Efficacy and Safety of a Proposed Ranibizumab Biosimilar Product vs a Reference Ranibizumab Product for Patients With Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial

Abstract

Importance: Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment.

Objective: To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab.

Design, setting, and participants: This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis.

Interventions: Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48.

Main outcomes and measures: Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of -3 letters to 3 letters for BCVA and -36 μm to 36 μm for CST.

Results: Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of -0.8 letter (90% CI, -1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were -108 (5) μm in the SB11 group vs -100 (5) μm in the ranibizumab group, with an adjusted treatment difference of -8 μm (95% CI, -19 to 3 μm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group.

Conclusions and relevance: These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration.

Trial registration: ClinicalTrials.gov Identifier: NCT03150589.

Figure 1.. CONSORT Diagram of Participant Flow Through the Trial

Primary end point analysis groups are indicated in the bottom 2 boxes. BCVA indicates best-corrected visual acuity; CST, central subfield thickness; FAS, full analysis set; IP, investigational product; PPS, per-protocol set; and SB11, ranibizumab biosimilar product. ^aOne participant was incorrectly randomized and did not receive any IP. This participant was excluded from the FAS. ^bAvailable data as of the cutoff date in May 2019. Missing participants are classified as neither discontinued nor completed the study. ^cIncluding all randomized participants except the participant who was inadvertently randomized and did not receive IP injection. ^dIncluding participants in the FAS who had received the first 2 study drug injections and completed the procedures at week 8 without any major protocol deviation that affected BCVA assessment. ^eIncluding participants in the FAS who had received the first study drug injection and completed the procedures at week 4 without any major protocol deviation that affected CST measurement.

Figure 2.. Primary Efficacy End Points: Difference of Mean Change in Best-Corrected Visual Acuity (BCVA) and Central Subfield Thickness (CST) Between SB11 and Reference Ranibizumab (RBZ)

A, Difference of mean change from baseline in BCVA at week 8 (SB11 − RBZ); whiskers represent the 90% CI that is contained within the predefined equivalence margins of −3 to 3 letters, represented by the dashed lines. There was a total of 10 people missing BCVA data (5 from SB11 and 5 from RBZ); the missing data were imputed. B, Difference of mean change from baseline in CST at week 4 (SB11 − RBZ); whiskers represent the 95% CI that is contained within the predefined equivalence margin of −36 to 36 μm, represented by the dashed lines. Inferential statistics were based on an analysis of covariance model with the baseline BCVA or CST as a covariate and region (country) and treatment as fixed factors.