For nearly 130 years, pharmaceutical company Merck & Co (“Merck” or “MSD”) has been working to develop unique therapeutic solutions for those with rare cancers and a variety of other conditions. Recently, the company shared that its New Drug Application (NDA) for its investigational drug candidate belzutifan received Priority Review status from the FDA. The treatment is designed for patients with von Hippel-Lindau (VHL) syndrome-associated renal cell carcinoma (RCC), specifically in patients who do not need immediate surgery.
So what is belzutifan? This novel HIF-2a inhibitor works to suppress hypoxia-inducible factors, a type of protein that regulates cancerous cells’ responses in oxygen-low areas. In patients with VHL syndrome, a tumor-suppressor protein called VHL is deficient or inactive. This causes HIFs to accumulate throughout the body and allows cancerous cells to grow and proliferate. In fact, HIFs allow tumors to grow and survive. An estimated 90% of RCC tumors also hinge on inactive VHL. Previously, VHL research that discovered HIF-2a received the Nobel Prize in Physiology or Medicine in 2019. Now, belzutifan offers a potential avenue for improving patient outcomes and for preventing VHL syndrome from progressing to become RCC.
According to the FDA, a New Drug Application (NDA) is:
the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.
In this case, the data supporting the NDA comes from a Phase 2 clinical trial evaluating belzutifan for patients with VHL-associated RCC. 61 patients enrolled. During the trial, patients received 120mg oral belzutifan each day. Beyond VHL-associated RCC, the trial also evaluated belzutifan for patients with pancreatic neuroendocrine tumors, retinal hemangioblastomas, and other tumors. Patients received treatment until their condition progressed or the dosage reached unacceptable toxicity. Overall, belzutifan was found to be relatively safe and well-tolerated, with an overall response rate (ORR) of 36.1%.
Von Hippel-Lindau (VHL) Syndrome
Von Hippel-Lindau syndrome (VHL) is a rare inherited disorder caused by VHL gene mutations. However, up to 20% of patients have no family history of VHL. This genetic disorder is characterized by the formation of cysts and tumors throughout the body. Typically, these develop in the spine, kidneys, brain, pancreas, adrenal gland, retina, inner ear, and genital tract. But these tumors or cysts may form in other areas as well. These blood vessel tumors (hemangioblastomas) may be cancerous, but they may also be benign. Having VHL syndrome increases the risk of develop pancreatic neuroendocrine tumors and RCC. In many cases, VHL begins to manifest while patients are in their 20s. Symptoms include:
- Hemangioblastomas in the brain, spine, or retina
- High blood pressure
- Anxiety and/or panic attacks
- Vision loss and/or blindness
- Treatment-averse high blood pressure
- Loss of healing
- Balance issues
- Heavy sweating
Renal Cell Carcinoma (RCC)
Renal cell carcinoma (RCC) is a form of easily metastasizing kidney cancer which often spreads to the lungs or other organs. An estimated 9 in every 10 diagnosed kidney cancer cases are RCC. Typically, RCC begins as one tumor in the kidney, although it is possible to have tumors in both kidneys at the same time. RCC generally occurs between the ages of 50-70. It is also more common in males than in females. Risk factors include a history of kidney issues, obesity, and smoking. However, in recent years, researchers have also determined that there might be a genetic underpinning to RCC, including PRC, TFE 3, and VHL gene mutations. Symptoms include:
- Abdominal pain
- Unintended weight loss
- High blood pressure
- Bloody or rust-colored urine
- Enlarged testicle or varicose testis veins
- Appetite loss