Drug Developed by UTSW Spinoff Now Approved for Metastatic Kidney Cancer
May 8, 2024
FDA’s expanded use for belzutifan culminates decades-long journey from gene discovery to first-in-class drug.
The U.S. Food & Drug Administration (FDA) has expanded the approved use of belzutifan for treatment of metastatic kidney cancer, marking another milestone for the novel, first-in-class hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor initially discovered at UT Southwestern.
“This remarkable journey exemplifies UT Southwestern's dedication to converting important scientific discoveries into improvements in patient care and underscores the power of innovation and team science in advancing health care,” said James Brugarolas, M.D., Ph.D., Professor of Internal Medicine in the Division of Hematology and Oncology and founding Director of the Kidney Cancer Program at Harold C. Simmons Comprehensive Cancer Center. “With the FDA’s approval, thousands of patients in need will gain access to this important new treatment.”
Belzutifan was initially approved by the FDA in 2021 as a renal cancer medication for adult patients with familial kidney cancer with mutations in the von Hippel-Lindau (VHL) gene. The latest approval broadens the drug’s label to anyone with metastatic clear cell renal cell carcinoma (ccRCC).
A Journey of Discovery
HIF-2α was discovered in the late 1990s by Steven McKnight, Ph.D., Professor of Biochemistry, and David Russell, Ph.D., Professor Emeritus of Molecular Genetics, at UT Southwestern. Research elsewhere subsequently showed that it played a key role in the growth of kidney cancer. Kevin Gardner, Ph.D., and Richard Bruick, Ph.D., both former UTSW professors, then studied the protein, identifying an unusual cavity within the HIF-2α molecule. They speculated that this cavity may provide a foothold for a new drug for kidney cancer and performed a screen of UT Southwestern’s chemical library to identify specific compounds that could bind to and thus block HIF-2α function. In 2010, UT Southwestern started Peloton Therapeutics with the purpose of clinically developing HIF-2α inhibitors as an anti-cancer targeted therapy.
Lead compounds developed by Peloton were evaluated in Dr. Brugarolas’ lab, where they were tested for activity against human kidney tumors transplanted in mice. These studies provided the first evidence that the compounds had activity against human kidney cancer. Kevin Courtney, M.D., Ph.D., Associate Professor of Internal Medicine, Division of Hematology and Oncology, conducted a clinical trial along with Dr. Brugarolas and several other investigators from other institutions. Their study showed for the first time that HIF2α inhibitors were safe and may be effective in treating renal cancer patients.
Pharmaceutical giant Merck acquired Peloton in 2019 and now markets belzutifan under the brand name Welireg.
Latest FDA Approval for Kidney Cancer Therapy
In 2023, results evaluating belzutifan for treatment of metastatic renal cell carcinoma (ccRCC) showed a statistically significant and clinically meaningful delay in tumor progression compared with everolimus, the former standard of care. The results led to the expanded FDA approval.
“Imagine being stage 4 and then getting a restart,” said Texas businessman Mark Hilz, who was initially diagnosed with kidney cancer in 2011 and started taking belzutifan last year after transferring to UT Southwestern and Dr. Brugarolas’ care. “I’m also able to maintain a great quality of life on this treatment.”
The Kidney Cancer Program within UTSW’s Simmons Cancer Center is one of only two National Cancer Institute-designated Specialized Programs of Research Excellence (SPORE) in kidney cancer. Established in 2013, the program has become a leader worldwide.
Disclosures: UT Southwestern and some of its researchers will receive financial compensation, through prior agreements with Peloton, based on belzutifan’s FDA approval.
James Brugarolas, M.D., Ph.D., is Professor of Internal Medicine in the Division of Hematology and Oncology at UT Southwestern. He is founding Director of the Kidney Cancer Program at Simmons Cancer Center. He also holds the Sherry Wigley Crow Cancer Research Endowed Chair in Honor of Robert Lewis Kirby, M.D, and is a member of the Cellular Networks in Cancer Research Program at Simmons Cancer Center.
