Biosimilar SB11 versus reference ranibizumab in neovascular age‑related macular degeneration: 1‑year phase III randomised clinical trial outcomes
• NCT03150589 • EudraCT: 2017 000422 36 | Biosimilar SB11 versus reference ranibizumab in nAMD: 1‑year phase III randomised clinical trial outcomes | Bressler NM et al. (2023)
Bressler NM, Veith M, Hamouz J, et al. Biosimilar SB11 versus reference ranibizumab in neovascular age‑related macular degeneration: 1‑year phase III randomised clinical trial outcomes. Br J Ophthalmol 2023; 107:384–391. doi:10.1136/bjophthalmol-2021-319637
Locations
75 centres in 9 countries
Study Period
March 2018 to December 2019
Study Design
Randomised, double‑masked, parallel‑group, multicentre, 52‑week phase III clinical trial
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 (Primary Outcome):
• SB11: +6.2 letters (SE 0.5)
• RBZ: +7.0 letters (SE 0.5)
• The adjusted treatment difference between groups was −0.8 letters (90%CI, −1.8 to 0.2) letters
Changes in BCVA in the FAS at all times to week 24 were comparable between treatment groups:
• SB11: +9.8 letters (SE 0.8)
• RBZ: +10.4 letters (SE 0.7)
• Adjusted treatment difference: –0.6 letters (90% CI: –2.1 to 0.9) letters.
Vision Maintaining
Patients with <15 Letter Loss:
• SB11: 96.8%
• RBZ: 97.9%
• Adjusted difference: –1.2% (95% CI: –3.8 to 1.3)
Patients with ≥15 Letter Gain:
• SB11: 34.6%
• RBZ: 37.6%
• Adjusted difference: –3.2% (95% CI: –10.5 to 4.2)
Other
Quality of Life (QoL)
NEI VFQ- 25 Score
The mean change from baseline to week 52:
• SB11: 4.54
• RBZ: 6.47
Immunognicity
• The cumulative incidence of ADAs up to week 24 was low and similar between treatment groups (SB11, 10 of 330 [3.0%]; ranibizumab, 10 of 327 [3.1%]).
• 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
Serum concentration profiles up to week 52 were comparable between SB11 and RBZ, with levels below the 11–27 ng/mL threshold required for 50% inhibition of VEGF‑A
Anatomic
Central Retinal Lesion Thickness (CRLT)
The least-squares mean (SE) changes in CRLT from baseline at week 52:
• SB11: –161 (5.1) μm
• RBZ: –149.5 (4.9) μm
• Difference: –11.5 μm (95% CI: –23.2 to 0.1)
Central Subfield Thickness (CST)
The least-squares mean (SE) changes in CST from baseline at week 52:
• SB11: –140.0 μm (SE 4.5)
• RBZ: –125.1 μm (SE 4.3)
• Adjusted treatment difference: –14.9 μm (95% CI: –25.3 to –4.5)
Choroidal Neovascularisation (CNV)
The least-squares mean (SE) changes in NV size from baseline at week 52:
• SB11: –5.2 mm² (SE 0.3
• RBZ: –4.6 mm² (SE 0.3)
• Difference: –0.6 mm² (95% CI: –1.2 to 0.1)
Patients with active CNV leakage:
• SB11: 158 (52.1%)
• RBZ: 185 (59.1%)
• Adjusted difference: –7.4% (95% CI: –15.0 to 0.2)
Safety
TEAEs
Patients with any TEAE:
• SB11: 72% vs RBZ: 72.3%
Ocular TEAEs in the study eye:
• SB11: 32% vs RBZ: 29.7%
Ocular TEAEs in the fellow eye:
• SB11: 26.3% vs RBZ: 21.8%
Non-ocular TEAEs:
• SB11: 55.4% vs RBZ: 57.9%
Patients with any serious TEAE:
• SB11: 14.3% vs RBZ: 14.4%
Serious AEs (SAEs)
Patients with any SAE
• SB11: 14.9% vs RBZ: 14.7%
Serious ocular AE (Study Eye)
Patients with any ocular SAE:
• SB11: 2.9% vs RBZ: 2.3%
Visual acuity reduced:
• SB11: 0.6% vs RBZ: 0.3%
Endophthalmitis:
• SB11: 0.6% vs RBZ: 0
Cataract:
• SB11: 0.6% vs RBZ: 0
Iridocyclitis:
• SB11: 0.3% vs RBZ: 0
Macular oedema:
• SB11: 0.3% vs RBZ: 0.3%
Retinal haemorrhage:
• SB11: 0.3% vs RBZ: 0.3%
Retinal pigment epithelial tear:
• SB11: 0.3% vs RBZ: 0
Subretinal fluid:
• SB11: 0.3% vs RBZ: 0.3%
Uveitis:
• SB11: 0.3% vs RBZ: 0
Vitritis:
• SB11: 0.3% vs RBZ: 0
Cataract subcapsular:
• SB11: 0 vs RBZ: 0.3%
Macular degeneration:
• SB11: 0.3% vs RBZ: 0.6%
Retinal artery occlusion:
• SB11: 0.3% vs RBZ: 0.3%
Serious ocular AE (Fellow eye)
Patients with any ocular SAE:
• SB11: 0.9% vs RBZ: 0.6%
Retinal haemorrhage:
• SB11: 0.6% vs RBZ: 0
Age- related macular degeneration:
• SB11: 0.3% vs RBZ: 0
Vitreous haemorrhage:
• SB11: 0.3% vs RBZ: 0
Choroidal neovascularisation:
• SB11: 0 vs RBZ :0.3%
Retinal artery occlusion:
• SB11: 0 vs RBZ: 02.3%
Serious non-ocular AE
Patients with any non-ocular SAE:
• SB11: 11.7% vs RBZ: 11.9%
Atrial fibrillation:
• SB11: 1.1% vs RBZ: 0.8%
Cardiac failure congestive:
• SB11: 0.6% vs RBZ: 0.6%
Pancreatitis acute:
• SB11: 0% vs RBZ: 0.6%
Cystitis:
• SB11: 0% vs RBZ: 0.6%
Femoral neck fracture:
• SB11: 0.3% vs RBZ: 0.6%
Acute kidney injury:
• SB11: 0.9% vs RBZ: 0.3%
Chronic obstructive pulmonary disease:
• SB11: 0.6% vs RBZ: 0
Hypertension:
• SB11: 0.9% vs RBZ: 0
TEAEs leading to IP discontinuation
Patients with any TEAEs leading to investigation production (IP) discontinuation:
• SB11: 2.6% vs RBZ: 1.4%
Ocular TEAEs in the study eye leading to IP discontinuation:
• SB11: 2.0% vs RBZ: 1.0%
Ocular TEAEs in the fellow eye leading to IP discontinuation:
• SB11: 0 vs RBZ: 0
Non-ocular TEAEs leading to IP discontinuation:
• SB11: 0.6% vs RBZ: 0.3%
Death
• SB11: 0.6% vs RBZ: 1.1%
Conclusion
The 52‑week outcomes demonstrate that SB11 and RBZ have comparable efficacy, safety, immunogenicity, and pharmacokinetics profiles in patients with nAMD, thereby supporting the biosimilarity of SB11 to the reference ranibizumab product.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “… participants were randomized in a 1:1 ratio (randomization blocks of fixed size=4) by the Interactive Web Response System (IWRS)…” “Baseline demographic and disease characteristics appeared comparable between the treatment groups”.
Missing Outcome Data
Low risk
Note: The evidence that the result was not biased by missing outcome data (sensitivity analysis): “The PK analysis set (PKS) included participants who had at least one PK sample analyzed”
Selection of the Reported Results
Low risk Note: registration with protocol.
Deviations from Intended Observations
Low risk Note: This is a double-masked study. mITT principle was applied as the primary outcome analysis using “the full analysis set (FAS)”.
Measurement of the Outcome
Some concerns Note: this is a double-masked study. However, as an international multiple-site study, the measurement of primary outcome may be inconsistent.
Overall
Some concerns
Categories: Wet AMD