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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Age-related Macular Degeneration Underdiagnosed in Primary Care

MedicalResearch.com Interview with:

David C Neely, MD The University of Alabama at Birmingham

Dr. Neely

David C Neely, MD
The University of Alabama at Birmingham

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

Response: This study examined the prevalence of eyes with age-related macular degeneration (AMD) in patients seen in primary eye care clinics who purportedly have normal macular health.

Approximately 25.0% of eyes deemed to be normal based on dilated eye examination by primary eye care providers had macular characteristics that indicated age-related macular degeneration. Continue reading

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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Severe Diabetic Macular Edema: EYLEA® Had Better Outcomes Than Avastin® or Lucentis® At One Year, But at Much Greater Cost

Adam Glassman, M.S. Director, DRCRnet Coordinating Center Jaeb Center for Health Research Tampa, FL 33647

Adam Glassman

MedicalResearch.com Interview with:
Adam Glassman, M.S.
Director, DRCRnet Coordinating Center
Jaeb Center for Health Research
Tampa, FL 33647

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

Response: Diabetic macular edema (DME) is the most common cause of vision loss in patients with diabetes, impairing the vision of approximately 750,000 people in the United States. The most common treatment involves the injection into the eye of one of 3 drugs that inhibit vascular endothelial growth factor (VEGF). The Diabetic Retinopathy Clinical Research Network, funded by the National Institutes of Health, conducted a randomized clinical trial on the comparative effectiveness of the 3 anti-VEGF drugs EYLEA®, Avastin®, or Lucentis® for eyes with decreased vision from diabetic macular edema. There are substantial cost differences between the three drugs. In the United States, EYLEA® costs approximately $1850, repackaged (compounded) Avastin® $60, and Lucentis® $1170 per injection. In eyes with relatively good starting vision, there were no differences in vision outcomes; all three groups, on average, had improved vision. In eyes with starting vision of 20/50 or worse, EYLEA® had better vision outcomes at 1 year than either Avastin® or Lucentis®, and better vision outcomes at 2 years than Avastin®. However, given that, on average, eyes will receive 9 to 10 injections within the first year of treatment and 5 injections in the second year, neither EYLEA® nor Lucentis® would be considered cost effective by standard benchmarks compared with Avastin® unless their prices decrease substantially.

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Macular Degeneration May Improve with High Dose Statin Therapy

MedicalResearch.com Interview with:

Demetrios Vavvas, M.D., Ph.D. Co-Director Ocular Regenerative Medical Institute Clinician scientist at Mass. Eye and Ear and Co-Director of the Ocular Regenerative Medicine Institute at Harvard Medical School

Dr. Demetrios Vavvas

Demetrios Vavvas, M.D., Ph.D.
Co-Director Ocular Regenerative Medical Institute
Clinician scientist at Mass. Eye and Ear and Co-Director of the Ocular Regenerative Medicine Institute at Harvard Medical School

Medical Research: What is the background for this study?

Dr. Vavvas: There is a lack of effective therapies for dry age-related macular degeneration (AMD), one of the leading causes of blindness affecting millions. Although AMD shares similarities with atherosclerosis, prior studies on statins and AMD have failed to show improvement. A limitation of these studies has been the heterogeneity of  age-related macular degeneration disease and the lack of standardization in statin dosage. We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in age-related macular degeneration.

Medical Research: What are the main findings?

Dr. Vavvas: Here, we present for the first time evidence that treatment with high-dose atorvastatin (80mg) is associated with regression of lipid deposits and improvement in visual acuity, without atrophy or neovascularization, in high-risk age-related macular degeneration patients.

Medical Research: What should clinicians and patients take away from your report?

Dr. Vavvas:

  • High dose lipophilic statin administration was associated with regression of large soft drusen and vision gain in 10/23 age-related macular degeneration patients.
  • Duration of treatment before a positive response was observed was usually 1-1.5 years.
  • Patients on high-dose statin appeared to be protected from progression to “wet” neovascular-AMD.

Cholesterol reduction was similarly drastic in responders and non-responders, which suggests that genetic variation may be important in determine who will benefit and who may not.

Age-related macular degeneration is a heterogeneous disease and that targeting the lipid pathway in the appropriate manner and to the appropriate populations we may have the potential not only to slow down or arrest the disease but all to reverse it.

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LUCAS: Lucentis Compared to Avastin Treat and Extend Study For Macular Degeneration

Karina Birgitta Berg MD Department of Ophthalmology Oslo University Hospital Oslo, Norway

Dr. Berg

MedicalResearch.com Interview with:
Karina Birgitta Berg MD
Department of Ophthalmology
Oslo University Hospital
Oslo, Norway 

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

Dr. Berg: Neovascular age-related macular degeneration (nAMD) has been the leading cause of vision loss in the elderly population of Western countries. Inhibition of vascular endothelial growth factor (VEGF) with medications such as bevacizumab and ranibizumab injected into the eye, has dramatically reduced the incidence of social blindness from this disease. Bevacizumab was marketed for intravenous cancer treatment, while ranibizumab was later developed and approved for intraocular treatment of nAMD. Due to similar clinical effects and a strikingly low cost compared to ranibizumab, bevacizumab has remained widely used as an off-label treatment for the treatment of nAMD. In order to preserve vision results over time, most patients need injections repeatedly. Treatment on a monthly basis has shown good vision improvement, while monitoring monthly and treating only when signs of recurrences appear, is less successful. The aim of a treat-and-extend protocol is to gradually increase the treatment intervals, while avoiding potentially harmful recurrences. This treatment modality has become commonly used, entailing fewer patient visits and less burden upon health care systems.

The multicenter prospective randomized Lucentis Compared to Avastin Study (LUCAS) was aimed at comparing the efficacy and safety of bevacizumab versus ranibizumab when following a treat-and-extend protocol. The patients received monthly injection treatment until inactive disease was achieved. The treatment interval was then increased by two weeks at a time up to a maximum of 12 weeks. In the event of a recurrence, the treatment interval was reduced by two weeks at a time. The study demonstrated equivalent results in vision improvement with bevacizumab and ranibizumab after two years of treatment. Treatment according to a treat-and-extend protocol was safe with good visual results when extending up to 10 weeks, while recurrences at 12-week intervals had a negative impact on the final results on vision.

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Parkinson’s Drug L-DOPA May Protect Against Macular Degeneration

Brian S. McKay, Ph.D Associate Professor Department of Ophthalmology and Vision Science University of Arizona Medical Research Building, Room 212 Tucson, AZ 85724

Dr. McKay

MedicalResearch.com Interview with:
Brian S. McKay, Ph.D

Associate Professor
Department of Ophthalmology and Vision Science
University of Arizona
Medical Research Building, Room 212
Tucson, AZ 85724 

Medical Research: What is the background for this study?

Dr. McKay: AMD (age-related macular degeneration) is a disease that is race-related. White people get the disease and lose vision to AMD at much higher rate than Blacks or Hispanics.

Thus, while race is complex, pigmentation may protect from the disease. With this starting point, my laboratory went after the pigmentation pathway to determine how pigment may affect photoreceptor (the retinal cells that actually catch the light) survival. The  pigmented cells in the back of the eye are the retinal pigment epithelial cells (RPE), the rest of the retina does not pigment, it is clear not brown. We discovered that when the RPE make pigment they turn on molecular pathways to foster photoreceptor survival. Next we discovered the ligand for a receptor on the RPE that was tied to governing photoreceptor survival and pigmentation. That ligand was L-DOPA.

Knowing that L-DOPA is given to many aging individuals (those at risk of AMD), we developed a team to ask whether those taking L-DOPA for movement disorders are protected from AMD.

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Promising Study Supports Gene Therapy For Wet Macular Degeneration

Professor P. Elizabeth Rakoczy Centre for Ophthalmology and Visual Sciences The University of Western Australia Head of Department - Molecular Ophthalmology Lions Eye Institute AustraliaMedicalResearch.com Interview with:
Professor  P. Elizabeth Rakoczy
Centre for Ophthalmology and Visual Sciences
The University of Western Australia
Head of Department – Molecular Ophthalmology
Lions Eye Institute Australia


Medical Research: What is the background for this study?

Prof. Rakoczy: Wet age related macular (wet-AMD) is the major cause of blindness in the developed world. It is treated with frequent anti-VEGF injections into the eye. Our preclinical studies demonstrated that following the subretinal injection of a recombinant adeno-associated vector (rAAV) carrying a natural inhibitor of neovascularization (sFlt-1), leaky new, abnormal vessels can be controlled and retinal anatomy improved. The rAAV.sFlt-1 based Ocular Biofactory™ platform has potentially significant advantages over existing technologies as it is designed to provide sustained production of a naturally occurring antiangiogenic agent, sFlt-1, in situ in the eye. In this trial we investigated the safety of rAAV.sFlt-1 in patients diagnosed with wet-AMD.

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Novel Therapeutic Target Identified For Treatment Of Proliferative Diabetic Retinopathy Identified

MedicalResearch.com Interview with:
Akrit Sodhi, M.D., Ph.D.
Assistant Professor of Ophthalmology
Retina Division
Wilmer Eye Institute
Johns Hopkins Medical Institutions

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

Dr. Sodhi: Diabetic eye disease is the most common cause of severe vision loss in the working age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In proliferative diabetic retinopathy, retinal ischemia leads to the upregulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization, in some, but not all diabetic patients, implicating additional factor(s) in proliferative diabetic retinopathy pathogenesis. In our study, we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identified angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is upregulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from proliferative diabetic retinopathy patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of proliferative diabetic retinopathy and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.

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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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