Belzutifan, known by its brand name Welireg, is a targeted cancer therapy medication. It belongs to a class of drugs called hypoxia-inducible factor inhibitors, which interfere with specific molecules involved in cancer cell growth and survival. This treatment focuses on the cellular pathways that tumors exploit to develop.
Conditions Treated by Belzutifan
Belzutifan is approved for treating adults with von Hippel-Lindau (VHL) disease who have specific types of tumors. VHL is a rare genetic disorder that causes tumors and cysts to grow in various parts of the body. The medication is used for VHL patients with associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, and pancreatic neuroendocrine tumors (pNET). These tumors are not always cancerous but can cause serious problems as they grow.
The medication is intended for patients with these VHL-associated tumors that do not require immediate surgery, providing a systemic treatment option. The goal is to shrink the tumors or stop their growth.
Belzutifan is also used to treat adult patients with advanced renal cell carcinoma. This indication is for patients whose cancer has progressed after treatment with an immune checkpoint inhibitor and a VEGF-targeted therapy. This provides a therapeutic avenue for this more common, non-hereditary form of kidney cancer.
The Mechanism of Action
Belzutifan’s mechanism is directly linked to the function of the von Hippel-Lindau (VHL) protein. Under normal conditions, the VHL protein helps degrade another protein called hypoxia-inducible factor 2-alpha (HIF-2α). This process prevents HIF-2α from accumulating in cells and is part of the body’s system for adapting to oxygen levels.
In individuals with VHL disease, the gene that produces the VHL protein is mutated, leading to a non-functional protein. Without a functional VHL protein, HIF-2α is not broken down and accumulates within cells, even when oxygen levels are normal. This buildup is a primary driver of tumor development in VHL disease.
Accumulated HIF-2α moves into the cell’s nucleus and pairs with another protein, HIF-1β, to form a complex. This complex activates genes that promote cell proliferation and angiogenesis—the formation of new blood vessels. These new blood vessels supply the tumor with the oxygen and nutrients it needs to grow.
Belzutifan is a small molecule inhibitor that targets and binds to HIF-2α. By attaching to HIF-2α, belzutifan blocks its ability to partner with HIF-1β. This action prevents the activation of the downstream genes that fuel tumor growth and blood vessel formation, reducing the stimuli cancer cells need to thrive.
Administration and Patient Monitoring
Belzutifan is an oral medication administered as a tablet. Patients take it once daily, with or without food, and it is recommended to be taken at the same time each day to maintain steady drug levels in the body.
Treatment requires careful and consistent patient monitoring due to its potential effects. A primary concern is anemia, so healthcare providers will perform blood tests to check hemoglobin levels before starting treatment and regularly throughout therapy. Another aspect of monitoring involves checking for hypoxia, or low blood oxygen levels, by periodically checking oxygen saturation.
Adjustments to the dosage or temporary discontinuation of the treatment may be required based on the severity of side effects like anemia or hypoxia.
Common Side Effects and Risks
The most frequently reported side effects are a decrease in hemoglobin, leading to anemia, and feelings of fatigue or low energy. Patients may also experience musculoskeletal pain, headaches, dizziness, and nausea. Laboratory tests might show changes such as increased creatinine or glucose levels.
The drug also carries more serious risks that require immediate attention. Belzutifan has a boxed warning, the most serious type from the FDA, for severe hypoxia. This condition involves dangerously low levels of oxygen in the blood and can manifest as shortness of breath, chest pain, or exercise intolerance. Patients experiencing these symptoms should seek medical help right away.
Anemia is another significant risk, which can be severe in some cases, with symptoms including unusual tiredness, pale skin, and dizziness. Belzutifan may also cause harm to a developing fetus, so it should not be used during pregnancy. Women of reproductive potential must use effective non-hormonal contraception during treatment and for one week after the final dose because the drug can make hormonal contraceptives less effective.