Anthony Obeid, MD, MPH
Wills Eye Hospital
Michael N. Cohen, MD, presented the results of the phase 1 study evaluating the safety and tolerability of JNJ-1887. JNJ-1887 is a one-time intravitreal gene therapy that targets the complement system in eyes with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Dysregulation of the complement pathway secondary to genetic mutations has been previously implicated in the pathogenesis of GA and dry-AMD. The protein of interest in this study is CD59, a naturally occurring protein that inhibits C9, which in turn inhibits the formation of the membrane attack complex, the terminal step in the complement pathway. JNJ-1887 is known to augment the levels of CD59, hence targeting this terminal step in attempts to halt the progression of GA secondary to AMD.
Based on preclinical data, 3 dose cohorts were enrolled sequentially: 3 patients in the low dose cohort, 3 patients in the intermediate dose cohort, and 11 patients in the high dose cohort. The primary endpoint of the study was at 6 months with additional follow-up to 12 and 24 months. Inclusion and exclusion criteria were consistent with other clinical trials on GA. Visual acuity had to be 20/200 or worse in the low dose cohort, and 20/80 or worse in the intermediate and high dose cohort. GA lesion size had to measure between 5-20 mm2. Key exclusion criteria included any geographic atrophy that was from etiologies other than AMD as well as the presence of choroidal neovascularization in the study eye.
The primary objectives were safety and tolerability. Secondary objectives included changes in the geographic atrophy lesion size, conversion to neovascular AMD, and clinically significant changes in vision. No steroid prophylaxis was administered during this trial.
The primary study endpoints for safety and tolerability were met in all doses evaluated. No serious adverse events or systemic serious adverse events were noted during the study period of 24 months. There was one study discontinuation due to death secondary to leukemia and this was deemed unrelated to the study intervention. Inflammation was a key adverse event with 29% of patients developing “mild” inflammation that resolved with either topical steroids or observation alone. The only inflammation that did not resolve was in the patient with leukemia that died prior to completion of the study. There was no incidence of endophthalmitis and no new-onset choroidal neovascularization. Finally, the optic cup to disc ratio increased in 2 patients bilaterally over the 2-year study period.
Although the efficacy of the treatment was not a primary endpoint, GA lesion growth rate was evaluated as a supportive endpoint. The growth rate was similar between all cohorts, however, no formal analysis was performed comparing the rates between all doses given the small sample sizes. Further evaluation of the mean square root change in GA lesion growth was analyzed in six-month increments in the high-dose cohort. Results demonstrated a continued decline in growth over time up until the 24-month time period.
In summary, JNJ-1887 was found to be safe and well-tolerated in all dose cohorts. Additionally, preliminary observations suggest a decrease in GA lesion growth rate in the high-dose cohort. we look forward to the phase 2 clinical trial evaluating JNJ-1887 as a treatment for GA secondary to AMD.