X-Linked Lymphoproliferative Disorder

EPP causes severe burn injuries on the skin after as little as ten minutes of exposure to visible light. Credit: Korawat photo shoot via Shutterstock. Disc Medicine has announced a US Food and Drug Administration (FDA) agreement on the regulatory path for its investigational drug bitopertin in treating the rare skin condition erythropoietic protoporphyria (EPP). Following an end of Phase II meeting, the FDA indicated support for an accelerated approval application based on existing clinical data, with the upcoming Phase III trial serving as a confirmatory study. The agency has agreed with Disc’s proposed trial design and endpoints, including the use of protoporphyrin IX (PPIX) reduction as a surrogate marker. This potential approval would hinge on bitopertin’s ability to enable pain-free sunlight exposure for patients with EPP and X-linked protoporphyria (XLP). EPP is a genetic disorder that causes a phototoxic heme precursor to build up in the red blood cells. Both conditions are associated with severe burn injuries on the skin after as little as ten minutes of exposure to visible light. Data from the Phase II trial showed that once-daily doses of bitopertin at 20mg and 60mg were well tolerated over 24 weeks in 22 patients, with no serious adverse events reported. Participants also had the option to continue in an open-label extension of the study for an additional 24 weeks. Disc plans to launch the Phase III APOLLO trial by mid-2025. The FDA agreed that the trial’s primary endpoint – measuring average monthly time in sunlight without pain during the final month of a six-month treatment – appropriately reflects the drugs’ potential benefit. The agency also approved a 60mg dose of bitopertin and a six-month trial duration, along with secondary outcome measures such as PPIX levels, phototoxic reactions, cumulative pain-free sunlight exposure, and patient global impression of change. The APOLLO study will include patients aged 12 and older with EPP or XLP and will follow a single, randomised, double-blind, placebo-controlled design. The company expects to finalise details with the FDA and provide an update on the NDA timeline in Q1 2025. A patient with the rare skin disorder recently highlighted the ethical challenges in EPP trials at the Outsourcing in Clinical Trials (OCT) DACH 2024 conference, in Zurich, Switzerland, between 29 and 30 October. EPP trials have to reckon with the potential for phototoxic burns in participants randomized to control groups, and the risk of a bias in patient selection, as more severely affected patients may hesitate to participate. In the announcement accompanying the update, Disc’s CEO John Quisel said: “We’re particularly excited by the potential to file under the Accelerated Approval Program based on our existing data and use of PPIX reduction as a surrogate endpoint.” There is only one approved treatment for the condition: Scenesse (afamelanotide), developed by Australia-based biotech Clinuvel Pharmaceuticals . The drug increases skin pigmentation and has anti-inflammatory properties, offering protection against light-induced skin damage. The results from a pivotal trial (NCT01605136) showed that patients receiving Scenesse could spend, on average, an additional 20 minutes in sunlight daily without experiencing pain, compared to those on a placebo.

A research team has published rigorous new research that advances a quest to understand a puzzling -- and heartbreaking -- ultra-rare disease that's found almost exclusively in boys. A University of Ottawa-led research team has published rigorous new research that advances a quest to understand a puzzling -- and heartbreaking -- ultra-rare disease that's found almost exclusively in boys. XLP-2 is a genetic X-linked lymphoproliferative disease first described in 2006. It typically has severe complications among patients who become infected with the Epstein-Barr virus, an exceedingly common virus that infects most people without problems in their teenage years or young adulthood. But when the few individuals with XLP-2 encounter the Epstein-Barr virus the experience is often fatal because it results in immunodeficiency -- a derailing of the immune system. The team aimed to examine how the inactivation of a protein-coding gene called XIAP triggers this immunodeficiency, according to senior author Dr. Subash Sad, whose uOttawa Faculty of Medicine lab studies the mechanisms that maintain a healthy immune system and prevent the development of inflammatory diseases. "How inactivation of XIAP results in immunodeficiency was not clear. It was speculated that an inactivation of XIAP impacts T cells directly. However, our work demonstrates that this is not entirely true. We showed inactivation of XIAP impacts the survival of T cells through direct and indirect effects which comprehensively result in a state of immunodeficiency," says Dr. Sad, a cellular immunologist and professor in the Faculty's Department of Biochemistry, Microbiology and Immunology. First author Parva Thakkar and the other researchers used recombinant bacteria and T cell transgenic cells to monitor the impact of XIAP on the differentiation and memory development of T cells following infection. Most of the experiments were done in vivo with a mouse model. Other mechanistic experiments were done in various cells of the immune system. Ultimately, the team's efforts revealed two underlying mechanisms: 1) Inactivation of XIAP results in poor expression of Interleukin-6 (IL-6) which compromises the proliferation of activated T cells, and 2) inactivation of XIAP compromises the ability of activated T cells to survive long-term. The consequence of this phenomenon is that memory T cells, which patrol the body and are induced during prior infections or vaccinations, survive poorly if there is an inactivating mutation in XIAP. This explains the reasons behind immunodeficiency in XLP-2 patients, Dr. Sad says. The study was recently published in PLOS Pathogens. The work was supported by funding from NSERC and CIHR, and it could not have been done without the expertise of the Faculty's Flow cytometry core facility. As the team explores questions suggested by this study, they are interested in examining downstream mechanisms and pathways that can be targeted for therapy. They are also interested in working with patient samples. Dr. Sad encourages families with such mutations to get in contact with CHEO, an institutional partner of the uOttawa Faculty of Medicine.

Consistent and dose-dependent reductions of protoporphyrin IX (PPIX), the disease-causing metabolite in EPP, were observed in patients treated with bitopertin Patients reported significant improvements in sunlight tolerance and measures of quality-of-life Bitopertin was well-tolerated, with no meaningful changes in hemoglobin observed Disc Medicine to host an investor conference call today at 7:30 AM ET WATERTOWN, Mass., June 09, 2023 (GLOBE NEWSWIRE) -- Disc Medicine, Inc. (NASDAQ:IRON), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of novel treatments for patients suffering from serious hematologic diseases, today presented preliminary findings from its ongoing, Phase 2 open-label BEACON trial evaluating bitopertin, an orally administered glycine transporter 1 (GlyT1) inhibitor, in patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) at the European Hematology Association (EHA) 2023 Congress in Frankfurt, Germany. The initial trial data demonstrated consistent decreases in PPIX, significant increases in reported sunlight tolerance and improvements in measures of patient quality of life. “We’re delighted to share these initial, positive data from BEACON, which provide the first clinical evidence supporting our therapeutic hypothesis of bitopertin in EPP. Over the next 12 months, we plan to build on this momentum with a series of additional clinical read-outs across our portfolio,” said John Quisel, J.D., Ph.D., Chief Executive Officer and President of Disc Medicine. “This is an important moment for Disc as a company, and I want to extend my gratitude to our team, collaborators, and most importantly, the patients and families participating in BEACON.” “We are excited to share these initial data from the BEACON trial, where we observed consistent and sustained suppression of PPIX, the disease-causing metabolite in EPP, in patients treated with bitopertin,” said Will Savage, M.D., Ph.D., Chief Medical Officer at Disc Medicine. “Importantly, this reduction translated into significant improvements in the time that patients can spend in sunlight without reporting pain or symptoms related to their disease. We’re encouraged by the data and plan to present additional data at the end of the year.” The BEACON trial is a randomized, open-label, parallel-arm trial enrolling up to 22 patients with EPP or XLP at trial sites in Australia. This trial was designed to assess changes in levels of PPIX, as well as measures of photosensitivity, quality of life, and safety and tolerability. Subjects are randomized to receive either 20 mg or 60 mg of bitopertin once-daily for 24 weeks, after which patients have the option of continuing in an open-label extension of the trial for up to an additional 24 weeks. The trial is ongoing and these data reflect initial data from 15 subjects enrolled as of the data cutoff of May 8, 2023, with a range of treatment durations from 18 days to 6 months. Due to batch processing of samples, the data cutoff for PPIX data was April 7, 2023. Highlights of the initial data presented: Protoporphyrin IX (PPIX) levels: Significant, consistent, dose-dependent, and sustained reductions of whole-blood, metal-free PPIX; mean reduction of >40% when compared to baseline Measures of light tolerance (individual) from two participants with the longest follow-up demonstrated substantial increases in sunlight tolerance as measured by time in sunlight without experiencing a prodrome (initial symptoms that signal a pain attack), or “sunlight challenge”: A participant on 20 mg bitopertin reported a >80-fold increase in sunlight tolerance on day 88 of treatment, increasing from 4.5 minutes at baseline to over 6 hours; the participant did not report a prodrome during any sunlight challenge after Day 20 A participant on 60 mg bitopertin reported a >200-fold increase in sunlight tolerance on day 74 of treatment, increasing from 1.25 minutes at baseline to over 4 hours, and did not report a prodrome during any sunlight challenge after Day 120 Measures of light tolerance (aggregated across participants from whom data was available in the trial): Average weekly total time spent in sunlight: increased from 344 minutes (approximately 49 minutes per day) to 1,200 minutes at Week 24 Time to prodrome during sunlight challenge (averaged over a two-week period): increased >7-fold, from 25 minutes at baseline to 182 minutes at Week 24 Increased proportion of days without symptoms: 75% vs. 25% (baseline) Increased proportion of sunlight challenges without prodromes: 50% vs. 0% (baseline) Phototoxic reactions: 96% reduction in patient-reported phototoxic reactions while on treatment compared to baseline (n=15) Measures of patient quality of life Patient Global Impression of Change (PGIC): All 10 patients that had completed a day 43 visit reported their disease was much better (n=8) or a little better (n=2) in the last 7 days Patient Global Impression of Severity (PGIS): Nine out of 10 patients that had completed a day 43 visit reported their EPP was mild (n=3) or not at all severe (n=6) EPP Impact Questionnaire (EPIQ): For patients whose most recent data was Day 43, 4/8 patients reported an improvement in the impact of EPP on quality of life and 4/8 reported no change in the impact of EPP on quality of life. For patients whose most recent data was after Day 43, 2/2 reported marked improvement in the impact of EPP on quality of life, reporting no impact of EPP on quality of life. Bitopertin was well-tolerated at both dose levels with no reported serious adverse events, no reported discontinuations or dose reductions, no reported adverse events greater than Grade 1, and no meaningful changes observed in mean hemoglobin levels These data were presented at the European Hematology Association 2023 Congress in Frankfurt, Germany and the poster is available on the EHA Congress platform at . Management will host a call to review the presented data on Friday, June 9th at 7:30 am ET. Please register for the event on the Events and Presentations page of Disc’s website ( ). About Bitopertin Bitopertin is an investigational, clinical-stage, orally-administered inhibitor of glycine transporter 1 (GlyT1) that is designed to modulate heme biosynthesis. GlyT1 is a membrane transporter expressed on developing red blood cells and is required to supply sufficient glycine for heme biosynthesis and support erythropoiesis. Disc is planning to develop bitopertin as a potential treatment for a range of hematologic diseases including erythropoietic porphyrias, where it has potential to be the first disease-modifying therapy. There are currently two ongoing Phase 2 clinical trials of bitopertin in patients with erythropoietic porphyria, including an open-label trial called BEACON and a randomized, double-blind placebo-controlled trial called AURORA. Bitopertin is an investigational agent and is not approved for use as a therapy in any jurisdiction worldwide. Disc obtained global rights to bitopertin under a license agreement from Roche in May 2021. About Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP) Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, debilitating and potentially life-threatening diseases caused by mutations that affect heme biosynthesis, resulting in the accumulation of a toxic, photoactive intermediate called protoporphyrin IX (PPIX). This causes severe reactions when patients are exposed to sunlight, characterized by excruciating pain, edema, burning sensations and potential blistering and disfigurement. PPIX also accumulates in the hepatobiliary system and can result in complications including gallstones, cholestasis, and liver damage in 20-30% of patients and in extreme cases liver failure. Current standard of care involves extreme measures to avoid sunlight, including restricting outdoor activities to nighttime, use of protective clothing and opaque shields, and pain management. This has a significant impact on the psychosocial development, quality of life, and daily activities of patients, particularly in young children and families. There is currently no cure for EPP and only one FDA-approved therapy, a surgically implanted synthetic hormone designed to stimulate melanin production called Scenesse® (afamelanotide). About Disc Medicine Disc Medicine is a clinical-stage biopharmaceutical company committed to discovering, developing, and commercializing novel treatments for patients who suffer from serious hematologic diseases. We are building a portfolio of innovative, potentially first-in-class therapeutic candidates that aim to address a wide spectrum of hematologic diseases by targeting fundamental biological pathways of red blood cell biology, specifically heme biosynthesis and iron homeostasis. 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