Ixifi Has Similar Efficacy to Remicade in RA, With or Without Dose Escalation

Pfizer’s Ixifi, a biosimilar infliximab product that was approved for all indications of its reference in the United States in December 2017, received FDA clearance with a data package that included findings from a phase 3, randomized, double-blind, active-controlled, multinational study comparing the biosimilar with the reference infliximab in combination with methotrexate in patients with rheumatoid arthritis (RA). The data were presented in an abstract at the American College of Rheumatology’s annual meeting in 2017, and the results for the initial 30-week treatment period have now been published in Arthritis Research and Therapy.

The study compared the efficacy, safety, pharmacokinetics (PK), and immunogenicity of the biosimilar with the reference in patients with RA receiving background methotrexate for whom response to methotrexate alone was inadequate. Patients were randomized to receive either the EU-licensed reference (n = 326) or the biosimilar (n = 323), and were treated at 174 centers in 28 countries.

While patients began with a dose of 3 mg/kg of their infliximab product, delivered intravenously at week 0, 2, and 6, then every 8 weeks thereafter, dose escalation to 5 mg/kg was allowed at week 14 for patients whose response was inadequate. A total of 86.4% and 87.7% of patients in the biosimilar arm and the reference arm, respectively, completed the full 30 weeks.

The primary endpoint of the study was meeting ACR criteria for 20% improvement (ACR20) at week 14, and therapeutic equivalence was determined if the 95% CI for the treatment difference was within the predefined equivalence margin of ±13.5%.

A total of 203 (62.7%) of patients in the biosimilar arm and 209 (64.1%) in the reference arm achieved ACR20 at week 14, and using nonresponder imputation, a total of 198 (61.1%) of patients in the biosimilar arm and 207 (63.5%) in the reference arm had an ACR20 response at week 14, resulting in a treatment difference of —2.39% (for which the corresponding 95% CI fell within the prespecified margin). ACR20 responses were similar between the 2 arms for patients who escalated their doses to 5 mg/kg at week 14 and those who remained on the 3 mg/kg dose.

Furthermore, ACR20, ACR50, and ACR70 response rates were similar between the 2 arms at all time points through week 30, and similar percentages of patients achieved remission at each study visit. Measured by disease activity score, at week 30, 19.1% of the biosimilar arm and 16.6% of the reference arm had reached remission; measured by ACR or European League Against Rheumatism scores, 9.3% and 7.1% of patients, respectively, had reached remission.

The number of patients reporting all-cause treatment-emergent adverse events (TEAEs) was similar—185 patients (57.3%) in the biosimilar arm and 176 patients (54.0%) in the reference arm—with infections and infestations being the most commonly reported and with infusion reactions reported in 19 (5.9%) and 21 (6.4%) of patients, respectively.

The majority of infusion reactions in both arms, say the researchers, appeared to be associated with the development of antidrug antibodies (ADAs). The incidence of ADAs was similar in both arms at all timepoints, with 157 (48.6%) and 167 (51.2%) of patients in the biosimilar and reference arms, respectively, having at least 1 postdose sample that tested positive for ADAs. Patients who qualified for dose escalation had higher ADA rates.

Trough serum concentrations at week 2, 4, 6, 14, 22, and 30 and immediate postdose serum concentrations on the first day and at week 14 were similar between arms, and were lower in ADA-positive patients than ADA-negative patients.

The biosimilar and the EU-licensed reference were similar in efficacy, safety, immunogenicity, and PK, write the authors, who note that full data for 2 subsequent 24-week treatment periods, during which patients receiving reference infliximab switched to the biosimilar, are forthcoming.

Despite the positive findings of this study, Pfizer has indicated that it does not seek to sell Ixifi in the United States, but will instead concentrate on commercializing its already launched infliximab biosimilar, Inflectra, in this market. However, in February 2016, Sandoz acquired the rights from Pfizer for the development, commercialization, and manufacture of the product in the European Union, and Sandoz received marketing authorization from the European Commission for the product—under the commercial name Zessly—in May 2018.

Reference

Cohen SB, Alten R, Kameda H, et al. A randomized controlled trial comparing PF-06438179/GP1111 (an infliximab biosimilar) and infliximab reference product for treatment of moderate to severe active rheumatoid arthritis despite methotrexate therapy. Arthritis Res Ther. 2018;27(20):155. doi: 10.1186/s13075-018-1646-4.