Dordaviprone under FDA priority review for aggressive glioma type
Chimerix therapy designed to treat brain tumors due to H3 K27M mutation
The U.S. Food and Drug Administration (FDA) has agreed to a priority review of a Chimerix application seeking accelerated approval of dordaviprone, its oral therapy candidate for people with recurrent, diffuse glioma — a group of brain tumors — positive for the H3 K27M mutation.
Recurrent means the cancer has come back after initial treatment, while diffuse means it’s spread from its initial location and has widely infiltrated healthy brain tissue. Should dordaviprone be approved, it could be the first therapy specifically indicated for this aggressive type of brain cancer, according to Chimerix.
U.S. regulators have now granted the application — which Chimerix submitted at the end of last year — priority review, which shortens the standard review time from about 10 months to six. A decision is expected by Aug. 18.
“This significant milestone brings us one step closer to our goal of accelerating access to the first medicine specific to patients diagnosed with recurrent H3 K27M-mutant diffuse glioma,” Mike Andriole, CEO of Chimerix, said in a company press release.
With FDA priority review, an approval decision is now due by Aug. 18
Meanwhile, an ongoing Phase 3 trial, dubbed ACTION (NCT05580562), is testing dordaviprone’s ability to extend patient survival versus a placebo. The global trial enrolled people with newly diagnosed H3 K27M-mutant diffuse glioma who had received first-line radiation therapy. It’s still recruiting at more than 150 sites worldwide.
Certain patients who cannot access the therapy in clinical trials may also be able to receive it through an ongoing expanded access program (NCT04617002) that’s available at 25 U.S. sites.
Gliomas are tumors that form in the support cells of the nervous system. H3 K27M-positive gliomas are an aggressive form of this cancer that most often occurs in children and young adults.
The H3 K27M mutation disrupts processes that normally regulate genes. In turn, abnormal gene activity contributes to uncontrolled cell growth that allows the tumor to take over healthy brain tissue. H3 K27M-positive gliomas are generally resistant to standard treatments.
“Patients with this form of high-grade glioma face a very difficult prognosis with few treatment options beyond palliative care,” Andriole said.
Our team is working expeditiously with FDA to facilitate their review as we simultaneously prepare for a potential commercial launch in order to ensure rapid availability to patients in need.
Dordaviprone, also known as ONC201, is a first-in-class oral small molecule designed to interfere with two processes that glioma cells use to survive. Chimerix is also looking at its potential to treat other forms of advanced cancer.
First, dordaviprone blocks the dopamine receptor D2, or DRD2, a protein that helps activate a cell growth-promoting signaling pathway in the brain on which glioma cells rely. By inhibiting it, dordaviprone aims to prevent the cancer cells from multiplying.
The medication also activates ClpP, an enzyme involved in maintaining the health of mitochondria, the organelles responsible for producing cellular energy. By increasing ClpP activity, dordaviprone degrades mitochondrial proteins needed for energy production, thereby depriving tumor cells of the energy they need to survive.
Chimerix is seeking dordaviprone’s approval under the FDA’s accelerated review pathway. This allows the regulatory body to conditionally approve a treatment based on preliminary evidence suggesting that it will be of benefit; to convert to a full approval, confirmatory studies are still required.
“Our team is working expeditiously with FDA to facilitate their review as we simultaneously prepare for a potential commercial launch in order to ensure rapid availability to patients in need,” Andriole said.
Over 25% of patients saw reductions in tumor growth with dordaviprone
Some of the data supporting the application are from an analysis covering 50 people with recurrent H3 K27M-positive diffuse gliomas who received dordaviprone across five different studies. [here]
The results showed that more than a quarter of patients (28%) experienced at least a partial reduction in tumor growth with dordaviprone. A total of 40% experienced either tumor shrinkage or stable disease. Responses lasted a median of 10.4 months, with 27% of patients alive without cancer progression after a year.
With some FDA submissions, the agency will hold an advisory committee meeting before making a decision, in which scientific experts discuss the application and offer independent advice. Chimerix indicated that there are no plans to hold such a meeting prior to the FDA’s decision on dordaviprone.
Dordaviprone has been granted orphan drug designation in the U.S., the European Union, and Australia, as well as fast-track designation in the U.S. These statuses offer various financial incentives and regulatory support to help speed a treatment’s development.
The therapy also holds rare pediatric disease designation in the U.S. This status allowed Chimerix to apply for a rare pediatric disease priority review voucher when it submitted the application.
That means that, should dordaviprone be approved, the company could receive a voucher it can redeem to receive priority review for another product later on. The voucher can also be transferred or sold.
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