Dataset Information

Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration.

ABSTRACT: This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy associated with dry age-related macular degeneration.Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity after a photobleach was measured by electroretinography. Safety evaluations included analysis of adverse events and ophthalmic examinations.Seventy-two subjects (54 emixustat and 18 placebo) were evaluated. Emixustat suppressed rod photoreceptor sensitivity in a dose-dependent manner. Suppression plateaued by Day 14 and was reversible within 7 days to 14 days after drug cessation. Most systemic adverse events were not considered treatment related. Dose-related ocular adverse events (chromatopsia, 57% emixustat vs. 17% placebo and delayed dark adaptation, 48% emixustat vs. 6% placebo) were mild to moderate in severity, and the majority resolved on study or within 7 days to 14 days after study drug cessation. Reversibility of these adverse events with long-term administration, however, is undetermined.In this Phase II study, emixustat produced a dose-dependent reversible effect on rod function that is consistent with the proposed mechanism of action. These results support further testing of emixustat for the treatment of geographic atrophy associated with dry age-related macular degeneration.

SUBMITTER: Dugel PU

PROVIDER: S-EPMC4452434 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration.

Dugel Pravin U PU Novack Roger L RL Csaky Karl G KG Richmond Preston P PP Birch David G DG Kubota Ryo R

Retina (Philadelphia, Pa.) 20150601 6

<h4>Purpose</h4>This study assessed the safety, tolerability, and pharmacodynamics of emixustat hydrochloride (ACU-4429), a novel visual cycle modulator, in subjects with geographic atrophy associated with dry age-related macular degeneration.<h4>Methods</h4>Subjects were randomly assigned to oral emixustat (2, 5, 7, or 10 mg once daily) or placebo (3:1 ratio) for 90 days. Recovery of rod photoreceptor sensitivity after a photobleach was measured by electroretinography. Safety evaluations includ ...[more]

PMID: 25932553

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Project description:Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular-associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this condition due to the aging of the general population lends urgency to the search for a therapy to ameliorate GA.

Project description:ImportanceSensitive outcome measures for disease progression are needed for treatment trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).ObjectiveTo quantify photoreceptor degeneration outside regions of GA in eyes with nonexudative AMD, to evaluate its association with future GA progression, and to characterize its spatio-temporal progression.Design, setting, and participantsMonocenter cohort study (Directional Spread in Geographic Atrophy [NCT02051998]) and analysis of data from a normative data study at a tertiary referral center. One hundred fifty-eight eyes of 89 patients with a mean (SD) age of 77.7 (7.1) years, median area of GA of 8.87 mm2 (IQR, 4.09-15.60), and median follow-up of 1.1 years (IQR, 0.52-1.7 years), as well as 93 normal eyes from 93 participants.ExposuresLongitudinal spectral-domain optical coherence tomography (SD-OCT) volume scans (121 B-scans across 30° × 25°) were segmented with a deep-learning pipeline and standardized in a pointwise manner with age-adjusted normal data (z scores). Outer nuclear layer (ONL), photoreceptor inner segment (IS), and outer segment (OS) thickness were quantified along evenly spaced contour lines surrounding GA lesions. Linear mixed models were applied to assess the association between photoreceptor-related imaging features and GA progression rates and characterize the pattern of photoreceptor degeneration over time.Main outcomes and measuresAssociation of ONL thinning with follow-up time (after adjusting for age, retinal topography [z score], and distance to the GA boundary).ResultsThe study included 158 eyes of 89 patients (51 women and 38 men) with a mean (SD) age of 77.7 (7.1) years. The fully automated B-scan segmentation was accurate (dice coefficient, 0.82; 95% CI, 0.80-0.85; compared with manual markings) and revealed a marked interpatient variability in photoreceptor degeneration. The ellipsoid zone (EZ) loss-to-GA boundary distance and OS thickness were prognostic for future progression rates. Outer nuclear layer and IS thinning over time was significant even when adjusting for age and proximity to the GA boundary (estimates of -0.16 μm/y; 95% CI, -0.30 to -0.02; and -0.17 μm/y; 95% CI, -0.26 to -0.09).Conclusions and relevanceDistinct and progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. The degree of photoreceptor degeneration outside of regions of retinal pigment epithelium atrophy varied markedly between eyes and was associated with future GA progression. Macula-wide photoreceptor laminae thinning represents a potential candidate end point to monitor treatment effects beyond mere GA lesion size progression.

Project description:PurposeWe sought to determine whether genotype is associated with rate of growth of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD).DesignProspective analysis of participants in a randomized controlled clinical trial.ParticipantsWe included 114 eyes of 114 participants in the Age-Related Eye Disease Study (AREDS).MethodsFundus photographs from AREDS participants with GA from whom a DNA specimen had been obtained and serial photographs had been taken over a minimum of 2 years were evaluated for progression as determined by change in cumulative area of GA. All fundus photographs were scanned, digitized, and centrally graded longitudinally for area of GA. The relationship of GA progression with previously identified genetic variants associated with AMD was assessed.Main outcome measuresGenotype frequencies and change in cumulative area of GA.ResultsThe mean growth rate of GA for the 114 eyes was 1.79 mm(2)/year (range, 0.17-4.76). No association between growth rate and genotype was present for variants in the CFH, C2, C3, APOE, and TLR3 genes. For the single nucleotide polymorphism rs10490924 in LOC387715/ARMS2, there was a significant association of GA growth rate, both adjusted and unadjusted for initial lesion size, with the homozygous risk genotype as compared with the homozygous nonrisk genotype (unadjusted P = 0.002; Bonferroni-corrected P = 0.014) and for allelic association (Bonferroni-corrected P value = 0.011). Analyses of other measures of GA progression (progression to central GA from extrafoveal GA and development of bilateral GA in those initially with unilateral GA) showed no statistically significant association between progression and the LOC387715/ARMS2/HTRA1 genotype.ConclusionsGrowth rates of GA calculated from digitized serial fundus photographs showed no association with variants in the CFH, C2, C3, APOE, or TLR3 genes. There was a nominally significant association with the LOC387715/ARMS2/HTRA1 genotype, although this finding was not supported by analyses of secondary measures of GA progression. Replication in other populations is needed to establish the existence of an association.

Project description:PURPOSE:In an eye with geographic atrophy (GA) secondary to age-related macular degeneration, we correlated ex vivo histologic features with findings recorded in vivo using optical coherence tomography (OCT), near-infrared reflectance imaging, and fundus autofluorescence. METHODS:In the left eye of an 86-year-old white woman, in vivo near-infrared reflectance and eye-tracked OCT B-scans at each of 6 clinic visits and a baseline fundus autofluorescence image were correlated with high-resolution histologic images of the preserved donor eye. RESULTS:Clinical imaging showed a small parafoveal multilobular area of GA, subfoveal soft drusen, refractile drusen, hyperreflective lines near the Bruch membrane, subretinal drusenoid deposit (reticular pseudodrusen), and absence of hyperautofluorescent foci at the GA margin. By histology, soft drusen end-stages included avascular fibrosis with highly reflective cholesterol crystals. These accounted for hyperreflective lines near the Bruch membrane in OCT and plaques in near-infrared reflectance imaging. Subretinal drusenoid deposit was thick, continuous, extracellular, extensive outside the fovea, and associated with distinctive retinal pigment epithelium dysmorphia and photoreceptor degeneration. A hyporeflective wedge corresponded to ordered Henle fibers without cellular infiltration. The external limiting membrane descent, which delimits GA, was best visualized in high-quality OCT B-scans. Retinal pigment epithelium and photoreceptor changes at the external limiting membrane descent were consistent with our recent histologic survey of donor eyes. CONCLUSION:This case informs on the extent, topography, and lifecycle of extracellular deposits. High-quality OCT scans are required to reveal all tissue features relevant to age-related macular degeneration progression to GA, especially the external limiting membrane descent. Histologically validated signatures of structural OCT B-scans can serve as references for other imaging modalities.

Project description:PURPOSE:To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. DESIGN:Prospective cohort study within a controlled clinical trial. PARTICIPANTS:Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50-85 years. METHODS:Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. MAIN OUTCOME MEASURES:(1) Presence or development of GA; (2) change in the square root of GA area over time. RESULTS:At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27-0.30) and incident GA (0.28 mm/year; 0.27-0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes. CONCLUSIONS:Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Project description:PURPOSE:To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch membrane-choriocapillaris complex and associated extracellular deposits. METHODS:Geographic atrophy was delimited by the external limiting membrane (ELM) descent towards Bruch membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models. RESULTS:On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Müller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch membrane thinned, and choriocapillaris density decreased. CONCLUSION:The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Müller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.

Dataset Information

Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration.

Publications

Phase ii, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration.

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