FDA Grants Priority Review to Merck’s Welireg for Advanced, Unresectable, or Metastatic Pheochromocytoma, Paraganglioma

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The FDA has granted Priority Review to Merck's supplemental new drug application (sNDA) for Welireg (belzutifan), an oral HIF-2α inhibitor, for treating adult and pediatric patients over 12 years of age with advanced, unresectable, or metastatic pheochromocytoma and paraganglioma (PPGL). According to the company, the sNDA is supported by findings from the Phase II LITESPARK-015 trial, which demonstrated a promising objective response rate (ORR) and duration of response (DOR). Currently, there are no approved therapies for PPGL in the United States.¹

“Pheochromocytoma and paraganglioma 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,” said Marjorie Green, SVP, head of oncology, global clinical development, Merck Research Laboratories, in a press release. “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.”

The open-label, single-arm, multi-cohort LITESPARK-015 trial evaluated the efficacy and safety of Welireg as a monotherapy. Consisting of 322 patients, the primary endpoint of the study was ORR per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as assessed by blinded independent central review (BICR). Key secondary endpoints included DOR, time to response, disease control, progression-free survival, overall survival, and safety.

Currently, Welireg is the only therapy approved in the United States for adult patients with von Hippel-Lindau (VHL) who require therapy as a result of associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery. The treatment in also approved in the United States 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.¹

According to a study published in the National Center for Biotechnology Information, PPGLs are known to be rare. However, results of the study indicated that the yearly incidence has risen over time, mainly due to incidental identification of tumors on imaging. The authors of the study stated that more studies on PPGL are required moving forward.²

According to Orpha, PPGLs occur in 0.1 to 0.6% of patients with hypertension and 5% with adrenal incidentaloma, with an incidence rate of approximately 0.57 per 100,000 people. Additionally, hypertension is the most common sign and can be permanent. While blood pressure levels can be normal, headaches, sweating, and palpitations can occur. Further, 40% of PPGLs occur as an inherited syndrome.³

According to Medscape, 85% of pheochromocytomas occur in the adrenal glands and 98% in the abdomen. Additionally, 10% of pheochromocytomas and 35% of extra-adrenal pheochromocytomas are malignant.⁴

According to Medline Plus, hereditary PPGL occurs in an estimated one in one million people globally. They are also common in people with inherited disorders such as VHL, Carney-Stratakis syndrome, and certain types of multiple endocrine neoplasia, which have several of different tumor types and genetic causes.⁵

The FDA has set a Prescription Drug User Fee Act target action date for the sNDA of May 26, 2025. Currently, Merck is also investigating Welireg in several rare diseases, RCC, and multiple tumor types, including as a monotherapy in combination with other treatments.¹

References

1. FDA Grants Priority Review to Merck’s Application for WELIREG® (belzutifan) for the Treatment of Patients With Advanced Pheochromocytoma and Paraganglioma (PPGL). Merck. January 27, 2025. Accessed January 27, 2025. https://www.merck.com/news/fda-grants-priority-review-to-mercks-application-for-welireg-belzutifan-for-the-treatment-of-patients-with-advanced-pheochromocytoma-and-paraganglioma-ppgl/

2. Systematic Review: Incidence of Pheochromocytoma and Paraganglioma Over 70 Years. NIH. Accessed January 27, 2025. https://pmc.ncbi.nlm.nih.gov/articles/PMC9334688/#:~:text=Of%20these%20cases%2C%202047%20(50.4,years%20by%202015%20%5B11%5D.

3. Pheochromocytoma-paraganglioma. Orphanet. Accessed January 27, 2025. https://www.orpha.net/en/disease/detail/573163#:~:text=The%20incidence%20is%20approximately%200.57,even%20sometimes%20completely%20non%2Dexistent.

4. Pheochromocytoma. Accessed January 27, 2025. https://emedicine.medscape.com/article/124059-overview?form=login

5. Hereditary paraganglioma-pheochromocytoma. Medline Plus. Accessed on January 27, 2025. https://medlineplus.gov/genetics/condition/hereditary-paraganglioma-pheochromocytoma/#inheritance