Regulatory Decision Summary for Welireg

Currently there are no approved systemic therapies available for VHL disease-associated localized RCC in Canada, highlighting an unmet medical need for this population.

The evaluation of efficacy and safety for this submission was supported by a Phase 2, single-arm study in patients with VHL disease-associated RCC.

Welireg (belzutifan) is a HIF-2α inhibitor. The pivotal Study-004, was an ongoing, open-label, multicenter, nonrandomized, single-arm, interventional study to evaluate the efficacy and safety of Welireg in adult patients with VHL disease and at least 1 measurable RCC tumour, and no evidence of metastatic disease. Welireg 120 mg was administered orally once daily until unacceptable treatment-related toxicity or disease progression.

The primary efficacy endpoint was confirmed objective response (complete response or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 based on Independent Review Committee (IRC) evaluation. In Study-004 (N = 61), after a median duration of follow-up of 94.8 weeks (21.8 months; range 4.2, 30.1 months), the objective response rate (ORR) was 49.2% (95% Confidence Interval [CI]: 36.1, 62.3). No responders achieved complete response. One patient had confirmed progressive disease, and one patient had unconfirmed progressive disease. The median duration of response (DOR), a secondary endpoint, was not reached (range: 12.1+, 96.9+ weeks).

Although ORR is a surrogate endpoint, it is considered a direct measure of a drug antitumour activity. ORR can be evaluated in a single-arm study and is assessed by its magnitude and duration. The impact of RCCs on mortality is driven by end-stage renal failure secondary to (multiple) surgical resections or the development of metastatic RCC. A clinically meaningful ORR with a durable duration of response can directly reduce these undesirable outcomes.

In the pivotal Study-004, treatment-emergent adverse events (TEAE) were reported by 100% of patients after a mean duration of exposure of 94 weeks (range 8.4 to 130.9 weeks) with 90% exposed for 18 months or longer. Grade ≥3 TEAE occurred in 32.8% of patients, with Grade 3, Grade 4, and Grade 5 TEAEs observed in 29.5%, 1.6%, and 1.6%, respectively. The most common (≥20%) TEAE were anemia, fatigue, headache, dizziness, nausea, and dyspnea. There were no deaths from treatment toxicity. There was one fatal case of toxicity to various agents, which was not related to treatment with Welireg. Based on combined IRC and Sponsor assessment, the adverse events identified to have the strongest causal relationship with Welireg were anemia, hypoxia, fatigue, dyspnea, nausea, and dizziness. Anemia and hypoxia were determined to be on-target adverse events of special interest and are included as Warnings and Precautions in the Product Monograph.

There was no human data available regarding the potential effect of Welireg on fertility, pregnancy or development of the embryo or fetus. However, based on findings in animal studies, belzutifan may impair fertility irreversibly and cause fetal harm, including fetal loss, in humans. The reversibility of the effect on fertility is unknown. In vitro studies have shown that belzutifan induces CYP3A4 and other compounds that are CYP3A4 substrates (including hormonal contraceptives) may have decreased plasma concentrations and reduced efficacy when co-administered with belzutifan. Given the relatively young patient population and potential for long-term use of Welireg, the risk of embryofetal toxicity and the interaction with hormonal contraceptives has been labelled for via a Serious Warnings and Precautions Box.

Based on physiological pharmacokinetic model analyses, co-administration with inhibitors of UGT2B17 or CYP2C19 is expected to increase plasma exposure of belzutifan. Dose adjustment is not recommended on co-administration with inhibitors of UGT2B17 or CYP2C19. A high-fat, high-calorie meal did not have a meaningful effect on steady state exposure. Therefore, Welireg can be taken without regard to food.

A Risk Management Plan (RMP) for Welireg (belzutifan) was submitted by Merck Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimise risks associated with the product.

The observed ORR and durable DOR (median not reached) are considered substantial evidence supporting clinical benefit in patients with VHL disease-associated non-metastatic RCC not requiring immediate surgery. On the basis of the information reviewed, Welireg presents an acceptable and manageable safety profile in consideration of the intended population. Based on the benefit-harm-uncertainty profile of the product, it is recommended that Welireg be granted authorization.