Europe Approves Its First Drug for Von Hippel-Lindau Tumors

The European Medicines Agency (EMA) has recommended that a new oral agent, Welireg (belzutifan), be granted conditional marketing authorization for treatment of two different diseases: the rare genetic disorder von Hippel-Lindau disease (VHL) and a type of advanced renal cell carcinoma often featuring the same gene fault.

Welireg represents the first drug treatment for VHL, a life-threatening condition in which multiple cysts and tumors develop in various organs, often affecting the eyes, brain, spine, kidneys, and pancreas. The growths may be benign or malignant and cause long-term debilitating symptoms, which may include visual disturbance, headaches, and hypertension. 

Current Management Not Curative

VHL is caused by a single defect in a gene responsible for the production of a protein that normally prevents tumor formation. It affects an estimated 3 in 100,000 people in the European Union. Current European management centers on localized procedures such as surgery, radiation, or ablation of the tumors. However, these options are not curative, new tumors continue to occur, and there have been no approved systemic therapeutic options for when such procedures are unsuitable or undesirable. 

Therefore, the EMA said, there is an unmet need for treatment options to reduce the size and/or growth rate of VHL tumors. 

Belzutifan is indicated as monotherapy to treat adult patients with von Hippel-Lindau disease who require therapy for associated localized renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, and for whom localized procedures are unsuitable.

Defective VHL protein is also present in most cases of advanced clear cell renal cell carcinoma (RCC), so a recommendation for belzutifan was issued to also cover this condition. The drug is indicated as monotherapy for the treatment of adult patients with advanced RCC that progressed following two or more lines of therapy that included a PD-L1 inhibitor and at least two VEGF-targeted therapies. The US Food and Drug Administration approved the drug for use in RCC in the United States at the end of last year.

Drug Inhibits Disease-Associated Tumors

The drug is an antineoplastic agent that acts by blocking the activity of hypoxia-inducible factor 2 alpha (HIF-2α), which regulates cellular proliferation, angiogenesis, and tumor growth. By inhibiting HIF-2α, belzutifan counters the effects of the defective VHL protein, thereby reducing VHL disease-associated tumors. 

The EMA’s recommendation was based on the results of two main clinical studies showing significant responses among treated patients. 

Sixty-one patients with at least one VHL-associated tumor in their kidneys were evaluated in an ongoing phase 2, single-arm, open-label study. Belzutifan effected a partial or complete durable response in 39 patients (63.9%), which the EMA described as a “clinically relevant percentage.”

The other trial compared belzutifan with everolimus in 746 patients with unresectable, locally advanced, or metastatic RCC that had progressed after prior targeted therapies. A statistically significant improvement in progression-free survival was observed in patients treated with belzutifan. The EMA’s recommended indication concerns a subgroup of patients from this trial.

Belzutifan will be available as 40 mg film-coated tablets to be administered orally once daily. Treatment should be prescribed and supervised by physicians experienced in the treatment of cancer. The most common side effects are anemia, fatigue, nausea, dyspnea, dizziness, and hypoxia. Anemia and hypoxia can be severe and lead to dose interruption, dose reduction, or discontinuation of the treatment.

The opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. Once this is granted, decisions about price and reimbursement take place at the level of each member state, taking into account national considerations.

Dr Sheena Meredith is an established medical writer, editor, and consultant in healthcare communications, with extensive experience writing for medical professionals and the general public. She is qualified in medicine and in law and medical ethics.