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

Written by: Katherine E. Talcott, MD

October 2020

Jaffe GJ, Westby K, Csaky KG, Monés J, Pearlman JA, Patel SS, Joondeph BC, Randolph J, Masonson H, Rezaei KA, C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial, Ophthalmology (2020), doi: https://doi.org/10.1016/j.ophtha.2020.08.027.

While there are multiple treatment options for neovascular age-related macular degeneration (AMD), there are no approved treatments for geographic atrophy (GA). The complement pathway may play a key role in the pathogenesis of AMD and avacincaptad pegol, a pegylated RNA aptamer, has been investigated as a complement C5 inhibitor. Jaffe et al present the results of a study assessing the safety and efficacy of intravitreal administration of avacincaptad pegol in slowing GA growth.

This was a pivotal phase 2/3 clinical trial that enrolled 286 participants with GA secondary to AMD. At baseline, best corrected visual acuity had to be between 20/25-20/320 in the study eye and GA within 1500 microns from the foveal center. There were two parts to the study, but the majority compared a sham cohort to 2mg and 4mg avacincaptad pegol cohorts. Avacincaptad pegol 2mg is administered as a single injection while the 4mg dose is administered as two injections (appropriate sham injections were used to mask this difference). Both were given as monthly injections for 12 months. The primary efficacy endpoint was the mean rate of change in GA over 12 months as measured by fundus autofluorescence (FAF) at baseline, month 6 and month 12.

Overall, there was a significant reduction in the mean rate of GA growth (square root transformation) over 12 months for the avacincaptad pegol 2mg (27.4%; p=0.0072) and 4mg cohorts (27.8%; p=0.005) compared to the sham cohorts. There was no significant change in best corrected visual acuity (BCVA) or low luminance BCVA. Patients who developed a choroidal neovascular membrane (CNV) in the study eye were removed from the study, given possible impact on the accurate analysis of FAF measurements (18 patients). There were no reported avacincaptad pegol-related adverse events, including intraocular inflammation or endophthalmitis.

Overall, intravitreal administration of both 2mg and 4mg avacincaptad pegol led to a significant reduction of GA growth over 12 months. This is an exciting finding as there are no approved treatments for GA. The results also show promise for complement C5 inhibition as a therapeutic target in GA. Safety outcomes from the trial also suggest that the injections were well tolerated but validation is needed in additional trials. Unfortunately, there was no significant vision change as measured by BCVA but this was not unexpected given the disease’s natural history as well as the way the study was constructed. Since both treatment cohorts met the primary endpoint, the avacincaptad pegol 2mg dose (administered as a single intravitreal injection) will be used in the company’s confirmatory Phase 3 study.