Merck known as MSD outside the United States and Canada, announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion recommending the conditional approval of WELIREG® (belzutifan), an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, as monotherapy for two indications:
- Treatment of adult patients with von Hippel-Lindau (VHL) disease requiring therapy for associated localized renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), where localized procedures are unsuitable.
- Treatment of adult patients with advanced clear cell RCC that progressed following two or more lines of therapy, including a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and at least two vascular endothelial growth factor (VEGF) targeted therapies.
The CHMP recommendation will now be reviewed by the European Commission for marketing authorization in the European Union (EU), with a final decision expected in the first quarter of 2025.
“Today’s positive CHMP opinion brings us closer to offering WELIREG, a first-in-class HIF-2α inhibitor, to certain patients in the European Union to address critical gaps in care,” said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. “We are committed to providing innovative treatment options that address serious unmet needs for patients globally and look forward to the European Commission’s decision.”
Data Supporting Approval
The CHMP’s recommendation for VHL disease-associated tumors is based on results from the LITESPARK-004 trial. If approved, WELIREG would be the first systemic treatment available in the EU for patients with VHL disease-associated tumors.
In the LITESPARK-004 trial, WELIREG demonstrated a 49% objective response rate (ORR) (95% CI, 36-62) in patients with VHL-associated RCC (n=30/61), all of which were partial responses (PR). 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.
The trial also evaluated other VHL-associated tumors. In patients with CNS hemangioblastomas (n=24), WELIREG showed an ORR of 63% (95% CI, 41-81), including a complete response (CR) rate of 4% and a PR rate of 58%. The median DOR was not reached, with responses ranging from 3.7+ to 22+ months. Among responders, 73% maintained a response for at least 12 months. For patients with VHL-associated pNET (n=12), the ORR was 83% (95% CI, 52-98), including a CR rate of 17% and a PR rate of 67%. The median DOR was also not reached, with responses ranging from 11+ to 19+ months, and 50% of responders maintained a response for at least 12 months.
The CHMP recommendation for advanced clear cell RCC is based on results from the LITESPARK-005 trial, the first positive Phase 3 trial in this population.
In the LITESPARK-005 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. The median progression-free survival (PFS) was 5.6 months (95% CI, 3.9-7.0) for WELIREG and 5.6 months (95% CI, 4.8-5.8) for everolimus. The ORR for WELIREG was 22% (95% CI, 18-27), including a CR rate of 3% and a PR rate of 19%. In comparison, the ORR for everolimus was 4% (95% CI, 2-6), with no CRs and a PR rate of 4%.
Regulatory Status
WELIREG was first approved in the United States in August 2021 for the treatment of adult patients with VHL disease requiring therapy for associated RCC, CNS hemangioblastomas, or pNET, based on the LITESPARK-004 trial. In December 2023, the U.S. expanded the approval to include advanced RCC after progression on a PD-1/PD-L1 inhibitor and VEGF-targeted therapy based on LITESPARK-005.
If approved by the European Commission, WELIREG will provide a significant new option for patients with these challenging conditions, reinforcing Merck’s commitment to advancing oncology care worldwide.
