C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial

Ophthalmology. 2021 Apr;128(4):576-586. doi: 10.1016/j.ophtha.2020.08.027. Epub 2020 Sep 1.


Purpose: The complement pathway may play a key role in the pathogenesis of age-related macular degeneration (AMD). The safety and efficacy of avacincaptad pegol (Zimura, IVERIC bio Inc, New York, NY), a C5 inhibitor, were assessed in participants with geographic atrophy (GA) secondary to AMD (GATHER1 Study).

Design: International, prospective, randomized, double-masked, sham-controlled, pivotal phase 2/3 clinical trial.

Participants: A total of 286 participants with GA secondary to AMD.

Main outcome measures: The primary efficacy endpoint was the mean rate of change in GA over 12 months measured by fundus autofluorescence (FAF) at 3 timepoints: baseline, month 6, and month 12.

Results: The reduction in the mean rate of GA growth (square root transformation) over 12 months was 27.4% (P = 0.0072) for the avacincaptad pegol 2 mg cohort and 27.8% (P = 0.0051) for the avacincaptad pegol 4 mg cohort compared with their corresponding sham cohorts. The results for both dose groups were statistically significant. Avacincaptad pegol was generally well tolerated after monthly administration over 12 months. There were no avacincaptad pegol-related adverse events (AEs) or inflammation. Further, there were no ocular serious AEs (SAEs) and no cases of endophthalmitis. The most frequent ocular AEs were related to the injection procedure.

Conclusions: Intravitreal administration of avacincaptad pegol 2 mg and 4 mg led to a significant reduction of GA growth in eyes with AMD over a 12-month period. Because C5 inhibition theoretically preserves C3 activity, it may offer additional safety advantages. A second confirmatory pivotal clinical trial is underway to confirm the efficacy and safety of avacincaptad pegol in slowing the GA growth (GATHER2 Study).

Keywords: C5 inhibitor; Complement; GATHER1; GATHER2; Zimura; age-related macular degeneration; avacincaptad pegol; dry; geographic atrophy.

Publication types

  • Clinical Trial, Phase II
  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aptamers, Nucleotide / therapeutic use*
  • Complement C5 / antagonists & inhibitors*
  • Complement Inactivating Agents / therapeutic use*
  • Double-Blind Method
  • Female
  • Fluorescein Angiography
  • Follow-Up Studies
  • Geographic Atrophy / diagnosis
  • Geographic Atrophy / drug therapy*
  • Geographic Atrophy / physiopathology
  • Humans
  • Intravitreal Injections
  • Macular Degeneration / diagnosis
  • Macular Degeneration / drug therapy
  • Macular Degeneration / physiopathology
  • Male
  • Prospective Studies
  • Visual Acuity / physiology


  • Aptamers, Nucleotide
  • Complement C5
  • Complement Inactivating Agents