FDA Grants Priority Review for Vorasidenib in IDH-Mutant Diffuse Glioma


The FDA has accepted and granted priority review for the new drug application for vorasidenib for the treatment of IDH-mutant diffuse glioma, with a PDUFA action date set for August 20, 2024.

  • The FDA and European Medicines Agency (EMA) accepted vorasidenib (AG-881) applications, suggesting imminent approval for the treatment of IDH-mutant diffuse glioma.
  • Vorasidenib significantly improved progression-free survival (PFS) and time to next intervention (TTNI).
  • Vorasidenib reduced tumor volume, showing potential for disease control, and had manageable adverse effects (AEs), mainly liver enzyme increases.

The FDA has filed an acceptance and priority review for a new drug application (NDA) for vorasidenib for the treatment of patients with IDH-mutant diffuse glioma. A Prescription Drug User Fee Act (PDUFA) action date of August 20, 2024, has been set.1

Findings from the pivotal phase 3 INDIGO trial support this regulatory decision as the study met its primary end point of PFS per blinded independent review committee (BIRC) and key secondary end point of TTNI at the prespecified second interim analysis. Vorasidenib demonstrated a statistically significant and clinically meaningful PFS (HR, 0.39; 95% CI, 0.27-0.56; P =.000000067) with a median PFS of 27.7 months (95% CI, 17.0-not estimated) vs 11.1 months (95% CI, 11.0-13.7) in the placebo arm.2,3

“What's exciting is this is a development that we haven't seen in over 20 years, and what we found is that when we looked at our patients that received vorasidenib in comparison with the placebo, those patients had a much improved prognosis, such that their progression-free survival was extended to 27.7 months compared with 11 months, which is a very large, statistically significant difference,” explained Katherine B. Peters, MD, PhD, neuro-oncologist at Duke Cancer Center, in an interview with Targeted Oncology.

TTNI was also statistically significant and in favor of vorasidenib (HR, 0.26; 95% CI, 0.15-0.43; P =.000000019) and while the median TTNI was not reached for vorasidenib, it was 17.8 months among patients in the placebo arm. Reduced tumor volume was also observed in the vorasidenib arm by a mean of 2.5% (95% CI, -4.7% to -0.2%) every 6 months compared with the placebo arm where tumor volume increased by a mean of 13.9% (95% CI, 11.1%-16.8%) every 6 months.

Human Brain Activity: © See Less - stock.adobe.com

Human Brain Activity: © See Less - stock.adobe.com

"In the realm of glioma treatment, innovation has been stagnant for nearly a quarter-century, posing challenges for patients who, postsurgery, may opt to defer treatment due to concerns around potential toxic [adverse] 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."

In addition, the EMA granted accelerated assessment for the vorasidenib marketing authorization application in this indication. The European Commission anticipates approval for the in the second half of 2024.

“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," stated Claude Bertrand, executive vice president of research & development and chief scientific officer at Servier, in a press release. "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."

About the INDIGO Study

Vorasidenib is an oral, selective, highly brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes for the treatment of IDH-mutant diffuse glioma. If data remain positive and regulatory approval is granted, the innovative targeted therapy would become a first-in-class option for patients with IDH-mutant gliomas and would mark the sixth approval for Servier across cancers with IDH mutations.

Vorasidenib was granted an FDA fast track designation in February 2023 and breakthrough therapy designation in August 2023.

In the phase 3 INDIGO study, a registration-enabling, global, randomized, double-blind placebo-controlled study, vorasidenib was used for the treatment of patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation who have undergone surgery as their only treatment. Results from the study were presented at the 2023 ASCO Annual Meeting and simultaneously published in the New England Journal of Medicine.2,3

A total of 331 patients were randomly assigned to receive oral vorasidenib (n = 168) at 40 mg once daily or matched placebo (n = 163) in 28-day cycles. The median age of patients in the vorasidenib arm was 40.5 years vs 39.0 years in the control arm histologic subtypes of low-grade glioma were evenly distributed between oligodendroglioma and astrocytoma. All patients harbored an IDH mutation, with the majority having an IDH1 alteration, which was present in 97% of those in the vorasidenib arm and for 93.3% in the placebo group. More than half of patients also had a codeletion in chromosome 1p/19q.

With vorasidenib, the median follow-up was 14.0 months (IQR, 10.1-17.9) vs 14.3 months (IQR, 10.0-18.1) for placebo. Additional findings from the study showed that at 18 months, the PFS rate was 60.4% (95% CI, 48.3%-70.5%) with vorasidenib vs 26.7% (95% CI, 17.1%-37.4%) with placebo, and the rates at 24 months were 50.7% (95% CI, 36.2%-63.5%) and 17.6% (95% CI, 7.1%-31.9%), respectively.

The objective response rate was 10.7% (95% CI, 6.5%-16.4%) with vorasidenib vs 2.5% (95% CI, 0.7%-6.2%) for placebo (OR, 4.88; 95% CI, 1.56%-15.25%). The vorasidenib arm had 2 patients achieve partial responses (1.2%) and 16 who had minor responses (9.5%). In the placebo arm, all were minor responses. Most patients had stable disease, with progressive disease seen in 6.0% and 8.6% of those in the vorasidenib and placebo arms, respectively.

For safety, AEs of any grade were observed in 94.6% of patients in the vorasidenib arm vs 93.3% in the placebo arm with grade 3 or higher AEs seen in 22.8% vs 13.5% of patients. The most common AEs among those treated with vorasidenib were related to liver enzyme increases, including increases in alanine aminotransferase (ALT; 38.9%; 9.6% grade 3 or higher), aspartate aminotransferase (28.7%; 4.2%), and gamma-glutamyl transferase (15.6%; 3.0%).

In the vorasidenib arm, there were 3 serious AEs reported and were deemed to be associated with the treatment, specifically ALT increase, hepatic failure, and hepatitis. All serious AEs were considered resolved at the time of the analysis in September 2022. With vorasidenib, 3.6% of patients discontinued treatment vs 1.2% in the placebo arm and dose reductions were required in 10.8% of patients in the vorasidenib arm compared with 3.1% in the placebo group.

1. FDA and EMA accept vorasidenib regulatory submissions for the treatment of IDH-mutant diffuse glioma. News release. Servier. February 20, 2024. Accessed February 20, 2024. http://tinyurl.com/5bh59swj
2. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N Engl J Med. Published online June 4, 2023. doi:10.1056/NEJMoa2304194
3. Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. 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. J Clin Oncol. 2023;41(suppl 17):LBA1. doi:10.1200/JCO.2023.41.17_suppl.LBA1
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