Phase I Study Shows IV Gene Therapy May Improve Macular Degeneration

MedicalResearch.com Interview with:

Prof Peter A Campochiaro MD Director, Retinal Cell and Molecular Laboratory Professor of Ophthalmology Johns Hopkins University School of Medicine Baltimore, MD

Dr. Campochiaro

Prof Peter A Campochiaro MD
Director, Retinal Cell and Molecular Laboratory
Professor of Ophthalmology
Johns Hopkins University School of Medicine
Baltimore, MD

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Patients with wet age-related macular degeneration (AMD) have increased levels of vascular endothelial growth factor (VEGF) in their eyes resulting in growth of abnormal blood vessels that leak fluid into the retina and reduce vision. The current treatment is to inject proteins that block VEGF which initially provides a very good effect, but repeated injections are needed.

Patients sometimes are unable to keep up the frequency of visits and injections needed to keep the disease quiet and over time there is often gradual loss of vision. The aim of this study was to test a new approach through which a viral vector is injected into the eye resulting in production of a protein that block VEGF in the eye reducing the need for repeated injections.

These are the major findings:

1) Intravitreous injection of an AAV2 vector expressing a protein that blocks vascular endothelial growth factor (VEGF) was safe and well-tolerated.

(2) 5 of 10 patients injected with the highest dose (2 × 10¹⁰ vector genomes) had measurable levels of the therapeutic protein in samples removed from the front of the eye- all of these patients had no or very low levels of anti-AAV2 serum antibodies and 4 of the 5 patients who did not show expression had high anti-AAV2 serum antibodies

(3) Eleven patients had fluid in or under the retina before vector injection and 6 of them showed substantial reduction of the fluid which is the desired outcome.

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New Technology May Allow Topical Delivery of Anti-VEGF Drugs For Macular Degeneration

MedicalResearch.com Interview with:

Dr Felicity de Cogan PhD</strong> Institute of Inflammation and Ageing University of Birmingham

Dr Felicity de Cogan

Dr Felicity de Cogan PhD
Institute of Inflammation and Ageing
University of Birmingham

MedicalResearch.com: What is the background for this study?

Response: The University of Birmingham has a unique approach to developing technologies. By locating chemists, engineers, biologists and clinicians in the same department it revolutionised the way research problems are solved.

Initially, Felicity de Cogan was researching cell penetrating peptides (CPP) and their uses in microbiology. However, after joining forces with Neuroscientists, Dr Lisa Hill and Professor Ann Logan at the National Institute for Health Research Surgical Reconstruction and Microbiology Research Centre (NIHR SRMRC) together with the clinicians and Vision Scientists, Dr Mei Chen and Professor Heping Xu at the Queen’s University Belfast it became evident that there was huge potential to deliver drugs in the eye. This was the start of the project and it developed rapidly from there.

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Economic Evaluation of a Home-Based Age-Related Macular Degeneration Monitoring System

MedicalResearch.com Interview with:
John Wittenborn

Senior research scientist
NORC’s Public Health Analytics
University of Chicago

MedicalResearch.com: What is the background for this study? What are the main findings?

Response:The emergence of anti-VEGF treatment for wet-form AMD (choroidal neovascularization) has had a dramatic impact on preserving vision for many Americans. However, community-based studies show that most patients are not diagnosed with wet-form AMD until they have already lost a significant, and largely unrecoverable amount of their vision.  Early detection of wet-form AMD is key to effective treatment and the preservation of vision. The ForeseeHome telemonitoring technology provides patients with a means to check their own eyes on a daily basis to detect the earliest signs of vision loss from wet-form AMD.

This is a novel technology that has the potential to improve visual health outcomes for AMD patients.  A prior clinical trial (the AREDS-2 HOME study) demonstrated that this technology can detect wet-form AMD earlier, and with less vision loss than standard care alone. However, that is exactly where that study ended as it reported no cost information nor follow-up. Since the end of this study, the device has been cleared by the FDA and approved for reimbursement by Medicare for certain higher risk patients, but no study has yet considered the long-term implications of adoption of this technology.

In our analysis, we use a computer simulation model to essentially estimate what will come next, after patients realize earlier detection of wet-form AMD by utilizing home monitoring. Basically, we follow simulated patients from the time they begin monitoring for the rest of their lives, recording the likely impacts of home monitoring on patients’ long term outcomes including visual status, costs and quality of life.

We find that home telemonitoring among the population indicated for reimbursement by Medicare would cost $35,663 per quality adjusted life year (QALY) gained.  Medicare would expect to incur $1,312 in net budgetary costs over 10 years for each patient who initiates monitoring.  However, Medicare patients may expect to achieve lifetime net savings when accounting for the chance of avoided vision loss and its associated costs later in life.

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Complement Genes Play Role in Age-Related Macular Degeneration

MedicalResearch.com Interview with:

dr-anneke-i-den-hollanderAnneke I. den Hollander, PhD
Department of Ophthalmology and Department of Human Genetics
Donders Institute for Brain, Cognition, and Behaviour
Radboud University Medical Center
Nijmegen, the Netherland

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Age-related macular degeneration is caused by a combination of genetic and environmental factors. Rare genetic variants in the complement system have been described in AMD, but their effect remains largely unexplored. In this study we aimed to determine the effect of rare genetic variants in the complement system on complement levels and activity in serum.

MedicalResearch.com: What are the main findings?

Response: Carriers of CFI variants showed decreased FI levels, carriers of C9 Pro167Ser had increased C9 levels, while C3 and FH levels were not altered. Carriers of CFH and CFI variants had a reduced ability to degrade C3b, which for CFI was linked to reduced serum FI levels.

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Age-Related Macular Degeneration: Computerized Imaging Predicts Risk Progression

Daniel L. Rubin, MD, MS  Assistant Professor of Radiology and Medicine (Biomedical Informatics) Department of Radiology | Stanford University Stanford, CA 94305-5488MedicalResearch.com Interview with:
Daniel L. Rubin, MD, MS 
Assistant Professor of Radiology and Medicine (Biomedical Informatics)
Department of Radiology | Stanford University
Stanford, CA 94305-5488

Medical Research: What is the background for this study? What are the main findings?

Dr. Rubin: Age-Related Macular Degeneration is the leading cause of blindness and central vision loss among adults older than 65. An estimated 10-15 million people in the United States suffer from the disease, in which the macula — the area of the retina responsible for vision — shows signs of degeneration. While about one of every five people with AMD develop the so-called “wet” form of the disease that can cause devastating blindness. In wet AMD, abnormal blood vessels accumulate underneath the macula and leak blood and fluid. When that happens, irreversible damage to the macula can quickly ensue if not treated quickly. Until now, there has been no effective way to tell which individuals with AMD are likely to convert to the wet stage. Current treatments are costly and invasive — they typically involve injections of medicines directly into the eyeball — making the notion of treating people with early or intermediate stages of Age-Related Macular Degeneration a non-starter. In our study, we report on a computerized method that analyzes images of the retina obtained with a test called spectral domain optical coherence tomography (SD-OCT), and our method can predict, with high accuracy, whether a patient with mild or intermediate Age-Related Macular Degeneration will progress to the wet stage. Our method generates a risk score, a value that predicts a patient’s likelihood of progressing to the wet stage within one year, three years or five years. The likelihood of progression within one year is most relevant, because it can be used to guide a recommendation as to how soon to schedule the patient’s next office visit. In our study, we analyzed data from 2,146 scans of 330 eyes in 244 patients seen at Stanford Health Care over a five-year period. Patients were followed for as long as four years, and predictions of the model were compared with actual instances of conversion to wet AMD. The model accurately predicted every occurrence of conversion to the wet stage of AMD within a year. In approximately 40% of the cases when the model predicted conversion to wet AMD within a year, the prediction was not borne out, however. We are currently refining the model to reduce the frequency of these false positives.
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Age-Related Macular Degeneration: Lucentis Raises Stroke Risk

MedicalResearch.com Interview with:
Takashi Ueta, M.D., Ph.D.
Assistant Professor, Department of Ophthalmology
Graduate School and Faculty of Medicine
The University of Tokyo

Medical Research: What is the background for this study? What are the main findings?

Dr. Ueta: In 2009 we had reported an initial systematic review and meta-analysis which include pivotal RCTs but the number of the included studies were only 3 (MARINA, ANCHOR, FOCUS). During the following several years, more trials comparing different dosages and frequencies of ranibizumab treatment were conducted, which made us to update our meta-analysis.

Based on our updated meta-analysis, increase in several systemic vascular adverse events was observed: 86% increase in odds ratio (OR) for the risk of cerebrovascular accident (CVA) when 0,5 mg ranibizumab used. 89% increase in OR for the risk of CVA when monthly ranibizumab of any dosage is used. 57% increase in OR for the risk of non-ocular hemorrhage when ranibizumab of any dosage with any frequency is used. Continue reading

Generic ‘Avastin’ May Not Be Suitable For Eye Injections

Szilárd Kiss, MD Director of Clinical Research Director of Compliance  Associate Professor of Ophthalmology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York 10021MedicalResearch.com Interview with:
Szilárd Kiss, MD
Director of Clinical Research
Director of Compliance  Associate Professor of Ophthalmology
Weill Cornell Medical College NewYork-Presbyterian Hospital
New York, New York 10021

Medical Research: What is the background for your study?

Dr. Kiss: There has been a good deal of publicity about bevacizumab (Avastin; a Genetech/Roche antibody originally developed for treatment of cancer but now used widely to treat macular degeneration and diabetic retinopathy) being prepared by (mostly unregulated) compounding pharmacies for injection into the eye, and being associated with pathogen contamination.

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Age-Related Macular Degeneration: Algorithm and App as Practical Prediction Tools

Chung-Jung Chiu DDS PhD Scientist II, JM USDA Human Nutrition Research Center on Aging Assistant Professor, School of Medicine Tufts University Boston MA 02111MedicalResearch.com Interview with:
Chung-Jung Chiu DDS PhD
Scientist II, JM USDA Human Nutrition Research Center on Aging
Assistant Professor, School of Medicine
Tufts University Boston MA 02111

MedicalResearch.com: What are the main findings of the study?

Answer: In this study, we found that advanced age-related macular
degeneration (AMD) is predictable by using clinically readily available
information. We devised a simple algorithm to summarize the clinical
predictors and showed the validity of our prediction model in both
clinic-based and community-based cohorts. We also develop an
application (App) for the iPhone and iPad as a practical tool for our
prediction model.

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Macular Degeneration: Incidence, Susceptibility and Dietary Antioxidants

Jie Jin Wang MMed (Clin Epi) MAppStat PhD Professor Australian NHMRC Senior Research Fellow (Level B) Centre for Vision Research Westmead Millennium Institute University of Sydney C24 Westmead Hospital, NSW 2145 AustraliaMedicalResearch.com Interview with:
Jie Jin Wang MMed (Clin Epi) MAppStat PhD
Professor Australian NHMRC Senior Research Fellow (Level B)
Centre for Vision Research
Westmead Millennium Institute University of Sydney C24
Westmead Hospital, NSW 2145 Australia

MedicalResearch.com: What are the main findings of the study?

Answer: We documented a consistent association between high dietary intake of lutein/zeaxanthin (LZ) and a reduced long-term risk of early age-related macular degeneration (AMD) in persons who carry ≥2 risk alleles of either or both the complement factor H (CFH-rs1061170) and/or the age-related maculopathy susceptibility gene 2 (ARMS2-rs10490924) in two older population-based cohorts.
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Age-Related Macular Degeneration: Ten Year Follow Up Study

Emily Y. Chew, M.D. Deputy Director, Division of Epidemiology and Clinical Applications National Eye Institute National Institutes of Health (NIH), Bethesda, MDMedicalResearch.com Interview
Emily Y. Chew, M.D.
Deputy Director, Division of Epidemiology and Clinical Applications
National Eye Institute
National Institutes of Health (NIH), Bethesda, MD

MedicalResearch.com: What are the main findings of the study?

Dr. Chew: We provided 10 year rates of development of advanced age-related macular degeneration (AMD), either neovascular (NV) AMD or central geographic atrophy (CGA).   We also presented the risk factors associated with progression to advanced AMD.   These risk factors that were associated with an increased risk of progression included drusen status at baseline (small drusen, intermediate, large drusen), presence of advanced AMD in the fellow eye, increasing age, female gender, smoking, and the white race.

This is the last cohort of patients in whom anti-vascular endothelial growth factor agents were not available during the course of the study.  The natural history of the vision loss for those who developed advanced is relentless, more gradual in those with geographic atrophy than neovascular AMD, and may occur even 1 year prior to the detection of advanced AMD by stereoscopic fundus photographs in obtained at study visits.

MedicalResearch.com: Were any of the findings unexpected?

Dr. Chew: We knew that the presence of large drusen increased the risk of developing advanced AMD.  However, we found that 36% of participants with medium sized drusen in one eye and 71% of those with bilateral medium sized drusen at baseline would develop large drusen by 10 years.

The risk of developing advanced AMD by 10 years was very low in participants with no drusen and in those with small drusen at baseline but 14% of participants with medium drusen in both eyes at enrollment developed advanced AMD by 10 years.

MedicalResearch.com:  What should clinicians and patients take away from your report?

Dr. Chew: The risk of progression to advanced AMD, neovascular or central geographic atrophy was increased in persons with large drusen, AMD retinal pigmentary changes, presence of advanced AMD in the fellow eye.  In addition, medium sized drusen may be another important risk for potential progression to advanced AMD.  The visual acuity loss is relentless once advanced AMD develops.

What recommendations do you have for future research as a result of this study?

Dr. Chew: We hope the progression rates found in this study will help facilitate future clinical research, both epidemiologic studies and clinical trials by providing accurate information for sample size calculations and for evaluation of risk factors.   Early AMD consisting of medium sized drusen may be an important stage for future evaluations of therapies.    We look forward to using other modalities of imaging to give us data on progression rates of AMD.

Citation:

Ten-Year Follow-up of Age-Related Macular Degeneration in the Age-Related Eye Disease Study: AREDS Report No. 36.

Chew EY1, Clemons TE2, Agrón E1, Sperduto RD2, Sangiovanni JP1, Davis MD3, Ferris FL 3rd1; for the Age-Related Eye Disease Study Research Group.

JAMA Ophthalmol. 2014 Jan 2. doi: 10.1001/jamaophthalmol.2013.6636.
[Epub ahead of print]