Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration
NCT03805100 (ClinicalTrials.gov), EudraCT (2018-002930-19) | XPLORE Trial | Loewenstein A et al. (2023)
Loewenstein A, Czumbel N, Ernest J, Dusová J, Pearlman J, Nowosielska A. Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration. Ophthalmology Retina, 2023; 7:753-761.
Locations
15 countries across the USA, Europe, the Middle East, and the Asia-Pacific region
Study Period
April 2019 – November 2021
Study Design
Phase 3, randomized, double-masked, parallel-group, multicenter biosimilarity 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 (LS) mean change in BCVA from baseline at Week 8 (Primary Outcome)
• XSB-001: +4.6 (SE 0.5) ETDRS letters
• Reference ranibizumab: +6.4 (SE 0.5) ETDRS letters
• Difference: -1.8 (95% CI -3.1 to -0.5); Within equivalence margin
The mean change in BCVA from baseline at Week 24:
• XSB-001: +5.8 (SE 0.6)
• Reference ranibizumab : +8.1 (SE 0.6)
• Difference: -1.5 (95% CI : -3.9 to -0.6)
The mean change in BCVA from baseline at Week 52:
• XSB-001: +6.4 (SE 0.8)
• Reference ranibizumab: +7.8 (SE 0.8)
• Difference: -1.5 (95% CI -3.6 to 0.7)
Vision Maintaining
Proportion of patients losing <15 ETDRS letters from baseline at Week 52:
• XSB-001: 94.8%
• Reference ranibizumab: 96.0%
• Difference: -1.0% (95% CI -5.9 to 3.9).
Other
N/A
Immunognicity
The incidence of ADAs was similar between the two groups:
• Baseline: XSB-001: 4.2% vs. Reference ranibizumab: 2.9%
• At Week 52: XSB-001: 11.3% vs. Reference ranibizumab: 13.1%
Pharmokinetics
Plasma ranibizumab mean (coefficient of variation) levels were similar between groups:
• XSB-001: 2230 pg/ml (64.0%) at Day one and 2450 pg/ml (56.5%) at Week 20
• Reference ranibizumab: 2190 pg/ml (61.2%) at Day one and 2150 (57.4%) at Week 20
Anatomic
Central Foveal Thickness (CFT)
The LS mean change in CFT from baseline to Week 52:
• XSB-001: -117.4 µm (SE 4.0)
• Reference ranibizumab: -115.1 µm (SE 4.1)
• Difference: -2.3 µm (95% CI -12.3 to 7.7).
Choroidal Neovascularization (CNV)
The LS mean change in CNV leakage area from baseline to Week 52:
• XSB-001: -4.1 mm²
• Reference ranibizumab: -3.7 mm²
• Difference: -0.4 mm² (95% CI -1.0 to 0.2)
The LS mean change in CNV size area from baseline to Week 52:
• XSB-001: -1.6 mm²
• Reference ranibizumab: -1.1 mm²
• Difference: -0.5 mm² (95% CI -1.2 to 0.2)
Retinal Fluid
The treatment difference in the percentage of patients without intraretinal or subretinal fluid for XSB-001versus reference ranibizumab:
• At week 24: 3.4% (95% CI: -5.0 to 11.8)
• At week 52: 5.4% (95% CI :-3.6 to 14.4)
Safety
Treatment-emergent AEs (TEAEs)
Patients with any TEAE:
• XSB-001: 67.5%
• Reference ranibizumab: 70.6%.
Ocular TEAEs
Patients with any ocular TEAE:
• XSB-001: 36%
• Reference ranibizumab: 36%
• Most common: conjunctival hemorrhage (5.1% vs. 5.5%).
Patients with ocular TEAE related to study treatment:
• XSB-001: 22 (7.5%)
• Reference ranibizumab: 28 (9.7%)
Patients with ocular TEAEs by severity:
• Mild: 78 (26.7%) for XSB-001 vs. 72 (24.9%) for Reference ranibizumab
• Moderate: 23 (7.9%) for XSB-001 vs. 26 (9.0%) for Reference ranibizumab
• Severe: 4 (1.4) for XSB-001 vs. 6 (2.1%) for Reference ranibizumab
Non-ocular TEAEs
The incidence of nonocular TEAEs:
• XSB-001: 45.9%
• Reference ranibizumab: 52.9%
Hypertension (most common non-ocular TEAE)
• XSB-001: 3.4%
• Reference ranibizumab: 5.9%
Coronavirus disease (most common non-ocular TEAE)
• XSB-001: 3.8%
• Reference ranibizumab: 2.8%
Serious ocular TEAEs
Patients with any Serious ocular TEAE:
• XSB-001: 1.4%
• Reference ranibizumab: 1.4%
• Includes: retinal pigment epithelial tear, retinal hemorrhage, endophthalmitis, and visual acuity reduced.
Patients with any serious non-ocular TEAE:
• XSB-001: 9.6%
• Reference ranibizumab: 10.7%
Study discontinuation
Patients with ocular TEAEs leading to study treatment discontinuation:
• XSB-001: 1 (0.3%)
• Reference ranibizumab: 2 (0.7%)
Patients with ocular TEAEs leading to study treatment discontinuation:
• XSB-001: 2 (0.7%)
• Reference ranibizumab: 5 (1.7%)
Death
• XSB-001: 8
• Reference ranibizumab: 3
• None of the deaths were considered related to study treatment.
Conclusion
XSB-001 demonstrated biosimilarity to reference ranibizumab in efficacy, safety, pharmacokinetics, and immunogenicity. Treatment for 52 weeks was well tolerated, with no clinically meaningful differences between groups.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Randomization was performed using an interactive web response system…”
“Patient characteristics were generally similar between the treatment groups (Table 1)”
Missing Outcome Data
Low risk
Note: the evidence that the primary outcome was not biased by missingness: “Sensitivity analyses were performed to assess the impact of missing data assumptions.”
Selection of the Reported Results
Low risk Note: registration with the protocol.
Deviations from Intended Observations
Low risk Note: This is a double -masked study. “The full analysis set, which included all randomized patients, was used for all efficacy analyses.”- ITT principle was applied.
Measurement of the Outcome
Some concerns Note: This is a double -masked study. However, this is an multiple-site study, the BCVA assessment may exist diversity among different sites.
Overall
Some concerns
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