Introduction
Welireg (belzutifan) is an oral hypoxia-inducible factor (HIF)-2α inhibitor developed by Merck & Co. It represents a novel therapeutic approach for treating certain cancers associated with von Hippel-Lindau (VHL) disease. Approved by the FDA in August 2021, Welireg is the first HIF-2α inhibitor to enter clinical practice, offering a targeted treatment option for patients with VHL-associated tumors.
Mechanism of Action
Belzutifan selectively inhibits hypoxia-inducible factor 2 alpha (HIF-2α), a transcription factor that plays a crucial role in cellular adaptation to hypoxia. Under normal oxygen conditions, HIF-2α is degraded by the von Hippel-Lindau tumor suppressor protein. In VHL disease, mutations in the VHL gene prevent proper degradation of HIF-2α, leading to its accumulation and subsequent activation of genes involved in angiogenesis (VEGF, PDGF), erythropoiesis (EPO), and cell proliferation (TGF-α). By inhibiting HIF-2α, belzutifan disrupts this pathogenic signaling cascade, reducing tumor growth and angiogenesis.
Indications
Welireg is indicated for the treatment of adults with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.
Dosage and Administration
Standard dosing: 120 mg orally once daily until disease progression or unacceptable toxicity Administration:- Take with or without food
- Swallow tablets whole; do not crush or chew
- If a dose is missed or vomiting occurs, resume the next scheduled dose
- Anemia: Withhold until hemoglobin ≥9 g/dL, then resume at same dose or reduced dose (90 mg or 60 mg)
- Severe hypoxia: Withhold until resolved, then resume at reduced dose or permanently discontinue
- Renal impairment: No dose adjustment necessary for mild to moderate impairment (eGFR ≥30 mL/min/1.73m²)
- Hepatic impairment: No dose adjustment necessary for mild to moderate impairment (Child-Pugh A or B)
- Pediatrics: Safety and effectiveness not established
- Geriatrics: No overall differences in safety or effectiveness observed
Pharmacokinetics
Absorption: Median Tmax is 1-2 hours. High-fat meal decreases Cmax by 36% and AUC by 13%. Distribution: Apparent volume of distribution is 92 L. Protein binding is 61%. Metabolism: Primarily metabolized by CYP2C19 and CYP3A4. No major circulating metabolites. Elimination: Half-life is approximately 14 hours. 58% excreted in feces and 22% in urine.Contraindications
- Hypersensitivity to belzutifan or any component of the formulation
Warnings and Precautions
Anemia: Welireg can cause severe anemia requiring blood transfusions. Monitor hemoglobin before treatment and periodically during therapy. Hypoxia: May cause severe hypoxia requiring discontinuation, supplemental oxygen, or hospitalization. Monitor oxygen saturation periodically. Embryo-Fetal Toxicity: Can cause fetal harm. Verify pregnancy status before initiation and advise use of effective contraception. Adrenal Insufficiency: May occur due to effects on steroidogenesis. Monitor for signs and symptoms. Renal Effects: May cause elevated serum creatinine. Monitor renal function during treatment.Drug Interactions
Strong CYP3A4 Inducers: Avoid concomitant use with drugs such as rifampin, carbamazepine, St. John's wort, as they may decrease belzutifan exposure. CYP2C19 Substrates: Belzutifan may decrease exposure to drugs metabolized by CYP2C19 (e.g., omeprazole, diazepam). Hormonal Contraceptives: May decrease efficacy of hormonal contraceptives. Use alternative non-hormonal contraception.Adverse Effects
Most common (≥20%):- Anemia (90%)
- Fatigue (64%)
- Headache (39%)
- Nausea (31%)
- Dizziness (26%)
- Increased creatinine (24%)
- Severe anemia (7%)
- Severe hypoxia (1.5%)
- Adrenal insufficiency
Monitoring Parameters
- Hemoglobin: Before initiation, every 2 weeks for first 3 months, then monthly
- Oxygen saturation: Periodically during treatment
- Pregnancy testing: Before initiation in females of reproductive potential
- Renal function: Serum creatinine at baseline and during treatment
- Adrenal function: Monitor for signs/symptoms of adrenal insufficiency
- Tumor response: Imaging per standard guidelines
Patient Education
- Take Welireg exactly as prescribed at the same time each day
- Report signs of anemia (fatigue, dizziness, shortness of breath)
- Monitor for symptoms of hypoxia (difficulty breathing, chest pain)
- Use effective non-hormonal contraception during treatment and for 1 week after discontinuation
- Inform all healthcare providers about Welireg use before starting new medications
- Do not breastfeed during treatment and for 1 week after final dose
- Report any missed doses or vomiting to your healthcare provider
- Regular blood tests are necessary to monitor safety and effectiveness
References
1. FDA Approval Letter: Welireg (belzutifan). August 2021 2. Jonasch E, et al. Belzutifan for Renal Cell Carcinoma in Von Hippel-Lindau Disease. N Engl J Med. 2021;385(22):2036-2046 3. Welireg [package insert]. Merck & Co., Inc.; 2023 4. National Comprehensive Cancer Network. Kidney Cancer Guidelines Version 4.2023 5. Chen W, et al. Targeting HIF-2α as a Therapeutic Strategy for Renal Cell Carcinoma. Drug Discov Today. 2021;26(9):2136-2144 6. Courtney KD, et al. HIF-2 Complex Dissociation, Targetability, and Resistance Mechanisms. JCI Insight. 2020;5(4):e133577
This information is provided for educational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional for personalized medical guidance.