New class of therapy benefits AMD patients five years on

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Patients with age-related macular degeneration (AMD), the most common cause of major vision loss in older people, still show benefits from a new class of therapy – originally developed to treat cancer – after long-term treatment.

The finding comes from a follow-up study of patients in a large clinical trial who were treated with drugs that inhibit vascular endothelial growth factor (VEGF). After an average of 5.5 years from starting treatment, half the patients retained visual acuity in the affected eye of 20/40 or better, which is normally sufficient for driving without glasses. Before anti-VEGF drugs became available a decade ago, AMD patients fared much worse.

The study, coordinated by a team at the Perelman School of Medicine at the University of Pennsylvania, confirms the long-term clinical value of targeting VEGF, a molecule whose abnormal overproduction in the eye drives vision loss in AMD. Patients in the study took Avastin (bevacizumab) or Lucentis (ranibizumab), the first two widely used anti-VEGF drugs.

“The good news is that patients are having much better visual outcomes than even dreamed about ten years ago–but there’s still a considerable proportion of patients for whom long term outcomes are not good, and we need better treatments for them,” said senior investigator Dr Maureen G Maguire, Carolyn F Jones professor of pphthalmology at Penn Medicine.

AMD in all its forms is estimated to affect about 6.5% of people in the US over age 40, or roughly 10m Americans. It features the degeneration of the macula, the central region of the retina, in which a concentration of colour-sensing cone cells normally provides high-resolution colour vision wherever the gaze is directed.

The most severe AMD-related vision loss comes from “wet” or “neo-vascular” AMD, in which new blood vessels grow under or into the retina. The resulting vessels, that depend on VEGF, are abnormally fragile and leaky, and their proliferation and associated fluid build-up lead to macular damage and increasing loss of vision in the central visual field, making it increasingly difficult for sufferers to drive, read, and recognise faces. Left untreated, patients can lose most of their central vision in their eye within 1 to 2 years and about half will lose vision in their second eye within another 5 years.

Before anti-VEGF treatments were available, ophthalmologists used light-activated (photodynamic) drugs to block and destroy the abnormal vessels. This approach had a small impact on the course of disease, but in the 1990s, researchers discovered the link between wet AMD and VEGF, and in 2004, the first anti-VEGF drug for treating wet AMD received FDA approval.

In 2006, the FDA approved a more effective anti-VEGF treatment for wet AMD, Lucentis (ranibizumab), a fragment of an antibody that binds to the VEGF protein. Around this time, ophthalmologists also began to treat wet AMD with a closely related anti-VEGF antibody fragment, Avastin (bevacizumab), which was FDA-approved for treating cancers but is much cheaper than Lucentis at the doses used for AMD therapy.

In 2008, Maguire and colleagues at Penn Medicine, along with Cleveland Clinic researchers led by Dr Daniel F Martin and researchers from other institutions, set up a large clinical trial, CATT (Comparison of AMD Treatments Trials) to compare the two anti-VEGF therapies. Working with almost 900 collaborators at dozens of eye clinics across the nation, with sponsorship from the National Eye Institute, they found that Avastin and Lucentis have essentially the same effectiveness and safety after one and two years of treatment.

In the new study, the CATT Follow-up Study, Maguire and colleagues examined visual acuity and other outcomes in CATT patients who continued to receive treatment after the end of the two-year trial. During this follow-up period, which averaged 3.5 years, most patients continued to be treated with either Avastin or Lucentis, although some switched from one to the other. Thus the study was meant not to compare the drugs again but merely to gauge the longer-term collective impact of these anti-VEGF therapies.

Of the 647 patients for whom visual acuity measurements were available during the follow-up period, 321 (49.6%) had at least 20/40 vision in the affected eye – vision that allows driving or reading a newspaper. By contrast, prior studies have found that at two years after diagnosis, fewer than 10% of untreated wet AMD eyes retain 20/40 vision, and fewer than 15% retain 20/40 vision if treated with photodynamic therapy.

Even so, the CATT patients did experience some vision loss during the follow-up period. The nearly 50% retention of 20/40 vision was a drop from nearly 70% at the end of the two-year trial. Moreover, the percentage of eyes with 20/200 vision (commonly considered “legally blind”) or worse jumped to 20% during the follow-up period, from just 5% at two years. Measurements of retinal thickness and imaging of the back of the eye and its vessels, which were available for more than 500 patients during the follow-up period, also revealed signs of modestly worsening disease.

“When we first treat neo-vascular AMD patients, after they’ve noticed some initial vision loss, they typically gain about two lines worth of visual acuity on the eye chart, and what we’ve seen in this study is that between year two and about year five of anti-VEGF treatment they lose most of that improvement,” said Maguire. “On the other hand, if they had been untreated they never would have seen any improvement at all – their vision would have gotten worse and worse.”

Future advances in AMD therapy are likely to come in part from anti-VEGF treatments that are more effective and/or less burdensome to administer. Avastin and Lucentis are meant to be administered by injection into the eye at a clinic up to every four weeks. A newer anti-VEGF therapy, Eylea (aflibercept) has been shown to work well with injections every eight weeks. “Ideally what we’d like is a treatment that doesn’t require the patient to come back for evaluation until six to twelve months later,” said Maguire.

Targeting factors other than VEGF, she added, will also probably be necessary to provide a more comprehensive prevention of AMD disease processes, including those that do not directly involve new blood vessel growth.

Abstract
Purpose: To describe outcomes 5 years after initiating treatment with bevacizumab or ranibizumab for neovascular age-related macular degeneration (AMD).
Design: Cohort study.
Participants: Patients enrolled in the Comparison of AMD Treatments Trials.
Methods: Patients were assigned randomly to ranibizumab or bevacizumab and to 1 of 3 dosing regimens. After 2 years, patients were released from the clinical trial protocol. At 5 years, patients were recalled for examination.
Main Outcome Measures: Visual acuity (VA) and morphologic retinal features.
Results: Visual acuity was obtained for 647 of 914 (71%) living patients with average follow-up of 5.5 years. The mean number of examinations for AMD care after the clinical trial ended was 25.3, and the mean number of treatments was 15.4. Most patients (60%) were treated 1 time or more with a drug other than their assigned drug. At the 5-year visit, 50% of eyes had VA of 20/40 or better and 20% had VA of 20/200 or worse. Mean change in VA was −3 letters from baseline and −11 letters from 2 years. Among 467 eyes with fluorescein angiography, mean total lesion area was 12.9 mm2, a mean of 4.8 mm2 larger than at 2 years. Geographic atrophy was present in 213 of 515 (41%) gradable eyes and was subfoveal in 85 eyes (17%). Among 555 eyes with spectral-domain optical coherence tomography, 83% had fluid (61% intraretinal, 38% subretinal, and 36% sub–retinal pigment epithelium). Mean foveal total thickness was 278 μm, a decrease of 182 μm from baseline and 20 μm from 2 years. The retina was abnormally thin ( Conclusions: Vision gains during the first 2 years were not maintained at 5 years. However, 50% of eyes had VA of 20/40 or better, confirming anti–vascular endothelial growth factor therapy as a major long-term therapeutic advance for neovascular AMD.

University of Pennsylvania School of Medicine material
Ophthalmology abstract


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