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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.
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.”
Study design and data
The Phase 2 trial was a proof-of-concept study and was double-masked. It randomized 191 patients ages 55 years and older into 4 treatment groups to receive monthly intravenous administration of placebo or GSK933776 at doses of 3, 6, or 15 mg/kg.
To be eligible, the study eye of patients had to have well-demarcated GA due to AMD, measuring 1.9 to 17 mm2 (~0.76 to 6.7 DA). If there were multifocal GA lesions, at least 1 focal lesion had to be ≥1.9 mm2 (0.75 DA), and the total lesion area could not exceed 17 mm2.
Best corrected visual acuity (BCVA) had to be ≥35 ETDRS letters and patients could have no history of or current choroidal neovascularization (CNV), other ocular disease that could confound assessments, or previous treatment for AMD. Prior to randomization, patients entered a 4-month observation period, and after the 18-month treatment period, they were followed for another 3 months.
The 4 study groups were well-balanced at baseline with respect to mean age, gender distribution, and study eye characteristics of GA with the exception that the percentage of eyes with multifocal GA, which was slightly lower in the placebo group than in the GSK933776 groups.
After controlling for baseline lesion size and growth rate during the 4-month, lead-in observation period, the analysis of change from baseline to month 18 in GA area showed no effect of treatment with GSK933776.
“The results were the same with the square-root transformation of GA area measurements, which is a method that eliminates growth rate dependence on baseline lesion areas and the technique we advocate at Bascom Palmer,” Dr. Rosenfeld said.
Overall, the analysis of mean change from baseline BCVA showed a downward drift in all groups and no significant treatment-related effect.
No effect on growth rate
Analyses of outcomes with patients stratified by pharmacogenetic markers showed that the CFI genetic biomarker status did not affect GA growth rate during the pre-randomization observation period or during the treatment period.
“The distribution of pharmacogenetic markers in this study population was very similar to that of patients in the MAHALO study of lampalizumab (Genentech),” noted Dr. Rosenfeld.
Importantly, the low-luminance visual acuity deficit at baseline was highly predictive of the rate of GA progression during the 18-month post-randomization phase with eyes having a greater deficit at baseline experiencing a greater change in GA area.
“This finding confirmed our previous finding in the COMPLETE study in which there was an association between a faster growth rate of GA and an increased baseline low luminance deficit, and this finding may help with patient selection for future trials,” Dr. Rosenfeld reported.
A large number of brain MRIs were done as part of the safety assessments. There were two serious non-ocular adverse events considered related to study treatment, which were a cerebral hemorrhage and a cerebral infarct found on MRI. Both were in the 15 mg/kg group and asymptomatic. The only significant ocular safety event was development of CNV in 3 study eyes, and study treatment was withdrawn from those affected patients.
Philip J. Rosenfeld, MD, PhD
This article is based on a presentation given by Dr. Rosenfeld at the 2016 Retina Subspecialty Day meeting. Dr. Rosenfeld received research grant support from GlaxoSmithKline as a study investigator. He is a consultant to and/or received research grants from other companies that market or are developing treatments for AMD.