Combination of complement factor 5, anti-vascular endothelial growth factor therapy inhibition promising

October 1, 2010

Preliminary results of a phase I/II study suggest that targeting complement factor 5 in combination with anti-vascular endothelial growth factor therapy may have a role for improving visual acuity outcomes to eyes with exudative age-related macular degeneration.

The study was an open-label, dose-escalating, multiple dose, uncontrolled trial. It included 58 patients with treatment-naïve choroidal neovascularization (CNV) secondary to AMD who received one of five doses of an investigational anti-C5 aptamer (ARC1905, Ophthotech), plus ranibizumab 0.5 mg (Lucentis, Genentech) every 4 weeks for a total of up to six administrations. Final evaluations were performed 1 month after the last treatment.

The patients could have any angiographic subtype of subfoveal CNV due to AMD but with a lesion size not to exceed 5 disc areas. In addition, they had to have baseline best-corrected visual acuity (BCVA) between 20/63 and 20/200 in the study eye.

VA and changes in optical coherence tomography (OCT)-measured retinal thickness were evaluated as secondary endpoints. VA results showed a dose-dependent improvement. Among patients treated with the highest dose of ARC1905, 60% achieved a 3-line gain in ETDRS BCVA and the mean improvement from baseline in this subgroup was 15.3 letters.

There also was dramatic reduction in OCT-measured central foveal thickness as would be expected with ranibizumab treatment, according to Dr. Cousins.

"Among historical controls treated with ranibizumab monotherapy, represented by patients in the MARINA and ANCHOR studies, 34% to 40% of patients achieved a 3-line or greater improvement in vision," he said. "The relatively greater benefit observed in the current study combining ARC1905 with ranibizumab is only an observation and not necessarily meaningful because the trial was uncontrolled.

"However, the results support further investigation," Dr. Cousins added. "Ophthotech is preparing to conduct a controlled study that will evaluate whether the combination improves VA results compared with ranibizumab alone."

ARC1905 blocks the enzymatic activation of C5 and its resultant cleavage into C5a and C5b. C5a is an anaphylatoxin and C5b results in cytotoxic effects secondary to formation of the membrane attack complex.

"One of the issues in developing a complement-based therapeutic modality for exudative AMD is to decide which molecule to target in the complement cascade," he said. "An investigational compound being developed by another company [Compstatin, Alcon] blocks activation of C3, which is involved earlier in the complement cascade than C5. As a theoretical advantage, inhibition of C5 instead of C3 may reduce the risk of infection as a potential adverse event."

Since inhibition of C5 activation would be expected to block recruitment of inflammatory cells into the eye that could independently diminish vision, a subgroup analysis was performed to investigate whether the functional benefit in the study might be explained by an antipermeability effect alone. Changes from baseline vision were analyzed with patients divided into two groups by 50% percentile central subfield thickness, and the results showed those who presented with a "thinner" retina (<347 µm) had a better gain in vision than those with a "thicker" retina (>347 µm) at baseline, 14.45 versus 11.94 letters, respectively.

"The fact that greater pretreatment OCT thickness did not predict final thickness suggests that the benefit of the combination involves a mechanism beyond just reducing leakage," Dr. Cousins said.

FYI

Scott W. Cousins, MD
E-mail: scott.cousins@duke.edu

Dr. Cousins is a paid consultant to Alcon Laboratories, Genentech, and Ophthotech.