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Spotlight on GA: A bright future with potential treatments

Published on: 
Ophthalmology Times Europe, Ophthalmology Times Europe November 2022, Volume 18, Issue 09

Giving patients access to new treatments and information on changing their lifestyle habits could result in major steps towards minimising or even preventing geographic atrophy.

Reviewed by Dr Rishi P. Singh.

For nearly 20 years, neovascular age-related macular degeneration (AMD) has been getting all the attention owing to the introduction of intravitreally administered anti-vascular endothelial growth factor (anti-VEGF) drugs. These agents have successfully stopped disease progression and saved vision in many affected patients.

However, focus has been shifting to the overwhelmingly large population of patients who have the dry, or non-exudative, form of AMD, the insidious type that does not involve the growth of abnormal blood vessels but erodes vision over time. This point was made by Dr Rishi P. Singh, president of Cleveland Clinic Martin North and South hospitals in Stuart, Florida, United States, and professor of ophthalmology at Cleveland Clinic Lerner College of Medicine in Ohio, US.

The end stage of dry AMD is known as geographic atrophy (GA). At this stage of the disease, the activities of daily living—reading, driving, facial recognition and so on—are severely affected, leading to overall serious deterioration of the patient’s condition and quality of life.

Current status of GA therapy

Recent clinical trials1,2 have provided evidence that intravitreal injection of certain inhibitors can cause regression or slowing of vision loss over time in people with GA. “This is how clinicians are currently attempting to treat GA,” said Dr Singh. Findings from these studies have shown advancements in the ability to prevent progression of GA by 15–25%. In the case of GA outside the fovea, that ability increased to 35% — “a good step in the right direction,” he stated.

Dr Singh pointed out that previously, physicians had not looked at GA as closely as they could have, mainly because treatments are only now on the horizon. Optical coherence tomography (OCT) is the main imaging modality, and the emphasis in these images is on identifying exudative AMD and its characteristic fluid or haemorrhages during clinical evaluations. “GA requires reappraisal of these diagnostic techniques to ascertain that the patients with the most need are identified for treatment through the clinical trials,” Dr Singh said.

Real-world practice versus trials

Dr Singh explained that in routine clinical practice, a few factors come into play, and he acknowledged the need to do better when evaluating and treating patients with neovascular AMD. For example, the number of treatments prescribed is substantially lower in clinical practice than in clinical trials. Additionally, fluorescein angiography is not carried out routinely in clinical practice as it is in clinical trials, although this test may not always be necessary in the clinical setting.

In studies of GA, numerous tests are performed, such as microperimetry and low-luminance vision testing, that are also not routinely performed in clinics; Dr Singh noted that the added benefits in the clinical setting are questionable. In clinical trials, these tests quantify the benefit of the drugs under evaluation for treating GA.

“If I want a very precise measurement of the clinical effect of a drug, tools such as low-luminance vision and microperimetry are invaluable to determine the treatment effect over time,” Dr Singh explained. Although these specific tests are not used often by ophthalmologists, fundus autofluorescence and OCT are used to determine the size and spread of the GA as patients are followed.

Regarding treatments, the effects of the drugs being evaluated are individualised to each patient. “Each patient dictates the clinical suspicions based on how much the disease has progressed and [whether] further intervention is needed,” Dr Singh said.

He noted that he is very pragmatic in these cases when ordering testing. “I use an evidence-based treatment approach, in that if I order a particular test or additional imaging, it is going to help me make useful decisions about a particular patient’s treatment plan,” he explained. This more thoughtful approach will ease the burden in the clinic.

Ongoing studies

There are several ongoing clinical trials for GA candidates, all of which attack the complement cascade, C3 and C5, both of which are in the alternative complement cascade. Pegcetacoplan (Empaveli, Apellis Pharmaceuticals), a targeted C3 therapy, was recently fast-tracked by the US Food and Drug Administration (FDA) based on the results of three studies: the OAKS, DERBY and FILLY trials.3

The drug successfully slowed the progression of GA. “Pegcetacoplan showed significant benefit in its Phase 3 trial and it has a relatively good safety profile. [However], some patients converted to neovascular AMD as a result of treatment with pegcetacoplan, which we need to learn more about,” Dr Singh observed.

Avacincaptad pegol (Zimura, Iveric Bio), a C5 inhibitor, is now being evaluated in a Phase 3 study. The results of the GATHER1 study were similar to those of the OAKS and DERBYstudies. GATHER2,4 which compared monthly avacincaptad treatment with sham treatment, will report results during autumn 2022. “These findings will determine how we will use the drug in clinical practice,” Dr Singh stated.

Dr Singh believes the future of these therapies is very bright, especially concerning the approximately 50% of patients who require the assistance of carers to travel to appointments and other activities. Considering this patient burden, a reduction in disease progression would be a major step forward for patients and carers.

Three messages for patients with GA

Data from the current studies clearly indicate that there is a great deal of hope for beneficial future therapies for this patient population. Dr Singh recommended that patients under the care of a retina specialist or ophthalmologist should determine whether they are candidates for treatment with these drugs when they become clinically available.

Patients should recognise the importance of family history and lifestyle in the development of GA, both of which are strong predictors of disease development. Smoking, a diet high in saturated fat and not eating fish or green leafy vegetables are key elements in GA development. A change in habits is a good step towards possibly preventing the disease.

Dr Singh is hoping that future versions of drugs for GA could involve sustained drug delivery, eliminating the need for monthly or every-other-month treatments, and combination therapies.

Rishi P. Singh, MD
E: Singhr@ccf.org
Dr Singh serves as a consultant to Allergan, Bausch + Lomb, Genentech, Regeneron Pharmaceuticals, Novartis, AsclepiX Therapeutics, Gyroscope Therapeutics and Apellis Pharmaceuticals.
References
1. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. Ophthalmology. 2020;127:186-195.
2. Apellis announces top-line results from phase 3 DERBY and OAKS studies in geographic atrophy (GA) and plans to submit NDA to FDA in the first half of 2022. Press release. Apellis Pharmaceuticals, Inc. 9 Sep 2021. Accessed 4 Oct 2022. investors.apellis.com/news-releases/news-release-details/apellis-announces-top-line-results-phase-3-derby-and-oaks
3. Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial. Ophthalmology. 2021;128:576-586.
4. Iveric Bio completes patient enrollment of GATHER2 pivotal clinical trial of Zimura ahead of schedule. Press release. Iveric bio, Inc. 26 Jul 2021. Accessed 4 Oct 2022. investors.ivericbio.com/news-releases/news-release-details/iveric-bio-completes-patient-enrollment-gather2-pivotal-clinical

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