17 March 2021 - - The US Food and Drug Administration has accepted and granted priority review for a New Drug Application for the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor belzutifan (pronounced bell-ZOO-ti-fan), a novel investigational candidate in US-based pharmaceutical company Merck's (NYSE: MRK) oncology pipeline, for the potential treatment of patients with von Hippel-Lindau disease-associated renal cell carcinoma, not requiring immediate surgery, the company said.

This NDA is based on data from the Phase 2 Study-004 trial, in which belzutifan showed a confirmed overall response rate of 36.1% (n=22/61) (95% CI:24.2-49.4) in patients with VHL disease-associated RCC. The FDA has set a Prescription Drug User Fee Act (PDUFA), or target action, date of September 15, 2021.

Merck is also studying belzutifan in advanced RCC and other tumor types through a broad clinical program.

In addition to the ongoing Phase 2 Study-004 trial, belzutifan is being evaluated in Phase 3 trials as monotherapy and as part of a combination regimen in previously treated patients and as part of a combination regimen as a first-line treatment for advanced clear cell RCC.

This application is based on data from Study-004 (ClinicalTrials.gov, NCT03401788), which is a Phase 2, open-label trial evaluating belzutifan for the potential treatment of patients with VHL disease who had at least one measurable solid tumor localized to the kidney and who did not require immediate surgery.

The study enrolled 61 patients who received belzutifan 120 mg orally once daily until disease progression or unacceptable toxicity.

The primary endpoint was objective response rate in VHL disease-associated RCC. Secondary endpoints in RCC tumors include disease control rate, duration of response, time to response, progression-free survival, time to surgery and safety.

Additionally, this study evaluated response rates in other common VHL disease-associated tumors, including pancreatic cysts, pancreatic neuroendocrine tumors, central nervous system hemangioblastomas, and retinal hemangioblastomas.

Belzutifan (MK-6482) is a novel, potent and selective inhibitor of HIF-2α. Proteins known as hypoxia-inducible factors, including HIF-2α, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated.

If not properly regulated, the accumulation of HIF-2α can stimulate several oncogenes associated with cellular proliferation, angiogenesis and tumor growth, leading to the growth of both benign and malignant tumors.

This inactivation of VHL has been observed in more than 90% of clear cell RCC tumors. Research into VHL biology that led to the discovery of HIF-2α was awarded the Nobel Prize in Physiology or Medicine in 2019.

Von Hippel-Lindau disease is a rare genetic disease that affects one in 36,000 people (200,000 cases worldwide and 10,000 cases in the US alone).

Patients with VHL disease are at risk for benign blood vessel tumors as well as several cancers, including RCC. As many as 70% of people with VHL disease develop RCC.

Renal cell carcinoma is by far the most common type of kidney cancer; about nine of 10 kidney cancers are RCCs, and about seven of 10 RCCs are clear cell.