Regulatory Decision Summary for Alsitek

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Alsitek (masitinib mesylate), filed by AB Science SA. The sponsor was seeking the approval of their submission for Alsitek for the treatment of patients with amyotrophic lateral sclerosis (ALS) under the Advance Consideration-Notice of Compliance with conditions (NOC/c) policy. Major deficiencies were identified during review which precluded continuing the review and a Notice of Deficiency (NOD) was issued on December 9, 2022. While the sponsor provided a response to the NOD, the responses were inadequate for considering approval of Alsitek for the treatment of ALS in the proposed patient population. Overall, the sponsor’s responses were not sufficient to resolve major objections related to the submission and a NOD - Withdrawal was issued.

The single 48-week pivotal clinical trial, Study AB10015, that was conducted to evaluate the efficacy and safety of two doses of Alsitek (3 milligrams per kilogram per day [mg/kg/day] and 4.5 mg/kg/day) compared to placebo, as adjunct to riluzole for the treatment of patients with amyotrophic lateral sclerosis (ALS) raised several major concerns during the initial review of the New Drug Submission (NDS). Despite statistically significant outcomes for the pre-specified primary endpoint and some of the pre-specified secondary endpoints for Alsitek 4.5 mg/kg/day in the Normal Progressors subgroup (pre-specified primary analysis population), there were major objections/deficiencies leading to uncertainties about the conduct of Study AB10015, the quality and reliability of the data, and the reported treatment effect of Alsitek that precluded a conclusion about the overall benefit-harm-uncertainty for Alsitek. Consequently, the overarching position expressed in the Notice Of Deficiency (NOD) comments was that a well-conducted Phase 3 clinical trial, demonstrating statistically and clinically significant evidence of efficacy and an acceptable safety profile of Alsitek was required to establish the benefit-harm-uncertainty (BHU) of Alsitek to consider marketing authorization in Canada. Several major deficiencies in the clinical pharmacology data , cardiovascular safety studies, and the non-clinical data were also identified in the NOD. Furthermore, the Risk Management Plan (RMP) was also deemed unacceptable.

In the Response to the NOD, the sponsor did not provide any new unreviewed clinical studies.

Information submitted to respond to the major objections and other concerns related to the assessment of efficacy and safety, consisted of publications to justify protocol amendments; expanded discussions of the extensive corrective actions in response to study audits (by external auditors and the European Medicines Agency [EMA], Health Canada and Infarmed [Portugal] Good Clinical Practice [GCP] inspection findings); an impact analysis of hundreds of eligibility criteria protocol deviations; re-analyses of the efficacy data in a post-hoc defined, “prior to any loss of function”, subgroup of patients; and, incomplete information/rationales to justify the higher cardiorespiratory arrest Adverse Events (AEs) and serious respiratory AEs in patients that received Alsitek. Most of the efficacy/safety issues identified in the NOD were not adequately addressed and were not resolved. In addition, the extensive corrective actions taken by the sponsor to respond to many issues identified by external auditors and GCP inspections did not compensate for the deficiencies in the conduct of the study that may have compromised the quality and reliability of the efficacy and safety data in the single pivotal trial.

To respond to the major objections related to deficiencies in the clinical pharmacology data, the sponsor submitted a new population pharmacokinetic (PK) report and a new report describing the analysis of PK parameters in patients with ALS in AB10015, new data (auxiliary reports related to the mass balance study AB17001), and provided rationales in their responses. The responses were inadequate to determine whether the proposed dosing regimen is appropriate for treatment of ALS in the proposed patient population. Overall, the sponsor’s responses were not sufficient to resolve the major objections related to clinical PK.

The majority of the non-clinical Response to NOD were not sufficient to resume the review of the submission. To address safety concerns that were raised from the initial non-clinical toxicology review, revisions to the Alsitek Product Monograph (PM) were recommended to capture the identified concerns.

In the Response to NOD, the sponsor generally addressed all NOD comments related to the proposed Canadian RMP, but revisions were recommended from the review of the proposed RMP.

A review of the safety data from Study AB10015 was conducted, with a focus on the safety concerns the sponsor proposed to highlight in Serious Warnings and Precautions of the proposed Alsitek PM. Masitinib is a tyrosine kinase inhibitor (TKI) and several of the AEs reported more frequently with Alsitek than placebo in Study AB10015 are known class effects of tyrosine kinase inhibitors (TKIs), such as: gastrointestinal AEs, rash/skin AEs, edema AEs, some cardiovascular AEs, elevations in transaminases, anemia, neutropenia, proteinuria, and hypophosphatemia. Several of these class effects would require close monitoring to mitigate serious harms. There are no data for use of Alsitek in pregnant or breast-feeding women with ALS and nonclinical toxicology studies showed fetal abnormalities. The characterization of the cardiovascular safety profile of Alsitek was inconclusive. Masitinib is intended to be used in combination with riluzole and there is some overlap in the harms reported with both drugs, for example, elevations in transaminases and bilirubin and hepatic AEs, decreases in white blood cells, red blood cells and hemoglobin (anemia), and interstitial lung disease (ILD).

Most of the TKI class-related adverse effects reported with Alsitek were dose-related and the majority were reported most frequently during the first 2 to 4 months of treatment. In Study AB10015 the time course of the effect of Alsitek on the change from baseline in mean ALSFRS-R total score (primary efficacy variable) showed that on average there was an approximately 9-month lag in therapeutic benefit, that is, a separation between Alsitek 4.5 mg/kg/day and placebo was only observed at Weeks 36 and 48. This suggests that for the first several months of treatment some patients may only experience AEs of Alsitek + riluzole without any meaningful slowing of the decline in function, compared to being on riluzole alone. Some of the AEs reported within the first 6 months of treatment with Alsitek in Study AB10015 were serious AEs (hepatitis of probable drug origin [Hy’s criteria met] and autoimmune-like hepatitis with mild jaundice, and two potential severe cutaneous adverse reactions [SCARs]) that are usually reported rarely after large cumulative exposure in the post-marketing setting, and are not generally expected to occur in a clinical trial setting with limited patient exposure. In the context of a progressive disease such as ALS, which can be terminal within 3 to 5 years of diagnosis, this does not suggest a favorable benefit-harm profile for Alsitek. The efficacy and some important aspects of the clinical safety profile of Alsitek for the treatment of ALS remain uncertain and require further characterization in additional studies. There are also several harms associated with Alsitek indicating that the safety profile is not acceptable in the context of the uncertain efficacy.

In conclusion, during review of the submission for Alsitek, deficiencies and/or significant omissions were identified pertaining to clinical and non-clinical information that preclude continuing the review. Therefore, a Notice of Deficiency-Withdrawal (NOD-W) was recommended. The clinical, non-clinical, quality and labelling reviews were not completed at the time of the NOD-W, and deficiency comments so far identified were included with the NOD-W.

AB Science S.A. submitted to Health Canada a request for reconsideration on May 9, 2024. While the reconsideration review was underway, the sponsor withdrew the reconsideration request on October 22, 2024.