Regulatory Decision Summary for Welireg

This Priority Review Supplement to a New Drug Submission (SNDS) was filed to obtain market authorization for the expanded indication for Welireg for the treatment for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated central nervous system (CNS) hemangioblastomas, or non-metastatic pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery.

In addition, the Welireg Product Monograph (PM) was updated with longer follow up efficacy and safety data with a median duration of 37.7 months, from the pivotal Study 004 for the current approved target population of adult patients with VHL disease who require therapy for associated non-metastatic renal cell carcinoma (RCC), not requiring immediate surgery.

Welireg was evaluated in an ongoing single-arm phase 2 pivotal Study 004 in 61 adult patients with VHL disease and at least 1 measurable solid tumor localized to the kidney, and who did not require immediate surgery. Enrolled patients included those with VHL disease-associated tumors such as pancreatic lesions, pancreatic neuroendocrine tumors (pNETs), central nervous system hemangioblastomas (CNS HB) and retinal hemangioblastomas, based on central independent review committee (IRC). Welireg was administered orally 120 mg (3 x 40 mg tablets) once daily until unacceptable treatment-related toxicity or disease progression. The data cutoff (DCO) was April 1, 2022 with a median duration of follow up of 37.7 months, representing approximately 16 months additional follow up versus the original new drug submission (NDS) dataset.

The primary efficacy endpoint for VHL disease-associated renal cell carcinoma (RCC) was objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) based on Independent Review Committee (IRC) evaluation using Integrated Radiology and Oncology Assessment (IRO) procedures. Secondary efficacy outcomes were duration of response (DoR), time to response (TTR), progression free survival (PFS), time to surgery (TTS) for VHL-RCC, and efficacy in VHL disease-associated non-RCC tumors (retinal and CNS hemangioblastomas, pancreatic, adrenal, endolymphatic sac tumor and epididymal cystadenomas). Additional secondary endpoints included safety, tolerability and pharmacokinetics (PK) of belzutifan. Exploratory efficacy analyses included evaluation of the number of patients who undergo surgical intervention and/or procedures for their RCC and/or non-RCC tumors, evaluation of the number of patients who develop metastatic RCC and linear growth rate (LGR).

Belzutifan showed a clinically meaningful ORR of 44% in participants with CNS HB, with 8% achieving complete response (CR) and 36% achieving partial response (PR). The median DoR was not reached. Based on Kaplan-Meier estimates, the majority of responders (90%) remained in response ≥12 months. The median TTR was 5.4 months. Assessment of VHL-CNS HB’s was done according to two methodologies which were based on measurement of the solid tumor and cystic component, or the solid tumor only. Data which is based on a greater significance on the tumor and cystic component was considered appropriate to include in the labelling.

Belzutifan showed a clinically meaningful ORR of 90.9% in patients with VHL-pNET; 31.8% had CR’s and 59.1% had PR’s. The median DoR was not reached. Based on Kaplan-Meier estimates, 100% of responders remained in response ≥12 months. The relatively long median TTR of 8.2 months suggests slow kinetics of response, which may underestimate the benefit of Welireg. The absence of meaningful tumor growth, a median PFS not reached and negative post-treatment LGR suggests that patients may have achieved a clinical benefit despite not having reached PR or CR; however conclusions based on these endpoints should be interpreted cautiously given that this is a single arm study. The need for surgery is potentially prevented or delayed in participants who have reductions or no increases in tumor size. The median time to surgery for VHL-associated pancreatic lesions was not reached.

A retrospective review (of radiographic images obtained for assessment of VHL-RCC) was done to assess pancreatic lesions. Some discordance occurred among IRC readers and between the investigators and IRC. This was likely attributed to differences in identification of pNETs by the different readers rather than measurement of these tumors.

This SNDS also included updated efficacy in the VHL disease-associated RCC population based on a DCO of April 1, 2022, with a median follow up of 37.7 months, representing approximately 16 months of additional follow up versus the original NDS. With longer follow up, there was an increase in ORR of 63.9% (with 6.6% CR’s and 57.4% PR’s) supported by a consistent positive trend in secondary endpoints, median DoR (not reached), and 100% of patients with a response ≥12 months, in addition to a median TTR of 11.1 months. These data support the continued long-term benefit of Welireg in this target patient population.

As of the Apr 01, 2022 DCO, the median duration of exposure was 37.3 months with 90% exposed for 18 months or longer. The most frequently reported adverse events were anemia, fatigue, headache, dizziness, nausea, dyspnea, myalgia, constipation, arthralgia, and vision blurred. Overall, the updated safety profile of Welireg remains acceptable for the treatment of adult patients with VHL disease-associated CNS HB or non-metastatic pNET, not requiring immediate surgery. The identified safety issues can be managed through labelling, including adequate monitoring and dose modifications. A Serious Warnings and Precautions box conveys the risk of embryofetal toxicity.

A Canadian-specific risk management plan (RMP) Annex Version 3.0 dated 01 December 2022 was reviewed by Marketed Health Products Directorate (MHPD) which recommended to continue to monitor events of visual impairment in PSURs/PBRERs. Overall, the RMP is acceptable.

The goal of current management for VHL-associated disease utilizing surgery or local procedures is to prevent metastases with RCC and/or pNET, or ameliorate the development of symptoms associated with CNS HB while preserving normal organ function. VHL patients are typically managed via lifelong surveillance and multiple surgeries/procedures on the various organs, which contributes to substantial morbidity and mortality. Surgery/local procedures are not curative, are limited, and recurrence is common. There are no approved pharmaceutical treatments in Canada for patients with VHL disease-associated CNS-HB or pNET in a localized setting. An unmet need exists for a systemic therapy that offers a clinically meaningful benefit for VHL-CNS HB and VHL-pNET and can delay or obviate the need for surgery.

Welireg is currently approved to treat patients with VHL-RCC, and many of these patients have multiple tumors and cysts in other organs, including the CNS and pancreas. All patients enrolled in pivotal Study 004 had other VHL-associated non-RCC tumors. While the study was not primarily designed to evaluate efficacy in these non-RCC tumors (given the retrospective assessment for these tumors), the secondary efficacy endpoints for VHL-CNS HB and VHL-pNET were, in the context of a single arm study, evaluated with the same statistical approach as for the primary endpoint. As such, the substantial evidence of tumor responses observed in VHL-CNS HB and VHL-pNET in this SNDS is clinically meaningful across tumor types over a period of more than 3 years of follow up. This benefit is demonstrated by reduced tumor size (as evidenced by objective response). Toxicities associated with Welireg are well managed via revised labelling. Based on a favourable benefit:harm:uncertainty profile, a NOC is recommended for Welireg for the proposed expanded indication.

For further details about Welireg, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.