All right. Good morning, everyone. Thanks for joining us here at the SVB Securities Global Biopharma Conference. My name is Tom Smith, one of the senior biotech analysts here at SVB, really excited to be hosting this next fireside chat with Disc Medicines. From the company happy to welcome CEO and President John Quisel. John, thanks for joining us.
Thanks, Tom. Good to see you.
Likewise. Just one key quick housekeeping note here, for investors joining us on the webcast, feel free to submit any questions for John into the webcast portal or you can email them to me directly at thomas.smith@svbsecurities.com. With that, John, maybe you could just kick us off here by giving a brief overview of Disc and for those in the audience who may be a little less familiar with the story.
Sure thing, Tom. That, yeah, sounds good. Yeah, Disc Medicine, we're building a great hematology company here. We just split public at the end of last year, trading under the ticker symbol IRON. The reason for that is everything we do is focused on controlling heme and iron metabolism, particularly in red blood cells. With this mechanism, we're able to address a wide range of disorders that arise in the red blood cell compartment. We have now three novel clinical programs. We're in phase two with the lead program. We're in phase 1B/2 with the second program and cleared the IND with a third program that we just didn't license. We're very active.
This biology we're going after, all of it has been validated in human genetics and in one case, even in as much as 3,000-plus patients in the clinic. All the mechanisms are well understood, how they'll perform in the clinical setting. We have three readouts across three disease states this year. Our lead program will be reading out in a porphyria indication called erythropoietic protoporphyria, which is a mouthful, so we call it EPP. We'll be having readouts in the middle of the year and at the end of the year in a definitive way from that program. Our second program is designed broadly to treat anemias of inflammation.
We're already open and enrolling in a myelofibrosis trial and actually just announced today we're open and enrolling on a anemia of chronic kidney disease trial in a non-dialysis setting, where there's very little therapeutic option available for patients and a very thin pipeline. So both of those trials are going to read out with preliminary phase 1B type information by the end of the year. And then the third program we in-licensed an anti-TMPRSS6 antibody designed to restrict the iron, which has been proven out to be useful in the setting of polycythemia vera. That molecule will be able to start in the clinic, second half of this year, a healthy volunteer study with a proof of mechanism data coming then in 2024.
That's the brief story of where we are. Again, a hematology company focused on genetically or clinically defined mechanisms for controlling iron and heme biosynthesis. With these fundamental mechanisms, we're able to affect red blood cell biology and disorders across a wide therapeutic space, ranging from, you know, rare disorders like porphyria all the way up to, you know, major market indications like anemia chronic kidney disease.
Perfect. Thanks, John. Yeah, that's a great, that's a great overview of where you guys are, and it sounds like, you know, certainly busy times at the company, and you'll have three clinical stage assets here by the end of the year, which is incredible progress, I think over, you know, over the over the last, phew, six or 12 months or so. I guess, maybe if we could start at just kind of the expertise of the company and you mentioned, you know, hematology focus, but quite a bit of expertise in understanding heme synthesis and iron and red blood cell biology. Just, strategically, you've been licensed, you've been quite active on the business development front.
Maybe if you could just talk about how all of these assets kind of fit together and kind of the genesis of the expertise in some of these areas.
Yeah, absolutely. We were founded in Atlas with a focus around this area of iron metabolism where, you know, there's been a few decades of academic research that have really defined the genetic targets that control iron metabolism in the body and been relatively little pipeline development against that space. I think it's heating up now with us and others. Putting the company together, you know, we really gathered some of the top KOLs in the area to help us think through this. Myself, I actually spent the prior 13+ years at Acceleron Pharma with significant work on a program called luspatercept or now approved as REBLAZYL, which was one of the first non-EPO mechanisms for treating anemia to come along. I have some experience in this area.
Also, these pathways are what are called BMP, controlled by BMP signaling, which is near and dear to what everything was, you know, being done at Acceleron at the time. And, you know, one of our founders, Brian MacDonald, had worked previously in the hep side and area, and our chief medical officer, Will Savage, came out of the Harvard and Johns Hopkins system as a pediatric hematologist. You know, between our advisors and our internal expertise, we think we have a great view into this field, and we're able to pick assets that have really compelling potential. You know, what we call DISC-0974 is a directed against a target called hemojuvelin, which is known as a knockout in humans.
This is a very, clearly a very powerful target for controlling iron metabolism. In the case of Bitopertin, our lead program, that would be in license from Roche, and it was not being developed in the hematology space, but clearly controlled heme biosynthesis. It was this network of people, KOLs, who were focused on iron metabolism and some of the overlapping disease areas that really clued us in that this might be interesting given that there are actually no approved agents that control heme biosynthesis in red blood cells. Kind of a huge potential, mechanism that's essentially unaddressed at this point.
Great. Yep, that makes sense. I think, let's dive into Bitopertin, the lead program, and, as you mentioned, in license from Roche, has had pretty extensive development program conducted around the asset. More broadly, I think they were running a pretty sizable CNS development program in schizophrenia. Maybe if you could just tie those things together in terms of well-established mechanism, you know, how this is, you know, specifically addressing the porphyria lead indications here, and then just kind of tie that in with the some of the previous data that Roche generated around the compound?
Yeah, absolutely. Roche was working on controlling glycine uptake in synapses in the brain through a target called GlyT1, glycine transporter 1. There was a theory that inhibiting the reuptake of glycine in the synaptic space would be beneficial for cognition or other negative symptoms in the schizophrenia area. Roche ran extensive clinical studies, thousands of patients dosed. There were positive signals in phase two, but ultimately, lack of efficacy led to failure in phase three. In that process, they established, you know, really comprehensive safety profile that looks quite benign. Then very intriguingly, they found actually a new component of the heme biosynthetic pathway in red blood cells. You know, heme synthesis has been known for decades, of course, and red blood cells are professional heme synthesis cells.
This is what they do, make tons of heme. They do this by turning on this whole pathway, all these enzymes. What was unappreciated is that these cells also have to turn on GlyT1, which to provide access to extracellular glycine sources. The reason for this is that glycine is the first metabolite consumed in heme biosynthesis. What Roche saw during their development program is a persistent side effect that Bitopertin would suppress heme biosynthesis in patients dosed. They engaged with the KOL community, happened to be the same community we were working with, to help them understand this, figure this out. It tipped us off as to, you know, to look into the potential for what disorders could be treated by controlling heme biosynthesis.
As we dug into it, we saw some really compelling links between that and these indications called porphyrias. Porphyrias are genetic disorders of the heme biosynthetic pathway. These patients, their heme, there's usually a loss of function mutation somewhere in that pathway. It leads to the production of toxic metabolites that shouldn't be in the body. The theory was really quite simple. Suppress the flow of glycine through heme biosynthesis, you can suppress the production of toxic metabolites in patients with porphyrias. We were able to do some of the first cellular models to test this hypothesis, build an IP position around that, and then that enabled us to go to Roche and negotiate the in-license, which they were, you know, great collaborators and we're happy they were willing to let us take a shot at this.
Got it. Yeah, that's excellent. On, I do get the sense, you know, it is a relatively rare disease and it's probably an area that many investors are kind of less familiar with. Maybe if you could just talk through high level, I guess, how you think about the opportunity, like help characterize sort of the pathophysiology of the disease and kind of the disease course for these patients? If you could speak to there's very limited treatment options for this, but what is out there and what do you guys kind of potentially benchmark against?
Right. Yeah, it's a very severe disease. These patients, so with erythropoietic protoporphyria or EPP, these patients, usually as young kids, have extreme photosensitivity. If they spend, you know, on average, it's no more than about 30 minutes of sunlight, and that can include light coming through windows, they get an extreme pain that is described as being a burning under the skin. The pain attack will last for, you know, a week plus. It's debilitating. The patients have to kind of move their entire life indoors. If they venture outdoors, you know, typically, considerable measures to try to protect themselves from the sunlight. It's really a life-altering disease.
It also, the metabolite in this case called protoporphyrin IX, PP9, builds up in the liver and bile systems, and can lead to, you know, 5% of patients' liver failure, which needs a transplant, can be fatal. About 20% have kind of a slow smoldering liver disease that can lead to gallbladder removal. Really, you know, kind of a terrible disease. It affects. Well, genetically, in the U.S., you would predict based on a recent Massachusetts General Hospital paper, about 20,000 people carry the genotype for this disease. Again, in the U.S., about 3,000 of those have presented themselves to the healthcare system. Their disease is severe enough, been properly diagnosed, that they're, you know, seeking treatments and therapies and management for that disease.
When you see numbers for this disorder, you typically see, you know, about an estimate of about 3,000 patients in the US with this, you know, estimate of a larger population carrying the genotype. Then if you go to Europe and include those patients, you know, it's about 7,000-8,000 of these identifiable patients in the healthcare system. Really, you know, this size of indication is similar to some other indications where, you know, orphan companies have built successful orphan drug franchises, you know, notably Alexion, the HAE space. These are similar size. Remarkably, you know, there's really only one therapy that's been approved. It's a therapy called Scenesse, which is delivered as a small molecule delivered by a surgical implant at specialized centers.
It works by causing some tan, which provides protection against this photo attack. What our drug is doing is really getting at the root cause of the disease. I should mention it's a small molecule, you know, very high quality Roche kind of asset, given once daily, and as a tablet. The goal for us, we're trying to really modify the disease by eliminating the production of that toxic metabolite, which is at the root cause of the disease. By doing that, we hope to address both the photosensitivity as well as the underlying liver disease.
In fact, we just presented some data from mouse model at the American Society of Hematology meeting in December, where we showed that the drug at pharmacologically relevant doses is resolving the liver disease as it builds up in the mouse model. We think this has great potential for these patients. Like I mentioned before, we're in two phase two trials now.
Right. Right. Okay. Yeah, the first potentially disease modifying therapy for a patient population that has a pretty unfortunately dismal prognosis and extremely limited treatment options. Okay. Yeah. I want to talk about, John, the two studies that you have ongoing, the BEACON study and the AURORA study. Maybe if you could just speak to kind of the design of those studies, what you're looking for there. You've pointed to I guess the first interim data here from BEACON, which is the open label study being available in kind of the first half of 2023. If you could just kind of help set expectations ahead of that data set, that would be great.
Yeah. The BEACON trial, it's in Australia at two sites, designed as a small open label study, about 20 patients. We're looking first to see if we're able to prove out the mechanism of the drug, reducing the level of this metabolite PP9, we can measure it in the blood. We'll also be measuring a whole battery of tests for patients' photosensitivity, which is the clinical, I should say the regulatory endpoint for the disease. Middle of the year, you know, we'll have data available from a fraction of the patients that will be enrolled in the study. We expect to be able to present data around the PP9 target, also safety in the patient population. Right.
This Bitopertin, as I mentioned before, has been tested in over 3,000 people, but these weren't porphyria patients. While the profile of the drug is understood in the general population, we'll also, you know, try to be showing that it's safe in the EPP population. Lastly, you know, because we are measuring a host of different light sensitivity endpoints, you know, the ideal data set would be one where we're able to show a reduction in the PP nine levels and, you know, 30% or greater reduction has been associated with disease modification in a variety of pieces of literature that are out there. We look for that target of a greater than 30% reduction in PP nine, and then some evidence that we're having an effect on photosensitivity.
I think that would be a great initial package to show that we're on a path here with this drug. By the end of the year, we'd expect to have top line data from our 75 patient placebo-controlled trial called AURORA that we're running here in the U.S. That should provide, you know, the definitive data and really define the path to approval here.
Right. Okay. Yeah, that's helpful. I want to come back. You, you did mention, you know, characterizing the safety here in this specific patient population, but can you just remind us, I guess, of kind of the safety profile as Roche was studying this in, you know, thousands of patients. Are there any kind of notable signals or other things to watch with that are either, target specific or compound specific?
The kind of short statement of safety is dizziness, somnolence, headaches. All mild, all, you know, transient in nature. In the big phase three trials, you know, the rate was like 5% in the placebo group, 10% in the treatment group for these things. I think a question we get from a lot of folks who hear our story as well, if you're restricting heme biosynthesis in EPP patients, will you have an effect on their hemoglobin levels that's not helpful? Our belief is we will not. We haven't seen that in the mouse models. The effects in, you know, even the hematological normal patients that Roche shows were pretty mild.
That's actually I think something that we'll pay attention to and make sure that we give comfort to in the data we present midyear.
Right. Right. Okay. Well, we'll stay tuned for that. I mean, I think, yeah, that midyear readout where you have some pretty objective biomarkers that you're looking at and you're seeing how that translates into clinical efficacy, I think will end up being pretty meaningful. Maybe if you could just talk last question on the Tobrutin, and then I want to pivot to the rest of the pipeline, but I think you're also exploring this in some other indications. I think you've talked about an investigator-sponsored study in Diamond-Blackfan anemia. If you could just talk to, I guess the broader potential beyond the initial porphyria indications and how you're thinking about those opportunities.
Yeah, great question. That is one of our key objectives this year is part of why we went into heme biosynthesis is because it is a fundamental pathway in red blood cell biology. It turns out there are many diseases that could potentially be addressed by that mechanism. One of the most straightforward that presented itself early to us was a rare anemia called Diamond-Blackfan anemia. It's quite severe. There's really no therapy for these patients. Maybe they get some steroid treatment. Basically the bone marrow in these patients doesn't produce red blood cells. And one prominent hematologist had demonstrated that the issue in erythropoiesis here may be heme toxicity. There's essentially a mismatch between globin and heme biosynthesis in red blood cell development.
You get free heme building up in the cells, and that ends up killing the cells, at an early stage, leading to this kind of anemia. She had demonstrated that heme biosynthesis inhibitors, which are not, you know, clinically usable, could have great effects on survival of cells from patients than actually even in mouse models of disease. We struck up a collaboration, and we've got investigators there, really excited to get going with testing this in these patients to see whether, again, by reducing the flux through the heme biosynthetic pathway, we can decrease heme toxicity, in DBA patients. The same story comes up actually for a wide range of other indications that we'll be looking at. Myelodysplastic syndrome has a heme toxicity story.
sickle cell disease actually is fundamentally a story of hemoglobin toxicity, the sickling material, and we hope to build that story out. polycythemia vera, a disease of excess red blood cell production where we know iron restriction can be helpful. heme restriction may be able to do the same thing. A lot of potential here. Like you said, we expect this Diamond-Blackfan anemia or DBA, as we call it, study to kick off in the first half of this year. Look forward to having some kind of press release around that soon.
Okay, that's great. Yeah, it sounds like quite a bit of optionality there beyond the porphyria side of the story. Okay. Well, let's pivot here and talk about the hepcidin suppression.
Sure.
-piece of your portfolio. You did in-license an anti-hemojuvelin antibody from AbbVie. Was just wondering, you know, if you could kind of put the hemojuvelin inhibition into context and its role within treating anemia and then I guess where you see 0974. You mentioned the couple of studies that you have up and running, including the announcement this morning, across CKD.
Right.
Maybe if you could just kind of help put that into context and how you're thinking about that opportunity.
Yeah, yeah. I mean, you know, really big picture, right? There are two major drivers, or necessary parts for red blood cell production. One is you need the EPO or ESA signal to drive red blood cell production, but you also have to have iron in order for the red blood cells to form. It turns out that when iron supplies are low or restricted in the body, the red blood cell compartment will not respond to the ESA signal, and it won't make the red cells because your body's trying to spare that iron for other uses. That leads to a kind of anemia called anemia of inflammation. That's because often in the inflammatory setting you get high levels iron regulator called hepcidin. When hepcidin becomes high, it basically traps your iron stores away.
Newly forming red blood cells can't get access to it, and you get this kind of anemia that is referred to as anemia of inflammation. It's the second most common cause of anemia worldwide. It's a huge medical need. By and large, you know, the tools for addressing it are not great. You know, ESAs don't work for the reasons that I gave. Don't work well in the absence of iron. You have, you know, essentially oral and IV iron as the only approach to managing this. What hemojuvelin does is it regulates the production of hepcidin. You know, people have tried to directly target hepcidin with antibodies and the like. It doesn't work because the body just produces more hepcidin.
What people in this field are doing now is trying to control the production of hepcidin at its source, which is in hepatocytes in the liver. And hemojuvelin has been defined through human genetics as one of the, actually really the most powerful regulator of hepcidin. A hemojuvelin knockout in human causes really just one phenotype, which is a loss or near loss of hepcidin production, which leads to an iron overload phenotype. But really no other safety issues.
It tells you that this is a target that if you can hit it selectively with an antibody, which is what we're doing, you can have a really powerful effect on reducing hepcidin levels in the system Inflammation and driving the release of iron for red blood cell production without having other effects throughout the body. We think, you know, the, the underlying premise here is a genetically validated approach for getting what should be a very powerful and hopefully very safe antibody. We've run now our phase one study. We presented that data both at European Hematology Meeting and the American Hematology Meeting. The data is great.
I mean, it has a very powerful effect at a 56 mg fixed dose, which is less than one mg per kg, so very potent SubQ delivery, changes iron on a, you know, for a whole month with a single dose. You know, remarkably, we even saw an increase in hemoglobin in these healthy volunteers by one gram per deciliter. Which is, you know, I think unprecedented for this kind of agent and really proves out what we've been saying, that the genetics show this is a very powerful, and you know, and the safety profile is great. It looks so far like a very safe molecule as well. With that, you know, the question is, okay, anemia of inflammation, where do you go?
Two stories have really emerged where hepcidin is really driving, playing a significant role in anemia. One is in myelofibrosis. Interestingly, you know, a lot of discussion about that at the American Society of Hematology Meeting in December this year. Which is, you know, a pre-oncology state, quite severe, about 20,000 patients in the U.S. You know, anemia of chronic kidney disease is, you know, fundamentally two problems in these patients. One is a loss of EPO production in the kidney as it fails, and the other is the derangement of iron metabolism, which is probably driven by an elevation of hepcidin.
That's well understood, and in fact, hepcidin is actually eliminated through the kidneys, so a natural consequence of that disease is that when the kidneys fail, hepcidin levels increase in a way that becomes pathologic and drives what becomes an IRON deprivation status in these patients. We're again looking to get to the root cause of that anemia. In the non-dialysis setting, there's millions of patients of which very few are treated for their anemia, and it's largely because of challenges associated with the ESA class of drugs as well as the IV IRON group of drugs. We think we have a really attractive group of patients. Like you mentioned, today was the day we kicked off that trial, so we're excited.
Yeah. No, a lot to be excited about there. Yeah, as you said, two very distinct indications with distinct commercial opportunities, certainly also clinical regulatory considerations.
Sure.
Just very briefly on sort of the cadence of data updates for the hemojuvelin side of the house.
As I said, we presented the phase one healthy volunteer package last year. We're now in these phase 1b/2 trials for both myelofibrosis and chronic kidney disease. That means we're doing some dose escalation, and then we'll expand at the appropriate dose. You know, we're able to measure iron. It's a very good biomarker for the drug's activity. We'll look for some hemoglobin effects, which is really telling us about the clinical benefit for the drug. We expect that kind of first dose escalation and expansion data with hemoglobin effects to be available by the end of this year. That's when we think we'll get some indication of how well the drug's working in both MF and CKD.
Okay, great. Yeah, we'll be tuned into that. I want to pivot to your most recently in-licensed asset...
Sure.
...which is an antibody from Mabwell. I would just ask you, John, to kind of set the stage on the mechanism here, but also we did have an inbound question from an investor. If you could just talk about kind of the TPP that you have in mind for this asset, and do you envision this being dosed IV or subQ? What's kind of the ideal dosing frequency as you see it today?
Well, if the hemojuvelin antibody we just talked about, that's designed to release iron in the body when you need it, the setting of inflammation and anemia, this program is designed to restrict iron. There are settings where actually the iron is problematic or by controlling we can have a therapeutic benefit. The target we're going after is called TMPRSS6 or also Matriptase-2 or Matriptase-2. This is a protease that destroys hemojuvelin, actually, and it's also known as a human knockout. The phenotype of the knockout is elevated hepcidin and restricted iron availability and reduced red blood cell production. And again, no other sequelae, no other side effects. Another really great genetically defined target. What we hope to do with this...
I should mention it was actually one of the founding programs of this company to make a small molecule against this target. We think it's a great target. The small molecule's been tough sledding. We're still working on that. The antibody, we've learned a lot, and this antibody we think has great potential. The profile we think we can get to is SubQ once monthly dosing. Protagonist has been working in this area and shown that iron restriction can treat polycythemia vera, which is, I think a, an important indication of a lot of commercial potential and a lot of unmet need. We're hoping to follow that path with this with this profile, which we think will really offer a lot to the patients.
Okay. Yeah, that's great. Just in the last minute or so that we have, similar sort of cadence of data updates from this program?
The IND is already cleared. I should say this antibody was designed by the person who actually figured out the TMPRSS6-controlled iron metabolism. I think it's a great provenance for this. The IND's already cleared. We just have some tech transfer type stuff to get us to the clinic. We're guiding to second half of this year to start up a healthy volunteer study. By, you know, likely the middle of next year, we'd have data showing the PK, subQ route of administration, iron restriction, potentially even some effects on hematologic parameters. A real great proof of mechanism we can get in the healthy, then off to the disease states.
Got it. All right. Well, yeah, unfortunately, we're up against time, John.
Yeah.
Really appreciate you joining us and thanks for sharing the updates and the insights and, certainly an exciting time at the company.
Great. Thanks for the conversation. Good to talk to you.
Thanks, John.
Bye. Take care.