Written By Yogita Bhadane, B.Pharm
Reviewed and Fact Checked by Vikas Londhe M.Pharm (Pharmacology)
Introduction
Welireg (belzutifan), a significant advancement, has been approved by the European Medicines Agency (EMA) as the first clinically approved pharmaceutical therapy for tumors associated with von Hippel-Lindau (VHL) disease and for adults with advanced renal cell carcinoma (RCC) who have already received treatment. As a new targeted therapy for unmet medical needs, this approval holds promise for clinicians treating these difficult conditions.
Understanding VHL Disease and RCC
Von Hippel-Lindau disease (VHL) is a rare genetic disorder that predisposes people to develop tumors and cysts in the kidneys, pancreas, and central nervous system, with kidney cancer being the most common type. Renal cell carcinoma occurs in an abnormal 70% of individuals with VHL syndrome. These tumors are caused by mutations in the VHL gene, which affects how the gene regulates the breakdown of proteins called hypoxia-inducible factor (HIF), which are sensitive to tissue oxygen levels. Tumor formation results from aberrant HIF activation brought on by VHL mutation. Conventional management techniques involved frequent surgical procedures and constant monitoring, which increased risks and lowered patient living standards. Immunocheckpoint inhibitors and anti-angiogenic therapies are used in the treatment of advanced renal cell carcinoma; however, post-progression care options are still scarce.
Hemangioblastomas
These non-cancerous growths mostly appear in the retina, spinal cord, and brain tissue. Brain hemangioblastoma patients are more likely to experience symptoms like headaches, vision issues, and neurological impairments.
Renal Cell Carcinomas (RCC)
The risk of kidney cancer, primarily clear cell renal carcinoma, is increased in people with VHL disease. In addition to renal impairment, these disorders often manifest bilaterally and cause hematuria and dysuria. Some examples show that (heterogeneous) petrocalcic deposits give rise to saddle-shaped inclusions.
Pheochromocytomas:
High blood pressure, headaches, sweating, and palpitations are some of the symptoms caused by these tumors growing on the adrenal gland, which strictly adhere to EPI while binding to norepinephrine. Although phenochromocytomas usually appear as benign tumors, if left untreated, they have the potential to become fatal.
Pancreatic Cysts and Tumors:
Patients with VHL may develop pancreatic cysts. Although the majority of them are benign, tiny molecules have the potential to develop into pancreatic neuroendocrine tumors, which may release hormones that result in various symptoms.
Endolymphatic Sac Tumors (ELSTs):
Almost all of these are tumors that are located in the patient’s ear near the inner ear. Tinnitus, instability, and hearing loss are possible symptoms for those who have this condition. Chemotherapy or even stereotactic radiation may be used to treat general growth and low-grade ELSTs.
Retinal Angiomas:
Hemangioblastomas, also known as retinal angiomas, are tumors of the blood vessels that frequently develop in the membrane of the eye and can cause partial blindness. Hemangioblastomas appear when they cause bleeding or retinal detachment, or when they are discovered during an eye exam.
Welireg’s Mechanism:
Angiogenesis (the formation of blood vessels), erythropoiesis (the production of red blood cells), and tumor growth are all regulated by HIF-2α.
The Von Hippel-Lindau (VHL) protein breaks down HIF-2α under normal oxygen conditions.
HIF-2α builds up in tumors that lack VHL, such as clear cell renal cell carcinoma and von Hippel-Lindau disease-associated tumors, which causes the tumor to grow out of control.
Blocking HIF-2α Dimerization with HIF-1β:
By binding specifically to HIF-2α, belzutifan stops it from interacting with HIF-1β, which is a prerequisite for HIF-2α to activate target genes.
VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor), and EPO (erythropoietin) are among the genes involved in tumor survival whose transcription is inhibited by this.
Anti-Tumor Effects:
Welireg is effective in cancers caused by HIF-2α overactivity, especially VHL-associated renal cell carcinoma (RCC), central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors, because it inhibits HIF-2α signaling, which in turn reduces tumor growth, angiogenesis, and erythropoiesis.
An important tumor growth pathway is disrupted by the oral hypoxia-inducible factor 2 alpha (HIF-2α) inhibitor belzutifan. HIF-2α builds up in low oxygen environments, activating genes that support angiogenesis and cell division. Welireg deprives tumors of these signals by blocking HIF-2α, which slows growth and causes shrinkage. This mechanism is revolutionary because it provides a precision medicine approach that is specific to the molecular drivers of RCC and VHL.
Clinical Trial Efficacy
VHL-Associated Tumors: Belzutifan is being evaluated in patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) in the Phase 2 open-label clinical trial NCT03401788 (Study 004). 61 adults with at least one detectable RCC tumor and a germline VHL alteration were enrolled. Additionally, patients may have pancreatic neuroendocrine tumors (pNETs) or CNS hemangioblastomas. Prior use of HIF-2α inhibitors, systemic therapy, surgical necessity, and metastatic disease were excluded. Until toxicity or progression, participants were given 120 mg of belzutifan every day. Overall response rate (ORR), the main outcome, was 49% in RCC, 63% in CNS hemangioblastomas, and 83% in pNETs. With more than half of respondents continuing to respond for more than 12 months, the median response duration was not reached.
Advanced RCC: Belzutifan, a hypoxia-inducible factor 2α (HIF-2α) inhibitor, is being evaluated in patients with advanced solid tumors as part of the LITESPARK-001 trial (NCT02974738), a phase 1 clinical study. 55 patients with advanced ccRCC who had previously received treatment were given 120 mg of belzutifan orally once daily as part of this cohort. The objective response rate (ORR), which included one complete response and thirteen partial responses, was 25% following a median follow-up of more than three years. The median progression-free survival (PFS) was 14.5 months, and the disease control rate (DCR) was 80%. Anaemia (24% grade 3) and hypoxia (13% grade 3) were the most common treatment-related adverse events; no grade 4 or grade 5 treatment-related adverse events were noted. These findings show that belzutifan has a manageable safety profile and long-lasting antitumor activity in patients with ccRCC who have received extensive pre-treatment.
Glioblastoma (GBM) Cohort: A cohort of 25 patients with recurrent IDH wild-type glioblastoma after radiation therapy and temozolomide was also included in the trial. Belzutifan 120 mg was given orally to the patients twice a day. There were no objective responses after a median follow-up of 1.9 months; the median PFS was 1.4 months, and the clinical benefit rate was 8%. Every patient had at least one adverse event, and 60% of them had grade 3-5 events. Anaemia (64%), exhaustion (52%), headache (32%), and muscle weakness (32%), were the most frequent adverse events. There were no deaths brought on by the treatment. These results imply that in this GBM cohort, belzutifan did not exhibit antitumor activity.
Belzutifan’s potential for treating advanced ccRCC is generally highlighted by the LITESPARK-001 trial, but its effectiveness in treating GBM has not yet been established.
Safety and Tolerability
Administration of Welireg during pregnancy can cause embryo-fetal harm. It was highly recommended to confirm the pregnancy status before initiating Welireg.
Anaemia (71%), Hypoxia (48%), and nausea (31%), which are usually mild to moderate, are common side effects. It is advised to regularly check oxygen and hemoglobin levels. When compared to intravenous treatments, the ease of oral administration (120 mg once daily) improves patient adherence.
EMA Approval and Patient Impact
With the EMA’s support, access is made possible throughout the EU, changing the way that care is provided. Welireg preserves organ function and quality of life for VHL patients by lowering the need for invasive surgeries. It closes a crucial gap left by post-standard therapies for advanced RCC. “Belzutifan represents a paradigm shift, offering a non-invasive option with meaningful clinical benefits,” says oncologist Dr. Maria Ruiz.
Future Directions
Belzutifan is being studied for combination treatments and other cancers driven by HIF-2α. Its success highlights how hypoxia pathways can be targeted in oncology.
Conclusion
The approval of Welireg, which addresses long-standing issues in the management of VHL and RCC, is a victory for precision medicine. Belzutifan sets a new standard by focusing on innovation in rare and complex cancers and coordinating treatment with disease biology. This milestone opens the door for future advancements in targeted therapies in addition to providing immediate clinical benefits.
References:
1. First medicine to treat rare genetic disorder causing cysts and tumours, European Medicine Agency, 13 December 2024
2. WELIREG® (belzutifan) Receives First European Commission Approval for Two Indications, Merck, 18 February 2025
3. Kim E, Zschiedrich S. Renal Cell Carcinoma in von Hippel-Lindau Disease-From Tumor Genetics to Novel Therapeutic Strategies. Front Pediatr. 2018 Feb 9;6:16. doi: 10.3389/fped.2018.00016. PMID: 29479523; PMCID: PMC5811471.
4. Ashouri K, Mohseni S, Tourtelot J, Sharma P, Spiess PE. Implications of Von Hippel-Lindau Syndrome and Renal Cell Carcinoma. J Kidney Cancer VHL. 2015 Sep 25; 2(4):163-173. Doi: 10.15586/jkcvhl.2015.41. PMID: 28326271; PMCID: PMC5345519.
5. Eric Jonasch, Frede Donskov, Othon Iliopoulos, Belzutifan for Renal Cell Carcinoma in von Hippel–Lindau Disease, n engl j med 385;22, November 25, 2021.
6. Hu, J., Tan, P., Ishihara, M. et al.Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma. Sig Transduct Target Ther8, 155 (2023). https://doi.org/10.1038/s41392-023-01362-2
7. Roy E. Strowd et al., Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: Results of the glioblastoma cohort. JCO 42, 2054-2054(2024). DOI:10.1200/JCO.2024.42.16_suppl.2054
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