Regulatory Decision Summary for Albrioza

Amyotrophic lateral sclerosis (ALS) is a serious, severe and life-threatening condition. An estimated 3,000 Canadians are currently living with ALS. Approximately 1,000 Canadians will die from ALS each year and a similar number of Canadians will be diagnosed with ALS.

The efficacy of Albrioza in the treatment of ALS is derived from a single phase 2, 24-week randomized, double-blind placebo-controlled Centaur trial designed to assess whether Albrioza plus standard of care could provide superior outcomes to standard of care alone. The study enrolled 137 patients, 89 randomized to Albrioza and 48 to placebo, with ALS symptom onset ≤18 months prior and slow vital capacity (SVC) ≥60% of predicted capacity.

The study primary efficacy outcome was met, with slowing of the rate of decline in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score comparing placebo and Albrioza-treatment arms. Although trending in favour of Albrioza, none of the secondary endpoints reached statistical significance against placebo, including the rate of decline of muscle strength (Accurate Test of Limb Isometric Strength [ATLIS]), biomarkers of neuronal death, measure of lung function, measured SVC, rates of survival (time to death, tracheostomy/permanent assisted ventilation [(PAV], tracheostomy) and hospitalization,

Although data from the single phase 2 trial were promising, as the primary efficacy endpoint was met, data were not assessed as substantial or persuasive. Some issues with the study conduct and analyses from the Centaur trial limited interpretability and robustness of results, including its small sample size, short study duration, baseline imbalances in disease characteristics and use of riluzole and edaravone, higher rate of post-baseline initiation of edaravone or riluzone in the Albrioza-treatment arm, assumption of linearity of functional decline over time in the primary efficacy slope analysis, which was not established, potential unblinding due to gastro-intestinal (GI) events and bitter taste, missing data at week 24, and significant patient dropouts. Of note, more Albrioza-treated patients than placebo-treated patients discontinued due to adverse events (AE) and disease progression and more placebo-treated patients completed the trial. In addition, results of the primary endpoint were modest, the secondary endpoints did not reach statistical significance, there was no account for loss of data due to death rate in the primary analysis, tracheostomy and hospitalizations were included in the definition of survival without assessing deaths alone, and no survival benefit was found at 24 weeks. Furthermore, as evidence was based on a population with a recent diagnosis and good respiratory function, efficacy in patients with more advanced disease could not be determined.

The ongoing open-label extension (OLE) phase’s primary objective was to assess long-term safety of Albrioza in patients who had completed the 24-week placebo-controlled phase, all of which were treated with Albrioza. Secondary efficacy analyses compared the 56 patients randomized to Albrioza in the main study to 34 patients who were randomized to placebo in the main study even if not enrolled in the OLE. Endpoints included, in hierarchical order, the rate of decline in ALSFRS-R score, rate of key study events including death, tracheostomy, hospitalization and PAV, rate of progression in upper and lower ATLIS scores, rate of progression of SVC, rate of progression on ALSFRS-R domains, and rate of progression of total ATLIS score.

Treatment with Albrioza in the main study resulted in a statistically significant slowing in loss of function measured by the ALSFRS-R total score compared to the placebo group. However, patients initially randomized to Albrioza had more disease progression and AEs leading to discontinuations than patients initially randomized to placebo.

Issues with the study conduct and analyses from the OLE phase limited interpretability and robustness of results, including its open-label nature, low patient participation from the controlled phase, number of patient dropout, missing data from discontinuations (only 40% with week 48 ALSFRS-R measurements) and deaths during study which were not included in the functional analyses. Moreover, linearity assumption for efficacy endpoints over a longer period was uncertain, death alone was not pre-specified, inclusion of tracheostomy and hospitalizations in the survival analysis had limitations, and these events were not collected in survival follow-up.

In addition, review concluded that better evaluation of the multiple-dose pharmacokinetic (PK), pharmacodynamic (PD) profile of phenylbutyrate and ursodoxicoltaurine in Albrioza and dosing recommendations when Albrioza is used in patients with renal or hepatic impairment or in combination with other commonly used medication in people with ALS was required.

From a safety perspective, there was an imbalance in treatment-emergent cardiac events and electrocardiogram (EKG) abnormalities between groups, with all cardiac events occurring in Albrioza-treated patients, for a total of 17 events (8 cardiac events, 9 EKG abnormalities, of which 3 patients had both). Of those, 8 patients had 11 events in the main phase (6 cardiac events, 5 EKG abnormalities and of which 3 patients had both), and 6 patients in the OLE (2 cardiac events and 4 EKG abnormalities). Cardiac events assessed as possibly related to Albrioza included first degree atrioventricular block, atrial fibrillation (2), left bundle branch block, left anterior hemi block, tachycardia, palpitations (2), inverted T waves, flat T waves, and intraventricular conduction delay.

A Risk Management Plan (RMP) was considered acceptable by the Marketed Pharmaceuticals Bureau with additional pharmacovigilance activities for cardiac arrhythmias and atrial fibrillation, identified as an important potential risk. 

Although the data from the single phase 2 trial were promising, data were not substantial or persuasive. Further evidence from a placebo controlled trial in a larger population is needed to confirm benefits and further assessment of cardiovascular safety in this population is also requested. In addition, further evaluation of multiple dose PK, PD activity, renal impairment and hepatic impairment PK and drug-drug interaction studies are required. On the basis of the information reviewed, Albrioza presents an acceptable safety profile in consideration of the intended population.

A decision to issue a Notice of Compliance with conditions (NOC/c) was made following the review as Albrioza is intended for treatment of a serious, life-threatening and severely debilitating disease, and has shown promising evidence of clinical effectiveness for a disease that is not adequately managed by a drug currently marketed in Canada.

The response to the Qualifying Notice was acceptable by the Central Nervous System Division, the Bureau of Medical Sciences, the Labelling Division and the Marketed Health Products Directorate.

Based on the benefit-harm-uncertainty profile of the product, Health Canada granted the issuance of a NOC/c for Albrioza under the NOC/c guidance, requiring the results of a confirmatory trial to verify its clinical benefit. Amylyx Pharmaceuticals has committed to provide the final report for the confirmatory phase 3 placebo-controlled study to verify clinical benefit, to conduct and submit multiple dose PK and PD studies, renal and hepatic impairment PK studies and drug-drug interaction analyses. A status report on the progress of the ongoing confirmatory trials has been requested to be submitted by the sponsor on an annual basis. Post-market safety monitoring commitments were also agreed upon by the sponsor.

For more information on Health Canada's decision, please view the Summary Basis of Decision.