Please be advised that today's conference is being recorded. I would now like to hand the conference over to your speaker today, Chief Executive Officer John Quisel. Please go ahead.
Good morning, and welcome to the Disc Medicine Management Call. We are here in San Diego at the 66th ASH annual meeting, where we presented data across our entire portfolio. Today, we will review key aspects of the data and provide additional updates and perspective on our plans moving forward. As a reminder, this is John Quisel speaking, CEO here at Disc, and I'll be joined by Will Savage, our Chief Medical Officer, and Pamela Stephenson, our Chief Commercial Officer. 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 as therapies in any jurisdiction worldwide.
To lay out our agenda today, I'll begin with a summary of key points from our ASH presentations, and then we will walk through each of our three programs, reviewing the data presented, as well as some market context for bitopertin and DISC-0974. This is an overview of our pipeline, which most of you are familiar with, and shown here, we have our three clinical-stage programs: bitopertin with its lead indication in EPP, DISC-0974 in anemias of inflammation, and DISC-3405 with currently completed healthy volunteer studies and now moving forward into polycythemia vera. We've made excellent progress across these three programs this year, and we are excited about the updates we'll be providing today. Starting with bitopertin, we presented data from our two phase 2 studies, Beacon and Aurora, where we showed clear correlations between protoporphyrin IX reductions and clinical outcomes.
For the first time, we shared data from adolescents in the Beacon trial, which were similar to results in adults, giving us confidence as we move towards including adolescents in our Apollo study. We also presented powerful results from a burden of illness study with almost 200 EPP patients participating and highlighting the immense toll that EPP can take on those living with the disease. We are moving this program forward on an accelerated approval pathway, and we're excited about the potential to provide benefit to patients and the market opportunity here, which Pamela will speak to later in the call. Now, for DISC-0974, we presented updated data from our phase 1b study in patients with anemia and myelofibrosis, showing durable hematologic response across all relevant patient types.
The response rate is remarkable, and most patients had a strong response to the drug, regardless of their transfusion status or background therapy such as Jakafi. We are pleased to share that we recently initiated a phase two study in MF anemia, encompassing the full range of patients with the disease, and we'll provide more detail on that study today. We also presented positive preclinical data in a mouse model of anemia of inflammatory bowel disease, or IBD, which, if combined with the human chronic kidney disease data that we presented in October, really highlights the potential to take this drug into a broad range of anemias of inflammation.
Finally, for our third program, DISC-3405, we presented multiple ascending dose data from our phase one healthy volunteer study that confirmed the proof of mechanism we saw in the single dose portion, with significant increases in hepcidin that translated to significant reductions in serum iron, up to 80%, and meaningful changes in hematologic parameters. These data are supportive of starting a phase two study in polycythemia vera in the first half of 2025. We also presented preclinical data in sickle cell disease, which adds to the growing body of evidence supporting the potential for iron restriction to be a disease-modifying approach for these patients. So, all in all, it has been a very successful ASH with positive updates across our entire portfolio, not only supporting the path forward in our existing indications, but providing evidence for potential areas of expansion into other hematologic conditions.
I'll now hand you over to Will to provide more detail on the bitopertin data that we presented.
Thanks, John. On this slide, as a reminder, we have the three clinical studies for bitopertin and EPP: Beacon, an open-label study of adults and adolescents in Australia; Aurora, a double-blind study in adults in the U.S.; and Helios, our long-term extension study that we've seen more than 80% of patients from Aurora and Beacon choose to roll over into, and as we discussed in November, we had a very successful end-of-phase 2 meeting with the FDA, which has put us on a path for accelerated approval with the confirmatory Apollo study expected to start mid-2025. This slide is a refresher on the key data set from the Aurora trial at the 60 milligram dose. We saw significant reductions in PPIX levels, around 40% reduction from baseline, and improvements in pain-free time in light that reaches 2x over baseline at the end of study.
There was a 75% reduction in the rate of phototoxic reactions versus placebo, and notably, in the last 60 days of the study, there were zero phototoxic reactions among the patients in the 60 milligram group. These improvements in clinical parameters showed an association with the degree of PPIX reduction in these patients. So, this is a great data set supportive of the use of bitopertin in EPP. On this slide, we summarize the new data from our Beacon study that we shared at ASH, and it's a very similar story to Aurora. We're seeing deep reductions in PPIX with similar results between adults and adolescents. There is a similar trend in phototoxic reactions as in Aurora, where there are essentially no events once PPIX has reached its nadir, versus 16 reactions in the four-week baseline period.
We also see the same association between PPIX and clinical outcomes, where the patients with the greater reductions in PPIX perform better on different measures of light tolerance. The Beacon study confirms the efficacy seen in Aurora with significant reductions in PPIX and phototoxic reactions and improvements in light tolerance and quality of life. Another interesting data set we presented at ASH came from a burden of illness study we conducted with almost 200 EPP patients to understand how EPP impacts their daily life. This survey really underscores how significant that impact really is, and the fact that we were able to recruit 200 people in about two months highlights how engaged the patient population is. The vast majority of surveyed patients had recent phototoxic reactions that are very painful and that took an average of five days for pain to improve.
When looking at their comorbidities, the data are consistent with what has been reported previously with issues beyond phototoxicity. In terms of impact on daily life, when looking at people who work or attend school, we saw that 22% report having missed work and 33% missed school due to their EPP in the past month. Taking all these data into account, we really get a sense of the extraordinary burden of living with EPP and the impact it has across all facets of life. In terms of next steps for bitopertin, we shared in November that we had a successful end-of-phase 2 meeting with FDA, in which they agreed with all of our proposed study parameters, including using the average monthly time in sunlight without pain at the end of the six-month treatment period as the primary endpoint.
Most significantly, the FDA noted that the reduction in PPIX observed in Aurora may be sufficient as a surrogate endpoint that is supportive of an accelerated approval pathway. So, this is the path we are currently working towards, part of which includes the initiation of the Apollo study, which would be a confirmatory study under this path. So, we have alignment with the FDA and are looking forward to providing an additional update on the development plan in Q1. I'll now turn it over to Pamela, our Chief Commercial Officer, to speak to the market opportunity in EPP.
Thanks, Will. As John and Will have said, we believe bitopertin has the potential to be a transformative treatment for EPP, given the disease-modifying mechanism and the results we have seen to date in our clinical trials. We're also very excited about the opportunity in EPP, given the strength of the market. As was outlined in the EPP Light survey, these patients have a high unmet need as the condition has a significant impact on their health and quality of life with limited treatment options available. EPP is a robust, rare disease market with 6,000 engaged patients in the U.S., a well-defined and focused physician network, and strong patient advocacy groups. All of these factors come together to form a sizable opportunity for bitopertin.
As we've presented before, we conducted an analysis of EPP patients in healthcare claims using the ICD-10 code specific to EPP, and this showed us that there are 3,000-6,000 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. 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 for the launch of bitopertin. So, 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 commercialization model using a targeted field team focused on key treatment centers.
Another indicator of how advanced the EPP market is for a rare disease is the number of remarkable physician and patient organizations that exist worldwide. These are groups that work to advance research and support EPP patients, and we are proud of the relationships we have built to date with these organizations. These groups are fundamental to advancing patient care and health outcomes, and we look forward to continuing to work with them as we move closer to launch. I also want to take a moment to highlight the important work the team has done and continues to do as we prepare for a commercial launch, especially in light of the potential for an accelerated approval. We have taken activities like patient identification, which started with a claims analysis, further to actually link those patients to key treatment centers and map out the referral networks.
We are working with payers to build the value proposition for bitopertin, and we continue to generate evidence to support this value proposition from both a clinical and HEOR perspective, and we have begun the processes to support operational readiness, including working with our new Chief Technical Officer, Rahul Kaushik, to ensure that commercial supply will be available upon approval. We are continuing to move forward our launch readiness activities with deliberate speed so we can be well-positioned to bring bitopertin to patients as soon as we receive regulatory approval. I'll now hand it back to John to wrap us up on bitopertin.
Thanks, Pamela. So, in summary, we have a very robust data set that was augmented by additional data cuts that we shared at ASH, a clear regulatory path forward with the potential for accelerated approval, and we feel great about the market opportunity in EPP. Additionally, many of you asked about our Diamond-Blackfan anemia trial, and I'm happy to report that enrollment has been going well, with 14 patients enrolled to date through our partners at the NIH. We do not have data to share at this time, but the operational progress is excellent, and we appreciate the efforts of our collaborators and the patients.
Looking ahead, we will continue to move our EPP program forward in 2025 with a discussion with the FDA on the design of our confirmatory Apollo study, the subsequent initiation of that study projected for mid-2025, and parallel conversations with European regulators, all side by side with the launch preparations that Pamela updated you on. I'll now hand it back to Will to discuss updates for the rest of our pipeline.
Thanks, John. DISC-0974, as a reminder, is a monoclonal antibody that works by inhibiting the hemojuvelin co-receptor, which suppresses hepcidin, thus mobilizing iron stores into blood. This increases iron availability for red blood cell production, giving DISC-0974 the potential to treat a wide range of anemias. Our lead program for DISC-0974 is in myelofibrosis anemia. I'll go through the results of our phase 1b trial, which were shared in an oral presentation at ASH earlier today. This slide gives an overview of the study design and enrollment to date. So, we are looking at 35 patients on monthly subcutaneous doses, and we included both patients on concomitant JAK inhibitor therapy and those not on JAK inhibitors. In previous data readouts we've shared and in much of the historical literature, MF patients with anemia have been characterized as either non-transfusion dependent or transfusion dependent.
Based on discussions we had with FDA on clinically meaningful patient segments, as well as newly published clinical guidelines, we will be looking at three categories of patients based on transfusion burden moving forward: non-transfusion dependent patients with baseline hemoglobin less than 10 but not receiving any transfusions, transfusion dependent with low transfusion burden of one to two transfusions within a 12-week period, and transfusion dependent with high transfusion burden of three or more transfusions within 12 weeks. Getting into the results, we saw pharmacodynamics that were consistent across doses and consistent with previous data cuts, in line with our expectations based on the drug's mechanism. DISC-0974 drove a 75% reduction in serum hepcidin, which translated into sustained increases in serum iron and increases in both reticulocyte hemoglobin and overall blood hemoglobin. This translated into hematologic response and improvement in anemia.
We will look at hematologic response for each of the patient groups we discussed earlier, starting with the non-transfusion dependent ones. In these patients, 68% saw any hemoglobin response greater than 1.5 grams per deciliter. 59% achieved overall response, which we define as a mean hemoglobin increase of at least one gram per deciliter sustained for 12 weeks, and 50% achieved a major response, which is an increase of 1.5 grams per deciliter sustained for at least 12 weeks. We also saw clinically meaningful improvements in FACIT-Fatigue scores, which is an important measure of patient impact. Moving on to the TD patients with low transfusion burden, there were five evaluable patients in the study, and all of them achieved an overall response of greater than 50% reduction in transfusion requirement.
Four out of the five, or 80%, also achieved a major response of transfusion independence, defined as no transfusions over a 16-week period. Finally, there were five evaluable TD high patients. 60% achieved an overall response of greater than 50% reduction in transfusion requirement, and 40% achieved a major response of transfusion independence over a 12-week period. So, regardless of the baseline transfusion burden, we saw strong hematologic responses translating to clinically meaningful improvements in anemia. As mentioned, we include patients with and without concomitant JAK inhibitor therapy in the trial. There were 13 patients enrolled on concomitant JAK therapy, and these patients fell into the NTD and TD high groups. Overall, 54% of patients on JAK inhibitor therapy achieved a major hematologic response relative to their baseline transfusion status. So, DISC-0974 is working well in the JAK inhibitor treated population.
This is an important segment given that JAK inhibitors like ruxolitinib are the standard of care for controlling spleen volume and symptoms in MF and are known to worsen anemia in many cases due to their impact on EPO signaling. We investigated the relationship between DISC-0974 and JAK inhibition further in a preclinical study, which was presented in a poster at ASH yesterday. In this study, we treated wild-type mice with ruxolitinib, which decreased hemoglobin and induced anemia. When we added DBIO-100, which is a mouse analog of DISC-0974, we saw these effects reversed. We see the expected reduction in hepcidin, and this target engagement translated into an increase in hemoglobin of around a gram per deciliter as opposed to the approximately one gram decrease seen with ruxolitinib.
Together, with the strong response among patients on JAK inhibitors in our phase 1b study, it appears that DISC-0974 can improve anemia in these patients. Finally, in terms of safety and tolerability, the profile was generally consistent with past data sets. The related AE that occurred in two or more patients was diarrhea, and the majority of AEs were deemed non-related. Let's step back and look at the overall MF anemia market. We estimate that there are over 20,000 patients with MF and anemia, and based on our data, it appears that however you slice this market, either by transfusion burden or by use of disease-directed therapy, DISC-0974 works to treat anemia. In terms of transfusion status, we observed meaningful major responses across all three categories of patients. We believe there is high unmet need across all of these patient types.
For NTD patients, their quality of life is significantly impacted by anemia symptoms, and we know that almost all MF patients eventually become transfusion dependent over the course of their disease. For TD patients, whether low or high burden, the transfusion experience carries additional negative impact on health and quality of life, and on top of that, it is associated with worse overall survival regardless of other risk factors. Then, in terms of concomitant JAK inhibitor therapy, with DISC-0974, we have observed greater than 50% response rates for patients both on and off JAK inhibitors. So, for patients with anemia, whether or not you're on a disease-directed therapy, DISC-0974 appears to be effective at treating the anemia.
We know that many MF patients have to change from their optimal treatment approach due to worsening anemia, whether that means changing to a different JAK inhibitor, lowering their dose, or discontinuing altogether, and that may leave their spleen or symptoms less optimally controlled, so having a separate anemia-specific treatment on top of the JAK inhibitor could potentially bring those patients back to their optimal disease-directed regimen, so we think that the potential market for DISC-0974 is quite broad. Based on the current data set, we view it as a treatment for essentially everyone with MF and anemia. With these encouraging data, we are pleased to share that we have initiated the phase two trial. We plan to enroll approximately 90 adults with Intermediate-1 to high-risk MF and anemia with or without concomitant JAK inhibitor treatment.
Note that there are 12 patients who are eligible to be carried over from the phase 1b part at the phase 2 dose, which is 50 milligrams. The phase 2 has the same phase 1b six-month treatment period and optional continuation period. We will include three cohorts: NTD, TD low, and TD high, with approximately 30 patients per cohort. We are also planning an exploratory cohort of patients on momelotinib or pacritinib and are maintaining flexibility to add additional exploratory cohorts. The key metric we are looking at is anemia response, which is defined differently by cohort and based on our discussions with FDA and updated clinical guidelines. We expect to share initial data from this trial in the second half of 2025.
Looking beyond MF, I'd like to briefly remind everyone of the data we shared at ASN in October from our phase 1b SAD cohorts in anemia of non-dialysis dependent CKD. Again, in this trial, we saw substantial dose-dependent reductions in hepcidin, which translated into increases in serum iron and TSAT, and in turn, hemoglobin response. We also conducted a study that will be presented in an ASH poster tomorrow in mice with DSS-induced colitis and saw again that DISC-0974 suppressed hepcidin, increased serum iron, and increased hemoglobin and red cell counts. Interestingly, we also saw evidence of IBD disease modification, including decreased disease activity scores and anti-inflammatory effects, including decreased white blood cell counts. These data, in combination with our CKD data, help illustrate the potential for DISC-0974 to treat additional anemias of inflammation.
In summary, for DISC-0974, we have strong proof of concept in anemia of myelofibrosis across all clinically meaningful patient segments and an early indicator of efficacy in the anemia of non-dialysis dependent CKD patients based on single dose data. The CKD results, plus the preclinical data in IBD that was presented here at ASH, provide support for DISC-0974's broader potential in the anemias of inflammation. We are moving forward in both clinical programs with our phase 2 trial for myelofibrosis patients recently initiated, and we're expecting initial data from that trial in the second half of 2025 and data from the phase 1b multiple dose CKD trial expected by the end of the year. Now I'll turn it back to Will to discuss our third program, DISC-3405.
As a quick reminder, DISC-3405 is a monoclonal antibody that works in the opposite direction of DISC-0974. DISC-3405 suppresses TMPRSS6 in order to increase hepcidin, which leads to iron restriction, which can be beneficial in conditions like polycythemia vera and iron overload disorders. In order to test the mechanism of DISC-3405, we ran a phase 1 study in healthy volunteers in which we tested single doses at 75-300 milligrams in two multiple dose cohorts, one at 75 milligrams and one at 150 milligrams, dosed every four weeks. We shared the results from the SAD portion of the study in June, which confirmed the mechanism of action, showing increases in hepcidin and meaningful reductions in iron.
These results were confirmed with the MAD portion, which are presented here at ASH, where we saw up to 80% reductions in iron from baseline and meaningful changes in other hematologic parameters such as reticulocyte hemoglobin, overall hemoglobin, and hematocrit. DISC-3405 was also well tolerated, and we saw no injection site reactions. All of these data taken together are supportive of moving DISC-3405 forward into polycythemia vera and iron overload conditions with a once-monthly dosing regimen. With this proof of mechanism, 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 Townes 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 indication of interest for DISC-3405. I'll now turn it back to John to wrap up.
Thanks, Will. Taking all these data into account, we see three domains where TMPRSS6 inhibition with DISC-3405 could prove beneficial: polycythemia vera, sickle cell disease, and other iron overload disorders. We plan to initiate a phase 2 study in polycythemia vera in the first half of 2025, and we will continue to explore DISC-3405 in additional indications. That concludes the review of each program. I'll now provide just a few closing remarks. Overall, it was another great conference for DISC, where we were able to showcase the significant progress we have made this year in advancing all three of our programs in the clinic. We also showed for the first time some interesting preclinical data opening up the possibility of expansion indications for both DISC-0974 and DISC-3405.
With all of this progress, we're feeling great about our portfolio and the direction the company is going in, and we look forward to continued progress next year. Speaking of next year, we have some exciting catalysts to look forward to. For bitopertin, we will be providing an update in Q1 on our Type C meeting with the FDA, in which we plan to discuss the design of the confirmatory trial. At that point, we will also provide more granular guidance on the timing of our NDA filing. And then we plan to initiate the confirmatory Apollo study by mid-year. We will also be continuing our collaboration with the NIH in Diamond-Blackfan anemia.
For DISC-0974, we're excited to announce today that we've initiated the myelofibrosis phase 2 study, and we will provide an interim look at data from that study likely in the second half of 2025. In CKD anemia, we are starting the multiple dose portion of the phase 1b study soon, and we expect to provide a look at data from that study by the end of the year in 2025, with the goal of starting a phase 2 study by 2026. And finally, for DISC-3405, we'll begin our phase 2 study in polycythemia vera in the first half of next year, with data coming in 2026. So overall, it's been a really great 2024 here at DISC. A lot of progress across the portfolio, and I think there's a very exciting next 18 months to come where we'll be moving the entire portfolio forward in meaningful ways.
So thank you all for your attention, and I'll now 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. Please stand by as we compile the Q&A roster. Our first question comes from the line of Ben Burnett from Stifel. Please go ahead with your question.
Okay, great. I'll be the first to say congrats on these updates. This is very exciting. I thought it was interesting how on the DISC-0974 section in the myelofibrosis presentation that you're kind of outlining three different groups of patients. I was wondering if maybe you could just kind of talk about the kind of what are the regulatory hurdles that you see in each of those different categories?
Yeah, thanks for the question, Ben. As we've noted, we have had some regulatory interaction. It's, of course, the end of phase one type meeting, so we don't have complete clarity on every step of the way, but I think we have a sense for what the FDA is looking for in these groups. And maybe, Will, you want to take it over?
Sure. I think overall that there's flexibility demonstrated on behalf of FDA to have a number of different categorizations as we see fit, and we're going to follow our data and provide clinically meaningful definitions. Hence, we are based on guidelines, and we'll have endpoints that address benefits.
Okay. Fantastic. And oh, go ahead.
Oh, we didn't say.
Apologies. Go ahead, John.
Sorry, you go.
I just wanted to ask one other question around the bitopertin EPP program. So I understand that there's going to be an update in a meeting next year, and I think you kind of talked about how that discussion will be around the confirmatory study. But I guess, is there any further clarification needed on using PPIX as a surrogate endpoint?
Nothing that we're aware of. As we've described our end of phase 2 meeting, we were invited to move down an accelerated approval pathway using PPIX as the surrogate endpoint. The key request from the FDA was to come back and have a Type C meeting to discuss the detailed design of the confirmatory Apollo trial. So that's where we stand, and right now, we're working out the time that will bind us to an NDA filing. And then, with the full data set in front of them, then the FDA will evaluate that package and hopefully move ahead with an approval of the drug on this basis.
Okay. Excellent. All right. Thanks so much. I appreciate it.
Thanks, Ben.
Thank you. Our next question comes from the line of Roger Song from Jefferies. Your line is now open.
Great. And my congratulations for the successful ASH updates. So maybe a couple of questions from us focusing on the anemia myelofibrosis. Maybe the first one is very good that you have the data from the JAK versus non-JAK. So just curious, mechanistically, how do you think 0974 is going to combine with other upcoming MF therapy? How likely they can add additional anemia benefit on top of the other myelofibrosis drug, which are not specifically addressing anemia? Thank you.
Yeah, thanks. Good question. As a general answer, we expect our mechanism of iron mobilization to essentially stand alone and be able to work fine with any disease-directed therapy. But Will, do you want to add something to that?
No, that's exactly. I think it's that simple that there's going to be no drug interaction that we'd anticipate using a monoclonal antibody, and the hepcidin mechanism we anticipate to be independent of any MF-directed therapy and can be added on to any current or new treatment.
Got it. Yeah, that's helpful. And then another one is just follow-up with the previous question related to different categories for the myelofibrosis anemia. And then you mentioned clinical meaningful benefit. Can you just elaborate on that point? So how should we think about the clinical meaningfulness given this potentially can be an adjunct therapy on top of the future MF standard of care or other standard of care? Thank you.
Sure. So there is a precedent for achieving transfusion independence as a clinically meaningful benefit, and that's what we outlined in our TD high and TD low cohorts. It can also be used as a preservation of transfusion independence in an NTD cohort, but there are other ways to show it as well besides the hemoglobin increase in the NTD cohort, such as PROs. We showed the FACIT-Fatigue improvement. That's another way to show clinically meaningful benefit.
Got it. Thank you. Last question from us is related to the EPP. Maybe any updated thoughts around or any kind of additional feedback from the FDA in terms of how much confirmatory study enrollment is needed before you can file for accelerated approval and then even the final approval? Thank you.
There's no specific feedback on that. As we're guiding to start the Apollo trial in mid-year, the trial will be well underway, and we are anticipating approximately 12 months to fully enroll the study, which is precedented in our past studies as well as other EPP studies. So I don't anticipate it will be a question.
Excellent. Thank you. Thank you very much.
Thanks, Roger.
Thank you. Our next question comes from the line of Thomas Smith from Leerink Partners. Please go ahead.
Hey, guys. Thanks for taking the questions. And let me add my congrats on the updates. Maybe just one on 974 and myelofibrosis. I think you had some patients in the phase 1b study that were on background pacritinib and momelotinib, and I believe this came up during the Q&A at the ASH presentation. But could you just comment on any responses seen in these patients and your expectations for the exploratory cohort in the phase 2?
Sure. So with only about three patients on momelotinib or pacritinib, there's not much of a statement we can make about that population versus others. As we mentioned before, the anti-hemojuvelin mechanism can be added onto anything, including momelotinib or pacritinib. The expectations for the exploratory cohort are really no different than they are for the three main cohorts. The reason we just carved them out is just for homogeneity in understanding our phase 2 signal because the key is, we think we've established proof of concept, and the phase 2 is really just about setting up the clearest signal out of our cohorts. We don't have evidence that there's a difference, again, with pacritinib or momelotinib, but it is a question, and we just want to answer it in parallel rather than all mixed together. That's all.
Understood. That makes sense. And then we saw the preclinical data for 974 in anemia and IBD. I'm just wondering if you could elaborate a little bit more on how you're thinking about indication expansion for 974, any updated thoughts on how you plan to select across a number of anemias of inflammation here, any thoughts on potential timing for moving into other indications?
Yeah, that's a good question, so we're certainly excited, right, and we think that these data collectively do point towards expansion to cover many, many different kinds of anemia of inflammation. What we've done so far is to target this indication by indication with myelofibrosis and NTD chronic kidney disease. Now we have some preclinical evidence for one additional inflammatory disorder. I think where we go from here still remains to be determined. We could continue to pick off additional indications and look to start, for example, a signal-seeking study in the IBD patient population with anemia. We could also start to think about whether there's groups of patients that could be collected together to do more of a basket-type trial, but these are all just still in kind of the brainstorming and formation stages.
We'll look to update people as soon as we can as we turn this into concrete trial designs.
Got it. That makes sense. And then maybe just one last one, just for a bit of burden in EPP. And yeah, I appreciate the data updates here. I just wonder if you could elaborate on some of the ongoing pre-commercial activities and specifically with respect to payer engagement, I guess how much payer engagement you've undertaken to date and if you have any updated thoughts on potential pricing and indication like EPP.
Yes, hi. It's Pamela. We have engaged with payers across the U.S., and what we hear from payers is a couple of things really important. They understand EPP and the fact that it's the size of the population. It's a rare disease market. And secondly, from our phase 2 data, they see the impact of PPIX, the lowering of PPIX, and they get that that is really addressing the underlying cause of disease and therefore sort of ascribe value to that. And so we're calling on the rare disease pricing model, and we'll continue to engage with payers and build the evidence base needed that we always need to do to support that, which we've already done through the EPP Light survey that Will mentioned. So yeah, positive feedback from the payers.
Understood. That makes sense. Thanks for taking the questions, guys. Congrats again.
Thanks, Thom.
Thank you. Our next question comes from the line of Evan Seigerman from BMO Capital Markets. Please go ahead.
Hi, guys. Thank you so much for taking our questions, and my congrats on the data as well. I'm only really on the CKD program. I'm looking at slides from EHA to now, and I've noticed that the timing for the phase 2a top-line data seems to have slipped a bit. Can you maybe walk me through what's happening there? That seemed to be a pretty important program, and with this timeline, are things being deprioritized? Maybe help us understand kind of how to think about this.
Yeah, thanks for the question, Evan. So we are working very hard on this trial. There's absolutely no deprioritization. We're quite excited about it. We're headed into this multiple-dose stage of the trial. We haven't had experience enrolling patients in this part of the study yet. So I think we've provided guidance that we feel very comfortable that we can hit at this point, and we'll do everything we can to pull those timelines in, but remains to be seen at this point.
Okay. I guess, maybe asked another way. I guess what was the cause for the change in timing from June to now? Is it just enrollment, complexities of the trial? I'm just trying to understand what some of the factors behind this were.
One thing that we've seen is that we get good responses. It's clear that we can get a better response by using multiple doses. We chose to pursue that through kind of multiple-dose work in the phase 1b program. So that's now kind of interposed itself between what we were thinking about a SAD directly to a phase 2 design. We think it's advantageous to continue with the phase 1b program to really understand the multiple-dose work and come out with that data and then move with a lot of speed into phase 2 from there.
Okay. No, that's very helpful. And then just on, what is it, 3405, we had some competitive siRNA data presented at the meeting today. Maybe walk me through how you see this space evolving. Clearly, a lot of activity of different types of modalities, but there was a lot of enthusiasm around this. Maybe talk me through the competitive dynamics you see.
Yeah, right. Exactly. So yeah, Silence presented their data in the same session as our myelofibrosis data, showing looks like good activity. Clearly, patients are requiring phlebotomy after they go on to that kind of TMPRSS6 inhibitor. And I think it does a lot to validate this target as being a place where substantial control over this disease can be achieved. So I think that's all to the good. We think our antibody modality will have a lot of benefits. Still to be proven out, but we think that it will allow titration to suit patients' needs, and we'll have to let that play out in the clinic. And then I guess the other program in the space for Regeneron has an anti-TMPRSS6 antibody as well.
At this point, it appears that they're pursuing trials in kind of decreasing iron loading in beta thalassemia patients, which we think is also quite an interesting indication. I think there's going to be a lot of patients who may benefit from this drug. We're seeing essentially what I call phase two proof of concept in polycythemia vera. We see Regeneron going after the beta thalassemia iron loading condition. That may point to future endeavors in hereditary hemochromatosis. And then we have our own. There's this rising interest in the sickle cell community at the potential for iron restriction and a TMPRSS6 mechanism there. And we've got some preclinical data starting to show positive effects. I think we have these three agents that are progressing right now.
I think it should be very exciting for patients with all these diseases, and I'm confident that our agent will be quite competitive amongst all these.
Thank you so much for the call .
Thanks.
Thank you. Just a moment. So next question, please. Next, we have Jeff Hung from Morgan Stanley. Your line is now open.
Congratulations on the progress, and thanks for taking my questions. From DISC-0974, you indicated that you're starting with 50 milligrams in the phase 2 study. Can you just talk about the rationale for starting at 50 milligrams versus 75 or 100 milligrams? And is there an option built in for patients to increase the dose while on treatment? And if so, how high could they go? Or if not, what is the highest dose that you're studying? And then I have a follow-up.
Sure. So from the data we presented, which is consistent with prior, you achieve maximal hepcidin reduction at 50 milligrams. And because there's such a tight relationship between the PD effect and clinical effect, we don't see that there's any additional benefit to be gained by dosing above 50 milligrams. That said, we are in the phase 2 going to have an option to dose escalate patients up to 75 milligrams for failure to achieve response. So that's our approach in phase 2.
Great. And then for the 0974 phase 1b data, how were the major responses distributed over doses? Was there a dose-dependent relationship? And then for those who did not experience a response, were there any consistent themes that you saw that could predict why they didn't respond? Would it be possible that some of those would actually respond with a higher dose of 0974, particularly if they were on a lower dose like 28 milligrams? Thanks.
Sure. So the dose dependency just follows the hepcidin curve, essentially, that 14 and 28, where you get good, but not as maximal hepcidin suppression. You see lower response, but once you get the hepcidin down at 50, you see the hemoglobin maximized and the transfusion independence responses. So at 50 milligrams, it's basically all a blended group at 50 milligrams and other dose levels once you hit that hepcidin. Regarding, it is an ongoing search to find biomarkers that predict response. We are achieving consistent hepcidin reduction, so it's in patients. So that it's not a failure to lower hepcidin that's leading to a lack of response. I think it's a fundamental issue of the inability to define how much of any given patient's anemia is due to splenomegaly or JAK inhibition or marrow fibrosis.
You just have to try 0974 and see what you get.
Thank you.
Thanks, Jeff.
Thank you. Our next question comes from a line of Kristen Kluska from Cantor Fitzgerald. Your line is now open.
Hi, everyone. Congrats on all the updates that ASH had some on 0974. So for the three buckets that you laid out as it relates to transfusion dependence, how would you roughly split these three groups on prevalence in real life? And then as a second part, how might physicians assess willingness or ability to lower transfusions, and what would be considered meaningful for them, especially as these transfusions only get higher with longer and longer follow-up?
Yeah, thanks for the question, Kristen. Actually, I have Jonathan Yu here who's been doing a lot of work on this question.
Yeah. And hi, Kristen. I think largely these distinctions are primarily a regulatory distinction. I think the way that the market thinks about it is, are you anemic, and then are you being transfused? And I think we have very good data showing that almost every patient with MF has some degree of severe anemia that is refractory to treatment. I think the other statistic that's out there is that within one year, almost half of patients require some level of transfusion. And then that grows over time to nearly every patient requiring some level of transfusion. I say all of that just because to reinforce how serious anemia is in this patient population. And the data that we presented today really reinforces that independent of whatever segment you're on, and specifically if you're on ruxolitinib, treatment with 0974 is able to improve your anemia.
I hope that's helpful.
Thank you.
And then I could add regarding the transfusion reduction meaningfulness, what clinicians would care about. The other part of your question, I think our endpoints reflect input from the guidelines and our discussions with KOLs about what is clinically meaningful. And even at ASH, there's a few posters looking at the patient perspective of the impact of transfusion burden, and every single transfusion is a burden from the patient perspective.
Thank you. Just a moment for our next question, please. Next, we have Martin Fan from Wedbush Securities. Your line is now open.
This is David Nierengarten, not Martin. Sorry. I had a couple of questions mechanistically just on 0974. What do you think is causing the improvements or changes in white blood cell count for anemias of inflammation in the model? I'm just curious if there's a mechanistic explanation. And then similarly for 3405 and sickle cell, when you talk about changes in sickling hemoglobin in the model, is it due to some what is the mechanism for that besides just reducing red cell counts? Thanks.
Yeah. Thanks for the question, David. So in terms of the effects we saw in the IBD model, where there's a marked anti-inflammatory and kind of disease resolution effect of the drug, we're still working on trying to establish evidence for what that mechanism is. If I engage in some speculation based on what's out there in the literature, there's a certain amount of literature about the effect of iron loading on macrophage activation, the role that can play. There's also a decent amount of literature suggesting that oral iron exacerbates disease in these patients. So there's maybe something about iron dynamics in the intestinal lining that has an effect. And DISC-0974 may modulate that in a way that's helpful. So stay tuned. We're working hard on building a data set around that that will put some real meat on those bones.
But we think it's pretty interesting and potentially something that might translate to the clinic. To your second question about sickle cell and the mechanism there, maybe Will, you should speak to that.
Sure. So the phenomenon of sickling of hemoglobin within a red cell is exquisitely concentration dependent, something like on the order of the 30th power of hemoglobin concentration. So even small reductions in the intracellular hemoglobin concentration are thought to have a profound impact on the propensity to sickle. When you iron restrict, of course, you need iron and heme and globin to make hemoglobin. When you iron restrict, the cells make less hemoglobin, as seen in general iron deficiency. People get anemic. They make less hemoglobin per cell. So by leaning into that mechanism softly with some degree of intracellular iron restriction, cells make less hemoglobin. Thus, the hemoglobin S concentration goes down, and there is thought to be less sickling and less hemolysis and potentially deriving clinical benefit from that.
That's essentially the pattern of data that we saw in our mouse model.
Got it. Thanks.
Thank you. Our next question comes from a line of Rami Katkhuda from LifeSci Capital. Your line is now open.
Hey, guys. Congrats on the update, and thanks for taking my questions as well. Just a couple of quick ones. I guess first, is there any hypothesis as to why the diarrhea rates with 0974 increased from the EHA updates now? And is the AE transient, or does it last through the duration of treatment here?
Yeah. So the diarrhea is self-limited. It's mild. It's being reported from one site. It's something that is duly noted as an AE, but it doesn't have any meaningful impact on dosing or patient tolerance.
Got it. Fair enough. And then as you look to expand into other anemias of inflammation, when do you think your long-acting anti-hemojuvelin antibody could come online?
Yeah. It's a good question. We are working hard on that, and we have kicked it into development. As you know, it's a biologic, so the standard GMP processes have to be followed before you can get into the clinic. But we're excited about that. We think there's broad opportunity. And just to remind, we may be able to approach multiple different patient needs in different disease states, even with different presentations of DISC-0974. And then that long-acting agent can also come in and be used as a tool to optimize for patient need.
Got it. Thank you, guys, and congrats again.
Thanks.
Thank you. Our next question comes from a line of Danielle Brill from Raymond James. Your line is now open.
Hey, guys. This is Alex on for Danielle. Thanks for taking our question. Question on bitopertin EPP. It looked like in a subgroup analysis in the Aurora poster that you presented yesterday, there appeared to be a diminished PPIX response in patients over 65 years old. Just a multi-part question. One, is there any biological rationale for an age-related lack of response? Two, curious whether you saw anything similar in Beacon or the open-label extension studies. And finally, has the FDA given any indication that they're concerned about this and might consider an age restriction in the label? Thanks so much.
Thanks for the question. I think the key takeaway is there are very few patients who are over 65 years of age, and there are very wide confidence intervals. And so I think the small endpoint isn't interpreted as a diminished efficacy. It's just a reflection of a very small number of patients. So there's no mechanistic rationale for that. I mean, heme synthesis is a stable process from prenatally to end of life. So we have no concern about that.
And I think your last question was, did the regulators have any concerns about that? Absolutely not. They saw all this data, and it was not a topic of discussion.
Thanks so much, on the call .
Thanks.
Thank you. Our next question comes from Douglas Tsao from H.C. Wainwright. Your line is now open.
Hi. Good evening. Thanks for taking the question. Just maybe first on bitopertin, obviously, good to see the data in adolescents. I'm just curious, when you think about the potential for accelerated approval, would you anticipate you would have labeling to include those patients? And I assume that's down to age 12.
It's something we're certainly going to push for. We think we have some data there. We think we have a great safety database. But that remains a topic of discussion. And what we know now is that the FDA is comfortable with us including those patients in our confirmatory Apollo trial. So I think that's a great sign. But in terms of getting on the label, let's wait and see. But it's something we do want to accomplish, that.
Okay. Great. Thanks. And in terms of DISC-0974, you mentioned considering doing a basket study. I guess maybe, John, maybe some thoughts on the value or the pros and cons of pursuing a basket study versus identifying one or two indications that you would potentially pursue. Thank you.
Yeah. It's an interesting question. I'll probably regret bringing up that basket trial concept. But it is, in all transparency, something we're thinking through right now. I think getting the broadest label possible is always desirable, right? Our mission is to find patients who need this therapy. We think there are a lot of patients out there who have an anemia that's going to be characterized by an elevated hepcidin, and the drug really ought to be useful for all of them. Now, you can get there through many different paths, but there may be some appeal or efficiency to a basket design. But that said, to date, we've taken the indication-by-indication approach, and that's still something we're thinking about as well.
Okay. Great. Thank you.
Thanks.
Thank you. Our last question comes from a line of Greg Harrison from Scotiabank. Your line is now open.
Hi. This is Teresa Vitale on for Greg Harrison. Congrats on all of the progress, and thanks for taking my question. Just a quick one on bitopertin and the Apollo study. Would time and sunlight be averaged across the entire treatment period or just one month once six months of treatment has occurred? And can you provide any additional color on the evaluation of baseline light tolerance and what metrics and thresholds will be applied?
Sure. So it's a longitudinal analysis for each individual patient that takes into account both the baseline and the monthly time and light. And then the statistical test is the last month on study. But you're using data in that longitudinal analysis across the entire study to help inform that last statistical comparison. Regarding baseline assessment, we are imposing rigor with the way we are assessing that in terms of minimal degree of diary compliance and capturing light tolerance in the two weeks immediately adjacent to the initiation of the trial. So it's very similar to how we did it in Apollo and Beacon. It's just we're applying some more rigor in how we do baseline.
Okay. Great. Thank you.
Thank you.
Thank you. This concludes the Q&A session. I will now hand back to John for closing remarks.
Great. Thank you. As we've said, it was an exciting ASH, and we're really pleased with the progress we've seen across the whole portfolio. Obviously, the marquee here was the oral presentation of myelofibrosis. I think that data looks about as good as we could have ever expected. Really nice response rates across all categories of patients, and we're excited to be rolling and live with the phase 2 trial, so thanks again, everyone. Appreciate your time tonight.
This concludes today's conference call. Thank you all for participating. You may now disconnect.