Regulatory Decision Summary for Scemblix

The Sponsor conducted a global, phase III, multi-center, active-controlled, open-label randomized (2:1) pivotal study (ASCEMBL CABL001A2301) to compare the efficacy and safety of Scemblix with bosutinib in the treatment of 233 patients with chronic myeloid leukemia chronic phase (CML-CP), who received at least two prior tyrosine kinase inhibitors (TKIs). In addition, CML-CP patients were evaluated in a supportive single arm phase I study (X2101). The pivotal study was well balanced with respect to patient demographics and disease characteristics. The primary endpoint was the major molecular response (MMR) at 24 weeks while on study treatment without meeting any treatment failure prior to 24 weeks. A key secondary endpoint was MMR at 96 weeks. MMR is a validated endpoint that is associated with and predictive of long-term survival.

In the primary efficacy analysis of patients with CML-CP, Scemblix, administered at a dose of 40 mg twice daily, demonstrated a durable, consistent, clinically meaningful and statistically significant superior MMR rate compared to bosutinib at 24 weeks (26% compared to 13%, respectively). Subgroup analyses also favoured Scemblix across all categories. Results for the key secondary endpoint of MMR were immature. In a supportive non-randomized single arm phase I study (X2101), Scemblix-treated CML-CP patients achieved a MMR of 23% and 39% at 24 weeks and 96 weeks, respectively. These results were similar and consistent with the MMR observed in the primary analysis. The treatment effect in CML-CP patients from the phase I study was observed irrespective of the line of therapy (third, fourth, fifth, or higher line).

The overall safety profile of Scemblix has been evaluated in 356 patients from pivotal study A2301 and supportive study X2101 with Ph+ CML in chronic (CP; N = 341) and accelerated (AP; N = 15) phases receiving Scemblix as monotherapy. The clinically significant safety risks identified from the All Patient safety pool were cardiovascular toxicity, arrhythmias (including QTc prolongation), hypertension, myelosuppression, pancreatic toxicity (including asymptomatic elevation of serum lipase and amylase), hepatitis B reactivation, hypersensitivity, and embryo-fetal toxicity. While there was an increased incidence of thrombocytopenia in the Scemblix arm, GI toxicity, rash, and transaminase increase were notably less frequent compared to the bosutinib arm. Importantly, the increased frequency of thrombocytopenia did not lead to an increased risk of hemorrhage. Notably, there were fewer dose reductions, dose interruptions and permanent discontinuations in the Scemblix arm compared to the bosutinib arm. All significant safety risks are clearly highlighted in the Adverse Reactions table, and Warnings and Precautions section of the product monograph (PM). Moreover, as demonstrated in the pivotal trial, the significant risks are manageable by dose modification, dose discontinuation and/or standard medical practice. These mitigation strategies were clearly outlined in the PM.

The clinical pharmacological and non-clinical data support the intended use of Scemblix in the target population. Key clinical pharmacology and non-clinical findings, relevant risks, and uncertainties were properly addressed in the final PM.

This submission was considered to comply with the Quality data requirements of Section C.08.002 of the Food and Drug Regulations.

The labelling documents conform to the necessary regulatory requirements and are consistent with the labelling guidance documents.

The Risk Management Plan was considered acceptable provided that the Sponsor addresses the concerns raised by the Marketed Health Products directorate (MHPD) as a result of this review.

In conclusion, the pivotal study met its primary endpoint, which was supported by a consistent effect identified in the subgroup analyses, sensitivity analyses, and by other secondary endpoints. Moreover, the primary analysis was also supported by results from a phase I study. The safety-assessment-identified toxicities were generally consistent with the safety profile of BCR-ABL inhibitors, and demonstrated that clinically meaningful safety differences favored Scemblix treatment compared to bosutinib. The key safety concerns are sufficiently labeled in the PM and are considered manageable and tolerable. As such, Scemblix is considered to have a benefit-risk profile that is considered positive and clinically meaningful under the proposed conditions of use.