On August 6, 2024 Servier reported that the U.S. Food and Drug Administration (FDA) has approved VORANIGO, an isocitrate dehydrogenase-1 (IDH1) and isocitrate dehydrogenase-2 (IDH2) inhibitor, indicated for the treatment of adult and pediatric patients 12 years and older with Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery including biopsy, sub-total resection, or gross total resection (Press release, Servier, AUG 6, 2024, View Source [SID1234645443]). VORANIGO is available and offers glioma patients the ability to actively manage their disease with the convenience of a once-daily pill.
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Gliomas are types of brain cancer that can hinder normal brain function and cause a variety of symptoms. Diffuse gliomas with IDH mutations represent the most common malignant primary brain tumors diagnosed in adults younger than 50 years of age. They are not curable with current therapies and without treatment they continue to grow and infiltrate normal brain tissue.
"Today’s approval of VORANIGO is an enormous leap forward in cancer care, and a defining moment for people living with Grade 2 IDH-mutant glioma," said Arjun H. Prasad, Chief Commercial Officer, Servier Pharmaceuticals. "VORANIGO, which is the first breakthrough in this specific disease area in nearly 25 years, offers patients unprecedented improvement in progression free survival. We are proud to deliver this first-of-its-kind therapy to patients in need, and we remain committed to bringing innovative targeted therapies to people with cancer."
In healthy human cells, a family of genes called isocitrate dehydrogenases (IDH) help break down nutrients and generate energy for cells. Mutations in IDH1 and IDH2 are associated with a variety of cancers, where they prevent cells from differentiating, or specializing, into the kind of cells they are ultimately supposed to become. When cells cannot differentiate properly, they may begin to grow out of control.4 In IDH-mutant gliomas, VORANIGO works by reducing the activity of the mutant IDH1 and IDH2 enzymes, to help control the disease.
"Patients living with Grade 2 IDH-mutant gliomas have long faced the harsh reality of an incurable disease with very limited post-surgery treatment options," said Ralph DeVitto, President & CEO, of the American Brain Tumor Association. "The FDA approval of VORANIGO marks a monumental breakthrough in glioma treatment, offering renewed hope for patients and their families living with this relentless disease."
The approval of VORANIGO is supported by results from the pivotal Phase 3 INDIGO clinical trial published in The New England Journal of Medicine and presented during the Plenary Session at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), which showed that VORANIGO significantly extended progression free survival and time to next intervention, when compared to placebo. The INDIGO study showed that VORANIGO was well tolerated, and its safety profile was consistent with results from the Phase 1 studies. The most common (≥15%) adverse reactions were fatigue, COVID-19, musculoskeletal pain, diarrhea and seizure.5
"Glioma is a unique cancer. Many of the patients I’ve met are in their 30’s and 40’s and in the prime of their lives. They have small children and are at the height of their careers. A glioma diagnosis is devastating. VORANIGO can offer patients and their families hope for the future," said David K. Lee, CEO, Servier Pharmaceuticals. "As we advance more targeted therapies, identifying mutations and understanding how these mutations impact cancer and its progression are key to helping the right patients find the right treatment, at the right time. We are humbled to lead the field of IDH-mutant inhibition, and we are committed to researching its applicability in glioma and other cancers."
About the INDIGO Phase 3 Trial (NCT04164901)5
INDIGO, the pivotal Phase 3 clinical trial, met its major efficacy outcome of progression free survival (PFS) per a blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) at the prespecified second interim analysis. The major efficacy outcome, PFS was statistically significant and clinically meaningful in favor of the vorasidenib arm. Median PFS was 27.7 months in the vorasidenib group, compared with 11.1 months in the placebo group (Hazard Ratio [HR], 0.39; 95% Confidence Interval [CI], 0.27 to 0.56; 1-sided P<0.001). TTNI was also statistically significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P<0.001). Median TTNI was not reached for vorasidenib and was 17.8 months for placebo. Vorasidenib was also shown to reduce the tumor volume by a mean of 2.5% (TGR of –2.5%; 95% CI: -4.7% to -0.2%) every 6 months, while tumor volume increased by a mean of 13.9% (TGR of 13.9%; 95% CI: 11.1% to 16.8%) every 6 months for patients randomized to the placebo arm, as measured by a BIRC.
The INDIGO study showed that vorasidenib was well tolerated, and its safety profile was consistent with results from the Phase 1 studies.
INDIGO was a registration-enabling Phase 3 global, randomized, double-blind placebo-controlled study of vorasidenib in patients with residual or recurrent Grade 2 glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation who have undergone surgery as their only treatment.
About Glioma6
Gliomas are tumors that arise from glial or precursor cells within the central nervous system (CNS). The 2021 World Health Organization (WHO) classification recognizes four general groups of gliomas, one of which is adult-type diffuse gliomas. These diffuse gliomas are the most common primary malignant brain tumors in adults. The pathogenesis and prognosis of these tumors are tightly linked to mutations (or lack thereof) in the metabolic enzyme isocitrate dehydrogenase (IDH), and molecular testing is required for proper diagnosis. As of 2021, adult-type diffuse gliomas are sub-divided into only three categories:
Astrocytoma, IDH-mutant (CNS WHO grades 2-4)
Oligodendroglioma, IDH-mutant and1p19q-codeleted (CNS WHO grades 2-3)
Glioblastoma, IDH-wildtype (CNS WHO grade 4)