APLS 2017 Annual Report

3 protein in the body that causes the growth of abnormal blood vessels and leakage in the eye. There was no meaningful negative impact on visual acuity resulting from the new onset exudations. Following discussions with the FDA in December 2017, we have finalized the trial design for a Phase 3 clinical program to evaluate APL-2 for the treatment of GA. The Phase 3 program, which we plan to begin in the second half of 2018, will consist of two identical 600-patient prospective, multicenter, randomized, double-masked, sham-injection controlled trials to assess the efficacy and safety of multiple intravitreal injections of APL-2 in patients with GA. The Phase 3 trials will be similar in design to the Phase 2 trial, including the eligibility criteria and primary endpoint of GA lesion growth at 12 months. However, unlike the Phase 2 trial, patients who develop new onset exudation in the study eye will continue to be treated with APL-2 along with VEGF injections, the current standard of care for wet AMD. We also plan to initiate a Phase 1b/2, multi-center, open label clinical trial to evaluate the safety of intravitreal APL-2 therapy when administered in parallel with anti-VEGF treatments in patients with wet AMD in the study eye in the second quarter of 2018. In this trial, we will evaluate whether treatment with APL-2 may allow wet AMD patients to reduce their dependence on anti-VEGF treatments. We believe that the data from this trial may support the use of APL-2 in eyes afflicted with both wet AMD and GA. In PNH, we are developing APL-2 to be injected subcutaneously as a monotherapy. PNH is a rare, life-threatening, chronic, debilitating blood disorder characterized by the absence of certain proteins that normally regulate complement activity on the surface of blood cells. As a consequence, patients with PNH suffer from significant and chronic red blood cell loss, or hemolysis. The only therapy currently approved for the treatment of PNH, eculizumab (Soliris), inhibits the complement system by targeting C5, a protein that is downstream from C3 in the complement cascade. Inhibitors that target C5 are limited to addressing only one of the two mechanisms of hemolysis in PNH. Consequently, many patients with PNH who are on treatment with eculizumab remain anemic and continue to require frequent transfusions, conditions associated with a poor quality of life. By contrast, APL-2, because it targets C3, addresses both mechanisms of hemolysis and, we believe, may therefore significantly ameliorate these conditions. In our ongoing Phase 1b trials of APL-2 for the treatment of PNH, treatment with APL-2 has been associated with improvements in transfusion dependency, levels of hemoglobin—the protein that carries oxygen from the lungs to the tissues of the body—and other hematological indicators that we believe are clinically meaningful. We made these observations both in patients who had not been treated with eculizumab, who we refer to as treatment-naïve patients, and in patients being treated with eculizumab who remained anemic and required frequent blood transfusions. In these trials, APL-2 has been generally well tolerated. As of February 28, 2018, four of the six patients who had been treated with daily doses of 270 mg of APL-2 and with eculizumab remain on treatment in the trial, having received treatment with APL-2 for a total of between 16 and 19 months. Due to the response observed with the APL-2 treatment for each of the four remaining patients, the treating physicians have individually taken the decision either to reduce the dose of eculizumab to the label dose for patients who had received a higher dose of eculizumab or to withdraw eculizumab treatment. We intend to report additional data from these patients in the second quarter of 2018. Additionally, we initiated enrollment of additional treatment-naive patients in our Phase 1b trial in the first quarter of 2018. We plan to report additional data from our Phase 1b trial in treatment-naïve patients in the second quarter of 2018. We plan to initiate a Phase 3 clinical trial in patients with PNH comparing treatment with APL-2 to treatment with eculizumab as a monotherapy in the second half of 2018. We plan to enroll up to 70 patients with PNH in this trial who are then receiving eculizumab. The treatment period of the trial will consist of three parts: a four-week run-in period, a 16-week randomized treatment period and a 32-week open-label APL-2 only period. During the run-in period, all patients will receive twice-weekly subcutaneous doses of 1,080 mg of APL-2 in addition to patients’ then current dose of eculizumab. The run-in period is designed to provide patients with sufficient plasma concentration of APL-2 to provide for what we expect to be adequate complement inhibition before withdrawing eculizumab. Following completion of the run-in period, patients will receive either 1,080mg of APL-2 twice per week or their current dose of eculizumab through the duration of the 16-week randomized treatment period. We expect that the primary endpoint will be the week 16 change from baseline in hemoglobin level. Following completion of the randomized treatment period, all patients will receive APL-2 only for 32 weeks in the open-label part. We are currently discussing with the FDA, the European Medicines Agency, or EMA, and the Japanese Pharmaceuticals and Medical Devices Agency, or PMDA, the trial program that we will need to conduct to submit APL-2 for regulatory approval for PNH. In April 2014, we received orphan drug designation from the FDA for APL-2 for PNH, and in December 2016 we received fast track designation from the FDA for APL-2 for PNH. If our clinical development of APL-2 for PNH is successful, we believe that APL-2 could be a best-in-class therapy for PNH, differentiated by mechanism, and has the potential to significantly increase the quality of life of patients with PNH as compared to the current standard of care.