Gui-shuang Ying

Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

BACKGROUND Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. METHODS In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. RESULTS Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. CONCLUSIONS At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).

Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results

OBJECTIVE To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. DESIGN Multicenter, randomized clinical trial. PARTICIPANTS Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. INTERVENTIONS At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. MAIN OUTCOME MEASURES Mean change in visual acuity. RESULTS Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). CONCLUSIONS Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial

BACKGROUND Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Lebers congenital amaurosis. METHODS We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Lebers congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years. FINDINGS AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov, number NCT00516477. INTERPRETATION The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. FUNDING Center for Cellular and Molecular Therapeutics at the Childrens Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.

Gene Therapy for Leber's Congenital Amaurosis is Safe and Effective Through 1.5 Years After Vector Administration

The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Lebers congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.

AAV2 Gene Therapy Readministration in Three Adults with Congenital Blindness

Repeat administration of gene therapy to the contralateral retina of three congenitally blind patients was safe and resulted in improved vision. Shining a Light with Gene Therapy Gene therapy has great potential for treating certain diseases by providing therapeutic genes to target cells. Administration of a gene therapy vector carrying the RPE65 gene in 12 patients with congenital blindness due to RPE65 mutations led to improvements in retinal and visual function and proved to be a safe and stable procedure. In a follow-up study, the same group of researchers led by Jean Bennett set out to discover whether it would be possible to safely administer the vector and the therapeutic transgene to the contralateral eye of the patients. A big concern was whether the first gene therapy injection might have primed the patients’ immune system to respond to the adeno-associated virus (AAV) vector or the product of the therapeutic transgene that it had delivered. To test the safety and efficacy of a second administration of gene therapy to the second eye, the authors demonstrated that readministration was both safe and effective in animal models. Then, they selected 3 of the original 12 patients and readministered the AAV vector and its RPE65 transgene to the contralateral eye. They assessed safety by evaluating inflammatory responses, immune reactions, and extraocular exposure to the AAV vector. Efficacy was assessed through qualitative and quantitative measures of retinal and visual function including the ability to read letters, the extent of side vision, light sensitivity, the pupillary light reflex, the ability to navigate in dim light, and evidence from neuroimaging studies of cortical activation (which demonstrated that signals from the retina were recognized by the brain). The researchers did not discover any safety concerns and did not identify harmful immune responses to the vector or the transgene product. Before and after comparisons of psychophysical data and cortical responses provided the authors with evidence that gene therapy readministration was effective and mediated improvements in retinal and visual function in the three patients. The researchers report that the lack of immune response and the robust safety profile in this readministration gene therapy study may be due in part to the immune-privileged nature of the eye, and the low dose and very pure preparation of the AAV vector. Demonstration of safe and stable reversal of blindness after a single unilateral subretinal injection of a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2) prompted us to determine whether it was possible to obtain additional benefit through a second administration of the AAV vector to the contralateral eye. Readministration of vector to the second eye was carried out in three adults with Leber congenital amaurosis due to mutations in the RPE65 gene 1.7 to 3.3 years after they had received their initial subretinal injection of AAV2-hRPE65v2. Results (through 6 months) including evaluations of immune response, retinal and visual function testing, and functional magnetic resonance imaging indicate that readministration is both safe and efficacious after previous exposure to AAV2-hRPE65v2.

Longitudinal study of vision and retinal nerve fiber layer thickness in multiple sclerosis

Cross‐sectional studies of optical coherence tomography (OCT) show that retinal nerve fiber layer (RNFL) thickness is reduced in multiple sclerosis (MS) and correlates with visual function. We determined how longitudinal changes in RNFL thickness relate to visual loss. We also examined patterns of RNFL thinning over time in MS eyes with and without a prior history of acute optic neuritis (ON).

Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization.

Purpose To determine the safety and efficacy of small interfering RNA (siRNA) directed against vascular endothelial growth factor (VEGF) in a nonhuman primate model of laser-induced choroidal neovascularization (CNV). Methods Each animal received laser rupture of Bruch’s membrane to induce CNV in both eyes. Each animal was then randomized to receive 0.05 mL of either vehicle alone or VEGF siRNA at 70 &mgr;g, 150 &mgr;g, or 350 &mgr;g in both eyes by intravitreal injection. Eyes were monitored weekly by ophthalmic examination, color photography, and fluorescein angiography for 36 days after laser injury. Electroretinograms were measured at baseline and at 5 weeks after laser. CNV on fluorescein angiograms were measured for area and graded for clinically significant leakage in a standardized, randomized, and double-masked fashion on days 15, 22, 29, and 36 after laser. Results VEGF siRNA did not cause any change in electroretinographic, hemorrhage, inflammation, or clinical signs of toxicity. A single administration of VEGF siRNA significantly inhibited growth of CNV and attenuated angiographic leakage in a dose-dependent manner. Conclusion Intravitreal injection of VEGF siRNA is capable of inhibiting the growth and vascular permeability of laser-induced CNV in a nonhuman primate in a dose-dependent manner. This study demonstrates preclinical proof of a principle that supports proceeding to clinical studies of VEGF siRNA in patients with exudative age-related macular degeneration.

In Vivo Human Choroidal Thickness Measurements: Evidence for Diurnal Fluctuations

PURPOSE The authors applied partial coherence interferometry (PCI) to estimate the thickness of the human choroid in vivo and to learn whether it fluctuates during the day. METHODS By applying signal processing techniques to existing PCI tracings of human ocular axial length measurements, a signal modeling algorithm was developed and validated to determine the position and variability of a postretinal peak that, by analogy to animal studies, likely corresponds to the choroidal/scleral interface. The algorithm then was applied to diurnal axial eye length datasets. RESULTS The postretinal peak was identified in 28% of subjects in the development and validation datasets, with mean subfoveal choroidal thicknesses of 307 and 293 microm, respectively. Twenty-eight of 40 diurnal PCI datasets had at least two time points with identifiable postretinal peaks, yielding a mean choroidal thickness of 426 microm and a mean high-low difference in choroidal thickness of 59.5 +/- 24.2 microm (range, 25.9-103 microm). The diurnal choroidal thickness fluctuation was larger than twice the SE of measurement (24.5 microm) in 16 of these 28 datasets. Axial length and choroidal thickness tended to fluctuate in antiphase. CONCLUSIONS Signal processing techniques provide choroidal thickness estimates in many, but not all, PCI datasets of axial eye measurements. Based on eyes with identifiable postretinal peaks at more than one time in a day, choroidal thickness varied over the day. Because of the established role of the choroid in retinal function and its possible role in regulating eye growth, further development and refinement of clinical methods to measure its thickness are warranted.

Adherence with Topical Glaucoma Medication Monitored Electronically: The Travatan Dosing Aid Study

PURPOSE To assess patient adherence and behaviors with topical once-daily therapy for glaucoma. DESIGN Prospective, observational cohort study. PARTICIPANTS One hundred ninety-six patients with glaucoma who were being treated with a prostaglandin analog in 1 or both eyes at the Scheie or Wilmer Eye Institutes between August 2006 and June 2007. METHODS Detailed medical history was obtained from each patient. All subjects used the Travatan Dosing Aid (DA; Alcon, Fort Worth, TX) to administer travoprost as prescribed. Devices were collected at 3 months and the data of drop usage was downloaded using software provided with the dosing aid. Data were analyzed for the 8-week period starting 2 weeks after the enrollment visit and ending 2 weeks before the 3-month visit. MAIN OUTCOME MEASURES Assessment of adherence and patterns of drop usage as indicated by the DA. RESULTS A total of 282 subjects consented to be in the study and 86 (30%) withdrew before study completion or had device errors, leaving 196 subjects (70%) with evaluable data at 3 months. The overall mean (+/-standard deviation) adherence rate was 0.71 (+/-0.24), ranging from 0.02 to 0.97. One hundred nine of these patients (55.6%) took greater than 75% of the expected doses. Those with adherence of less than 50% of expected doses showed substantially increased dose taking immediately after the office visit and just before the return visit at 3 months (P = 0.03). The mean adherence rate estimates of the physician and patient self-report were 0.77 and 0.95, respectively. The agreement between the physician assessment and DA-recorded adherence rate showed poor correlation for individual cases (intraclass correlation coefficient, 0.09; 95% confidence interval, 0.00-0.19). CONCLUSIONS Nearly 45% of patients using an electronic monitoring device who knew they were being monitored and were provided free medication used their drops less than 75% of the time. Patients reported far higher medication use than their actual behavior. The ability of the physician to identify which persons are poorly adherent from their self-report or from other subjective clues is poor. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Baseline Predictors for One-Year Visual Outcomes with Ranibizumab or Bevacizumab for Neovascular Age-related Macular Degeneration

OBJECTIVE To determine the baseline predictors of visual acuity (VA) outcomes 1 year after treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration (AMD). DESIGN Cohort study within the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). PARTICIPANTS A total of 1105 participants with neovascular AMD, baseline VA 20/25 to 20/320, and VA measured at 1 year. METHODS Participants were randomly assigned to ranibizumab or bevacizumab on a monthly or as-needed schedule. Masked readers evaluated fundus morphology and features on optical coherence tomography (OCT). Visual acuity was measured using electronic VA testing. Independent predictors were identified using regression techniques. MAIN OUTCOME MEASURES The VA score, VA score change from baseline, and ≥3-line gain at 1 year. RESULTS At 1 year, the mean VA score was 68 letters, mean improvement from baseline was 7 letters, and 28% of participants gained ≥3 lines. Older age, larger area of choroidal neovascularization (CNV), and elevation of retinal pigment epithelium (RPE) were associated with worse VA (all P<0.005), less gain in VA (all P<0.02), and a lower proportion gaining ≥3 lines (all P<0.04). Better baseline VA was associated with better VA at 1 year, less gain in VA, and a lower proportion gaining ≥3 lines (all P<0.0001). Predominantly or minimally classic lesions were associated with worse VA than occult lesions (66 vs. 69 letters; P=0.0003). Retinal angiomatous proliferans (RAP) lesions were associated with more gain in VA (10 vs. 7 letters; P=0.03) and a higher proportion gaining ≥3 lines (odds ratio, 1.9; 95% confidence interval, 1.2-3.1). Geographic atrophy (GA) was associated with worse VA (64 vs. 68 letters; P=0.02). Eyes with total foveal thickness in the second quartile (325-425 μm) had the best VA (P=0.01) and were most likely to gain ≥3 lines (P=0.004). Predictors did not vary by treatment group. CONCLUSIONS For all treatment groups, older age, better baseline VA, larger CNV area, predominantly or minimally classic lesion, absence of RAP lesion, presence of GA, greater total fovea thickness, and RPE elevation on optical coherence tomography were independently associated with less improvement in VA at 1 year. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.