Efficacy and Safety of Biosimilar FYB201 Compared with Ranibizumab in Neovascular Age-Related Macular Degeneration
NCT02611778 | COLUMBUS-AMD | Holz FG et al. (2022)
Holz, F. G., Oleksy, P., Ricci, F., Kaiser, P. K., Kiefer, J., Schmitz-Valckenberg, S. for the COLUMBUS-AMD Study Group. Efficacy and Safety of Biosimilar FYB201 Compared with Ranibizumab in Neovascular Age-Related Macular Degeneration. Ophthalmology, 2022; 129(1):54-63.
Locations
12 countries (Austria, Czech Republic, France, Germany, Hungary, Israel, Italy, Poland, Russia, Spain, Ukraine, United Kingdom)
Study Period
Not reported
Study Design
Phase 3, multicenter, randomized, evaluation-masked, parallel-group trial
Study Population
Experimental Group
Control Group
Follow-up Time: 48 Weeks
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA)
The change from baseline to 8 weeks (Primary Outcome):
• FYB201 = +5.1 ETDRS letters
• Ranibizumab = +5.6 letters
• ANCOVA least squares mean difference = -0.4 (90% CI: -1.6 to 0.9)
The change from baseline to week 24:
• FYB201 = 6.9 ± 10.1 letters
• Ranibizumab = +7.1 ±10.4 letters
• ANCOVA least squares mean difference = -0.0 (90% CI: -1.6 to 1.5).
The change from baseline to week 48:
• FYB201 = +7.8±11.7 letters
• Ranibizumab = +8.0 ±11.7 letters
• ANCOVA least squares mean difference = -0.1 (90% CI: -1.8 to 1.7)
Other
N/A
Immunognicity
Positive for anti-drug antibodies (ADA) up to week 48:
• FYB201: 5.9%
• Ranibizumab: 5.9%
Pharmokinetics
Geometric mean concentration (geometric coefficient of variation) concentrations after the first injection:
• 2330.91 pg/ml (61.36%) in the FYB201
• 2551.51 pg/ml (61.16 %) in the reference ranibizumab group
Geometric mean concentration (geometric coefficient of variation) concentrations after the six injections:
• 2333.15 pg/ml (67.69%) in the FYB201
• 2792.75 pg/ml (58.38 %) in the reference ranibizumab group
Anatomic
Change in Foveal Center Point (FCP) Thickness
The reduction from baseline to week 24:
• FYB201 = 203.9 µm
• Ranibizumab = 205.5 µm
• ANCOVA least squares mean difference = 0.69 (90% CI: -18.22 to 19.60)µm
The reduction from baseline to week 48:
• FYB201 = 213.3 µm
• Ranibizumab = 211.0 µm
• ANCOVA least squares mean difference = 2.68 (90% CI: -16.5 to 21.9)µm
Foveal Central Subfield (FCS) Thickness
The reduction from baseline to week 24:
• YB201 = 180.4 µm
• Ranibizumab = 181.6 µm
• ANCOVA least squares mean difference = -5.91 (90% CI: -22.62 to 10.80) µm
The reduction from baseline to week 48:
• YB201 = 182.9 µm
• Ranibizumab = 190.8 µm
• ANCOVA least squares mean difference = 3.68 (90% CI: -13.3 to 20.6) µm
Fluid-free macula
Increase in the proportion of patients with fluid-free macula from baseline to week 48:
• FYB201 = 37.9%
• Ranibizumab = 43.3%
Increase in the proportion of patients with fluid-free macula from baseline to week 48:
• FYB201 = 46.7%
• Ranibizumab = 48.9%
Total lesion area
Mean (SD) total lesion area decreased from baseline to week 24:
• YB201 = -0.57 (4.79) mm2
• Ranibizumab = -0.7113 (5.36) mm2
Mean total lesion area decreased from baseline to week 48:
• YB201 = -0.64 (4.8) mm2
• Ranibizumab = -1.18 (5.43) mm2
Choroidal neovascularization (CNV) leakage
Reduction in the proportion of patients with CNV leakage from baseline to week 48:
• FYB201 = 52.0%
• Ranibizumab = 50.7%
Reduction in the proportion of patients with CNV leakage from baseline to week 48:
• FYB201 = 56.4%
• Ranibizumab = 58.7%
Safety
Treatment-emergent AEs (TEAEs)
Total patients with TEAEs up to week 48:
• FYB201: 154/238, 64.7%
• Ranibizumab: 167/239, 69.9%
The number of patients with TEAEs in study eyes up to week 48:
• FYB201: 86/238, 36.1%
• Ranibizumab: 97/239, 40.6%
The number of patients with systematic TEAEs up to week 48:
• FYB201: 123/238, 51.7%
• Ranibizumab: 147/239, 61.5%
Serious TEAEs Total patients with TEAEs up to week 48:
• FYB201: 19/238, 8.0%
• Ranibizumab: 32/239, 13.4%
The number of patients with serious TEAEs in study eyes up to week 48:
• FYB201: 2/238, 0.8%
• Ranibizumab: 3/239, 1.3%
The number of patients with serious systematic TEAEs up to week 48:
• FYB201: 17/238, 7.1%
• Ranibizumab: 29/239, 12.1%
Patients with eye disorders in ≥2%
nAMD:
• FYB201: 19/238, 8.0%
• Ranibizumab: 22/239, 9.2%
Conjunctival hemorrhage:
• FYB201: 14/238, 5.9%
• Ranibizumab: 19/239, 7.9%
Punctate keratitis:
• FYB201: 8/238, 3.4%
• Ranibizumab: 12/239, 5.0%
Visual acuity reduced:
• FYB201: 6/238, 2.5%
• Ranibizumab: 11/239, 4.6%
Eye pain:
• FYB201: 9/238, 3.8%
• Ranibizumab: 6/239, 2.5%
Cataract:
• FYB201: 1/238, 0.4%
• Ranibizumab: 11/239, 4.6%
Lacrimation increased:
• FYB201: 9/238, 3.8%
• Ranibizumab: 2/239, 0.8%
CNV:
• FYB201: 6/238, 2.5%
• Ranibizumab: 4/239, 1.7%
Conjunctival hyperemia:
• FYB201: 4/238, 1.7%
• Ranibizumab: 6/239, 2.5%
Retinal hemorrhage:
• FYB201: 7/238, 2.9%
• Ranibizumab: 3/239, 1.3%
Vitreous detachment:
• FYB201: 6/238, 2.5%
• Ranibizumab: 4/239, 1.7%
Patients with systemic AEs in ≥2%
Nasopharyngitis:
• FYB201: 12/238, 5.0%
• Ranibizumab: 16/239, 6.7%
Bronchitis:
• FYB201: 9/238, 3.8%
• Ranibizumab: 5/239, 2.1%
Upper respiratory tract infection:
• FYB201: 8/238, 3.4%
• Ranibizumab: 6/239, 2.5%
Conjunctivitis:
• FYB201: 9/238, 3.8%
• Ranibizumab: 2/239, 0.8%
Intraocular pressure increased:
• FYB201: 11/238, 4.6%
• Ranibizumab: 12/239, 5.0%
C-reactive protein increased:
• FYB201: 10/238, 4.2%
• Ranibizumab: 5/239, 2.1%
Back pain:
• FYB201: 5/238, 2.1%
• Ranibizumab: 8/239, 3.3%
Headache:
• FYB201: 4/238, 1.7%
• Ranibizumab: 9/239, 3.8%
Hypertension:
• FYB201: 3/238, 1.3%
• Ranibizumab: 14/239, 5.9%
Cough:
• FYB201: 5/238, 2.1%
• Ranibizumab: 5/239, 2.1%
Fatal TEAEs
• FYB201: 2/238, 0.8%
• Ranibizumab: 1/239, 0.4%.
TEAEs leading to withdrawal of study drug
• FYB201: 6/238, 2.5%
• Ranibizumab: 6/239, 2.5%.
Conclusion
FYB201 demonstrated clinical equivalence to reference ranibizumab regarding efficacy, safety, and immunogenicity, supporting its use as a biosimilar for nAMD treatment.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Randomization was performed using an interactive voice or web response system…” “Patient characteristics were well balanced between study arms.”
Missing Outcome Data
Low risk
Note: The evidence that the result was not biased by missing outcome data: “…a sensitivity analysis on the corresponding per-protocol sets…”
Selection of the Reported Results
Low risk Note: Registration with the protocol
Deviations from Intended Observations
Low risk Note: “…the study was evaluation-masked, with both patient and other study staff (including the investigator who performed evaluations) being masked to treatment assignment.” “The primary endpoint analysis was performed on both the US- and EU-relevant patient populations…” (ITT)
Measurement of the Outcome
Some concerns Note: “…the study was evaluation-masked…” “Measurements of BCVA were performed by certified visual acuity examiners masked to treatment and previous BCVA results.” However, this is a multiple–site clinical trial and measurement diversity may exist among various sites.
Overall
Some concerns
Categories: Wet AMD