FDA Accepts Application, Grants Priority Review to Vorasidenib for IDH-Mutant Diffuse Glioma

The FDA has accepted the New Drug Application and granted Priority Review for vorasidenib (Servier) for the treatment of isocitrate dehydrogenase (IDH)-mutant diffuse glioma. A Prescription Drug Unser Fee Act (PDUFA) action date was set for August 20, 2024.¹

Vorasidenib is an oral, selective, highly brain-penetrant dual inhibitor of mutant IDH 1 and 2 (IDH1/2) enzymes, according to study authors.¹

IDH mutation impacts 20% of individuals diagnosed with primary malignant brain tumors with adult-type diffuse gliomas. The study authors noted that this includes 100% of grade 2 and grade 3 adult-type diffuse gliomas. To properly assess and diagnose an individual, testing for IDH mutations could provide more clarity on the prognosis of the 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 & Immuno-Oncology at 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

The approval was based on findings from the phase 3 global, randomized, double-blind, placebo-controlled INDIGO clinical trial. The study evaluated the tolerability and safety of vorasidenib compared with placebo among individuals with residual or recurrent grade 2 glioma with IDH1/2 who received surgery as their only form of treatment.¹

According to study authors, the trial met its primary endpoint of progression-free survival (PFS) per blinded independent review committee (BIRC) and its secondary endpoint of time to next intervention (TTNI) at the prespecified second interim analysis.¹

Compared with the placebo, vorasidenib demonstrated significant impact in PFS per BIRC among patients who were randomly assigned to receive the injection (Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.27 to 0.56; 1-sided P=0.000000067). The median PFS in the placebo group was 27.2 and 11.1 months. Similarly, TTNI was also significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P=0.000000019), although median TTNI was not met for vorasidenib and was 17.8 for the placebo.¹

Other results displayed a reduction in tumor volume with vorasidenib, by 2.5% every 6 months, compared to an increase of 13.9% every 6 months in the placebo group, according to study authors.¹

The safety of vorasidenib was consistent with results previously found in the phase 1 trial. Additonally, vorasidenib was reported to have low-grade toxic effects.^1,2

"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," said Claude Bertrand, Executive Vice-President of Research & Development and Chief Scientific Officer at Servier, in a press relase. "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 2 decades without access to new therapeutic solutions.”¹

The study authors noted that if vorasidenib receives approval, it would be the first-in-class target therapy to treat individuals with IDH-mutant gliomas.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.

2. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. The New England Journal of Medicine. News release. August 17, 2023. Accessed February 20, 2024. https://www.nejm.org/doi/full/10.1056/NEJMoa2304194.