Treatment of exudative age-related macular degeneration with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study

PURPOSE To evaluate the safety, tolerability and bioactivity of ascending doses of MP0112, a designed ankyrin repeat protein (DARPin) that binds with high affinity to vascular endothelial growth factor-A (VEGF-A), in treatment-naive patients with exudative age-related macular degeneration (AMD). DESIGN Phase I/II, open-label, multicenter, dose-escalation study. METHODS Patients were to receive a single intravitreal injection of MP0112 at doses ranging from 0.04 to 3.6 mg and be monitored for 16 weeks for safety, efficacy, pharmacokinetics, and dose response. RESULTS Altogether, 32 patients received a single injection of MP0112. The maximum tolerated dose was 1.0 mg because of a case of endophthalmitis in the 2.0 mg cohort. Drug-related adverse events were reported by 13 (41%) of 32 patients; they included ocular inflammation in 11 patients (7 mild, 4 moderate in severity). Visual acuity scores were stable or improved compared with baseline for ≥4 weeks following injection; both retinal thickness and fluorescein angiography leakage decreased in a dose-dependent manner. Rescue therapy was administered to 20 (91%) of 22 patients who received 0.04-0.4 mg MP0112 compared with 4 of 10 (40%) patients who received 1.0 or 2.0 mg. Of patients in the higher-dose cohorts who did not require rescue treatment, 83% (5/6) maintained reductions in central retinal thickness through week 16. CONCLUSIONS A single injection of 1.0 or 2.0 mg MP0112 resulted in mean decreases in retinal thickness and leakage area despite ocular inflammation. Larger-scale studies are warranted to confirm these observations.

Demographic model of the Swiss cattle population for the years 2009-2011 stratified by gender, age and production type

Demographic composition and dynamics of animal and human populations are important determinants for the transmission dynamics of infectious disease and for the effect of infectious disease or environmental disasters on productivity. In many circumstances, demographic data are not available or of poor quality. Since 1999 Switzerland has been recording cattle movements, births, deaths and slaughter in an animal movement database (AMD). The data present in the AMD offers the opportunity for analysing and understanding the dynamic of the Swiss cattle population. A dynamic population model can serve as a building block for future disease transmission models and help policy makers in developing strategies regarding animal health, animal welfare, livestock management and productivity. The Swiss cattle population was therefore modelled using a system of ordinary differential equations. The model was stratified by production type (dairy or beef), age and gender (male and female calves: 0-1 year, heifers and young bulls: 1-2 years, cows and bulls: older than 2 years). The simulation of the Swiss cattle population reflects the observed pattern accurately. Parameters were optimized on the basis of the goodness-of-fit (using the Powell algorithm). The fitted rates were compared with calculated rates from the AMD and differed only marginally. This gives confidence in the fitted rates of parameters that are not directly deductible from the AMD (e.g. the proportion of calves that are moved from the dairy system to fattening plants).

Randomized Trial to Evaluate Tandosporine in Geographic Atrophy Secondary to Age-Related Macular Degeneration: the GATE Study.

PURPOSE To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression. DESIGN Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial. METHODS Setting: 48 clinical sites. PATIENTS Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. Intervention Procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop. MAIN OUTCOME MEASURES The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging. RESULTS A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (N=250), AL-8309B 1.75% (N=258), or vehicle (N= 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76 and 1.71 mm(2) for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively. CONCLUSIONS AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons.

Scheduled versus Pro Re Nata Dosing in the VIEW Trials

PURPOSE To analyze visual acuity (VA) outcomes before and after preplanned treatment regimen change in the VIEW studies at week 52 (W52). DESIGN Multiple post hoc analyses for retrospectively defined subgroups in 2 multicenter, multinational, double-masked trials. PARTICIPANTS Two thousand four hundred fifty-seven neovascular age-related macular degeneration (AMD) patients. METHODS Patients were randomized to treatment with 0.5 mg ranibizumab given monthly, a 0.5-mg or 2-mg intravitreal aflibercept injection given monthly, or 2 mg intravitreal aflibercept given every other month, after 3 initial monthly doses, up to W52. From W52 through W96, patients received their original dosing assignment using a capped pro re nata (PRN) regimen, with defined retreatment criteria based on VA and morphologic signs of disease activity and mandatory dosing at least every 12 weeks. MAIN OUTCOME MEASURES Best-corrected VA (BCVA) and optical coherence tomography assessments were mandatory at all visits from baseline to W96. Outcomes were changes in BCVA and central retinal thickness. Outcomes were evaluated in all patients who completed 2 years of the VIEW studies using the last observation carried forward method for missing data at interim visits. RESULTS After W52, approximately 20% of patients lost 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or more across all treatment arms with PRN treatment. Patients who met the retreatment criterion of loss of 5 ETDRS letters or more in the first quarter of the PRN dosing phase did not recover; mean final VA loss across the 4 study arms was -4.4 to -5.8 letters. Outcomes of these patients up to W52 were indistinguishable from those of the overall population. There were no differences between groups in serious ocular adverse events or Anti-Platelet Trialists' Collaboration arterial thromboembolic events through W96. CONCLUSIONS These analyses suggest that there are subgroups of patients for whom VA outcomes in the second year of the VIEW studies were less stable than in the first year and for whom W52 seems to be an important inflection point. Although alternate reasons specific to the nature of the underlying AMD cannot be fully excluded, the switch in treatment regimen at W52 is a plausible explanation.

Prevention of increased abnormal fundus autofluorescence with blue light-filtering intraocular lenses

PURPOSE To observe changes in fundus autofluorescence 2 years after implantation of blue light-filtering (yellow-tinted) and ultraviolet light-filtering (colorless) intraocular lenses (IOLs). SETTING Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan, and the Department of Ophthalmology, University of Bern, Bern, Switzerland. DESIGN Prospective comparative observational study. METHODS Patients were enrolled who had cataract surgery with implantation of a yellow-tinted or colorless IOL and for whom images were obtained on which the fundus autofluorescence was measurable using the Heidelberg Retina Angiogram 2 postoperatively. The fundus autofluorescence in the images was classified into 8 abnormal patterns based on the classification of the International Fundus Autofluorescence Classification Group, The presence of normal fundus autofluorescence, geographic atrophy, and wet age-related macular degeneration (AMD) also was recorded. The fundus findings at baseline and 2 years postoperatively were compared. RESULTS Fifty-two eyes with a yellow-tinted IOL and 79 eyes with a colorless IOL were included. Abnormal fundus autofluorescence did not develop or increase in the yellow-tinted IOL group; however, progressive abnormal fundus autofluorescence developed or increased in 12 eyes (15.2%) in the colorless IOL group (P = .0016). New drusen, geographic atrophy, and choroidal neovascularization were observed mainly in the colorless IOL group. The incidence of AMD was statistically significantly higher in the colorless IOL group (P = .042). CONCLUSIONS Two years after cataract surgery, significant differences were seen in the progression of abnormal fundus autofluorescence between the 2 groups. The incidence of AMD was lower in eyes with a yellow-tinted IOL. FINANCIAL DISCLOSURE No author has a financial or proprietary interest in any material or method mentioned.

Fluctuations in Pigment Epithelial Detachment and Retinal Fluid Using a Bimonthly Treatment Regimen with Aflibercept for Neovascular Age-Related Macular Degeneration

PURPOSE To assess the effect of a bimonthly treatment regimen with intravitreal aflibercept on retinal fluid and pigment epithelial detachment (PED) in patients with neovascular age-related macular degeneration (AMD). METHODS Twenty-six treatment-naive eyes of 26 patients with choroidal neovascularisation secondary to AMD were included. The patients received three initial monthly (mean 30 days) intravitreal injections of aflibercept followed by a bimonthly (mean 62 days) fixed regimen for a total of 1 year. Best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) measurements were recorded at monthly intervals. In addition, the presence of intraretinal fluid (IRF) or subretinal fluid (SRF) or a combination of both as well as serous and fibrovascular PEDs were assessed. RESULTS The mean patient age was 80 years (range 54-93). There were 14 male and 12 female patients. The mean gain in BCVA at 1 year was 9.3 letters (SEM ±3) with a mean reduction of the central retinal thickness of 154 µm (SEM ±50). After 3 monthly injections of aflibercept, there was resolution of IRF and SRF in 80% of the treated eyes; the amount of fluid increased at months 4, 6 and 8 with troughs in between. Whereas fibrovascular PEDs remained stable after the loading phase, serous PEDs displayed a seesaw pattern. Patients without retinal pigment epithelium (RPE) atrophy at the end of the 1-year period had significantly better BCVA compared to patients with RPE atrophy (p = 0.03). CONCLUSION Despite significant overall BCVA gain, bimonthly intervals seem insufficient to maintain the morphological improvements after the initial loading dose with intravitreal aflibercept.

Oral Lutein Supplementation Enhances Macular Pigment Density and Contrast Sensitivity but Not in Combination With Polyunsaturated Fatty Acids.

Purpose It has been shown that lutein and zeaxanthin accumulate in the macula where they enhance contrast sensitivity and may reduce the risk of progression to advanced age-related macular degeneration (AMD). Furthermore, omega-3 long-chain polyunsaturated fatty acids (PUFA) might further reduce this risk. However, controversy exists regarding whether PUFA may reduce the bioavailability of lutein. Methods This was a prospective 12-month, randomized, open label study evaluating the effect of supplementation with lutein, other antioxidants, and minerals on contrast sensitivity (CS) and macular pigment optical density (MPOD) in patients with age-related maculopathy. A total of 79 patients were randomized to either lutein (10 mg) and antioxidant supplement or lutein and antioxidant supplement in combination with PUFA. Patients received supplementation for a period of 6 months and were followed for a total of 12 months. Results Serum lutein and zeaxanthin increased significantly by the first follow-up visit at 1 month, and remained elevated throughout the intervention period of 6 months in the lutein-only group but not in the lutein+PUFA group. Macular pigment optical density and CS increased significantly in the lutein-only group (P < 0.005) but not in the lutein+PUFA group (P = 0.059) compared to baseline. Best-corrected visual acuity remained unchanged during the entire study period in both groups. Conclusions Addition of PUFA may reduce the bioavailability of lutein and therefore lessen the beneficial effect on macular pigment and CS. This needs to be considered when prescribing lutein supplements to patients with low lutein levels. (ClinicalTrials.gov number, NCT00563979.).

Retinal ganglion cell layer change in patients treated with anti-VEGF for neovascular age related macular degeneration.

PURPOSE To evaluate macular retinal ganglion cell thickness in patients with neovascular age-related macular degeneration (AMD) and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. DESIGN Retrospective case series with fellow-eye comparison METHODS: Patients with continuous unilateral anti-VEGF treatment for sub- and juxtafoveal neovascular AMD and a minimum follow-up of 24 months were included. The retinal nerve fiber (RNFL) and retinal ganglion cell layer (RGCL) in the macula were segmented using an ETDRS grid. RNFL and RGCL thickness of the outer ring of the ETDRS grid were quantified at baseline and after repeated anti-VEGF injections, and compared to the patients' untreated fellow eye. Furthermore, best-corrected visual acuity (BCVA), age, and retinal pigment epithelium (RPE) atrophy were recorded and correlated with RNFL and RGCL. RESULTS Sixty eight eyes of 34 patients (23 female and 11 male; mean age 76.7 (SD±8.2) with a mean number of 31.5 (SD ±9.8) anti-VEGF injections and a mean follow-up period of 45.3 months (SD±10.5) were included. Whereas the RGCL thickness decreased significantly compared to the non-injected fellow eye (p=0.01) the decrease of the RNFL was not significant. Visual acuity gain was significantly correlated with RGCL thickness (r=0.52, p<0.05) at follow-up and negatively correlated (r=-0.41, p<0.05) with age. Presence of RPE atrophy correlated negatively with the RGCL thickness at follow-up (r= -0.37, p=0.03). CONCLUSION During the course of long term anti-VEGF therapy there is a significant decrease of the RGCL in patients with neovascular AMD to the fellow (untreated) eye.

Macular atrophy in patients with long-term anti-VEGF treatment for neovascular age-related macular degeneration.

PURPOSE To identify the prevalence and progression of macular atrophy (MA) in neovascular age-related macular degeneration (AMD) patients under long-term anti-vascular endothelial growth factor (VEGF) therapy and to determine risk factors. METHOD This retrospective study included patients with neovascular AMD and ≥30 anti-VEGF injections. Macular atrophy (MA) was measured using near infrared and spectral-domain optical coherence tomography (SD-OCT). Yearly growth rate was estimated using square-root transformation to adjust for baseline area and allow for linearization of growth rate. Multiple regression with Akaike information criterion (AIC) as model selection criterion was used to estimate the influence of various parameters on MA area. RESULTS Forty-nine eyes (47 patients, mean age 77 ± 14) were included with a mean of 48 ± 13 intravitreal anti-VEGF injections (ranibizumab:37 ± 11, aflibercept:11 ± 6, mean number of injections/year 8 ± 2.1) over a mean treatment period of 6.2 ± 1.3 years (range 4-8.5). Mean best-corrected visual acuity improved from 57 ± 17 letters at baseline (= treatment start) to 60 ± 16 letters at last follow-up. The MA prevalence within and outside the choroidal neovascularization (CNV) border at initial measurement was 45% and increased to 74%. Mean MA area increased from 1.8 ± 2.7 mm(2) within and 0.5 ± 0.98 mm(2) outside the CNV boundary to 2.7 ± 3.4 mm(2) and 1.7 ± 1.8 mm(2) , respectively. Multivariate regression determined posterior vitreous detachment (PVD) and presence/development of intraretinal cysts (IRCs) as significant factors for total MA size (R(2) = 0.16, p = 0.02). Macular atrophy (MA) area outside the CNV border was best explained by the presence of reticular pseudodrusen (RPD) and IRC (R(2) = 0.24, p = 0.02). CONCLUSION A majority of patients show MA after long-term anti-VEGF treatment. Reticular pseudodrusen (RPD), IRC and PVD but not number of injections or treatment duration seem to be associated with the MA size.