Safety, Tolerability and Pharmacokinetics (PK) Investigation of GSK3494245 in Healthy Participants

A Randomized, Double-blind, Placebo-controlled, First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single (in Both Fed and Fasted States) Doses of GSK3494245 in Healthy Participants

This study is the first to test GSK3494245 in humans, to evaluate its safety, tolerability, and pharmacokinetics (PK) after a single dose. It involves 3 groups of participants and has a crossover design where each participant received a maximum of 3 ascending oral doses of GSK3494245 and 1 placebo dose under fasted conditions.

The first 2 Cohorts received up to 3 increasing doses of the drug and 1 dose of a placebo under fasted conditions, within each period, according to the randomization schedule, in a blinded manner. Cohort 3 is comprised of a 2-way crossover which includes 1 dosing regimen under fasted then fed conditions and 1 regimen under fed then fasted conditions in a 1:1 ratio.

The study originally planned to include 2 parts - a single ascending doses (SAD) part and a multiple ascending doses (MAD) part, incorporating a food effect component to investigate the influence of food on the PK of GSK3494245. However, only the SAD part was conducted due to a decision to terminate the study early.

Inclusion criteria

• Participant must have been 18 to lesser than or equal to (<=) 55 years of age, at the time of signing the informed consent.
• Participant must have been healthy as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac monitoring. A participant with a clinical abnormality or laboratory parameter(s) which was/were not specifically listed in the inclusion or exclusion criteria, outside the normal reference range for the population being studied may have been included only if the Investigator in consultation with the Medical Monitor (if required) agreed and documented that the finding was unlikely to introduce additional risk factors and was not going to interfere with the study procedures.
• Body weight greater than or equal to (>=) 50 kg and body mass index (BMI) within the range 18.5-28 kg per meter square (kg/m^2) (inclusive).
• Male participants only. A male participant with a female partner of reproductive potential must have agreed to use contraception during the intervention period and for at least 90 days after the last dose of study treatment and refrain from donating sperm during this period.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed consent form (ICF) and protocol.

Exclusion criteria

• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
• Abnormal blood pressure, as determined by the investigator.
• Previous history of leishmaniasis.
• Alanine transaminase (ALT) greater than (>) upper limit of normal (ULN) at screening or Day - 1. Total bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN was acceptable if total bilirubin was fractionated and direct bilirubin less than (<) 35 percent [%]).
• History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data.
• Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Current or history of clinically significant gastritis or gastroduodenal ulcers or regular use of non-steroidal anti-inflammatory drugs (NSAID).
• Consumption of more than 14 units/week alcohol.
• Current or history of change in taste or smell without any plausible clinical explanation based on investigator's clinical judgement.
• QTc >450 milliseconds (msec) based on average of triplicate ECGs.
• Waveform abnormalities including premature ventricular contraction (PVC) triplets and more than 500 single PVCs in 24 hours, or any other abnormalities at the discretion of investigator.
• Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
• Past or intended use of over-the-counter or prescription medication, including herbal medications, NSAIDs, proton pump inhibitors (PPIs) or anti-histamine 2 receptor (H2) antagonists within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is the longest) prior to dosing. Other concomitant medication may have been considered on a case by case basis by the investigator in consultation with the medical monitor. Paracetamol is permitted (capped to <=2 grams/day).
• Participation in the study that would result in loss of blood or blood products in excess of 500 mL within a 56-day period.
• Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day.
• Current enrollment or past participation within the last 30 days before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research.
• Current enrollment or past participation in this clinical study.
• Participants with renal function defined as Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) with an age appropriate Glomerular filtration rate (GFR) <90 (milliliter per minute per 1.73 meter square [mL/min/1.73m^2]).
• Screening urine albumin: creatinine ratio >30 milligram per gram (mg/g) (>3 milligram per millimole [mg/mmol])
• Presence of hepatitis B surface antigen (HBsAg) test result at screening.
• Positive hepatitis C antibody test result at screening.
• Positive hepatitis C Ribonucleic acid (RNA) test result at screening.
• Positive human immunodeficiency virus (HIV) antibody test.
• Presence of clinically significant hematuria and/or proteinuria.
• Carbon monoxide levels indicative of smoking or history or regular use of tobacco or nicotine-containing products within 3 months prior to screening.
• Positive pre-study drug/alcohol screen.
• Regular use of known drugs of abuse.
• Fed regimens only: Participant must have had no dietary restrictions (e.g., lactose intolerance) or inability to eat an adapted standard meal (includes 35-40% fat content).
• Fed regimen only: History of gall bladder surgery or gall bladder removal, or history of an acute disease state (e.g. cholelithiasis) within 14 days prior to receiving the study treatment. Inability to eat gelatin for bile sampling cohort.
• Participants must not have travelled to an area (as determined by the investigator) with a high prevalence of leishmanial/parasitic infections in the 6 months before screening or intend to do so in the 3 months after the final dose of study treatment.
• Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates participation in the study.
• A positive laboratory confirmation of corona virus disease 2019 (COVID-19) infection, or high clinical index of suspicion for COVID-19.