It is well established that the complement system plays an important role in the pathogenesis of age-related macular degeneration (AMD). Drusen in the retinas of AMD patients express proteins involved in inflammation and immunologic responses, including various components of the complement system (component 3 [C3], C5, and C5b-9 complexes).1-4 Several studies have reported strong association of variants in the genes of the complement system, including complement factor H (CFH),5-9 C2,10 complement factor B (CFB),10 and C311 genes, with AMD. Patients with AMD also exhibit higher serum levels of activation products C3d, Ba, C3a, C5a, SC5b-9; substrate proteins C3, C4, CFB; and regulators CFH and complement factor D (CFD), suggesting that AMD could be a systemic disease with a local manifestation.12,13
There has been growing interest in the development of drugs targeting the complement system as potential therapies for AMD, especially for the treatment of geographic atrophy (GA), which remains an enormous burden for patients worldwide with elusive treatment options. Multiple drug candidates targeting the complement system to treat GA have failed to show efficacy. These include lampalizumab, a humanized antigen binding fragment (Fab) targeting CFD (Genentech Inc. and F. Hoffmann-La Roche AG), which failed in phase 3 trials (CHROMA; NCT02247479, and SPECTRI; NCT02247531)14 despite a positive phase 2 trial (MAHALO, NCT01229215); eculizumab, a humanized anti-C5 antibody (Alexion Pharmaceuticals Inc.) (COMPLETE, NCT00935883);15 LFG316, a fully human anti-C5 antibody (Novartis International AG; NCT01527500); and CLG561, a humanized Fab targeting properdin (Novartis and Alcon Inc.; NCT02515942).
David S. Liao, MD, PhD, is a retina specialist with the Retina Vitreous Associates Medical Group in Beverly Hills, California. Ramiro Ribeiro, MD, PhD, is senior medical director at Apellis Pharmaceuticals. Ravi Metlapally, PhD, is a clinical scientist at Apellis Pharmaceuticals. Namrata Saroj, OD, is principal at All Eyes Consulting, LLC. Dr. Liao reports grant support from Apellis. Drs. Ribeiro and Metlapally report employment with Apellis Pharmaceuticals. Dr. Saroj reports consultancy to Apellis Pharmaceuticals. Reach Dr. Liao at email@example.com.
Other molecules targeting the complement system that are under development for GA therapy are avacincaptad pegol, an anti-C5 aptamer (Iveric bio, formerly Ophthotech Corporation); AAVCAGsCD59, a gene therapy to increase the soluble form of CD59 to inhibit the formation of the membrane attack complex (Hemera Biosciences); GT0005, a gene therapy of yet unrevealed mechanism (Gyroscope Therapeutics); NGM621, an antagonistic antibody binding complement C3 (NGM Biopharmaceuticals); and FB-LRx, an antisense inhibitor of CFB (Ionis Pharmaceuticals).
Pegcetacoplan (APL-2; Apellis Pharmaceuticals) is a pegylated cyclic peptide inhibitor of complement C3. Recently, APL-2 demonstrated significant reduction in the rate of growth of GA lesions in patients with dry AMD in a large phase 2 trial (FILLY), leading to 2 ongoing phase 3 studies (DERBY and OAKS). This article revisits the overall strategy for developing complement inhibitors for the treatment of AMD to understand why C3 inhibition might slow GA progression when other targets within the complement system have failed.
THE POTENTIAL FOR C3 INHIBITION AS A STRATEGY
C3 is the central molecule of the complement system onto which all 3 proteolytic cascades, the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP), converge, leading to the activation of the terminal pathway (TP) for cell lysis (Figure 1).16 Following the initial studies in the mid-2000s implicating CFH, belonging to AP, several other studies have identified gene variants in various complement pathways to be associated with AMD, which include CFB10,17 and CFI17-20 (AP); C210,17 (CP); and C920,21 (TP).
The first evidence of C3 involvement in AMD, to our knowledge, dates to 1992 when subretinal membranes from disciform AMD eyes were shown to have diffuse distribution of complement components C3c and C3d in the connective stroma and blood vessel walls.22 Subsequently, presence of C3 in drusen from donor eyes of AMD patients was reported.4,23 Worth mentioning in this context is complement component 3 glomerulopathy (C3G), which includes dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) due to abnormal complement activation.24,25 Patients with C3G present with drusen similar to those in AMD, suggesting a role for C3 in drusen biogenesis.3,26-29
Evidence for the association of C3 gene variants with AMD has also been demonstrated in parallel with early genetics studies.11,30,31 C3 variants have been implicated in increased risk of early AMD and all subtypes of late AMD32 as well as progression of intermediate to advanced AMD.33 Further evidence supporting the role for C3 in AMD pathogenesis through genetic association studies continued to accumulate for both common17,34-37 and rare20,36,38-40 variants of C3 in various populations by large collaborative efforts.
In a preclinical animal model, C3 was implicated in the formation of sub-retinal pigment epithelium (RPE) deposits and C3 inhibition prevented the formation of these deposits.41,42 Fernandez-Godino et al. demonstrated that formation of basal deposits by RPE cells is triggered by binding of C3 to abnormal extracellular matrix, mediated by C3a, and inhibiting C3a prevented the formation of basal deposits.43-45 Furthermore, in a light-induced model of progressive retinal degeneration, C3 was detected in retinal macrophages and the subretinal space, particularly at the margins of the emerging lesion, suggesting a similar role in atrophic AMD.46 More recently, local inactivation of C3 (via an intravitreal injection) was shown to be efficacious in a rat model of photo-oxidative damage in inhibiting retinal atrophy, suggesting that C3 inhibition could slow the progression of atrophy in AMD.47 While direct extrapolation from these models to human disease may not always be possible, preclinical studies provide evidence that supports the role of C3 as well as other complement components in AMD development.48,49
ROLE OF APL-2 IN DECREASING RATE OF GA PROGRESSION
APL-2 is a PEGylated peptide wherein a small pharmacologically active pentadecapeptide is chemically bound to each end of a linear polyethylene glycol (PEG) with average molecular weight of 40 kDa (PEG40). The peptide moiety binds to complement C3 and exerts a broad inhibition, blocking all 3 complement pathways and specifically inhibiting the AP C3 and C5 convertases. The PEG40 portion of the drug molecule imparts improved solubility and longer residence time in the body.
The FILLY study was a phase 2 prospective, multicenter, randomized, single-masked, sham injection-controlled study to assess the safety, tolerability, and evidence of activity of multiple intravitreal injections of APL-2 in subjects with GA secondary to AMD. Subjects with GA were randomized in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg APL-2 monthly or every other month (EOM) or sham injections monthly or EOM for 12 months followed by a 6-month off-drug safety period. Area and growth of GA were measured using fundus autofluorescence imaging, and the primary efficacy endpoint was mean change in square root GA lesion area from baseline to month 12. In subjects receiving APL-2 monthly or EOM, the GA growth rate was reduced by 29% (95% CI, 9-49; P=.008) for monthly treatment and 20% (95% CI, 0-40; P=.067) for EOM treatment compared with sham-treated subjects at month 12 (Figure 2). Ocular serious adverse events (SAEs) were observed in 3.6% of patients receiving APL-2 and 1.2% of patients receiving sham injections, similar to other IVT administration studies. Treatment-related ocular SAEs included endophthalmitis (1.8%), IOP increase (1.2%), and retinal detachment (0.6%). New-onset exudative AMD was also identified in 20.9%, 8.9%, and 1.2% in the APL-2 monthly, APL-2 EOM, and sham arms, respectively; this was a higher rate in patients receiving APL-2, and those patients were treated with anti-VEGF therapy.50 The safety profile was acceptable to proceed to phase 3 studies.
C3 INHIBITION: A PROMISING STRATEGY WORTH PURSUING
Evidence supports the involvement of various components of the complement system from the alternative, classical, and terminal pathways, including C3, in the pathogenesis of AMD. Regardless of the causal component, C3 inhibition strategy for the treatment of GA could prove effective for the following reasons:
- C3 being at the nexus of the CP, LP, and AP is the central molecule in the complement system and has a position of hierarchy uniquely suited as a target to achieve timely and broader inhibition and restore balance in complement activation, thus eliminating all subsequent deleterious effects of overactivation. The failures of strategies directed at other complement components at the fringes or further downstream also support this notion.
- Evidence for the role of AP and C3 in the pathogenesis of AMD has been present since the complement system was implicated in the disease process and continues to grow.
- Findings from the FILLY trial provide proof-of-concept support in favor of C3 inhibition strategy for controlling the progression of GA.
An approved treatment for GA would provide immense benefit for patients with this significant unmet medical need. RP
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