Targeting factor D of the alternative complement pathway reduces geographic atrophy progression secondary to age-related macular degeneration

Abstract

Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly ( = 42) and every other month ( = 41) versus sham control ( = 40) in patients with geographic atrophy secondary to AMD. The primary endpoint was the mean change in lesion area from baseline to month 18 as measured by fundus autofluorescence. Specific AMD-associated genetic polymorphisms were also analyzed. The MAHALO study met its primary efficacy endpoint with an acceptable safety profile; monthly lampalizumab treatment demonstrated a 20% reduction in lesion area progression versus sham control [80% confidence interval (CI), 4 to 37%]. A more substantial monthly treatment benefit of 44% reduction in geographic atrophy area progression versus sham control (95% CI, 15 to 73%) was observed in a subgroup of complement factor I () risk-allele carriers (57% of the patients analyzed were risk-allele carriers). The MAHALO study shows a potential treatment effect in patients with geographic atrophy and supports therapeutic targeting of the alternative complement pathway for treating AMD pathogenesis.

Potential Mechanisms Underlying TGF-β-mediated Complement Activation in Lung Fibrosis

“…Recent clinical reports indicate that targeting the complement cascade is gaining traction, e.g. C3 (compstatin/POT-4 peptide) [35], C5 antibody (Soliris; Alexion Pharmaceuticals) [36], Factor D (TNX-234 antibody) [37], C5aR 1 inhibitor, C1-INH (various manufacturers) in treating Paroxysmal Nocturnal Hemoglobinuria, atypical Hemolytic Uremic Syndrome, ARMD, gastrointestinal injury-related GVHD, C3 nephropathy, amyotrophic lateral sclerosis and other severe disorders. Our results in this report show that limiting complement activation may be a promising therapeutic strategy against TGF-β-induced lung fibrosis and is consistent with the report on the bleomycin injury model [4].…”

The renaissance of complement therapeutics

“…The high plasma turnover of FD and other pharmacokinetic challenges limit the systemic use of lampalizumab 129 ; however, this agent has been evaluated for intravitreal use in patients with geographic atrophy associated dry forms of AMD. In phase II studies 130 , lampalizumab treatment resulted in a 20% reduction in the progression of retinal lesions in the overall patient cohort, with a 44% reduction in a subgroup carrying polymorphisms in the genes for both FH and FI 131 . Two large phase III trials of lampalizumab for geographic atrophy in AMD with identical study designs were initiated in 2014 (REFS 132,133).…”

“…Local administration of a complement therapeutic may often circumvent pharmacokinetic issues observed during systemic use. For example, after intra venous administration, the AMD therapeutic lampalizumab is rapidly eliminated and plasma levels of FD increase, whereas the drug shows a largely extended residence and efficacy after direct administration into the eye as the target compartment 129,131 .…”

“…A Phase II trial of lampalizumab (anti-FD) in AMD demonstrated that even in a disease with clear complement involvement, only a fraction of patients may fully benefit from a certain treatment 130,131,199 . In this trial, patients carrying polymorphisms in both FI and FH experienced a substantially greater reduction in the progression of retinal lesions than that seen in those who carried only the FH polymorphism 131 . On the basis of this insight, the FI polymorphism was considered an important biomarker and was included as an assessment parameter in phase III trials of the drug 131–133 .…”

Multimodal Imaging Patterns for Development of Central Atrophy Secondary to Age-Related Macular Degeneration

“…15,16 Recently, several large-scale clinical studies have been initiated and completed, aiming to halt or slow GA lesion enlargement. [17][18][19] Typically, the minimum total atrophic lesion size for inclusion in clinical studies in GA is currently 0.5 to 1.0 disc areas (1.25-2.5 mm 2 ).…”