FDA Approves Merck’s WELIREG® (belzutifan) for Advanced Pheochromocytoma and Paraganglioma in Patients 12 Years and Older, Marking a New Era in Treatment of Rare Neuroendocrine Tumors
Merck, known as MSD outside of the United States and Canada, has announced a significant milestone in the treatment of rare neuroendocrine tumors: the U.S. Food and Drug Administration (FDA) has officially approved WELIREG® (belzutifan), an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for the treatment of adult and pediatric patients aged 12 years and older who are diagnosed with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma (PPGL).
This regulatory approval marks the third U.S. indication for WELIREG and expands its reach to a patient population with limited therapeutic options. Pheochromocytoma and paraganglioma, often referred to collectively as “pheo para,” are ultra-rare neuroendocrine tumors arising from the chromaffin cells of the sympathetic nervous system. Pheochromocytomas typically originate in the adrenal glands, whereas paragangliomas are located outside of the adrenal gland, often along the spine or in the head and neck region. Though rare—affecting an estimated 2,000 individuals annually in the U.S.—these tumors can present with complex clinical features, particularly when they are inoperable or have spread to other parts of the body.
The FDA’s decision is supported by results from the pivotal LITESPARK-015 trial, a Phase 2, open-label, single-arm study designed to assess the efficacy and safety of WELIREG in patients with measurable, advanced forms of PPGL. The study’s primary endpoint was objective response rate (ORR), a standard metric in oncology clinical trials that quantifies the proportion of patients who experience a partial or complete reduction in tumor burden.
A Critical Step Forward for Patients with Limited Treatment Options
“Pheochromocytoma and paraganglioma are rare and aggressive tumors that can lead to serious complications due to their potential to secrete catecholamines—hormones that can elevate blood pressure, heart rate, and cause a cascade of cardiovascular issues,” said Dr. Camilo Jimenez, professor in the department of endocrine neoplasia and hormonal disorders at The University of Texas MD Anderson Cancer Center. “For patients with locally advanced or metastatic disease, surgery is not always possible. Until now, there have been no FDA-approved non-surgical systemic therapies specifically indicated for this population.”
Dr. Jimenez emphasized that the approval of WELIREG introduces a novel, non-invasive therapeutic option that could redefine the standard of care for these patients. “This approval is based on rigorous response data from the LITESPARK-015 trial and presents a potential paradigm shift in managing this rare and complex disease,” he said.
Dr. Marjorie Green, senior vice president and head of oncology, global clinical development at Merck Research Laboratories, echoed the sentiment. “For individuals facing advanced PPGL, the treatment landscape has historically been sparse, with few options beyond surgery, radiation, or off-label systemic therapies. The FDA’s approval of WELIREG represents not only an expansion of our oncology portfolio but a reaffirmation of our dedication to developing innovative treatments for patients facing serious and often overlooked cancers,” Green stated.
Understanding the Mechanism: WELIREG and HIF-2α Inhibition
WELIREG (belzutifan) functions by inhibiting hypoxia-inducible factor-2 alpha (HIF-2α), a transcription factor that plays a crucial role in cellular adaptation to low oxygen conditions—a hallmark of solid tumors. HIF-2α has been implicated in the development and progression of several cancers, including PPGL, particularly those associated with genetic mutations that alter oxygen-sensing pathways, such as von Hippel-Lindau (VHL) disease.
By blocking HIF-2α activity, belzutifan disrupts a vital survival mechanism used by tumor cells in hypoxic environments, thereby impeding tumor growth and promoting cancer cell death. This mechanism of action is particularly relevant in PPGL, where dysregulated oxygen sensing contributes to disease pathology and progression.
Key Findings from the LITESPARK-015 Trial
The LITESPARK-015 trial (ClinicalTrials.gov identifier: NCT04924075) served as the foundation for the FDA’s decision. Conducted as a multicohort, open-label Phase 2 clinical trial, the study enrolled 72 patients in a single cohort (Cohort A1) with a histopathologically confirmed diagnosis of PPGL. Eligible patients had locally advanced, unresectable, or metastatic disease and had measurable tumors as assessed by blinded independent central review (BICR) according to RECIST v1.1 criteria.
To qualify, patients also needed to have adequately controlled blood pressure—defined as less than 150/90 mm Hg for adults and less than 135/85 mm Hg for adolescents—with stable antihypertensive regimens for at least two weeks prior to the initiation of study treatment. Patients with carcinomatous meningitis, an aggressive form of cancer spread to the meninges of the brain and spinal cord, were excluded from participation.
Participants received WELIREG at a daily oral dose of 120 mg and continued treatment until disease progression or the emergence of unacceptable toxicity. The primary endpoint was ORR, while secondary measures included duration of response (DoR) and time to response (TTR).
While specific numerical data were not disclosed in the announcement, the trial demonstrated meaningful tumor shrinkage in a significant proportion of patients, prompting the FDA to grant regulatory approval based on the clinical benefit observed.
Important Safety Information and Warnings
As with all cancer therapies, safety is paramount. WELIREG’s label includes a boxed warning concerning potential embryo-fetal toxicity. Because belzutifan can cause harm to a developing fetus, healthcare providers must verify pregnancy status before initiating treatment and advise patients on the use of effective non-hormonal contraception throughout therapy. Importantly, WELIREG can render hormonal contraceptives ineffective, necessitating alternative birth control strategies.
Another major risk associated with WELIREG is the potential for severe anemia, which in some cases may require blood transfusions. Patients should undergo regular monitoring of hemoglobin levels both before and during treatment. Additionally, WELIREG has been shown to cause hypoxia—low blood oxygen levels—which can range from mild to life-threatening. In some cases, supplemental oxygen therapy or treatment discontinuation may be required. Oxygen saturation should be closely monitored throughout the course of therapy.
Other potential adverse reactions observed in clinical trials include fatigue, headache, nausea, dizziness, and elevated liver enzymes. As with all medications, a thorough risk-benefit assessment is essential prior to initiating treatment.
A Growing Oncology Portfolio and a Broader Commitment to Rare Diseases
This approval not only marks a critical advancement in the management of PPGL but also further strengthens Merck’s growing oncology portfolio. WELIREG was initially approved in the U.S. for adult patients with von Hippel-Lindau disease-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors. Its expansion into PPGL illustrates the therapeutic versatility of HIF-2α inhibition and highlights Merck’s strategic focus on precision oncology.
“Innovation is at the heart of our mission, especially when it comes to addressing rare and neglected cancers,” said Dr. Green. “With the approval of WELIREG for advanced PPGL, we are proud to offer patients and providers a new tool to confront a disease that has long lacked adequate treatment options.”
The FDA’s approval of WELIREG for the treatment of locally advanced, unresectable, or metastatic PPGL in patients 12 years and older marks a pivotal moment in the management of these rare neuroendocrine tumors. For patients and families navigating the uncertainty of a PPGL diagnosis, the availability of a targeted, non-surgical systemic therapy offers new hope.
As Merck continues to explore the potential of HIF-2α inhibition in other cancers through its ongoing LITESPARK clinical development program, the approval of WELIREG in this new indication sets a precedent for what could be achieved in the realm of rare and difficult-to-treat tumors.
For more information, including full prescribing details and safety guidance, healthcare providers and patients are encouraged to consult the complete WELIREG prescribing information available through Merck or the FDA.
