Treatment for geographic atrophy lacks efficacy in Phase 2 study
Antibody targeting amyloid β has no effect on the growth of geographic atrophy or visual acuity over 18 months
Take-home: In a placebo-controlled, dose-finding, proof-of-concept study conducted in patients with geographic atrophy secondary to age-related macular degeneration, an anti-amyloid β monoclonal antibody (GSK933776, GlaxoSmithKline) was safe and well-tolerated, but did not meet primary or secondary efficacy endpoints.
Reviewed by Philip J. Rosenfeld, MD, PhD
While monthly treatment with GSK933776 (GlaxoSmithKline) for 18 months was safe and well-tolerated, the Phase 2 study investigating intravenous infusions of an anti-amyloid β monoclonal antibody as a treatment for geographic atrophy (GA), secondary to age-related macular degeneration (AMD), failed to meet its primary endpoint.
“There were no safety signals in the study that would preclude continued investigation of GSK933776,” said Philip J. Rosenfeld, MD, PhD, professor of ophthalmology, Bascom Palmer Eye Institute, University of Miami. “The pharmacokinetics and pharmacodynamics data were consistent with showing a dose-related increase in plasma antibody concentration and a decrease in free amyloid β in plasma with a near maximum reduction with the highest dose.
Dr. Rosenfeld pointed out that the primary analysis, however, showed no slowing in the rate of GA enlargement overall or among prospectively defined subpopulations.
“There was no clinically meaningful effect on the visual function measurements of subjects in the GSK933776 treatment groups relative to the controls receiving placebo injections,” Dr. Rosenfeld added. “Currently, there are no plans to investigate GSK933776 further as a treatment for late-stage AMD.”
Interest in investigating an anti-amyloid β antibody for treatment of GA stems in part from observations that amyloid β colocalizes with activated complement in drusen and is elevated in the plasma of GA patients. In addition, it is known that amyloid β causes upregulation of complement factor B (CFB) and inhibits complement factor I (CFI), which has been shown to increase the activity of the alternative pathway of complement.
“We know that complement risk alleles, particularly those within the alternative complement pathway, are associated with AMD,” Dr. Rosenfeld explained. “By removing amyloid β, we had hoped GSK933776 would normalize CFI and CFB, decrease the alternative pathway activation of complement, and slow the progression of GA. Data from preclinical studies involving both an animal model of AMD (cfh-/-) and in the APOE transgenic mouse on a high-fat diet showed that systemic administration of an anti-amyloid β monoclonal antibody depleted both complement and amyloid β from the retina in a dose dependent fashion.”