Regulatory Decision Summary for Hemgenix
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Blood Coagulation Factors
Type of Submission:
New Drug Submission (New Active Substance) - Priority Review
Authorized; issued a Notice of Compliance in accordance with the Food and Drug Regulations
What was the purpose of this submission?
The purpose of this New Drug Submission (NDS), accepted for review under the Priority Review Pathway, was to seek marketing authorization for Hemgenix (etranacogene dezaparvovec), an adeno-associated virus (AAV) vector-based gene therapy, indicated for the treatment of adults with Hemophilia B (congenital Factor IX deficiency) and with a preexisting neutralizing AAV5 antibody titer below 1:900 to reduce the frequency of bleeding episodes and the need for Factor IX replacement therapy who a) currently use Factor IX prophylaxis therapy, or b) have current or historical life-threatening hemorrhage, or c) have repeated, serious spontaneous bleeding episodes.
After evaluation, Health Canada authorized Hemgenix for treatment of adults (aged 18 years of age or older) with Hemophilia B (congenital Factor IX deficiency) who require routine prophylaxis to prevent or reduce the frequency of bleeding episodes, noting that there is no clinical experience of Hemgenix use in patients with mild or moderate Hemophilia B (FIX activity > 2%).
Why was the decision issued?
Marketing authorization for Hemgenix was based on the results of one Phase 3 open-label, single-arm trial, CT-AMT-061-02 study (HOPE B), that enrolled adult male Hemophilia B patients with severe or moderately severe disease treated with a single dose of 2 x 1013 genome copies (cg)/kg body weight of Hemgenix (etranacogene dezaparvovec). Sixty-seven patients were enrolled on study and were treated for a minimum of 6 months with Factor IX replacement therapy and of these fifty-four patients were treated with a single dose of Hemgenix – 13 patients did not meet eligibility criteria for this gene therapy. Patients acted as their own controls allowing comparison of their annualized bleeding rate (ABR) on prophylactic Factor IX to their ABR following treatment with Hemgenix (based on 7 to 18 months post-infusion). The primary objective was to demonstrate non-inferiority of Hemgenix to prophylactic Factor IX therapy based on ABR.
Patients treated with Hemgenix had a mean-adjusted ABR of 1.73 (95% CI: 0.64, 4.02) compared to an ABR of 4.13 (95% CI: 2.95, 5.22) for patients receiving prophylaxis with Factor IX replacement therapy, which met the primary objective of the study and where there was an overall reduction in all bleeding events following Hemgenix treatment compared to standard of care therapy. Pre-specified secondary efficacy outcomes for treated bleeds, joint bleeds, traumatic bleeds and spontaneous bleeds were also considered positive for Hemgenix, including independence of exogenous Factor IX use for many patients post- Hemgenix infusion.
Important safety concerns include transaminitis (hepatotoxicity) and infusion-related reactions. Immune-mediated events gave rise to significant elevations in liver enzymes and required corticosteroid use in 9 patients who had a numerically lower mean transgene Factor IX activity, noting that patients with significant liver impairment were excluded from clinical studies. Infusion-related reactions were reported in nearly one-third of patients, including some serious reactions resulting in a failure to deliver a full dose of Hemgenix to one patient who subsequently did not respond to treatment (i.e. no transgene Factor IX expression). Uncertainties of Hemgenix include the possibility of insertional mutagenesis leading to tumorgenicity and the potential for germ-line transmission of viral/transgene DNA to offspring. Patients at risk of liver cancer should be followed closely for five years following treatment of Hemgenix to monitor for potential insertional mutagenesis that may drive tumorigenesis in susceptible patients. In addition, it is recommended that male patients treated with Hemgenix and their female partners of childbearing potential use barrier contraception for 2 years after treatment with this gene therapy to prevent any possible germ-line transmission of viral/transgene DNA to offspring.
The overall benefit-risk profile of Hemgenix is considered favourable when the product is used in accordance with instructions provided in the product monograph.
A Notice of Compliance was recommended.
For further details about Hemgenix, please refer to the product monograph approved by Health Canada and available through the Drug Product Database.
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Hemgenix is both a Prescription and a Schedule D drug