FDA OK's HIF2α Inhibitor Belzutifan

Based on positive results of a phase II trial, the FDA has approved belzutifan (Welireg; Merck), the first drug for the treatment of tumors associated with von Hippel-Lindau (VHL) disease, and the first inhibitor of hypoxia-inducible factor-2α (HIF2α)—a target once considered “undruggable.” Until now, patients with VHL-driven renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors have been treated with surgery and/or radiation.

“It's been extremely gratifying on multiple levels to see the activity of belzutifan,” says William G. Kaelin Jr., MD, of Dana Farber/Harvard Cancer Center in Boston, MA, who won the 2019 Nobel Prize in Physiology or Medicine for his foundational research on HIF and VHL disease. “This whole story underscores the power of cancer genetics to help identify the targets that are near and dear to various cancers.”

HIF2α is a DNA-binding transcription factor that plays a key role in the proliferation of cells, angiogenesis, and tumor growth. Patients with VHL disease have a genetic mutation that inactivates the tumor suppressor VHL, thus causing HIF2α to accumulate—a process that drives the growth of benign and malignant tumors. Belzutifan binds directly to HIF2α and induces an allosteric change that prevents the protein from binding to DNA—prompting the development of the drug as a potential treatment for patients with VHL-associated tumors.

The Study 004 trial enrolled 61 patients with VHL-associated renal cell carcinoma with at least one measurable kidney tumor, 24 of whom also had central nervous system hemangioblastomas and 12 of whom also had pancreatic neuroendocrine tumors. The overall response rate was 49% for patients with renal cell carcinoma, 63% for those with central nervous system hemangioblastomas, and 83% for patients with neuroendocrine tumors; responses lasted for more than 12 months in 56%, 73%, and 50% of patients, respectively. The median duration of response was not reached in any group.

The most common side effects, seen in more than 20% of patients, were decreased hemoglobin, anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Overall, 90% of patients experienced anemia, and 7% had anemia classified as grade 3.

“I think the significance of this drug is manyfold,” says Celeste Simon, PhD, of Perelman School of Medicine at the University of Pennsylvania in Philadelphia, who has conducted in vitro and in vivo work on HIF2α. Notably, the drug is the first of its kind, and it inhibits a transcription factor, a category of molecules that researchers once thought couldn't be targeted.

“It shows that this common, conventional wisdom that you can't drug these kinds of targets is not true,” she says. Additionally, the drug is so selective that it doesn't inhibit HIF1α, the protein most closely related to HIF2α.

“It's just wonderful that we now have, perhaps, a therapeutic option for people with VHL disease,” Kaelin adds. He is hopeful that belzutifan will prove even more effective at preventing new tumors in patients with VHL disease than at treating existing tumors—something that will become apparent as more patients with VHL receive the agent. He is also optimistic that the drug may eventually be approved for sporadic kidney cancer, which is also frequently dependent on HIF2α.

Simon believes that the drug could treat conditions other than cancer. For example, it might be effective in pulmonary hypertension—another disease that relies on HIF2α—or for erythrocytosis. “We're just in our infancy of what it could be used for,” she says. “I think it could have many applications.” –Catherine Caruso

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