WELIREG® (belzutifan) Gains Initial EU Approval for Two Uses

On February 18, 2025, Merck, operating as MSD outside the U.S. and Canada, publicized that the European Commission has conditionally approved WELIREG® (belzutifan), marking a milestone in oncology treatments within the European Union. This oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor has been green-lighted as a monotherapy for two specific indications. Firstly, it's for adults with von Hippel-Lindau (VHL) disease needing treatment for localized renal cell carcinoma (RCC), central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, particularly when localized procedures are not feasible. Secondly, it's aimed at adults with advanced clear cell RCC who have experienced disease progression following at least two lines of therapy, including PD-1 or PD-L1 inhibitors and a minimum of two VEGF targeted therapies.

WELIREG's approval in the EU is grounded on data from the LITESPARK-004 and LITESPARK-005 clinical trials, which followed a positive nod from the Committee for Medicinal Products for Human Use in December 2024. This approval heralds WELIREG as the first sanctioned oral HIF-2α inhibitor in the EU, available for marketing across all 27 EU member states as well as Iceland, Liechtenstein, and Norway. However, this conditional approval is subject to annual reviews, contingent upon further data from ongoing trials, including LITESPARK-004.

Dr. Marjorie Green, a key figure at Merck Research Laboratories, highlighted the significance of this development, especially as WELIREG offers the first systemic treatment option for certain VHL disease-associated tumors in the EU. Additionally, it presents a novel therapeutic avenue for those with advanced clear cell RCC previously treated with PD-1 or PD-L1 inhibitors and VEGF targeted therapies.

WELIREG's first indication, treatment for VHL disease-associated tumors, is supported by findings from the LITESPARK-004 trial. It was previously approved in the U.S. in 2021 for similar indications, with the trial showing promising objective response rates (ORR) and duration of response (DOR) in patients with VHL disease-associated RCC, CNS hemangioblastomas, and pancreatic neuroendocrine tumors.

The second indication, for advanced RCC, is supported by the LITESPARK-005 trial, which is noteworthy for specifically evaluating patients whose conditions progressed after PD-1 or PD-L1 inhibitors and VEGF therapies. Results from this trial also led to WELIREG's approval in the U.S. in December 2023, revealing a 25% reduction in the risk of disease progression or death compared to everolimus.

Von Hippel-Lindau disease is a rare genetic condition, affecting about 200,000 people globally, with a significant presence in Europe. It predisposes individuals to a range of tumor types, including RCC, which affects roughly 70% of patients with this condition. RCC, particularly its clear cell variant, is the most prevalent kidney cancer form. In 2020, Europe saw over 130,000 new RCC cases, underscoring the need for innovative treatments like WELIREG.

WELIREG's approval signifies a major step forward in the treatment of these conditions, providing a new option for patients with limited therapeutic choices. As the first of its kind, this HIF-2α inhibitor promises to make a substantial impact on the lives of those affected by VHL disease and advanced RCC, aligning with Merck's broader commitment to pioneering cancer treatments.