Regulatory Decision Summary for Remsima SC

The purpose of this submission was to demonstrate comparability of maintenance dosing with infliximab administered either via subcutaneous (SC) injections or intravenous (IV) infusions in order to provide support for authorization of Remsima SC as maintenance therapy in adults with rheumatoid arthritis (RA).

A Phase 3 randomized controlled trial was conducted in adult RA patients. All patients received dose induction with IV infliximab at a dose of 3 mg/kg at Weeks 0 and 2, followed by randomization to either SC (120 mg every 2 weeks) or IV (3 mg/kg every 8 weeks) treatment from Weeks 6-30. All patients then received dosing with 120 mg SC every 2 weeks from Weeks 30-54.

At Week 22, SC therapy was shown to be non-inferior to IV therapy using the continuous endpoint of DAS28 (CRP). While no other endpoints were designed for formal statistical analysis, the similarity in efficacy for various endpoints was relatively consistent throughout the study. At Week 54, after all patients had undergone at least 24 weeks of SC maintenance, efficacy profiles were well-matched regardless of the maintenance group prior to Week 30.

The goal of the infliximab SC pharmacokinetic programme in RA patients was to support an SC dosage regimen that would maintain pre-dose infliximab concentrations greater than a threshold that correlated with improved efficacy outcomes and to allow for similar exposure to the currently authorized infliximab IV regimen (i.e. 3 mg/kg every 8 weeks). Pre-dose concentrations of infliximab, in the infliximab SC arm were generally above the minimum pre-dose concentration threshold associated with efficacy for most patients up to Week 30. Exposure was ~50% greater following infliximab SC relative to infliximab IV, supporting the selection of 120 mg infliximab SC every 2 weeks as the recommended dosage regimen in RA. Overall, anti-drug antibody development was similar between infliximab IV and SC groups.

The safety profile for patients treated with SC infliximab was consistent with the established profile for IV-administered infliximab. The exception was a greater incidence of localized injection site reactions (ISRs) in patients that received SC injections. Overall, the most common AEs fell under the categories of infections and administration site conditions. There is limited information on longer-term use of SC infliximab. Because of the higher exposure profile associated with SC dosing, long-term use of SC infliximab is listed as Important Missing Information in the Risk Management Plan.

The overall benefit-risk profile of infliximab administered via SC injection in adult RA patients is positive. Remsima SC is authorized as maintenance therapy in adults with rheumatoid arthritis at a recommended dose of 120 mg every two weeks administered via subcutaneous injection after an initial dose induction period with intravenous infliximab.