Merck’s HIF-2α Inhibitor Belzutifan Receives FDA Priority Review for Treatment of Rare Kidney Cancer Linked to VHL Disease
Mar 17, 2021 02:01
CST Updated
02:01
MSD
Pharmaceutical R&D and Manufacturer
FDA
U.S. Food and Drug Administration
March 16, 2021 /BioonBIOON/ -- Merck Sharp & Dohme AG (Merck & Co.) recently announced that the U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for the hypoxia-inducible factor-2α (HIF-2α) inhibitor belzutifan (MK-6482) and granted it priority review; the drug is from MSDTumora novel investigational drug in the pipeline for the treatment of patients with von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC) who do not require immediate surgery
The FDA has designated the Prescription Drug User Fee Act (PDUFA) target date for this NDA as September 15, 2021. Previously,FDABelzutifan has been granted Breakthrough Therapy Designation (BTD) and Orphan Drug Designation (ODD). Notably,The VHL biological research that led to the discovery of HIF-2α was awarded the Nobel Prize in Physiology or Medicine in 2019.
This NDA is based on data from the Phase II Study-004 (NCT03401788), which evaluated belzutifan in patients with VHL-associated clear cell renal cell carcinoma (ccRCC). The study results demonstrated durable responses to belzutifan in patients with VHL-associated ccRCC, with a confirmed objective response rate (ORR) of 36.1% (n=22/61; 95% CI: 24.2–49.4).
VHL syndrome is a rare condition that affects multiple organsHeredityhereditary diseases, which expose patients to the risk of various cancers, including renal cell carcinoma. Cancer remains one of the leading causes of death among patients with VHL syndrome, and there are currently no approved systemic treatment options; thus, there is an urgent need for new therapeutic approaches. Results from the aforementioned Phase II trial provide evidence of the potential benefits of belzutifan and support further investigation into how this HIF-2α inhibitor can exert a meaningful effect in these patients.
Dr. Scot Ebbinghaus, Vice President of Clinical Research at MSD Research Laboratories, stated, “VHL disease is a rareHereditydisease, for which there is currently no systematic treatment regimen, and it is associated with a high risk of cancer developing in multiple organs. In fact, up to 70% of patients with VHL will develop renal cell carcinoma during their lifetime. This priority review underscores our commitment to expanding and diversifying MSD’s portfolio through innovative new therapies.TumorSignificant progress in the therapeutic pipeline. We look forward to working withFDAWork closely together to provide belzutifan to patients in need.”
Chemical Structure of Belzutifan (MK-6482) (Image source: medchemexpress.com)
Von Hippel-Lindau (VHL) syndrome is a rareHereditydisease, with one in every 36,000 people affected (200,000 cases worldwide, including 10,000 in the United States alone). Patients with VHL syndrome are at risk of developing benign vascularTumoras well as the risk of various cancers, including RCC. Up to 70% of patients with VHL syndrome develop RCC, which is the leading cause of death in these patients.
Renal cell carcinoma (RCC) is currently the most common type of kidney cancer, accounting for approximately 9 out of 10 kidney cancer cases, with clear cell renal cell carcinoma (ccRCC) comprising about 7 out of 10 RCC cases. It is estimated that in 2020, there were approximately 431,300 new cases of kidney cancer diagnosed worldwide, and about 179,400 deaths from the disease. In the United States alone, it is estimated that there will be nearly 76,100 new cases of kidney cancer and nearly 13,800 deaths from the disease in 2021.
The VHL gene is an important tumor suppressor gene, and its mutations were first identified in patients with von Hippel-Lindau (VHL) syndrome. The VHL protein is a tumor suppressor whose inactivation can abnormally activate hypoxia-inducible factor-2α (HIF-2α) in cancer patients. This inactivation of the VHL tumor suppressor protein is observed in more than 90% of clear cell renal cell carcinoma (ccRCC) tumors, leading to the accumulation and activation of hypoxia-inducible factor (HIF) proteins within cancer cells. This falsely signals a state of hypoxia, thereby activating angiogenesis and stimulating both benign and malignantTumorgrowth.
Belzutifan (MK-6428) is a novel, potent, selective, oral HIF-2α inhibitor that targets and inhibits HIF-2α, thereby blocking cell growth and proliferation and preventing abnormal angiogenesis. Belzutifan was developed by Peloton Therapeutics, which was acquired by Merck & Co., Inc. (MSD) in May 2019 for an upfront payment of $1.05 billion and milestone payments totaling $1.15 billion.
Currently, belzutifan is being evaluated in multiple clinical studies. In addition to the Phase II trial for VHL-associated clear cell renal cell carcinoma (ccRCC) (NCT03401788), the clinical development program for belzutifan also includes a Phase III trial for advanced RCC (MK-6482-005; NCT04195750) and a Phase I/II dose-escalation and dose-expansion trial for advanced solid tumors, including advanced renal cancer (NCT02974738). (Bioon.com)