Clinuvel Pharmaceuticals Ltd.

EPP is a rare genetic disorder that causes severe burn injuries on the skin following exposure to visible light. Credit: Cavan Images via Getty Images. Disc Medicine has raised $225.5m through an upsized public offering to support the company’s pipeline, including its lead investigational drug, bitopertin. The therapy targets erythropoietic protoporphyria (EPP), a rare genetic disorder that causes extreme light sensitivity. Disc is preparing to file a new drug application (NDA) for the therapy this year, seeking accelerated approval from the US Food and Drug Administration (FDA). The drug candidate is designed to reduce levels of protoporphyrin IX (PPIX), a phototoxic compound that accumulates in the blood of EPP and X-linked protoporphyria (XLP) patients, causing severe pain and burns from even brief sun exposure. Earlier this week, Disc announced feedback from a Type C meeting with the FDA, where the agency finalised its agreement with the design of the upcoming Phase III APOLLO trial, which will evaluate the safety and efficacy of bitopertin. The meeting resulted in the addition of a co-primary endpoint to the trial, which will now assess both changes in PPIX levels and the average time patients can spend in sunlight without pain at the end of six months of treatment. These endpoints are designed to demonstrate bitopertin’s ability to improve a patient’s quality of life by reducing sensitivity to sunlight. This follows an earlier end-of-Phase II meeting with the FDA in which Disc secured support for an accelerated approval pathway based on existing clinical data. At that meeting, the regulator agreed that PPIX reduction could serve as a surrogate endpoint for efficacy. The agency also approved key elements of the Phase III trial design, including its randomised, double-blind, placebo-controlled structure, a six-month treatment duration, and a primary endpoint focused on pain-free sunlight exposure during the final month of treatment. Disc’s prior Phase II study showed that bitopertin was well-tolerated at 20mg and 60mg daily doses over 24 weeks in 22 patients, with no serious adverse events reported. Patients who opted to continue into an open-label extension study for another 24 weeks demonstrated further positive outcomes. These data supported Disc’s decision to pursue accelerated approval and informed the design of the Phase III APOLLO trial, which is set to begin in mid-2025. The APOLLO study will enrol patients aged 12 years and older with EPP or XLP and will include additional secondary endpoints such as cumulative time in sunlight without pain, reductions in phototoxic reactions, and patient-reported global impressions of change. If accelerated approval is granted, data from APOLLO would serve as a confirmatory trial to convert the conditional approval into a full approval. Bitopertin could become the second FDA-approved treatment for EPP, following Clinuvel Pharmaceuticals ’ Scenesse (afamelanotide). Scenesse increases skin pigmentation and protects against light-induced skin damage, allowing patients to spend an additional 20 minutes in sunlight daily without pain as demonstrated in a pivotal trial (NCT01605136). A patient with EPP 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 randomised to control groups, and the risk of a bias in patient selection, as more severely affected patients may hesitate to participate. However, this risk is met with the drive for new treatments and the unmet need for EPP patients.

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.

Dr Jasmin Barman-Aksӧzen speaking at the Outsourcing in Clinical Trials (OCT) DACH 2024 conference in Zurich, Switzerland. Credit: Jenna Philpott / GlobalData. When Dr Jasmin Barman-Aksӧzen began experiencing painful, unexplained burns on her skin, she turned to Wikipedia for answers. After discovering a possible diagnosis, she proposed it to her physician who confirmed that she had erythropoietic protoporphyria (EPP). This ultra-rare genetic disorder causes a phototoxic heme precursor to build up in the red blood cells, resulting in severe burn injuries on the skin after as little as ten minutes of exposure to visible light. At the time of her diagnosis, no treatment existed to alleviate or prevent the symptoms of EPP. “There was no cure, there was no therapy for the pain, and there were no preventive possibilities for this phototoxic reaction, so the only thing we could do was avoid visible light. As you can imagine, that’s socially very isolating, and it’s not compatible with a normal life, and having to avoid light also leads to depression. We sometimes see suicidal ideations,” she explained. Around the same time, Australia-based biotech Clinuvel Pharmaceuticals was in the process of developing afamelanotide – a slow-release treatment now known as Scenesse. The drug increases skin pigmentation and has anti-inflammatory properties, offering protection against light-induced skin damage. Speaking at the Outsourcing in Clinical Trials (OCT) DACH 2024 conference, taking place in Zurich, Switzerland, between 29 and 30 October, Barman-Aksӧzen explained that she joined a University of Zurich research group working on Scenesse as a PhD student. The treatment was already in Phase III trials, and she provided insights on clinical trial design and quality of life (QoL) measures for patients with EPP. See Also: Matinas BioPharma mulls wind-down as antifungal therapy deal falls through Amgen earns higher revenues in Q3 2024, puts rare diseases in the spotlight The results from the 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. Maximally, the patients can spend up to three hours a day in sunlight while using the treatment. They also experienced fewer phototoxic reactions, with symptoms that were less intense and shorter in duration, leading to an overall improvement in quality of life. Though an additional 20 minutes of sun exposure a day may sound minimal, Barman-Aksӧzen highlighted how significant this can be for patients with EPP. Recalling a trip to Berlin, she shared that, without treatment, she wouldn’t have been able to take a taxi with a sunroof without risking a severe phototoxic reaction. “Those are the moments when we are really happy to have the treatment,” she explained. Data from this clinical trial led to Scenesse receiving European approval in 2014. Notably, Barman-Aksӧzen became the first patient to present directly to the European Medicines Agency (EMA) committee before its approval vote, offering insights that clarified both the condition and the treatment’s impact. The EMA subsequently announced that Scenesse was the first drug approved through a European pilot programme that incorporated patient and physician clinical experiences in regulatory decisions – an approach now more widely adopted. In 2019, the US Food and Drug Administration (FDA) followed with its own approval of the drug. Barman-Aksӧzen continues her work advocating for EPP patients and co-founded the International Porphyria Patient Network (IPPN) alongside other patient advocates. While Scenesse brought a treatment option to EPP patients, Barman-Aksӧzen underscored its limitations; it’s a fixed-dose implant for symptomatic relief, which is not scalable and cannot be used for children. Two new candidates, Mitsubishi’s dersimelagon and Disc Medicine’s bitopertin, are being evaluated in clinical trials. These trials present ethical challenges such as the potential for phototoxic burns in control groups, and the risk of a bias in patient selection, as more severely affected patients may hesitate to participate. Barman-Aksӧzen added: “As patients, we’ve requested head-to-head studies. Besides the ethical aspects, I, as a patient, want to know how a new substance compares not only to placebo but also to the existing therapy.”