Regulatory Decision Summary for Beqvez

The purpose of this New Drug Submission, pursuant to section C.08.004 of the Food and Drugs Regulations, accepted for review under the priority review pathway, was to seek market authorization for Beqvez (fidanacogene elaparvovec), an adeno-associated virus (AAV) vector-based gene therapy, for the treatment of adult patients with moderately-severe and severe Hemophilia B.

After evaluation of the submitted data package, Health Canada authorized Beqvez for the treatment of adults (aged 18 years or older) with moderately-severe to severe Hemophilia B (congenital Factor IX deficiency) who are negative for neutralizing antibodies to variant AAV serotype Rh74.

Market authorization was based on the results of a Phase 3, open-label, single-arm study that enrolled 45 adult male Hemophilia B patients with severe or moderately-severe disease who were negative for neutralizing antibodies to variant AAV serotype Rh74. Patients completed at least 6 months of standard of care lead-in Factor IX prophylaxis prior to receiving a single intravenous infusion of 5 x 10¹¹ vector genomes per kg (vg/kg) of Beqvez. The results of the primary efficacy endpoint demonstrated that Beqvez was non-inferior to Factor IX prophylaxis as the upper bound for the 95% confidence interval (CI) of the treatment difference in the total Annualized Bleeding Rate (ABRtotal) (Beqvez – lead-in Factor IX prophylaxis) was lower than the pre-specified non-inferiority margin of 3 (from Week 12 to Month 15 post-infusion). The model-adjusted ABRtotal post-infusion of Beqvez was 2.17 (95% CI 0.64, 3.70) compared to 4.51 (95% CI 1.85, 7.17) with Factor IX prophylaxis.

The most frequently reported adverse reaction was transaminitis (hepatotoxicity) believed to be due to an immune-mediated response to the AAV vector following integration of the liver cells. Sixty-two percent (28/45) of patients in the Phase 3 clinical trial received corticosteroids due to presumed immune-mediated events including the elevation of liver enzymes and/or reduction in Factor IX. The use of corticosteroids was associated with numerically lower mean Factor IX activity. Uncertainties of Beqvez include the possibility of insertional mutagenesis leading to tumorgenicity, particularly liver cancer due to integration of the liver-targeting AAV vector, 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 Beqvez to monitor for potential insertional mutagenesis that may drive tumorigenesis in susceptible patients. In addition, it is recommended that male patients treated with Beqvez and their female partners of childbearing potential use barrier contraception for 1-year after treatment to prevent any possible germ-line transmission of viral/transgene DNA to offspring.

The overall benefit-risk profile of Beqvez is considered favourable when the product is used in accordance with the recommended conditions of use provided in the product monograph

An updated Risk Management Plan (RMP) for Beqvez was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Beqvez has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

A Notice of Compliance was recommended.

For further details about Beqvez, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.