Intraocular inflammation: A major risk factor resulting from use of anti-complement agents for GA

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The good news for patients is that GA is transitioning from an untreatable disease to a potentially treatable one with development of new therapies to reduce the growth rate, and use of anti-complement therapies have caused the growth rate of GA lesions to decrease.

Image credit: AdobeStock/PhotobyTawat

(Image credit: AdobeStock/PhotobyTawat)

Reviewed by Dinah Zur, MD

Dinah Zur, MD, urged clinicians to place their focus on patient safety and weigh the benefits versus the risks of use of anti-complement agents to treat geographic atrophy (GA) in a debate on the topic at the 15th annual Controversies in Ophthalmology Congress in Athens. Zur was given this topic as part of a debate at the meeting. She is Associate Professor of Clinical Ophthalmology and Head of Center for Retinal Degenerations at Ophthalmology Division, Tel-Aviv Medical Center Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.

She explained that the good news for patients is that GA is transitioning from an untreatable disease to a potentially treatable one with development of new therapies to reduce the growth rate, and use of anti-complement therapies have caused the growth rate of GA lesions to decrease.

However, she emphasized that physicians should carefully evaluate the therapeutic adverse events against the disease risk. While vision can be threatened by GA, vision loss also can occur as a result of intraocular inflammation caused by the drugs themselves.

Image courtesy of Dinah Zur, MD

Image courtesy of Dinah Zur, MD

GA therapies

Thus far, the FDA has approved 2 anti-complement drugs for GA: avacincaptad pegol intravitreal solution 2 mg (Izervay, Iveric Bio) and pegcetacoplan injection (Syfovre, Apellis Pharmaceuticals).

In the OAKS study, pegcetacoplan met the primary endpoint of the change in the total lesion area and showed a 22% decrease in GA growth when administered monthly compared to sham. In the DERBY study, pegcetacoplan did not meet the primary endpoint, and the differences in lesion growth did not differ significantly between the pecetacoplan and sham groups. At 2 years, however, an anatomic benefit was seen in both studies, with a 22% difference in growth rate in the OAKS and 19% difference in the DERBY in favor of monthly injection of pegcetacoplan.

The GATHER 2 study showed that avacincaptad pegol met the primary endpoint, with a 14% difference in GA area growth between the treated and the sham groups. However, the question arose over whether this anatomic difference is clinically significant.

Regarding the best-corrected visual acuity (VA), the combined data from the OAKS and DERBY studies showed that all patients lost vision at 24 months with disease progression, specifically, an average of 8 to 9 letters in the groups treated monthly, every other month,and those who received no treatment.

Data analysis also showed no differences among the groups in the monocular reading speed, functional reading independent index score, and the National Eye Institute visual functioning questionnaire. This prompted the question about the actual efficacy of the drug.

The combined data from the OAKS and DERBY studies showed that at 2 years monthly injections resulted in 16 cases (3.8%) of intraocular inflammation and 9 cases (2.1%) when injected every other month. At 2 years with both dosing schedules, there were 2 cases (0.5%) each of endophthalmitis.

Zur also reported that from April to October 2023, 32 eyes of 28 patients with intraocular inflammation after pegcetacoplaninjection were reported to the Research and Safety in Therapeutics Committee. Of these, 3 eyes of 2 patients did not have retinal vasculitis on imaging, while 14 eyes of 13 patients had confirmed retinal vasculitis. All cases developed at a mean of 12 days after the first injection of pegcetacoplan

The visual deterioration resulting from inflammation can be catastrophic, in that 8 eyes (57%) had a 3-line or greater loss of VA at the last follow-up, and 6 eyes (43%) had more than a 6-line VA loss at the last follow-up. The median vision was 20/200; 2 eyes were enucleated.

In addition, retinal occlusive vasculitis developed in 11 of 14 eyes (79%) and anterior neovascularization in 6 of 14 eyes (43%).

Zur explained that the incidence rate of retinal vasculitis was estimated to be about 1 in 10,000, based on the number of vials distributed, not the number of eyes. She emphasized that the incidence is higher because the retinal vasculitis developed after the first injection in all cases.

The take-away message is patient safety.

Zur concluded, “Prioritize patient safety. Seek clear evidence of the functional benefit of the use of anti-complement drugs to treated GA, and await the findings from long-term studies to assess the impact of anti-complement agents on disease progression, visual outcomes, and overall safety.”

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