Good day. Thank you for standing by. Welcome to the Disc Medicine Type C meeting for bitopertin in EPP conference call. At this time, all participants are in listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press *11 on your telephone. You will then hear an automatic message advising your hand is raised. Please note that this conference may be recorded. I will now hand the conference over to your speaker host, Mr. John Quisel, Chief Executive Officer. Please go ahead, sir.
Thank you. Good morning and welcome to the Disc Medicine Management Call. Today, we will review the feedback from our recent Type C interaction with the FDA on bitopertin and EPP and discuss our plans for advancing the program along the accelerated approval pathway. As a reminder, this is John Quisel speaking, CEO here at Disc. I'm joined today by Will Savage, our Chief Medical Officer, and Steve Caffé, our Chief Regulatory 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 is an investigational agent and is not an approved therapy in any jurisdiction worldwide. Okay, so turning to our agenda, I'll start off by saying that it should be a straightforward and encouraging update today.
Last November, we shared the positive feedback from our end of phase II meeting on bitopertin, in which the FDA acknowledged the potential for an accelerated approval pathway for bitopertin and separately agreed to all major parameters of our proposed APOLLO trial design. At that time, the agency recommended that we request an additional Type C meeting to further discuss the details of APOLLO in the context of a confirmatory trial, which aligns with recently issued FDA guidance on the accelerated approval pathway. That Type C meeting was completed in December and was a productive step forward in our collaboration with the FDA and a reflection of the agency's continued support for the EPP community. So today's update is focused on sharing our plans for the APOLLO trial, which, as you'll see shortly, looks very much like the study we outlined following the end of the phase II meeting.
We will also be able to provide new guidance on the process and the anticipated timeline for our planned NDA submission. To summarize, based on our recent regulatory interactions, we plan to pursue accelerated approval for bitopertin using PPIX reduction as the surrogate endpoint. This is an endpoint we know well and one we believe measures the true driver of this disease. Importantly, we also believe that we have shown through our phase II program that PPIX reduction is associated with outcomes that are meaningful to EPP patients, clinicians, and regulators, being able to spend more time in the sun with significantly fewer pain attacks while feeling much better. We achieved alignment with the FDA on the design of the APOLLO confirmatory trial, and we look forward to initiating that trial by the middle of this year.
Based on that timing, we expect to be able to sufficiently enroll the trial prior to a potential PDUFA date, assuming acceptance of our NDA for accelerated approval. We are actively working on our NDA package, and we have been since our end of phase II meeting. This package will leverage the PPIX reduction data from our phase II program, including data from the BEACON and AURORA studies. We expect to have everything in good shape for submission by the second half of this year. Stepping back to where we were a year ago, this is an incredible place to be, and we are appreciative of the collaboration with the FDA, our investigators, and the EPP community, all of which combined has put us in the position to deliver what we believe could be a truly life-altering therapy to patients in serious need.
Now our focus is on executing APOLLO and advancing our NDA preparation and commercial readiness activities to support the potential approval and launch of bitopertin. So now I'll hand it over to Will to discuss the APOLLO trial.
Thanks, John. So here is an updated look at APOLLO in the context of a confirmatory trial. This is similar to what we've presented before. We are planning to enroll approximately 150 patients across the U.S., Canada, Europe, and Australia, and our guiding that we expect to complete enrollment to take about a year. This is based on the rate at which we were able to enroll the AURORA trial in the U.S. alone, the level of enthusiasm among our investigators and patient community, and the fact that we are now including sites and geographies where bitopertin has not previously been studied. We will include both adults and adolescents in the trial and will aim for the 12 years and older population to be included in our initial label. This is an especially important population as adolescents do not currently have access to any approved therapy for EPP.
And as previously shared, we will bring forward the 60-milligram daily oral dose. There is a change from the details we've discussed previously, which is quite encouraging to us. In addition to the average monthly time in light without pain at the end of treatment, the FDA recommended we elevate PPIX reduction to a co-primary endpoint in the confirmatory study, which again is an endpoint we are familiar with and reflects the agency's understanding of the crucial role of PPIX in this disease and the differentiation of bitopertin's mechanism. We'll also be looking at the full range of clinical outcomes, including phototoxic reactions, time spent in light before an early warning symptom or prodrome, and patient global impression of change score as an exploratory endpoint. These are measures we showed improvement on in phase II and that were associated with PPIX reduction.
And taken together, they can start to form a picture of the true impact of bitopertin on patients' lives. So we believe this will shape into a rich data set. Now I'll review the co-primary endpoint in more detail. Again, these will be average monthly total time in sunlight without pain after six months of treatment and change from baseline in whole blood metal-free PPIX after six months of treatment. We have previously discussed the first one on the left, which is essentially looking at the amount of time patients can spend in light on a longitudinal basis. As the graph on the left shows, this endpoint was statistically significant versus placebo in a post-hoc analysis of AURORA when looking at the last two weeks or four weeks of the study. We'll be looking at the last four weeks in APOLLO.
And as we've discussed previously, we view this as a clinically meaningful and robust endpoint that minimizes the potential of a placebo effect and is quite well powered with our trial design across a wide range of data scenarios. And then our other co-primary endpoint will be change from baseline in PPIX after six months of treatment. This was suggested to us by FDA, and we were quite excited because we believe this is exactly how bitopertin works. PPIX reduction was our pre-specified primary endpoint in both BEACON and AURORA and was highly statistically significant in both studies. In AURORA, we saw around 50% PPIX reduction versus placebo at 60 milligrams, which translated into a p-value less than 0.001. That's the delta between the gray line and dark purple. And in BEACON, we saw over 40% PPIX reduction versus baseline, which again was squarely statistically significant.
To us, the elevation of this endpoint to co-primary is an indication that regulators understand the importance of the role of PPIX in this disease and understand that bitopertin's mechanism of lowering PPIX could be disease-modifying. It is the same endpoint that will be used as a surrogate for a potential accelerated approval. It is highly objective, and we are optimistic that we can meet this endpoint, so we feel that it strengthens the design of the confirmatory trial favorably. The ability to link these two elements, PPIX reduction and clinical benefit, is the premise of our potential accelerated approval path. So these make a lot of sense as co-primary endpoints. Now, when we discuss the details of these endpoints, it can be easy to lose the picture of what this actually means for patients.
It's hard to capture the stories we hear about our trial participants in any endpoint, but I just want to remind folks of the impact we've already seen in Beacon and AURORA. EPP is a disease where PPIX, a toxic precursor in the heme synthesis pathway, builds up in places like blood, skin, and liver and causes extreme sunlight sensitivity. These patients live their lives with a severe limitation on how much time they can spend in light, whether that's five minutes a day or 30, and end up designing their lives around sunlight avoidance, such as wearing head-to-toe coverings to go outside, choosing jobs and hobbies that don't involve sunlight, excluding themselves from social or daily life activities that could expose them to the sun, and other limitations.
Then if they do spend too much time in light, the consequence is a severely painful phototoxic reaction, which can be completely debilitating and last for multiple days on end. Beyond these reactions, buildup of PPIX in the liver can cause hepatobiliary complications such as elevated liver enzymes and gallstones in a significant portion of patients, and in the worst cases, life-threatening liver failure. You can imagine the lifestyle modifications necessary to live with this disease and the fear of its symptoms and complications exact a significant psychosocial toll. We know that bitopertin targets the underlying pathophysiology of EPP. That's the lowering of PPIX. It has also driven significant improvement in sunlight tolerance in clinical trials to date in the range of 2x- 3x, depending on the metric you look at.
For a patient, that could mean being able to spend the day at the beach for the first time or play outside with your child without worrying about triggering a reaction, and these are some of the stories that have been generously passed on to us by patient advocates, and that increased sunlight time has come with profound decreases in the rate of phototoxic reactions, a 75% decrease versus placebo in AURORA and 92% decrease versus baseline in BEACON. If you recall some of the temporal data we previously shared on AURORA, phototoxic reactions disappeared completely in the 60 mg group after PPIX reached its nadir, all while patients spend more time in light, and finally, in both studies, the vast majority of patients on bitopertin have said they felt better or much better. Patient Global Impression of Change scores significantly improved.
And as this is a subjective patient-reported outcome, we think it speaks to the meaningful impact of bitopertin across the full range of ways EPP affects patients. Taken together, this is a data set that motivates us to bring this program forward in an NDA submission and, if approved, get bitopertin to patients as quickly as possible. And I'll now pass it to Steve to discuss the regulatory path forward.
Thanks, Will. So the upshot of this meeting is that we have clarity from our collaboration with FDA's Division of Dermatology, and we can provide further guidance on our NDA plans. We have aligned on PPIX reduction as a surrogate endpoint for a potential accelerated approval path at the end of phase II meeting. And now we have ironed out the details of a post-marketing confirmatory trial. The next step is to get APOLLO running, which we have guided will happen by the middle of this year, which will give us plenty of time to achieve sufficient enrollment at the time of a potential approval. We are moving forward quickly on all the typical pre-NDA activities, both in terms of the internal work of pulling together the submission package and in terms of additional touch points with regulators between now and our planned submission.
The types of interactions we expect as part of this process include a CMC-focused meeting to gain feedback on the data expectations and completeness of that package, and a pre-NDA meeting which allows the sponsor and the FDA to discuss the proposed format, content, and organization of the NDA to ensure it meets regulatory requirements and facilitates efficient review. As mentioned, we are working on our NDA package and expect to submit it in the second half of the year. There is then a 60-day window in which the FDA reviews the submission to determine that it is complete and filable. If the NDA is filed, the review period begins and a PDUFA goal date is set. We'll continue to provide relevant updates as this process advances. I'll hand it back to John to close.
Thanks, Steve. So that is today's update. We are, of course, quite pleased with how the bitopertin program has advanced over just the past few months. But we also want to remind folks about what to expect this year across the rest of our portfolio, as our iron homeostasis programs, DISC-0974 and DISC-3405, are also making great progress. We have the initiation of APOLLO by mid-year and the anticipated NDA submission in the second half to look forward to for Bitopertin. And then on the DISC-0974 front, we recently initiated a phase II study in anemia of myelofibrosis, and we expect to share an initial cut of that data in the second half of 2025.
The data we shared in MF at ASH last year, which showed greater than 50% response rates across all segments in a heterogeneous patient population, gave us optimism that the drug candidate has the potential for best-in-class safety and efficacy and may be unique among the current field in its ability to improve anemia regardless of transfusion status, line of treatment, and concomitant medication. Myelofibrosis is, first and foremost, a bone marrow and red blood cell disease. Anemia is often the first manifestation of the disease, is strongly correlated with poor prognosis, and is not addressed by current therapies. So we believe DISC-0974 could play an essential transformative role in the treatment paradigm for these patients. Then we will also have an update in anemia of chronic kidney disease, or CKD, as well, which will include additional dose escalation and initial multiple dose cohorts.
And this could really open up the potential for DISC-0974 in a broad range of chronic disease and inflammation-driven anemias. That's coming up in the second half as well. And finally, turning to DISC-3405, we shared the complete phase I Healthy Volunteer package at ASH, and we are getting ready to start a phase II study in patients with polycythemia vera. And of course, we are continuing to explore next indications for each of our programs. Some of our thinking there has been previewed in preclinical data presentations at ASH in December, and we hope to be able to provide concrete updates on these efforts in the coming months. All of this is important to think about holistically because with bitopertin approaching possible approval and commercialization, the face of this medicine is changing, and hopefully we will be well positioned to execute across the breadth of opportunities here.
With that, I'll hand it back to the operator for questions.
Thank you. Please enter your comment to ask a question. You will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, simply press star one one again. Please stand by while we compile the Q&A roster. Our first question coming from the line of Roger Song with Jefferies. Your line is now open.
Thanks. Congrats for the regulatory update, and thanks for taking our questions. Maybe two quick ones from us. The first one is related to the co-primary endpoint, given this is new to the confirmatory study. Just curious about the statistics, how you split off to make sure both endpoints will be hit in order to have a positive confirmatory study, and then have follow-up regarding your confirmatory study enrollment. Thank you.
Okay, great. Thanks. Yeah, good question in terms of alpha spend on that co-primary endpoint structure. Will, why don't you take that?
There actually, that's true. Thanks. There is no alpha spend because both primary endpoints need to be hit, so the alpha is 0.05 for each of them. So we have to hit both of them, and you only split alpha when you need to get one or the other. But here we're getting light tolerance and PPIX.
Great. Thanks for the clarification. And then in terms of the confirmatory study enrollment, I think you used the word well underway. I believe that's the communication with the FDA. Just curious about the sites in the U.S., any guidance around what percentage of the clinical sites were coming from the U.S. or the enrollment were coming from the U.S. so we can understand a little bit better how much the enrollment needed for the U.S. patient in the confirmatory study? Thank you.
Yeah. Also, a good question. Will, you want to take that?
Sure. So we're projecting that a majority of patients will come from the U.S., and that's just based on the demand and what we've heard from sites and our feasibility assessment. We anticipate that overall there is a very large demand across all the geographies that we're going to be looking at.
Maybe just to clarify, as you said, Roger, the FDA is using the word well underway to describe the degree of trial completion that they'll be looking for from us ahead of PDUFA date. As noted, when you kind of line up our timelines and anticipated enrollment rate, we don't think we'll have any problem meeting that criterion.
Excellent. Thank you. That's it from us. Congrats again.
Thank you.
Thank you. Now, next question coming from the line of Tom Smith with Leerink Partners. Your line is now open.
Good morning and congrats on the progress. This is Matt Sterling with Leerink for Tom Smith. We have a couple of questions. So first, for the NDA filing for bitopertin and EPP expected in second half 2025, will the data packet include results from the ongoing HELIOS trial, and do you think this will be a standard or a priority review? I have a follow-up.
Yeah, for sure. So we won't know the review status, standard, or priority until we get to that stage with the agency. And then it's the second question, actually, your initial question, Will, you want to take that?
Sure. So yes, we expect that a data cut from HELIOS would be part of the submission. HELIOS, keep in mind, is primarily a long-term safety study. It's not designed to get efficacy signals in the same way that AURORA and Beacon were. So in other words, we're going to have safety data to submit along with our other data.
Got it. And for the APOLLO trial, do we expect the majority of the patients will be EPP patients, but do you have an expected number of XLP patients that you plan to enroll, and what are the gating factors for initiating the trial in mid-2025?
Sure. So about 5% of the EPP population is XLP. We know, for example, in BEACON, we had one XLP participant. And so we expect with a trial that's 150 that we will get anywhere from 5-10 people with XLP. So we expect to have representation of that group. There's nothing specific that's gating the opening of AURORA beyond the usual clinical startup activities.
I guess just to note that back in the preclinical setting, XLP mice responded very well to bitopertin therapy, and the one individual in the BEACON trial also responded well to therapy.
Got it. That's it from us. Thank you so much.
Thank you.
Thank you. Now, next question coming from the line of Ben Burnett with Stifel. Your line is now open.
Hello. Good morning. Congratulations on the update. And this is Carolina Ibanez on for Ben Burnett. Thank you for taking our questions. First, we were wondering what are your plans on commercial readiness this year?
Yeah. Thanks for the question. It's something we're thinking carefully about. As you know, we've hired almost a year ago now our Chief Commercial Officer, Pamela Stephenson, who has extensive experience launching rare disease drugs for rare disease indications. And in fact, Pamela is here with us today on the call if you want to give us a few comments on this point, Pamela.
Sure. Hi, everyone. So a couple of things we've been doing in terms of the readiness activities. The first is the patient identification. EPP, as we have stated before, has a specific diagnosis code. So we've been able to do a lot of work using the claims analysis to identify the number of patients in the U.S., 14,000 diagnosed patients with 3,000 to 6,000 patients who are engaged in the healthcare system and will be our primary target. We've also done extensive work in the last year working with payers to develop our value proposition and doing evidence generation to support our value proposition. And then finally, the standard operational readiness activities around looking at the field team size and focusing on the key treatment centers. This is a very efficient commercial model, and we're excited to move quickly forward.
Good. Thank you. That's very helpful. And as a second part of a previous question, of the 150 patients you are planning to recruit for the APOLLO, what's the proportion of adolescent patients you are targeting to enroll to support approval also for this patient population? And do you expect bitopertin also to have a similar profile in adolescents than in adults, both in terms of efficacy and safety?
So to answer the second part first, we think, and the data showed us from the BEACON trial that the safety and efficacy in adolescents is the same as adults. And as a reminder, in the accelerated approval path, data from APOLLO would be post-approval. So that adolescent data would not be contributing towards the label. It would be the four adolescents that we enrolled in the BEACON trial.
I think there was a question about how many adolescents we expect to enroll.
Oh, and then, how many to include in the trial? Well, we expect, because the disease is prevalent throughout life, that we would get a proportionate number of adolescents, so approximately 10% or so of the trial participants.
Okay. That's appreciated. Thank you.
Thank you.
Thank you. Now, next question coming from the line of Kristen Kluska with Cantor Fitzgerald. Your line is now open.
Hi, good morning, and congrats on all of these final alignments in place. I had two questions about the commercial opportunity. First, in rare diseases, we often see that the patient communities are quite close amongst each other, and I know that this is a community that is indeed that case. They have the different sonoscans and events to kind of meet as a community in a safe space. So I wanted to ask, for a launch, how much do you think is going to need to be dictated by physicians calling their patients to say, "Hey, there's a new therapy on board," versus patients just being aware of what's going on in the landscape, both through their patient advocacy groups as well as their friendships and connections that they have in the group?
Yeah. It's a good question. And I think today we've seen excellent engagement at both the patient and the physician level. But Pamela, why don't you provide some more detail?
Yeah, sure. As you stated, the patient community here in EPP is very close. The patient advocacy groups here in the U.S. and worldwide are strong, motivating. There's a lot of interconnectivity among the patients. So I think you'll see in sort of an initial target that I mentioned of patients, there's going to be a lot of drive from the patients themselves. But over time, that growth is going to come from physicians, physician education, physician outreach, and just physician telling their patients about this new oral therapy. So I think it's going to be a combination of the two factors.
Thank you for that. And then are there any rare disease comps that you can point that you're potentially framing about a similar cadence and size of the market opportunity for what you believe can be ahead as well?
So there are a number of different rare disease comps that we're tracking. I think the one thing I would say about rare diseases is that each one has its own nuances, different types of patients, drivers, etc. We're tracking a whole cohort, a whole set of rare disease analogs, and we expect this product to be right in line with others. We've been looking at Alnylam, the product Givlaari, obviously an AHP that we've been looking at. But there are a number of different products that we feel that this would be right in line with in terms of rare disease.
Yeah. Other indications we've looked at as comparers are well-known markets like PNH and HAE also.
Great. Thanks very much.
Thank you.
Thank you. Our next question coming from the line of Evan Seigerman with BMO Capital Markets. Your line is now open.
Hi, guys. Malcolm Hoffman on for Evan. I wanted to start with a question. With the AURORA and BEACON studies being tested in Australia and Europe and now APOLLO adding European and Canadian patients, how is the DISC team working to ensure enrollment proceeds swiftly for these Canadian and European sites and centers of excellence that the team may not have previously worked with? Thanks.
Yeah. It's a good question. And just to kind of review for everyone, so BEACON was conducted in Australia, the AURORA trial in the US. So we are now going for the first time to countries like Europe. Will, do you want to talk about thoughts on enrollment there?
Sure. So like in the U.S., these countries have centralized clinical and diagnostic centers of excellence for porphyria. There's also well-organized patient advocacy groups. And so we think that enrollment is going to proceed just as well there as in the U.S. And as I mentioned, we've already received a number of inbound, a lot of inbound interest from potential investigators about the number of participants they would expect to enroll.
Appreciate it. Thanks, guys.
Thank you.
Thank you. Now, next question coming from the line of Douglas Tsao's H.C. Wainwright. Your line is now open.
Hi, good morning. Thanks for taking the questions. Just for the first on APOLLO, I just want to confirm for the co-primary endpoints, will these be evaluated separately and each need to be hit, or will it be a responder analysis for the two endpoints, PPIX reduction and sunlight exposure together? And then I have a follow-up.
Sure. Yeah. They are analyzed separately. So you have to hit each of them independently.
Okay. Great. And then just I know you've talked about it, but any updated thoughts in terms of pursuing pediatrics with bitopertin below adolescents? Obviously, as you noted, they represent a pretty meaningful commercial opportunity. Has that topic come up in any of your subsequent conversations with the agency? Thank you.
Yeah. We've had discussions with both European regulators and U.S. regulators about a pediatric plan. And we've certainly built that plan as part of our development program overall. And we're following what I think is a pretty typical path in terms of we started with primarily adults, then moved and added a few adolescents to the BEACON trial. Now we'll be looking to add adolescents to the APOLLO confirmatory trial. And I think once that whole body of adults and adolescents has proven out well, then we would move on to introducing the therapy potentially for younger patients as well, which I think would be very important if we can bring that to market.
Okay. And John, just thanks. That's helpful. And so, John, just to confirm, so that would likely come well after completion of APOLLO?
Yeah. I mean, or at least after completion of APOLLO, yes.
Okay. Great. Thank you very much.
Thank you.
Thank you. And our next question coming from the line of Jeff Hung with Morgan Stanley. Your line is now open.
Thanks for taking my questions. In your meeting, did FDA give any indication if there are specific differences in each of the co-primary endpoints that they would look for, or is it just stat-sig? And then I have a follow-up.
Yeah. Will, you want to speak to that?
Sure. Just stat-sig.
Okay, and then now you have more feedback from FDA. Can you just talk about the powering assumptions for APOLLO? What are you expecting for the treatment and placebo response rates? Thanks.
Sure. So we're not providing specific details about the powering assumptions except to say that it is very conservative, and we have well over 80% power in all of the data scenarios we looked at, both in terms of the variability and in terms of the treatment effect. So even in the worst-case scenarios that seem plausible, we're still well-powered over 80%. And I'm speaking to the time in light. Of course, PPIX, we've already demonstrated that that's very well-powered as well.
Thank you.
Thanks, Jeff.
Thank you. Our next question coming from the line of Rami Katkhuda with LifeSci Capital. Your line is now open.
Hey, guys. Congrats on the update. Two quick questions for me as well. Maybe first, can you speak a bit more on how you plan to stratify patients in APOLLO to minimize potential confounding factors? Is it kind of the same things we've seen in BEACON and AURORA? And then secondly, can you remind us where you stand in terms of CMC given the advanced timelines to commercialization with bitopertin?
Yeah. Will, why don't you speak to the stratification? I'll talk to CMC.
Sure. So stratification is the same as in BEACON and AURORA with the addition of stratification by geography.
Yep. That's the only.
but disease severity and.
Yeah. So the other what was done previously is disease stratification by disease severity in terms of light tolerance. And now we're adding the geography on top of that.
Yep. And then as to CMC, I mean, I think it's a pretty typical cadence that we're working through here with the FDA, having a standard end-of-phase two discussion to ensure alignment with the FDA on the sufficiency of the CMC package.
Got it. Thanks so much.
Thank you.
Thank you. And as a reminder to ask a question, please press star one one. Our next question coming from the line of Greg Harrison with Scotiabank. Your line is now open.
Good morning. This is Teresa Vitale on for Greg Harrison. Congrats on all of the updates, and thanks for taking our question. Could you talk about your plans for regulatory filing outside of the U.S.? And is that something that we should look for post-readout of APOLLO, or is there any potential to accelerate on that front as well?
Yeah. That's a great question. We haven't provided a lot of information on that. No surprise. All along the way here, we have been having the usual discussions with the European regulators, the EMA as well. And the way we've designed this is to go first to speak with the FDA, get a sense of how our phase three or now, as we understand it, confirmatory trial would shape up in its details, and then bring that information and plan to the EMA to seek alignment there for the global trial. So we'll expect to have information from the EMA essentially across Q1 here. And I think we can plan to have some information for the public around the EMA status on that timeline. And yeah, so there is the potential for the European equivalent of accelerated approval. It's something we don't have any real insight into yet.
We'll have to kind of keep everyone updated as we move along.
Great. Thank you.
Thank you.
Thank you. Again, if you have a question, please press star one one. And I'm not showing any further questions in the queue at this time. I will now turn the call back over to Mr. John Quisel for any closing remarks.
Great. Thank you. And thank you, everyone, for tuning in today for our updates. And we're looking forward to progressing this program and the rest of our portfolio. Thanks again. Bye.
Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.