Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BLD-0409 in Healthy Subjects

The study will evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single ascending doses (SAD) and multiple ascending doses (MAD) of BLD-0409 in healthy volunteers (HV) to facilitate the dose/dosing regimen selection for future clinical studies with BLD-0409 in various chronic liver diseases.

The study consists of two parts:

Part 1: SAD in HV with up to 6 cohorts (including a food effect cohort). For SAD cohorts and planned dosing schedule.

Part 2: MAD over 14 days with up to 6 cohorts. For MAD cohorts and planned dosing schedule.

Inclusion criteria

Subjects are eligible to be included in the study only if all the following criteria apply:

Age and Gender

• Male and female subjects 18-55 years of age (inclusive) at the time of signing the PICF.

Diagnosis and disease characteristics

• Subjects must be in good general health, in the opinion of the Investigator, with no significant medical history, have no clinically significant abnormalities on physical examination at Screening, and/or before administration of the initial dose of study drug.
• Subjects must have clinical laboratory values within normal ranges or < 1.2 times upper limit of normal (ULN) as specified by the testing laboratory, unless deemed not clinically significant (NCS) by the Investigator, with exception of liver function tests which cannot be above the ULN.
• Body mass index (BMI) 18 to ≤ 32 kg/m2. Reproductive Considerations Contraception use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. For details refer to Appendix 4.
• Female subjects and female partners of male subjects must use double barrier contraception and refrain from oocyte donation from first dose of study drug and for 60 days after last dose of study drug. Estrogen-containing products are not allowed.
• Male subjects must agree to use highly effective, double barrier contraception and refrain from sperm donation from first dose of study drug and for 90 days after last dose of study drug.
• Females of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day -1. Females not of childbearing potential must be surgically infertile or post-menopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone (FSH) level > 40 mIU/mL at Screening.

Informed Consent

• Subjects must provide signed informed consent prior to study entry and have the ability and willingness to attend and comply with the necessary visits at the study site.

Exclusion criteria

Subjects meeting ANY of the following exclusion criteria are NOT eligible to be randomized into the study:

Medical Conditions

• Recent (less than 6 weeks) wound, or presence of an ongoing non-healing skin wound.
• Presence of any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the subject will complete the study per protocol.
• Active malignancy and/or history of malignancy in the past 5 years, with the exception of completely excised non-melanoma skin cancer or low grade cervical intraepithelial neoplasia.
• Serious local or systemic infection within 1 month of Screening requiring antibiotic treatment or history of recurrent infections.
• Surgery within the past 3 months prior to the first study drug administration determined by the Investigator to be clinically relevant.

Diagnostic Assessments

• Positive for human immunodeficiency virus (HIV) antibody or antigen.
• Positive hepatitis C virus (HCV) antibody or positive hepatitis B surface antigen (HBsAg).
• Systolic blood pressure (BP) > 150 mmHg or < 90 mmHg or diastolic BP > 90 mmHg or < 50 mmHg at Screening with one repeat allowed per the Investigator's discretion at Screening and Day -1.
• Heart rate < 40 beats per minute (bpm) or > 100 bpm at Screening.
• Prolonged QTcF (>450 ms for males and >470 ms for females), cardiac arrhythmia, or any clinically significant abnormality in the resting ECG, as judged by the Investigator.
• Females with heavy menstruating cycles and borderline-low iron studies. Prior Therapy
• All prescription and over the counter medications (including herbal medications), except for non-estrogen contraceptives, are prohibited within 7 days prior to the first study drug administration and throughout the entire duration of the study.
• Any estrogen-containing products, e.g., contraceptives, patch, cream, implants within 14 days prior to the first study drug administration.

Prior/Concurrent Clinical Study Experience

• Administration of investigational product in another study within 30 days prior to the first study drug administration, or five half-lives, whichever is longer.

Other Exclusions

• Significant weight loss or gain between Screening and first study drug administration.
• Blood donation or significant blood loss within 60 days prior to the first study drug administration.
• Plasma donation within 7 days prior to the first study drug administration.
• Females who are pregnant or breastfeeding.
• Diets that could alter metabolism (i.e., high protein, Slim Fast®, Nutrisystem®, etc.) within 7 days prior first study drug administration.
• History or presence of alcohol or drug abuse (including recreational marijuana use) within the 1 year prior to the first study drug administration, and unwillingness to be totally abstinent during the dosing period.
• Positive urine drug screen/alcohol breath test at Day -1 (admission). Repeat urine drug screens will be permitted for suspected false positive results.
• Intake of alcohol or caffeine-containing products from 48 hours before first study drug administration.
• Active smokers and users of nicotine-containing products.
• Failure to satisfy the Investigator of fitness to participate for any other reason.

Lifestyle Considerations Meals and Dietary Restrictions

• Subjects will fast from all food and drink except water for ≥ 10 hours before morning study drug administration on Day 1.
• Except during the periods of fasting, standard meals and snacks will be provided at the discretion of the Investigator while subjects are confined in the study site.
• For food effect Cohort 1e:

• On Day 8, subjects will be provided a standard high calorie breakfast from 30 minutes before dose administration (and to be consumed entirely within that 30 minutes). The meal is to follow United States Food and Drug Administration (FDA) guidance regarding caloric content and composition. The test meal should derive approximately 150, 250 and 500 600 calories from protein, carbohydrate, and fat, respectively. An example test meal would be two eggs fried in butter, two strips of bacon, and two slices of toast with butter, four ounces of hash brown potatoes and eight ounces of whole milk. Substitutions in this test meal can be made as long as the meal provided a similar amount of calories from protein, carbohydrate and fat and has comparable meal volume and viscosity. Vegetarians may be enrolled provided that there is a consultation with a dietician regarding comparable calories, volume and viscosity.
• Water restrictions may be needed. No water is allowed 1 hour before and after dosing, after which time, water is allowed ad libitum.
• Subjects will refrain from consumption of Seville oranges, grapefruit or grapefruit juice, from 48 hours before the start of study drug until after the final PK sample is obtained.
• Subjects will refrain from diets that could alter metabolism (i.e., high protein, Slim Fast®, Nutrisystem®, etc.) within 7 days prior to dosing on Day 1.

Caffeine, Alcohol, and Tobacco

• During each dosing session, subjects will abstain from ingesting caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours before the start of dosing until after collection of the final pharmacokinetic (PK) and/or pharmacodynamic sample.
• During each dosing session, subjects will abstain from alcohol for 48 hours before the start of dosing until EOS visit.
• Active smokers and users of nicotine-containing products will be excluded from the study.

Other Restrictions Subjects will avoid strenuous physical activity (e.g. weightlifting, running, bicycling) from 24 hours prior to Day 1 until discharge from the study site and for 24 hours prior to the EOS visit.