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 (n = 42) and every other month (n = 41) versus sham control (n = 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 (CFI) risk-allele carriers (57% of the patients analyzed were CFI 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.

• Authors: Brian L Yaspan, David F Williams, Frank G Holz, Carl D Regillo, Zhengrong Li, Amy Dressen, Menno van Lookeren Campagne, Kha N Le, Robert R Graham, Tatiana Beres, Tushar R Bhangale, Lee A Honigberg, Ashley Smith, Erin C Henry, Carole Ho, Erich C Strauss, MAHALO Study Investigators
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 395 (06 21 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 28637922 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Immunoglobulin Fab Fragments
• CFD protein, human
• Complement Factor D
• lampalizumab

Topics

• Aged
• Complement Factor D (antagonists & inhibitors, metabolism)
• Complement Pathway, Alternative
• Disease Progression
• Female
• Geographic Atrophy (drug therapy, metabolism, pathology)
• Humans
• Immunoglobulin Fab Fragments (therapeutic use)
• Macular Degeneration (drug therapy, metabolism, pathology)
• Male
• Middle Aged