Merck, Sharp & Dohme (MSD; NYSE: MRK) has revealed that the ongoing Phase III study evaluating the first-in-class HIF-2α inhibitor Welireg (belzutifan) in previously treated advanced renal cell carcinoma (RCC) has shown statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to everolimus, meeting its primary endpoint. However, the study missed the dual primary endpoint of significant improvement in overall survival (OS). Additionally, the key secondary endpoint of improved objective response rate (ORR) was achieved, with the safety profile consistent with previous observations.
Welireg’s Ongoing Development and Approvals
Welireg is currently being developed for RCC as adjuvant therapy and in second-line and treatment-naive advanced disease settings. The drug is already approved for von Hippel-Lindau (VHL)-related RCC, central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors (pNET) in markets such as Brazil, Canada, the UK, and the US.
Understanding the Role of HIF-2α in Tumor Biology
Cells rely on the HIF-2α transcription factor to sense oxygen levels and adapt to hypoxia, a characteristic of solid tumors that has been linked to aggressive phenotypes, including resistance to radiation and chemotherapy, metastasis, and poor patient prognosis. HIF-2α is involved in a transcriptional complex that induces the expression of genes associated with cellular proliferation, angiogenesis, and tumor growth. Welireg blocks these activities by targeting HIF-2α, preventing its interaction with binding partner HIF-1β, and resulting in an anti-tumor effect.-Fineline Info & Tech
