The underlying pathophysiology of geographic atrophy is not completely understood; however, complement hyperactivity leading to over-activation of the immune system and chronic inflammation in the macula is thought to be a contributing factor.1,5 At present, there are no approved treatments for geographic atrophy, and multiple investigational approaches targeting a range of therapeutic mechanisms are being explored.1,5-8 This review will focus on complement inhibition as a potential therapy for GA growth inhibition and prevention of visual loss.
The Complement System
The complement system consists of more than 30 proteins and is a key driver of the innate immune system.8,9 Complement proteins exist as either soluble blood proteins or membrane-associated protein complexes. Activation of the complement system may be initiated by one of three biochemical pathways: the classical; lectin; and alternative pathways.5,8,9 The classical pathway is driven primarily by the formation of antibody-antigen complexes, while the lectin pathway is activated by polysaccharides on microbial surfaces.9 Unlike the classical and lectin pathways, the alternative pathway is triggered by surface pathogens and does not rely on the formation of an immune complex.9,10 Each pathway converges on the cleavage of complement component C3 (the most abundant complement protein in the blood) resulting in the formation of the activation products C3a, C3b, C5a and the membrane attack complex (MAC=C5b-9).10
Complement activation through the alternative pathway is initiated through the continuous hydrolysis of C3 to C3b.5,10 Complement factor B (CFB) binds to C3b to form the C3bB complex. Complement factor D (CFD), a rate-limiting enzyme in the alternative complement pathway, in turn cleaves the C3bB complex to form active C3 and C5 convertases.10 C3 convertase can then cleave additional C3 into C3a and C3b forming an amplification loop. Complement factor H (CFH) and complement factor I (CFI) are negative regulators of the alternative complement pathway that work together to deactivate C3b and halt the cascade that triggers pro-inflammatory responses and ultimate cell death.1
The Complement System in AMD
Dysregulation of the complement system is thought to play an important role in the development and progression of AMD.9,11,12 Several potential triggers of the complement system in AMD have been described, including photo-oxidized A2E,13 amyloid beta14,15 and oxidative stress.16,17 A number of complement activation products have been identified in drusen, including C3a, C5a, C5b-9 (i.e., the MAC) and CFH.9,18,19 Furthermore, vitreous samples, Bruch’s membrane and choroid from patients with advanced AMD have shown elevated levels of complement proteins compared with controls.12,20,21
Along with these findings, complement inhibitors have been found to be lacking in eyes with GA.22 For example, CD59 is a membrane-bound inhibitor of MAC formation and has been found at reduced levels in GA patients.22 Similarly, MCP is a membrane-bound complement regulator that has cofactor activity for CFI, which serves to inactivate C3b and C4b and has been reported at reduced levels in GA.23
Although largely produced by the liver, complement synthesis has been found to occur extrahepatically in the neural retina, RPE and choroid.12,16,24 In addition, systemic plasma complement levels have been shown to be significantly elevated in patients with AMD.16 Whether elevations in local or systemic complement proteins play the leading role in GA pathogenesis is yet to be determined.16
A strong genetic correlation has been established between the risk of AMD and variations in genes encoding complement pathway proteins.5,9 CFH was the first complement gene shown to be associated with AMD risk.25-27 Additional genetic analyses, including a recent AMD gene consortium meta-analysis comprising more than 17,100 patients with advanced AMD and more than 60,000 controls identified genetic polymorphisms in complement pathway loci associated with advanced AMD risk, including complement component 2 (C2), C3, CFB, CFH and CFI.28 Rare variants in CFI have recently been shown to contribute to the pathogenesis of AMD through dysregulation of alternative complement activation.29 However, conflicting evidence regarding CFI and GA growth rates has been reported.30
| Geographic atrophy remains a significant unmet medical need with no approved or effective treatments. |
Not all complement activity in the eye is detrimental. In fact, complement activity has been shown to have both important developmental and protective effects in the retina.31,32,33 Ruslan Medzhitov, PhD, established the concept of para-inflammation: a beneficial, well-controlled, intermediate, inflammatory response to tissue stress or malfunction with the primary role of maintaining tissue homeostasis.34 This concept has been applied and studied in the aging retina.35 Although the process is certainly multifactorial, what remains to be fully determined is why, when and how this para-inflammatory mechanism changes from being protective to destructive.
Investigational Agents
Currently, several complement inhibitors targeting various points along the complement pathway are being investigated for the treatment of GA, but none are yet approved or proven to be effective.1,6-8 C5 inhibitors include eculizumab/SOLIRIS (Alexion), LFG-316 (Novartis/MorphoSys) and ARC-1905 (Ophthotech).1,6-8 Inhibition of the complement cascade at the level of C5 prevents the formation of C5a and the membrane attack complex (MAC=C5b-9).
Eculizumab was evaluated in the Phase II COMPLETE Study (NCT00935883).30 Eculizumab is a humanized monoclonal antibody derived from the murine anti-human C5 antibody. The COMPLETE study enrolled 30 patients aged 50 years and older, with a total GA area of 1.25 to 18 mm2, and visual acuity of 20/63 or better (ETDRS).30 Despite decreasing systemic C5 levels to less than 1 percent of normal by week two, the researchers found that intravenous administration of eculizumab did not significantly slow GA growth rates in patients with GA at the six-month endpoint or after an additional six months of follow-up.30 Furthermore, they did not detect an association between GA progression and at-risk alleles.30 Possible explanations for eculizumab’s failed effect include inhibition of the wrong complement component, or wrong delivery mechanism. Reports have shown Bruch’s membrane to become less permeable to serum proteins with age and involution of the choriocapillaris under areas of GA.36,37 These previous findings may result in subtherapeutic doses when given systemically.
LFG-316 (Novartis/MorphoSys) is a fully human, full-length monoclonal anti-C5 antibody. The drug was well-tolerated in Phase I testing by intravitreal administration.1,6 In a Phase II study, 150 patients with GA received monthly intravitreal injections of LFG-316 with the primary outcome measure being growth of GA at month 12. At the completion of the trial, LFG-316 was found to have an acceptable safety profile, but it was not efficacious in reducing GA lesion growth rate or improving visual acuity (NCT01527500).
ARC-1905 (Ophthotech) is an anti-C5 pegylated aptamer targeting C5 that has completed Phase I testing as an intravitreal injection for patients with GA (NCT00950638). Plans for initiating a Phase II/III trial of ARC-1905 are reported to be under way (ophthotech.com).
POT-4 (AL-78898A; Alcon) is a cyclic peptide comprising 13 amino acids derived from compstatin, which binds reversibly to C3 and prevents its proteolytic activation to C3a and C3b. A Phase I study looking at POT-4 for neovascular AMD has been completed (NCT00473928). A Phase II dry AMD study designed to demonstrate superiority of POT-4 intravitreal injections to sham injections by assessing GA lesion growth at month 12 was terminated due to slow recruitment (NCT01603043).
A complement inhibitor in advanced stages of clinical development is lampalizumab (FCFD45142), a humanized, monoclonal, antigen-binding fragment that specifically inhibits the alternative complement pathway by targeting CFD (Genentech/Roche).1,6 CFD is a chymotrypsin-like serine protease specific for factor B (fB). It is the rate-limiting factor in the ACP and has the lowest serum concentration of all the complement proteins.38 When associated with C3, fB is a substrate for fD. Cleavage of C3-fB to its active form fBb yields the ACP C3 convertase.38
The safety, tolerability and evidence of activity of lampalizumab in patients with GA were assessed in the MAHALO Phase II trial (NCT01229215) (Regillo C. Late Breaker Paper presentation, American Academy of Ophthalmology Retina Sub-day Meeting 2013). MAHALO was a prospective, multicenter, randomized, single-masked, sham-injection-controlled study in which 129 patients aged 60 to 89 years with GA secondary to AMD were randomized 2:1:2:1 to lampalizumab 10 mg monthly, sham monthly, lampalizumab 10 mg every other month, or sham every other month. The sham arms were pooled for the analyses. The primary endpoint was change in GA area from baseline to month 18, as assessed by fundus autofluorescence imaging. The relationship between specific genetic polymorphisms associated with GA characteristics and lampalizumab treatment response was also explored.
In total, 123 patients received ≥one sham or lampalizumab treatment and had at least one post-baseline primary efficacy measurement (sham pooled, n=40; lampalizumab monthly, n=42; lampalizumab every other month, n=41), which satisfied pre-specified criteria for evaluation. A 20-percent reduction in GA area progression was reported in the all-comer lampalizumab monthly arm relative to the pooled sham arm. This positive treatment effect was observed at month six through month 18. An even greater reduction in GA area progression relative to the sham control was observed in a CFI genetic biomarker-defined subpopulation treated monthly with lampalizumab and more than one-half of the tested study population was positive for this biomarker. Lampalizumab demonstrated an acceptable safety profile in the Phase II study; there were no ocular or systemic serious adverse events suspected to be study drug-related.
| Not all complement activity in the eye is detrimental. In fact, complement activity has been shown to have both important developmental and protective effects in the retina. |
Geographic atrophy remains a significant unmet medical need with no approved or effective treatments. Results from large-scale genetics studies support the role of aberrant activation of the alternative complement pathway in AMD pathophysiology. The lampalizumab Phase II clinical trial was the first study to show a positive treatment effect in reducing GA progression through complement inhibition. Additional Phase II and III trials investigating complement inhibition as a potential treatment for geographic atrophy are currently under way. REVIEW
Dr. Ehmann is a first-year retinal fellow at Wills Eye Hospital. Dr. Regillo is an attending retinal surgeon at Mid Atlantic Retina/Wills Eye Hospital. Contact Dr. Ehmann at 840 Walnut St. Ste. 1020, Philadelphia, PA 19107. (215) 928-3300, or dehmann@midatlanticretina.com.
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