Exploring the FDA Approval of Dordaviprone for Mutant Diffuse Midline Gliomas With Patrick Wen, MD

Recently, the FDA granted accelerated approval to dordaviprone (Modeyso™, Jazz Pharmaceuticals, Inc.), a protease activator, for adult and pediatric patients one year of age and older with diffuse midline glioma harboring an H3 K27M mutation and progressive disease following prior therapy. In this interview, Dr. Patrick Wen, one of the clinical trial authors and Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and Professor of Neurology at Harvard Medical School, sits down to discuss the approval of dordaviprone for diffuse midline gliomas, including: an overview of the clinical context, trial data, implications for practice, and future directions in glioma treatment.

Background and Clinical Context

Dr. Wen explains that the journey with dordaviprone began with its use in glioblastomas, and attention shifted to diffuse midline gliomas after a significant patient response was observed. Genetic sequencing revealed the presence of the H3 K27M mutation, which became the focus for subsequent research.

Diffuse midline gliomas are described as “perhaps the hardest to treat of all types of glioma.” Their location in the midline of the brain makes surgical intervention impossible, and they are typically unresponsive to standard chemotherapy such as temozolomide. “The only treatment that’s effective is radiation, and that usually helps for less than a year before the tumors come back,” Dr. Wen explains. Until now, no drug had been approved for this indication.

Mechanism of Action and Clinical Trial Data

Dordaviprone operates via two mechanisms: it is a dopamine receptor 2 and 3 inhibitor, which blocks pathways involved in tumor growth, and it stimulates caseinolytic protease P (ClpP), affecting mitochondrial metabolism and promoting tumor cell death. “The thought is that both mechanisms come into play in slowing down the growth of these tumors,” Dr. Wen states.

The pivotal study leading to approval focused on patients with measurable diffuse midline gliomas. Dr. Wen highlights a key challenge: “Many of the tumors are very difficult to measure,” particularly diffuse intrinsic pontine gliomas (DIPG) in children and in spinal cord tumors, which do not enhance on imaging. The FDA recommended a dataset of about 50 patients with measurable tumors, most of which were located high in the brainstem, usually in the thalamus. “These 50 measurable tumors allowed us to tell whether the drug produced a response or not. In a subset of these patients, there were responses that were quite durable, and that led to the approval of this drug.”

Dr. Wen also emphasizes the favorable safety profile: “Unlike many targeted therapies, it’s well tolerated. You take it once a week—it’s a pill. Although some patients can be tired or have mild nausea or headaches, most patients actually don’t feel like they’re on medicines that affect their quality of life.”

Implications for Practice and Future Directions

While the approval is a significant milestone, Dr. Wen cautions that “this drug still only helps a small subset of these patients, so we definitely need to develop additional therapies.” The current approval is for recurrent tumors, but a phase 3 trial is underway for newly diagnosed H3 K27M–mutated gliomas, with the hope that positive results will lead to full approval.

Dr. Wen sees broader implications for the field: “Now that this drug is available, I think there are a number of potentials. One is that because it’s so well tolerated, you can imagine combining it with other agents and developing more innovative therapies.” He also notes the importance of regulatory precedent: “This is an area where no drug has been approved before and the population is small, and many companies are not really interested in developing the drugs for this population, even though it’s so desperately needed for the patients that are affected. Now that there’s an approval, it shows that there’s a path to getting regulatory approval for these drugs.”

Advice for Clinicians

Dr. Wen advises clinicians that the strongest data for dordaviprone is in tumors “higher up in the brainstem, mainly thalamic gliomas.” While it has been evaluated in DIPG, these tumors are harder to measure, and up-to-date data may be available from the manufacturer.

Closing Thoughts

Dr. Wen concludes: “This is an important step forward for our patients. Even though it doesn’t help every patient, it does allow some patients to have a benefit from a drug that doesn’t have a lot of side effects. Hopefully, our field can build on this and develop better treatments for our patients.”

Key Takeaways

Dordaviprone is the first FDA-approved drug for diffuse midline gliomas, a highly challenging and previously untreatable form of brain tumor.
The drug works by inhibiting dopamine receptors and stimulating mitochondrial pathways, leading to tumor cell death.
Clinical trials demonstrated durable responses in a subset of patients with measurable tumors, particularly thalamic gliomas.
Dordaviprone is well tolerated, taken as a weekly oral pill, with minimal impact on quality of life.
The approval sets a regulatory precedent and may encourage further drug development for rare brain tumors.
Ongoing trials will determine its role in newly diagnosed patients and in combination therapies.
Clinicians should be aware that the strongest evidence supports use in thalamic gliomas, with further data pending for other subtypes.

About Dr. Wen

Patrick Wen, MD, is the Director of the Center for Neuro-Oncology at Dana-Farber Cancer Institute and Professor of Neurology at Harvard Medical School. His work primarily focuses on the treatment of various brain tumors, with a particular emphasis on gliomas. He played a pivotal role in the research and development of dordaviprone, a newly FDA-approved drug for diffuse midline gliomas.