On May 14, 2025, Merck announced that the U.S. Food and Drug Administration (FDA) has approved Welireg (belzutifan) for the treatment of adult and pediatric patients aged 12 years and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).
The press release noted that Welireg is the first oral treatment approved by the FDA for pheochromocytoma and paraganglioma.
Belzutifan, a selective small-molecule oral hypoxia-inducible factor-2α (HIF-2α) inhibitor, was initially approved by the FDA in August 2021 for the treatment of adult patients with Hipper-Lindau syndrome (VHL syndrome), and subsequently received FDA approval in December 2023 for the treatment of adult patients with advanced renal cell carcinoma (RCC) following treatment with programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors and vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs).
This approval is based on data from the open-label phase 2 LITESPARK-015 trial (ClinicalTrials.gov registration number: NCT04924075). This multi-cohort study enrolled 72 patients with locally advanced or metastatic lesions who were ineligible for surgery or radical treatment and whose blood pressure was adequately controlled.
Study participants received belzutifan 120 mg orally once daily until disease progression or unacceptable toxicity.
The primary endpoint of the trial was the objective response rate (ORR), assessed by a blinded, independent central review according to RECIST 1.1 criteria. Secondary endpoints included duration of response (DOR), time to response (TTR), and the proportion of patients who achieved a reduction of at least 50% in the dosage of at least one antihypertensive medication for at least 6 months.
Results showed an ORR of 26% (95% CI, 17-38). The median duration of response (a secondary endpoint) was 20.4 months (95% CI, 8.3, not reached); 53% of patients who achieved a response had a duration of response of at least 12 months.
Notably, among the 60 patients taking antihypertensive medication, 19 (32% [95% CI, 20-45]) achieved a reduction of at least 50% in the dosage of at least one antihypertensive medication for at least 6 months.
The most common reported adverse reactions included anemia, fatigue, musculoskeletal pain, lymphopenia, elevated alanine aminotransferase (ALT), elevated aspartate aminotransferase (AST), elevated serum calcium, dyspnea, elevated serum potassium, leukopenia, headache, elevated alkaline phosphatase (ALP), dizziness, and nausea.
According to the label, the recommended adult dose is 120 mg orally once daily. The recommended dose for children aged 12 years and older is based on weight. For pediatric patients weighing ≥40 kg, the dose is 120 mg orally once daily. For pediatric patients weighing <40 kg, the dose is 80 mg orally once daily. Continue belzutifan until the disease worsens or unacceptable toxicity occurs.
