Article

Complement Inhibitors for Treatment of Geographic Atrophy and Advanced Nonexudative AMD

Potential exists to slow or prevent disease progression.

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Although the treatment approach for age-related macular degeneration (AMD) has seen many advances in the treatment of exudative, or neovascular, AMD (nAMD) with the advent of anti-VEGF injections, a major limitation exists in our ability to prevent progression of nonexudative (NEAMD) to nAMD. Presently, the ability to delay progression of disease within early-stage NEAMD exists with use of Age-related Eye Disease Study (AREDS) and AREDS2 supplements, but clinicians have no options to delay or treat late-stage NEAMD. In particular, clinicians have no approved or effective therapies to prevent geographic atrophy (GA) development or progression. This is significant because more than 1 million Americans are afflicted with GA.1 An ongoing approach to address this problem utilizes complement inhibitors, a class of molecules that reduces the immune system’s complement activity. This article summarizes the current state of complement inhibitors aimed to delay advanced NEAMD progression and improve our ability to treat and prevent GA.

WHY COMPLEMENT INHIBITORS?

As the leading cause of legal blindness in the white population in the United States, AMD presents a severe threat to many people’s vision and quality of life.2 In a 10-year follow-up of the AREDS study, investigators established that 53.9% of the highest risk patients based on the AREDS simple scale were prone to having their intermediate AMD advance to GA.3 Previous studies establish age, family history, and genetic variants of a number of complement factor genes as risk factors for AMD.4,5

The complement pathway is one of the body’s immune defense systems and is part of the innate immune system. The complement pathway involves a group of “complement” proteins that triggers inflammation and destroys foreign intruders systemically or locally. One important protein to the complement pathway is factor H, which is an inhibitory regulator of the system. Genetic variants of complement factor H, the gene that produces factor H, is one of many genetic variants that have been shown to be a risk factor for AMD.6-8 Complement inhibitors have been shown to be successful in other diseases where excessive complement activity contributes, such as paroxysmal nocturnal hemoglobinuria and hereditary angioedema.9

The potential for complement inhibitors in NEAMD originated from the discovery of macular drusen in patients with complement-mediated renal diseases.10 Later, components of the complement system were confirmed to exist in macular drusen, Bruch’s membrane, and inner choroid, indicating that complement protein accumulation contributes to blood-retina barrier breakdown.11-14 The role of complement was further supported in a study of CNV in rodent laser models, where complement activation was demonstrated to play a role.15 Lastly, a number of complement genetic variants including C2, C3, C9, CFH, CFHR1, and CF1 have been associated with AMD (Figure 1).5

Figure 1. Components of the complement pathway that have been identified as an AMD-associated genetic variant are highlighted. CFI, complement factor I; CFH, complement factor H. Elements are not depicted to scale. Figure based on the scientific information from Owen J, et al, Kuby Immunology, 7th ed. New York: W.H. Freeman and Co Ltd; 2013; Walport MJ. N Engl J Med. 2001;344(14):1058-1066; Boyer DS, et al. Retina. 2017;37(5):819-835.22-24

CURRENT STATE OF COMPLEMENT INHIBITORS IN CLINICAL TRIALS

Complement inhibitors come in many forms, including protease inhibitors, soluble complement regulators, receptor antagonists, therapeutics antibodies, and complement component inhibitors.16 Currently, complement inhibitors intended to improve GA outcomes have been most commonly designed as therapeutic antibodies or complement component inhibitors. Over the years, there have been numerous uncertainties with complement inhibitor clinical trials, including the best clinical endpoint to study, dosing amount, dosing interval, and best complement to target. In this section, we review the complement inhibitors that are currently in clinical trials, which include anti-C5, anti-factor D antigen binding fragment, and anti-C3.

Anti-C5

Two subclasses of anti-C5 drugs exist: anti-C5 aptamer and anti-C5 monoclonal antibody. Intravitreal LFG316 (Novartis) and intravenous eculizumab (Soliris; Alexion Pharmaceuticals) are two anti-C5 monoclonal antibodies in clinical trials and ARC1905 (Zimura; Ophthotech Inc.) is an intravitreal anti-C5 aptamer. These therapeutics bind with high affinity to C5 to prevent C5 activation by preventing the formation of C5a, a key proinflammatory molecule in the complement cascade. Eculizumab was the first complement inhibitor therapeutic to receive FDA approval in March 2007 for treatment of paroxysmal nocturnal hemoglobinuria.

Eculizumab functions by binding to the C5 complement protein and prevents the cleavage of C5a and C5b, inhibiting the activation of the terminal complement.17 In the COMPLETE study, investigators evaluated the effectiveness of eculizumab on GA growth in patients with AMD (NCT00935883). In this phase 2 study, 30 patients were randomized 2:1 to receive intravenous eculizumab or placebo for 24 weeks with a primary endpoint evaluation of GA area growth at 26 weeks. At week 26, GA area grew by a mean of 0.19±0.12 mm in the eculizumab-treated eyes and by a mean of 0.18±0.15 mm in the placebo group (P=.96).18 Even at 52 weeks follow-up, the GA enlargement by mean was insignificant (0.37±0.22 mm in eculizumab-treated eyes and 0.37±0.21 mm in the placebo group, P=.93). In a separate analysis of the COMPLETE data, Garcia Filho et al determined that the mean drusen cube root volumes were not significantly reduced after 26 weeks of eculizumab treatment compared to placebo (0.51 mm eculizumab-treated vs 0.42 mm placebo, P=.17).19 Although eculizumab proved to be safe for at least 6 months, this therapeutic proved to be ineffective for reducing GA growth.

As an anti-C5 aptamer, ARC1905 is an oligonucleotide that binds to the C5 protein. In a phase 1 trial, ARC1905 was established to be safe up to 2 mg (NCT00950638). A separate phase 1 trial established the ARC1905 injection to be safe to administer concurrently with 0.5 g ranibizumab (Lucentis; Genentech), demonstrating that concurrent complement inhibitor and anti-VEGF injections are a possible treatment modality (NCT00709527).20 A recently completed phase 2a study tested the efficacy and safety of administration of ARC1905 in combination with Lucentis 0.5 mg for treatment neovascular AMD (NCT03362190). Currently, ARC1905 is being tested in a phase 2b clinical trial to determine effectiveness secondary to GA (NCT02686658).

The IgG1 antibody LFG316 was developed by phage-display technology with modifications to the Fc region.21 A phase 1 study established the tolerance as 5 mg (NCT01255462). In a phase 2 clinical trial, 150 patients with bilateral AMD and GA were randomly treated 2:1 with 5 mg monthly intravitreal LFG316 injection vs sham injection (NCT01527500). In this study, patients did not see an improvement in GA lesion size compared to placebo, and visual acuity gains between groups were nominal.25

Anti-Factor D Antigen Binding Fragment (Anti-FD)

Lampalizumab (Genentech/Roche) is a monoclonized antibody intravitreal injection that inhibits the C3/C5 alternative pathway convertases by binding to the complement factor D protein. The phase 1 trial for this drug established tolerance up to 10 mg. The MAHALO phase 2 study randomized 129 patients 1:2:1:2 to evaluate lampalizumab’s effectiveness to reduce GA area and safety for monthly vs bimonthly injections against placebo (NCT01229215). At 18 months, monthly-treated lampalizumab participants saw a reduction rate of 20% (80% CI, 4% to 37%; P<.117 at prespecified 0.2 significance level).26 Considering AMD’s strong genetic component, investigators further examined the role of various genetic biomarkers and discovered that the complement factor I (CFI) subpopulation had a 44% (95% CI, 15% to 73%) GA lesion reduction while 54% (95% CI, 21% to 88%; P=.0029) of CFI patients with visual acuity of 20/50 to 20/100 had a GA lesion area reduction. Consequently, the MAHALO study was significant because it was the first therapeutic to show the potential of a complement inhibitor in treating GA.

Although the MAHALO study demonstrated positive potential for lampalizumab to improve GA outcomes, Loyet et al expressed concern for the therapeutic’s effectiveness because their study in cynomolgus monkeys indicated that the desired result for advanced dry AMD was yielded only when the anti-factor D concentration was much stronger than the 10 mg dose used in GA patients.27 These concerns were confirmed in the identical phase 3 clinical trials CHROMA and SPECTRI that indicated different results compared to MAHALO. In the CHROMA study, 906 patients were randomized 2:1:2:1 receiving 10 mg intravitreal lampalizumab every 4 weeks, 6 weeks, or sham injection (NCT02247479). Nine hundred seventy-five patients were randomized similarly in SPECTRI (NCT02247531). In these studies, adjusted mean change from baseline in GA lesion area at 48 weeks were -0.02 mm2 (95% CI, -0.21 to 0.16 mm2; P=.80) for lampalizumab every 4 weeks in CHROMA and 0.16 mm2 (95% CI, 0.00-0.31 mm2; P=.048) for every 4 weeks in SPECTRI. The 6-week treatment values for lampalizumab in CHROMA were 0.05 mm2 (95% CI, -0.13 to 0.24 mm2; P=.59) and for SPECTRI were 0.09 mm2 (95% CI, -0.07 to 0.24 mm2; P=.27).28 Furthermore, a subgroup analysis of those with CFI biomarker showed no meaningful improvement. The insignificant results indicate that lampalizumab was ineffective for treatment of GA secondary to AMD.

Anti-C3

APL-2 (Apellis Pharmaceuticals) is a compstatin derivative composed of 13 amino acids that act as an anti-C3 cyclic peptide. Originally formulated as POT-4 (Potentia), APL-2 acts as a complement component inhibitor and inhibits C3 by steric hindrance.

FILLY was an 18-month phase 2 randomized, single-masked, sham controlled trial of APL-2 in GA with 246 patients (NCT02503332). Patients were randomized 1:1:1 to receive 15 mg APL-2 injections monthly or bimonthly vs sham injections for 12 months, followed by a 6-month follow-up period with no injections. Reducing GA area growth rate by measuring square root transformation of GA area lesion was the primary endpoint. A 29% reduction was noted between the 12-month groups for APL-2 monthly injection vs control (P=.008) and a 20% reduction was observed for bimonthly APL-2 injections vs control (P<.067).29 After cessation of treatment at 12 months, lesion growth differences remained notable, but declined as the bimonthly injection group experienced a 16% lesion growth difference vs sham (P=.097), and the monthly injection group experienced a 20% lesion growth difference vs sham (P=.044) (Figure 2). The 6 to 12 month period of the study was noteworthy, because the monthly injection group experienced a 47% lesion growth reduction (P<.001) vs sham, whereas the bimonthly injection group experienced a 33% lesion growth difference (P=.01).

Figure 2. After cessation of treatment at 12 months, GA growth resumes but treatment effect is maintained through 18 months (square root) as the bimonthly APL-2 group experienced a 16% lesion growth difference (P=.097) vs sham at 18 months while the APL-2 monthly group experienced a 20% growth difference (P=.044) vs sham.

Despite the positive outcomes, the FILLY study highlighted a possible association between exudation and APL-2, including 9% of the bimonthly group and 21% of the monthly group developing new-onset exudation at 18 months follow-up. Despite this drawback, FILLY demonstrated that APL-2 slows GA growth independent of genetics and monthly APL-2 injections for 12 months can show statistically significant differences in GA growth at 18 months. Consequently, the risk-benefit profile supports phase 3 testing, which is scheduled to commence in 2019 as the DERBY and OAKS trials (NCT03525613 and NCT03525600).

CONCLUSION

Many complement inhibitor therapeutics, such as anti-C5 and anti-factor D, have failed to improve GA outcomes in phase 2 and 3 clinical trials, but clinicians and researchers should be optimistic and continue to explore the potential of other complement inhibitors, such as anti-C3 as a novel approach to reduce GA growth and improve advance dry AMD outcomes. Complement inhibitors have significant potential as a treatment option for advanced dry AMD, an area where the need for better interventions clearly exist, due to the well-established role that complement proteins have in AMD progression. RP

REFERENCES

  1. Rudnicka AR, Kapetanakis VV, Jarrar Z, et al. Incidence of late-stage age-related macular degeneration in American whites: systematic review and meta-analysis. Am J Ophthalmol. 2015;160(1):85-93.e3.
  2. Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477.
  3. Chew EY, Clemons TE, Agrón E, et al. Ten-year follow-up of age-related macular degeneration in the Age-Related Eye Disease Study. JAMA Ophthalmol. 2014;132(3):272.
  4. Friedman DS, O’Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564.
  5. Geerlings MJ, de Jong EK, den Hollander AI. The complement system in age-related macular degeneration: A review of rare genetic variants and implications for personalized treatment. Mol Immunol. 2017;84:65-76.
  6. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308(5720):385-389.
  7. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308(5720):419-421.
  8. Sepp T, Khan JC, Thurlby DA, et al. Complement factor H variant Y402H is a major risk determinant for geographic atrophy and choroidal neovascularization in smokers and nonsmokers. Invest Opthalmol Vis Sci. 2006;47(2):536.
  9. Ricklin D, Lambris JD. New milestones ahead in complement-targeted therapy. Semin Immunol. 2016;28(3):208-222.
  10. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134(3):411-431.
  11. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond). 2001;15(3):390-395.
  12. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20(6):705-732.
  13. Johnson LV, Leitner WP, Staples MK, Anderson DH. Complement activation and inflammatory processes in drusen formation and age related macular degeneration. Exp Eye Res. 2001;73(6):887-896.
  14. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013;13(6):438-451.
  15. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103(7):2328-2333.
  16. Ricklin D, Lambris JD. Complement-targeted therapeutics. Nat Biotechnol. 2007;25(11):1265-1275.
  17. Slexion Pharma UK Ltd. Soliris - Summary of Product Characteristics (SmPC) - (eMC). medicines.org.uk . https://www.medicines.org.uk/emc/medicine/19966#FORM . Published 2018. Accessed January 8, 2019.
  18. Yehoshua Z, de Amorim Garcia Filho CA, Nunes RP, et al. Systemic complement inhibition with eculizumab for geographic atrophy in age-related macular degeneration: the COMPLETE study. Ophthalmology. 2014;121(3):693-701.
  19. Garcia Filho CA, Yehoshua Z, Gregori G, et al. Change in drusen volume as a novel clinical trial endpoint for the study of complement inhibition in age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2013;45(1):18-31.
  20. Cousins SW; Ophthotech Study Group. Targeting complement factor 5 in combination with vascular endothelial growth factor (VEGF) inhibition for neovascular age related macular degeneration (AMD): results of a phase 1 study. Invest Ophthalmol Vis Sci. 2010;51:1251.
  21. Roguska M, Splawski I, Diefenbach-Streiber B, et al. Generation and characterization of LFG316, a fully-human anti-C5 antibody for the treatment of age-related macular degeneration. Invest Ophthalmol Vis Sci. 2014;55:3433.
  22. Owen J, Punt J, Stranford S. Kuby Immunology, 7th ed. New York: W.H. Freeman and Co Ltd; 2013.
  23. Walport MJ. Complement. First of two parts. N Engl J Med. 2001;344(14):1058-1066.
  24. Boyer D, Schmidt-Erfurth U, van Lookeren Campagne M, Henry EC, Brittain C. The pathophysiology of geographic atrophy secondary to age-related macular degeneration and the complement pathway as a therapeutic target. Retina. 2017;37(5):819-835.
  25. Zamiri P. Complement C5 inhibition in AMD. Paper presented at the Angiogenesis meeting, February 6, 2016, Miami, FL.
  26. Yaspan BL, Williams DF, Holz FG, et al. Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration. Sci Transl Med. 2017;9(395):eaaf1443.
  27. Loyet KM, Good J, Davancaze T, et al. Complement inhibition in cynomolgus monkeys by anti-factor d antigen-binding fragment for the treatment of an advanced form of dry age-related macular degeneration. J Pharmacol Exp Ther. 2014;351(3):527-537.
  28. Holz FG, Sadda SR, Busbee B, et al. Efficacy and safety of lampalizumab for geographic atrophy due to age-related macular degeneration. JAMA Ophthalmol. 2018;136(6):666.
  29. Singh R. APL-2 (pegcetacoplan) geographic atrophy preliminary 18-month results. Presented at the 41st Annual Meeting of the Macula Society, February 22, 2018, Beverly Hills, CA.