Study to Evaluate Safety, PK and PD of Single and Multiple Ascending Doses of EP-7041 in Healthy Subjects
Study to Evaluate Safety, PK and PD of Single and Multiple Ascending Doses of EP-7041 in Healthy Subjects
This First-In-Human study will evaluate the safety and tolerability, pharmacokinetic profile,
 and pharmacodynamic effects of EP-7041, a novel Factor XIa inhibitor, following IV
 administration of single ascending doses in healthy normal volunteers, and following
 continuous IV infusions of multiple ascending doses in healthy normal volunteers.
This will be a single-center, Phase 1a/1b, placebo-controlled, randomized, double-blind,
 integrated sequential ascending dose / multiple ascending dose study.

 The study will be divided into two parts: the single ascending dose evaluation in healthy
 normal volunteers will constitute Part A and the multiple ascending doses evaluation in
 healthy normal volunteers will constitute Part B. The two study parts will be performed
 sequentially with partial overlapping.

 Part A will include up to 6 cohorts (1 cohort per dose level; 4 planned cohorts and 2
 optional adaptive cohorts). Each cohort will include 8 subjects - 6 on active drug and 2 on
 placebo - resulting in a maximum number of 48 subjects in the study - 32 planned and 16
 optional. Subjects in each cohort will receive a single IV slow bolus (50 mL over 5 minutes)
 administration of study medication or placebo. The dose of EP-7041 will be sequentially
 escalated cohort by cohort in Part A . A staggered dosing schedule will be used for each
 cohort of Part A: 2 sentinel subjects (1 active and 1 placebo) will be dosed first and the
 remaining 6 subjects will be dosed the next day (5 active and 1 placebo).

 Part B will include up to 4 cohorts (1 cohort per dose level; 3 planned cohorts and 1
 optional adaptive cohort). As in Part A, each cohort of Part B will include 6 subjects on
 active drug and 2 on placebo, for a total of 8 subjects per cohort. Part B will therefore
 involve, at maximum, 32 subjects, with 24 planned subjects an 8 optional subjects. Subjects
 in each cohort of Part B will receive a total of 5 sequential 24-hour IV infusions of EP-7041
 or matching placebo.

 Evaluation of safety and tolerability to EP-7041 will include adverse events (i.e.,
 seriousness, severity, relationship to EP-7041), vital signs, ECG, clinical laboratory
 parameters, physical examination, local response to each injection, and body weight.

 Pharmacokinetic analyses will be performed with measurements of EP-7041 plasma
 concentrations, following single and multiple IV doses.

 Pharmacodynamic effects of EP-7041 will be evaluated through the measurement of aPTT and PT
 in all subjects at multiple times throughout the course of both studies.
Inclusion Criteria:

 -  Male or female, non-smoker (no use of tobacco products within 3 months prior to
 screening), ≥18 and ≤60 years of age, with Body Mass Index (BMI) > 18.5 and < 32.0
 kg/m2 and a weight of at least 60 kg but not greater than 100 kg.

 -  Healthy as defined by:

 1. No history of abnormal bleeding episodes, e.g. nosebleeds, or abnormally heavy
 periods, or extensive bleeding after injury, surgery or dental work.

 2. A normal short physical examination and normal vital signs (heart rate (HR),
 blood pressure (BP) and tympanic body temperature).

 3. Normal laboratory tests (hematology, biochemistry, urinalysis, coagulation tests
 (aPTT and PT).

 4. the absence of clinically significant illness and surgery within 4 weeks prior to
 dosing.

 5. the absence of clinically significant history of neurological, endocrinal,
 cardiovascular, pulmonary, hematological, immunologic, psychiatric,
 gastrointestinal, renal, hepatic, and metabolic disease.

 Exclusion Criteria:

 -  Any clinically significant abnormality or abnormal laboratory test results found
 during medical screening which, at the investigator's discretion, warrants exclusion
 or positive test for hepatitis B, hepatitis C, or HIV.

 -  Use of any drugs known to induce or inhibit hepatic drug metabolism within 30 days
 prior to drug administration.

 -  Positive pregnancy test at screening or check-in (Day -1).

 -  Clinically significant ECG abnormalities or vital sign abnormalities (systolic blood
 pressure lower than 90 or over 160 mmHg, diastolic blood pressure lower than 50 or
 over 90 mmHg, or heart rate less than 40 or over 100 bpm) at screening or check-in
 (Day -1).

 -  Participation in a clinical trial involving the administration of an investigational
 or marketed drug within 30 days (90 days for biologics), or five (5) half-lives,
 whichever is longer, prior to the first dosing or concomitant participation in an
 investigational study involving no drug administration.

 -  Hemoglobin or hematocrit clinically significantly less than lower limits of normal at
 screening.