Rare Daily Staff

The U.S. Food and Drug Administration approved Merck’s Welireg for the treatment of certain adult patients with von Hippel-Lindau disease.

The approval covers von Hippel-Lindau disease patients who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery.

Von Hippel-Lindau disease (VHL) is a rare disease that causes tumors and cysts to grow throughout the body. The tumors are usually benign, but some tumors, can become cancerous. People with VHL are at risk for a specific form of kidney cancer and pancreatic cancer. VHL is caused by mutations in the VHL gene, which is a tumor suppressor that protects the body from uncontrolled cell growth.

Welireg is the first HIF-2α inhibitor therapy approved in the United States. As an inhibitor of HIF-2α, Welireg reduces transcription and expression of HIF-2α target genes associated with cellular proliferation, angiogenesis, and tumor growth.

The Welireg label contains a boxed warning that exposure to the drug during pregnancy can cause embryo-fetal harm. Welireg can also render some hormonal contraceptives ineffective. The warning also notes that Welireg can cause severe anemia and severe hypoxia.

Welireg had been the lead therapeutic candidate for Peloton Therapeutics when Merck acquired the company in 2019 for $1 billion in cash and another $1.2 billion in potential milestones.

The approval was based on data from Study 004, an open-label trial in 61 patients with VHL-associated RCC diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors. The study excluded patients with metastatic disease.

The major efficacy endpoint for the treatment of VHL-associated renal cell carcinoma was overall response rate measured by radiology assessment. Additional efficacy endpoints included duration of response and time to response.

In patients with VHL-associated renal cell carcinoma, Welireg showed an overall response rate of 49 percent. All responses were partial responses. Median duration of response had not yet been reached. Among responders, 56 percent were still responding after at least 12 months. Median time to response was eight months.

In patients with VHL-associated CNS hemangioblastomas, Welireg showed an overall response rate of 63 percent, with a complete response rate of 4 percent and a partial response rate of 58 percent. Median duration of response had not yet been reached. Among responders, 73 percent were still responding after at least 12 months. Median time to response was three months.

In patients with VHL-associated pancreatic neuroendocrine tumors, Welireg showed an overall response rate of 83 percent, with a complete response rate of 17 percent and a partial response rate of 67 percent. Median duration of response had not yet been reached (range, 10.8+ to 19.4+ months); among responders, 50 percent were still responding after at least 12 months. Median time to response was eight months.

Serious adverse reactions occurred in 15 percent of patients who received Welireg, including anemia, hypoxia, anaphylaxis reaction, retinal detachment and central retinal vein occlusion (one patient each). Permanent discontinuation of Welireg due to adverse reactions occurred in 3.3 percent of patients. Adverse reactions that resulted in permanent discontinuation of Welireg were dizziness and opioid overdose (1.6 percent each).

Dosage interruptions of Welireg due to an adverse reaction occurred in 39 percent of patients. Adverse reactions that required dosage interruption in more than 2 percent of patients were fatigue, decreased hemoglobin, anemia, nausea, abdominal pain, headache and influenza-like illness. Dose reductions of Welireg due to an adverse reaction occurred in 13 percent of patients. The most frequently reported adverse reaction that required dose reduction was fatigue (7 percent).

The most common adverse reactions (25 percent or more), including laboratory abnormalities, that occurred in patients treated with Welireg were decreased hemoglobin (93 percent), anemia (90 percent), fatigue (64 percent), increased creatinine (64 percent), headache (39 percent), dizziness (38 percent), increased glucose (34 percent) and nausea (31 percent).

“VHL disease is a rare and serious condition. Until today, there were no systemic therapies approved to help treat patients diagnosed with certain types of VHL-associated tumors,” said Eric Jonasch, principal investigator of the Welireg studies and professor at the University of Texas MD Anderson Cancer Center. “The approval of Welireg, which is based on data showing an overall response rate across three different types of VHL-associated tumors, addresses this significant unmet need by introducing a new option for physicians and their patients impacted by this disease.”

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