Accelerated FDA Approval Granted to First Treatment Targeting H3 K27M-Mutant Diffuse Midline Glioma
The Food and Drug Administration (FDA) granted accelerated approval to Modeyso (dordaviprone; Jazz Pharmaceuticals, Dublin, Ireland) for the treatment of adults and children aged ≥1 year with diffuse midline glioma harboring the H3 K27M mutation with disease progression following prior therapy. Modeyso is the first approved treatment for this aggressive and usually fatal brain tumor, which affects approximately 2000 people in the United States annually? including young adults and children. The medication—an oral, once-weekly small molecule that targets mitochondrial ClpP protease and dopamine D2 receptors—was developed to restore the epigenetic regulation disrupted by the H3 K27M mutation. According to a press release issued by Jazz Pharmaceuticals, Modeyso will be commercially available in the United States in Q2 of 2025.
The FDA based its decision to approve Modeyso on data from a phase 2 clinical trial program comprising 5 open-label studies. The integrated efficacy analysis included 50 participants who met prespecified eligibility criteria with recurrent H3 K27M-mutant diffuse midline glioma.
- The overall response rate (ORR) for participants treated with Modeyso was 22% (95% CI, 12 to 36).
- For those who responded to treatment
- The median duration of response was 10.3 months (95% CI, 7.3 to 15.2).
- 73% of responders had a maintained response for ≥6 months.
- 27% of responders had a maintained response for ≥12 months.
Modeyso’s safety was assessed in an analysis of 376 adult and pediatric participants from 4 open-label clinical studies. There were serious adverse reactions reported in 33% of participants, including, most commonly, hydrocephalus, vomiting, headache, seizure, and muscular weakness.
In their statement, Jazz Pharmaceuticals explained that Modeyso’s continued approval for its indication is contingent on the verification and description of clinical benefit and confirmatory results from the ongoing phase 3 ACTION clinical trial (NCT05580562). The company expects Modeyso to be available commercially in the United States soon.
“For the first time, we have an FDA-approved therapy for patients with recurrent H3 K27M-mutant diffuse midline glioma,” said Patrick Wen, MD, Director of the Center for Neuro-Oncology of the Dana-Farber Cancer Institute and Professor of Neurology at the Harvard Medical School. “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 tumor in mind and introduces a new treatment option for a population with historically limited choices.”