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Jazz Pharmaceuticals plc, a global biopharma company, announced that the US Food and Drug Administration (FDA) has granted accelerated approval for Modeyso (dordaviprone) for the treatment of adult and paediatric patients 1 year of age and older with diffuse midline glioma harbouring an H3 K27M mutation with progressive disease following prior therapy. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the phase 3 ACTION confirmatory trial.
Modeyso is the first and only treatment option approved by the FDA for this ultra-rare and aggressive brain tumour that affects an estimated 2,000 people in the US each year, many of whom are children and young adults. The disease is characterized by rapid progression and historically has had no effective systemic treatment options. To address this urgent unmet patient need, Modeyso is expected to be commercially available in the coming weeks.
"This is a major turning point in neuro-oncology," said Patrick Wen, M.D., director, Center for Neuro-Oncology, Dana-Farber Cancer Institute and Professor of Neurology, Harvard Medical School. "For the first time, we have an FDA-approved therapy for patients with recurrent H3 K27M-mutant diffuse midline glioma. While outcomes remain challenging for many patients, the objective responses observed with dordaviprone, including durable benefit in some patients, represent a meaningful advancement. This therapy was developed with the underlying biology of the tumour in mind and introduces a new treatment option for a population with historically limited choices."
Modeyso is administered as an oral capsule once weekly. The FDA's decision was based on an integrated efficacy analysis of 50 patients with recurrent H3 K27M-mutant diffuse midline glioma, selected from five open-label clinical studies based on prespecified eligibility criteria. The overall response rate (ORR), as assessed by blinded independent central review (BICR) using Response Assessment in Neuro-Oncology (RANO) 2.0 criteria, was 22% (95% CI: 12 to 36), with an additional responder identified by integrated RANO 2.0. Among responders, the median duration of response was 10.3 months (95% CI: 7.3 to 15.2), with 73% maintaining their response for at least six months and 27% for at least 12 months.
"The FDA approval of Modeyso is a milestone moment for the patients and families who have long needed new options, the clinicians who have tirelessly searched for solutions, and the researchers and advocates who never gave up," said Joshua E. Allen, Ph.D., chief scientific officer, Chimerix, a Jazz Pharmaceuticals Company. "We're proud to deliver precisely the kind of transformative innovation we strive for, and we congratulate our combined Chimerix and Jazz team, and the community who worked together tirelessly to bring this treatment forward. This approval not only equips clinicians with the first targeted option for this disease but also signals a meaningful shift in what patients and families can expect after diagnosis. We would like to extend our thanks to the patients, advocates, clinicians, principal investigators, scientists, regulators and partner institutions who made this possible."
"This approval represents a long-awaited treatment option for families affected by H3 K27M-mutant diffuse midline glioma," said David F. Arons, president and chief executive officer of the National Brain Tumour Society. "This is a fast-moving, devastating disease that turns families' lives upside down. For years, this diagnosis has lacked an approved treatment and today, that changes. Families finally have a treatment option, and a reason to believe in more time together to make memories that might not have otherwise been possible."
The safety of Modeyso was evaluated in 376 adult and paediatric patients with glioma across four open-label clinical studies. Serious adverse reactions occurred in 33% of patients. Serious adverse reactions reported in more than 2% of patients included hydrocephalus (5%), vomiting (4.3%), headache (3.2%), seizure (2.4%) and muscular weakness (2.1%). The most common adverse reactions in patients who received Modeyso (=20%) were fatigue, headache, vomiting, nausea and musculoskeletal pain.
The efficacy and safety of Modeyso were evaluated in adult and paediatric patients with glioma across five open-label, non-randomized clinical studies (ONC006, ONC013, ONC014, ONC016, and ONC018). A pre-specified integrated efficacy analysis included 50 patients with recurrent H3 K27M-mutant diffuse midline glioma who had measurable disease per Response Assessment in Neuro-Oncology (RANO) criteria. Tumour response was assessed every eight weeks by blinded independent central review (BICR). The primary efficacy endpoint was objective response rate (ORR). Safety was evaluated across four of the clinical studies.
H3 K27M-mutant diffuse midline glioma is a rare and highly aggressive brain tumour that primarily affects the midline structures of the brain and spinal cord. It is characterized by a specific genetic mutation (H3 K27M) that disrupts epigenetic regulation and drives tumour growth. Most commonly diagnosed in children and young adults, patients with this type of glioma often face an extremely poor prognosis, with limited therapeutic options and very low survival rates following recurrence. Median survival is approximately one year from diagnosis and less than six months after progressing following frontline therapy.
Modeyso (dordaviprone) is approved by the US Food and Drug Administration (FDA) for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy. Modeyso is an orally administered small molecule given once weekly. Modeyso is a protease activator of the mitochondrial caseinolytic protease P (ClpP) and also inhibits dopamine D2 receptor (DRD2). In vitro, dordaviprone activates the integrated stress response, induces apoptosis, and alters mitochondrial metabolism, leading to restored histone H3 K27 trimethylation in H3 K27M-mutant diffuse glioma.
Modeyso received accelerated approval based on a pre-specified integrated efficacy analysis of 50 adult and paediatric patients with recurrent H3 K27M-mutant diffuse midline glioma enrolled across five open-label clinical studies (ONC006, ONC013, ONC014, ONC016, and ONC018). Continued approval may be contingent upon verification and description of clinical benefit in the ongoing phase 3 ACTION trial (NCT05580562), which is evaluating the safety and clinical benefit of Modeyso in newly diagnosed patients with H3 K27M-mutant diffuse glioma following radiotherapy. Modeyso was developed by Chimerix prior to its acquisition by Jazz Pharmaceuticals in April 2025.
Modeyso (dordaviprone) is not approved anywhere else in the world.
Jazz Pharmaceuticals plc is a global biopharma company whose purpose is to innovate to transform the lives of patients and their families. The company is dedicated to developing potentially life-changing medicines for people with serious diseases – often with limited or no therapeutic options.
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