FDA Grants MK-6482 NDA Priority Review for von Hippel-Lindau Disease-Associated RCC

The FDA has granted priority review for a new drug application (NDA) for the hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor MK-6482 (belzutifana, Merck), which is a novel investigational candidate for the potential treatment of patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) that does not require immediate surgery.

Affecting one in 36,000 people with 200,000 cases worldwide, VHL is a rare genetic disease that puts patients with VHL at risk for benign blood vessel tumors as well as several cancers, such as RCC. Currently, approximately 70% of patients with VHL develop disease-associated RCC.

The phase 2 study-004 trial investigating MK-6482 for patients with VHL disease-associated RCC showed MK-6482 had an overall response rate of 36.1% (n=22/61) (95% CI: 24.2-49.4), leading the FDA to grant the NDA priority review and set a target action date of September 15, 2021.

“Von Hippel-Lindau disease is a rare genetic condition for which there is no systemic treatment option available and is associated with a high risk of cancer development in multiple organs. In fact, up to 70% of patients with VHL develop renal cell carcinoma during their lifetime,” said Scot Ebbinghaus, MD, vice president, clinical research, Merck Research Laboratories, in a press release.

MK-6482 is a selective inhibitor of HIF-2α, which is a protein that can accumulate in patients when VHL is inactivated. Without regulation, this accumulation can cause the stimulation of several oncogenes associated with cellular proliferation, angiogenesis, and tumor growth.

Since this oncogene stimulation can result in benign and malignant tumor growth, the inactivation of VHL is an area of concern, especially because VHL inactivation has been observed in more than 90% of clear cell RCC tumors, according to the researchers.

In the phase 2 study-004 trial evaluating MK-6482, the investigators enrolled 61 patients and gave them 120 mg of MK-6482 orally once daily until disease progression or unacceptable toxicity. The primary endpoint of the trial was objective response rate in VHL disease-associated RCC, while the secondary endpoints in RCC tumors included disease control rate, duration of response, time to response, progression-free survival, time to surgery, and safety.

In addition to the phase 2 study-004 trial, the investigators are also assessing MK-6482 in the treatment of advanced RCC and other tumor types in other clinical trials. For example, MK-6482 is being evaluated in phase 3 trials as a monotherapy, 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 priority review validates the important progress we have made to expand and diversify Merck’s oncology pipeline with innovative, new therapeutic approaches,” Ebbinghaus said in the press release. “We look forward to working closely with the FDA to bring belzutifan to patients in need.”

REFERENCE

Merck Receives Priority Review From FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482). Kenilworth, NJ: Merck; March 16, 2021. https://www.businesswire.com/news/home/20210316005293/en/Merck-Receives-Priority-Review-From-FDA-for-New-Drug-Application-for-HIF-2%CE%B1-Inhibitor-Belzutifan-MK-6482. Accessed March 17, 2021.