Clinical Trial to Investigate the Safety, Tolerability and Pharmacokinetics of BVL-GSK098 in Healthy Volunteers

This is an exploratory, first-in-human (FIH), double-blind, randomized, placebo-controlled, single and multiple ascending oral dose study in healthy volunteers.The study will be divided into two parts that will be conducted sequentially. Part A is a SAD study to determine the safety, tolerability and PK of single oral doses of BVL-GSK098 in healthy volunteers. In addition, the last cohort of Part A will investigate the effect of food on the PK of BVL-GSK098. Part B is a MAD study to determine the safety, tolerability and PK of BVL-GSK098 following multiple daily oral doses in healthy volunteers.

Inclusion criteria

• Volunteers aged 18 to 55 years inclusive and between 19 and 30 kg/m2 body mass index (BMI) with a minimum weight of 50 kg or men and 45 kg for women, at the time of signing the informed consent.
• Volunteers who are healthy as determined by the investigator based on medical evaluation including medical history, physical examination and cardiac monitoring.
• Volunteers who have a clinically acceptable temperature, blood pressure and pulse rate in supine and standing position (systolic blood pressure between 100-140 mm Hg/ diastolic blood pressure between 50-90 mm Hg / HR between 50-100 bpm). Blood pressure and pulse will be measured after a minimum of 3 minutes of resting.
• Volunteers whose clinical laboratory test results are not clinically relevant and are acceptable to the Investigator.
• Male volunteers must use appropriate contraception (e.g. condoms as part of a double barrier method) from the time of the first dose until 3 months after the post-study visit.
• A female volunteer is eligible to participate if she is of non-childbearing potential, defined as:

• Is equal to or older than 45 years of age and has not had menses for greater than 1 year,
• Amenorrheic for less than 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pretrial (screening) evaluation,
• Whose status is post hysterectomy, oophorectomy or tubal ligation.
• Nonsmokers (i.e., one who has abstained from use of tobaccco and other nicotine-containing products for the last 6 months).
• Willingness to stay in the investigational site for up to 11 days.
• Volunteers are capable of giving signed informed consent which included compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion criteria

• Women of childbearing potential
• Pregnant or lactating women
• Men with female partners who are lactating or are pregnant
• Glomerular Filtration Rate (GFR) < 90 mL/min/1.73m2 as calculated by the Chronic Kidney Disease Epidemiology Collaboration formula.
• Alanine aminotransferase (ALT), Gamma glutamyl transferase (GGT), Aspartate aminotransferase (AST), alkaline phosphatase or serum bilirubin levels must not exceed the upper limit of normal (ULN)
• A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening.
• A positive test for HIV antibody.
• A positive pre-study drug/alcohol screen.
• Volunteers who consume more than 21 units of alcohol per week or who have a significant history of alcoholism or drug/chemical abuse (one unit of alcohol equals ½ pint [285 mL] of beer or lager, one glass [125 mL] of wine, or 30 mL of 40% of alcohol by volume distilled spirits).
• Volunteers who are study site employees, or immediate family members of a study site or sponsor employee.
• Volunteers with ECG abnormalities (history, or evidence of second-degree heart block of Mobitz type II, third degree heart block, or any abnormality considered relevant by the Investigator), QTcB or QTcF >450 ms or PR>220 ms).
• Volunteers with a history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
• History of clinically significant cardiovascular, renal, hepatic, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
• History of seizures.
• Volunteers who have received any prescribed systemic or topical medication within 4 weeks of the first dose administration.
• Volunteers who have used any non-prescribed systemic or topical medication (including herbal remedies) or megadose vitamins (i.e. 20 to 600 times the recommended daily supplement dose) within 7 days of the first dose administration, unless in the opinion of the Investigator the medication will not interfere with the study procedures or compromise safety.
• Volunteers who have received any medications, including St John's Wort, known to chronically alter drug absorption or elimination processes within 30 days of the first dose administration.
• Volunteers who have participated in other clinical trials during the previous 90 days (drug to drug period) in which an investigational drug or a commercially available drug was tested.
• Exposure to more than 4 new chemical entities in the last 12 months before the first dosing day in this study.
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
• Failure to satisfy the investigator of fitness to participate for any other reason