FDA Accepts, Grants Priority Review to NDA for Vorasidenib in IDH-Mutant Gliomas

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The FDA has granted Priority Review status to a New Drug Application (NDA) for vorasidenib, Servier’s targeted therapy for isocitrate dehydrogenase (IDH)-mutant diffuse glioma. If approved, the oral, selective brain-penetrant dual inhibitor of mutant IDH 1 and 2 (IDH1/2) enzymes would be a first-in-class targeted treatment for IDH-mutant gliomas, as well as Servier’s sixth approved treatment across this disease.¹

“In the realm of glioma treatment, innovation has been stagnant for nearly a quarter-century, posing challenges for patients who, post-surgery, may opt to defer treatment due to concerns around potential toxic side effects. As a drug specifically designed to be highly blood-brain barrier penetrant, vorasidenib has demonstrated clinically meaningful efficacy in patients with IDH1/2 mutant gliomas alongside a consistently manageable safety profile,” said Susan Pandya, MD, head of Cancer Metabolism Global Development Oncology and Immuno-Oncology, Servier, in a press release. “This promising outcome brings hope to patients grappling with IDH-mutant diffuse gliomas, offering a potential breakthrough for those eagerly awaiting a new therapeutic option.”¹

Grade 2 gliomas are slow progressing, malignant brain tumors that carry a poor long-term prognosis. Low-grade, diffuse glioma is typically diagnosed in adults approximately 40 years of age. Further, mutations in IDH 1/2 have been observed in approximately 80% and 4% of grade 2 gliomas, respectively, and are classified as a disease-defining characteristic in the World Health Organization (WHO) 2021 definition.²

The 2021 WHO Classification addresses disease defining histologic and molecular features, such as IDH mutation status, to diagnose adult-type diffuse gliomas. Further, because IDH mutation status affects the diagnosis, prognosis, and treatment course for the disease, NCCN Guidelines recommend testing for IDH mutations in all patients with glioma.¹

The FDA based its regulatory action on findings from the pivotal, global, randomized, double-blind, placebo-controlled, Phase III INDIGO trial (NCT04164901). Investigators evaluated vorasidenib in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation who underwent surgery as their only treatment.

Vorasidenib achieved the trial’s primary endpoint of statistically significant and clinically meaningful progression-free survival (PFS) per blinded independent review committee, as well as key secondary endpoints of time to next intervention (TTNI) at the prespecified second interim analysis. Median PFS among patients administered was vorasidenib 27.7 months compared with 11.1 months in the placebo cohort. TTNI findings were statistically significant, with a median TTNI that was not reached in the vorasidenib cohort compared with 17.8 months in the placebo cohort.¹

Vorasidenib was found to reduce tumor volume by a mean of 2.5% every six months, compared with a tumor volume increase by a mean of 13.9% every six months in the placebo cohort, as measured by a blinded independent radiology committee. In terms of safety, vorasidenib was found to be well-tolerated, with a profile consistent with results from prior Phase I studies.

In prior studies, all-grade adverse events occurring in more than 20% of patients administered vorasidenib compared with placebo, respectively, were elevated alanine aminotransferase (38.9% vs 14.7%), COVID-19 (32.9% vs 28.8%), fatigue (32.3% vs 31.9%), headache (26.9% vs 27.0%,), diarrhea (24.6% vs 16.6%), and nausea (21.6% vs 22.7%).²

The FDA has assigned the NDA for vorasidenib with a Prescription Drug User Fee Act action date of August 20, 2024.

“As the pioneer in the field of mutant IDH inhibition, Servier has consistently spearheaded the development of cutting-edge treatment options for various cancer types characterized by IDH mutations,” said Servier Executive Vice President of Research and Development and Chief Scientific Officer Claude Bertrand, in a press release. “The compelling efficacy results observed with vorasidenib in the INDIGO study underscore its full potential to emerge as the benchmark treatment for patients grappling with IDH-mutant diffuse glioma harboring IDH1/2 mutations. The submission of global regulatory filings for vorasidenib serve as validation of Servier’s global oncology commitment while marking a possibly significant milestone for patients who have endured more than two decades without access to new therapeutic solutions.”¹

References

1. FDA and EMA Accept Vorasidenib Regulatory Submissions for the Treatment of IDH-mutant diffuse glioma. Servier. News release. February 20, 2024. Accessed February 20, 2024. https://servier.us/blog/fda-and-ema-accept-vorasidenib-regulatory-submissions-for-the-treatment-of-idh-mutant-diffuse-glioma/

2. Mellinghoff IK. INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. Presented at: 2023 ASCO Annual Meeting in Chicago, IL at press conference on June 3, 2023. https://meetings.asco.org/2023-asco-annual-meeting/15047.