Regulatory Decision Summary for Rebinyn

Market authorization was based on the results of clinical trials and nonclinical studies.

The main clinical trials were multi-centre, open-label, single-arm, non-controlled trials including 25 previously treated patients and 50 previously untreated patients aged 1 to 12 years to evaluate safety, efficacy, and pharmacokinetic (PK) of Rebinyn. Patients were exposed to Rebinyn for a mean exposure days (EDs) per patient of 317.0 EDs and 134.2 EDs, respectively. The study demonstrated efficacy of Rebinyn in preventing or reducing the frequency of bleeding episodes in terms of low annualized bleeding rate and high hemostatic success rate due to high FIX trough values at steady state. High treatment compliance was observed. For previously treated patients, the mean estimated annualised bleeding rate (ABR) was 0.85 and median ABR was 0.5 bleeds/patient/year for patients on prophylaxis. The hemostatic success rate for treatment of all bleeds was 89.1% (85.0% for spontaneous bleed, 90.5% for traumatic bleeds). The estimated mean FIX trough levels at steady state were 0.181 IU/mL. The treatment compliance was 96.5%. For previously untreated patients, the mean estimated ABR was 0.94 and median ABR was 0.25 bleeds/patient/year for patients on prophylaxis treatment. The hemostatic effect success rate was 96.4% for treatment of all bleeds (100% for spontaneous bleed, 95.1% for traumatic bleeds). Treatment compliance was 96.1%. The estimated mean steady state FIX trough level was 0.156 IU/mL for patients on prophylaxis treatment. No major safety issues or new safety signals were identified.

In non-clinical studies, PEG deposition was observed in the choroid plexus pituitary, circumventricular organs, and cranial motor neurons in animals treated with Rebinyn; however, there were no signs of neurobehavioral or neurocognitive alterations in the animals. The clinical implications of the findings in animals are unknown as the neurological and neurocognitive assessments performed in the two clinical trials did not identify any consistent pattern or unexpected trajectory across the different assessments of the PEG risks in children. However, the assessment of potential risks of Rebinyn on neurological development in the two clinical trials had some limitations, which results in some residual uncertainty.

In order to communicate and mitigate the potential risk of PEG in children, Novo Nordisk Canada Inc. has committed to continually monitor and examine any neurological symptoms for children receiving routine prophylaxis with Rebinyn, by using the established Canadian Bleeding Registry (CBDR) and informing Health Canada immediately if any signals of PEG-related adverse effects are identified. The sponsor also committed to submitting the results of post-market studies requested by the FDA and EMA when they are available, and monitor the safety of Rebinyn through routine pharmacovigilance activities, clinical trials and post-authorization safety studies and inform Health Canada immediately if any signals of PEG risk are identified. With these measures taken, the overall benefit-risk of Rebinyn, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in children, is favourable.