Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial
NCT02503332 | FILLY Trial | Liao DS et al. (2020)
Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial. Ophthalmology, 2020; 127(2):186-195.
Locations
46 sites in the United States, Australia, and New Zealand
Study Period
September 2015 – July 2016
Study Design
Phase 2, randomized, double-masked, sham-controlled multicenter trial
Study Population
Experimental Group
Control Group
Follow-up Time: 18 months
Outcomes
Durability
Not reported
Vision
Best-Corrected Visual Acuity (BCVA) The Least-squares (LS) mean change in BCVA (ETDRS letters):
• Sham: -4.4 letters at Month 12; -6.4 at Month 18
• Pegcetacoplan Monthly: -3.3 letters at Month 12; -7.7 at Month 18
• Pegcetacoplan EOM: -5.8 letters at Month 12; -8.8 at Month 18
• Difference: No statistical significance The LS mean change in low-luminance BCVA (ETDRS letters):
• Sham: -0.6 letters at Month 12; -2.1 at Month 18
• Pegcetacoplan Monthly: -2.7 letters at Month 12; -4.4 at Month 18
• Pegcetacoplan EOM: -3.2 letters at Month 12; -3.7 at Month 18
• Difference: No statistical significance The LS mean change in low-luminance visual acuity deficit (ETDRS letters):
• Sham: -3.6 letters at Month 12; -4.2 at Month 18
• Pegcetacoplan Monthly: -0.8 letters at Month 12; -2.4 at Month 18
• Pegcetacoplan EOM: -2.4 letters at Month 12; -4.6 at Month 18
• Difference: No statistical significance
Other
Efficacy: Progression Outcomes GA Mean change in square root GA area at 12 months (primary outcome):
• Sham: 0.35 mm
• Pegcetacoplan Monthly: 0.25 mm
• Pegcetacoplan EOM: 0.28 mm Reduction in GA growth at 12 months vs. sham:
• Monthly pegcetacoplan: 29% (95% CI: 9% to 49%; p = 0.008)
• EOM pegcetacoplan: 20% (95% CI: 0% to 40%; p = 0.067) Mean change in square root GA area at 18 months :
• Sham: 0.49 mm
• Pegcetacoplan Monthly: 0.39 mm
• Pegcetacoplan EOM: 0.41 mm Reduction in GA growth between months 6 and 12 vs. sham:
• Monthly pegcetacoplan: 45% (95% CI: 21% to 69%; p < 0.001)
• EOM pegcetacoplan: 33% (95% CI: 9% to 58%; p = 0.009) The observed mean changes from months 12 to 18 in the three groups were comparable. None of the 47 prespecified genetic variants, including variants in CFH, CFI, C2/CFB, and C3, significantly influenced the treatment effect of pegcetacoplan,
Immunognicity
Not reported
Pharmokinetics
Not reported
Anatomic
Choroidal Neovascularization (CNV) Incidence of CNV or neovascular AMD in the study eye:
• Sham: 1/81 eyes, 1.2% (95% CI: 0 to 6.7%)
• Monthly pegcetacoplan: 18/86 eyes, 1.2% (95% CI: 12.9% to 31.0%)
• EOM pegcetacoplan: 7/79 eyes, 8.9% (95% CI: 3.6% to 17.4%)
Safety
Ocular AEs Patients with ocular treatment-emergent AEs (TEAEs) in the study eye:
• Sham: 58.0%
• Pegcetacoplan Monthly: 75.6%
• Pegcetacoplan EOM: 62.0% Patients with ocular TEAEs in the contralateral eye:
• Sham: 44.4%
• Pegcetacoplan Monthly: 36.0%
• Pegcetacoplan EOM: 22.8% Patients with treatment-related ocular AEs in the study eye:
• Sham: 0
• Pegcetacoplan Monthly: 25.6%
• Pegcetacoplan EOM: 13.9% Non-ocular AEs Patients with systemic (nonocular) TEAEs:
• Sham: 79.0%
• Pegcetacoplan Monthly: 80.2%
• Pegcetacoplan EOM: 73.4% Patients with systemic (nonocular) treatment-related AEs:
• Sham: 0
• Pegcetacoplan Monthly: 0
• Pegcetacoplan EOM: 0 Serious AEs (SAEs) Patients with ocular SAEs in the study eye:
• Sham: 1.2%
• Pegcetacoplan Monthly: 4.7%
• Pegcetacoplan EOM: 2.5%
• Most common: Endophthalmitis, increased intraocular pressure, Retinal detachment, and Dry AMD Patients with ocular SAEs in the contralateral eye:
• Sham: 1.2%
• Pegcetacoplan Monthly: 0
• Pegcetacoplan EOM: 0 Patients with non-ocular SAEs:
• Sham: 28.4%
• Pegcetacoplan Monthly: 22.1%
• Pegcetacoplan EOM: 30.4% Study Discontinuation
• Sham: 4 due to AEs
• Pegcetacoplan Monthly: 17 due to AEs
• Pegcetacoplan EOM: 5 due to AEs Death
• Sham: 2 unrelated to treatment
• Pegcetacoplan Monthly: 0
• Pegcetacoplan EOM: 2 unrelated to treatment
Conclusion
Pegcetacoplan significantly reduced GA lesion growth compared to sham treatment. However, an increased risk of exudative AMD and endophthalmitis was observed in the treated groups. Phase 3 trials will further define the safety and efficacy profile of pegcetacoplan.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Randomization was performed using a web-based system, and the randomization schedule was blocked to ensure balanced treatment allocations within sites.”
Missing Outcome Data
Low risk
Note: the evidence of the primary outcome analysis was not biased by the missingness (sensitivity analysis): “The robustness of the primary efficacy results was supported by multiple sensitivity analyses…”
Selection of the Reported Results
Low risk Registration with protocol
Deviations from Intended Observations
Low risk Note: “Patients, study personnel responsible for performing imaging and visual acuity assessments, and reading center personnel were masked to treatment assignment.” “All efficacy analyses were performed on the modified intention-to-treat population, defined as all patients who received at least 1 injection and had undergone at least 1 examination at month 2 or later at which primary efficacy data were collected (Fig 1).”
Measurement of the Outcome
Low risk Note: “Patients, study personnel responsible for performing imaging and visual acuity assessments, and reading center personnel were masked to treatment assignment.” “Images were assessed by the central reading center.”
Overall
Low risk
Categories: Dry AMD Geographic Atrophy