Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-389949 in Healthy Subjects

A Single-center, Double-blind, Parallel-group, Randomized, Placebo-controlled, Multiple-ascending Oral Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ACT-389949 in Healthy Subjects

This is a single-center, double-blind, parallel-group, randomized, placebo-controlled, multiple-ascending oral dose study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-389949 in healthy subjects.

Part A of the study will evaluate the safety and tolerability following once a day oral dosing of ACT-389949 for 9 days and investigate ACT-389949 pharmacokinetics and pharmacodynamics.

Part B of the study will evaluate the safety and tolerability of ACT-389949 following a maximum of two different oral dosing regimens: ACT-389949 given either every 3 days for 13 days or every 2 days for 9 days (5 doses for each regimen).

Part C of the study, if required, will provide additional information to that obtained from Parts A and B in terms of safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-389949.

Inclusion Criteria:

• Signed informed consent in local language.
• Healthy Caucasian male subjects and female subjects of non-childbearing potential.
• Men with female partners of childbearing potential must agree to use 2 reliable methods of contraception from first drug administration up to a minimum of 90 days after the end of treatment.
• Male subjects must agree not to donate sperm from the first drug administration until 90 days after the end of treatment.
• Non-smokers, defined as never smoked or achieved cessation ≥ 12 months prior to screening.
• Body mass index of 18.0 to 28.0 kg/m^2 (inclusive) at screening.
• No clinically significant findings on the physical examination at screening.
• Negative results from urine alcohol and drug screen at screening and on Day -1.
• Systolic blood pressure 100-145 mmHg, diastolic blood pressure 50-90 mmHg, and pulse rate 45-90 beats per minute (inclusive) measured at screening.
• 12-Lead electrocardiogram without clinically relevant abnormalities at screening.
• Body temperature 35.5-37.7 °C at screening and prior to first dosing.
• C-reactive protein (CRP) and total and differential white blood cell (WBC)count within the local laboratory normal ranges at screening and on Day -1.
• Hematology, coagulation, clinical chemistry, and urinalysis results (other than total differential WBC and CRP), not deviating to a clinically relevant extent from the normal local laboratory range(s) at screening.
• Forced expiratory volume in 1 second (FEV1) ≥ 80% of predicted, FEV1 / Forced vital capacity ≥ 70%.
• Subjects must be able to provide adequate sputum following induction with hypertonic saline at screening.
• Able to communicate well with the investigator, in the local language, and to understand and comply with the requirements of the study.
• Able to stay in the unit for the entire duration required and undertake all study related procedures.

Exclusion Criteria:

• Circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.
• History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
• Previous history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
• Veins unsuitable for intravenous puncture on either arm.
• Loss of 250 mL or more of blood or blood donation, within 3 months prior to screening.
• Known allergic reactions or hypersensitivity to any excipient of the drug formulation(s).
• Previous exposure to ACT-389949.
• Exposure to lipopolysaccharide within the last year.
• Treatment with another investigational drug within 3 months prior to screening or participation in more than 4 investigational drug studies within 1 year prior to screening.
• History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening.
• Excessive caffeine consumption.
• Use of regular medication or therapy (including vaccines) or over-the-counter medications within 2 weeks prior to first study drug administration or 5 half-lives of the medication, whichever is longer.
• Positive results from the hepatitis serology, except for vaccinated subjects or subjects with past but resolved hepatitis, at screening.
• Positive results from the human immunodeficiency virus serology at screening.
• Vaccinations within the previous 6 months or foreign travel to areas within the last 6 months where infectious diseases are prevalent.
• Signs or symptoms suggestive of infection within 2 weeks prior to study screening and between screening and dosing.
• Signs of respiratory tract infections within 2 weeks prior to screening and between screening and dosing.
• History of atopic allergy.
• Hay fever, if within active season.
• Chronic diseases including those with recurring periods of flare-ups and remission.
• Legal incapacity or limited legal capacity at screening.