Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly population. AMD is characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). Regarding the latter type, there is growing evidence supporting an association between the pathophysiology of dry AMD and key proteins in the complement cascade. The complement cascade works as a central part of the innate immune system by defending against foreign pathogens and modified self-tissues. Through three distinct pathways, a series of plasma and membrane-associated serum proteins are activated upon identification of a foreign entity. Several of these proteins have been implicated in the development and progression of dry AMD. Potential therapeutic targets include C1q, C3, C5, complement factors (B, D, H, I), membrane attack complex, and properdin.
ANX007 (Annexon Inc., Brisbane, CA, USA) is a recombinant monoclonal antibody with an antigen-binding fragment that inhibits c1q. Through its action on c1q, the classical complement pathway is inhibited alongside C3 and C5 [60,61][38][39]. In a murine model of retinal photooxidative damage, ANX-M1, a monoclonal anti-C1q antibody similar to ANX007, reduced retinal atrophy [62][40]. Furthermore, a phase I trial (NCT04188015) using 2.5 mg and 5 mg of intravitreal (IVT) ANX007 demonstrated the safety and tolerability of both doses in 17 patients with primary open-angle glaucoma [60,61][38][39].
AMY-106, derived from Cp40-KKK, a fourth-generation compstatin analog, is a novel C3 inhibitor in development by Amyndas Pharmaceuticals [63,64][41][42]. This therapeutic maintained intraocular residence for more than 90 days after one 0.5 mg IVT injection in an investigation involving cynomolgus monkeys. Moreover, AMY-106 exhibited notable retinal tissue penetrance, as it localized with C3 in the choriocapillaris [63][41]. Provided its promise for dry AMD treatment, a phase I trial of AMY-106 is in development [64][42].
Pegcetacoplan, additionally denoted as APL-2, is a PEGylated peptide inhibitor of C3 formulated by Apellis Pharmaceuticals that is administered intravitreally [65][43]. The agent was evaluated in the FILLY trial (NCT02503332) [65][43], a multicenter, randomized phase II trial encompassing 246 patients with GA. Subjects were randomized in a 2:2:1:1 ratio to injections of 15 mg pegcetacoplan monthly or EOM, or sham injections monthly or EOM for 12 months. Follow-up was conducted at 15 and 18 months. Pegcetacoplan treatment produced statistically significant reductions in GA growth rates.
POT-4 (AL-78898A) is a compstatin analog originally developed by Potentia Pharmaceuticals that functions as a C3 inhibitor and was the first complement inhibitor tested in humans with AMD [60,70][38][44]. Phase I trial (NCT00473928) results revealed no adverse drug events (ADEs) or serious adverse events (SAEs) with doses of up to 450 mg for patients with wet AMD [70][44]. Based on the tolerability of POT-4, a multicenter, randomized phase II trial (NCT01603043) with 10 patients was conducted to assess its efficacy in reducing GA lesion growth among individuals with dry AMD. However, the study was terminated prematurely, as four of seven participants (57.14%) in the POT-4 group developed drug product deposits in the eye.
NGM621 (NGM Biopharmaceuticals, San Francisco, CA, USA) is a humanized immunoglobulin G1 monoclonal antibody formulated as a C3 inhibitor. A phase I trial (NCT04014777) included 15 patients with GA secondary to dry AMD [71][45]. Participants were treated with either single-ascending doses (2 mg, 7.5 mg, 15 mg) of NGM621 or two doses of 15 mg delivered 4 weeks apart. Monitoring occurred for 12 weeks within all cohorts, and results indicated an appropriate safety profile, with no SAEs, ADEs, or new-onset CNV reported.
Eculizumab (Alexion Pharmaceuticals, Inc) is a humanized monoclonal antibody directed against C5 [72,73][46][47]. Systemic eculizumab is currently approved for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Thus, considering the evidence for the relationship of the complement cascade with AMD, the COMPLETE study (NCT00935883) was designed [72,73][46][47].
Avacincaptad pegol (Zimura®), by Iveric Bio (Cranbury, NJ, USA), is a PEGylated RNA aptamer that operates as a C5 cleavage inhibitor, thereby impeding the complement cascade irrespective of the initial activation pathway. This agent was evaluated in the phase II/III GATHER1 trial (NCT02686658), a multicenter, randomized investigation. Randomization was conducted in two stages. In total, 77 part I participants were randomized in a 1:1:1 ratio to injections of 1 mg of avacincaptad pegol, 2 mg of avacincaptad pegol, and sham. Then, 209 part II participants were randomized in a 1:2:2 ratio to 2 mg of avacincaptad pegol, 4 mg of avacincaptad pegol, and sham. Relative to sham, subjects receiving 2 mg of avacincaptad pegol and 4 mg of avacincaptad pegol experienced a 27.4% (p = 0.0072) and 27.8% (p = 0.0051) reduction, respectively, in the mean rate of GA growth [74][48].
Tesidolumab (LFG316), a monoclonal C5 inhibitor developed by Novartis Pharmaceuticals (Basel, Switzerland), was investigated in a multicenter, randomized phase II clinical trial (NCT01527500). In the study, 158 patients were enrolled and separated into two groups. Part A examined the safety and efficacy of multiple 5 mg IVT injections of LFG316 relative to sham every 28 days over the course of 505 days. Part B examined the safety and pharmacokinetic properties of a single 10 mg IVT injection. Results revealed a relatively benign safety profile, with no demonstrable improvement in the primary outcome of GA lesion growth or the secondary outcome of BCVA.
IONIS-FB-lrx (Ionis Pharmaceuticals, Carlsbad, CA, USA) is a novel anti-sense oligonucleotide (ASO) targeting the gene encoding complement factor B (CFB), a moiety of the alternative complement pathway. When delivered subcutaneously, IONIS-FB-lrx reduced circulating levels of CFB in a dose-dependent manner among 54 healthy participants of a phase I trial [76][49]. No notable adverse effects were reported. Given these results, the multicenter, randomized phase II GOLDEN trial (NCT03815825) has been initiated to evaluate the influence of IONIS-FB-lrx administration on the progression of GA lesion size [76][49].
Complement factor D (CFD), a rate-limiting enzyme of the alternative pathway, converts proconvertases into active C3 and C5 convertases. Consequently, inhibition of CFD has surfaced as an attractive therapeutic option for dry AMD [77][50]. Lampalizumab, designed by Genentech (San Francisco, CA, USA), is a humanized monoclonal antibody with an antigen-binding fragment that inhibits complement factor D. In a phase I trial (NCT00973011), 18 participants received 10 mg of IVT lampalizumab. The agent had an acceptable safety profile without notable ocular or systemic ADEs or SAEs. To expand these findings, the MAHALO phase II trial (NCT01229215) was conducted to evaluate lampalizumab’s efficacy in reducing GA progression [78][51]. Monthly treatment with lampalizumab resulted in a statistically significant 20% reduction (p = 0.117) in mean GA lesion enlargement relative to sham. Patients with high-risk complement factor I (CFI) alleles displayed a greater response to monthly lampalizumab with a 44% reduction (p = 0.0037) in GA atrophy progression compared to sham. Similar to phase I findings, lampalizumab was well-tolerated [78][51]. CFH downregulates the alternative complement cascade by preventing C3 convertase formation from c3b; therefore, it has been postulated as a potential therapeutic for dry AMD. The injection of AdCAGfH, an adeno-associated virus (AAV) containing murine factor H, demonstrated an attenuation of C3-induced retinal inflammation [81][52]. This gene therapy is currently under consideration for human subjects [82][53]. GEM103 is a recombinant human CFH developed by Gemini Therapeutics (Cambridge, MA, USA). In a phase I clinical trial (NCT04246866) comprised of 12 participants, GEM103 demonstrated minimal adverse effects and a dose-dependent increase in levels of CFH [83][54]. Significantly, no CNV was observed, a phenomenon previously reported in the literature in association with repeated administration of IVT complement inhibitors [67][55]. CFI is a regulator of the alternative pathway. With the assistance of its cofactors, it cleaves C3b into pro-inflammatory ic3b, which is subsequently cleaved into inert c3dg. Thus, the protein is crucial for modulating the activation of the alternative pathway. Importantly, experimental investigations confirmed the ability of AAV-containing CFI cDNA to induce CFI protein expression in human RPE lines and murine retina, thereby stimulating the development of GT005 by Gyroscope Therapeutics. Regulators of the complement cascade are emerging targets for investigational compounds. AAVCAGsCD59, also denoted HMR59, is an intravitreally injected AAV vector developed by Hemera Biosciences that induces the formation of CD59, thereby preventing the binding of C9 required for the formation of a complete MAC [88][56]. Pre-clinically, HMR59 demonstrated efficacy in attenuating laser-induced CNV among murine models [89][57]. Properdin is a positive regulator of the alternative complement pathway, preventing the degradation of C3 and C5 convertases. Thus, CLG561, an anti-properdin antibody, was developed as a potential therapeutic by Alcon Research [91][58]. Results from a phase I trial (NCT01835015) showed IVT doses of CLG561 up to 10 mg were safe and well-tolerated, with no systemic or ocular ADEs reported [92][59].