Merck's belzutifan (Welireg) has received priority review from the FDA for the treatment of adult and pediatric patients (12 years and older) with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma (PPGL). The supplemental new drug application (sNDA) is based on data from the Phase 2 LITESPARK-015 trial, highlighting the potential of belzutifan as a novel therapy for this rare condition. The FDA has set a target action date of May 26, 2025.
Addressing an Unmet Need in Rare Adrenal Tumors
PPGL are rare tumors that develop in or around the adrenal glands. It is estimated that up to 2,000 new cases of PPGL are diagnosed each year in the U.S., and up to 52,800 new cases are diagnosed each year worldwide. Currently, there are no approved therapies available in the U.S. specifically for patients with this rare disease. Pheochromocytomas occur in the center of the adrenal gland, while paragangliomas occur in nerve tissue in the adrenal glands and near certain blood vessels and nerves. Up to 25% of PPGL cases are metastatic at diagnosis.
Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, stated, "Today’s US filing acceptance demonstrates our commitment to advancing novel therapies, such as WELIREG, to help treat patients with certain rare oncologic diseases. We look forward to working with the FDA to potentially provide this critical option to these patients who urgently need new innovative therapies."
LITESPARK-015 Trial Details
The sNDA is supported by objective response rate (ORR) and duration of response (DOR) data from the Phase 2 LITESPARK-015 trial (NCT04924075), an open-label, single-arm, multi-cohort study. The trial is evaluating the efficacy and safety of belzutifan monotherapy in patients with advanced PPGL (Cohort A1), pancreatic neuroendocrine tumors (pNETs, Cohort A2), von Hippel-Lindau (VHL) disease-associated tumors (Cohort B1), advanced gastrointestinal stromal tumors (Cohort C), or advanced solid tumors with HIF-2α-related genetic alterations (Cohort D). The trial enrolled an estimated 322 patients who received belzutifan 120 mg orally once daily.
The primary endpoint of the trial is ORR per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by blinded independent central review (BICR). Secondary endpoints include DOR, time to response, disease control, progression-free survival, overall survival, and safety.
Belzutifan's Existing Approvals
Belzutifan is currently approved in the U.S. for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors (pNETs) not requiring immediate surgery, based on results from the Phase 2 LITESPARK-004 trial. It is also approved in the U.S. and Canada for the treatment of adult patients with advanced RCC following a PD-1/PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI), based on results from the Phase 3 LITESPARK-005 trial.
Safety Profile
Belzutifan carries warnings for embryo-fetal toxicity, anemia, and hypoxia. It is crucial to verify pregnancy status prior to initiating belzutifan and to advise patients on the need for effective non-hormonal contraception. Anemia can be severe, potentially requiring blood transfusions, and hypoxia may necessitate supplemental oxygen or hospitalization. Common adverse reactions include decreased hemoglobin, fatigue, increased creatinine, headache, and nausea. Clinicians should monitor patients for these and other potential side effects.
