ARC1905 - Anti-C5 Aptamer

Aberrant activation of the complement system is implicated in the pathogenesis of a great majority of AMD (wet and dry forms) in the western world [1-3]. There is strong evidence that AMD is an inflammatory disease. Patients with AMD demonstrate elevated systemic inflammatory biomarkers of inflammation such as CRP, IL-6 and homocysteine. Furthermore, histopathological analysis of human AMD neovascular complex is associated with an inflammatory infiltrate. Furthermore, histopathologic analyses of human AMD neovascular complex specimens demonstrate inflammatory infiltrates. Systemic markers of complement activation are also elevated in AMD patients compared to age matched controls.

Recent studies have implicated local inflammation and activation of the complement cascade in the formation of drusen, the crystalline deposits under the retina which are the hallmark of dry AMD. Evidence of complement-mediated inflammation in AMD is further reinforced by multiple genetic linkage and association studies published in both Science [1-3] and the New England Journal of Medicine [4], suggesting that polymorphisms in genes coding for the complement regulatory proteins may account for approximately 50% to 75% of AMD cases and may increase the likelihood of AMD 7.4 to 10 times. Taken together, there is strong support for complement-mediated disease in wet and dry forms of AMD.

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 1 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 was initiated in Q2 2009.

References

1. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389.

2. Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, Farrer LA.Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424.

3. Haines JL, Hauser MA, Schmidt S, et al.Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419-421.

4. Yates JR, Sepp T, Matharu BK, et al; Genetic Factors in AMD Study Group. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553-561.