complement activation. POT-4 has unique slow-release properties due to the formation of an intravitreal gel at higher doses which provides sustained release of the drug and should permit less frequent intravitreal injections to achieve prolonged complement inhibition.

The phase I dose-escalation study, known as Assessment of Safety of Intravitreal POT-4 Therapy for Patients with Neovascular AMD (ASaP), was performed on patients with advanced neovascular lesions with the intention to pursue POT-4 as a treatment for dry AMD. POT-4 was shown to be safe up to a dose of 1.05 mg, with evidence of depot formation in the intravitreal cavity at doses of 0.45 mg and higher. A phase II study is being organized to further investigate the anti-VEGF properties of POT-4 identiÞed in the phase I study. POT-4 will be combined with ranibizumab therapy in eyes with wet AMD to investigate whether POT-4 prolongs the anti-VEGF effect of ranibizumab. This strategy will help estimate the appropriate dosing interval of POT-4 in future dry AMD trials (Table 17.3).

17.4.4.2 Complement Inhibition at C5

Inhibition at C5 is another strategy for the treatment of dry AMD and it may have some advantages over C3 inhibition. C5 inhibition still prevents terminal complement activity but the more proximal complement

functions are maintained such as production of C3a anaphylatoxin, and C3b which are required for opsonization and clearance of immune complexes and apoptotic bodies. These complement-mediated activities may be required to prevent bacterial infection and may preserve desired complement-mediated activities (Fig. 17.1).

Eculizumab

Eculizumab (SOLIRIS, Alexion Pharmaceuticals, Cheshire, CT) is a humanized monoclonal antibody derived from a murine antihuman C5 antibody. Eculizumab speciÞcally binds the terminal complement protein C5, thereby inhibiting its cleavage to C5a and C5b during complement activation. The strategic blockade of the complement cascade at C5 prevents the release of the downstream anaphylatoxin C5a and prevents the formation of the cytolytic membrane attack complex. Eculizumab is FDA-approved for the intravenous treatment of another complement-medi- ated disease known as paroxysmal nocturnal hemoglobinuria. At the Bascom Palmer Eye Institute, a phase II study is underway to evaluate the safety and efÞcacy of intravenous eculizumab for the treatment of patients with dry AMD. This trial is known as the COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration