FDA Approves First Targeted Therapy for Recurrent H3 K27M-Mutant Diffuse Midline Glioma
Washington D.C. – August 6, 2024 – In a landmark decision for neuro-oncology, the U.S. Food and Drug Governance (FDA) today approved dordaviprone (marketed as Modeysoยฎ by Jazz Pharmaceuticals) as the first and only treatment specifically for adults and pediatric patients (age 2+) with recurrent H3 K27M-mutant diffuse midline glioma (DMG). This approval marks a critically important breakthrough for a patient population with historically limited treatment options and a devastating prognosis.
Understanding Diffuse Midline Glioma & the H3 K27M mutation
Diffuse midline glioma is an aggressive and often fatal brain tumor that primarily affects children and young adults. DMG arises in the central nervous system, typically along the midline – the brain’s central axis. The H3 K27M mutation is a genetic alteration found in approximately 20-30% of DMGs, and its presence is strongly associated with poorer outcomes. Prior to dordaviprone,treatment options were largely limited to surgery,radiation,and standard chemotherapy,offering modest benefits and often significant side effects.The identification of the H3 K27M mutation as a key driver of tumor growth paved the way for the development of targeted therapies like dordaviprone.
Clinical Trial Results Demonstrate Promising Efficacy
The approval of dordaviprone is based on data from a pooled analysis of clinical trial results published in the Journal of Clinical Oncology in 2024. The analysis, assessed by blinded independent central review using RANO 2.0 criteria, showed an objective response rate of 22% (95% CI, 12%-36%). Integrated RANO 2.0 criteria identified an additional patient as a responder.key findings from the study include:
Duration of Response: the median duration of response was 10.3 months (95% CI, 7.3-15.2). A substantial 73% of patients maintained their response for at least 6 months, and 27% experienced a response lasting 12 months or longer.
Time to Response: The median time to response was 8.3 months (range, 1.9-15.9).
Corticosteroid Reduction: 46.7% (95% CI, 21.3%-73.4%) of evaluable patients (7 of 15) experienced a 50% or greater reduction in corticosteroid dosage, indicating a lessening of tumor-related swelling and pressure.
Safety Profile: The treatment was generally well-tolerated. 20% of patients experienced grade 3 treatment-related adverse events, with fatigue being the most common (affecting 10% of patients). No grade 4 adverse events,treatment discontinuations due to adverse events,or deaths related to the treatment were reported.
How Dordaviprone Works
Dordaviprone is an oral inhibitor of the bromodomain and extra-terminal domain (BET) protein family. BET proteins play a crucial role in regulating gene expression, and in H3 K27M-mutant DMG, they contribute to uncontrolled tumor growth. By inhibiting BET proteins, dordaviprone aims to disrupt the tumor’s growth cycle and induce cell death. The drug’s development was guided by a deep understanding of the underlying biology of the tumor, representing a precision medicine approach.
Expert Reactions & Patient Advocacy
“This is a major turning point in neuro-oncology,” stated Patrick Wen, MD, director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and professor of neurology at 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.”
David F.Arons, president and CEO of the National Brain Tumor Society, echoed this sentiment, emphasizing the hope this approval brings to families. “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.”
Looking Ahead
The approval of dordaviprone represents a critical step forward in the fight against H3 K27M-mutant DMG. Further research is ongoing to explore the potential of dordaviprone in combination with other therapies and to