Regulatory Decision Summary for Jivi

The purpose of this submission is to expand the indication for Jivi (recombinant Factor VIII, B-domain deleted) in children aged 7 to less than 12 years of age with hemophilia A (congenital Factor VIII deficiency). The smallest vial containing 250 International Unis (IU) of FVIII will be discontinued.

Jivi is a recombinant Factor VIII variant conjugated with a 60 kDa polyethylene glycol (PEG) moiety that increases the half-life of the product in circulation for patients with hemophilia A. Jivi had received marketing authorization in 2018 for routine prophylaxis, on demand treatment and surgical prophylaxis in adolescents and adults aged 12 years and older, based on three clinical studies that included previously treated patients (PTP) with severe hemophilia A between the ages of 2 to 61 years old. At the time, the indication in children aged 0 to less than 12 years was not granted due to the high immune reactions against the PEG moiety of Jivi observed mostly in patients aged less than 7 years old, which caused hypersensitivity reactions and loss of efficacy (LoE).

A pivotal pediatric study was thus repeated specifically in children aged 7 to less than 12 years old, in support for the use of Jivi in this age group. The study confirmed that the high immune and hypersensitivity reactions against this larger PEG moiety (as compared to other similar products) was typically observed in young children aged less that 7 years. For this reason, the safety and efficacy of Jivi have not been established in pediatric patients less than 7 years of age. Jivi is also not indicated for use in previously untreated patients.

The efficacy in children aged 7 to less than 12 years old is established in 60 boys based on pooled data obtained from the two pediatric studies. The results support the recommended initial regimen at 60 IU/kg twice weekly. Based on the bleeding episodes and in vivo FVIII recovery, the dose may be adjusted to 40-60 IU/kg twice weekly. Safety included all 108 boys aged 2 to 11 years old who participated in both studies. The safety profile in the 7 to less than 12 years old group was similar to the one in the 12 years and older group. A hypersensitivity reaction associated with high titers in anti-PEG antibodies was not observed in the 7 to less than 12 years old group.

A total of 8 out of 60 participants (13.3%) had positive anti-PEG titres which led to lower in vivo FVIII recovery. According to their FVIII recovery, patients were either switched to their previous Factor VIII product without any sequala, or their dose increased until their FVIII recovery normalized. The follow-up of these patients after a few months also showed the transient nature of the anti-PEG immune response. There was also no evidence of any significant accumulation of PEG molecules in patients’ plasma. None of the participants developed FVIII inhibitors (i.e. anti-FVIII antibodies) above the clinical significance threshold of positivity.

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

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

Overall, the risk of LoE associated with anti-PEG antibodies is low in children aged 7 to <12 years. The benefit in the use of Jivi is considered favorable over the risks in this age group, with risk mitigations described in the Product Monograph.

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