Journal
EXPERT OPINION ON INVESTIGATIONAL DRUGS
Volume 30, Issue 5, Pages 495-504Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/13543784.2021.1925248
Keywords
HIF 2 alpha inhibitor; MK-6482; renal cell carcinoma; RCC; von Hippel-Lindau disease; VHL
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Von Hippel-Lindau (VHL) disease is a genetic syndrome caused by mutations in the VHL gene, resulting in tumors and cysts in multiple organs. Surgery is the standard treatment for localized tumors, but repeated surgeries lead to significant morbidity. MK-6482, a small-molecule HIF 2 alpha inhibitor, has shown promising efficacy and safety in VHL disease-related tumors.
Introduction Von Hippel-Lindau (VHL) disease is an inherited autosomal dominant syndrome caused by a germline mutation and/or deletion of the VHL gene. Inappropriate hypoxia-inducible factor (HIF)-mediated transcription of proangiogenic and metabolic genes leads to the development of tumors and cysts in multiple organs. Surgery is a standard treatment for localized tumors with a risk of metastasis or organ dysfunction. Repeated surgeries cause substantial morbidity and have a major impact on quality of life. There is an urgent need to develop effective and safe systemic treatments for VHL disease manifestations. The small-molecule HIF 2 alpha inhibitor MK-6482 (belzutifan) has demonstrated significant efficacy in VHL disease related renal cell carcinomas, hemangioblastomas, and pancreatic neuroendocrine tumors while demonstrating an acceptable safety profile. Areas covered This paper reviews the development of the HIF-2 alpha inhibitor, MK-6482, and discusses preliminary results of ongoing phase I/II studies in renal cell carcinoma (RCC) and VHL disease. An examination of ongoing clinical development of MK-6482 and perspectives on potential future developments and challenges are offered. Expert opinion Because of its favorable safety profile, its clear efficacy in VHL disease, promising findings in sporadic, advanced RCC, and convenient oral formulation, MK-6482 is expected to become a leading treatment for VHL disease. Among other currently available oral agents, we believe that MK-6482 will be a preferred treatment for VHL-associated RCC.
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