Spotlight on GA: A bright future with potential treatments

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

Focus has been shifting to the overwhelmingly large population of patients who have the dry form of AMD, the insidious form without blood vessels that erodes vision over time, commented Rishi P. Singh, MD, president of Cleveland Clinic Martin North and South hospitals in Stuart, Florida.

This dry nonexudative form of dry AMD, the end stage of which is geographic atrophy (GA), has been the topic of the most recent study in this arena. 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

Some recent trials1,2 have provided evidence that intravitreal injection of certain inhibitors can cause regression or slowing of vision loss over time.

“This is how clinicians are currently attempting to treat GA,” said Singh, who is also

a professor of ophthalmology at Cleveland Clinic Lerner College of Medicine in Ohio.

Findings from these studies have shown advances in the ability to prevent progression of GA by 15% to 25%. In the case of GA outside the fovea, that ability increased to 35%, “a good step in the right direction,” Singh stated.

He also 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 hemorrhages 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,” Singh said.

Real-world practice vs clinical trials

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

In studies of GA, numerous tests are performed, such as microperimetry and low-luminance vision testing, that are also not performed routinely in clinics; the added benefits in the clinical setting are questionable, he noted. 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,” Singh explained.

Although those 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 individualized to each patient.

“Each patient dictates the clinical suspicions based on how much the disease has progressed and [whether] further intervention is needed,” Singh said.

He also 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.

The clinical trials of drugs for GA are ongoing. All the treatment candidates attack the complement cascade, C3 and C5, both of which are in the alternative complement cascade.

Pegcetacoplan (Apellis Pharmaceuticals), a targeted C3 therapy, was recently fast-tracked by the FDA based on the results of 3 studies: the OAKS (NCT03525613), DERBY (NCT03525600), and FILLY (NCT02503332) 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. Some patients converted to neovascular AMD as a result of treatment with pegcetacoplan, which we need to learn more about,” noted Singh.

Avacincaptad pegol (Zimura; Iveric bio), a C5 inhibitor, is now being evaluated in a phase 3 study. The results of the GATHER1 study (NCT02686658) were similar to those of the OAKS and DERBY studies. GATHER2 (NCT04435366),4 which compared monthly avacincaptad treatment with sham, will report results during fall 2022.

“These findings will determine how we will use the drug in clinical practice,” Singh pointed out.

Singh believes the future of these therapies is very bright, especially concerning the approximately 50% of patients who require the assistance of caregivers 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 caregivers.

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. 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 recognize 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 toward possibly preventing the disease.

Singh is looking past the first iterations of drugs for GA that may include sustained drug delivery to eliminate the need for monthly or every-other-month treatment, and then combination therapies.

Rishi P. Singh, MD

E: Singhr@ccf.org

Singh is president of Cleveland Clinic Martin North Hospital and Cleveland Clinic Martin South Hospital and a staff surgeon at Cleveland Clinic Florida in Stuart. He is also a professor of ophthalmology at Cleveland Clinic Lerner College of Medicine in Ohio. He serves as a consultant to Allergan, Bausch + Lomb, Genentech, Regeneron, Novartis, AsclepiX, Gyroscope, and Apellis.

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(2):186-195. doi:10.1016/j.ophtha.2019.07.011

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. September 9, 2021. Accessed October 14, 2021. 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(4):576-586. doi:10.1016/j.ophtha.2020.08.027

4. Iveric Bio completes patient enrollment of GATHER2 pivotal clinical trial of Zimura ahead of schedule. Press release. Iveric bio, Inc. July 26, 2021. Accessed October 14, 2021. investors.ivericbio.com/news-releases/news-release-details/iveric-bio-completes-patient-enrollment-gather2-pivotal-clinical