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, which we refer to as EPP. This is a rare and severe genetic disorder and our drug development program with a molecule called bitopertin that's now in multiple phase 2 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 D eybach, who joins us from Université Paris Cité and was the former head of the Centre Français des Porphyries.
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 what 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 and data-driven clinical development. We've chosen our targets and our drug candidates by focusing on fundamental biology of red blood cells, in particular iron and key metabolism. I'll talk about that more in a moment. 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 the human setting.
We have 3 clinical stage programs, each with broad potential. bitopertin that we'll be focusing on today is in multiple phase 2 pro-trials. DISC-0974, our second program, is in currently in 2 phase 1B/2 clinical trials. Our newest program, MWTX-003, is phase 1 ready with a 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. 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. Because they are such major components of this important cell type in the body, their metabolism is tightly controlled. 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 iron and heme 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 that afflicts patients with chronic kidney disease. 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. We're currently in 2 phase 2 studies in patients with EPP. We recently announced a collaboration with NIH to pursue a phase 2 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 are referred to as anemia of inflammation. This molecule is in trials in patients with anemia from myelofibrosis and a second trial in patients who have anemia as a consequence of chronic kidney disease.
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 a phase 1 trial in the second half of 2023. Today we'll be focusing on bitopertin and heme biosynthesis. The synthesis of heme is a complex process that begins with a common amino acid called glycine, which is 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. This is the familiar oxygen-carrying molecule that's in red blood cells. Hemoglobin, of course, becomes part of a final and mature red blood cell. 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 defects that can arise that result in an excess of each of these components that in turn can drive a disease. Most proximal to the beginning of the pathway, we have disorders caused by porphyrin toxicity. We have Erythropoietic protoporphyria that we'll talk about today, closely related X-linked protoporphyria, Congenital erythropoietic porphyria, and then a porphyria that arises in the liver called Hepatic porphyrias.
Next, there are disorders caused by an overload of heme, 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 glycine into this pathway, and thereby restrict the production of porphyrins, heme, hemoglobin, or even mature red blood cells. This is what our experimental agent, 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 space. We are working actively to expand the use of bitopertin across multiple indications.
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 primarily in newly forming red blood cells. This molecule was initially developed by Roche. It's been tested in many clinical trials. Over 4,000 patients have been dosed with bitopertin, we have great understanding of its pharmacologic effects, its TK, its safety, all the attributes of a late-stage drug development program. What is known from the clinical data as well as pre-clinical data is that bitopertin successfully blocks the uptake of glycine into newly forming red blood cells by blocking this GlyT1 transporter. As we discussed on the previous slide, glycine is the first metabolite consumed in the pathway that leads to heme biosynthesis.
Shown is the series of enzymatic steps that take glycine combined with another metabolite called succinyl-CoA to drive the synthesis of these porphyrin compounds, the last of which is protoporphyrin IX. Protoporphyrin IX is then charged with iron by an enzyme called ferrochelatase, leading to the formation of mature heme. That, of course, is incorporated into hemoglobin and mature red blood cells. Bitopertin is able to slow the flux of glycine or inhibit the flux of glycine into this heme biosynthetic pathway. 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.
The premise that you're gonna hear about today is that bitopertin, by reducing the accumulation of protoporphyrin IX, can lead to potentially disease-modifying treatment for these patients with EPP. That concludes my portion of the talk. I'll hand it off now to Dr. Wang to discuss EPP disease background and 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. Here are my disclosures. I'm gonna 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 porphyrias, specifically EPP. I'll talk about the biochemical changes that occur in EPP and how it leads to disease. Dr. Deybach will follow me and describe the clinical characteristics of EPP. Heme is a required protein for life. It is made primarily in two 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. It is made in an eight-step process, and that requires glycine as a critical initial substrate for this pathway. To make a protein of heme requires one atom of iron and eight molecules of glycine. 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. Shown here the biosynthesis pathway for heme.
Heme is made in an eight-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 two starting materials, glycine and succinyl-CoA, and is passed on through the subsequent eight enzymatic steps, which is carried out by each of these eight enzymes listed here, 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.
Within red blood cells, ALA synthase activity is further regulated by the availability of iron because, you know, 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. As in any assembly line process, a defect, or I should say a partial defect, since a completely non-functional step in any assembly line would completely stop it. A partial defect can lead to a bottleneck at the defective step. As a result, you can get abnormal accumulation of the things made in this assembly line prior to the bottleneck step. The same thing happens in heme production.
Inherited defects in each 1 of these 8 enzymes that are responsible for the production of heme results in 1 of the 8 porphyrias. This is summarized here. Disruptions in heme synthesis causes accumulation of porphyrins, which are the chemicals that are made during the process of heme production. There are 8 different porphyrias, each resulting from an inherited mutation in 1 of these 8 heme biosynthesis genes. The porphyrias, we can also classify them into 2 broad categories based on which body system is primarily affected. The first, the erythropoietic porphyrias are the porphyrias that primarily affect the production of heme in red blood cells.
In these porphyrias, the porphyrin intermediates 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. Now we get to EPP. Which is 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 a hydrophobic compound. It accumulates in red blood cells in the plasma and is primarily processed and excreted out of the body via the liver. Protoporphyrin IX is a highly photoreactive 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, excess protoporphyrin IX can crystallize and block bile ducts, which can lead to rapid and severe liver damage. The general symptoms that can present in patients with EPP in the skin because the porphyrin, the protoporphyrin IX chemicals, as I mentioned, can absorb 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 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 causes a very severe and rapid liver injury that can quickly develop into 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. 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.
Thank you very much, Dr. Wang, hello, ladies and gentlemen. I am Professor Deybach, a professor at Paris University, in France, and I was the past head of the French Reference Center for Porphyria and also the past president of the European Porphyria Network. I am a partial consultant for Alnylam Pharmaceuticals, Recordati Rare Diseases, Mitsubishi Tanabe, and also Disc Medicine. We speak today indeed about the clinical aspect of erythropoietic protoporphyria. On the first slide, I would like to remind you, if necessary, that it was the most recently described inherited porphyria. 62 years ago, it was described by Professor Magnus, a dermatologist in the U.K. The title is quite interesting because it was a new porphyria syndrome with solar urticaria due to porphyria anemia.
Everything was focused on the photodermatosis. What did we learn 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. Yes, EPP is a really distressing, painful skin photosensitivity. It starts in early childhood. The penetrance is almost 100%, 100% at the age of 12 or, or 15. Within minutes after exposure to light, especially outdoors, EPP patient experience acute phototoxic reaction that cause severely painful and 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.
Despite this sustained intensity of this burning sensation, at that time, at the beginning, external cutaneous manifestations are rare, and symptoms remain almost invisible. That when the reaction is particularly pronounced, swelling, edema, skin lesion, some type of erosion and crusting may appear hours and days later. Burning sensation can take several days to resolve, and during which patient hide from all light sources to avoid exacerbation. There are also indeed chronic lesion. Mostly, as you can see on the slide, thickened, waxy skin on the hands or linear scars around the mouth. As a first main point, these acute attacks of phototoxic reaction, as we say, they do not respond to painkillers or to anti-inflammatory drugs.
Diagnosis is therefore often delayed in emergency ward or even in internal medicine ward. Major impairment of quality of life for the patient, we will develop that later, and psychosocial complication are the main feature of the disease. On the next slide, as a result, patients with EPP take extreme measure to avoid sunlight. They spend indeed most of their time indoors, avoiding the light to prevent the phototoxic reaction. Indeed, this can cause patient to miss, for instance, at school, many daily activities and make them attending school or work difficult. This is really something difficult for young children at school mainly.
When patient do have to go outside, they completely cover their skin to avoid sun exposure. They wear long sleeves, hats and gloves, even in summer. This add indeed a psychological distress and social isolation to the physical effects of their disease. EPP is not limited to skin photosensitivity. It is not a purely dermatological disease with seasonal onset. It is a chronic metabolic multi-organ disease, as we can see. EPP is a multi-organ, multidimensional disease. It can affect several organs. First, skin, as we have seen, with severe disabling pain attacks. It is mainly affecting the liver and the bile ducts and hepatobiliary organs. We risk for gallstone or liver dysfunction or even liver failure. We will see that later. The bone marrow also with a mild microcytic anemia.
The bone with osteoporosis because of the vitamin D deficiency because of the lack of sun exposure and also systemic inflammation because of activation of the complement. EPP also presenting, as I already said, in early childhood, and this is therefore a lifelong disease. Hepatobiliary disease is potentially severe consequences of liver PP9 accumulation in EPP, because accumulation of protoporphyrin in the liver, as you can see on the right, this is a black liver due to the black color of protoporphyrin. This accumulation, as well as the capacity of the porphyrins 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 initiate a vicious cycle of worsening cholestasis and reduced protoporphyrin expression. It's really something that come over time. Patients can experience a variety of hepatobiliary symptoms that range from gallstone, more than around 25% has gallstone, so 25%-30%. Abnormal liver tests, 30%. Progressive liver disease that could lead to liver failure in, we should say 1%-5%, depend to geographical region. This require indeed liver transplantation, but not only because the new liver, the transplanted liver, could also be aggressed by the protoporphyrin accumulation.
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 limitation that are required to manage the disease can cause mainly anxiety, depression, and isolation. Due to their condition, if EPP patients experience 20% of them anxiety, around 10% of them real depression, I mean real depressive disease, and social isolation by most of the patients. They fear of fatal liver disease indeed, and they have anger and jealousy about missing school or missing works or missing their work or so on. This is a very difficult condition for that, for social, for social because of social isolation.
Many 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. Indeed there is also a lack of awareness of EPP that exacerbates these feelings. Because people around the patient, they don't appreciate the severity of the disease. There is also a lack of awareness in the physician. Also in the teacher at school.
EPP has a negative impact also on the caregivers, because the caregivers they do all their best to protect the EPP patient, but then they feel guilt over the other children because they miss some experiences. This is really true at school. EPP is a rare disease. It's a rare genetic disease but it is often unrecognized. Indeed it is new. 62 years, this is not so much. Indeed this is one of the third most common porphyria, and it is most common porphyria in children. There are only a few patient around the world.
If you look at the prevalence of EPP and also XLP, which is the same disease but not the same genetic background, there are approximately 1 to 75,000 persons. It makes a minimum prevalence of 8,000 EPP patients in the U.S. and E.U. Most patients are diagnosed in 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. There is also a high number of undiagnosed and misdiagnosed EPP patient. Mostly due to the lack of awareness of the disease by the physician who don't know the disease, and it is not yet very well. Porphyria is not well, very well developed at school of medicine.
It's really a problem, awareness, and we're trying to develop that. There are also probably some problem with the genetic prevalence, which is probably higher than we thought before. A recent study has suggested that the disease must have a higher prevalence. EPP treatment, there are really unmet needs and but fortunately there are emerging therapies. Well, actually the treatment of patients with EPP has previously built on photoprotection. By closing sunscreen or afamelanotide, which can protect from the sun and by tanning mostly. There is some effect indeed of this treatment. That is your only treatment available to date.
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. The only way to treat, and this is the emerging therapy that we need, is that to lower the circulating PP IX production of protoporphyrin IX by a VEC. This is a novel approach indeed, and which affects the pathophysiology of the disease. Excuse me. As an example, I want to underline this in very amazing, what you say amazing because the woman here is laughing. She is one of my EPP patient, and She was during the second trimester of pregnancy.
She was lying on a swimming pool under the sun. There is a natural function improvement in women's EPP level. 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 PP IX by roughly 50% decrease in the level. What we expect is a similar result by using a bitopertin treatment. 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 William 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 two types of genetic mutations that underlie 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 move through the pathway, there is a resultant accumulation of protoporphyrin IX that leads to the clinical manifestations just presented.
The right-hand side shows that with the effect of bitopertin treatment, we hypothesized that reducing glycine uptake into red cell precursors will decrease the flux of metabolites through this 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 hypothesize that a 30% or greater reduction in PP IX will lead to a very clinically significant improvement in EPP photosensitivity. On the left-hand side, as Jean-Charles just mentioned, there are literature reports of, and personal experience from Jean-Charles about pregnant people with EPP who have 30%-50% reductions in protoporphyrin IX levels during pregnancy. That reduction is accompanied by a full or near full improvement in light tolerance.
On the right-hand side, summarizing a study of protoporphyrin IX photoinactivation. This was an interventional trial in which patients' blood was removed from the body exposed to light to inactivate PP IX, and then the blood was returned to the patient. This procedure reduced PP IX levels on average by about 30%. The daylight tolerance as a result of this 30% decrease in PP IX increased 14-fold on average. A median amount of light tolerance for someone with EPP is about 30 minutes. 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. Disc Medicine has produced cell and animal models that support the hypothesis that bitopertin can reduce P IX 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. In both cases, treatment with bitopertin at roughly doses that equal a 20-milligram daily dose in humans, protoporphyrin IX is reduced by 45%-73%, well in the range that is observed clinically and that 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, at drug exposures that are we are gonna be using in the clinical trials. We have two ongoing phase 2 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 20 milligrams or 60 milligram doses of bitopertin. These represent mid and high dose levels for a treatment duration of 24 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, and quality of life and other PRO data. The other study is the AURORA trial, also a phase 2 study. This is a randomized, double-blind, placebo-controlled trial that has 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.
Now we have the addition of the placebo group, and we have the advantage of looking at light tolerance in a 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. 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 central role that protoporphyrin IX plays in the disease and the strong relationship between protoporphyrin IX and 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 symptom associated with sunlight exposure.
Prodromal symptoms are a hallmark of EPP. This prodrome or early warning symptom is a phenomenon that occurs in all patients, and it's early warning sensations that a phototoxic reaction is imminent. It's possible for people with EPP to expose skin to sunlight and measure the amount of time until this prodrome starts. Then once the person gets out of the sunlight, the prodrome will go away. This metric of how long it takes until a person gets that prodrome is a measure of their light tolerance. You can recall the photo from Jean-Charles about the pregnant woman in the sun, you know, 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. Upcoming milestones for the development in these two 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 Institutes of Health, that's expected to start in the middle of this year.
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. 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 wanna take that one?
Sure. Well, as you 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. I think a combination of protoporphyrin IX reduction and measures of the different measures of light tolerance are key.
Great. A follow-up question from Julian. What is the FDA's view on PP9 as a registrational endpoint for EPP and XLP?
PP9 is not a precedented surrogate marker in this disease at this time. There's You know, 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 Tadeo of Guggenheim, asking, how should we think about a 30%-50% reduction in PP9 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. The liver disease appeared because of the flow of the protoporphyrin IX through the liver. If you diminish the production of PP9 by the bone marrow, you will indeed decrease this flux across the liver.
I think we would expect the skin symptoms to improve as well. Although, you know, as has been mentioned, we, you know, thus far, don't really have any treatments that are, you know, really effective in sustained reduction of protoporphyrin IX levels. In general, our observations have been that the more severe cutaneous manifestations tend to occur in patients with higher levels of protoporphyrin IX. We would expect that a reduction within, you know, 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? Can we expect to see the initial measures of light tolerance and other PRO data along with the top line?
Yeah, thanks for the question. We've been guiding for our presentation in June, to expect, you know, in a study of total size of about 20 patients to enroll, that we'll have data from roughly 5 to 10 patients. Will, you wanna comment briefly on the kinds of data we may present?
Sure. We're going to be presenting metal-free protoporphyrin IX as our primary endpoint. We do have a number of measures of light tolerance that and PROs that we can select from. Until we, you know, we will be presenting data from that group, but we haven't made a final determination about which ones those will be. I should also add we are gonna present safety data as well.
All right. Next, we have a question from Benjamin Burnett of Stifel. Will he be asking his question live? Go ahead, Ben.
Okay, great. sounds like there's a pretty direct link between PP9 and sunlight-induced pain. I guess I would ask the physicians, is there a threshold of PP9 where above this level patients experience pain? Is that threshold known? if so, like, how does that threshold sort of vary between patients?
Well, I think there is a real threshold and. I'm sorry. Should I answer or-?
Go ahead, Dr. Deybach. Yeah, go ahead. Thank you.
Yeah. Okay. Thank you. Yes. I think there is really a threshold. The threshold is not really just a number. It is also dependent to people, to EPP patient indeed. The usual, I should say. Well, let's say the mean level of PP9 in most of EPP patient is 40. I don't take the other measure, just 40. 40 is the mean level of PP9 in EPP patients. If you have double, you are really painful patient, and you cannot live under the sun. You live in your cellar. You have rapidly liver disease here coming out. If you have 20, you have much less, you know.
If you go below 20, you have almost nothing. That's my experience. Indeed, you know, it's not really precise. The life is more complicated than that. You should also take into account the tanning of the person and everything like that, you know. The color of the skin and also the geography. For instance, which is very curious, there are in EU, so in my experience in the EU, you have more 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 the light, not the sun, but the light. How the light is distributed. In the northern country, the...
in the atmosphere, you have more water, and the diffraction of the light is different, and this selects some wavelengths that target specifically the protoporphyrin IX. It means that most of the patient, in my experience, if they go to the equator, they feel better than if they go to the north. That's quite funny. You know, it's difficult to say that a level of PP9 will be definitively a threshold. It depends where you are living also.
Okay. That's fascinating. Thank you. 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 an oral in this category as well?
Well.
Dr. Dr. Dr. Deybach, you wanna go ahead?
Well, yes, Bruce or myself. Yeah. Well, we have some experience with afamelanotide. Well, in fact, I participate to one of the first clinical trial with Scenesse from Clinuvel. It works quite well, you know. Patients are happy. At least, you know, it's an implant that you have every 2 months. It works really for the first month. After, it's not so good. I think EPP patients, they accept the treatment. Most of them, they feel better after that because it reduce it increase the time to prodrome as presented by Will. It also you can stay longer under the sun. I think it works.
You know, the experience, the most experience with afamelanotide, at least in the literature, come from the Switzerland and from the Netherlands. Because as you know, afamelanotide was Scenesse was approved by EMA first. The experience in EU is quite great. Not in France because Clinuvel decided that we not bring reimbursement so fast. They decided not to bring afamelanotide anymore in France. Our patients in France at least have no afamelanotide, but they go sometimes to Switzerland or to Belgium or whatever. They can have the product. You know, afamelanotide, even if there are. Well, at least I read a recent paper from Elisabeth Minder in Switzerland. Even they say, they say they suggest that afamelanotide could decrease PP9.
I'm not very confident with that results. I think, you know, you can combine both drugs. I think the best indeed is to lower PP IX. Definitely, it is the only way to get out of the liver disease. If you, if you have a drug that lower PP IX and if you need to be protected by another protection drug like afamelanotide, why not? You know, it's not. There are no contraindication to use those. 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 two months at least. There are some people who don't like the tanning at all.
As we know, there is on the, on clinical trial now another afamelanotide drug, like drug, MC1R drug, agonist drug, which is Dersimelagon from Mitsubishi, and this is a pill. I think this could work more easily than the implant from Clinuvel. That's my experience, you know. Definitely, you know, having treated EPP since 40 years, I can tell you that there are probably more confident by a drug which lower really the PP IX than protecting them by a tanning manner. Sorry for my English.
No, thank you.
It's very helpful.
Yeah. I can just, I can just add a little bit on. You know, I think my experience with patients in the U.S. has been similar to what Dr. Deybach just described in the French patients. You know, we also have some issues in the U.S. of access to Scenesse. I would just say that, you know, in general, my patients who are able to get Scenesse or are on it are quite happy with it. I would say that it really highlights the severity of the impact of this disease on the quality of life patients. You know, when you look at the actual improvement on these patients, you're talking about for most patients, maybe on average of 30 minutes, maybe up to 1 hour of additional, you know, direct sunlight time.
For most EPP patients, in fact, for all of my EPP patients, that is a significant improvement for them. That's, you know, and I think if anything, it highlights, you know, 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. I think especially from the patient's perspective that, you know, really any increase in their ability to be outside, matters a lot to the patients.
Yes, I agree indeed. Yes. Thank you, Bruce. The other thing is that Scenesse, the implant is, well, it's not a small implant and could be done for children for the moment, you know. It should be another, those, another type of implant.
Excellent. Okay.
I think it's very important to treat children, at least-
Yeah.
After a year, after 12 year. You know, because the impact at school starts really for not for very young children because while the parents can do that. At the age of 12, teenagers, they are really impacted by the disease, you know, because they cannot go outside, they cannot play any sports or whatever. They should be not under the light in the school. It's very difficult. The teachers, they don't really understand. For the caregivers, it is very difficult to explain to other people what EPP is and for the parents and so on. That's why, you know, we should understand also that EPP patients, they cope with their disease with the age, you know.
That's why we see patients very, with not diagnosed before the age of, I don't know, 40, 50, even 70, as I said before, you know. 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 themselves. Not all patients, and at least 80% of the patients cope really well with their disease. That's why it is sometimes difficult to produce a drug which will help them because they don't go outside. It's difficult to push them to go outside. That's very difficult for clinical trial. We have that.
Yeah. It's really a lifetime of learned behavior in these, you know, in EPP patients.
Great. Thank you. Ben, any more? That's great. Thank you. Thanks for your questions.
Great. Thank you, Ben. Next, we have a question from Jeffrey Hung at Morgan Stanley.
Thanks for taking my questions. I have 2 for Doctors Wang and Deybach. I guess in BEACON and AURORA, multiple types of measures are being made, including light tolerance and hepatobiliary markers. Can you talk about what improvements are most important to patients versus physicians?
Maybe I can start with this. I mean, I think we touched on this a little bit just, you know, with the last question. I think with from patients, I think my patients clearly it's the amount of time that they can spend, you know, in the sun and outside that really any appreciable increase is a huge change in their lifestyle for them. I think from my perspective as a, you know, as a clinician for porphyria patients, that clearly is really important because, you know, again, Dr. Deybach talked about all of the other psychosocial aspects that affect our patients.
Giving them more time to be out in the sun, to be able to lead a more, you know, normal life, I think will have significant impact beyond just, you know, 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. Also I'm a hepatologist, so I just tend to worry more about the liver aspect in EPP. Really, you know, most patients with EPP, you know, we talked about how significantly it affects their life. But it, you know, the cutaneous symptoms really don't, you know, they don't necessarily decrease life expectancy in those patients in EPP patients. It's the liver damage that will.
It's really severe and it progresses really fast. In those, you know, 1%-5% of patients that Dr. Deybach talked about who will develop EPP-induced liver damage, those patients are essentially gonna need a liver transplant or they're gonna die. We thus far have very limited ways of even temporizing that. From my perspective, that's sort of the most exciting thing about the potential for bitopertin 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. I guess given the seven-
with you, Bruce.
Sorry, go ahead.
All right.
He just said he agrees, I think. Go ahead, Jeff.
I guess given the 7-week shorter treatment duration in AURORA versus BEACON and the slight difference of not having XLP patients in AURORA, maybe Doctors Wang and Deybach, can you talk about what you would view as clinically meaningful improvements for these studies on some of those study measures, like changes in blood PP9 levels, the time in daylight without pain, and hepatobiliary markers? Thank you.
Yeah, I guess, I, you know, how I would evaluate the efficacy doesn't, you know, 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.
Yeah.
Okay.
Agreed. Yeah, completely.
Okay, great. Thank you.
Thanks, Jeff.
Great. Thank you, Jeff. Next we have Malcolm from BMO with a question.
Hey, guys. Malcolm Vaughn from Evan Seigerman's team. I just wanted to ask quick. This is more directed towards the Disc Medicine management team, but could you guys give us some more color on how you chose the 20-milligram and 60-milligram dosing for bitopertin in the BEACON trials? Especially given the preclinical mouse model data that we had previously seen. A little bit of color there would be great. Appreciate it.
Sure. I mean, in significant part, the 20 mg dose was chosen as a crosswalk from the dose we're using in the mouse studies. Will, you wanna comment a little more detail?
Sure. We know that protoporphyrin IX reduction is gonna be related to the amount of glycine uptake inhibition that there is. We know from Roche data that basically 20 milligram and 60 milligram daily doses give you mid and high level suppression of glycine uptake in red blood cells. The 20 milligram dose was used extensively in the phase 3 program for Roche, so we got to use a lot of the safety data as being applicable to the study. A 60 milligram dose was also used in phase 2 studies at Roche, but it essentially achieves a maximal suppression of glycine uptake. We wanted, we didn't want to miss because we didn't use a high enough dose.
We think that, you know, because of the mouse data, 20 milligrams, daily dose has a very reasonable chance of providing efficacy, but we wanted to see what maximal would look like as well.
Sure. Thank you. Yeah, it's definitely appreciated.
Great. Thank you, Malcolm, for your question. In the chat, we have a question from Rami Katkhouda of LifeSci Capital, asking, "Is there a lot of variability in measuring light tolerance and time to prodromal symptoms in clinical studies for EPP?
Who wants to start? Will, you wanna start and then see if our panel has comments?
I mean, I'm happy. From my, I mean, discussions with patients themselves and leaders like Bruce and Jean-Charles, I, and reading the literature, my understanding is that while there is some variability, what is key is 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 change within a person is pretty consistent. I would also add that that's why we measure, for example, our time to prodrome endpoint is measured once a week, and we measure it multiple times over the course of the study. For what variability there is, it's averaged over a number of observations.
I think indeed the best control is the patient itself, you know. Indeed, EPP symptoms are really related to many, many factors that are not only the PP IX level, but also, as I said before, where you live, where, what is it, the period of the year. Is that in spring? Is it in autumn or whatever? Where you are situated, you know. I think that's very important. It means that in studies, the best is the patient is itself the control, you know. It's not always possible. As he says to be, we have to obey to clinical trials rules, you know.
That's what is difficult for EPP, you know.
Great. Thanks.
Okay. 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, and we're looking forward to our data presentation in June. 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.
Thank you very much.
Thanks, everyone.
Yep. Thank you.
Great. Thanks, everyone. Goodbye.