Efficacy and safety of the aflibercept biosimilar SB15 in neovascular age-related macular degeneration: A Phase 3 randomized clinical trial
NCT04450329 | Not applicable | Woo SJ et al. (2023)
Woo SJ, Bradvica M, Vajas A, et al. Efficacy and safety of the aflibercept biosimilar SB15 in neovascular age-related macular degeneration: A Phase 3 randomized clinical trial. JAMA Ophthalmology, 2023; 141(7):668-676.
Locations
56 sites in 10 countries across North America, Europe, and Asia
Study Period
June 2020 – March 2022
Study Design
Phase 3, randomized, double-masked, parallel-group, multicenter biosimilarity trial
Study Population
Experimental Group
Control Group
Follow-up Time: 56 weeks
Outcomes
Durability
Vision
Best-Corrected Visual Acuity (BCVA)
The least squares (LS) mean change in BCVA from baseline at Week 8 (Primary Outcome):
• SB15: +6.7 letters (SE 0.56)
• ALF: +6.6 letters (SE 0.57)
• Difference: 0.1 letters (95% CI -1.3 to 1.4); Within equivalence margin
The LS mean change in BCVA from baseline at Week 32:
• SB15: +7.6 letters (SE 0.8)
• ALF: +6.5 letters (SE 0.8)
• Difference: 1.1 letters (95% CI -0.9 to 3.1)
Vision Maintaining
Proportion of patients gaining <15 ETDRS letters at Week 32:
• SB15: 214/219 (97.7%)
• ALF: 208/ 215 (96.7%)
• Adjusted risk difference: 1.0 (95% CI: -2.0 to 4.1)
Proportion of patients gaining ≥15 ETDRS letters at Week 32:
• SB15: 48/219 (21.9%)
• ALF: 40/215 (18.6%)
• Adjusted risk difference: 3.3 (95% CI: -4.23 to 10.8)
Other
Vision related Quality of Life (QoL) NEI VFQ-25 Composite Score The mean change in NEI VFQ-25 composite score from baseline at week 32:
• SB15: 3.1(SD 10.4)
• ALF: 2.8 (SD 11.2)
Immunognicity
Pre-existing ADAs
• Baseline: SB15: 1.3% vs. Reference aflibercept: 0.4%
• At Week 32: SB15: 1.0% vs. Reference aflibercept: 0.0%.
Pharmokinetics
Plasma drug levels were similar between groups; no meaningful differences in systemic exposure.
Anatomic
Central Subfield Thickness (CST)
The LS mean change in CST from baseline at Week 4:
• SB15 : -101.8 µm (SE 4.3)
• ALF: -112.9µm (SE 4.3)
• Difference : 11.1 (95% CI: 0.4 to 21.9)
The LS mean change in CST from baseline at Week 32:
• SB15 : -110.4 µm (SE 4.7)
• ALF: -115.7 µm (SE 4.9)
• Difference : 5.4 (95% CI: -6.7 to 17.4)
Total Retinal Thickness (TRT)
The LS mean change in TRT from baseline at Week 4:
• SB15: -128.2 μm (SE 5.4)
• ALF: -132.9 μm (SE 5.5)
• Difference : 4.6 (95% CI: -9.0 to 18.3)
The LS mean change in TRT from baseline at Week 32:
• SB15: -127.7 μm (SE 7.4)
• ALF: -131.9 μm (SE 7.6)
• Difference : 4.3 (95% CI: -14.4 to 22.9)
Retinal Fluid
Participants with intraretinal or subretinal fluid at Week 32:
• SB15: 128/219 (58.4%)
• ALF: 118/214 (55.1%)
• Adjusted risk difference: 3.2 (95% CI: -6.0 to 12.5)
Participants with subretinal pigment epithelium fluid at Week 32:
• SB15: 68/219 (31.1%)
• ALF: 64/214 (29.9%)
Choroidal Neovascularization (CNV)
Participants with active CNV leakage at Week 32:
• SB15: 187/212 (88.2%)
• ALF: 192/210 (91.4%)
• Adjusted risk difference: -3.5 (95% CI: -9.0 to 2.1)
The LS mean change in CNV area from baseline at Week 32:
• SB15: -1.0 mm² (SE 0.2)
• ALF: -0.4 mm² (SE 0.2)
• Difference: -0.6 mm² (95% CI -1.2 to -0.04)
Safety
Ocular TEAEs (study eye)
Ocular TEAEs by preferred term (SB15 vs. ALF):
• Visual acuity reduced: 8 (3.6%) vs. 5 (2.2%)
• Conjunctival hemorrhage: 9 (4.0%) vs. 3 (1.3%)
• Conjunctivitis: 2 (0.9%) vs. 3 (1.3%)
• Disease progression: 2 (0.9%) vs. 3 (1.3%)
• Neovascular age-related macular degeneration: 2 (0.9%) vs. 3 (1.3%)
• Retinal hemorrhage: 3 (1.3%) vs. 1 (0.4%)
• Cataracte: 0 vs. 4 (1.8%)
• Eye pain: 3 (1.3) vs. 0
• Posterior capsule opacification: 3 (1.3) vs. 0
Drug-related ocular TEAEs (SB15 vs. ALF): 3 (1.3%) vs. 1 (0.4%)
• Conjunctival hemorrhage: 1 (0.4%) vs. 0
• Macular hole: 1 (0.4%) vs. 0
• Retinal pigment epithelial tear: 1 (0.4%) vs. 0
• Iridocyclitis: 0 vs. 1 (0.4%)
Ocular TEAEs of special interest (SB15 vs. ALF): 3 (1.3%) vs 1 (0.4%)
• Intraocular inflammation: 0 vs. 1 (0.4%)
• Iridocyclitis: 0 vs. 1 (0.4%)
• Retinal pigment epithelial tear: 1 (0.4%) vs. 0
• Subretinal hemorrhage: 2 (0.9%) vs. 0
Nonocular TEAEs
Patients with any nonocular TEAEs (SB15 vs. ALF): 73 (32.6%) vs. 67 (29.9%)
Drug-related nonocular TEAEs (SB15 vs. ALF): 0 vs. 1 (0.4%)
• Ischemic stroke: 0 vs. 1 (0.4%)
Nonocular TEAEs of special interest (SB15 vs. ALF): 7 (3.1%) vs. 3 (1.3)
• Arterial thromboembolic events: 4 (1.8%) vs. 2 (0.9%)
• Nonocular hemorrhage: 3 (1.3%) vs. 1 (0.4%)
Serious TEAEs
Serious ocular TEAEs in the study eye (SB15 vs. ALF): 3 (1.3%) vs. 1 (0.4%)
• Device placement issue: 0 vs. 1 (0.4%)
• Disease progression: 1 (0.4%) vs. 0
• Retinal hemorrhage: 1 (0.4%) vs. 0
• Retinal vascular disorder: 1 (0.4%) vs. 0
Serious nonocular TEAEs (SB15 vs. ALF): 8 (3.6%) vs. 14 (6.3%)
Study Discontinuation
Chronic myelomonocytic leukemia:
• SB15: 0
• ALF: 1 (0.4%)
Death
Due to circulatory collapse:
• SB15: 0
• ALF: 1
Conclusion
SB15 demonstrated equivalent efficacy, safety, and pharmacokinetics compared to reference aflibercept for nAMD. The study confirmed biosimilarity with no clinically meaningful differences.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Some concerns
Note: No information on the method of randomization. However, the two groups were comparable at the baseline.
Missing Outcome Data
Low risk
Note: the evidence of the first primary outcome analysis was not biased by the missingness: “For primary end point analysis, missing data were imputed using multiple imputation under the missing-at-random assumption.” In addition, sensitivity analysis was conducted using per-protocol set data.
Selection of the Reported Results
Low risk Note: protocol was attached.
Deviations from Intended Observations
Low risk Note: this is double-masked study. “All analyses of efficacy end points were performed on the full analysis set.”
Measurement of the Outcome
Some concerns Note: “Participants, investigators, and site personnel remained masked throughout the study period.” Note: This was a multiple-site study. For the BCVA assessment, there may exist diversity between the different sites.
Overall
Some concerns
Categories: Wet AMD