Summary Basis of Decision for Welireg

 

As described above, the review of the clinical component of the New Drug Submission for Welireg was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration, the Australian Therapeutic Goods Administration, and the United Kingdom’s Medicines and Healthcare production Regulatory Agency as a Project Orbis Type B submission. The clinical review of the New Drug Submission for Welireg was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada .

Clinical Pharmacology

Findings from Study 001, a Phase I dose-escalation and dose-expansion study in patients with advanced solid tumours and advanced clear cell renal cell carcinoma (RCC), were used to determine the recommended dose of belzutifan (120 mg once daily [three 40 mg tablets]) that was used in the pivotal Phase II study (Study-004; see Clinical Efficacy section). The pharmacokinetics, pharmacodynamic response of reduction in the biomarker erythropoietin (EPO), and safety of belzutifan were investigated at doses ranging from 20 mg once daily up to 240 mg once daily (as well as 120 mg twice daily). A maximum tolerated dose was not reached. The maximum plasma concentration (C_max) and area under the curve (AUC) to the end of the dosing period (AUC_0-tau) for belzutifan generally increased with doses ranging from 20 mg to 120 mg once daily, with similar exposures observed at higher once daily doses within the dosing range. Reduction in EPO was observed at all dose levels thereby supporting the mechanism of hypoxia-inducible factor 2 alpha (HIF‑2α) inhibition. This effect appeared to be dose and concentration dependent, with a plateau of EPO reduction at doses beyond 80 mg to120 mg once daily.

This submission also included model-based estimates of population pharmacokinetic parameters representing exposure of oral belzutifan in healthy participants and patients with RCC, von Hippel-Lindau disease associated RCC (VHL-RCC), or solid tumours. The impact of intrinsic and extrinsic factors on the pharmacokinetics of belzutifan was determined based on pooled data from five Phase I and Phase II studies. The exposure-response for safety and efficacy was explored based on data from Study-004 and Study 001.

The model-predicted steady-state geometric means for 120 mg once daily belzutifan in patients with VHL-RCC were 1.3 mcg/mL for C_max and 16.7 mcg•hr/mL for AUC from 0 to 24 hours (AUC_0-24hr). Steady state was reached after approximately 3 days of once daily dosing. Both C_max and AUC increased proportionally to dose, from 20 mg up to the recommended dose of 120 mg daily. The covariates of age, sex, ethnicity, race, body weight, food, mild to moderate renal insufficiency, and mild hepatic insufficiency did not have a clinically meaningful impact on the pharmacokinetics of belzutifan.

A high-fat, high-calorie meal did not have a meaningful effect on steady state exposure. The Welireg Product Monograph recommends that dosing take place without regard to food.

Welireg is primarily metabolized by uridine 5'‑diphospho-glucuronosyltransferase (UGT) 2B17 (UGT2B17) and cytochrome P450 (CYP) 2C19 (CYP2C19). Based on population pharmacokinetic modeling, patients who are dual UGT2B17/CYP2C19 poor metabolizers (without enzyme activity) were projected to have up to 2.3‑fold higher Welireg exposures than UGT2B17 intermediate metabolizers or CYP2C19 non-poor metabolizers. Although the predicted Welireg exposure in dual poor metabolizers may be expected to be above the observed clinical exposure range, no dose adjustment is recommended since testing for UGT2B17 and CYP2C19 enzyme status is not typically done in clinical practice. Data from patients who are dual UGT2B17/CYP2C19 poor metabolizers were extrapolated to predict that coadministration of UGT2B17 and CYP2C19 inhibitors may be expected to increase belzutifan exposure. These issues have been addressed through appropriate labelling in the Product Monograph.

Based on model simulations, coadministration of belzutifan with midazolam (a CYP3A4 substrate) was predicted to decrease midazolam AUC from time zero extrapolated to infinity (AUC_inf) by approximately 50% to 70%. This drug interaction can substantially reduce exposure and efficacy of drugs that are CYP3A4 substrates, including hormonal contraceptives. These recommendations are supported by the animal findings of embryo-fetal toxicity of belzutifan (see Non-Clinical Basis for Decision section). The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Welireg:

Embryo-fetal toxicity:

• 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 hormonal contraceptives ineffective.

An exposure-response relationship was observed between belzutifan exposure and the probability of Grade 3 or higher anemia, and was dependent on baseline hemoglobin levels. In the VHL population with a mean baseline hemoglobin level of 138 g/L, this relationship was less substantial than that in patients with advanced solid tumors and who had a lower mean baseline hemoglobin level of 120 g/L. This issue has been addressed through appropriate labelling in the Welireg Product Monograph. While the exposure-response relationship between belzutifan exposure and Grade 3 or higher hypoxia was inconclusive due to limited data, the risk of hypoxia has been included in the Welireg Product Monograph to address the identified safety concern.

At the recommended dose of Welireg (120 mg once daily), there were no clinically relevant effects on cardiac electrophysiology. Based on concentration-QTc modeling in Study-004, the predicted mean change from baseline in QTcF (ΔQTcF) was 2.6 msec (90% confidence interval [CI]: 0.67 to 4.43 msec) for the dose of 120 mg daily (geometric mean C_max of 1.39 mcg/mL). The 90% two-sided upper confidence bound for ΔQTcF was below 10 msec at all time points, suggesting that belzutifan does not cause large mean increases in the QT interval. Since this analysis was not based on a thorough QT study, the conclusions should be interpreted with caution due to limitations, including exposure assessment restricted to the therapeutic dose level, lack of a positive control, and a large exposure margin. In addition, the cardiac parameters were assessed up to Week 13 of treatment with belzutifan, and the target population would be expected to receive belzutifan for a more prolonged period. Therefore, there are uncertainties regarding the long-term cardiac effects of treatment with belzutifan. Based on current data, this risk is manageable through clear and detailed labelling regarding cardiac electrophysiology. In addition, the potential impact of belzutifan on reducing the exposure of CYP3A4 substrates, such as proarrhythmic macrolide antibiotics, for instance, suggests a minimal risk due to this interaction. Nevertheless, it is recommended to include cardiovascular monitoring in the Welireg Periodic Safety Update Reports and the Canadian Risk Management Plan in order to allow Health Canada to evaluate latent or exposure-related effects of the long-term use of belzutifan.

Exposure-response analysis suggested no statistically significant exposure effect of belzutifan across the observed exposure range, thereby supporting the recommended dose of belzutifan 120 mg and the dose modification recommendations available in the Welireg Product Monograph.

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

Clinical Efficacy

The efficacy and safety of Welireg for the treatment of adult patients (18 years of age and older) with VHL disease-associated non-metastatic RCC tumours was evaluated in the ongoing pivotal Phase II Study-004. This open-label, multicentre, single-arm, interventional study enrolled 61 patients with VHL disease and at least 1 measurable RCC tumour, as defined by the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1). Welireg was administered orally at a dosage of 120 mg once daily. Participants were evaluated radiologically approximately 12 weeks after initiation of study intervention and every 12 weeks thereafter while continuing in the study to assess response to treatment for VHL disease-associated RCC. Participants continued to receive treatment until unacceptable treatment-related toxicity or disease progression.

Key inclusion criteria included a diagnosis of VHL disease based on a germline VHL alteration and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Participants could have VHL disease-associated tumours in other organ systems. Key exclusion criteria included any previous systemic anticancer therapy (including anti- vascular endothelial growth factor [VEGF] therapy or another HIF‑2α inhibitor), recent radiotherapy, or surgical procedure for VHL disease or any major surgical procedure completed within 4 weeks prior to study enrollment. Patients were excluded if they had an immediate need for surgical intervention for tumour treatment or had evidence of metastatic disease on screening imaging.

The baseline demographic and disease characteristics of enrolled patients were the following: most participants were white (90.2%) and had an ECOG performance status of 0 (82%) or 1 (16.4%), the median age was 41 years (range: 19 to 66 years), and 47.5% were female. All participants had at least 1 additional VHL disease-associated non-RCC tumour.

As of the data cut-off (DCO) on December 1, 2020, 54 (88.5%) patients were still receiving study treatment and 58 (95.1%) patients remained on study. The median drug exposure was 94.1 weeks (range: 8.4 to 130.9 weeks), with 90% exposed for 18 months or longer. The median duration of follow-up was 94.8 weeks (21.8 months; range of 4.2 to 30.1 months).

Efficacy analyses were conducted using data from the efficacy analysis set, which included all 61 participants in Study-004 who received at least one dose of study intervention. No participants initially enrolled in the study were excluded from the analysis.

The primary objective of Study-004 was the efficacy of Welireg for the treatment of VHL disease-associated RCC as measured by objective response rate (ORR; complete response or partial response) per RECIST 1.1. The confirmed ORR was 49.2% (95% CI: 36.1, 62.3), 30 out of 61 patients. All responders achieved a partial response.

The key secondary objectives were duration of response (DOR) and time to response (TTR). The median DOR was not reached (range: 12.1+ to 96.9+ weeks) and TTR was 35.8 weeks (range: 11.6 to 82.9 weeks).

One key limitation of Study-004 is that it was a single-arm Phase II trial and there is no plan to conduct a Phase III study in patients with VHL disease. The sponsor identified several barriers and challenges which significantly impact the feasibility of a Phase III randomized control trial, including the rarity of VHL disease, the high unmet need of this population, and the strong biological rationale of HIF‑2α inhibition with Welireg in this disease.

Other key limitations of Study-004 include the fact that ORR is a surrogate endpoint and there were no complete responses. The impact of RCCs on mortality is driven by the development of metastatic RCC or end-stage renal failure secondary to (multiple) surgical resections. A clinically meaningful ORR with a durable DOR may reduce these undesirable outcomes. It has been shown that for tumours smaller than 3 cm in size, the risk of metastasis is exceedingly low. This means that if patients respond even partially, they may avoid or delay the need of surgery and minimize the risk of metastatic RCC if tumours shrink and/or stay under the 3 cm threshold.

Overall, the efficacy results from pivotal Study-004 support the proposed indication for the targeted population. The efficacy data submitted adequately demonstrated the ability of Welireg to provide benefit for adult patients with VHL disease-associated RCC tumours. This was shown in the primary endpoint with a clinically meaningful ORR for RCC tumours, and was further supported by the durability of the response with a secondary endpoint of median DOR not reached.

Indication

The New Drug Submission for Welireg was filed by the sponsor with the following indication:

• Welireg (belzutifan) is indicated for the treatment of patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC), not requiring immediate surgery.

To support safe and effective use of the product, Health Canada approved the following indication:

• Welireg (belzutifan) is indicated for the treatment of adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated non-metastatic renal cell carcinoma (RCC), not requiring immediate surgery.

• Efficacy in patients with VHL disease-associated RCC was based on objective response rate and duration of response in a single-arm study.

For more information, refer to the Welireg Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

Clinical Safety

The primary safety analyses were conducted using data from the Study-004 safety analysis set, which included all participants in Study-004 (see Clinical Efficacy section) who received at least one dose of study intervention (number of patients = 61). No participants initially enrolled in the study were excluded from the analysis.

In the pivotal Study-004, a treatment emergent adverse event (TEAE) was reported by all 61 (100%) patients. The most common TEAEs (≥20%) reported with Welireg treatment were anemia (90.2%), fatigue (65.5%), headache (41%), dizziness (39.3%), nausea (34.4%), and dyspnea (23.0%).

A total of 11 (18.0%) participants in Study-004 experienced 15 serious adverse events (SAEs); each individual SAE was experienced by 1 participant only. There was 1 Grade 4 SAE of retinal detachment and 1 Grade 5 SAE of toxicity to various agents (acute fentanyl overdose). The other SAEs experienced were intracranial hemorrhage, skin laceration, urinary tract infection dyspnea, hypotension, seizure, abdominal pain, anaphylactic reaction, cholecystectomy, coronary artery dissection, cystitis, hypoxia, and anemia. Only hypoxia, anemia, and urinary tract infection were considered drug-related per investigator assessment.

Grade 3, Grade 4, and Grade 5 TEAEs were observed in 29.5%, 1.6%, and 1.6% of patients, respectively. The most common Grade 3 or higher TEAEs were anemia (8.2%), hypertension (8.2%), and fatigue (4.9%). One patient (1.6%) experienced Grade 4 retinal detachment, and there was one fatal case of toxicity to various agents (1.6%); the latter two were included in the SAE above and were not considered drug-related per investigator and sponsor assessment.

A total of 26 (42.6%) participants in Study-004 experienced adverse events (AEs) resulting in study treatment interruption. The most frequently (≥3%) reported AEs leading to treatment interruption were fatigue (13.1%), anemia (4.9%), nausea (6.6%), influenza-like illness (3.3%), abdominal pain (3.3%), and headache (3.3%). The occurrence of a TEAE resulted in the permanent discontinuation of Welireg for 2 (3.3%) patients; 1 due to Grade 1 dizziness and the other due to Grade 5 toxicity to various agents.

Nine (14.8%) participants reported AEs leading to dose reduction in Study-004. Fatigue (8.2%) was the most frequently reported AE that led to dose reduction, while the other individual AEs (anemia, coronary artery dissection, arthralgia, headache, seizure, hypoxia, and hypotension) occurred in one participant each.

Anemia occurred in 55 (90.2%) participants in Study-004, including 5 (8.2%) participants with Grade 3 anemia and 1 (1.6%) participant with an SAE of anemia. There were no study treatment discontinuations due to anemia in Study-004. Although the rates of anemia were high, anemia was an on-target effect due to the induction of EPO synthesis being HIF‑2 dependent in the kidney and liver. Appropriate warnings, precautions, and dosing adjustment parameters are in place in the Welireg Product Monograph to address the identified safety concerns of anemia.

Hypoxia occurred in one (1.6%) patient in Study-004. This single event was Grade 3 and an SAE. A total of 18 (31.0%) participants experienced hypoxia in a Phase I supportive study (Study 001). Hypoxia was more prevalent in Study 001 and had most often been observed with concomitant, chronic-morbid conditions, or acute events such as pleural effusion, pneumonia, pulmonary hemorrhage, pneumonitis, and coronary artery disease. Appropriate warnings, precautions, and dosing adjustment parameters are in place in the Welireg Product Monograph to address the identified safety concerns of hypoxia.

Clinically relevant laboratory abnormalities that changed from baseline in 10% or more of the population in Study-004 include increased creatinine (64%), increased glucose (39%), increased potassium (10%), increased alanine transaminase (20%), increase aspartate aminotransferase (16%), decreased corrected calcium (10%), decreased phosphate (11%), decreased hemoglobin (93%), decreased leukocytes (11%), and decreased platelets (11%). The vast majority of laboratory abnormalities were Grade 1 with some Grade 2 abnormalities. The exceptions, which had Grade 3 changes, were increased glucose (5%), decreased phosphate (2%), and decreased hemoglobin (7%). There were no Grade 4 laboratory abnormalities.

There are no human data available regarding the potential effect of Welireg on pregnancy or development of the embryo or fetus. However, based on findings in animal studies (see Non-Clinical Basis for Decision section), Welireg may cause fetal harm, including fetal loss, in humans. Also, based on findings in animal studies, Welireg may impair fertility in males and females of reproductive potential. The reversibility of the effect on fertility is unknown. Given the relatively young patient population and potential for long-term use of Welireg, the risk of embryo-fetal toxicity has been included in a Serious Warnings and Precautions box in the Welireg Product Monograph.

One limitation in Study-004 was that there were only 2 patients over the age of 65 years. Based on the limited numbers of patients over the age of 65 years, the safety profile in these patients did not appear to differ from that of patients under the age of 65 years. Based on population pharmacokinetic modeling, age (range: 19 to 84 years) does not have a clinically meaningful effect on the pharmacokinetics of Welireg.

Another limitation in Study-004 was that there was a lack of data for long-term safety. The safety of Welireg will continue to be monitored through routine proactive pharmacovigilance activities in the post-market context.

Finally, the majority of patients were white (90.2%) and therefore limited information regarding efficacy across different racial groups, particularly the East Asian population which is known to have some of the highest proportions of UGT2B17 poor metabolizers (70%), CYP2C19 poor metabolizers (13%), and dual UGT2B17 and CYP2C19 poor metabolizers (9%). This risk of increase in exposure is reflected in the Welireg Product Monograph.

Overall, the safety profile of Welireg therapy is considered acceptable for the treatment of adult patients with VHL disease-associated non-metastatic RCC not requiring immediate surgery. The identified safety issues can be managed through labelling, adequate monitoring, and dose modifications.

For more information, refer to the Welireg Product Monograph, approved by Health Canada and available through the Drug Product Database.