FDA Approves First-in-Class HIF-2α Inhibitor Welireg (Belzutifan) Targeting Nobel Prize-Winning Pathway for VHL-Associated Cancers

On August 13, 2021, the U.S. FDA approved Welireg (belzutifan), a hypoxia-inducible factor inhibitor developed by MSD, for the treatment of von Hippel-Lindau (VHL) disease-associated cancers, such as renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), in patients who do not require immediate surgery.

VHL is a rare genetic disease that abnormally activates hypoxia-inducible factor-2α (HIF-2α) in cancer patients. The HIF-2α factor subsequently accumulates in patients, leading to the formation of both benign and malignant tumors. Belzutifan is a potent, selective, novel oral HIF-2α inhibitor. Research on the HIF-2α pathway was awarded the 2019 Nobel Prize in Physiology or Medicine. Based on the positive results achieved by belzutifan in clinical trials, the US FDA granted the product Breakthrough Therapy designation and Orphan Drug designation.

This approval was based on results from an ongoing phase 2 clinical trial. The trial results demonstrated an objective response rate (ORR) of 49% (95% CI: 36, 62) in patients with VHL-associated RCC. All VHL-RCC patients who achieved a response had been followed for at least 18 months from treatment initiation. The median duration of response (DoR) was not reached, with 56% of responders maintaining a DoR ≥ 12 months. In patients with other VHL-associated non-RCC tumors, the ORR was 63% in 24 evaluable patients with CNS hemangioblastomas and 83% in 12 evaluable patients with pNET. The duration of response was ≥ 12 months in 73% and 50% of patients with CNS hemangioblastomas and pNET, respectively.

▲ Molecular structure of belzutifan (Image source: DMacks, Public domain, via Wikimedia Commons)

Regarding safety, the most commonly reported adverse reactions in patients in the belzutifan group were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan may cause severe anemia and hypoxia; anemia occurred in 90% of patients, with 7% experiencing Grade 3 anemia, and hypoxia occurred in 1.6% of patients.

References:

[1] FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. Retrieved August 13, 2021, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease

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