APLS 2017 Annual Report

9 The activity of APL-2 was also shown in a post hoc analysis of the impact of APL-2 on patients with GA in both the study eye and the fellow eye, or bilateral GA. A published study has shown that growth rates of GA lesion size are similar in both eyes of patients with bilateral GA. We also made this observation in patients with bilateral GA in the sham group. In the trial, patients with bilateral GA received treatment with APL-2 in one eye and did not receive treatment in the other eye. We conducted this post hoc analysis because a comparison of effects in both eyes of individual patients allows the treatment effect of APL-2 to be analyzed independently of potential differences in the baseline characteristics of patients in each arm of the trial. In the trial, the rate of GA lesion growth in the study eye of patients with bilateral GA receiving administration of APL-2 every month was slower than the rate of growth in their fellow eye, with a p-value of 0.083. For the patients with bilateral GA receiving administration of APL-2 every other month, the rate of GA lesion growth was also slower in the study eye than the rate of growth in their fellow eye, but with a p- value greater than 0.1. In addition, in both treatment groups the rate of GA growth in the untreated fellow eye was slower than in the sham group. These results are shown in the figure below. AM – APL-2 monthly; AEOM – APL-2 every other month. As part of our review of the data, we also conducted an analysis of the treatment effect as measured by the rate of GA lesion growth in patients treated with APL-2 across multiple genetic subpopulations, including complement factor I (CFI) genotypes. We did not observe any difference in treatment effect across the subpopulations. After the 12 month treatment period, patients were monitored for a further six months without treatment. During the monitoring period, the GA lesions in the previously treated groups grew at a rate similar to sham. Patients for whom images were available at 12 and 18 months who received monthly APL-2 showed a 12% reduction over the six-month monitoring period compared to sham, while patients who received every other month administration of APL-2 showed a 9% reduction compared to sham. These differences are not considered to be statistically significant. Safety Analysis . The most frequently reported adverse events in the trial were associated with the injection procedure in the study eye. These adverse events included two cases of confirmed endophthalmitis and one case of presumed endophthalmitis where the culture tested negative for bacterial growth. In the latter case, the patient fully recovered visual acuity. In our Phase 2 trial, we observed an incidence rate of endophthalmitis of 0.21% per injection. We believe the incidence of endophthalmitis may be due in part to our use of a freeze-dried material requiring reconstitution prior to injection during our Phase 2 trial, which introduced an additional risk of contamination. We intend to use a liquid instead of the freeze-dried formulation in our Phase 3 trial, which we believe may reduce the incidence of endophthalmitis. In addition, during the 12-month treatment period and the six-month monitoring period, we observed a higher incidence of new onset exudation in the study eyes treated with APL-2 as compared to sham, predominantly in patients with a history of wet AMD in fellow eye. Specifically, we observed that, after the 12 month treatment period and the six-month monitoring period, 18 patients (21%) receiving administration of APL-2 every month and seven patients (9%) receiving administration of APL-2 every other month showed new onset exudation, which is a sign of wet AMD, as compared to one patient (1%) in the sham group. Patients who experienced new onset exudation in the study eye were discontinued from treatment with APL-2 and, in all but one case, treated with standard of care anti-VEGF injections under supervision. There was no meaningful negative impact on visual acuity resulting from the new onset exudations. The development of new onset exudation by patients in the trial was communicated to the safety monitoring committee after six months of study data were available. The safety monitoring committee reviewed the cases of new onset exudation, and met several times to discuss the study data, including visual acuity, assessed the risks and benefits of continued treatment and decided that the trial