Regulatory Decision Summary for Wyost

The purpose of the submission was to seek marketing authorization for Wyost (denosumab) as a biosimilar to Xgeva (denosumab)), the reference biologic drug in Canada, on the basis of comparative quality and clinical PK/PD studies. The following indications for Wyost are being sought:

• Reducing the risk of developing skeletal-related events in patients with multiple myeloma and in patients with bone metastases from breast cancer, prostate cancer, non-small cell lung cancer, and other solid tumours.

• Treatment of adults and skeletally mature adolescents with giant cell tumour of bone that is unresectable or where surgical resection is likely to result in severe morbidity. 

• Treatment of hypercalcemia of malignancy that is refractory to intravenous bisphosphonate. 

All the indications are currently authorized for the reference biologic drug in Canada.

Comparable clinical pharmacokinetics/pharmacodynamics (PK/PD) between Wyost and United States (US)-Xgeva (the suitable proxy for the Canadian reference product) was established in a single dose comparative PK/PD study conducted in healthy male subjects.

For evaluation of the PK/PD comparability, a three-way, single dose, parallel design study in healthy male subjects comparing the pharmacokinetics and pharmacodynamics profile of Wyost to US-Xgeva and European Union (EU)-Xgeva was conducted. Results from the comparison of Wyost to US-Xgeva showed that the point estimate for the Wyost and US-Xgeva geometric least square mean ratio for C_max was 100.0%, and the 90% confidence interval (CI) for geometric least square mean ratio for the AUC_last was 99.0 - 111.0%. PK comparability was demonstrated and was within the equivalence margins of 80.0% to 125.0%. PD comparability (C-terminal telopeptide of type-1 collagen (CTX) as the relevant PD marker) was also demonstrated as the 95% confidence interval for area under the effect curve (AUEC) of % change from baseline (%CfB) in serum CTX were within the equivalence margins of 80.0% to 125.0%_.

The immunogenicity incidence for Wyost was comparable to both US-Xgeva and EU-Xgeva but higher than the incidence labeled in the Canadian Product Monograph (PM) for Xgeva, however, this is attributed to the higher sensitivity of the immunogenicity test used.

The safety profile of Wyost is generally consistent with the known safety profile of Xgeva and no new safety signals were observed in healthy subjects from the submitted clinical study. The known risks of Xgeva have been included in the Product Monograph (PM) for Wyost.

A rationale was provided to support the extrapolation across indications held by the reference product, Xgeva. The rationale comprised of analytical and functional characterization, description of the mechanism of action, pathological similarity in disease progression, comparative PK/PD studies, and comparable safety and immunogenicity profile. The scientific rationale provided by the Sponsor to support the authorization of Wyost in other indications held by the reference biologic drug is considered adequate. The mechanism of action of Xgeva is similar across all indications and the pathophysiological progression of diseases treated by Xgeva is also similar. No clinically meaningful differences in PK/PD between Wyost and US-Xgeva in healthy male subjects.

Based on the totality of evidence derived from the comparative structural, functional, and clinical PK/PD data, similarity between Wyost and Xgeva has been demonstrated. Furthermore, in accordance with Health Canada’s biosimilar guidance document, a scientific rationale was provided to support the authorization of Wyost in the proposed indications held by the reference product Xgeva and the rationale is considered satisfactory.

An updated Risk Management Plan (RMP) Wyost was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the Risk Management Plan, with routine and non-routine pharmacovigilance activities.

The chemistry and manufacturing information submitted for Wyost has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Wyost for the approved indication when used under the conditions of use recommended in the approved Product Monograph. Therefore, a Notice of Compliance (NOC) was recommended.

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