Belzutifan (Welireg)

Mechanism of action

From the NCI Drug Dictionary: An orally active, small molecule inhibitor of hypoxia inducible factor (HIF)-2alpha (HIF-2a), with potential antineoplastic activity. Upon oral administration, belzutifan binds to and blocks the function of HIF-2alpha, thereby preventing HIF-2alpha heterodimerization and its subsequent binding to DNA. This results in decreased transcription and expression of HIF-2alpha downstream target genes, many of which regulate hypoxic signaling. This inhibits cell growth and survival of HIF-2alpha-expressing tumor cells.

Diseases for which it is used

• CNS hemangioblastoma
• Pancreatic NET
• Renal cell carcinoma
  • VHL-associated RCC

History of changes in FDA indication

• 2021-08-13: Approved for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. (Based on MK-6482-004)
• 2023-12-14: Approved for patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). (Based on LITESPARK-005)

Also known as

• Code names: MK-6482, PT-2977
• Brand name: Welireg