A study to investigate the safety of ACH-0144471 in healthy volunteers.

INTERVENTION: Subjects will receive either active (ACH‐0144471) or placebo. At least three dose groups are planned. Group 1 will receive a single 200mg dose (consisting of two 100mg capsules), Group 2 will receive a single dose up to 600 mg and Group 3 will receive a dose up to 1500mg. ACH‐0144471 may be given as divided doses over a 24‐hour period. The maximum daily dose for this study will be calculated so that the predicted Cmax and ACH‐0144471 AUC0‐24 do not exceed the NOAEL observed in nonclinical studies, and may be adjusted upward or downward based on emerging nonclinical and clinical safety, PK, and PD data. Treatment compliance will be observed by the research staff to ensure the subjects have taken his/her dose, and the time will be recorded in the source notes. In order to ensure adequate placebo subjects for comparison at the first dose, the first dose group (Group 1) will have will have 12 subjects, randomized 1:1 to active and placebo (six active and six placebo subjects); the remaining dose groups will have eight subjects per group randomized 3:1 to active and placebo (six active and two placebo subjects per group). In Group 1, a sentinel group consisting of one active and one placebo subject will be dosed before the other ten subjects in Group 1. If no significant drug‐related toxicity is identified in the first 24 hours in the opinion of the PI, then remainder of Group 1 may be dosed. All dose escalation decisions will be made based on review of safety data through at least Day 4 from the preceding dose. However, after review of emerging data, the planned doses may be reduced, or a prior dose may be repeated. Higher than planned doses may also be considered, provided that previous doses were well‐tolerated, and projected exposures at the higher than planned doses do not exceed the pre‐specified exposure limits of the study, and do not exceed three times (3X) the corresponding exposures at the highest dose already studied. Based on emerging data from the first three dose groups, it will be determined if additional dose groups are warranted, and if so, at which doses and/or regimens (fed or fasted). These additional groups may be used to ensure adequate study of potential therapeutic doses, and/or to study the effect of food on the PK of ACH‐0144471. A Dose Escalation Team (DET) consisting of, at a minimum, Principal Investigator, Medical Monitor, Clinical Pharmacologist, will review available safety, PK and PD data from preceding groups to decide whether the next group will proceed, and if so, at which dose level, and if at single administration or divided doses over 24 hours." CONDITION: Complement‐mediated diseases. PRIMARY OUTCOME: To evaluate the Safety and tolerability of single ascending oral doses of ACH‐0144471 in healthy volunteers. This outcome is assessed using the following tests and assessments: ; Assessment of AEs/SAEs, recording concomitant medications, obtaining vitals, ECGs and collection of blood and urine samples. SECONDARY OUTCOME: To evaluate the pharmacokinetic (PK) profile of ACH‐0144471 in healthy volunteers following administration of single ascending oral doses. This outcome is assessed using the following tests: Pharmacokinetic Assessments: Serial blood samples will be collected throughout Days ‐1 to 4 and concentrations of ACH‐0144471 and any potential metabolites will be determined in serum and plasma using validated methods. To evaluate the relationship between ACH‐0144471 pharmacokinetics and inhibition of alternative pathway activity (PK/PD) as measured by the AP Wieslab assay. INCLUSION CRITERIA: Healthy adult male or female subjects. Females must be of non‐child bearing potential. Healthy is defined as having no clinically relevant abnormalities identified by a detailed medical history, physical exam, blood pressure and pulse rate measurements, 12lead ECG, and clinical laboratory tests. Healthy volunteers must have a normal weight defined as minimum body weight of 50 kg and a BMI of 18 to 30kg/m2.