ACHN 2017 Annual Report

completed the three-month trial and have entered the long-term extension trial. A fourth patient voluntarily withdrew from the trial on day 41 for reasons unrelated to safety. In August 2017, we announced interim data from this trial in which ACH-4471 demonstrated that it mechanistically inhibited factor D, its intended target, and meaningfully improved LDH, hemoglobin, fatigue score, and other measures of response, including PNH clone size. We also plan to conduct a phase II clinical trial evaluating ACH-4471 in PNH patients currently receiving eculizumab, a therapy for patients with PNH, and are deemed to be sub-optimal responders who have hemoglobin levels below 10 gm/dL and require transfusions with red blood cells. This trial is designed to evaluate 6 months of treatment with ACH-4471 plus eculizumab with the potential for patients to transition to a long-term treatment extension. We anticipate initiating this trial in the first half of 2018. ACH-5228. ACH-5228 is one of our next-generation factor D inhibitors for oral administration. The compound demonstrated complete inhibition of the complement alternative pathway after repeat, twice-daily dosing in non-human primates over a seven-day period. The compound also has the following characteristics based on our preclinical research to date: • Pharmacokinetics and Metabolism . Pharmacokinetic characteristics for ACH-5228 suggest the possibility of less frequent dosing as compared to ACH-4471. • Safety . We have completed short-term, non-clinical studies in rats and dogs in which ACH-5228 demonstrated tolerability and safety margins supportive of progression into human clinical development. • Potency . ACH-5228 is also specific for factor D inhibition and demonstrated a two to three-fold greater potency than ACH-4471 in preclinical studies, delivering similar inhibition of the complement alternative pathway at inhibitory concentrations of approximately half that of ACH-4471. We initiated a first-in-human randomized, placebo-controlled, single-ascending dose phase I study of ACH-5228 administered to healthy volunteers in December 2017. Approximately 28 subjects are expected to be enrolled. The primary endpoint for the trial is the safety and tolerability of ACH-5228. Secondary endpoints include assessments of pharmacokinetics, pharmacodynamics, and evaluation of alternative pathway inhibition in ex vivo laboratory assessments of blood samples from subjects in order to establish a PK/PD relationship for ACH-5228. We expect to report interim data from this study during the second half of 2018. ACH-5548. ACH-5548 is another of our next-generation factor D inhibitors for oral administration. The compound has the following characteristics based on our preclinical research to date: • Pharmacokinetics and Metabolism . Pharmacokinetic characteristics for ACH-5548 suggest the possibility of less frequent dosing as compared to ACH-4471. • Safety . We are completing short-term, non-clinical studies in rats and dogs in which ACH-5548 demonstrated tolerability and safety margins supportive of progression into human clinical development. • Potency . ACH-5548 is also specific for factor D inhibition and demonstrated greater potency than ACH-4471 in preclinical studies, delivering similar inhibition of the complement alternative pathway at inhibitory concentrations four to six-fold lower than that of ACH-4471. We anticipate that ACH-5548 will enter phase I clinical development in the second quarter of 2018. Next Generation Factor D Inhibitors for geographic atrophy. Our research team has selected several compounds from our library for the physicochemical properties that may be advantageous for delivery to the back of the eye for treatment of geographic atrophy, or GA, with the goal of achieving treatment duration of three 5