Fda approves idh1 and idh2 inhibitor for brain cancer

The FDA approved Servier’s IDH1 and IDH2 inhibitor vorasidenib (Voranigo) for IDH-mutant glioma following surgery, providing the first new drug in decades for this rare cancer. Around 2,500

people are diagnosed with IDH-mutant grade 2 glioma each year in the USA. Most of these patients undergo surgery to remove the tumour, and this can be followed by chemotherapy or

radiotherapy to slow tumour growth. In low-risk cases, however, a watch-and-wait strategy is sometimes recommended after surgery to reduce the burden of treatment-related side effects

including radiation-induced neurocognitive dysfunction and chemotherapy-associated DNA hypermutation. Better treatments are needed, and oncologists have long hoped that more targeted drugs

might have fewer side effects. Vorasidenib, a brain-penetrant IDH1/IDH2 inhibitor, now provides this option. The IDH proteins are key metabolic enzymes that are mutated in various cancers,

including glioma. In 2009, researchers reported that gain-of-function mutations in IDH1 result in the build-up of the oncometabolite 2-hydroxyglutarate. In 2012, another team further showed

that IDH mutations lead to oncogenesis by driving epigenetic changes. The FDA approved the small molecule on the basis of the phase III INDIGO trial, involving 331 patients with residual or

recurrent grade 2 IDH-mutant glioma who had undergone surgery and no other prior treatment. Participants received oral vorasidenib or placebo in 28-day cycles. The trial hit its primary

endpoint, showing a significant benefit on imaging-based progression-free survival. The median progression-free survival reached 27.7 months in the vorasidenib group, versus 11.1 months in

the placebo group. The median time to next intervention was not reached for the vorasidenib recipients, and was 17.8 months for placebo recipients. Common side effects included fatigue,

headache, COVID-19 infection, musculoskeletal pain, diarrhoea, nausea and seizure. Nearly 10% of patients had grade 3 or higher increases in alanine aminotransferase levels. These data were

published last year in _The New England Journal of Medicine_. Overall survival data is still being collected. There results “were striking”, wrote University of Virginia neurologist David

Schiff in an accompanying editorial. But the single-agent activity of the drug, compared to the combination effect of radiation and chemotherapy, is “modest” he noted. Further data and

trials are needed to assess the longer-term effects of the drug, as well as its combination potential. Vorasidenib was discovered by Agios Therapeutics. Agios sold its oncology business,

including vorasidenib and mutant IDH1 inhibitor ivosidenib (Tibsovo), to Servier in 2020 for US$1.8 billion plus milestones. Earlier this year, Royalty Pharma paid $905 million to Agios to

acquire royalty rights to vorasidenib. Royalty forecasts peak sales of over $1 billion for the drug.