This series of reports is based on presentations by scientists and clinicians at the 2011 annual meeting of the Association for Research in Vision and Ophthalmology (“ARVO 2011”). The theme of the meeting was visionary genomics and the object of the meeting was to provide a forum for worldwide exchange of information that will lead to discoveries and better treatments for eye and vision disorders. Approximately 11,000 scientists and clinicians from around the globe attended this May 1–5 event in Fort Lauderdale, Florida.
We learned of significant advances in the field of retinal degenerative diseases. Perhaps the biggest news at ARVO 2011 came from a report of the 1-year results of the Comparison of AMD Treatments Trials (CATT). See below. Among the many other areas were potential treatments related to the use of neurotrophic compounds, small molecules, and anti-neovascular agents; gene therapies, retinal prostheses; and stem cells treatments. Read below for reports on these topics and more.
At every annual ARVO meeting one report garners the most attention. 2011 it was the one-year findings of the planned two-year Comparison of AMD Treatments Trials (CATT). In this study, run by the National Eye Institute of the US National Institutes of Health, the safety and efficacy of two Genentech drugs - ranibizumab (Lucentis) and bevacizumab (Avastin) - was being compared (Outside the USA Avastin is marketed by Roche and Lucentis is marketed by Novartis). Both drugs are used to treat potentially blinding abnormal blood vessel growth beneath the macula in patients with age-related macular degeneration (AMD).
Both are given by intravitreal injection, i.e . by an injection into the eye. Of the two drugs that share many similarities, only Lucentis is approved around the world for treating AMD, while Avastin is approved for use in oncology to treat cancer, but not for the treatment of any eye disease. However, Avastin is consistently used off-label by ophthalmologists because of its lower price tag and (formerly anecdotally) comparable result.
This one year report from CATT presented at the ARVO meeting is based on findings from treatment of nearly 1200 AMD patients randomized into four treatment arms with one drug or the other. Both drugs were applied either monthly to find out the maximal possible response or based on need (PRN), the latter being very much the way the drugs are used in clinical routine.
When looking at the improvement in visual acuity (that is the ability to read more letters on an eye chart than before treatment), the CATT results after 1 year show virtually identical outcomes when comparing Lucentis and Avastin given monthly.
When given PRN, Lucentis showed slightly less visual acuity gain in comparison to Lucentis or Avastin given monthly, but it remained within the pre-defined margin that was set as “non-inferiority margin” for these comparisons. In other words, the PRN treatment with Lucentis was statistically not worse than Lucentis or Avastin given monthly. While the PRN treatment of Lucentis required a little less than 7 injections per patient and year on average, monthly treatments obviously result in 12 injections per patient and year.
When Avastin was given PRN, almost 8 injections were required per patient and year and the change in visual acuity did not reach the level that allowed judging non-inferiority in comparison to monthly treatments. In other words, the data for Avastin given PRN were not strong enough to conclude that it is not worse than Avastin or Lucentis given monthly.
In general, other outcomes like preventing the leakage of fluid into the retina were better if patients received monthly intraocular injections rather than PRN. Particularly, Lucentis given monthly was more effective in getting rid of fluid in the macula as indicated by OCT measurements. The implication of prolonged fluid in the macula may become more clinically relevant with longer-term follow up.
The results of further studies on the safety aspects of Avastin are still needed as CATT revealed an increased risk for rare and atypical serious adverse events with Avastin given PRN. These events are under further investigation and the 2-year results of CATT will shed further light on this outcome.
CATT results were first reported in the April 28, 2011, online edition of the New England Journal of Medicine.
Caveat: Scientists from the Johns Hopkins University, presenting a late-breaking paper at ARVO 2011, reported on adverse effects of Avastin and Lucentis when used to treat AMD. Their findings are based on an analysis of the Medicare claims database and include over 77,000 patients. The results of this analysis seem to indicate a higher risk of overall mortality, hemorrhagic stroke, ocular inflammation, and subsequent cataract in patients treated with Avastin group. Also here, additional research is needed to explain the findings, which could be influenced by confounding factors such as smoking, lipid and blood pressure levels, and age.
Also in clinical trials for preventing choroidal neovascularization (CNV) and improving visual acuity in patients with AMD is Regeneron’s compound called VEGF Trap-Eye (VTE). Results of the VTE VIEW 2 trial were reported at ARVO 2011 by Ursula Schmidt-Erfuth of the Medical University of Vienna and colleagues. VTE is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A, thereby blocking VEGF and halting abnormal blood vessel formation. The researchers tested the compound in approximately 3000 patients that were randomized to receive intravitreal injection of VTE at 4 or 8 week intervals or the FDA-approved anti-angiogenic drug Lucentis. The primary endpoint was the proportion of patients maintaining vision at 52 weeks. A secondary endpoint was mean change in best corrected visual acuity.
At 52 weeks, the proportion of patients maintaining vision was better than 94% for all treatment arms (1 of 2 dosing levels; 4 or 8 week intervals) and mean improvements in best corrected visual acuity exceeded nine letters. None was inferior to ranibizumab treatment. The US Food and Drug Administration will be reviewing the company’s biologics license application on a priority basis.
Florian Gekeler of Okuvision GmbH, Reutlingen, Germany, and colleagues reported finding a possible therapeutic effect on the retina in rats following treatment with (TES). The rats had retinal degeneration caused by light damage. TES was applied using corneal electrodes. Retinal histology showed a significant preservation of thickness in the outer nuclear layer in TES-treated animals compared to sham-treated animals and to animals exposed to light damage but no treatment at all. There was also a tendency in the TES-treated group for higher ERG potentials in the first week after light damage and subsequently.
In another investigator blinded sham controlled GCP study of TES, Florian Gekeler and colleagues studied its safety and efficacy in patients with retinitis pigmentosa. The researchers applied TES for 30 minutes per week for 6 weeks in 24 patients, some of whom were sham-treated or treated at two different dosage levels. Patients were examined for changes in visual function. The findings were that TES is safe and that a small improvement occurs in the area of kinetic visual fields and in scotopic (rod-mediated) ERG b-wave amplitude in patients receiving the higher doses. The research will continue with a larger number of patients. They believe that the TES effect could be mediated through an increase in insulin-like growth factor, ciliary neurotrophic factor, and other proteins. (Note: Patients with Stargardt disease who were similarly treated with high dose TES experienced a significant increase in electrically evoked phosphenes.)
Researchers from the Argus II™ Study Group reported at ARVO 2011 on the reading ability of 3 patients whom they had described at ARVO 2010 as the best performing of 24 recipients of the Argus™ II Retinal Prosthesis.
They had the three patients practice at home viewing certain large text (60 - 95 point Century Gothic text in short sentences) while wearing the prosthesis. Subsequently, patients were tested on their ability to read 4-word sentences on a computer monitor. At one month, two of the three patients were able to read the sentences, albeit at the slow average rate of 0.65 words/minute for one patient and 1.14 words/minute for the other. At two months, reading speed increased slightly in one patient and nearly 5-fold in the other. The results show visual improvement in RP patients implanted with the Argus II Retinal Prosthesis and also the important effect of training on outcome.
In another study of nine RP patients implanted with the Argus II Retinal Prosthesis, researchers demonstrated color perception. By stimulating different groups of electrodes they were able to elicit eight colors (orange, yellow, red, blue, green, pink, gray and white).
Retina Implant AG from Germany (Zrenner et al.) has presented data in eighteen patients with a 3x3 mm chip. This device has 1.500 light sensitive photodiodes, amplifiers and electrodes with wireless transmission of data and power in the latest model, EMS Alpha, for unlimited use. All the prosthesis parts are in the body; patients just wear regular correction glasses as the light sensitive “camera chip” is in the eye under the retina..
Visual acuity has been reached up to 20 /1000, reading of letters and words is possible and patients can take the implant home or use it outside. Within few days of use some of the patients can differentiate objects such as plates, forks, glasses of beer, flowers, door handles, smiling faces, car shapes, moving animals.
Robert K. Koenekoop of McGill University and colleagues reported encouraging results from their Phase Ib proof-of-concept trial of QLT091001, an oral synthetic cis-retinoid prodrug, in 12 subjects with LCA that was caused by a lecithin:retinol acyltransferase (LRAT) gene mutation or a retinal pigment epithelial 65 protein (RPE65) gene mutation. Patients were treated for 7 days and tested for systemic effects and changes in visual function. QLT091001 had previously been shown to improve vision in mouse and dog models of LCA.
Eight of the 12 participants experienced improvement in best corrected visual acuity and/or visual fields. Visual field gains ranged from 22% to 217% above baseline. For some subjects, improvement persisted for more than a year. Improvements in performing activities of daily living and in seeing at night were also reported. The mechanism of action behind the effect of QLT091001 is under investigation.
The biotechnology company Neurotech has reported encouraging results showing cone photoreceptor preservation in three retinitis pigmentosa patients treated with their NT-501 encapsulated cell technology. The intraocular implant contains genetically-modified cells that secrete ciliary neurotrophic factor capable of nourishing retinal photoreceptor cells. Researchers used adaptive optics scanning laser ophthalmoscopy (AOSLO) to assess the rate of cone photoreceptor degeneration in the treated eye, comparing it to the patient’s opposite sham-treated eye. They assessed photoreceptor degeneration by measuring cone density and average cone spacing and found significantly less decrease in density or increase in spacing in the NT-501 treated eyes compared to the sham-treated eyes. Phase 3 trials are planned.
At ARVO 2011, Shuichi Yamamoto of Chiba University Graduate School of Medicine, Chiba, Japan, and his colleagues reported results from their Phase 2 clinical trial showing that a medication taken by eyedrop and approved in the U.S. for lowering intraocular pressure can also improve mean retinal sensitivity and quality of life in patients with retinitis pigmentosa. Study participants (100+) were instructed to self-administrator one or two drops of the compound (unoprostone isopropyl) twice daily for 6 months. The researchers used as their primary endpoint the change in mean retinal sensitivity of the central 2 degrees of the visual field.
Results were dose dependent. By comparing changes (from baseline) in retinal sensitivity threshold among patients in the high dose, low dose, and a placebo group, the researchers found a statistically significant increase in retinal sensitivity in the high-dose group and a trend toward significance in the low dose group. Improvement began in the high dose group as early as 4 weeks and continued over time.
Additionally, the proportion of patients with ≥4 decibel (dB) worsening of the retinal sensitivity was significantly greater in the placebo group (21.2%) than in the high dose group (2.6%). The VFQ-25 questionnaire further revealed a statistically significant, dose-dependent improvement in “social life functions due to vision.”
The mechanism of action of unoprostone isopropyl is unknown. The compound is a potent vasorelaxant and its effect could be through an effect on the choroidal circulation.
RN6G is an antibody against amyloid beta, which is a main constituent of brain plaques in people with Alzheimer’s disease and in drusen in the eyes of patients with AMD. RN6G was previously shown to decrease drusen-like deposits in the basal membrane of eyes of a mouse model of dry AMD. A Phase 1 clinical trial completed in 2010 showed the compound to be safe and well-tolerated in human subjects. Double-masked, placebo-controlled studies comparing several doses are planned in patients with advanced dry AMD.
Quality of life (QOL) measurements are valuable for understanding the effect of vision disorders on patients with age-related macular degeneration and for assessing the impact of new drugs and devices for treating the condition. Wiley Chambers of the FDA emphasizes the importance of relating quality of life measures to changes in visual function and structural changes in the eye.
Researchers from the Los Angeles Latino Eye Study (LALES) Group reported at ARVO 2011 on their assessment of health-related quality (HRQOL) of life in early and late AMD in Latino adults. They defined severity of disease by a modified WARMGS scale and HRQOL by the SF-12 and NEI-VFQ-25 scales. No surprise that they found an inverse relationship between severity of disease and HRQOL. The fact the QOL decreases as the disease progresses is a reminder of the importance of interventions to stop disease progression or improve vision.
Along those lines a study, by Rohit Varma of Doheny Eye Institute and others, of AMD patients being treated with Lucentis found that treated patients experienced an improvement in their performance of everyday tasks. (Tasks included a range of activities like finding an item on a crowded shelf and recognizing someone from across a room.) Using NEI VFQ-25 scales, the researchers assessed patient-reported level of difficulty on near and distance activities at baseline and 24 months later. They found that twice as many patients in the Lucentis-treated group improved their performance compared to sham-treated patients, hence wedding measures of QOL and changes in visual function.
Low serum vitamin levels continue to be reported as contributors to the development of AMD and this time it is vitamin D. In an ancillary study to the Women’s Health Initiative, Amy Millen of the University of Buffalo in New York and her colleagues reported findings that higher levels of vitamin D appear to reduce the risk of early onset AMD in women 50–74. Women with the highest serum concentrations of 25(OH)D (at least 75 nmol/L) were significantly less likely to develop AMD than women with the lowest concentration (<38nmol/liter). Fifty-nine percent lower odds of developing AMD was associated with consuming at least 720 IU/day. The same association was not seen in women 75 and older, for unknown reasons.
Oxidative damage to the retina plays a role in the pathogenesis of macular degeneration. Carmelo Romano of Alcon reported results of a study testing the ability of a serotonin receptor agonist (5-HT1A; AL8309B) to protect the retina from oxidative damage. In vitro, AL8309B has been shown to protect retinal pigment epithelial cells.
Subsequent studies in rats also showed protection. The animals were exposed to intense blue light—a method for inducing oxidative damage to the eye—shortly after dosing with AL8309B. Electroretinograms (ERGs) showed significantly greater retinal activity in AL8309B-treated rats compared to untreated rats. Histological assessments of the retina showed no lesions in the treated animals.
AL-8309B is under evaluation in the clinic for dry AMD. Two different doses of AL-8309B and a placebo, all applied by eyedrop twice a day, are being compared. The primary endpoint is mean annualized atrophic lesion growth. The secondary endpoint is visual acuity. Results are expected in 2012.
Jean Bennett of the Children’s Hospital of Philadelphia has reported continued visual improvement in patients with Leber’s congenital amaurosis (LCA) who the researchers treated with a subretinal injection of a normal version of the gene. (LCA in all the study patients was caused by mutations in the RPE65 gene.) The normal gene was delivered into patients’ worse-seeing eye or into both eyes via a recombinant adeno-associated virus serotype 2 (rAAV2) vector.
In addition to increased sensitivity to light and improved visual acuity, peripheral vision, and contrast sensitivity, the researchers have detected activity in the occipital cortex. The activity, seen using functional MRI, maps to the region of the retina where the normal gene was injected. The response is most robust in younger patients; the youngest in this study was 8 years old. A study that is planned to begin in September 2011 will include children as young as 3.
There is good evidence that the effect of this RPE65 gene therapy in patients with Leber’s congenital amaurosis is sustained over time.
Jean Bennett and colleagues are also researching fundus autofluorescence (FAF) patterns in the retina of patients with Leber congenital amaurosis, looking for patterns that will help assess efficacy and safety of gene replacement or drug therapies. They are looking for baseline measures of autofluorescence in patients who are blind from LRAT or RPE65 mutations. All LCA patients studied showed some FAF, suggesting a low level of retinoid cycle activity. Three predominant patterns were detected, which the researchers are matching to age, OCT parameters, genotype, and mutation severity. They hope that changes in patterns will correlate with therapy-related changes in activity of the retinoid cycle and viability of the PR-RPE interface.
Neuroscientists have shown that environmental enhancement (EE) can slow neuronal degeneration in the brain of mice. Now, researchers including Enrica Strettoi of the CNR Neuroscience Institute, Pisa, Italy, report finding similar effects of EE on photoreceptor cell survival in the rd10 mutant mice, an animal model of retinitis pigmentosa. They compared numbers of surviving photoreceptors in rd10 mice reared under conditions of abundant stimuli to rd10 mice raised in standard laboratory cages. Photoreceptors and cone-driven ERG responses were greatly preserved in the EE-exposed animals. Furthermore, at postnatal day 60, visual acuity was similar to that of wild type mice. The researchers suggest that environmental enhancement might improve photoreceptor survival in patients with an inherited retinal disorder.
Similarly, Peter Campochiaro of Johns Hopkins University and his colleagues showed an effect on photoreceptor survival in rd10 mice treated with dextromethorphan, phenyl-n-tert-butylnitrone, and N-acetylcysteine in drinking water. Mean cone density and ERG b-wave amplitudes were significantly greater in treated animals compared to untreated controls. Each of the regimens reduced carbonyl adducts, an indicator of oxidative damage. The compounds are being considered for study in clinical trials.
Researchers at ARVO 2011 reported on the new RetinoStat® lentiviral vector-based gene therapy under investigation as a treatment for wet AMD. The treatment is designed to be injected once subretinally and to express the angiostatic proteins endostatin and angiostatin. In rabbits and monkeys the researchers looked for signs of a toxic or immune response and for the presence of vector in the eye. No overt toxicity or antibody responses was detected nor was vector found outside the ocular compartment. Therapeutic levels of the two angiostatic proteins were detected in rabbit eyes at 6 months post-injection.
The FDA has approved Oxford BioMedica’s Investigational New Drug (IND) application for a Phase 1 dose-escalation study of RetinoStat. They study is designed to evaluate three dose levels in patients with advanced neovascular AMD. The primary outcome measure is the incidence of adverse events. The secondary outcome measure is change from baseline in subretinal and intraretinal fluid as measured by OCT. If successful, this therapy could be an alternative to the need for regular injections of anti-VEGF medications.
A gene therapy under development by Genable Technologies, Ltd., of Dublin, Ireland, has the potential to overcome the challenge of inherited disorders of the eye related to multiple gene mutations. It is being studied in the P347S mouse, a model of rhodopsin (RHO)-linked autosomal dominant retinitis pigmentosa (adRP). The technology uses adeno-associated viral vectors to “obtain expression of RNA interference (RNAi) molecules which suppress the expression of both the faulty and normal gene copies and replaces this with a [codon-modified rhodopsin replacement gene] resistant to suppression subtly altered to become refractory to suppression but still encoding a normal wild type protein. The combination of suppression and replacement (S&R) overcomes the significant hurdle in dominant disease of mutation variability by eliminating the need to target specific mutations in a wide range of disorders.” The company’s first product, GT038, is aimed at treating RHO-adRP.
In recently reported studies, the researchers injected subretinally a single dose of the S&R compounds in young animals and examined the eyes by electroretinography and microscopy. At 20 weeks post-injection, rod-isolated ERG responses were significantly greater in treated eyes than in control eyes. Ultrastructually, in treated animals only, outer photoreceptor segment were preserved.
The researchers, including Paul Kenna, believe that the results demonstrate clear proof-of-principle. Studies in larger animal models are planned.
Researchers reported the start of a Phase 1 gene therapy trial for a newly identified form of retinitis pigmentosa caused by a mutation of the MERKT gene. This gene encodes the proto-oncogene tyrosine-protein kinase MER enzyme. Mutations have been linked to disruption of phagocytosis by retinal pigment epithelial cells of naturally degenerated photoreceptors. Phagocytosis is essential for cleaning debris from the subretinal space. The gene defect leads to a build up of debris followed by photoreceptor cell death possibly related to inflammatory cytokines signaling cell necrosis or apoptosis.
Researchers recently showed in a rat model with a similar mutation that subretinal injection of recombinant adeno-associated virus (AAV) expressing the murine Mertk gene decreased the quantity of debris in the subretinal space and prolonged the integrity of photoreceptor cells. The study provided support for the development of AAV-mediated gene therapy for mutations in the MERTK gene in humans, specifically in patients with RP. Kang Zhang of the University of California, San Diego, and Fowzan Alkuraya of King Faisal Specialist Hospital and Research Center, Saudi Arabia, are conducting a study in Saudi Arabia of seven people with the retinal dystrophy associated with the MERKT gene defect.
Stem cells, in particular human embryonic stem cells (hES), are showing promise as possible sources of replacement cells for retinal pigment epithelial cells and photoreceptors that degenerate in retinal degenerative diseases such as age-related macular degeneration. Researchers from the London Project to Cure Blindness, including Peter Coffey, have chosen to use hES cells after finding in preclinical studies that mature autologous cells that had been coaxed into a pluripotent state failed to have the desired effect. Instead, they found that by placing embryonic stem cells on a membrane and inserting it subretinally that it was possible to regenerate RPE cells and restore visual function. The researchers hope to start safety studies in human patients at Moorfields Eye Hospital before the end of 2011 pending approval of UK regulatory bodies. They are also investigating the optimal number of cells needed to successfully seed the subretinal space.
Morphological studies of cultured hES cells during their transformation into RPE cells show that the cells gradually form highly organized tight junctions that are triggered by cell-to-cell contact. Work by researcher Virpi Savolainen of Tampere University of Technology, Tampere, Finland, and colleagues, indicates that it may be possible to use electric impedance spectroscopy (EIS) to assess the readiness of hES cells for transplantation.
Other researchers continue to study additional cell types—e.g., skin, bone marrow, peripheral blood, limbal—for their possible ability to replace missing retina cells including photoreceptor and even retinal ganglion cells.