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
NCT03150589 | Not reported | Woo SJ et al. (2021)
Woo, S. J., Veith, M., Hamouz, J., Ernest, J., Zalewski, D., Studnička, J., Vajas, A., Papp, A., Gabor, V., Luu, J., Matuskova, V., Yoon, Y. H., Pregun, T., Kim, T., Shin, D., Bressler, N. M. 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. JAMA Ophthalmol, 2021; 139(1):68-76.
Locations
75 centers in 9 countries
Study Period
March 14, 2018 – December 9, 2019
Study Design
Phase 3, randomized, double-masked, parallel-group, equivalence study
Study Population
Experimental Group
Control Group
Follow-up Time: 52 weeks
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA)
The least-squares mean (SE) changes in BCVA from baseline at week 8:
• SB11 = +6.2 letters (SE 0.5)
• Ranibizumab = +7.0 letters (SE 0.5)
• Adjusted treatment difference = -0.8 letters (90% CI: -1.8 to 0.2)
The least-squares mean (SE) changes in BCVA from baseline at week 24:
• SB11 = +8.6 letters (SE 0.7)
• Ranibizumab = +9.3 letters (SE 0.6)
• Adjusted treatment difference = -0.8 letters (90% CI: -2.0 to 0.5)
Vision Maintaining
Participants who lost <15 letters in BCVA at week 24 compared with baseline:
• SB11 = 327 (97.9%)
• Ranibizumab = 336 (99.4%)
• Adjusted difference = -1.5% (95%CI: -3.3% to 0.2%)
Participants who lost ≥15 letters in BCVA at week 24 compared with baseline:
• SB11 = 86 (25.7%)
• Ranibizumab = 92 (27.2%)
• Adjusted difference = -1.7 (-8.3% to 5.0%)
Other
N/A
Immunognicity
Cumulative incidence of antidrug antibodies (ADAs) at week 24:
• SB11 = 3.0% (10/330)
• Ranibizumab = 3.1% (10/327)
A minority of ADA-positive participants had neutralizing antibodies.
The incidence of ADAs and neutralizing antibodies by visit to week 24 was similar between treatment groups.
Pharmokinetics
Only 3 participants in the PK analysis set were ADA positive, preventing an assessment of the effect of immunogenicity on PK.
Anatomic
Central Subfield Thickness (CST)
The least-squares mean (SE) changes in CST from baseline to week 4:
• SB11 = -108 µm (SE 5)
• Ranibizumab = -100 µm (SE 5)
• Adjusted treatment difference = -8 µm (95% CI: -19 to 3)
The least-squares mean (SE) changes in CST from baseline to week 24:
• SB11 = -136 µm (SE 4)
• Ranibizumab = -126 µm (SE 4)
• Adjusted treatment difference = -10 µm (95% CI: -19 to 0)
Choroidal Neovascularization (CNV)
The least-squares mean (SE) changes in CNV size from baseline to week 24:
• SB11 = -4 (0) mm2
• Ranibizumab = = -4 (0) mm2
• Adjusted treatment difference = 0 (95% CI: -1 to 1) mm2
Participants with active CNV leakage at week 24:
• SB11 = 211(64.7%)
• Ranibizumab = 218 (66.3%)
• Adjusted difference = -1.7% (95%CI: -8.9% to 5.5%)
Central Retinal Lesion Thickness (CRLT)
The least-squares mean (SE) changes in CRLT from baseline to week 24:
• SB11 = -148 µm (SE 5)
• Ranibizumab = -139 µm (SE 5)
• Adjusted treatment difference = -10 µm (95% CI: -21 to 2)
Safety
Treatment-emergent AEs (TEAEs)
Any TEAE:
• SB11: 231/350 (66.0%)
• Ranibizumab: 237/354 (66.9%)
Ocular TEAEs in the study eye:
• SB11: 97/350 (27.7%)
• Ranibizumab: 91/354 (25.7%)
Ocular TEAEs in the fellow eye: 69 (19.7) 61 (17.2) 130 (18.5)
• SB11: 69/350 (19.7%)
• Ranibizumab: 61/354 (17.2%)
Nonocular TEAEs:
• SB11: 178/350 (50.9%)
• Ranibizumab: 191/354 (54.0%)
Mild TEAEs:
• SB11: 109/350 (31.1%)
• Ranibizumab: 119/354 (33.6%)
Moderate TEAEs:
• SB11: 95/350 (27.1%)
• Ranibizumab: 97/354 (27.4%)
Severe TEAEs:
• SB11: 27/350 (7.7%)
• Ranibizumab: 21/354 (5.9%)
Related TEAEs:
• SB11: 21/350 (6.0%)
• Ranibizumab: 10/354 (2.8%)
Not related TEAEs:
• SB11: 210/350 (60.0%)
• Ranibizumab: 227/354 (64.1%)
Serious TEAEs Total:
• SB11: 44/350 (12.6%)
• Ranibizumab: 44/354 (12.4%)
Serious Ocular AE (Study Eye)
Any ocular SAE in the study eye:
• SB11: 9/350 (2.6%)
• Ranibizumab: 7/354 (2.0%)
Visual acuity reduced:
• SB11: 2/350 (0.6%)
• Ranibizumab: 1/354 (0.3%)
Endophthalmitis 2 (0.6) 0 2 (0.3)
• SB11: 2/350 (0.6%)
• Ranibizumab: 0
Cataract:
• SB11: 1/350 (0.3%)
• Ranibizumab: 0
Iridocyclitis:
• SB11: 1/350 (0.3%)
• Ranibizumab: 0
Macular edema:
• SB11: 1/350 (0.3%)
• Ranibizumab: 1/354 (0.3%)
Retinal hemorrhage:
• SB11: 1/350 (0.3%)
• Ranibizumab: 1/354 (0.3%)
Retinal pigment epithelial tear:
• SB11: 1/350 (0.3%)
• Ranibizumab:0
Subretinal fluid:
• SB11: 1/350 (0.3%)
• Ranibizumab: 0
Vitritis:
• SB11: 1/350 (0.3%)
• Ranibizumab: 0
Cataract subcapsular:
• SB11: 0
• Ranibizumab: 1/354 (0.3%)
Macular degeneration:
• SB11: 0
• Ranibizumab: 2/354 (0.6%)
Serious Ocular AE (Fellow Eye)
Any ocular SAE in the fellow eye:
• SB11: 3/350 (0.9%)
• Ranibizumab: 1/354 (0.3%)
Retinal hemorrhage:
• SB11: 2/350 (0.6%)
• Ranibizumab: 0
Visual acuity reduced:
• SB11: 1/350 (0.3%)
• Ranibizumab: 0
Vitreous hemorrhage:
• SB11: 1/350 (0.3%)
• Ranibizumab: 0
Retinal artery occlusion 0 1 (0.3) 1 (0.1)
• SB11: 0
• Ranibizumab: 1/354 (0.3%)
Serious Nonocular AE (≥0.5%)
Any nonocular SAE:
• SB11: 35/350 (10.0%)
• Ranibizumab: 37/354 (10.5%)
Atrial fibrillation:
• SB11: 3/350 (0.9%)
• Ranibizumab: 3/354 (0.8%)
Cardiac failure, congestive:
• SB11: 2/350 (0.6%)
• Ranibizumab: 2/354 (0.6%)
Acute kidney injury:
• SB11: 2/350 (0.6%)
• Ranibizumab: 1/354 (0.3%)
Chronic obstructive pulmonary disease:
• SB11: 2/350 (0.6%)
• Ranibizumab: 0
TEAEs leading to drug discontinuation Any TEAEs leading to investigation production (IP) discontinuation:
• SB11: 8/350 (2.3%)
• Ranibizumab: 5/354 (1.4%)
Ocular TEAEs leading to IP discontinuation in the study eye:
• SB11: 6/350 (1.7%)
• Ranibizumab: 4/354 (1.1%)
Nonocular TEAEs leading to IP discontinuation:
• SB11: 2/350 (0.6%)
• Ranibizumab: 1/354 (0.3%)
Death
• SB11: 1/350 (0.3%)
• Ranibizumab: 4/354 (1.1%)
Conclusion
SB11 demonstrated equivalent efficacy and similar safety, and immunogenicity profiles compared with ranibizumab, supporting its use as a biosimilar for patients with neovascular AMD.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “a randomization list produced by a validated, interactive web recognition system.” “Baseline demographic and disease characteristics were similar between treatment groups.”
Missing Outcome Data
Low risk
Note: The evidence that the result was not biased by missing outcome data: Per protocol analysis was performed as sensitivity analysis.
Selection of the Reported Results
Low risk Note: have registration with protocol.
Deviations from Intended Observations
Low risk Note: this is a double-masked study. “The full analysis set (FAS) included all randomized participants, excluding 1 inadvertently randomized participant who did not receive the study drug.”
Measurement of the Outcome
Some concerns Note: This is double masked study. However, this is a multiple-site study. The measurement of the primary outcome may be different among different sites.
Overall
Some concerns
Categories: Wet AMD