In this episode of Evidence Based Retina, Rishi P. Singh, MD, FASRS is joined by Ferhina S. Ali, MD, MPH to discuss findings from the phase 3 OAKS (NCT03525613) and DERBY (NCT03525600) trials on pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals) for geographic atrophy (GA).
Dr. Ali is a vitreoretinal surgeon at Westchester Medical Center in Hawthorne, New York and an Assistant Professor of Ophthalmology at New York Medical College in Valhalla, New York.
OAKS and DERBY trials fast facts
- OAKS and DERBY design: Randomized, double-masked, and sham-controlled trial to assess the safety and efficacy of pegcetacoplan in patients randomly assigned to monthly or every-other-month (EOM) injections of pegcetacoplan or sham.
- Investigators assessed the change in total area of GA lesions from baseline measured by fundus autofluorescence at 12 months. Patients continued to receive masked treatments for 24 months.1,2
- Participants: 637 (OAKS) and 621 (DERBY) patients with GA secondary to age-related macular degeneration (AMD).
- OAKS 24-month findings: Pegcetacoplan administration reduced GA lesion growth compared to sham by 22% and 19% in monthly and EOM treatment groups, respectively.2
- DERBY 24-month findings: Pegcetacoplan administration reduced GA lesion growth compared to sham by 18% and 17% in monthly and EOM treatment groups, respectively.2
- Note: In both OAKS and DERBY, when comparing the effect of pegcetacoplan treatment between months 12 to 18 and 18 to 24 there was an accelerated effect as compared to sham.1
- Safety: The most common adverse reactions (≥5%) reported in patients receiving pegcetacoplan injections were ocular discomfort, neovascular AMD, vitreous floaters, and conjunctival hemorrhage.3
- Apellis recently reported 5-year data from the GALE extension study (NCT04770535), which enrolled patients from OAKS and DERBY.
Identifying natural history parameters associated with faster GA progression and vision loss
Earlier this year, Dr. Ali presented at the Atlantic Coast Retina Club on a post hoc analysis of pooled data from the sham arms of the OAKS and DERBY trials on factors predicting faster GA progression and vision loss. This analysis included over 400 patients from OAKS and DERBY and enabled researchers to observe the natural history of their disease progression over the 2-year course of the trials.
The analysis found that the following factors were associated with accelerated GA progression and vision loss:
- Faster GA progression:
- Fewer intermediate or large drusen
- Less circular and larger-perimeter lesions
- Lesions farther from the fovea
- Overweight BMI
- Faster vision loss:
- Higher baseline BCVA
- Slower reading speed
- Fewer large drusen
- Larger low-luminance deficit
- Smaller baseline GA lesion size
Although fewer drusen being associated with GA progression may sound counterintuitive, Dr. Ali explained that this is likely related to the lifecycle of drusen and how reductions in soft drusen have been found to occur at the site of subsequent GA incidence or progression.4
She added that the circularity index of GA lesions was a new risk factor identified in this study, and remarked that this was consistent with findings from previous studies that multifocal GA lesions are associated with increased rates of GA growth in eyes.5
How do these findings translate to treatment decisions in clinical practice?
The two key considerations for clinical practice that Dr. Ali has taken away from this study include assessing the location of GA lesions, as those further from the fovea progress faster, and observing that earlier intervention had a notable impact on slowing the rate of vision loss.
Discussing intravitreal complement inhibitors with GA patients
She added that when discussing these treatments with patients, it is important to note that they stave off vision loss, and while they may not produce the same rapid treatment results in vision and anatomy seen with anti-VEGF agents, research has shown that patients who receive complement inhibitor treatments have slower disease progression than those who do not receive treatment.6
Ultimately, the goal is to preserve as much vision as possible as the disease progresses, which they know will continue no matter what they do, and there are currently no other FDA-approved treatments.
Side effect profile of pegcetacoplan
Of note, Dr. Ali was on the ASRS Research and Safety in Therapeutics (ReST) Committee during the time that intravitreal complement inhibitors were approved and commercially launched.
It is known that the rate of retinal vasculitis in pegcetacoplan is 1 in 4,000 from the first injection.7 That being said, she added that the incidence rate reported to ASRS and Apellis has decreased over time, though the exact reason for this phenomenon is currently unclear.
When considering intravitreal complement inhibitors, Dr. Ali weighs the potential treatment risks with patient factors, such as their monocular status, which eye should be treated first, and which agent is the best fit.
Conclusion
The findings from this study highlight clinically measurable factors associated with GA progression that can be considered when developing individualized treatment decisions for patients.
Dr. Ali noted that there are ongoing analyses of the patients in the treatment arms of OAKS and DERBY to identify parameters associated with GA progression in patients undergoing therapeutic intervention to elucidate the potential efficacy of these treatments and how they can hone in on the best candidates for treatment.
