The U.S. Food and Drug Administration (FDA) has accepted a supplemental new drug application (sNDA) with priority review for treatment with Welireg (belzutifan), among adult and pediatric patients aged 12 years and older with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma (PPGL), according to a press release from Merck.
Notably, Welireg is Merck’s oral HIF-2α inhibitor, and if approved, would be the only available therapy in the U.S. for eligible patients with advanced PPGL. According to the release, the sNDA was accepted based on objective response rate (ORR) and duration of response (DOR) data from the phase 2 LITESPARK-015 trial studying Welireg in this patient population.
The ORR and DOR data which supported the sNDA will be presented at an upcoming medical meeting. A Prescription Drug User Fee Act (PDUFA), or target action, date of May 26, 2025, has been set by the regulatory agency.
“PPGL are rare tumors that form in and around the adrenal glands, and currently, there are no approved therapies available in the U.S. for patients with this rare disease,” Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, said in the release. “Today’s U.S. 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.”
Regarding safety, Welireg carries some safety concerns, including embryo-fetal toxicity, severe anemia and hypoxia. Severe anemia may require blood transfusions, with treatment adjustments or discontinuation based on severity. Hypoxia, potentially requiring oxygen therapy or hospitalization, mandates monitoring and immediate intervention for symptomatic cases. In clinical trials, common adverse reactions included decreased hemoglobin, fatigue, increased creatinine, headache and nausea, with serious reactions such as hypoxia, anemia, pneumonia and hemorrhage reported. Side effects led to treatment interruptions, dose reductions and or discontinuation in a significant proportion of patients.
Understanding the LITESPARK-015 Trial
PPGL, otherwise known as rare adrenal tumors, are caused by certain genetic syndromes or mutations. PPGL is estimated to have up to 2,000 new cases that are diagnosed each year in the U.S., though this number is approximately 52,800 worldwide. According to the release, PPGL occur in the center of the adrenal gland and in the nerve tissue of the adrenal glands and near certain blood vessels and nerves, respectively. Nearly 25% of PPGL cases are metastatic at diagnosis.
The open-label, single-arm, multi-cohort LITESPARK-015 clinical trial is investigating the efficacy and safety of Welireg monotherapy in patients with advanced PPGL in cohort A of the study, as well as pancreatic neuroendocrine tumors (pNETs) in cohort A2, von Hippel-Lindau (VHL) disease-associated tumors in cohort B1, advanced gastrointestinal stromal tumors in cohort C and advanced solid tumors with HIF-2α-related genetic alterations in cohort D.
ORR per RECIST v1.1 as assessed by blinded independent central review (BICR) serves as the study primary end point. Secondary end points of LITESPARK-015 include DOR, time to response, disease control, progression-free survival, overall survival and safety.
Moreover, the press release highlighted that the study has enrolled approximately 322 patients who have received 120 mg of Welireg orally once daily.
More On Welireg
Among adult patients with VHL disease who require therapy for associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pNETs not requiring immediate surgery, Welireg is the first and only HIF-2α inhibitor therapy approved for treatment in the U.S. This is based on data from the phase 2 LITESPARK-004 trial. Moreover, the HIF-2α inhibitor is approved for patients with VHL disease-associated tumors in China and 16 additional countries around the world.
Also, in the U.S. and Canada, Welireg is approved for the treatment of adult patients with advanced RCC following a PD-1 or PD-L1 inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI). This regulatory approval is based on results from the phase 3 LITESPARK-005 trial.
The press release goes on to state that the Company is evaluating Welireg in rare oncologic diseases, RCC and other tumor types across phase 2 and 3 trials as a monotherapy and in combination with other medicines.
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