Merck announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to the hypoxia-inducible factor-2 alpha (HIF-2a) inhibitor MK-6482, a novel investigational candidate in Merck’s oncology pipeline, for the treatment of patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC)with nonmetastatic RCC tumors less than three centimeters in size, unless immediate surgery is required. The FDA also granted orphan drug designation to MK-6482 for VHL disease. These designations are based on data from a phase 2 trial evaluating MK-6482 in patients with VHL-associated clear cell RCC, which were presented at the 2020 American Society of Clinical Oncology Annual Meeting.
“Merck’s diverse and expansive oncology pipeline is focused on bringing forward innovative new treatments to patients in need and continues to show important progress,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “These designations for MK-6482 support the potential of targeting HIF-2a in certain patients with von Hippel-Lindau disease, who currently have limited treatment options and face an increased risk for benign tumors as well as several types of cancer, including renal cell carcinoma.”
The FDA’s Breakthrough Therapy designation is granted to expedite the development and review of medicines that are intended to treat serious or life-threatening conditions and that have demonstrated preliminary clinical evidence indicating that the medicine may provide a substantial improvement over available therapy on at least one clinically significant endpoint. The FDA’s orphan drug designation is granted to medicines that are intended for the treatment, prevention or diagnosis of rare diseases that affect fewer than 200,000 people in the US.
MK-6482 (formerly PT2977) is an investigational, novel, potent, selective, oral HIF-2a inhibitor that is currently being evaluated in a phase 3 trial in advanced RCC, a phase 2 trial in VHL-associated RCC and a phase 1/2 dose-escalation and dose-expansion trial in advanced solid tumors, including advanced RCC. Proteins known as hypoxia-inducible factors, including HIF-2a, can accumulate in patients when VHL, a tumor-suppressor protein, is inactivated. The accumulation of HIF-2a can lead to the formation of both benign and malignant tumors. This inactivation of VHL has been observed in more than 90% of ccRCC tumors. Research into VHL biology that led to the discovery of HIF-2a 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 60% of people with VHL disease develop RCC, which is a leading cause of death for patients with VHL disease.
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. Worldwide, it is estimated there were about 403,000 cases of kidney cancer diagnosed and about 175,000 deaths from the disease in 2018. In the US alone, it is estimated there will be nearly 74,000 new cases of kidney cancer diagnosed and almost 15,000 deaths from the disease in 2020