@article{09f2cfe2560d41db852932d557dd77b8,
title = "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 dys-regulation 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.",
author = "Yaspan, {Brian L.} and Williams, {David F.} and Holz, {Frank G.} and Regillo, {Carl D.} and Zhengrong Li and Amy Dressen and {Van Lookeren Campagne}, Menno and Le, {Kha N.} and Graham, {Robert R.} and Tatiana Beres and Bhangale, {Tushar R.} and Honigberg, {Lee A.} and Ashley Smith and Henry, {Erin C.} and Carole Ho and Strauss, {Erich C.}",
note = "Funding Information: Genentech Inc. supported and contributed to all aspects of the study, including the study design, data collection and analyses, statistical analyses, data interpretation, and report writing. Support for third-party writing assistance for this article was provided by the sponsor. All authors had access to the data, contributed to the manuscript, and provided approval for publication. The corresponding author had final responsibility for the decision to submit the manuscript for publication. Author contributions: E.C.S., T.B., Z.L., K.N.L., and R.R.G. contributed to the study design; Z.L., E.C.S., and T.B. contributed to safety and efficacy data acquisition; B.L.Y. and A.D. contributed to genetic data acquisition; K.N.L. contributed to pharmacokinetic data acquisition; T.R.B. contributed to eQTL data acquisition; L.A.H. and A.S. contributed to serum and aqueous data acquisition; D.F.W., F.G.H., and C.D.R. contributed to clinical examination data acquisition; E.C.H. contributed to enrollment and retention data acquisition; and Z.L., E.C.S., C.H., B.L.Y., A.D., R.R.G., K.N.L., M.v.L.C., T.R.B., L.A.H., and A.S. contributed to data analysis. All authors contributed to data interpretation and critically reviewed and approved the manuscript. Competing interests: B.L.Y., Z.L., A.D., M.v.L.C., R.R.G., T.B., T.R.B., E.C.H., L.A.H., and E.C.S. are employees of Genentech Inc. and have Roche stock/stock options. K.N.L., A.S., and C.H. were employees of Genentech Inc. at the time of the MAHALO study and during manuscript development; K.N.L. is currently an employee of Agios Pharmaceuticals, and C.H. is currently an employee of Denali Therapeutics. D.F.W. has received advisory board funds from Genentech Inc. and is a cofounder/owner of Vestrum Health (financial contractual relationship with Genentech Inc.). F.G.H. has received research support from Allergan, Bayer, Genentech Inc., Heidelberg Engineering, Novartis, and Roche and consulted for Alcon, Bayer, Genentech Inc., Heidelberg Engineering, Novartis, and Roche. C.D.R. has received research support from Acucela, Allergan, Genentech Inc., GlaxoSmithKline, Ocata, Regeneron, and ThromboGenics and consulted for Acucela, Allergan, Genentech Inc., Regeneron, and ThromboGenics. A patent (#CA2920666 A1) has been granted entitled {"}Compositions and method for treating complement-associated conditions.{"} Publisher Copyright: Copyright {\textcopyright} 2017 The Authors.",
year = "2017",
month = jun,
day = "21",
doi = "10.1126/scitranslmed.aaf1443",
language = "English",
volume = "9",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "395",
}