POT-4 developed by Potentia Pharmaceutical (Potencia Pharmaceutical, inc., Louiseville) affects the body’s “complement” system. Inflammation plays a role in developing macular degeneration.

Eight complement proteins are associated with AMD and POT-4 affects C3.

The problem is that inflammation is useful in fighting infections.

If the complement system is completely shut down, there is an increase risk for the development of bacterial infection.

Potentia has completed a phase I trial for POT-4 (called ASap) in patients with wet AMD.

The trial was designed to determine the safety and tolerability of an intravitreal injection of POT-4, as well as its stability and depot-forming properties.

In the study investigators observed only minimal and mild local adverse events related to the injection with no serious adverse events related to the drug itself^{(53, 54)}.

JPE-1375 (Jerini AG, Berlin Germany) is a small molecule peptidomimetic antagonist targeting the complement pathway, a highly validated target for dry AMD.

It targets C5aR, the receptor for complement factor C5a, which is a key component involved in the activation of inflammatory cells⁽⁵⁵⁾.

JPE-1375 has shown significant efficacy in multiple preclinical models.

ARC 1905 (Ophthotech Corp. Princeton, NJ) is a PEGylated, stabilized aptamer targeting complement factor C5.

ARC1905 inhibits activation of the downstream proinflammatory complement cascade (including generation of C5a and the membrane attack complex).

“Ophthotech’s anti-C5 aptamer, ARC1905, is a potent and selective inhibitor of factor C5 of the complement cascade.

Inhibition of the complement cascade at the level of C5 prevents the formation of the key terminal fragments responsible for tissue pathology, C5a and the membrane attack complex (MAC: C5b-9).

The C5a fragment is pro-inflammatory, while the membrane attack complex initiates cell lysis and releases proangiogenic molecules (eg. PDGF and VEGF).

Histopathologic specimens of human dry AMD lesions strongly stain for C5 and MAC at the key sites of pathology.

ARC1905 spares the formation of upstream complement components such as C3b, which are important in host defense mechanisms.

By inhibiting C5-mediated inflammatory and MAC activities, therapeutic benefit may be achieved in both dry and wet AMD while sparing the immunoprotective functions of the complement system.

A phase I open-label, multicenter study of ARC1905, in combination with an anti-VEGF agent (Lucentis^®), in patients with wet AMD is ongoing.

In addition, a study investigating ARC1905 in patients with dry AMD will be initiated in Q2 2009.”⁽⁵⁶⁾

Eculizumab (Soliris, Alexion Pharmaceuticals) is a humanized monoclonal antibody derived from a murine antihuman C5 antibody.

Eculizumab specifically inhibits the terminal complement protein C5, thereby preventing 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 (MAC).

Eculizumab is FDA-approved for the intravenous treatment of another complement-mediated disease known as paroxysmal nocturnal hemoglobinuria.

Currently a phase II study with eculizumab for the treatment of patients with dry AMD, known as the Complement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-related Macular Degeneration (COMPLETE) Study.⁽⁵⁷⁾

Patients with GA or high-risk drusen are being randomized 2:1 to receive intravenous infusions of eculizumab or placebo.