Modeyso Approved for H3 K27M-Mutant Diffuse Midline Glioma

The Food and Drug Administration (FDA) has granted accelerated approval to Modeyso^™ (dordaviprone), a protease activator, for the treatment of adult and pediatric patients aged 1 year and older with diffuse midline glioma harboring an H3 K27M mutation with progressive disease following prior therapy.

The approval was supported by data from 5 open-label, nonrandomized, clinical trials: ONC006 (ClinicalTrials.gov Identifier: NCT02525692), ONC013 (ClinicalTrials.gov Identifier: NCT03295396), ONC014 (ClinicalTrials.gov Identifier: NCT03416530), ONC016 (ClinicalTrials.gov Identifier: NCT05392374), and ONC018 (ClinicalTrials.gov Identifier: NCT03134131). 

The efficacy population included 50 patients with diffuse midline glioma harboring an H3 K27M mutation who had progressive and measurable disease per Response Assessment in Neuro-Oncology-High Grade Glioma (RANO-HGG) criteria.

To be included in the study, participants also had to meet the following criteria:

• At least 90 days post radiation therapy;
• Adequate washout period from prior anticancer therapies;
• Karnofsky Performance Status/Lansky Performance Status score of 60 or more; and
• Stable or decreasing corticosteroid use.

Findings showed the overall response rate (primary endpoint; assessed by blinded independent central review according to RANO 2.0 criteria) was 22% (95% CI, 12-36), with 16% of patients experiencing a partial response and 6% experiencing a minor response.

Median duration of response was 10.3 months (95% CI, 7.3-15.2). Among responders (n=11), 73% maintained a response for at least 6 months and 22% maintained a response for at least 12 months. The median time to response was 3.6 months (range, 1.6-15.6).

The most common adverse reactions reported with dordaviprone were fatigue, headache, vomiting, nausea, and musculoskeletal pain. Grade 3 or 4 laboratory abnormalities that occurred in at least 2% of patients were decreased lymphocytes, decreased calcium, and increased alanine aminotransferase. 

Additional warnings and precautions included hypersensitivity, QTc interval prolongation, and embryo-fetal toxicity. Given the risk of QT interval prolongation, electrocardiograms and electrolytes should be monitored before starting Modeyso and periodically during treatment as clinically indicated.

Modeyso is supplied as a 125mg capsule. Patients should be selected for treatment based on the presence of an H3 K27M mutation from tumor specimens. The recommended dosage for adults is 625mg orally once weekly, taken on an empty stomach. For pediatric patients, the dose is based on body weight; a recommended dosage has not been established for patients weighing less than 10kg. 

Treatment should continue until disease progression or unacceptable toxicity. If adverse reactions occur, dosage modification is recommended. Capsules may be opened and mixed with a liquid to ease administration for younger patients.

Continued approval of this indication is contingent upon verification of clinical benefit in the confirmatory phase 3 ACTION trial (ClinicalTrials.gov Identifier: NCT05580562). The trial will evaluate the safety and efficacy of dordaviprone in newly diagnosed patients with H3 K27M-mutant diffuse glioma following radiotherapy. 

According to Jazz Pharmaceuticals, Modeyso is expected to be available in the coming weeks.

This article originally appeared on MPR