Okay, take two. So, I'm Douglas Tsao, Senior Analyst at H.C. Wainwright. Thank you, everybody, for joining us today. Next, we have Disc Medicine, represented by the company's CEO, John Quisel. It has been a very eventful sort of 12+ months for you, or this is coming up on, like, 18 months as a public company?
Yeah, that's right.
And most recently, with the release of the data, phase II data for your lead asset, bitopertin and EPP. You characterized AURORA as a, as a complex data set. And I think, there were very high expectations following the sort of top-line data that you had released from, from BEACON. And I think bitopertin again performed probably reasonably consistently with what we saw on BEACON and aligned with our expectations, although we saw a very high placebo response, which was quite surprising, just given sort of what we've seen on placebo rates in, in precedent trials. I guess, you know, it's now been almost two months since you released AURORA . Have you been able to untangle some of that complexity? I'm just curious if you can share some of the feedback from KOLs in terms of their interpretation of how bitopertin performed and how it would fit into the sort of treatment landscape for EPP.
Yeah, thanks for the question. It's great to be here. So as you say, eventful 18 months, eventful last quarter. The KOL feedback actually has been excellent. So, you know, in many ways, the BEACON, AURORA dataset was a very successful phase II program. We established unambiguously in open label and placebo-controlled data that the drug achieves its target reduction of protoporphyrin IX, so we're reducing the toxic metabolite by the requisite amount, you know, call it 40-ish%. That looks great, and the safety profile in these patients has been excellent so far, and obviously, we're sitting on top of a 4,000-patient safety database from Roche. So we don't expect any surprises, and we haven't seen any so far. So that all looks great.
The drug's doing what it's supposed to do at the metabolic level. The safety profile is consistent with everything that's been seen before. And on the clinical endpoints, we obviously actually did hit stat sig with several clinically meaningful endpoints, most notably the rate of phototoxic reactions. That endpoint has served us well, both in the placebo-controlled setting and in the open-label setting, where we had about 90% reduction versus baseline in open label and about 75% reduction versus placebo in the placebo-controlled trial. So that's performed well. Measures of quality of life have performed very well, and unfortunately, the endpoint that has the precedented, where the FDA has approved one, the one prior therapy in this indication, that's the place where we were tripped up by a significant performance from the placebo group.
So the KOL feedback on this whole package has been uniformly positive. I think there were a number of calls organized by various analysts in the aftermath of that data release. And I think what you hear from the KOLs is largely, yeah, you know, these endpoints in this disease are kind of necessarily subjective, and so they weren't, you know, shocked to see a placebo effect, I guess. But by and large, to them, the PPIX is really what matters, right? That's what you heard them say over and over again is, "Well, look, we've seen you know, significant reduction in PPIX. We wish that was the, you know, the endpoint to get approval." But as we've always been guiding, we don't expect that to be the endpoint to get to approval.
We do need to find something that the regulators can agree with and align with us on as being clinically meaningful. And I think that segues into EHA, where we're going to take this data package that we received. Now that we're past the kind of rigid top-line set of analyses, we've been able to go through the data more extensively, and we have tremendous conviction in this, in this drug and its activity for these patients. And we're hoping to show a series of analyses that will really help kind of show different paths we may go down from a regulatory point of view, different endpoints we could probe.
I think, you know, you use the word subjective, but I think, you know, it, it's also important to recognize that it's not just the sort of subjectivity in terms of how a patient experiences, but also sort of their behavioral responses, right? I mean, the challenge in EPP is you're fighting patients, their entire lives have been trained, if you will, to behave a certain way, right, in terms of sunlight avoidance. And so all of a sudden, forcing them to potentially expose themselves creates some risk. I guess, how focused are you in terms of trying to mitigate that risk, and do you have some early ideas in terms of ways to minimize the behavioral elements of the disease when you design your study?
Yeah, I think there's many options there. If you go into other fields where placebo effects can be a significant confounding feature of clinical trial work, there are many tools that are available. You know, I think one thing that's conspicuously absent from the set of top-line analyses we presented is really a time course of a lot of these data points. And if you look at other in kind of the pain field, for example, often you'll see a placebo effect that's more prominent early in a trial, and then it tends to wane. It's interesting to look at our PPIX effect, and you see that it takes about eight weeks for that to reach its maximum. So you might expect that our drug effect would be kind of modest early and then reach its maximum later.
So that's the kind of thing where looking at a time course for some of these endpoints may be revealing, right? If it shows a pattern that is consistent with the biology and the biomarkers that we have, that would be very encouraging. If it shows the reverse, obviously, that would be very discouraging. So that's the kind of analyses I think we can bring to EHA, should be very discriminatory between a true drug effect versus a kind of statistical noise.
I'm curious: will we get data? I believe you use light dosimetry devices in AURORA, which actually would sort of capture the amount of light exposure rather than it being sort of patient-reported element, which obviously can be subjective, and maybe patients might mischaracterize or misremember things when they're entering it into their diaries. Will that data be released at EHA, or will that be released subsequently?
That data will not be available by EHA. And actually, I don't have kind of access to that data now. I think the growing conviction we have around this program is based on just the data set that we have in hand. We are excited, and I'm gratified by—we see tremendous KOL interest in that light dosimetry data. It's a highly exploratory endpoint. We're the first people to, you know, implement a device like this in a clinical trial, and so I do wanna manage expectations around what that data will be because it's literally the first time that we're gonna see how this has performed in the field, if you will. It could be transformative in our view of this data and really provide tremendous insights. It could be, you know, incredibly noisy, and we just don't know yet.
Okay. And you mentioned, you know, that, that you don't have an expectation that PPIX levels would be your primary endpoint. I know some KOLs who think that that should be. Have you had interactions with the agency, and is it just simply you're trying to be level set expectations now, or has the agency given you feedback that they really still wanna focus on some of these sunlight tolerance issues, measures?
Yeah, I mean, I think anytime you're looking at what would be called a surrogate endpoint, right? That's what PPIX levels would count as. The go-to playbook for the agency is that it has to be shown with a relationship to a clinically meaningful endpoint in order to validate that as a surrogate, and then you can go use it as such. So I think the question for us has always been one of, okay, if we're gonna do all the work to show a relationship between this, you know, metabolite level and a clinically meaningful benefit, it means we're winning on the clinically meaningful benefit. So then maybe we just use that, right? It's just, it's not really clearly presenting us any efficiencies right now. And yes, the agency is following their typical playbook here. I mean, definitely, discussions around PPIX have oriented towards prove it out by correlating it with, with clinically meaningful endpoints.
When do you expect to have visibility on your phase III plan, and be able to share it with the investment community?
Yeah, so I think the plan basically is to present a series of analyses at EHA. That should give, I think, a very nice menu or a spectrum of potential endpoints that investors can look at and think about through the lens of, you know, the easiest regulatory path would be an endpoint that's as close as possible to the precedented endpoint. And then you have other endpoints that are gonna be more distant from that. They may have attractive attributes as well. That requires a bigger regulatory discussion. So that's the spectrum, a kind of menu of options we intend to show at EHA, and then, we will go and have end of phase II discussions with the regulators and come back to the investor community with our phase III plan.
Okay. So is that something that you expect to have completed by the end of the year?
Yeah, guidance is second half.
Okay. Now, EPP isn't the only potential indication for bitopertin. You already have started a study in Diamond-Blackfan anemia, although there are others that you have highlighted, I think, like, beta thalassemia is another. How are you prioritizing those, and their development in terms of relative to EPP?
Yeah, so in the background, across actually all three of our clinical stage molecules, all of which have multiple indications, we have a vigorous set of preclinical activities going on, you know, mouse models, that kind of stuff, cellular models, to assess, you know, scientific probability of its success. And then I think no different from any other company, we're gonna take the evidence from that preclinical work, mesh it with an assessment of the unmet need seen with the patients, the commercial opportunity, and then come forward with anything that we think is worthwhile.
Okay. And when do we expect to get the data from Diamond-Blackfan anemia?
We've guided to some initial data this year.
Okay.
As always, we kind of caution that it's not entirely in our control. You know, that study, we're thrilled to have the NIH and their enthusiasm behind it, but it's largely in their control.
Okay. And, you know, at ASH you released some initial data for DISC-0974, which showed it clearly impacted the hepcidin levels. When we think about sort of finishing out that data, and the data was in myelofibrosis patients with myelofibrosis, what should we be looking for, or how are you gonna sort of evaluate that program, as we look ahead?
Yeah. So our guidance for EHA is assume we'll bring data of roughly twice as many patients. So our patient count for ASH, we set at 11, so assume we'll roughly double that. In at EHA, we'll have the same types of data, you know, hepcidin, like you mentioned, serum iron levels, and then hemoglobin and potentially transfusion burden. We should also have, for some patients, a longer period of follow-up that gives us some visibility into the durability of the anemia effect. And all in, I mean, the data we saw at ASH, yeah, lowering hepcidin, that was great. We, we sort of assumed that, but it was good to see it. What really excited us and that we're excited about coming into EHA is the degree to which patients were responding and the magnitude of those responses.
So as a reminder, at ASH, we were seeing about 60% of the patients, or 50-60, depending on kind of subgroup, but essentially all subgroups of patients, with very nice responses, those in combination with Jakafi, those who are transfusion dependent, and then the bulk of them in the non-transfusion-dependent group. So if we can show that level of response rate in a more durable setting, in a larger N, that starts to be a pretty compelling package and a predictor of success that I'll be ready to lean into more. And our objective for the year is basically picking a dose, so we will be showing some higher doses at EHA. If you recall, we at ASH we showed 14, which was inactive, 28, which was high, was surprisingly active, 50, which we just barely had a few patients' data's worth. And we've got it to being able to show some higher doses now at EHA as well. So our goal is pick a dose, design our phase II expansion cohorts, and get that rolling by the end of the year.
I think you had 1/5, some limited data for one patient on a very short amount of time.
That's right. We had three patients enrolled.
Yep.
We had. I think one of them was only on study for a week or two, so we didn't show data from that patient.
Yep.
We had two patients who'd been on for, oh, long enough to have hemoglobin data, but not long enough to have the hepcidin data, which is a lab value that takes longer to get the data from the laboratory. So that's all we had at the 50, as of ASH. Sorry, I might have said EHA. As of ASH last year, that's all we had.
But one of those patients in the 50 had a very strong hemoglobin response.
Very strong response, yeah, remarkably.
Which I think was really encouraging. And then you also have that being developed, you have myelofibrosis as well as chronic kidney disease.
Yeah.
You know, how do you sort of measure up those two indications, and your ability, you know, one, and chronic kidney disease is a much larger indication from a, from a number of patients' standpoint, pursuing that, with DISC-0974, and would you want to do it on your own, or is that one where you would think you might need an external partner?
Yeah, I think partnering is always an option. We are always talking to potential strategic partners. As an overall philosophy, I'm a big believer in getting to phase II proof of concept, and because I think that establishes a value point, it establishes a clear trajectory for the drug. That's the point at which you usually get urgency from a larger pharma partner. So to me, that represents the optimum time to drive a partnership. But yeah, I mean, CKD stands there as an obvious, very large indication where strategic interest should be high, and potential benefits, kind of synergies with a partner are obvious.
Okay. And then I also wanted to touch on DISC-3405, which is your monoclonal antibody targeting the TMPRSS6 target. And you're initially targeting polycythemia vera, which has-
Correct
Become an area of intense interest across the industry. What's the advantage from your perspective, versus the approach taken by one of your competitors, who's using a hepcidin mimetic, to great effect? And how would you compare your approach versus something like an RNAi, which is another approach that somebody is using, in PV?
Yeah, I mean, I think our profile that we're looking to establish and that may be apparent even in healthy volunteer data, would be meaningful iron restriction, which is the pharmacodynamic objective of the drug. And by meaningful, I mean, you know, achieving, say, 50% reduction in serum iron, with a dose that's consistent with subcutaneous administration, right? So kind of an ease of administration, I think, is very important in this field, with a frequency of, you know, call it, two weeks to a month, one, you know, once every other week or once monthly type of profile.
That, I think, would compare favorably to the rusfertide program, which is in phase III, and hats off to Protagonist for all the work they've done establishing the space, and their agent, I think, is teed up to be basically once weekly. Right, so I think we can establish a profile that has a rationale for patient convenience. And then as you mentioned, there's, you know, a couple of companies working on antibody approaches, including us, and a couple of companies working on nucleic acid-type approaches. And I think, you know, what we like about the antibody space is that it's a very well-understood way of making a drug, right? Everybody understands now how to administer, how to titrate doses with an antibody, and we think that's something that will be attractive to physicians and patients. I think it's also well understood now that the antibody framework in itself presents no meaningful clinical, safety profile, right? So it's all about target risk, and the nice thing about this target is it does have knockouts in humans, meaning we have a strong rationale for why a selective inhibitor of this target shouldn't have, meaningful side effects.
How are you thinking about development for this asset beyond PV?
Yeah, thanks for asking that. You know, one thing that really jumped out at me looking at the book of abstracts from EHA is that, yes, this is a competitive space. As you mentioned, there's many molecules coming here, and I think it's partly competitive because everybody sees that it could be pretty large. In the benign hematology space, you see some groups headed off towards sickle cell disease. You see some groups headed off to beta thal, but this time not to chase hemoglobin, but to chase iron overload, which is a very good idea, right? That is a severe issue for those patients. Some groups are pursuing a similar iron overload thesis in MDS patients. Obviously, PV is the place that we and Protagonist are going first. So you see also this wide range of indications covering a pretty significant swath of benign hematology with this mechanism, and I think that's why this mechanism has always been of high interest to Disc, right? This was one of the founding targets for the company.
And so I guess, though, how are you thinking, how quickly would you go into something?
Oh, that was your actual question, yes.
That's what I really wanted to sort of understand and just sort of think about.
Yeah, yeah.
Because, you know, and obviously, you know, I'm not trying to— you know, PV is a really attractive indication. But you do have, in this mechanism, potentially sort of what, you know, the pipeline and a product kind of approach.
Right, right
Or opportunity.
Yeah. So I think, you know, this becomes a question of portfolio management because, I think additional indications are sitting right there for DISC-0974, and they are now sitting right there for DISC-3405 as well for the anti-TMPRSS6 antibody. And so we just have to be smart about the level of capital we're deploying across the portfolio, as we think about, you know, adding some number of signal-seeking studies, across those second two molecules as well. So we haven't specifically guided to that, but I think the way we would look to bring that forward would be to provide our own preclinical data, you know, linking up, hopefully consistent with preclinical data from others, and then, you know, kind of showing how we plan to get to some kind of meaningful readout. But the great thing is that, by the end of this year, the anti-TMPRSS6 antibody will have its foundation of healthy volunteer data, essentially allowing us to spring into whatever indication we want to, and we're already at that point with the anti-hemojuvelin antibody. We can now, whenever we want from a, from a clinical trial point of view, you know, go establish new studies in, in other indications to start to demonstrate the breadth of the, opportunity.
Okay. Well, I think, John, we're unfortunately, we're out of time, so thank you so much. And we look to hear what you have to tell us at EHA next month.
Great. Thank you for your time.