January 2015, Issue 77

Complement Inhibition as a Potential Treatment
for Geographic Atrophy

Carl D Regillo, MD, FACS Wills Eye Hospital Thomas Jefferson University Philadelphia, PA

Introduction
Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) characterized by loss of the retinal pigment epithelium in the macula that can lead to profound and irreversible visual acuity decreases if it progresses to involve the center of the fovea.¹ Patients with earlier stages of GA typically experience visual function deficits, even before visual acuity is affected.^1,2 The underlying pathophysiology of GA is not completely understood; however, complement hyperactivity leading to overactivation of the immune system and chronic inflammation in the macula is thought to be a contributing factor.^1,3 At present, there are no approved treatments for GA, and multiple investigational approaches targeting a range of therapeutic mechanisms are being explored.^1,3-6

The Complement System
The complement system is a key driver of the innate immune system.^6,7 Activation of the complement system may be initiated by 1 of 3 biochemical pathways, including the classical, lectin, and alternative pathways.^3,6,7 The classical pathway is driven primarily by the formation of antibody-antigen complexes, while the lectin pathway is activated by polysaccharides on microbial surfaces.⁷ 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.^7,8 Each pathway converges on the cleavage of complement component C3 to C3b, which is a central step in complement activation and formation of the membrane attack complex (MAC).⁹

Complement activation through the alternative pathway is initiated through the continuous hydrolysis of C3 to C3b.^3,8 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, cleaves the C3bB complex to form active C3 and C5 convertases.⁹ 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 cascades that trigger pro-inflammatory responses and cell death.^1,9

The Role of the Complement System in AMD
Dysregulation of the complement system is thought to play an important role in the development and progression of AMD.^7,10,11 A number of complement activation products have been identified in drusen, including C3a, C5a, C5b-9 (ie, the MAC), and CFH.^7,12,13 In addition, a strong genetic correlation exists between the risk of AMD and variations in genes encoding complement pathway proteins.^3,7 CFH was the first complement gene shown to be associated with AMD risk.^14-16 Additional genetic analyses, including a recent AMD gene consortium meta-analysis comprising more than 17,100 patients with advanced AMD and over 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.¹⁷ Rare variants in CFI have recently been shown to contribute to the pathogenesis of AMD through dysregulation of alternative complement activation.¹⁸

Investigational Agents Targeting the Complement Pathway
Currently, several complement inhibitors targeting various points along the complement pathway are being investigated for the treatment of GA, but none are yet approved.^1,4-6 C5 inhibitors include eculizumab (a humanized monoclonal antibody; Alexion), LFG-316 (a fully human, full-length monoclonal antibody; Novartis/MorphoSys), and ARC-1905 (an aptamer; Ophthotech).^1,4-6 Eculizumab was evaluated in the phase 2 COMPLETE Study (NCT00935883); however, intravenous administration of this C5 inhibitor did not significantly slow GA growth rate in patients with AMD at the 6 month endpoint or after an additional 6 months of follow-up after treatment cessation.¹⁹ LFG-316 is currently being investigated in a phase 2 study in patients with GA.^1,4 Plans for initiating a phase 2/3 trial of ARC-1905 are reported to be underway.²⁰ Investigations of the C3 inhibitor POT-4 (a cyclic peptide; Alcon) are being considered.⁴

A complement inhibitor in advanced stages of clinical development is lampalizumab, a humanized, monoclonal, antigen binding fragment that specifically inhibits the alternative complement pathway by targeting CFD (Genentech, a member of the Roche Group).^1,4 The safety, tolerability and evidence of activity of lampalizumab in patients with GA was assessed in the MAHALO phase 2 trial (NCT01229215).²¹

Lampalizumab MAHALO Phase 2 Study Results
MAHALO was a prospective, multicenter, randomized, single-masked, sham-injection-controlled study in which 129 patients aged 60–89 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 ≥1 sham or lampalizumab treatment and had at least 1 post-baseline primary efficacy measurement (sham pooled, n=40; lampalizumab monthly, n=42; lampalizumab every other month, n=41), which satisfied prespecified criteria for evaluation. A 20.4% 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 6 through month 18. Furthermore, a 44% reduction in GA area progression relative to the sham control was observed in a CFI genetic biomarker-defined subpopulation treated monthly with lampalizumab; 57% of the patients who had DNA available for testing in the MAHALO study were CFI biomarker positive. Lampalizumab demonstrated an acceptable safety profile in the phase 2 study; there were no ocular or systemic serious adverse events suspected to be related to the study drug.

Conclusion
There are currently no proven effective treatments for GA. Results from large-scale genetics studies support the role of aberrant activation of the alternative complement pathway in the pathophysiology of AMD. The lampalizumab phase 2 clinical trial is the first study to show a positive treatment effect in reducing GA progression through complement inhibition. The positive effect observed following monthly lampalizumab treatment in the all-comer population was further magnified in the CFI biomarker-defined subpopulation. Phase 3 trials of lampalizumab are currently underway.

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