WELIREG® (belzutifan) Gains First European Commission Approval for Two Indications
Merck (NYSE: MRK), known as MSD outside the United States and Canada, has announced that the European Commission (EC) has conditionally approved WELIREG® (belzutifan), an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, for two important indications. WELIREG will be used as monotherapy for:
- The treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated localized renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), where localized procedures are unsuitable.
- The treatment of adult patients with advanced clear cell RCC who have progressed after two or more lines of therapy, including a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor, as well as at least two vascular endothelial growth factor (VEGF)-targeted therapies.
The EC’s approval is based on the positive results from the LITESPARK-004 and LITESPARK-005 trials, which supported these indications. This approval follows the positive recommendation from the Committee for Medicinal Products for Human Use (CHMP), adopted in December 2024. Notably, this is the first approval for WELIREG in the European Union (EU). With this approval, WELIREG is now available in more than 30 countries for certain adult patients with advanced RCC and in more than 40 countries for those with eligible VHL disease-associated tumors.
Dr. Marjorie Green, Senior Vice President and Head of Oncology, Global Clinical Development at Merck Research Laboratories, emphasized the significance of this approval. “The approval of WELIREG in the EU introduces the first and only systemic treatment option for adult patients with certain VHL disease-associated tumors for whom localized procedures are unsuitable.
It also offers a new treatment option for adult patients with advanced clear cell RCC who have progressed following a PD-1 or PD-L1 inhibitor and at least two VEGF-targeted therapies,” Dr. Green stated. “We are excited that WELIREG, as a first-in-class HIF-2α inhibitor, can now potentially provide help to patients in need.”
This conditional approval allows the marketing of WELIREG for these indications across all 27 EU member states, as well as Iceland, Liechtenstein, and Norway. The approval will remain valid for one year, with yearly renewals, contingent on additional clinical data from the LITESPARK-004 trial and another ongoing Phase 2 trial of WELIREG in patients with specific VHL disease-associated tumors. The timing of WELIREG’s commercial availability will vary by country, depending on national reimbursement procedures.
Results in Patients with VHL Disease-associated Tumors (LITESPARK-004)
WELIREG is now the first and only systemic therapy approved for VHL disease-associated tumors in the EU. The approval for adult patients with certain VHL disease-associated tumors is based on positive results from the LITESPARK-004 trial, which evaluated WELIREG in patients with VHL disease-associated RCC, CNS hemangioblastomas, and pNET. In this study, WELIREG showed promising results:
- In patients with VHL-associated RCC (n=61), WELIREG demonstrated an objective response rate (ORR) of 49% (95% CI, 36-62). All responses were partial responses, and the median duration of response (DOR) was not reached, with ongoing responses ranging from 2.8+ to 22+ months. Among responders, 56% maintained a response for at least 12 months.
- For patients with VHL-associated CNS hemangioblastomas (n=24), WELIREG showed an ORR of 63% (95% CI, 41-81), with a complete response (CR) rate of 4% and a partial response (PR) rate of 58%. The median DOR was also not reached, and 73% of responders maintained a response for at least 12 months.
- In patients with VHL-associated pNET (n=12), WELIREG demonstrated an ORR of 83% (95% CI, 52-98), with a CR rate of 17% and a PR rate of 67%. Again, the median DOR was not reached, but 50% of responders maintained a response for at least 12 months.
Results in Advanced RCC (LITESPARK-005)
The second indication for WELIREG is for adult patients with advanced clear cell RCC that has progressed after two or more lines of therapy, which included a PD-1 or PD-L1 inhibitor and at least two VEGF-targeted therapies. The approval is based on data from the LITESPARK-005 trial, the first trial to specifically evaluate patients who progressed after these treatments.
WELIREG showed encouraging results in this patient group:
- In the trial, WELIREG reduced the risk of disease progression or death by 25% (HR=0.75 [95% CI, 0.63-0.90]; p=0.0008) compared to everolimus. Median progression-free survival (PFS) was 5.6 months for both WELIREG and everolimus, but WELIREG showed significantly higher response rates.
- The objective response rate for WELIREG was 22% (n=82) (95% CI, 18-27), with a CR rate of 3% and a PR rate of 19%. In comparison, the ORR for everolimus was 4% (n=13) with no complete responses and a PR rate of 4%.
