Clinical Studies:
OAKS and DERBY
Citation: Heier JS et al; OAKS and DERBY study investigators. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023 Oct 21;402(10411):1434-1448.
Key Points
- Intravitreal pegcetacoplan administered monthly or every other month slowed the rate of geographic atrophy growth, with increased effect over time, compared to sham.
-
Objective
To evaluate the efficacy and safety of pegcetacoplan for geographic atrophy (GA).
-
Study Design
Two 24 month, multicenter, randomized, double-masked, sham-controlled phase 3 clinical trials.
Subjects
- Inclusion:
- 60 years or older
- BCVA of 24 ETDRS letters (20/320) or better
- Diagnosis of geographic atrophy (GA) secondary to AMD
- Total GA area of 2.5 to 17.5 mm² or, if multifocal, at least one lesion was 1.25mm² or larger
- Both subfoveal and non-subfoveal lesions were allowed
- In OAKS, patients also required to be able to complete microperimetry assessment (not assessed in DERBY)
- Exclusion:
- Atrophy due to another cause
- History of or active choroidal neovascularization (CNV) (CNV in the fellow eye was not an exclusion criterion)
Randomization Scheme/Study Interventions
- Patients were randomized 2:1:1:1 to:
- 15 mg per 0.1 mL of pegcetacoplan monthly
- 15 mg per 0.1 mL of pegcetacoplan every other month
- Sham injection monthly
- Sham injection every other month
Results
- 637 patients in OAKS and 621 patients in DERBY were randomized. 89% of patients in both trials completed the first 12 months, and 74% and 76% in OAKS and DERBY, respectively, completed 24 months.
- GA Lesion Area:
- OAKS:
- 12 months: Primary endpoint was met. -21% difference in total GA lesion area for monthly pegcetacoplan and -16% for every other month compared to sham (statistically significant for both groups).
- 24 months: Pegcetacoplan monthly slowed GA lesion growth by 22% compared to sham (significant); every other month slowed by 18% (significant).
- DERBY:
- 12 months: Primary endpoint not met. -12% difference in total GA lesion area for monthly pegcetacoplan and -11% for every other month compared to sham (not statistically significant).
- 24 months: Pegcetacoplan monthly slowed GA lesion growth by 19% compared to sham (significant); every other month slowed by 16% (significant).
- Combined OAKS and DERBY:
- 12 months: Growth difference in GA lesions was -16% with pegcetacoplan monthly and -14% with every other month compared to sham (significant).
- 24 months: Growth difference in GA lesions was -21% with pegcetacoplan monthly and -17% with every other month compared to sham (significant).
- GA lesion growth by location (subfoveal vs non-subfoveal) in OAKS and DERBY (combined):
- At 12 months:
- Patients with non-subfoveal GA at baseline: Differences in lesion growth were -26% and -23% in patients receiving pegcetacoplan monthly and every other month, respectively (compared to sham; significant).
- Patients with subfoveal GA at baseline: Differences in lesion growth were -11% and -8% in patients receiving pegcetacoplan monthly and every other month, respectively (compared to sham; not significant).
- Visual function endpoints:
- At 24 months, no difference between patients receiving pegcetacoplan or sham in best corrected visual acuity, functional reading independence index scores, monocular maximum reading speed, mean threshold sensitivity, and National Eye Institute Visual Functioning Questionnaire 25 distance activity subscale score.
- Difference in the mean change in the number of scotomatous points in the junctional zone was not significant with pegcetacoplan monthly but was significant with pegcetacoplan every other month compared to sham.
- Adverse events:
- Intraocular inflammation (OAKS and DERBY combined): 0.24% per injection at 24 months. No cases led to permanent severe vision loss or had retinal involvement.
- Rate of ischemic optic neuropathy (OAKS and DERBY combined): Pegcetacoplan monthly: 1.7%; every other month: 0.2%; Sham: 0%.
- Rate of new onset wet AMD at 24 months: Pegcetacoplan monthly: 11% in OAKS, 13% in DERBY; every other month: 8% in OAKS, 6% in DERBY; Sham: 2% in OAKS, 4% in DERBY.
Conclusions
- Pegcetacoplan monthly and every other month slowed the rate of geographic atrophy growth, with increased effect over time, compared to sham.
- In these two clinical trials, the safety profile of pegcetacoplan appeared similar to that of other intravitreal injections, with the exception of the increased risk for development of neovascular AMD.