Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial
NCT04435366 | GATHER2 Trial | Khanani AM et al. (2023)
Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet, 2023; 402:1449-1458.
Locations
205 sites across the USA, Europe, and other global locations
Study Period
June 22, 2020 – July 23, 2021
Study Design
Phase 3, multicenter, randomized, double-masked, sham-controlled trial
Study Population
Experimental Group
Control Group
Follow-up Time: 24 months
Outcomes
Durability
Not reported.
Vision
Best-Corrected Visual Acuity (BCVA)
The mean change in BCVA (ETDRS letters) from baseline at Month 12:
• Avacincaptad pegol: +1.34 (SE 1.48)
• Sham: +0.96 (SE 1.51)
• Difference: +0.38 letters (95% CI -1.5 to 2.2); p= 0.68
The mean change in low-luminance BCVA (ETDRS letters) from baseline at Month 12:
• Avacincaptad pegol: -4.35 (SE 2.30)
• Sham: -2.29 (SE 2.36)
• Difference: -2.06 letters (95% CI -5.5 to 1.4); p= 0.15.
Vision Maintaining
Risk proportion of patients with the observed loss of 15 or more ETDRS letters from baseline to Month 12:
• Avacincaptad pegol: 3.1% (95% CI 1.6–6.9)
• Sham: 7.7% (95% CI 5.0–12.6)
• HR: 0.41; p-value: 0.042.
Other
Efficacy: Progression Outcomes GA Lesion
The mean rate of square root-transformed GA area growth at 12 months (Primary Outcome):
• Avacincaptad pegol: 0.336 mm/year (SE 0.032)
• Sham: 0.392 mm/year (SE 0.033)
• Difference: -0.056 mm/year (95% CI -0.096 to -0.016); p=0.0064
The mean rate of observed GA area growth at 12 months (Primary Outcome):
• Avacincaptad pegol: 1.745 mm²/year (SE 0.202)
• Sham: 2.121 mm²/year (SE 0.207)
• Difference: -0.376 mm²/year (95% CI -0.122 to -0.631); p=0.0039
Immunognicity
Not reported.
Pharmokinetics
Not reported.
Anatomic
Not reported.
Safety
Non-ocular Treatment-Emergent Adverse Events (TEAEs)
Patients with any non-ocular TEAE:
• Avacincaptad pegol: 125 (56%)
• Sham: 127 (57%)
Patients with any non-ocular TEAE related to injection procedure:
• Avacincaptad pegol: 2 (<1%)
• Sham: 7 (<1%)
Patients with any non-ocular TEAE related to study drug:
• Avacincaptad pegol: 0
• Sham: 0
Patients with any severe non-ocular TEAE:
• Avacincaptad pegol: 31 (14%)
• Sham: 25 (11%)
Ocular TEAEs
Patients with any ocular TEAE:
• Avacincaptad pegol: 110 (49%) for study eye; 50 (22%) for fellow eye
• Sham: 83 (37%) for study eye; 42 (19%) for fellow eye
• Most common events: increased intraocular pressure; macular neovascularisation;
Patients with any severe ocular TEAE:
• Avacincaptad pegol: 5 (2%)
• Sham: 1 (<1%)
Patients with any non-ocular TEAE (study eye) related to injection procedure:
• Avacincaptad pegol: 63(28%)
• Sham: 43 (19%)
Patients with any non-ocular TEAE (study eye) related to treatment:
• Avacincaptad pegol: 4 (2%)
• Sham: 2 (<1%)
Serious TEAEs
Patients with any serious non-ocular TEAE:
• Avacincaptad pegol: 29 (13%)
• Sham: 35 (16%)
Patients with any serious ocular TEAE:
• Avacincaptad pegol: 2 (<1%) for study eye; 0 for fellow eye
• Sham: 2 (<1%) for study eye; 0 for fellow eye
Study Discontinuation
Patients with any non-ocular TEAE (study eye) leading to study drug discontinuation:
• Avacincaptad pegol: 4 (2%)
• Sham: 2 (<1%)
Patients with any ocular TEAE leading to study drug discontinuation:
• Avacincaptad pegol: 2 (<1%)
• Sham: 0
Death
• Avacincaptad pegol: 2
• Sham: 1
• None of the death was determined by the investigator to be related to injection procedure or the study drug
Conclusion
Monthly avacincaptad pegol 2 mg significantly slowed GA lesion growth over 12 months compared to sham, with a 14% reduction in the primary endpoint. The drug was well tolerated, though an increased risk of macular neovascularization was observed in the treatment group.
Risk of Bias Assessment for Primary Outcome
Randomization Process
Low risk
Note: “Randomisation was performed by an independent vendor using an interactive response technology system…”; “Masking remained from the time of randomisation until the database lock at month 12…”
“Demographics were well balanced between the two treatment groups…”
Missing Outcome Data
Low risk
Note: The evidence of the primary outcome was not biased by missingness (sensitivity analysis): “This analysis provided valid estimates if the missing data mechanism fulfilled the missing-at-random assumption; moreover, sensitivity analyses were performed to assess the potential magnitude and direction of the impact of missing data.”
Selection of the Reported Results
Low risk Note: Protocol attached to the paper.
Deviations from Intended Observations
Low risk Note: This is a double-masked study. ITT was applied for the data analysis.
Measurement of the Outcome
Low risk Note: “All others, patients, investigators, assessors, and sponsor roles involved in the conduct of the ongoing study remained masked.” “An independent and masked reading centre (the Duke Reading Centre, Durham, NC, USA) assessed all ocular images.…”
Overall
Low risk
Categories: Dry AMD Geographic Atrophy