Disc Medicine, Inc. (IRON) Earnings Call Transcript & Summary

Good afternoon. Thank you for joining us today. My name is John Quisel, and I'm the CEO here at Disc Medicine. Today, we're going to discuss a disorder called Erythropoietic Protoporphyria, we refer to as EPP. This is a rare and severe genetic disorder. And our drug development program for the molecule called Bitopertin, that's now in multiple Phase II trials to treat this disorder. Before I begin, I should note that we may be making forward-looking statements today. These should be taken in context with the language on this slide as well as in our 10-K and other securities filings. We've got an exciting program today. We're delighted to be joined by Professor Bruce Wang, from the University of California San Francisco and also Professor Jean-Charles Deybach, who joins us from Paris University and with the former head of the French Porphyria Center. And then lastly, we'll have a presentation from Will Savage, the Chief Medical Officer here at Disc Medicine. First, I'll provide a background about Disc Medicine. We are building -- we hope to be a leading company dedicated to the treatment of hematologic disorders. We focused in this area because we believe there are tremendous unmet medical needs as well as unparalleled tools for information on data-driven clinical development. We've chosen our targets and our drug candidates by focusing on fundamental biology or red blood cells, in particular, iron and heme metabolism. I'll talk about that more in a moment. And all of our targets are validated pathways, meaning that we have evidence from humans either through genetics or through clinical trial experience that demonstrates that each of our target mechanisms is in fact engaged and active in human setting. We have 3 clinical stage programs, each with broad potential to Bitopertin that we'll be focusing on today is in multiple Phase II pro trials. DISC-0974, our second program is in -- currently in 2 Phase Ib/II clinical trials and our newest program, MWTX-003 is Phase I ready with the trial expected to start later this year. Because of all of this activity in clinical programs, we have several upcoming data readouts, the soonest one will be with Bitopertin in EPP indication, notably expected in an interim analysis in June of this year. So when we say that we're targeting fundamental pathways that impact the biology of red blood cells, we mean we're focusing on iron and heme. These are 2 of the key building blocks for red blood cells. These are major components of this cell type. They perform the fundamental oxygen carrying role of red blood cells. And because they are such major components of this important cell type in the body, their metabolism is tightly controlled. And with our experimental therapeutic candidates, we're able to manipulate the metabolism of heme as well as iron. And in doing so, we hope to affect a wide range of hematologic disorders. If you look at the bottom of the slide, you can see the range of potential indications where mechanisms controlling [ IRT ] may be applicable. They range from very rare disorders like Diamond-Blackfan Anemia, Erythropoietic Porphyrias which we'll discuss today. All the way up to some very common disorders such as Anemia, Beta-Thalassemia outpatients with [ cardiac ] disease. So our portfolio, as I mentioned, addresses a broad spectrum of hematologic disorders. Our lead program is focused on the modulation of Heme Biosynthesis and it's called Bitopertin and we're currently in 2 Phase II studies in patients with EPP. And we recently announced a collaboration with NIH to pursue a Phase II trial in patients with Diamond-Blackfan anemia. Our additional programs target iron metabolism, one program called DISC-0974, increases iron availability to broadly treat kinds of anemia that I referred to as Anemia of Inflammation. And these molecules and trials in patients with Anemia from Myelofibrosis and the second trial in patients with Anemia as a consequence of productivity. And then our newest program, is designed to actually restrict iron in the body. And this may be generally useful to treat indications where patients have iron overload or an excess production of red blood cells. Most notably Polycythemia Vera referred to as PV on this slide. This antibody, the IND has been accepted, and we expect to start the Phase I trial in the second half of 2023. So today, we'll be focusing on Bitopertin and Heme Biosynthesis. So the synthesis of heme is a complex process that begins with a common amino acid called glycine, which has taken up and converted in newly forming red blood cells into a series of metabolites called Porphyrins on the way to forming a mature heme molecule, which is finally charged with iron. Once heme is formed, it's complexed with a protein called Globin to form hemoglobin, and this is the familiar heme carrying molecule that's in red blood cells. And hemoglobin, of course, becomes part of a final and mature red blood cell. So as you can see in this diagram, all along this pathway running from glycine through to the formation of mature red blood cells, there are a host of a defects that can arise that result in an excess of each of these components that, in turn, can drive the disease. So most proximal to the beginning of the pathway, we have the disorders caused by Porphyrin Toxicity. We have a Ertythropoietic Protoporphyria that we'll talk about today, closely related X-Linked porphyria in general erythropoietic porphyria and then a Protoporphyria that arises in the liver called Hepatic Porphyrias. Next, there are disorders caused by an overload of hemes, such as Diamond-Blackfan Anemia and certain Myelodysplastic Syndromes and disorders caused by excess of Globin itself, Hemoglobin or even an excess production of mature red blood cells that can be found in Polycythemia Vera patients. It's our belief that all of these indications can be potentially addressed if you can restrict the flow of Glycin into this pathway and thereby, restrict the production of Porphyrins, Heme, Hemoglobin or even mature red blood cells. And this is what our experimental agents that Bitopertin is intended to do. As you can see, the most proximal diseases to the beginning of this pathway are the Porphyrias and hence, we've started our program in the clinic in that indication phase, but we are working actively to expand the use of Bitopertin across multiple locations. So to speak briefly about Bitopertin, this is an oral selective inhibitor of a target called GlyT1. GlyT1 is a transporter that controls the uptake of glycine with considerable specificity early in newly forming red blood cells. This molecule was initially developed by Roche. It's been tested in many, many clinical trials over 4,000 patients have been dosed with their [ pertains ]. And so we have great understanding of its pharmacologic effects, it's PK, it's safety, all the attributes of a late-stage drug development program. And what is known from the clinical data as well as preclinical data is that Bitopertin successfully blocks the uptake of glycine into newly forming red blood cells by blocking the GlyT1 transporter. And as we discussed on the previous slide, glycine is the first metabolite in the pathway of these heme biosynthesis. So showing is the series of enzymatic path steps, the take glycine combined with another metabolite Protoporphyrin or [indiscernible] to drive the synthesis of these porphyrial compounds, the last of which is Protoporphyrin IX. In Protoporphyrin IX, has been charged with iron by an enzyme called ferrochelatese leading to the formation of mature team. And that, of course, is incorporated into hemoglobin and mature red blood cells. So Bitopertin is able to slow the flux of glycine or or give it the flux of glycine into this Heme Biosynthesis Pathway. And what we've shown in animals and you'll hear later today, that, that is able to reduce the accumulation of this metabolite Protoporphyrin IX, which is the key driving toxin that underlies the disease called EPP. So the premise that you're going to hear about today is that Bitopertin by reducing the accumulation of Protoporphyrin IX, and we need to potentially disease-modifying treatment for these patients with the disease. That concludes my portion of the talk and I'll hand it off now to Dr. Wang to discuss EPP disease background in pathophysiology.

Okay. My name is Bruce Wang. I am a hepatologist at the University of California, San Francisco. I run the UCSF Porphyria Center, and I'm also a member of the NIH-sponsored Porphyrias Consortium, and here are my disclosures. So I'm going to talk about how heme is produced in the body, primarily in the red blood cell, how defects in the production of heme leads to the porphyria specifically EPP. And I'll talk about the biochemical changes that occur in EPP and how it leads the disease. Dr. Deybach will then follow me and describe the clinical characteristics of EPP. So heme is a required protein for life. It is made primarily in 2 parts of the body: In red blood cells, in the bone marrow and within the liver. Heme is a major structural component of hemoglobin which is the main component of red blood cells and crucial for oxygen carrying the function of red blood cells. And it is made in a 8-step process and that requires glycine as a critical initial substrate for this pathway to make a protein of heme requires one item of iron and 8 molecules of glycine. And this is -- the reason why we think glycine, which is supplied by the glycine transporter-1 (GlyT1) may be a potential therapeutic target for the treatment of EPP. So shown here the biosynthesis pathway for heme. Heme is made in an 8-step assembly line, if you will, which occurs within every single cell of the body, but it is made in particular within red blood cells. It starts with the 2 starting materials, glycine and succinyl CoA and it's passed on through the subsequent 8 enzymatic steps, which is carried out by each of these 8 enzymes listed starting with Aminolevulinic Acid and ending with ferrochelatase to produce a protein of heme. This process is very tightly regulated. The very first enzymatic step ALA Synthase is the rate-limiting step for the whole pathway. And within red blood cells, ALA Synthase activity is further regulated by the availability of iron because in red blood cells, you don't want to start the production of heme if you don't have enough iron to ultimately produce a functional heme protein. So as in any assembly line process, a defect or I should say, a partial defect since a completely nonfunctional step in any assembly line would completely stop it, but a partial defect can lead to a bottleneck at the defective step and as a result, you can get abnormal accumulation of the things made in the assembly line prior to the bottleneck step. And the same thing happens in heme production, and inherited defects in each one of these 8 enzymes that are responsible for the production of heme results in one of the 8 Porphyrias. So this is summarized here, disruptions in heme-synthesis causes accumulation of porphyrins, which are the chemicals are made during the process of heme production. There are 8 different porphyrias each resulting from an inheriting mutation in one of these 8 heme biosynthesis genes. But the porphyria is we can also classify them into 2 broad categories based on which body system is primarily affected. In the first, the Erythropoietic Porphyrias are the porphyrias that primarily affect the production of heme and red blood cells. In these porphyrias, the porphyrin interomediax that accumulate tend to be the ones that are phototoxic and generally leads to skin manifestations of porphyrias. The second broad category are the Hepatic Porphyrias where heme biosynthesis in the liver is affected. In these porphyrias, typically what accumulates are heme precursors, which are neurotoxins leading to episodic neurovisceral attacks. So now we get to EPP which is a Erythropoietic protoporphyria. This is typically caused by a defect in the final step in heme production carried out by the enzyme ferrochelatase. This results in abnormal accumulation of the protoporphyrin IX. Protoporphyrin IX is hydrophobic compound. It accumulates red blood cells in the plasma and is primarily process and discreted out of the body via the liver. Protoporphyrin IX is a highly photo reactive chemical. It is able to absorb sunlight -- energy from light and resulting in reactive oxygen species that are produced leading to tissue damage through membrane lipid peroxidation, complement activation, as well as mast cell degranulation. In the liver, proto -- excess protoporphyrin IX can crystallize and block bile ducts, which can lead to rapid and severe liver damage. So the general symptoms that can present in patients with EPP in the skin because the porphyrin -- the protoporphyrin IX chemicals, as I mentioned, can absorbs light and emit energy and heat leads to pain, burning sensation, swelling, inflammation and then over time, some chronic skin lesions as well. As a result of this, patients essentially live their entire lives in fear and avoidance of sunlight. This causes significant lifestyle modifications and leads to a significant decrease in their quality of life, also leads to significant amounts of psychosocial issues in the patients. I mentioned that Protoporphyrin IX in the liver when it is in excess in a small number of percentage of EPP patients can accumulate abnormally and create crystals in bile ducts. This is a very severe and rapid liver injury that can quickly develop into liver -- advanced liver cirrhosis and patient death and is only curable with a liver transplant. As a result of patients avoiding light, basically their entire lives, there are a number of nutritional deficiencies that result in other complications of EPP, including osteoporosis. And with that, I will stop and hand over to Dr. Deybach, which -- who will tell you more about the EPP patient experience and unmet needs in the treatment for EPP.

So thank you very much, Dr. Wang, and hello, ladies and gentlemen. So I am professor Deybach, professor at Paris University in France. And I was the first, the past head of the French Reference Center for porphyria and also the past President of the European Porphyria Network. I am a powerful consultant for Alnylam Pharmaceutical, Recordati Rare Diseases, Mitsubishi Tanabe and also Disc Medicine. So we speak today indeed about clinical aspects of Erythropoietic porphyria. And on my first slide, I would like to remind you it necessary that it was the most recently described in [ eryted ] porphyria. So 62 years ago, it was described by professor Magnus, a dermatologist in U.K. And the title is quite interesting because it was a new porphyria syndrome with solar urticaria due to porphyrinaemia. So everything was focused on a photo dermatosis. But what we learned about EPP in the last 62 years. We learned mostly that it is now a multifaceted, Multigene, multi-organ disease that still has unmet needs. So yes, EPP is really [ disfacing ] painful skin photosensitivity. And it's not in early childhood. The [indiscernible] is almost 100% at the age of 12 or 15. And within minutes after exposure to light, especially outdoors, EPP patient experienced acute phototoxic reaction that goes certainly painful incapacitating burning sensation in their skin in the end in their hand, mainly. This indeed occur even when it is overcast or with some artificial light. But despite this sustained intensity of this burning sensation, excel at that time, at the beginning, external cutaneous manifestation Are rare and symptoms remain almost invisible. That's when the reaction is particularly pronounced swelling, oedema, skin lesion, some type of erosion and crusting may appear hours and days later. The earnings sensation can take several days to resolve and during which patients hide from all light sources to avoid [indiscernible]. And there are also in the chronic lesion, mostly, as you can see on the slide, thickened waxy skin under the hands or linear scars around the nostrils. So as the first main point, these acute attacks of phototoxic reaction, as we say, they do not respond to pain killers or to anti-inflammatory drugs. So diagnosis is, therefore, often delayed in emergency ward on even in internal medicine ward. Major impairment of quality of life for the patient who will develop that later and psychosocial complications is the -- are the main feature of the disease. On the next slide, and as a result, patient with EPP take extreme measure to avoid sunlight. They spend indeed most of the time indoors avoiding the light to prevent the phototoxic reaction. And indeed, this can cause patients to miss for instance, at school, many daily activities and make them attending school are quite difficult. And this is really something difficult for young children at school mainly. When patients do have to go outside, say, may completely cover their skin to avoid sun exposure, say, wear a long sleeves, hats and gloves even in summer. And these are indeed a psychological distress and social isolation to the physical effects of the disease. But EPP is not limited to skin photosensitivity. It is not a purely dermatological disease with seasonal one set. It is a chronic metabolic multi-organ disease as we can see. EPP is a multiorgan, multidimensional disease. It can affect several organs, first skin as we have seen with severe disabling pain attacks, but it is mainly affecting as a liver and by that and hepatobiliary organs, [indiscernible] gallstones, or liver dysfunction or even liver failure. We'll see that later. The bone marrow also with a mild microcytic anemia, bone with osteoporosis because of the vitamin D deficiency because of the lack of sun exposure and also a systemic inflammation because of activation of the complement. So EPP is also presenting, as I already said, in early childhood, and this is, therefore, a lifelong disease. So hepatobiliary disease is potentially severe consequences of liver PPIX accumulation in EPP because accumulation off protoporphyrin in the liver, as you can see on the right, this is a black liver due to the black color of protoporphyrin. So this accumulation as well as the capacity of the porphyrin to have -- to provoke, to induce oxidative stress can lead to liver damage. Over time, indeed, excess amount of free protoporphyrin lead to obstruction in the bile flow, and this led to Cholestasis that initiated in a vicious cycle of worsening cholestasis and reduced protoporphyrin excretion. So it's really something that come over time. And that so patients can experience a variety of hepatobiliary symptoms. So it's ranged from gallstone -- more than to what around 25% as gallstone, that goes to 25% to 30%. Abnormally liver test, 30% and progressive liver disease that could lead to liver failure in, we should say, 1% to 5% depend to geographical region requiring this -- this require indeed liver transplantation, but not only because the new liver, [indiscernible] liver could also be addressed by the protoporphin accumulation. So now we are trying to do a combined bone marrow graft because the disease is indeed mostly in the bone marrow producing a high level of protoporphyrin. The lifestyle modifications, that I would try to manage the EPP disease can cause mainly anxiety, depression and isolation. So due to their condition, EPP patient experience -- 20% of them, around 10% of them real depression, I mean, real depressive disease, and social isolation by most of the patients. A fear of future liver disease indeed, and they have anger and jealousy about missing school or missing works or missing their work and so on. This is a very difficult condition for that for social -- for social because of social isolation. And mainly they are also very embarrassed to explain their disease because most of the time, you cannot see anything. You can't see anything on their skin. So it's very difficult to explain to teacher or to your boss and so on in your company where you work. It's very difficult. So -- and indeed, there is also a lot of awareness of EPP that exacerbates its feelings because people around the patient, they don't appreciate the severity of the disease. And there is also a lack of awareness in the physician and also in the teacher in schools. So EPP has a negative impact also on the caregivers because the caregivers their -- they do all their best to protect the EPP patient. Then they feel guilty -- children because they miss some experiences and this is really true at school. So if it is a rare disease, it's a rare genetic disease and -- but it is often unrecognized. Indeed, it is new, 62 years -- this is not so much. And indeed, this is one of the third most common porphyria and it is most common porphyria in children, but they are only a few patients around the world and if you look at the prevalence on EPP and also XLP, which is the same disease but not the same genetic background. There are approximatively 1 to 75,000 person. So it makes a minimum prevalence of a 8,000 EPP patients in the U.S and EU. So most patients are diagnosed in the early childhood though some diagnosis take more than a decade from symptoms. This is also a problem. You can make the diagnosis at 70 years. This is my experience for years. And there is also a high number of undiagnosed and misdiagnosed EPP patients mostly due to the lack of awareness of the disease by the physician. We don't know the disease and is not yet very well. Porphyria is not well -- very well developed at School of Medicine. So it's really a problem awareness and we are trying to develop that. And there are also probably some problem with genetic prevalence, which is probably higher than we saw before. And so a recent study has show -- has suggested that the disease must have a higher prevalence. So EPP treatment, there are really unmet needs and -- but unfortunately, are emerging therapies. Well, actually, the treatment of patients with EPP is previously built on photoprotection. By clothing, sunscreen or afamelanotide, which can perfect from the sum and by tanning mostly and there is some effect indeed to -- of this treatment, that the only treatment available to date. And there is some effect on acute photosensitivity. But there is absolutely no impact on protoporphyrin IX accumulation in the skin, and there is no impact on liver toxicity indeed. So the only way to treat, and this is the emerging therapies that we need is that to lower the circulating PPIX production of protoporphyrin IX by a drug. And this is a novel approach indeed and which affects the pathophysiology of the disease. And as an example, I want to underline this very amazing, I should say, amazing because the woman here is laughing. She is one of my EPP patients. And this is -- she was during the second trimester of pregnancy, she was lying on the swimming pool under the sun. And so there is a natural function of improvement in women CP pillar. This is pregnancy. Most, if not all, pregnant women with EPP become tolerant to sun exposure after the second trimester. Why? Because of a concomitant significant decrease of circulating PPIX by roughly 50% decrease in the level. And so what we expect is a similar results by using Bitopertin treatment. And I think Dr. Will Savage now will present the development of this drug and how this will go on to have that on the market, I hope. Thank you very much for your attention.

Thank you, Jean-Charles, for the presentation and the introduction. I'm Will Savage, Chief Medical Officer at Disc Medicine. As a reminder, Bitopertin is an investigational agent that is not approved for use as a therapy. This slide presents why we think Bitopertin can be a potential disease-modifying treatment. As reviewed earlier in the presentation, on the left-hand side is the heme synthesis pathway. Glycine is a substrate that lies at the top of this pathway and highlighted through the course of the enzymes in this pathway are the 2 types of genetic mutations the underlying EPP. There's the ALAS2 gain-of-function mutation and a ferrochelatase, loss of function mutation. In either case, as glycine and the other metabolites moved through the pathway, there is a resultant accumulation of protoporphyrin IX that leads to the clinical manifestations just presented. On the right-hand side shows that with the effect of Bitopertin Treatment, we have hypothesize that reducing glycine uptake into red cell precursors will decrease the flux of metabolites through the heme synthesis pathway, thereby reducing the amount of protoporphyrin IX and thus becoming potentially the first disease-modifying treatment for EPP. An important question is how much reduction is needed in order to be disease modifying. Well, we hypothesized that a 30% or greater reduction in PPIX will lead to a very clinically significant improvement in EPP photosensitivity. So on the left-hand side, as Jean-Charles just mentioned, there are literature reports of a personal experience from Jean-Charles about pregnant people with EPP who have 30% to 50% reductions in protoporphyrin IX levels during pregnancy and that reduction is accompanied by full or near full improvement in light tolerance. On the right-hand side, summarizing a study of protoporphyrin IX photo inactivation. So this was an interventional trial in which patients' blood was removed from the body exposed to light to inactivate PPI and then the blood was returned to the patient. This procedure reduced PPIX levels on average by about 30%. And the daylight tolerance as a result of this 30% decrease in PPIX increased 14-fold on average. And so a median amount of light tolerance for someone with EPP is about 30 minutes. So a 14-fold increase reflects taking somebody with a 30-minute light tolerance and converting it to 7 hours post treatment, which is a remarkable change. This medicine has produced cell and animal models that support the hypothesis that bitopertin can reduce PPIX levels. On the left-hand panel is the mouse model of the ferrochelatase mutation in the middle panel is a mouse model of an XLP or ALAS2, Gain-of-Function Mutation. And in both cases, treatment with bitopertin at roughly doses that equal 20-milligram daily dose in humans, protoporphyrin IX is reduced by 45% to 73%. And well in the range that is observed clinically and to be associated with significant improvement in light tolerance. Furthermore, on the right-hand panel, there is shown data from the ferrochelatase mouse model that shows that we can prevent liver fibrosis again, a drug exposures that are -- we are going to be using in the clinical trials. So we have 2 ongoing Phase II clinical trials in EPP/XLP. The first is the BEACON Trial. This is an Open-label parallel dose study of people with EPP and XLP 18 years and older, who are randomized to receive either a 20 milligrams or 60-milligram doses of Bitopertin. These represent mid- and high-dose levels for a treatment duration 4 weeks. The primary endpoint is changes in metal-free protoporphyrin IX levels. We also have a number of measures of light tolerance looking at hepatobiliary biomarkers, quality of life and other PRO data. The other study is the AURORA trial, also a Phase II study, but this is a randomized, double-blind, placebo-controlled trial that has a larger sample size, anticipated enrollment of about 75 participants. This is for patients with EPP 18 years or older, also evaluating the mid and high doses of Bitopertin. But now we have the addition of the placebo group, and we have the advantage of looking at a light tolerance in the double-blind placebo-controlled manner. We have the same primary endpoint of changes in metal-free protoporphyrin IX levels, and we have the same measures of light tolerance as well in this study. So categorizing the endpoints that we're looking at in these studies, I mentioned we're looking at changes in metal-free protoporphyrin IX in both studies. That's because of the role that protoporphyrin IX plays in the disease and the strong relationship between protoporphyrin IX and end disease severity. We're looking at another group of key endpoints in both of these studies. First is total hours of sunlight exposure on days without pain from 10:00 a.m. to 6:00 p.m. Next is time to first prodromal symptoms associated with sunlight exposure. So prodromal symptoms are a hallmark EPP, this prodrome or early warning symptom is a phenomenon that occurs in all patients and its early morning sensations that a phototoxic reaction is imminent. And it's possible for people with EPP to expose skin to sunlight and measure the amount of time until this prodrome starts. And then once the person gets out of the sunlight, the prodrome will go away. And so this metric of how long it takes until a person gets that prodrome is a measure of their light tolerance. And you can recall the photo from Jean-Charles about the pregnant women in the sun, not experiencing any sort of prodrome or early warning symptom is just able to live her life out in the sun without concern about having to find shade somewhere. We're also measuring pain intensity of phototoxic reactions and we have a number of PRO questions on light tolerance as well as a suite of questions that measure the impact of the disease on quality of life. So upcoming milestones for the development in these 2 trials. We have interim open-label data from BEACON that we are going to present in June data will be drawn from the endpoints I just discussed in the previous slide. AURORA trial data, top line is expected by the end of this year as well as top line from the BEACON trial. Of note, on the right-hand side, we also have a Diamond-Blackfan anemia trial that started up at the National Institute of Health that's expected to start in the middle of this year. And we are also actively pursuing additional indications where there's a therapeutic rationale for glycine and heme restriction. Thank you. We're happy to take any questions.

Okay. And our first question in the queue comes from Julian Harrison at BTIG. He's asking about read-through from the interim BEACON data to Aurora. What would you highlight as most important? And how are you framing expectations around those data points?

Great. Thanks for the question. Will, do you want to take that one?

Sure. Well, as I mentioned, we have the same endpoints measured in both. I think it's -- there's not one endpoint that necessarily measures the entire disease picture. So I think a combination of protoporphyrin IX reduction and measures of the different measures of light tolerance are key.

Great. And a follow-up question from Julian. What is the FDA's view on PPIX as a registrational endpoint for EPP and XLP?

So PPIX is not a precedented surrogate marker in this disease at this time. So there's I think it's certainly can be viewed as supporting evidence at this stage in development that we're at.

Great. Another question from Evan Taddeo of Guggenheim asking how should we think about a 30% to 50% reduction in PPIX in terms of affecting some of the other quality of life issues or downstream effects like liver disease. Would you expect this degree of reduction to have a benefit on these complications?

I think yes, indeed, yes, because the liver disease appeared because of the flow of the protoporphyrin IX through the liver. So if you diminish the production of PPIX [indiscernible] in marrow, you will indeed decrease these flips across the liver.

And I think we expect the skin symptoms to improve as well, although, as has been mentioned, we thus far don't really have any treatments that are really affected and sustain a reduction of protoporphyrin IX levels. But in general, our observations have been that the more severe manifestations tend to occur in patients with higher levels of protoporphyrin IX.So we would expect that a reduction within that group of patients would improve their skin symptoms.

Great. Thank you for those answers. We also have a question from Tom Smith of SVB Securities asking what are the expectations for the number of patients and amount of follow-up we can expect to see with the interim BEACON data and can we expect to see the initial measures of light tolerance and other PRO data along with the top line?

Yes. Thanks for the question. We've been guiding for our presentation in June to expect in a study of total size of about 20 patients to enroll that we'll have data from roughly 5 to 10 patients. And Will, do you want to comment briefly on the kinds of data we may present?

Sure. So we're going to be presenting metal-free protoporphyrin IX as our primary endpoint. And we do have a number of measures of light tolerance and PROs that we can select from. But until we will be presenting data from that group, but we haven't made a final determination about which ones those will be. And I should also add, we are in a present safety data as well.

All right. Next, we have a question from Ben Burnett of Stifel. He will be asking his question live. Go ahead then.

Okay. Great. So it sounds like there's a pretty direct link between PPIX and sunlight induced pain. I guess I would ask the physicians. Is there a threshold of PPIX we're above this level, patients experience pain. Is that threshold known? And if so, like how does that threshold sort of vary between patients?

Well, I think there is a real threshold -- and I'm sorry. Yes, I think there is really a threshold. The threshold is not really just a number. It is also dependent to people to EPP patients indeed. But the usual, I should say, well, let's say, the mean level of PPIX in most EPP patients is 40. I don't take the other measure -- just 40. What is the mean level of PPIX in EPP patients. If you have double you are really painful patient. You cannot live under the sun and you live in your cellar. And you have rapidly liver disease coming out. And -- but if you have 20, then you have much less. And if you go below 20, you have almost nothing. That's my experience. Indeed, it's not really -- the life is more complicated than that. And you should also take into account the tanning of the person and everything like that, the color of the skin and also the geography. For instance, something which is very curious, they are in EU, sorry, my experience in the EU, you have more patient EPP, patient in the northern country than in the Southern country. It's quite funny because you have more sun in the southern countries than in the northern country. Another thing playing a role is light, not the sun, but the light. How is the light is distributed and in the northern trees, in the atmosphere, you have more water and the deflection of the light is different, and this selects some wave lengths that target specifically is the photo [indiscernible] in line. So it means that most of the patient in my experience is they go to the Equator, they feel better than if they go to the north. So that's quite funny. So it's difficult to say that level of PPIX will be definitively a threshold. It depends where you are living also.

Okay. That's fascinating. And if I could also ask for some additional commentary around the use of afamelanotide, and I guess what would it mean to you to have access to oral in this category as well?

Well, should you might -- yes, Bruce, myself, yes. So we have some experience with afamelanotide. Well, in fact, I participate to the one of the first clinical trial with Scenesse from[indiscernible]. It works quite well. Patients are at least -- it's an implant that you have every 2 months. And it works really for the first month, after it's not so good. And I think EPP patients, they accept the treatment as most of them, they feel better after that because it's reduced -- it increased time to [ prolong ] as presented by [indiscernible], and it also -- you can stay a longer under the sun. I think it works. In the experience -- the most experienced of these afamelanotide, at least in the literature, come from Switzerland and from the Netherlands. Because, as you know, afamelanotide, was Scenesse was approved by EMA first. And so the experience in EU is quite great. Not in France because clinically decided that we -- not bring reimbursement so fast and so they decided not to bring afamelanotide anymore in France. So our patients in France at least have no afamelanotide but they go sometimes to Switzerland -- to Belgium or whatever, they can have the product. So -- but afamelanotide, even if there are -- Well, at least I read a recent paper from Isabelle Minder in Switzerland, even the -- they suggest that afamelanotide could decrease PPIX. I'm not very confident with that result. And I think you can combine both drugs. I think the best indeed is to lower PPIX. Definitely, EPP [ CCO ] is the only way to get out of the liver disease. And so if you have a drug that lower PPIX and if you need to be protected by another protection drug like afamelanotide, it's not -- there are no contraindication to use those. So well, my experience is that afamelanotide works, I don't like at all implants because this is not so easy to have. You cannot -- indeed, you have the product for 2 months, at least, there are some people who don't like the tanning as well. And -- but -- as we know, there is under clinical trial now another afamelanotide drug like drug. NSE1 agonist drug, which is dersimelagon from Mitsubishi. And this is a pill. And I think this would work more easy than the implant from Scenesse, that's my experience. So definitely, I think treated EPP since 40 years, I can tell you that there are probably more confident by a drug which lower really a PPIX that protecting them by a planning manner. Sorry for my English.

And I can just add a little bit on. I think my experience of patients in the U.S. has been similar to what Dr. Deybach just described in the French patients. We also have some issues in the U.S. of access to Scenesse. But I would just say that in general, my patients who are able to get Scenesse or on it are quite happy with it. But I would say that it really highlights the severity of the impact of this disease on the quality of live patients because when you look at the actual improvement of these patients here, you're talking about for most patients, maybe on average of 30 minutes, maybe up to an hour of additional direct sunlight time, but for most EPP pay. In fact, for all of my EPP patients, that is a significant improvement for them. And that's -- and I think if anything, that highlights the severe impact on quality of life in these patients, that just having a little bit more time that they can spend outside is a big deal to them. So I think especially from the patient's perspective that really any increase in their ability to be outside, matters a lot to the patients.

Yes. Agree. Indeed, yes. Thank you, Bruce. And the other thing is that Scenesse as a implant is -- well, it's not a small implant and could be done for children for the moment. It should be another dose, another type of implant. I think it's very important to treat children. And at least after a year, after 12 years because the impact of school starts really not for very young children because the parent can do that. But at the age of 12 teenagers, they are really impacted by the disease because I cannot go outside, I cannot play any sport or whatever they should be not under the light in the school. And so it's very difficult, and the teachers, they don't really understand or the caregivers. It is very difficult to explain to other people what EPP is and for the parents and so on. So that's why we should understand also that EPP patients, they cope the disease with the age -- that's why we see patients very -- with an un -- not diagnosed before the age of I don't know, 40, 50, even 70, as I said before, it's true because they cope with the disease, and they know exactly what they feel under the sun and what they should do to protect their self, not all patients. And at least 80% patients cope really well with the disease. And so it is also since that's why it is sometimes difficult to produce a drug, which will help them because they don't go outside that it's difficult to go outside. That's very difficult for clinical trial. We have that type of product.

It's really a lifetime learning behavior in the EPP patients. Great. Thank you, Ben, anymore?

Great. Thank you, Ben. Next, we have a question from Jeff Hung at Morgan Stanley.

I have 2 for Dr. Wang and Deybach. I guess in BEACON and AURORA, multiple types of measures are being made, including light tolerance and hepatobiliary markers. So can you talk about what improvements are most important to patients versus physicians?

Yes. Maybe I can start with this. I think we touched on this a little bit just with the last question. I think what -- from patients, I think my patients, clearly, it's the amount of time that they can spend in the side and outside that really -- any appreciable increase is a huge change in their lifestyle for them. And I think from my perspective, as a clinician for porphyria patients, that clearly is really important because again, Dr. Deybach talked about all of the other cyclosocial aspects that affect our patients. And so giving them more time to be out in the sun, to be able to lead a more normal life, I think will have significant impact beyond just improvement in symptoms. But I think I'm actually most excited about the ability to really lower protoporphyrin IX levels because that really has something that has not been available and also I'm a hematologist. So I just tend to worry more about the liver aspect in EPP. And really, most patients with EPP, we talk about how significantly it affects our life, but the cutaneous symptoms really don't -- they don't necessarily decrease life expectancy in those patients -- in EPP patients. But it's the liver damage that will -- it's really severe and it progresses really fast. So in those 1% to 5% of patients that Dr. Deybach talked about, who will develop EPP induced liver damage, those patients are essentially going to need a liver transplant or they're going to die. And we thus far have very limited ways of even temporizing that. So from my perspective, that's sort of the most exciting thing about the potential for good pertain is that it will actually lower protoporphyrin IX levels, which now will allow us to not just give symptomatic improvement in the cutaneous symptoms, but then hopefully also protection against what will kill these patients.

Great. And then I guess -- Okay. So I guess given the 7-week shorter treatment duration in AURORA versus BEACON and a slight difference of not having XLP patients in AURORA. Maybe Dr. Wang and Deybach, they talk about what you would view as clinically meaningful improvements for these studies on some of those study measures like changes in blood PPIX level, the time in daylight without pAIN and hepatobiliary markers.

Yes. I guess my -- how I would evaluate the efficacy doesn't really change with a slightly shorter duration from, I think, 24 weeks down to 17 weeks. I think I would expect to see similar degrees of change.

Great. Thank you, Jeff. Next, we have Malcolm from BMO.

It's Malcolm on from [indiscernible]. I just wanted to ask if you guys is more directed to the Disc management team, but could you guys give us some more color on how you chose the 20-milligram and 60-milligram dosing for a bitopertin in the BEACON trials? And then especially given the preclinical mouse metal data that we had previously seen. So just a little bit of color there would be great. I appreciate it.

Sure. I mean a significant part of the 20 mg dose was chosen as a crosswalk from the dose we are using in the mouse studies. But Will, do you want to comment a little more detail?

Sure. So we know that protoporphyrin IX reduction is going to be related to the amount of glycine uptake in inhibition that there is. And we know from Roche data that you can -- that basically 20-milligram and 60-milligram daily doses give you mid- and high-level suppression of glycemia uptake in red blood cells. The 20-milligram dose was used extensively in the Phase III program for Roche. So we got to use a lot of the safety data is being applicable to the study. And then a 60-milligram dose was also used in Phase II studies at Roche, but it essentially achieves a maximal suppression of glycine uptake. So we wanted to -- we didn't want to miss because we didn't use a high enough dose. We think that because of the mouse data, 20 milligrams daily dose has a very reasonable chance of providing efficacy, but we wanted to see what maximum would look like as well.

Great. Thank you, Malcolm, for your question. In the chat, we have a question from Rami Katkhuda of LifeSci Capital. I'm asking a lot of variability in measuring light tolerance and time prodromal symptoms in clinical studies for EPP.

Who wants to start, Will, do you want to start and then see if our panel has comments?

Yes. I mean I'm happy for my -- I mean, discussions with patients themselves and leaders like Bruce and Jean-Charles and reading the literature, My understanding is that the -- while there is some variability, what is keep measuring the change within a person and that, that is the most reliable way so that if somebody has very little sunlight tolerance and they get more while you might have differences across people that full of change within a person is pretty consistent. And I would also add that, that's why we measure, for example, our time to prodrome end point is measured once a week, and we measure it multiple times over the course of the study. So for what variability there is, it's averaged over a number of observations.

I think indeed, the best control is a patient itself because indeed, EPP symptoms are really related to many factors that are not only the PPIX level, but also, as I said before, where you live, where what is the period of the year -- is that in spring? Is it in Newton or whatever? And where you're situated. I think that's very important. So it means that in studies, the best is a patient is itself a control, but it's not always possible. And we have to obey to clinical trials rules. That's what is difficult for EPP.

Those are all the questions that we have. John, pass it back to you for any final comments.

All right. Great. Well, thank you, everyone. We appreciate your attention today. We're looking forward to our data presentation in June. And additionally, I'd like to thank our panelists who've been extremely helpful to us, advising us throughout this program and really appreciate your time joining us today. Thank you so much.