence into account, we have initiated a phase 2 study in PV. In this study, we will be enrolling patients into an observation period, then in the first cohort, conducting a 12-week dose escalation period before moving into a first maintenance period, dosing DISC-3405 at 300 milligrams every two weeks, followed by a period of 300 milligrams every four weeks.
We also have the option to add an additional cohort for eight patients or more to explore additional dose levels or dose regimens. We are looking forward to this study, which will have initial results in 2026. I'll now turn it back to John to close.
Thanks, Will. To summarize, it's been another successful EHA and a great first half of the year at Disc. On bitopertin, the Helios data supports the durability of bitopertin's efficacy and safety and gives an indication of potential liver benefit. We continue to progress well toward our NDA submission with successful FDA meetings, as well as the initiation of the Apollo confirmatory study. Looking ahead, our pre-NDA meeting is scheduled, and we expect to submit our NDA in the second half of the year, all while continuing to make progress on our commercialization plans. For DISC-0974, we continue to progress well in MF. The EHA data showed the durability of anemia response in these patients, and our RALI-MF phase 2 trial is underway, with the momelotinib exploratory cohort already fully enrolled and with initial positive results being seen in these patients to date.
We will be sharing initial data from this study later this year, as well as data from the multiple dose portion of our phase 1b study in non-dialysis dependent chronic kidney disease. Finally, for DISC-3405, we have demonstrated proof of mechanism with our phase 1 study and the iron pulse study, providing further evidence of DISC-3405's potential to treat polycythemia vera and diseases of iron overload. We have initiated a phase 2 study in PV and expect to share initial data from that study next year. Overall, we continue to make great progress at Disc Medicine across our portfolio and have an exciting set of milestones in the next six months. With that, thank you for joining, and I'll hand it back to the operator for Q&A.
Thank you. As a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Our first question will come from Thomas Smith with Leerink Partners. Your line is open.
Hey, guys. Good morning. Thanks for taking the questions, and congrats on the data updates. Just on the liver function data for bitopertin and Helios, it looks like you're seeing a really rapid decline in that 60 mg group. It's pretty much sustained over the course of the data set. Just wondering if you could comment on the kinetics there. Would you expect that sort of rapid decrease? Can you just help put those data into context and how you think these early signals on ALT and serum bile acids could translate into improved liver outcomes?
Good morning, Tom. Yeah, good question. Will, if you're on, you can take that.
Yeah, sure. Happy to. I think one thing that we have not presented much of is plasma protoporphyrin IX. We do see rapid reduction in the plasma compartment of protoporphyrin IX. That might have some relationship to the quick reduction at the 60 mg dose. I think one thing we have to keep in mind is that the participants for this study were excluded if they had significant liver injury. A lot of these ALT values are within the normal range. While there still can be dysfunction that is going on even with normal or slightly elevated ALTs, it is not the optimal population to show improvement of liver injury. That would require a separate study of people with documented liver impairment.
Got it. That makes sense. And then just in terms of the regulatory next steps for bitopertin in EPP, it sounds like you have the pre-NDA meeting that's right here on the horizon. Can you just remind us of any other outstanding gating factors or any other things to work through the agency as you work towards that NDA submission?
Yeah, the pre-NDA meeting is really the next step. I think after that, we'll have a clear path towards the presumed NDA filing in the second half of the year.
Got it. Maybe just one last question on 3405, as you alluded to the potential for indication expansion. Can you just walk through? I know we've seen some preclinical data around sickle cell, just how you're thinking about indication selection and maybe timing for moving another program forward there. Thanks so much.
Yeah, sure. Right. We do believe both 974 and 3405, with their iron-on and iron-off mechanisms, have broad applicability beyond the patient populations we're studying now. As you noted, we've seen nice data in mouse models of particularly the anemia of IBD for 974 and sickle cell disease for 3405. With that kind of positive information preclinically, as well as a lot of growing information about these drugs and their activity and apparent safety in the clinic, these additional indications become increasingly interesting to us to pursue. Behind the scenes, we're working on it. We probably would only disclose that kind of thing as we get right up to the edge of a clinical trial. Yeah, we're working on these things.
Okay. Our next question will come from Roger Song with Jefferies. Your line is open.
Great. Congrats for the data, and thank you for taking our question. Maybe as a follow-up for the liver function data, just curious, you said on the call physicians seem well-received that data. Just curious how critical for physicians to make their prescription decision based on the data. Maybe just understanding you already improved a lot of the other benefits. With this data, will they be more comfortable prescribing to more EPP patients? Thank you.
Yeah, it's a good question. We believe that this mechanism of reducing PP9 will lead to resolving essentially all attributes of EPP disease. While we've provided extensive evidence about sunlight tolerance as well as just overall quality of life and wellness for these patients, we haven't yet been able to provide any clinical evidence along the lines of improving liver health. Now, notably, we do have a lot of preclinical data we've seen in liver cell lines. Certainly in the mouse model, we've seen really nice reduction of liver fibrosis in EPP mice. A lot of reasons to believe this mechanism will work in the clinic. We're just excited to have some data that's coming out of the long-term extension, which frankly is where you'd expect to see that information that we can share. I don't think it's essential.
I think there's the mechanistic rationale is so strong here that there's a lot of belief that there will be an improvement in liver health if you reduce PP9. It has a sense of kind of mechanistic determination to it. I don't think it's an essential piece of data. It's kind of a nice-to-have and something that does support the general mechanistic rationale here.
Got it. Yeah, that makes sense. In terms of the PV, this new data, also very interesting. We see the PV space is getting more attention with some of the other companies reporting phase 3 data. Just curious, what is your goal to achieve here? Is that reduce the phlebotomy or control the hematocrit or even reduce the other cytoreductive therapy? Maybe one quick clarification is, can your drug be used on top of the current standard of care, including those cytoreductive therapies? Thank you.
Yeah. This concept of iron restriction as a treatment for polycythemia vera has become quite exciting thanks to what's been done with rusfertide by Protagonist. Our goal is to basically deliver a molecule that can achieve the same outcomes for patients, which, as a reminder, are controlling hematocrit below target to avoid thromboembolic events, allowing people to go off phlebotomy. The consequence of these things, which I think is really compelling about this class of drugs, is that patients end up feeling a lot better. That package is something we hope to be able to deliver on in a format of a monoclonal antibody where we think we can administer it once monthly. You'll see in our trial, we're exploring once every other week as well. I think we're just doing that to kind of see the maximum effect.
Somewhere in that convenient dosing interval range of about once monthly and achieving the same degree of, I believe, it was about 75% phlebotomy-free and control of hematocrit while allowing people to feel better. I think that would be a very attractive package for what is a pretty substantial number of patients with unmet medical needs.
Excellent. Yeah, that makes sense. Just one last quick question. Regarding the 0974, you will report the MF anemia data later this year. What is current thinking about the expectation? Because in the past, you haven't really guided how many patients we're going to see and then how much follow-up we're going to see from that initial data result. Thank you.
Yeah. I mean, as per usual, we don't guide to specific enrollment events. I think the only exception here has been this kind of intriguing dynamic we've had going on in the momelotinib cohort, where we've already shared that the cohort was fully enrolled and very rapidly so, which we think in a kind of unscientific sampling is telling us something about the unmet need for anemia therapy, even for patients who are on momelotinib. The next step was seeing preliminary evidence that the drug, the 974, is improving anemia in combination with momelotinib, pretty much just the same as it does on top of Jakafi, as we shared last December. With that, we felt like we are going to amend the protocol to allow those exploratory cohort patients to kind of expand into the main cohorts of 30 patients each.
We think that's going to give us a nice sample size now, and we don't need to worry that there's anything strange about the interaction between 974 and momelotinib at this point. That is exciting. It does drive clinicaltrials.gov amendments. Back to our usual disclosure habits, we prefer to share clinical data at conferences, and we prefer not to share enrollment data as we go along. In this case, we can tell you clearly that cohort exploratory of 10 did fully enroll, and we will have data from that as we come into the end of the year. That much is crystal clear. If we present at ASH, you probably have close to six months of data from that entire cohort. Pretty nice data set there.
Across the other cohorts of patients, it's going to be a slice of data in time, probably a few months ahead of whatever conference we're presenting at. It's hard to sit here and predict exactly how much data that will be. I think we'll get a pretty good look at how this is all progressing and what the interim data looks like.
Excellent. Thank you. Thanks for the comments.
Our next question comes from Evan Seigerman with BMO Capital Markets. Your line is open.
Hi there. This is Connor on for Evan. Thanks for taking our question. I guess given the data you've seen preclinically for 0974, can you maybe talk a little bit about how you're thinking about the potential combination of this asset with luspatercept in clinic? How would you think about the opportunity for such a combo? Thank you.
Yeah. Thanks for the question. I think these very simple mouse experiments we're doing illustrate what I think intrinsically should be the case, which is that mobilizing iron will support red blood cell formation regardless of what drug you're using to accomplish that. We're showing it with the EPO or ESA class of drugs, and we're showing it with luspatercept as well, which, as you know, is in development for treatment of anemia in certain MF patients. Exciting, but also kind of perhaps a bit expected that our iron mobilizing agent will synergize with these agents. I think that's only to the good for these patients. In terms of how much will these therapies be used in combination, we're not developing with that with a particular objective.
I think it's great that there will be an option to kind of go to a doublet therapy potentially for anemia in these patients. I guess it's worth noting that the luspatercept phase 3 program, which I think is expected to read out later this year, is restricted to those patients who are highly transfused and also on Jakafi. That was based on phase 2 data, suggesting that that was the primary group of patients where there would be a response to luspatercept in myelofibrosis. We'll get that data. It will tell us something about whether luspatercept works in that subset of patients. That is a subset we're exploring as well with 974.
I think what we see is the vast majority of patients, and certainly the highest enrolling, continues to be those who are either not yet transfused or lightly or sporadically transfused. It will be interesting to see. I guess if both drugs play out well, we could have a situation where 974 becomes the drug for kind of the frontline anemic patients. As they progress, maybe luspatercept would be added onto that. We will see how it all plays out.
Great. Thank you.
The next question will come from Cara Bancroft with TD Cowen. Your line is open.
Hi. Good morning. I'm wondering on bitopertin. We were wondering if you have perhaps a target for enrollment in the confirmatory Apollo trial prior basically to enable the NDA submission. More as we think about the opportunity, what do you think is driving the delta between the diagnosed EPP patients that are actively engaged with the healthcare system versus not? Is it the lack of available therapies? Is it milder patients who may not need treatment? From your research, what portion do you think would be eligible and willing to receive bitopertin if it's approved?
Yeah. Thanks. Will, do you want to speak to our enrollment targets in the Apollo trial? Pamela will touch on the patients.
Sure. Importantly, the guidance about a trial being underway applies to the time of approval. There is not a check-in on how enrollment is going. The study has been open for a few months now. By some definitions or perspectives, we are already well underway with our study. Certainly by a potential PDUFA date, we would expect to be mostly enrolled. We have guided that enrollment for EPP trials takes about 12 months. That is what we are expecting here. Q2 next year is when we expect to finish enrollment.
On the second part of your question, you're exactly right. The delta is driven primarily by the lack of available therapies. That delta between within the diagnosed patient groups, those who are highly engaged versus less engaged. The other comment I'll make there is what we learned from our market research is many of these patients have been living with EPP for a long time, and they've sort of adjusted to their lives. They don't engage that much with the healthcare system. When we go through the research with them and talk to them about what their lives could look like, being back in the light and the sun again, they really do become motivated. That just gives us a lot of confidence that these patients will begin to engage with the healthcare system again.
Okay. Thank you so much.
Thank you.
The next question will come from Kristen Kloska with Cantor Fitzgerald. Your line is open.
Good morning. This is Ayan on the line for Kristen. Congratulations on the data update. Thank you for taking our questions. Just two from us. On bitopertin, do you have any anecdotes from longer-term data that's related to some of the clinical measures like ALT and the average sunlight exposure? Second, on 0974, now that you've separated these two groups out, the major responders and the non-major responders, are there any baseline characteristic similarities that stand out?
Yeah. Good questions. We are aware of a lot of patient anecdotes that are floating around in patient groups on the internet. We as a company do not access those, but we are occasionally informed of them by others. It sounds collectively to be incredibly exciting. We do get some of that feedback directly. We have not gathered any of it up in a way that is fit for presentation at this point. We could look forward to doing something in the future. The second part of the question, I apologize, was 974. Oh, yes. Will, do you want to speak to that baseline criteria?
Yeah. Sure. One thing to keep in mind with this data presentation is that because it was the phase 1b data, it was a mixture of all the dose groups that we previously presented. Now that we're at the 50 milligram dose, we're going to have some more homogeneity going forward to be able to do more precisely what you're describing. It's always of interest to us to identify baseline characteristics that would predict response. For us, that's an iterative process. We look at every data set that comes in. The ultimate goal would be to find something that enriches for response and incorporate that into inclusion/exclusion criteria. I mean, thus far, we haven't modified our inclusion/exclusion criteria. We see responses across a wide range of baseline characteristics. It's something we'll keep looking at.
Thank you so much. The next question will come from Vikram Purohit with Morgan Stanley. Your line is open.
Hi. Good morning. Thanks for taking our question. Just a couple of quick follow-up questions. First, on bitopertin regulatory progress, obviously, based on some of the news in the past few months regarding FDA staffing changes and cuts, we just wanted to see if you'd glean from your interactions at the agency any reason to believe there could be any slowness or lags with your regulatory review process. It sounds like that's unlikely given your commentary at the start of the call, but we just wanted to revisit that point to be sure. Secondly, going back to the 0974 preclinical data you presented in combination with the ESA and luspatercept, we're just curious in your perspective and in your experience how predictive the mouse models you were presenting have proven to be in similar settings in the past.
Finally, on PD, I know you spoke in response to a prior question about kind of broader expectations for that program. For the update expected in 2026, just wanted to double-click on specifically kind of what we can expect to see and what you're looking at as kind of the marker for success from your perspective. Thank you.
Okay. Great. Let's see. I'm sorry. Can you just remind me the first question? The FDA changes. Yeah. Thanks. Right. That is part of why we are giving fairly granular disclosure of each step along the way. Our experience has been that our reviewing team is intact and that they've been working hard and doing everything on a timely basis and generally constructive with us. We've been incredibly appreciative of that team and how they're performing. We haven't seen any disruptions on timelines or real changes in policy. I think we acknowledge that there are instances where there have been changes in timeline that other sponsors have experienced. You never know what's going to happen next. So far, everything has been actually, they've been doing a commendable job. Okay. Part two is the mouse models of luspatercept.
I mean, I was, as you know, at Acceleron. I think if you look at the published literature, I think every mouse model where luspatercept promoted red blood cell formation, if it's been tested in the clinic, it played out reasonably well. I think on the specific question of driving erythropoiesis, mice have done a decent job of mimicking humans. And in our data case, I think it's pretty good. It's a very stripped-down wild-type animal receiving one of these agents where we're really just looking for synergy between iron and the positive pressure on red blood cell production that either EPO or luspatercept can provide. It's great to see that working more or less as we might have expected. The third part is, yeah. PD data, we are guiding to 2026. The trial's just opened.
Let us get in there and start enrolling patients before we provide a lot more guidance. I think we're hoping to see the same kind of robust elimination of phlebotomy and hematocrit control that's been seen with other agents.
Great. Thanks so much.
The next question will come from Martin Oster with Raymond James. Your line is open.
Hey, guys. Thanks for taking my question. I think most of them have been asked. I guess just out of curiosity, on the bitopertin, the Grade 3 treatment emergent adverse event, the hypertransaminitis, I was curious if that was related to the underlying disease or that was just sort of related to some other infection or something like that, if you had any color on that. Thanks.
Yeah. Will, please speak on that.
Sure. We don't have any other clinical information on that case. We just have it reported as transaminitis.
Okay. Thanks.
Great. Thank you.
The next question will come from Douglas Chow with DC Wainwright. Your line is open.
Hi. Good morning. Just a couple of follow-ups for me. First, I'm just curious. I know you said in terms of bitopertin and the liver injury issue, you would sort of need to do work in patients who sort of had suffered liver injury or had sort of greater evidence of liver injury. I'm just curious, though, when you think about the value, it sort of comes in prevention. When you just think about elucidating that, I'm curious if there's a sense of how great a correlation sort of ALT levels may be in terms of long-term liver function. Or do you really need to run a study that you sort of track patients over a very long time period? I understand the challenges and limitations of that. I have a follow-up.
Sure. I can take that. There is not a good correlation with ALT and long-term outcomes. It's just because ALT is transient. With the previous question, we had a transient transaminitis that went away. It's something that requires a long-term, multiple-year study. We may get a hint of this in Helios for patients that are in the study for multiple years. Ultimately, I think in looking at prevention, we will probably need to look towards real-world evidence and kind of case control type data.
Okay. Great. I guess in terms of 3405, John, I was sort of curious because you listed beta thalassemia as a potential indication or indication that you are looking pursuing with a POC study. A competitor had a trial using hepcidin mimetic Protagonist that had sort of mixed results. I guess I'm curious what gives you the confidence that 3405 may have sort of demonstrated sort of a more compelling outcome in beta thal patients. Thank you.
Yeah. It's a good question and timely with this data set because the iron uptake study where we've already shown that the drug will control iron availability in the blood, which is relevant to polycythemia vera and also sickle cell disease. What we hadn't really shown is that it would also block the uptake of dietary iron, which we would anticipate to be most helpful in diseases of iron overload. The two that people talk about there are hereditary hemochromatosis, a genetic iron-loading disease, and then also beta thalassemia where the defect in hemoglobin leads to a very low hepcidin level due to a high degree of unproductive erythropoiesis. Therefore, those patients will tend to iron load even in the absence of transfusion. Your question is right on.
I think you see that we're kind of leaning into while we're obviously working on PD, we're leaning into sickle cell disease. We're excited by this data that we have a solution to control iron uptake in iron-overloaded patients. We're still working through our thoughts on whether it's something we would pursue. Your point is well taken. Many drugs have tried in the past to look at beta thal with hepcidin restriction. However, they've usually looked at endpoints related to hemoglobin, asking for that to somehow increase hemoglobin levels. That has not played out. I think what's more interesting is to look at liver iron levels and whether you're able to essentially assist chelation in the deironing of liver in patients who are overloaded. I don't think that specific study has necessarily read out.
In some cases, I think there's even hints of positive data on that. I think jury's still out. We're still thinking about how to deploy our capital, and whether we're going to take on these iron-loading indications remains an open question to us.
Okay. Great. That's very helpful.
The next question will come from Rami Kakuda with LifeSci Capital. Your line is open.
Hey, guys. Congrats on the update. Thanks for taking my questions as well. I guess with regards to 3405, can you touch on why you chose to take forward the 300 mg dose in the PD study given the MAD results with 75 and 150 mg doses look positive as well? Secondly, maybe given luspatercept's clinical and commercial success in MDS-associated anemia and the potential synergistic benefits, I guess, you showed in preclinical studies, is that an indication you expect to pursue with 0974 in the future?
Yeah. I'll hit the last question first, just real quickly. There is an MDS cohort open right now. It was added as a kind of small side cohort to the phase 1B MF study, essentially at the request of some of the KOLs running a DMF study. So we will get an answer to that question. We are very interested. MDS tends to be heterogeneous in terms of hepcidin levels and iron levels. Whereas MF tends to be pretty uniformly high hepcidin and iron-restricted, MDS is much more checkered in that regard. We may see responses there. It may be in a subset of patients. We'll wait and see on that. As to dose selection in the PD trial, Will, do you want to speak to that?
Sure. I think with the profile of 3405, we have no injection site reactions. We see great PD effect at all doses. There is no reason for us really to start low and then work up. I think there is flexibility in the protocol. Should an individual or a cohort need to go down a dose level, we could. I think this is in distinction from rusfertide where their dosing paradigm is to build up a dose within each patient and try to find the right dose. I think for us, we see an opportunity to have a fixed dose from the outset for all patients.
Makes sense. Thank you.
The next question comes from Greg Harrison, William Blair. Your line is open.
Good morning. This is Theresa Vitale on for Greg Harrison. Congrats on all of the positive updates. Thanks for taking our question. Just wanted to see if you can comment on the very few patients who did not experience improvements in quality of life measures in the Helios trial and if there were any trends in baseline characteristics among these patients. Thanks.
Yeah. Thank you for pointing that out. I mean, it was actually remarkable data that essentially everyone in the long-term follow-up was reporting marked improvements in their quality of life. But you're right. There are a couple who seem not to. Will, do you want to speak to that?
Sure. We do not have specific information about why people answered as they did. It is not that there is anything on a PD level that would be related to this. I think when dealing with PROs such as that are broad as this, there is, I think, an expectation that there is going to be a curve to some extent. As John pointed out, it is very skewed in the positive direction. It is not surprising that there is one or two who say not. We do not have kind of a drug-related explanation for that.
I am showing no further questions at this time. I would now like to turn the call back over to John for closing remarks.
Yeah. Thank you, everyone, for your attention today. It was a very exciting EHA with a lot of information that we've been able to share across the portfolio. We'll look forward to some of the catalysts coming as we close in towards the end of the year. Thanks again.
This concludes today's conference call. Thank you for your participation. You may now disconnect.