Qualifying notice for Albrioza

Pharmaceutical Drugs Directorate
Holland Cross, Tower "B"
6th Floor, 1600 Scott Street
Address Locator #3106B
Ottawa ON  K1A 0K9

Dossier ID: e239160
Control #: 253502

[employee name removed]
[employee title removed]
Amylyx Pharmaceuticals Inc.
43 Thorndike Street
Cambridge, Massachusetts
United States, 02141

[employee name removed]:

This Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN), issued in accordance with the Health Canada Guidance Document: Notice of Compliance with Conditions (NOC/c), is to advise you that information submitted in support of the New Drug Submission for Albrioza, Control Number 253502, for the indication of Treatment of patients with amyotrophic lateral sclerosis, qualifies to be considered for authorization in accordance with the NOC/c Guidance. In keeping with the provisions outlined in the NOC/c Guidance, the following additional information is requested to complete the assessment:

1. A letter, signed by the Chief Executive Officer or designated signing authority of Amylyx Pharmaceuticals Inc., indicating that you agree to have this submission considered under the NOC/c Guidance. Please be reminded that in agreeing to accept a Notice of Compliance (NOC) under the NOC/c Guidance, Amylyx Pharmaceuticals Inc. consents to the posting of this NOC/c-QN on Health Canada's website once market authorization has been received.
2. A Letter of Undertaking signed by the Chief Executive Officer or designated signing authority of Amylyx Pharmaceuticals Inc., having a form and content satisfactory to Health Canada, as indicated in NOC/c Guidance, including commitments to provide the following:

Confirmatory studies

1. A Phase 3 placebo-controlled efficacy and safety trial of AMX0035 of at least 48-week duration in the randomised double-blind period in a sufficient number of patients preferably with varying severity of disease to provide statistically significant results on functional (ALSFRS-R) and survival endpoints and to further characterise the benefit-harm-uncertainty profile of Albrioza. Also, the completion and submission of the planned sub-study of QTc interval prolongation and AMX0035 exposure in a total of at least 50 participants. Expected completion date of study is March 1, 2024. Analysis report of study expected to Health Canada within 3 months after completion date

Additional studies

2. An evaluation of multiple dose pharmacokinetics of phenylbutyrate (PB) and taurursodiol (TURSO) (in proprietary combination of Albrioza), as well as surrogate Pharmacodynamic (PD) activity via measurement of Histone 3 and Histone 4 acetylation levels. An analysis report is expected to be submitted to Health Canada within 3 months after the study completion date. This study is currently ongoing, with an estimated study completion date of August 2022:
   [n = 14 ALS patients; In Period 1, subjects receive AMX0035 daily for approximately 14 days; In Period 2, subjects receive AMX0035 twice a day, morning and evening, for up to 25 days.]
3. A dedicated renal impairment PK study, and a dedicated hepatic impairment PK study (standard design that may include the use of otherwise healthy participants), given the significant hepatic and kidney clearance/metabolism/elimination with Albrioza. The reports are expected to be submitted along with the results of the Phase 3 analysis within 3 months of completion (Expected completion: March 1, 2024).
4. Analyses of potential drug-drug interaction effects, which would also include a safety assessment, from concurrent use of Albrioza with the most commonly co-administered medications in the ALS population. In the absence of dedicated human drug interaction studies, this could be based on the most comprehensive Phase 2/3 pooled patient data set available. Reports expected to be submitted along with the results of the Phase 3 analysis (Expected completion: March 1, 2024).

Progress reports of confirmatory trials

5. On an annual basis, within 60 calendar days of the market authorization anniversary or a date agreed upon at the time of the issuance of the market authorization, status reports on the progress of ongoing confirmatory trials, as per section 3.2 and Appendix 4 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). The details of the requirements for filing and termination of the annual status report as agreed upon by the Amylyx Pharmaceuticals Inc. and Health Canada should be outlined in the Letter of Undertaking.

Post market safety monitoring

6. Provision of Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Reports-C for NOC/c Products (PSUR-Cs or PBRER-Cs) on an annual basis until such time as conditions associated with the market authorisation are removed or as deemed necessary following PBRER-C/PSUR-C reviews. PSUR-Cs/PBRER-Cs should be prepared in accordance with the E2C(R1) and E3C(R2) ICH Guidelines, including format and content, as per section 3.4.2 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that once all the commitments are fulfilled, annual summary reports (e.g. Periodic Benefit-Risk Evaluation Reports-Pharmacovigilance (PBRER-PV) or Periodic Safety Update Reports-Pharmacovigilance (PSUR-PV)) should be submitted as stipulated in the regulations (subsection C.01.018(4)), upon request or in situations where the Market Authorization Holder (MAH) identifies any negative safety findings and/or significant change in the product’s overall benefit-risk and safety profile.
7. Notification and reporting on specific issues of concern, as outlined in Section 3.4.4, Post-Market Commitments: Notification and Reporting of Specific Issues of Concern, of the Health Canada NOC/c Guidance.
8. Report(s) of all serious adverse drug reactions (ADRs) that occurred in Canada and all serious unexpected ADRs that occurred outside of Canada should be forwarded within 15 days to the Marketed Health Products Directorate, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents.

3. A draft of the Product Monograph (PM) that is consistent with the requirements outlined in section 5.2.1 of the Guidance Document: Notice of Compliance with Conditions (NOC/c). Please note that boxed text should appear on the cover page as well as at the beginning of each major section of the Product Monograph (Parts I, II and III, as applicable), disclosing the nature of the authorization granted for Albrioza for the indication of Treatment of patients with amyotrophic lateral sclerosis.
4. A final mock-up of the Package Insert (if applicable), in line with the requirements outlined in Health Canada's Guidance Document, Questions and Answers: Plain Language Labelling Regulations (Q&A: PLL), containing boxed text disclosing the nature of the authorization granted for Albrioza for the indication of Treatment of patients with amyotrophic lateral sclerosis.

I wish to advise you that this Qualifying Notice is being issued in accordance with Health Canada's guidance documents on the Management of Drug Submissions and Applications and Notice of Compliance with Conditions. Sponsors are instructed to submit a complete response [refer to Guidance Document: Notice of Compliance with Conditions (NOC/c)] with the requested information within 30 calendar days of the date of this letter.

In order to facilitate and to ensure proper processing, please quote the product name and control number in your response, and please provide transactions directly to the Office of Submissions and Intellectual Property (OSIP) via the Common Electronic Submissions Gateway (CESG) using the Regulatory Enrolment Process (REP):

1. For transactions in e-CTD format, as indicated in the Guidance Document: Preparation of Regulatory Activities in the eCTD Format and the Guidance Document: The Regulatory Enrolment Process (REP): Drugs for Human/Veterinary Use and Disinfectants
2. For transaction in non-eCTD format, as indicated in the Guidance Documents: Preparation of Regulatory Activities in the Non-eCTD Format and the Guidance Document: The Regulatory Enrolment Process (REP): Drugs for Human/Veterinary Use and Disinfectants

Yours sincerely,

Melissa Hunt for Dr. J. Patrick Stewart, MD, CCFP(EM)
Director General
Pharmaceutical Drugs Directorate
JPS/jg