Welireg (belzutifan) - 2 indications

• for the treatment of von Hippel-Lindau (VHL) disease; approved August of 2021
• for the treatment of advanced renal cell carcinoma; approved December of 2023

General Information 

Welireg (belzutifan) is a hypoxia-inducible factor inhibitor.

Welireg is specifically indicated:

• for treatment of adult patients 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.
• for treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI)

Dosing/Administration

Welireg is supplied as tablets for oral administration. The recommended dosage is 120 mg administered orally once daily until disease progression or unacceptable toxicity. Welireg should be taken at the same time each day and may be taken with or without food. Advise patients to swallow tablets whole. Do not chew, crush, or split Welireg prior to swallowing. If a dose is missed, it can be taken as soon as possible on the same day. Resume the regular daily dose schedule the next day. Do not take extra tablets to make up for the missed dose. If vomiting occurs any time after taking Wwelireg, do not retake the dose. Take the next dose on the next day.

Mechanism of Action

Welireg (belzutifan) is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α). HIF-2α is a transcription factor that plays a role in oxygen sensing by regulating genes that promote adaptation to hypoxia. Under normal oxygen levels, HIF-2α is targeted for ubiquitin-proteasomal degradation by VHL protein. Lack of functional VHL protein results in stabilization and accumulation of HIF-2α. Upon stabilization, HIF-2α translocates into the nucleus and interacts with hypoxia-inducible factor 1 beta (HIF-1) to form a transcriptional complex that induces expression of downstream genes, including genes associated with cellular proliferation, angiogenesis, and tumor growth. Belzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function, belzutifan blocks the HIF-2α-HIF-1 interaction, leading to reduced transcription and expression of HIF-2α target genes. In vivo, belzutifan demonstrated anti-tumor activity in mouse xenograft models of renal cell carcinoma.

Side Effects

Adverse effects associated with the use of Welireg for VHL may include, but are not limited to, the following:

• decreased hemoglobin
• anemia
• fatigue
• increased creatinine
• headache
• dizziness
• increased glucose
• nausea

Adverse effects associated with the use of Welireg for advanced RCC may include, but are not limited to, the following:

• decreased hemoglobin
• fatigue
• musculoskeletal pain
• increased creatinine
• decreased lymphocytes
• increased alanine aminotransferase
• decreased sodium
• increased potassium
• increased aspartate aminotransferase

The Welireg drug label comes with the following Black Box Warning: Exposure to Welireg during pregnancy can cause embryo-fetal harm. Verify pregnancy status prior to the initiation of Welireg. Advise patients of these risks and the need for effective non-hormonal contraception. Welireg can render some hormonal contraceptives ineffective.

Indication 1 - von Hippel-Lindau (VHL) disease 

Approved August of 2021

Clinical Trial Results

The FDA approval of Welireg for the treatment of adult patients 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 was based on results from the open-label Study 004 trial. The trial enrolled 61 patients with VHL-associated RCC diagnosed based on a VHL germline alteration and with at least one measurable solid tumor (as defined by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) localized to the kidney. Enrolled patients had other VHL-associated tumors, including CNS hemangioblastomas and pNET. CNS hemangioblastomas and pNET in these patients were diagnosed based on the presence of at least one measurable solid tumor in the brain/spine or pancreas, respectively, as defined by RECIST v1.1 and identified by an independent review committee (IRC). The study excluded patients with metastatic disease. Patients received Welireg at a dose of 120 mg once daily until progression of disease or unacceptable toxicity. The major efficacy endpoint for the treatment of VHL-associated RCC was ORR measured by radiology assessment using RECIST v1.1 as assessed by IRC. Additional efficacy endpoints included duration of response (DoR) and time to response (TTR). In patients with VHL-associated RCC, Welireg showed an ORR of 49%; all responses were partial responses. Median DoR had not yet been reached; among responders, 56% (n=17/30) were still responding after at least 12 months. Median TTR was eight months.

Indication 2 - advanced renal cell carcinoma

Approved December of 2023

Clinical Trial Results

The FDA approval of Welireg for the treatment of adult patients with advanced renal cell carcinoma (RCC) following a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) was based on statistically significant and clinically meaningful results from LITESPARK-005, which is the only trial in advanced RCC to specifically evaluate patients who have progressed following a PD-1 or PD-L1 inhibitor and a VEGF-TKI. In the trial, Welireg demonstrated superior progression-free survival (PFS) versus everolimus in advanced RCC following treatment with both a PD-1 or PD-L1 checkpoint inhibitor and a VEGF receptor targeted therapy, given in sequence or in combination. Welireg showed an objective response rate (ORR) of 22% (n=82)  versus 4% (n=13) for everolimus.