Regulatory Decision Summary for JIVI

Hemophilia A is a hereditary bleeding disorder characterized by recurrent bleeding, which if left untreated may lead to chronic arthropathy, muscular atrophy and deformities.

JIVI is a recombinant factor VIII replacement therapy for treatment of patients with hereditary FVIII deficiency (hemophilia A). It is specifically conjugated with a 60 kDa branched polyethylene glycol (PEG). Thus this product could have a benefit over other FVIII replacement therapies of having an extended half-time through reduced clearance from plasma by PEGylation, while retaining the normal activity of the FVIII molecule. This could result in the potential for FVIII infusions only twice a week which could increase compliance and encourage a prophylactic schedule. Prophylaxis is the preferred approach to managing patients with hemophilia A, as there are decreased bleeding episodes and less risk of joint damage.

Overall, JIVI demonstrated efficacy in subjects over 6 years of age for on-demand treatment to control bleeding episodes, perioperative management of bleeding, and routine prophylaxis. Due to a higher annualized bleeding rate (ABR) in the every 7-day dosing regimen and increased bleeding requiring increasing dose or frequency, this dosing regimen is not routinely recommended.

The most substantial risks of treatment with JIVI are the development of FVIII inhibitors. Serious adverse events of hypersensitivity, antibody development, and loss of efficacy occurred in the pediatric population. As such, off-label use of JIVI <12 years of age is an important potential risk if physicians intentionally or unintentionally prescribe the product to a patient <12 years of age. The sponsor has outlined a communication plan to inform prescribers about the age restriction associated with JIVI.

To conclude, the benefit risk profile in patients 12 years of age and older is favorable; however, given the risk of anti-PEG antibodies and hypersensitivity reactions noted in pediatric subjects less than 12 years of age, the risk outweighs the benefit, and approval in this age group was not recommended. These recommendations are consistent with the sponsors requested indication.

One-hundred and twenty-six completed the study (including 13 subjects between 12 and 18 years of age) who were treated with JIVI for either on-demand (n = 18) or prophylactic treatment (n = 108).

The three dosing regimens evaluated under prophylaxis included 30 IU/kg twice per week, 45-60 IU/kg every 5 days and 60 IU/kg every 7 days. Prophylactic infusion with JIVI was effective for prevention of bleeds at dose intervals of 2x/week and every 5 days. However, the every 7-day treatment group had bleeding events which caused 26% of those in that group to discontinue treatment. Therefore a starting dose of 30-40 IU/kg twice weekly is recommended, and based on the bleeding profile, the patients regimen may be adjusted to 45-60 IU/kg every 5 days. A more or less frequent schedule may also be considered.

A Risk Management Plan (RMP) was also submitted and reviewed, recommending that risk for off-label use in children under 12 years of age be addressed in the Risk Management Plan, concern of PEG accumulation after long-term treatment be addressed as well and Periodic Benefit-Risk Evaluation Reports (PBRER) every 6 months for the first three years of market authorization be submitted.