Merck's First-in-Class HIF-2α Inhibitor Belzutifan Receives IND Approval in China for Renal Cell Carcinoma

Text | Pharma Outlook

On September 2, the latest announcement from the Center for Drug Evaluation (CDE) under China's National Medical Products Administration indicated that the Class 1 innovative drug belzutifan tablets, submitted by MSD, has received implied approval for clinical trials, intended for development in renal cell carcinoma (RCC). Public information shows that belzutifan (MK-6482) targets a signaling pathway associated with hypoxia-inducible factor-2α (HIF-2α), research on which was awarded the Nobel Prize in Physiology or Medicine in 2019. Additionally, it is the first hypoxia-inducible factor inhibitor approved by the FDA.

Image source: CDE official website

Belzutifan is an investigational, novel, potent, and selective oral HIF-2α inhibitor currently being evaluated in multiple clinical trials for the treatment of patients with Von Hippel-Lindau (VHL) disease-associated renal cell carcinoma, advanced renal cell carcinoma, and advanced solid tumors, among others. Inactivation of the VHL protein, a tumor suppressor, leads to aberrant activation of HIF-2α in cancer patients, resulting in HIF-2α accumulation and driving the formation of both benign and malignant tumors.

Previously, based on the positive results of belzutifan in clinical trials, the U.S. FDA granted the product Breakthrough Therapy designation and Orphan Drug designation. In August 2021, the FDA approved belzutifan for the treatment of VHL disease-associated cancers, such as renal cell carcinoma, central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs), in patients who do not require immediate surgery.

The approval was based on the results of a Phase 2 clinical trial. Data showed that belzutifan achieved an objective response rate (ORR) of 49% in patients with VHL-associated renal cell carcinoma. All VHL-RCC patients who achieved a response were followed up for at least 18 months from treatment initiation. The median duration of response (DoR) was not reached in the trial, with 56% of responders having a DoR of ≥12 months.

Among patients with other VHL-associated non-renal cell carcinoma tumors, the ORR was 63% in 24 evaluable patients with CNS hemangioblastomas and 83% in 12 evaluable patients with pNETs. The duration of response was ≥12 months in 73% and 50% of patients with CNS hemangioblastomas and pNETs, respectively.

Von Hippel-Lindau (VHL) disease is a rare genetic disorder that predisposes patients to benign vascular tumors and several types of cancer. Statistics indicate that up to 60% of patients with VHL disease may develop renal cell carcinoma, which is the leading cause of death in this population. Clinical study results for belzutifan have demonstrated its potential in targeting HIF-2α in certain patients with VHL disease, who currently have limited treatment options and face an increased risk of developing multiple types of cancer.

References:

[1]Center for Drug Evaluation, National Medical Products Administration. Retrieved Sep 2, 2021, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=25

[2] FDA Grants Breakthrough Therapy Designation to Merck’s Novel HIF-2α Inhibitor MK-6482 for Treatment of Certain Patients With Von Hippel-Lindau Disease- Associated Renal Cell Carcinoma. Retrieved July 29, 2020, from https://www.businesswire.com/news/home/20200729005246/en

[3] FDA approves belzutifan for cancers associated with von Hippel-Lindau disease. Retrieved August 13, 2021, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-cancers-associated-von-hippel-lindau-disease

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