Regulatory Decision Summary for Ravicti

The data derived from studies in pediatric patients < 2 years of age with UCDs, provided evidence to support the efficacy of Ravicti as an effective nitrogen scavenging agent for chronic management of ammonia in these patients. In both studied age groups, birth to < 2 months (n = 16) and 2 months to < 2 years age (n = 17), all patients achieved successful transition to Ravicti by end of the transition period (1-4 days) with controlled ammonia, defined as ammonia < 100 µmol/L and no signs of hyperammonemia. Controlled ammonia continued in the safety extension period for the majority of treated patients. There was a mean decrease in the baseline ammonia level in the transition period and most visits in the safety extension period. The percentage of patients with all ammonia levels < 100 µmol/L ranging from 83.3% to 100.0% at the individual safety extension visits for patients aged 2 months to < 2 years and from 57.1% to 100% for patients aged < 2 months. The frequency of HACs decreased after the patients began Ravicti treatment.

The pharmacokinetic data demonstrated adequate absorption and metabolism of Ravicti to the active metabolite (PAA) and final metabolite (PGAN) in pediatric patients, birth to < 2 years of age. The pharmacokinetic data provided evidence of successful scavenging of nitrogen and bypassing urea cycling defect in this age group.

Overall, Ravicti therapy was safe and well tolerated in patients < 2 years of age (n = 33). The safety profile in this age group was consistent with the known safety profile of Ravicti in adults and pediatric patients ≥ 2 years with no new safety signal identified. There were no serious adverse events (SAEs) in patients < 2 years of age that were assessed as related with Ravicti. There was one death (pneumatosis) assessed as not related to Ravicti but rather related to bowel perforation during the placement of a gastric tube. The most common treatment emergent adverse events (TEAEs) reported in the 2 months to < 2 years age group were upper respiratory tract infection, hyperammonemia, vomiting, pyrexia, cough, gastroenteritis, hypophagia, and nasal congestion and in the < 2 months age group were dermatitis diaper, gastroesophageal reflux disease, hyperammonemia, vomiting, diarrhea, rash, and upper respiratory tract infection, cough, nasopharyngitis, anemia, dehydration, ear infection, flatulence, and urinary tract infection. Most TEAEs were mild to moderate in severity and assessed as not related to Ravicti. The drug-related TEAEs were rash and diarrhea.

The Product Monograph was revised to address uncertainties and to improve the clarity of safety concerns. Due to the very rare nature of the UCDs and difficulty with studying these conditions, the exposure upon which approval was based was small. The numbers of subjects included in the analyses at various visits in the extension period were different due to discontinuation or missing data or blood volume limits in this age group. These limitations led to different numbers (and sometimes small numbers) of evaluable samples included at various visits in the extension period. Moreover, large inter-subject variability in the pharmacokinetic (PK) data was observed due to different Ravicti starting doses and dosing regimens (3-6 times). There were also restrictions with collection of samples due to the age group.

High plasma levels of PAA concentration and high PAA/PAGN ratio were noted in pediatric patients < 2months of age. While the high levels of PAA and PAA/PGAN ratios were not associated with any symptoms of PAA neurotoxicity, PAA neurotoxicity should be monitored in this age group. This has been reflected in the Product Monograph which recommends monitoring of plasma ammonia, glutamine, U-PAGN, and/or plasma PAA and PAGN as well as the ratio of plasma PAA to PAGN and that there should be consideration of reducing the dose of Ravicti and/or increasing frequency of dosing if aforementioned values are abnormal.

Safety and efficacy for treatment of patients with N-acetylglutamate synthase (NAGS) deficiency have not been established as this patient population was excluded from the study. All safety concerns and uncertainties were adequately addressed in the Canadian PM and/or through the Risk Management Plan.

Overall, based on the totality of the data, Ravicti has a favourable benefit-harm-uncertainty profile to support the expansion of the indication to include pediatric subjects < 2 years of age, when it is used as directed in the revised Product Monograph.