The FDA has approved Merck’s Welireg (belzutifan), a hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adults and pediatric patients aged 12 and older with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).

What Drove the FDA’s Approval of Welireg for PPGL?

The approval, which marks the first non-surgical treatment for this population, was based on objective response rate (ORR) data from the Phase II LITESPARK-015 trial.¹

“PPGL, sometimes referred to as pheo para, is a rare condition affecting up to 2,000 people each year in the United States,” said Camilo Jimenez, professor, department of endocrine neoplasia and hormonal disorders, University of Texas MD Anderson Cancer Center, in a press release. “Patients with these tumors, which arise from the adrenal glands and the extra-adrenal paraganglia, may require specialized care due to their complexity and rare nature, often posing significant challenges for both diagnosis and treatment. This approval, which is based on objective response rate data from the LITESPARK-015 trial, introduces belzutifan as the only approved and available non-surgical option for locally advanced, unresectable, or metastatic PPGL and could represent a change to the treatment paradigm for eligible patients.”

LITESPARK-015 Clinical Trial Overview and Outcomes

LITESPARK-015 was an open-label, multicohort trial that evaluated the safety and efficacy of Welireg as a monotherapy. In Cohort A1, 72 patients were enrolled with measurable PPGL confirmed by blinded independent central review (BICR) using RECIST v1.1 criteria.

Eligible participants had a histopathologically confirmed diagnosis of pheochromocytoma or paraganglioma, with locally advanced or metastatic disease not suitable for surgery or curative intent. To qualify, patients with hypertension were required to have stable and adequately controlled blood pressure with no changes to antihypertensive regimens for at least two weeks prior to treatment initiation.

Individuals with carcinomatous meningitis were excluded. All patients received 120 mg of Welireg once daily, continuing until either disease progression or the onset of unacceptable toxicity. The primary endpoint of the study was ORR measured by BICR using RECIST v1.1. Key secondary endpoints included duration of response (DOR) and time to response.¹

Results demonstrated a median DOR of 20.4 months (95% CI: 8.3, NR). Among the 60 patients who were on antihypertensive medications at baseline, 32% experienced a ≥50% reduction in at least one of those medications sustained for six months or longer. The most common adverse events, which included laboratory abnormalities, were anemia; fatigue; musculoskeletal pain; decreased lymphocytes and leukocytes; increased alanine aminotransferase; aspartate aminotransferase, calcium, potassium, and alkaline phosphatase; dyspnea; headache; dizziness; and nausea.²

PPGL Broader Context and Market Expansion

According to a study published in the National Center for Biotechnology Information, the global prevalence of PPGL is estimated to range from one in 2,500 to one in 6,500 individuals, with 20% of cases occurring in pediatric populations.³

“For patients with advanced PPGL, there has been a lack of approved systemic treatment options available to help manage their disease, underscoring the importance of this approval in the US,” said Marjorie Green, SVP, head, oncology, global clinical development, Merck Research Laboratories, in the press release. “This approval marks the third indication for Welireg in the US and demonstrates our company’s commitment to providing innovative cancer therapies for patients in need, including those with rare diseases.”

In January, the FDA granted Priority Review to Welireg for the treatment of advanced, unresectable, or metastatic PPGL. The drug is currently the only FDA-approved therapy in the United States for adult patients with von Hippel-Lindau disease who require treatment for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors that do not require immediate surgery.⁴

References

1. FDA Approves Merck’s WELIREG® (belzutifan) for the Treatment of Adults and Pediatric Patients 12 Years and Older With Locally Advanced, Unresectable, or Metastatic Pheochromocytoma or Paraganglioma (PPGL). Merck. May 14, 2025. Accessed May 15, 2025. https://www.merck.com/news/fda-approves-mercks-welireg-belzutifan-for-the-treatment-of-adults-and-pediatric-patients-12-years-and-older-with-locally-advanced-unresectable-or-metastatic-pheochromocytoma-or-par/

2. FDA approves belzutifan for pheochromocytoma or paraganglioma. FDA. May 14, 2025. Accessed May 15, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-belzutifan-pheochromocytoma-or-paraganglioma

3. Pheochromocytoma and Paraganglioma: From Epidemiology to Clinical Findings. PubMed. Accessed May 15, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC7326683/#:~:text=The%20incidence%20of%20PCC%20and,aggressiveness%20of%20this%20tumor%20group.

4. FDA Grants Priority Review to Merck’s Welireg for Advanced, Unresectable, or Metastatic Pheochromocytoma, Paraganglioma. PharmExec. January 27, 2025. Accessed May 15, 2025. https://www.pharmexec.com/view/fda-grants-priority-review-merck-welireg-for-advanced-unresectable-metastatic-pheochromocytoma-paraganglioma