Title:Belzutifan: A Narrative Drug Review
Volume: 14
Issue: 2
Author(s): Vysakh Visweswaran and Keechilat Pavithran*
Affiliation:
- Department of Medical Oncology, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham,
Kochi, Kerala, India, 682041
Keywords:
VHL, belzutifan, PT2977, MK-6482, HIF, RCC.
Abstract: Von Hippel-Lindau disease is an autosomal dominant disorder characterised by renal
cell carcinomas, pancreatic neuroendocrine tumours, central nervous system hemangioblastomas,
retinoblastomas, and tumours of the reproductive tract. This disease results from loss of function
mutations in the tumour suppressor gene known as the Von Hippel-Lindau gene, located on
chromosome 3. Loss of function mutation in the Von Hippel-Lindau gene results in the
accumulation of a protein known as a hypoxia-inducible factor, which promotes cellular
proliferation and angiogenesis, leading to cancer. Belzutifan inhibits the hypoxia-inducible factor
by binding to the Per-ARNT -Sim-B binding pocket on the hypoxia-inducible factor -2α, inhibiting
cellular proliferation and angiogenesis. In our thorough literature review, we identified 37 relevant
articles. Belzutifan showed clinically meaningful response rates for both Von Hippel-Lindau
disease-associated renal cell carcinomas and non-renal cell cancers. The pharmacokinetic profile
of belzutifan was much better than its congener molecules due to the optimisation of its dihalide
groups from germinal to vicinal. The pharmacodynamic effect of belzutifan was confirmed by its
ability to decrease serum erythropoietin, which is a direct result of hypoxia-inducible factor- 2α
inhibition. The significant side effects observed were anaemia, hypoxia, fatigue, hypertension,
visual impairment and weight gain. Multiple clinical trials are currently underway to determine the
role of beluztifan as part of combination regimens in treating Von Hippel-Lindau diseaseassociated
malignancies.
