APLS 2017 Annual Report

11 Planned Phase 3 Clinical Trials Following discussions with 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, GA lesion size will be measured by total area rather than mean change in the square root of GA lesion size. We expect that we will set statistical significance as a p-value of 0.05 or less, meaning that there is a 1 in 20 or less probability that the observed results occurred by chance. 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. The observation intervals in pivotal studies in AMD are typically 24 months in total duration in order to meet regulatory requirements for long-term safety and to demonstrate durability of the treatment effect on anatomical and functional endpoints. However, based on our experience in the Phase 2 trial, we believe that APL-2 can show treatment effect at 12 months and we therefore plan to analyze the data after all patients have completed 12 months of treatment in the trial. This approach was agreed to by the FDA. Planned Phase 1b/2 Clinical Trial in Wet AMD We plan to initiate a Phase 1b/2, multi-center, open label 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 second quarter of 2018. In this trial, we will evaluate whether treatment with APL-2 may allow patients with wet AMD in the study eye 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. Supporting Trial We plan to initiate a long-term safety extension clinical trial in the second half of 2018 to support continued intravitreal dosing with APL-2 for patients with GA who have previously participated in a clinical trial with APL-2. Preclinical Studies We have conducted preclinical studies in monkeys to assess the safety of APL-2 injected intravitreally. A full toxicological review, including histopathological examinations of both eyes and of multiple additional tissues from each monkey revealed no evidence of APL-2-related toxicity changes at any of the doses tested. Hematology (systemic APL-2) Paroxysmal Nocturnal Hemoglobinuria Background PNH is a rare, chronic, debilitating blood disorder that is most frequently acquired in early adulthood and usually continues throughout the life of the patient. Some of the prominent symptoms of PNH include severe anemia, a condition that results from having too few red blood cells, severe abdominal pain, severe headaches, back pain, excessive weakness, fatigue and recurrent infections. If not treated, PNH results in the death of approximately 35% of affected individuals within five years of diagnosis and 50% of affected individuals within ten years of diagnosis, primarily due to the formation of life-threatening blood clots inside the blood vessels, or thrombosis. Based on prevalence data published in an abstract in a peer-reviewed journal, we estimate that there are approximately 4,700 patients with PNH in the United States. PNH is caused by the presence of mutant stem cells in the bone marrow that lack important proteins on their surface that protect against activation of the complement system. In patients with PNH, an autoimmune response targets and eliminates normal stem cells, enabling mutant cells to become dominant in the bone marrow. These mutant stem cells lead to mutant platelets and red blood cells that, unlike normal cells, are overly susceptible to activation or destruction by the complement system. Mutant platelets, activated by the membrane attack complex, increase the risk of thrombosis, which is the leading cause of mortality in patients with PNH. Mutant red blood cells are susceptible to destruction by intravascular and extravascular hemolysis. Intravascular hemolysis, which involves the destruction of blood cells within the blood vessels, is caused by the formation of the membrane attack complex on the surface of red blood cells causing them to rupture. Intravascular hemolysis causes severe anemia and contributes to the risk of thrombosis. Extravascular hemolysis, which involves the destruction of blood cells outside the blood vessels, is caused by C3-related opsonization on red blood cells leading to removal of the cells from the blood stream by the liver and the spleen. Extravascular hemolysis further contributes to severe anemia and transfusion dependency in patients with PNH.