Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Disc Medicine with CEO, John Quisel. Welcome.
Thank you. Good to be here.
For those who may not be familiar with Disc, can you provide a brief introduction?
Sure. Disc is, we're obviously publicly traded under the same symbol, IRON, and, we're about four and a half years out from our Series A, focused on the area of hematology, benign hematology, a little bit of hemonc.
Great. Well, maybe let's start with Bitopertin. Can you just give an overview of what you saw pre-clinically that gave you confidence to go after erythropoietic porphyrias?
Yeah, sure. So we've built a portfolio around the control of iron and heme metabolism as a way of controlling red blood cell biology. And so we've taken focus on, you know, broadly, diseases that arise in red blood cells. And Bitopertin is a molecule that actually inhibits heme biosynthesis in newly forming red blood cells. And these porphyria diseases, like erythropoietic protoporphyria, or EPP, as we like to shorten it to, arise from genetic defects in the heme biosynthetic pathway that give rise to the production of toxic byproducts. So these patients basically produce a toxic product called protoporphyrin nine, or PP9, and that chemical causes a lot of pathology in these patients. It absorbs sunlight energy and causes extreme pain on exposure to sunlight, and it can also accumulate in the liver and cause liver damage.
So we have this syndrome of sunlight sensitivity and liver damage, all caused by a toxic metabolite, protoporphyrin IX, being produced by a broken heme synthesis pathway. And what Bitopertin was designed to do is down-regulate the flow of metabolite through that heme biosynthetic pathway, and our hypothesis was that it would reduce the level of this toxic molecule, and that would provide clinical relief for these patients. So we did cellular models. We ran mouse models. All of those showed very nice reduction in PP9. In fact, the literature would suggest if you can decrease PP9 by about 30%-40%, you should get a major clinical improvement.
And so armed with that information, and quite a large safety database that came with the molecule when we in-licensed it from Roche, we were able to start two phase 2 trials: the BEACON trial in Australia, open label, and the AURORA trial, in the U.S., placebo-controlled, with the goal of showing a primary endpoint of reducing PP9 levels and then, hoping to see that translate into any of a number of different metrics of light tolerance for these patients.
Now, you presented phase 2 open label data from BEACON at ASH. Can you just remind us what you saw?
Yeah. So in the open label trial, we saw really great results of reduction of protoporphyrin IX, you know, in the ballpark of 30%-40% at the low dose level, and the ballpark of, you know, 40%-60% at the higher dose level. So definitely hitting the primary endpoint very well. And then if you look at the battery of different ways of measuring patients' tolerance to light, we saw marked improvements from baseline across all of those to a point where, you know, for example, the rate at which these patients experienced phototoxic reactions was reduced by about 90%, and we saw, you know, somewhere between 3-7x improvements in other measures of light tolerance.
And then you reported data from AURORA earlier this year. What did you see? And then can you just talk about, you know, your thoughts on what drove the outsized placebo response and cumulative time in light without pain?
Right. Correct. Yeah, so we had the open label study. The data looked really excellent from drug therapy. We unblinded in early April the placebo-controlled trial which was run in the U.S., AURORA. What we saw was that the treatment arm, you know, particularly at the high dose, continued to deliver an excellent profile. Great stat sig reduction of PPIX hit the primary endpoint. Patients were spending more time in light. The rate of phototoxic reactions, once again, stat sig improvement, this time over placebo. Quality of life, patients felt much better. Almost 90% of patients felt much better. That also stat sig over placebo. Safety was good.
The rude surprise, as you noted, was the placebo group also performed quite well, much better than we had anticipated, much better than some of the literature experience with prior agents and studies would have suggested, and the places where we really saw the most placebo influence were in this metric where patients are keeping a diary of the amount of time they spend in light and another endpoint where they're measuring kind of what's called a prodrome or an early warning sign. That was clearly placebo affected, that actually disrupted the... You know, while we hit our primary endpoint, it disrupted the stat sig on the, what was viewed as the key secondary endpoint, because there's a precedented endpoint that's been used to approve the one agent for these patients.
And so we obviously wanted to understand this effect because we're faced with kind of two questions. One is, gosh, the treatment arm looks like it's working really, really well, and you know, in a prospective way, stat sig on some things that are very meaningful to these patients, like the rate of phototoxic reactions. But on other endpoints, we were seeing you know some disruption of the magnitude of effect because of the placebo group performance. And so the question was, you know, what's going on here? We need to get bring in. That was top-line data, so we spent the month of April bringing in kind of the full stated dataset, so we could run some additional analyses.
You know, what emerged pretty quickly and what anyone who works in a disease area that tends to have a placebo influence and, you know, a lot of pain, psychiatric type disorders, there's significant placebo effects. We saw what you call a paradigmatic placebo effect, which is that you saw an improvement in the time these patients were spending in light during the first month or so, and then it slowly declined back to essentially their original level by month four, at the end of the study. Meanwhile, the treatment arms, you know, went up also during that first month, which is probably time in light we shouldn't get credit for, because protoporphyrin isn't even controlled at that point. But then they stayed up, right?
And continued to rack up larger amounts of time they were able to tolerate in sunlight, and of course, all the time having this, you know, central absence of phototoxic reactions. So that led us to understand, okay, we have a placebo effect. It's kind of the classic type of effect. As you run a longer and longer trial, the magnitude of placebo reaction should decline. And moreover, if you focus your statistical analysis on the later time points, which is common practice in many clinical trial areas, that actually post-hoc would lead to a stat sig result. Which gave us a lot of confidence that if we wanted to use that kind of endpoint, which is really only just a minor step removed from the precedented endpoint, we should be able to power a robust phase III program around that.
Just to clarify what you just said, so then is the thinking that that change would be on the timing, or are you considering perhaps some of the other endpoints as well, or a combination? Like, how are you thinking about that?
Right. Right. So I think what we saw when we looked at the various ways of evaluating the clinical benefit of the drug really three endpoints that performed very well across both studies. One is looking at this so-called time in light endpoint, using those patient diaries, but rather than taking the sum of all that time, including the placebo-affected first four to eight weeks, we would just look at, call it the last interval or last two or three intervals of the study, that would give us a very robust endpoint. Although, to be fair, that was all analyzed post-hoc, and I think you combine that with running a six-month study rather than four months, which is what the AURORA was. You should get a very robust signal from that, so that's one endpoint that we could use.
The other, I've mentioned already, the reduction in rate of phototoxic reactions performed, you know, 90% reduction versus baseline in the open label study, 75% reduction versus placebo in the placebo-controlled study. Both of those pre-specified, you know, traditional stat sig kind of results. So that's endpoint number 2 we could use. And the third is actually quality of life. I mean, it's actually pretty astonishing to get major improvement in quality of life recorded in a PRO in a study of 25 patients per arm. We were really excited about that. That's, you know, less likely to be the kind of thing you want to use as a primary endpoint. It's more of a kind of supporting evidence type of endpoint.
It's those first two phototoxic reactions and what we call, for shorthand, a longitudinal assessment of time and light. Those look like very good endpoints we could use in a pivotal trial, and that forms, you know, the basis for discussion with the FDA in an upcoming end-of-phase II meeting.
I was just about to ask you if you've-
Yeah
...already had your end-of-phase II meeting yet, and I guess, do you have a sense... So it sounds like not yet, but do you have a sense for how amenable FDA will be to evaluating different registrational endpoints given that precedented endpoint?
Yeah, we think they'll be amenable. And to speak briefly to the timing of the meeting, you know, we've been guiding to providing feedback to the public in the second half of the year. Obviously, we're well into the second half now, and what we're saying is it'll, the guidance will come in the fourth quarter. You know, the plan is to have the meeting, give it time, usually thirty days, to get the minutes, and then come out with some feedback to the public. So expect that in the fourth quarter. And then, I'm sorry, the other part of your question was? Oh, the adaptability of the FDA-
Yeah
Around this. Right. So we only have one approval, where they use this total time in light endpoint. There is a competitive product called Dersimelagon, essentially an oral version of that same drug, is running their second phase 3 trial now, and they are using a different endpoint, right? So it is a different way of looking at time in light. They call it something like daily time to prodrome. But it tells us that within this kind of small neighborhood of time in light metrics, that all essentially rely on patients keeping a diary, that the FDA has been apparently permissive to two different variants of that. So it feels like a permissive setting to bring forward a third variant. So I think we're optimistic that-
Mm-hmm.
If that's the endpoint that we want to propose, then, you know, the FDA should be open to that.
Now, Scenesse's label was updated, I believe, last month, to include warnings of serious hypersensitivity reactions, including anaphylaxis, that were reported, you know, post-market. Does this change the way that you're thinking about Bitopertin's positioning or market opportunity?
Not dramatically, I have to say. Scenesse, you know, it's surgically implanted, right? And I think, you know, public knowledge that there's not a huge usage of the drug. The sales are not, you know, under $100 million or so. And I think, you know, the surgical mode of implantation is a significant barrier to patients and probably represents the main reason why the drug is not used more widely. And I think what we plan to offer in terms of profile that we think would be more well-received is having a simple oral pill, right? You just take a pill a day, that's our modality. And then we also think there's a lot of support for the concept behind our drug, which is reducing protoporphyrin nine, right?
Everybody knows that's the driver of this disease. Reducing that should be beneficial. We're proving it out on light tolerance, but it also should be beneficial for things like liver health, which these other agents that focus on tanning really can't necessarily expect to address. So I think those are the major reasons why we think our drug will be, you know, warmly welcomed by patients if we're able to get it approved for them, and should present a benefit relative to the Scenesse profile.
Mm-hmm. Now, Bitopertin is also being evaluated for Diamond-Blackfan anemia. You know, can you just talk about this program and remind us of when we might see data from the study?
Yeah, so our guidance is by the end of the year to have some data. It is a rare - a very rare condition. There is a pool of prevalent patients at the NIH that they kind of keep track of and are able to enroll in successive studies. And so we were delighted when the NIH reached out to us and, you know, wanted to test out our drug and the hypothesis that it might work in these patients. But on the other hand, you know, we don't really control what the NIH is doing, right? So we're delighted to have them as partners, and we think there's really no one better to be running a study like this. But because there's one layer removed, we don't really have control over it.
Our guidance here, I would call with an asterisk. We're sort of estimating that we should have something to say by the end of the year, but that timeline may deviate, and it's really, you know, in the hands of the NIH.
Great. Let's shift to DISC-0974 for non-dialysis dependent chronic kidney disease and anemia of myelofibrosis. Can you just talk about hepcidin suppression and how DISC-0974 enhances iron availability?
Yeah, sure. Right. So as you mentioned, hepcidin is the central regulator of iron in the body. When hepcidin becomes elevated, typically because of inflammatory disease, it traps the body's iron reserves into primarily macrophages, but into a variety of tissues, and makes that iron unavailable for formation of red blood cells, leading to what's called anemia of inflammation. And so the premise here is to suppress hepcidin, and we know genetically that our target, hemojuvelin, is you know really good at accomplishing that. People and mice who have loss of function in that hemojuvelin target tend to have exceptionally low levels of hepcidin, and as a result, they have highly mobilized iron reserves, and over a lifetime, actually leads to significant iron overload.
So the premise of our drug is use an antibody, inhibit that target, Hemojuvelin, mobilize the iron, to provide additional iron availability to patients who have anemia as a consequence of inflammatory disease, and myelofibrosis represents, you know, kind of a very severe poster child of that kind of anemia.
Now, for anemia of MF, can you just remind us of the data that you've generated?
Yeah, sure. So, we've done a dose-escalating phase Ib trial in myelofibrosis patients. It's designed, by and large, as an all-comers type of study. We've progressed from a dose of 14 milligrams, this is fixed dose, not mg per kg, all the way up to 100 milligrams fixed dose. And the total, the data we presented at EHA, European Hematology Association meeting in June, was from, I think it was 34 patients. And, you know, the response in these patients is measured by a hemoglobin increase. For patients who are not regularly transfused, the bar for a responder is a 1.5-gram hemoglobin increase, sustained over a 12-week period. And for patients who are regularly transfused, it's creating a 12-week window of time in which there are no transfusions.
So those two responder analyses, you apply that to our thirty-four patients, and what we saw was, in aggregate, about a 60% response rate, which, it's, you know, always hard to do apples to apples comparisons across different agents. So I have to say with some caution, but honestly, really a very good response rate. I mean, I think, a program I used to work on called Luspatercept, that's now with, BMS, you know, the response rate in that phase II trial were around 30% or 40%.
Great. And for CKD anemia, can you just talk about the data that you've generated, and what should we expect to see with the updated phase Ib data?
Yeah. So we're projecting phase 1b data from our single ascending dose study in non-dialysis dependent CKD patients. We're expecting to present that at ASN Kidney Week conference at the end of October. The abstract's actually published on October eleventh, and that's the moment at which it becomes clear whether we are or not presenting there. But you know so our data will come sometime in that time frame. And what we showed at ASH in December last year was just the first cohort. So it's designed kind of like a healthy volunteer study, but just with these patients. Six active at each dose level, starting at a 28 milligram fixed dose and two placebo, and then you progress to 40, 60, and 90 as the dose groups. At ASH, we showed the 28 milligram dose group.
Just beginning to see some suppression of hepcidin, just beginning to see some mobilization of iron. These being the precedents to getting a benefit on hemoglobin. So it looks like, you know, the drug is starting to work in those patients. It's similar to what we saw with healthy volunteers, where the dose that really seemed to work was about 56 milligrams. So I think our expectation is that as we ramp up, you'd hope to see in, you know, dose-dependent decreases in hepcidin, elevation of iron, and then once that iron elevation is stable for two to three weeks, that's when you might be able to see it convert to some degree of improvement in erythropoiesis. But I think, you know, we all just need to remember it is a single dose, right?
So we're just looking for some sign that there's some improvement in these patients, and then we can go on and do multiple dose work.
Now, given how challenging it is to develop drugs for CKD, you know, how is DISC-0974 differentiated, and what gives you confidence it can succeed in this indication?
Yeah, so there's been, I think, two major drug development pushes in the non-dialysis CKD population for management of anemia. One area that received a lot of attention are the so-called HIF-PHI agents, which are, you know, essentially an oral way of activating an EPO or ESA-based mechanism. Those drugs, you know, they ran very, very large trials. The efficacy side of the equation feels pretty straightforward. It tends to be satisfied by showing essentially any stat sig improvement of hemoglobin over a comparator arm. Those HIF-PHIs, it ranged from 0.7 grams per deciliter to about 1.5 grams, and that seemed to be sufficient for efficacy. That feels like a pretty achievable bar.
You know, you've heard me just say in myelofibrosis, we're showing about 60% of patients getting a 1.5 gram per deciliter better increase, so the efficacy side of the CKD trial program seems fairly straightforward to prove out. We would expect our drug to be able to deliver that because we know these patients do have very high hepcidin and restricted iron availability, so it's chosen to be an on-mechanism disease. The challenges you speak about come from the safety side of the equation, so those HIF-PHIs I was mentioning tended to run studies in the 3,000-5,000 patient range, and that's largely because of the FDA's request to really have a comprehensive view of cardiovascular safety.
And that's because the EPO-based agents, the ESA class of drugs, did over time turn up a cardiovascular risk profile. So those trial designs were quite involved, and none of those drugs were approved in this indication in the U.S. as a consequence, because they were unable to show, you know, a better safety profile than the ESA-based agents. I think there is some contrast there with the iron approach, right? So we're coming at this through an iron angle. We're trying to mobilize patients' iron reserves, and the best comparator for that would be IV irons, which are used for those CKD patients who actually become iron deficient, right? Which, you know, is a problem for some of these patients. And those trials have usually, the approval packages, have used about 1,000-1,500 patients.
There's still a big program, and you do still have to do an assessment of cardiovascular safety. But unlike the ESA side of the equation, iron-based agents tend to show a trend towards improvement in cardiovascular health. We're optimistic that, you know, in relatively small studies, we can show the efficacy side of the equation, you know, a gram of hemoglobin or thereabouts. And then even in the larger studies, because we're following an iron modality, hopefully we're able to show that in somewhat smaller studies than the HIF-PHIs, and with greater optimism that we'll get some kind of positive effect.
Now, I know it's still relatively early, but, you know, what kind of feedback have you heard on DISC-0974 from physicians or patients?
Yeah, I mean, I think the feedback has been very positive. I think, you know, we don't often comment on study enrollment, but there's something, you know, somewhat instructive there, which is that enrollment was a bit slow early on in the first six to nine months of the study. And then as we were able to start showing some data with the kind of efficacy that we're seeing, enrollment just took off. You know, we ended up with a waiting list of patients, because... and I think that's pretty typical, right? That when you start out with a new agent, a new disease area, it's tough to get people to sign up for that experiment.
But once you start to get some signs of efficacy, you start to see enthusiasm build in the community, and I think it's fair to say that's, you know, the general feedback we're getting.
Great. Let's shift to DISC-3405. Can you just talk about hepcidin induction and the data you've generated on the impact to serum iron levels?
Sure, yeah. So DISC-3405, an antibody against a target called TMPRSS6. Here, the objective is essentially the opposite of DISC-0974. We're trying to elevate hepcidin, restrict iron, and thereby restrict red blood cell formation. And the first indication we're going after is polycythemia vera, a disease of excess red blood cell production, where the objective is to get the hematocrit down to about 45%. So we're doing the typical SAD, MAD, healthy volunteer work. We just presented data at EHA from the single ascending dose part of that study. And the data looked good, where, you know, what we modeled out is a target of achieving 50% reduction in serum iron as an indicator that the drug ought to translate into a clinical benefit in PV.
And we were hoping to achieve that effect at a dose that was consistent with, call it, once-monthly dosing. We felt like that would be a really good profile for patients. And you know, hopefully without any safety side effect kinds of things. And we achieved that. We really did see that kind of iron reduction at doses as low as a 75 milligram fixed dose. We went to 150, 300, all of those could be achieved sub-Q, no problem, and the effects on serum iron were quite durable for, you know, sometime in some cases, like 60 days, not just 30 days. So we felt very good about the profile.
We're seeing there a lot of ability to choose the right dose and right dosing interval, that we hope will maximize benefit for the patient population.
What should we expect to see from the multiple ascending dose data later this year? You know, like, I don't know, to the extent you can talk about it, like, how many patients might we expect the data, that kind of thing?
Yeah. I think there's nothing that remarkable to expect. It's a pretty standard. You know, we picked a dose or two, did some additional dose work there, and really just looking to show continued iron restriction as we go out through multiple doses.
Okay. And then are there any gating factors or decision points, you know, in pursuing some of the other indications that you've suggested as potential proof of concept candidates?
Yeah, we do think there's a lot of other indications. It is also, to be fair, a competitive field. There are others targeting TMPRSS6 with either an antibody or an siRNA modality. And, you know, one of those competitors has declared their intent and is actually reporting some initial data in polycythemia vera. Another one of those competitors has declared intent in iron-loaded beta thalassemia patients. Others have presented preclinical data suggesting that the drug may have applicability in sickle cell disease by reducing the concentration of the hemoglobin that's responsible for sickling. And then there's a disease called hereditary hemochromatosis, which is a genetic iron overload syndrome, where this drug should essentially perfectly correct, through biochemical means, the genetic basis of the disease.
So all those are in scope for what we're doing, and I think we haven't committed to a specific timeline in which to announce other indications, but but it's, you know, within the foreseeable future. It's not that far away that will be able to come out. Our methodology is to try to build a robust preclinical package, and then once we feel good about that, feel good about the phase 1 healthy volunteer foundation, get that first indication, you know, on its way into the clinic, then that would be the time to start thinking about the second indication.
Great. Well, we'll leave it there. Thanks so much for your time.
All right, great. Thank you.