Efficacy and Safety of the Aflibercept Biosimilar SB15 in Neovascular Age-Related Macular Degeneration

Abstract

ImportanceAflibercept biosimilars can expand available treatment options in retinal diseases and have the potential to improve patient access to safe and effective therapy.ObjectiveTo establish equivalence in efficacy and similarity in safety, pharmacokinetics, and immunogenicity of SB15 and reference aflibercept (AFL) in neovascular age-related macular degeneration (nAMD).Design, Setting, and ParticipantsThis was a randomized double-masked parallel group phase 3 trial conducted at 56 centers in 10 countries from June 2020 to March 2022, including follow-up through 56 weeks. Of 549 screened participants, 449 participants 50 years and older with treatment-naive nAMD were included and randomly assigned to SB15 (n = 224) or AFL (n = 225). Key exclusion criteria included considerable scarring, fibrosis, atrophy, and hemorrhage. This report includes results up to the end of the parallel group period at week 32. Of the 449 randomized participants, 438 (97.6%) completed week 32 follow-up.InterventionParticipants were randomized 1:1 to receive 2 mg of SB15 or AFL every 4 weeks for the first 12 weeks (3 injections), followed by dosing every 8 weeks up to week 48, with final assessments at week 56.Main Outcomes and MeasuresThe primary end point was the change in best-corrected visual acuity (BCVA) from baseline to week 8 with predefined equivalence margins of −3 letters to 3 letters. Other key end points were changes in BCVA and central subfield thickness up to week 32, safety, pharmacokinetics, and immunogenicity.ResultsThe mean (SD) age among the 449 included participants was 74.0 (8.1) years, and 250 participants (55.7%) were female. Baseline demographic characteristics and most disease characteristics were comparable between treatment groups. The least squares mean change in BCVA from baseline to week 8 in the SB15 group was equivalent to that in the AFL group (6.7 letters vs 6.6 letters, respectively; difference, 0.1 letters; 95% CI, −1.3 to 1.4). Comparable efficacy between treatment groups was maintained up to week 32 (least squares mean change from baseline in BCVA: SB15, 7.6 letters vs AFL, 6.5 letters; least squares mean change from baseline in central subfield thickness: SB15, −110.4 μm vs AFL, −115.7 μm). No clinically relevant differences were observed in the incidence of treatment-emergent adverse events (TEAEs) (SB15, 107/224 [47.8%] vs AFL, 98/224 [43.8%]) and ocular TEAEs in the study eye (SB15, 41/224 [18.3%] vs AFL, 28/224 [12.5%]). The serum concentration profiles and cumulative incidences of overall antidrug antibody positive participants were comparable.Conclusions and RelevanceIn this phase 3 randomized clinical trial, SB15 and AFL showed equivalent efficacy and comparable safety, pharmacokinetics, and immunogenicity in participants with nAMD.Trial RegistrationClinicalTrials.gov Identifier: NCT04450329

Biosimilars for Retinal Diseases: A Review of the Literature

“…Aflibercept biosimilars are also underway of development, with MYL-1710 (Momenta Pharmaceuticals and Mylan) being investigated for DME and ALT-L9 (Altos Biologics), FYB-203 (Formycon), SB-15 (Samsung Bioepis), and SCD-411 (Sam Chun Dang Pharmaceuticals) for nAMD. A recent phase III trial published in July 2023 successfully showed no clinically significant differences between SB-15 (n=224) and aflibercept (n=225) with regard to both efficacy and safety profile in patients with nAMD 27 . The primary endpoint of this trial was a change in BCVA from baseline after 8 weeks, and secondary endpoints were BCVA and CST changes at 32 weeks, safety and PK profiles, and immunogenicity 27 .…”

“…A recent phase III trial published in July 2023 successfully showed no clinically significant differences between SB-15 (n=224) and aflibercept (n=225) with regard to both efficacy and safety profile in patients with nAMD 27 . The primary endpoint of this trial was a change in BCVA from baseline after 8 weeks, and secondary endpoints were BCVA and CST changes at 32 weeks, safety and PK profiles, and immunogenicity 27 . Formycon recently announced the submission of a BLA for another aflibercept biosimilar, FYB-203; a decision is expected by late August 2023.…”

“…In this process, predetermined primary endpoints—most often the best-corrected visual acuity (BCVA) and central subfield thickness (CST)—are measured in a study population randomized to either the biosimilar or reference biologic arm. The risk difference is measured between endpoints in both groups, 26 and equivalence is established using a predetermined equivalence margin 27 . However, clinical trials for biosimilars observe these primary endpoints over shorter time periods, often using a primary endpoint of 4 to 8 weeks.…”

Severe Intraocular Inflammation Following Intravitreal Faricimab

“…Acute, severe, sterile IOI after intravitreal injections have been reported with many commonly used anti-VEGF agents, including aflibercept and ranibizumab . More recently, this type of IOI as well as relatively rare reports of acute severe IOI associated with occlusive retinal vasculitis have been reported with more recently approved intravitreal agents for retinal diseases, including brolucizumab, pegcetacoplan, and faricimab as well as biosimilar agents ranibizumab and aflibercept . Nevertheless, these clinical trial reports, including those for faricimab, have reported infrequent severe IOI events .…”

“…More recently, this type of IOI as well as relatively rare reports of acute severe IOI associated with occlusive retinal vasculitis have been reported with more recently approved intravitreal agents for retinal diseases, including brolucizumab, pegcetacoplan, and faricimab as well as biosimilar agents ranibizumab and aflibercept . Nevertheless, these clinical trial reports, including those for faricimab, have reported infrequent severe IOI events . Inflammatory complications following intravitreal anti-VEGF injections that are sterile are characterized by acute-onset IOI without infection that resolve without antibiotic treatment .…”