Moderators: Kevin Courtney MD/PhD; Panel (left to right): Hans Hammers MD/PhD, Qian Qin MD, James Brugarolas MD/PhD
Summary:
Belzutifan is the first FDA-approved drug for treating VHL-associated tumors.
UT Southwestern contributed to the discovery and development of belzutifan.
Belzutifan is manufactured by Merck.
Research History:
Over 100 years of research contributed to belzutifan’s development:
Von Hippel-Lindau Syndrome was named after Eugen von Hippel and Arvid Lindau, who first identified key features of the disease in the early 1900s.
Eugen von Hippel described retinal hemangiomas.
Arvid Lindau connected CNS hemangioblastomas with retinal hemangiomas.
Scientific Breakthroughs (1991-2001):
Major discoveries include the identification of HIF (hypoxia-inducible factor) proteins, the VHL tumor suppressor gene, and the link between VHL and HIF proteins.
Inhibiting HIF2 was shown to block tumor growth in cells with VHL mutations.
HIF2α was discovered by Steven McKnight and David Russell at UT Southwestern.
Nobel Prize: In 2019, William G. Kaelin, Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza won the Nobel Prize in Physiology or Medicine for their discoveries on how cells sense and adapt to oxygen.
FDA Approval:
In 2021, belzutifan, a HIF-2 inhibitor, was approved by the FDA for treating VHL-associated cancers.
In 2023, belzutifan was approved for treating advanced renal cell carcinoma in patients previously treated with PD-1/PD-L1 inhibitors and VEGF-TKI.
Mechanism of Action:
Normal Oxygen Conditions: Oxygen binds to the HIF2α protein, causing HIF2α to be recognized and destroyed by the VHL protein.
Low Oxygen Conditions: HIF2α moves to the cell nucleus and interacts with HIF1β, triggering signals for cell growth, survival, metastasis (spreading to other parts of the body), and blood vessel growth.
In VHL syndrome, reduced function or loss of the VHL protein leads to an abnormal buildup of HIF2α. This buildup results in uncontrolled cell growth, survival, metastasis, and blood vessel growth.
95% of clear cell renal carcinomas are caused by defects in the VHL protein.
Development of Belzutifan:
Early drug development focused on blocking the interaction between HIF2α and HIF1β, thus preventing signals for cell growth, survival, metastasis, and blood vessel growth.
PT2399 was an early version of belzutifan, proving that blocking HIF2α-HIF1β interactions could reduce tumor growth in VHL-associated cancer.
Belzutifan, also known as PT2977 or welireg, was shown to be effective in 50% of advanced kidney cancer samples derived from patients, leading to its further development and eventual FDA approval.
Phase 1 Clinical Trial (2021):
Led by Eric Jonasch and other physicians, the first clinical trial tested belzutifan in patients with VHL-associated kidney cancer.
Phase 1 clinical trial means it is the first time the drug has been tested in humans. The purpose is to determine a new drug’s safety, side effects, and ideal dosage.
61 patients participated in the trial.
Results:
30 patients (49%) experienced 30% or greater shrinkage of their kidney tumors.
The remaining 30 patients saw no tumor growth or had tumors shrink by less than 30%.
No patients experienced tumor growth.
Side Effects of Belzutifan:
Fatigue and Low Red Blood Cell Count (Anemia):
These occur because HIF2α is linked to these processes, indicating the drug is working as expected.
Anemia can be treated with injections to stimulate red blood cell growth.
Low Oxygen Levels (Hypoxia):
The most serious side effect.
Patients starting belzutifan are advised to monitor oxygen levels to ensure they don’t drop too low.
Monitoring:
Liver and kidney function are monitored monthly via blood tests during belzutifan treatment.
Tolerance:
If side effects are severe, treatment can be paused, the dosage reduced, or the drug given less frequently.
Most patients are able to tolerate the full dose of belzutifan.
