Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial

NCT02686658 | GATHER1 Trial | Patel SS et al. (2023)

Patel SS, Lally DR, Hsu J, Wykoff CC, Eichenbaum D, Heier JS, Jaffe GJ, Westby K, Desai D, Zhu L, Khanani AM. Avacincaptad pegol for geographic atrophy secondary to age-related macular degeneration: 18-month findings from the GATHER1 trial. Eye, 2023; 37:3551–3557.

Locations

63 sites across the United States, Europe, and Israel

Study Period

January 2016 - October 2018

Study Design

Phase 2/3, multicenter, randomized, double-masked, sham-controlled trial

Study Population

Characteristic:

Type of AMD:

1 (Dry AMD)

AMD Stage:

3 (Late)

Total Sample Size:

286 patients (77 eyes for part 1 of the study;

Age:

Phase 2/3, multicenter, randomized, double-masked, sham-controlled trial

Sex (Male) n%:

Not explicitly reported

Experimental Group

Intervention Therapy:

Not explicitly reported

Dose & Frequency:

Intravitreal avacincaptad pegol (ACP) 2 mg or 4 mg monthly

Age (Years):

2 mg group: 67; 4 mg group: 83

Number of Patients:

18 months

Male N %:

• ACP 2 mg group: 78.8 • ACP 4 mg group: 79.2

Patients Followed Up:

• ACP 2 mg group: 22 (32.8%) • ACP 4 mg group: 25 (30.1%)

Control Group

Intervention Therapy:

Sham injection

Dose & Frequency:

Sham injection every 4 weeks for 18 months

Age (Years):

78.2

Number of Patients:

• 110 (2 mg sham) • 84 (4 mg sham)

Male N %:

• ACP 2 mg: 31 (28.2%) • ACP 4 mg: 23 (27.4%)

Patients Followed Up:

Sham group: 78 (70.9%) (2 mg sham), 64 (76.2%) (4 mg sham)

Follow-up Time: 18 months

Outcomes

Durability

Not reported.

Vision

Best-Corrected Visual Acuity (BCVA) The mean change in BCVA (ETDRS letters) from baseline to Month 18:
• ACP 2 mg: -12.7 (SE 4.29) vs. Sham 2 mg: -15.1 (SE 4.12); Difference: 2.37 letters
• ACP 4 mg: -4.27 (SE 4.24) vs. Sham 4 mg: -7.07 (SE 4.06); Difference: 2.80 letters.

The mean change in LL-BCVA (ETDRS letters) from baseline to Month 18:
• ACP 2 mg: -2.72 (SE 4.29) vs. Sham 2 mg: -3.10 (SE 4.03); Difference: 0.37 letters.
• ACP 4 mg: 2.85 (SE 3.86) vs. Sham 4 mg: 1.68 (SE 3.70); Difference: 1.17 letters.

Other

Efficacy: Progression Outcomes
GA Lesion (Primary Outcomes)
The mean change in GA lesion area in square root transformation at Month 6:
• ACP 2 mg vs Sham: 0.054mm (95% CI: 0.006 to 0.103); Difference: 30.7%.
• ACP 4 mg vs Sham: 0.053mm (95% CI [0.007, 0.100]); Difference: 26.9%

The mean change in GA lesion area in square root transformation at Month 12:
• ACP 2 mg vs Sham: 0.097mm (95% CI: 0.017 to 0.177); Difference: 25.3%.
• ACP 4 mg vs Sham: 0.117mm (95% CI [0.033, 0.202]); Difference: 28.0%

The mean change in GA lesion area in square root transformation at Month 18:
• ACP 2 mg vs Sham: 0.168 mm (95% CI: 0.066 to 0.271); Difference: 28.1%.
• ACP 4 mg vs Sham: 0.167 mm (95% CI [0.062, 0.273]); difference: 30.0%.

The GA lesion growth reduction (absolute values) at Month 18:
• ACP 2 mg group: -1.156 mm² (95% CI [0.480, 1.833])
• ACP 4 mg group: -1.029 mm² (95% CI [0.345, 1.708])

Macular Neovascularization Conversion
Macular neovascularization conversion at Month 18:
• ACP 2 mg: 11.9%
• ACP 4 mg: 15.7%
• Sham: 2.7%

Immunognicity

Not reported.

Pharmokinetics

Not reported.

Anatomic

Not reported.

Safety

Ocular Treatment-emergent AEs (TEAEs)
Patients with any ocular TEAE (study eye):
• ACP 2 mg: 39 (58.2%)
• ACP 4 mg: 61 (73.5%)
• Sham: 45 (40.9%)

Patients with any ocular TEAE (fellow eye):
• ACP 2 mg: 15 (22.4%)
• ACP 4 mg: 24 (28.9%)
• Sham: 25 (22.7%)

Patients with study drug-related ocular TEAEs (study eye):
• ACP 2 mg: 0
• ACP 4 mg: 0
• Sham: 0
Systemic TEAEs Patients with systemic TEAEs:
• ACP 2 mg: 41 (61.2%)
• ACP 4 mg: 53 (63.9%)
• Sham: 66 (60.0%)

Patients with study drug-related systemic TEAEs
• ACP 2 mg: 0
• ACP 4 mg: 0
• Sham: 0

Serious TEAEs
Patients with ocular SAEs (study eye):
• ACP 2 mg: 1 (1.5%, optic ischemic neuropathy)
• ACP 4 mg: 1 (1.2%, retinal detachment)
• Sham: 0

Patients with ocular SAEs (fellow eye)
• ACP 2 mg: 0
• ACP 4 mg: 0
• Sham: 0

Patients with systemic SAEs:
• ACP 2 mg: 11 (16.4%)
• ACP 4 mg: 20 (24.1%)
• Sham: 28 (25.5%)

Patients with study drug-related systemic SAEs:
• ACP 2 mg: 0
• ACP 4 mg: 0
• Sham: 0

Study Discontinuation
Discontinuation from trial related to study drug:
• ACP 2 mg: 0
• ACP 4 mg: 0
• Sham: 0

Outcomes

Conclusion

Avacincaptad pegol significantly slowed GA lesion growth over 18 months. The drug was well tolerated but showed a higher incidence of macular neovascularization.

Risk of Bias Assessment for Primary Outcome

Randomization Process

Some concerns

Note: No information on randomization method. However, the two groups were comparable at the baseline.

Missing Outcome Data

Low risk

Note: The evidence that the primary outcome was not biased by the missingness: “The primary efficacy analysis and 18-month analysis used the mixed-model with repeated measures (MMRM) analysis to compare the treatment arms, which uses all observed data with the assumption of data missing at random.”

Selection of the Reported Results

Low risk Registration with protocol

Deviations from Intended Observations

Low risk Note: this is a double-masked study. “All efficacy analyses were conducted for the intent-to-treat (ITT) population…”

Measurement of the Outcome

Low risk Note: “Participants, investigators, independent reading center personnel (Duke Reading Center, Duke University, Durham, NC), and sponsor personnel were masked to the treatment.” “Independent masked readers (Duke Reading Center) measured the GA area on FAF images using the RegionFinderTM software (Heidelberg Engineering), while OCT and IR images were used to help define GA boundaries.”

Overall

Low risk