Immunogenicity With Ranibizumab Biosimilar SB11 (Byooviz) and Reference Product Lucentis and Association With Efficacy, Safety, and Pharmacokinetics

Abstract

ImportanceSB11 and reference ranibizumab (RBZ) are monoclonal anti–vascular endothelial growth factor (VEGF)–A antibodies approved for the treatment of neovascular age-related macular degeneration (nAMD) and other retinal diseases. The association of ranibizumab immunogenicity and treatment outcomes in patients with nAMD is unclear but relevant regarding concerns about immunogenicity of anti-VEGF biological products.ObjectiveTo examine the association of immunogenicity to ranibizumab products (SB11 and RBZ) with efficacy, safety, and pharmacokinetics.Design, Setting, and ParticipantsThis was a post hoc analysis of a randomized, double-masked, parallel-group phase 3 equivalence study with participants from 75 centers in 9 countries conducted from March 14, 2018, to December 9, 2019. Included were participants 50 years or older with nAMD and active subfoveal choroidal neovascularization lesions.InterventionsIntravitreal injection of SB11 or RBZ, 0.5 mg, every 4 weeks through week 48.Main Outcomes and MeasuresSerum antidrug antibodies (ADAs) were analyzed during the study period until week 52 to measure immunogenicity. Analyses were performed on immunogenicity (overall ADA positivity) with best-corrected visual acuity (BCVA) and central subfield thickness (CST). Adverse events associated with intraocular inflammation (IOI) and serum ranibizumab levels were compared between overall ADA-positive and ADA-negative participants.ResultsA total of 705 participants (mean [SD] age, 74.1 [8.5] years; 403 female individuals [57.2%]) were included in the study. The overall incidence of ADA-positivity was 32 of 657 (4.9%) at week 52. The least-squares mean (SE) differences between overall ADA-positive and ADA-negative participants up to week 52 for BCVA and CST, respectively, were 1.6 (2.2) letters (95% CI, −2.7 to 5.8; P = .46) and 3 (13) μm (95% CI, −23 to 29; P = .83). IOI-related events occurred in 1 of 32 overall ADA-positive participants (3.1%) and 4 of 620 overall ADA-negative participants (0.6%). Mean (SD) serum ranibizumab concentrations over time were slightly lower in overall ADA-positive participants compared with those of ADA-negative participants, with a maximum value of 1389.3 (875.4) pg/mL at week 16 vs 1665.4 (1124.0) pg/mL at week 36, respectively.Conclusions and RelevanceResults of this post hoc analysis of an equivalence trial suggest that immunogenicity was not associated with efficacy and safety of SB11 and RBZ in participants with nAMD. With a low overall ADA incidence, no clear association was identified between overall ADA positivity and pharmacokinetics. These findings support the biosimilarity of SB11 and RBZ, with no safety concern identified for SB11 vs RBZ associated with immunogenicity.Trial RegistrationClinicalTrials.gov Identifier: NCT03150589

Biosimilar Ranibizumab and Innovator Ranibizumab—Immunogenicity Assessment and Its Impact on Safety and Efficacy

“…1 The post hoc analysis of phase 3 data of SB11 vs reference ranibizumab by Bressler et al 2 has focused on the immunogenicity of biosimilar ranibizumab-nuna (Byooviz) and innovator ranibizumab (Lucentis) by assessing antidrug antibodies (ADAs) and their effect on safety and efficacy of ranibizumab. 2 Every biologic, irrespective of innovator or biosimilar, has exogenous proteins and therefore has the potential to be immunogenic by nature. 3 With the observation of severe intraocular inflammation (IOI) in patients undergoing brolucizumab therapy, a spotlight has been brought on ADAs and their potential postulated role in immunogenicity.…”

“…There was a higher percentage of patients with IOI among patients testing positive for antibrolucizumab antibodies (6%) compared with patients without these antibodies (2%). This was also true in the current study by Bressler et al, where IOI related events occurred in 1 of 32 overall ADA-positive participants (3.1%) and 4 of 620 overall ADA-negative participants (0.6%). Other anti-VEGFs, such as ranibizumab and aflibercept, have shown 0% to 3% of patients with ADAs before treatment initiation and 1% to 9% of patients with ADAs after a 2-year treatment course in clinical trials.…”

“…At the study’s end, ADA-negative patients taking brolucizumab had a somewhat higher BCVA (gain in letters) compared with the aflibercept group. This was not found in the study by Bressler et al, where the least-squares mean differences between overall ADA-positive and ADA-negative participants up to week 52 for BCVA and central subfield thickness (CST) were not significantly different. These findings suggest that at least for ranibizumab, immunogenicity measured by ADAs does not appear to have a significant impact on safety and efficacy…”

“…The current post hoc analysis of a phase 3 trial by Bressler et al provides useful and important information because it is anticipated that many more biosimilar ranibizumab and aflibercept molecules will be approved in the future. According to a poll by the International Retina Biosimilar Study Group (Inter BIOS Group), many retinal physicians in Europe and the US are concerned about the safety of biosimilars .…”

“…According to a poll by the International Retina Biosimilar Study Group (Inter BIOS Group), many retinal physicians in Europe and the US are concerned about the safety of biosimilars . The current post hoc analysis by Bressler et al may alleviate some of these concerns as they have concluded that immunogenicity had no apparent effects on efficacy and safety of SB11/ranibizumab-nuna (Byooviz) and innovator ranibizumab (Lucentis) in participants with neovascular AMD. With a low overall ADA incidence, no clear relationship was identified between overall ADA positivity and pharmacokinetics.…”