Modeyso (dordaviprone)

The first and only FDA-approved drug for H3 K27M-mutant diffuse midline glioma, for use after the tumor has grown despite earlier treatment. Its approval rests on tumor response, and whether it helps people live longer is still being tested.

Diffuse midline gliomas with the H3 K27M mutation carry a change in a histone, one of the proteins that package DNA. The mutation is linked to the loss of a chemical tag on histones called H3 K27 trimethylation, which helps keep certain genes turned off. Dordaviprone switches on ClpP, an enzyme inside mitochondria (the cell's power plants), and also blocks the dopamine D2 receptor. In lab studies of H3 K27M-mutant glioma, this set off a cellular stress response, changed the tumor cells' energy use, restored the missing histone tag and caused the cells to die^[1]. Whether these effects help patients live longer is still being tested in confirmatory trials^[2].

Modeyso has no boxed warning and no contraindications. It can cause severe allergic reactions (grade 3 in 0.3% of patients), with signs such as rash, hives, fever, low blood pressure, wheezing or swelling of the face or throat. It can lengthen the QT interval, a measure of the heart's electrical recovery, which can lead to dangerous heart rhythms: among 82 patients with a follow-up heart tracing, 6% had an increase of more than 60 milliseconds and 1.2% reached more than 500 milliseconds. It can harm an unborn baby, so females who could become pregnant and males with such partners need effective birth control during treatment and for 1 month after, and breastfeeding should stop until 1 week after the last dose. It may also reduce fertility. In 376 people with glioma across 4 studies with no placebo group, the most common side effects were fatigue (34%), headache (32%), vomiting (24%), nausea (24%), muscle and bone pain (20%), trouble walking (16%), cranial nerve problems such as facial weakness (16%), weakness on one side of the body (15%), slurred speech (13%), dizziness (13%), trouble swallowing (13%) and muscle weakness (13%). Serious side effects occurred in 33%, most often fluid buildup in the brain (hydrocephalus, 5%), and 1% had fatal reactions. Only 2.1% stopped treatment because of side effects^[1].

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Approved for adults and children 1 year and older with diffuse midline glioma that carries an H3 K27M mutation and has progressed after earlier treatment. The mutation must be confirmed in a tumor sample, and the label notes there is no FDA-approved test for it yet. A dose has not been set for children under 10 kg. The efficacy analysis required patients to be at least 90 days past radiation, with measurable tumor and a performance score of 60 or higher, and it excluded DIPG, spinal tumors and spread to the spinal fluid. About a third (33%) of the 376 patients in the safety data had DIPG. The ACTION trial for newly diagnosed patients also excludes DIPG.

Source: ChimerixCares patient support

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Accelerated approval rested on an integrated analysis of 50 patients with recurrent H3 K27M-mutant diffuse midline glioma who took Modeyso alone in 5 open-label studies with no comparison group: ONC006 (NCT02525692), ONC013 (NCT03295396), ONC014 (NCT03416530), ONC016 (NCT05392374) and ONC018 (NCT03134131). The median age was 31, only 4 patients were aged 9 to 17, and patients with DIPG, spinal tumors or spread to the spinal fluid were excluded. Tumors responded in 22% by blinded independent review using RANO 2.0 criteria (16% partial and 6% minor responses), and responses lasted a median of 10.3 months, with 73% lasting at least 6 months and 27% at least 12 months^[1][5]. The confirmatory Phase 3 ACTION trial (NCT05580562) is comparing once-weekly and twice-weekly Modeyso with placebo after radiation in an estimated 510 people with newly diagnosed H3 K27M-mutant diffuse glioma, with overall survival as the main measure, and it excludes DIPG^[6][4].

Chimerix developed dordaviprone under the code ONC201^[4]. It submitted its new drug application on December 18, 2024, and the FDA granted accelerated approval on August 6, 2025 under priority review, with a rare pediatric disease priority review voucher and without an advisory committee meeting^[2][3]. Jazz Pharmaceuticals, which acquired Chimerix in April 2025, announced the approval and named the Phase 3 ACTION trial as the confirmatory study^[4]. The FDA's approval letter requires a randomized, multiregional trial with overall survival as the main measure, due to finish in January 2031, and a separate trial in patients under 17 that includes enough children with DIPG, with a final protocol due in August 2026 and a final report in July 2031^[2].