A phase 1 study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of TLC-1180 in healthy subjects and an open-label assessment of the relative bioavailability of, and effect of food on, a tablet formulation of TLC-1180
Healthy volunteers
The study will proceed in four parts (Parts A-D), where Parts A-C are randomized, blinded (sponsor-unblinded), placebo-controlled, and Part D is open-label. Part A will evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of escalating single oral doses of TLC-1180 or matching placebo over 5 cohorts (within each cohort, 8 subjects will be randomized 3:1 to receive either blinded TLC-1180 or placebo-to-match [PTM]). To maximize subject safety, in single-ascending dose (SAD) cohorts in Part A, two sentinel subjects (one randomized to TLC-1180 and one to PTM) will be dosed, and safety and tolerability data will be evaluated before dosing of the remaining subjects in each cohort. Within SAD cohorts in Part A and C, initiation of single-dose administration at escalating dose levels will be based on recommendations by the Safety Review Committee (SRC), where the SRC will evaluate cumulative safety data, and relevant and available PK and/or PD data, following single-dose administration of the previous dosing cohort. Part B will evaluate the safety, tolerability, PK, and PD of escalating multiple doses of TLC-1180 or matching placebo over 5 cohorts (within each cohort, 10 subjects will be randomized 4:1 to receive either blinded TLC-1180 or PTM) for 14 days. The dose for the first multiple-ascending dose (MAD) cohort will be selected such that predicted steady-state exposure (Cmax and AUCtau) will not exceed single dose exposures (Cmax and AUCinf) observed in the highest dose Part A SAD cohort considered safe and well tolerated based on evaluation of cumulative safety, tolerability, and any relevant and available PK and/or PD data from all subjects enrolled in prior relevant SAD cohort(s). For the remaining Part B cohorts, dose selection and initiation of additional Part B MAD cohorts will be based on recommendation by the SRC, where the SRC will evaluate cumulative safety, tolerability, and any relevant and available PK and/or PD data from al
1. Non-smoking, healthy male or female subject between 18 and 55 years of age, inclusive 2. Body mass index from 19 to 35 kg/m2, inclusive 3. Estimated glomerular filtration rate ≥ 80 mL/min 4. Normal liver biochemistry tests 5. Screening laboratory evaluations (hematology, chemistry, and urinalysis) must fall within the normal range of the local laboratory's reference ranges unless the results have been determined by the investigator to have no clinical significance 6. Subject must have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator 7. Females of childbearing potential must have a negative pregnancy test at Screening and clinic admission 8. Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception 9. Must, in the opinion of the investigator, be in good health based upon medical history and physical examination, including vital signs
1. Pregnant or lactating subjects 2. Subjects who have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with the subject's treatment, assessment, or compliance with the protocol 3. Subjects who have received any investigational compound within 30 days or 5 half-lives, whichever is longer, prior to study drug dosing 4. Current alcohol abuse that is judged by the investigator to potentially interfere with the subject's compliance or safety 5. Current substance abuse that is judged by the investigator to potentially interfere with the subject's compliance or safety 6. A positive test result for human immunodeficiency virus (HIV-1) antibody, hepatitis B (HBV) surface antigen, or hepatitis C (HCV) antibody 7. Subjects who have taken any prescription medications or over-the-counter medications, including herbal products, within 28 days prior to start of study drug dosing, with the exception of vitamins, acetaminophen (paracetamol), ibuprofen, and/or hormonal contraceptive medications 8. Subjects who have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to Screening or expected to receive these agents during the study (e.g., corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies) 9. Medical history of serious skin disease in the opinion of the investigator, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria 10. Medical history of drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity) 11. Presence or history of cardiovascular disease, including significant cardiovascular disease (including a history of myocardial infarction based on ECG and/or clinical history), history of cardiac conduction abnormalities (including any history of ventricular tachycardia), congestive heart failure, cardiomyopathy with left ventricular ejection fraction < 40%, a family histor