First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
First-time-in-Human (FTIH) Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single (in Both Fed and Fasted States) or Repeat Doses of GSK3358699
This FTIH study, intends to identify the doses of GSK3358699, which are well tolerated by the
 subjects whilst delivering a robust pharmacodynamic (PD) response. This study will evaluate
 the safety, tolerability, pharmacokinetic (PK) and PD profile of single (in both fed and
 fasted states) and multiple ascending doses of GSK3358699 in healthy male subjects within a
 pre-defined and controlled pharmacodynamic and pharmacokinetic range for each cohort. It also
 intends to understand the effect of GSK3358699 on systemic markers of inflammation following
 low dose in vivo lipopolysaccharide (LPS) or Granulocyte-Macrophage Colony-Stimulating Factor
 (GM-CSF) challenge and local inflammation in cantharidin-induced blisters. The study has been
 carefully designed to explore the in vivo biology of the target and the potential for the
 study drug to become a transformative medicine for subjects in multiple immuno-inflammatory
 disease indications.
Subjects who are enrolled in the dose escalation treatment Periods of Part A may choose to
 only take part in the dose escalation treatment Periods 1-3, or may choose to also take part
 in the challenge Treatment Period (Period 4). If a subject chooses to participate in the dose
 escalation treatment Periods 1-3 only, or does not (at screening) meet the eligibility
 criteria specific to challenges (treatment Period 4), a new subject will be recruited for
 treatment Period 4 only and will be regarded as a replacement subject. The study will be
 conducted in three Parts. Total duration for participation will be approximately 19 weeks for
 subjects taking part in all three dose escalation treatment Periods and 23 weeks if a subject
 takes part in all four treatment Periods of Part A. For replacement subjects only taking part
 in the challenge treatment Period (Period 4), approximate study duration will be 10 weeks.
 Total duration for participation will be approximately 9 weeks for Part B and 12 weeks for
 Part C. The study will be conducted in up to 80 subjects.
Inclusion Criteria: - Subjects enrolled into the study, where they will be administered LPS
 or GM-CSF challenge, must be 18 to 55 years of age inclusive, at the time of signing the
 informed consent. Subjects enrolled into the study where they will not be administered LPS
 or GM-CSF challenge must be 18 to 65 years of age inclusive, at the time of signing the
 informed consent. - Subjects must be overtly healthy as determined by medical evaluation
 including medical history, physical examination, laboratory tests and cardiac monitoring. -
 Body weight must be > = 50 kilogram (kg) and body mass index (BMI) within the range
 18.5-35.0 kg per square meter (kg/m^2) (inclusive). - Male subjects agreeing to use
 contraceptive methods during the treatment Period and for at least 91 days, after the last
 dose of study treatment and refrain from donating sperm during this Period. - Capable of
 giving informed consent. Exclusion Criteria: - Current or chronic history of pancreatitis,
 diabetes mellitus or impaired glucose tolerance, gastrointestinal disease, liver disease,
 or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or
 asymptomatic gallstones), anaphylaxis, and /or anaphylactoid (resembling anaphylaxis)
 reactions [Sampson et al 2006], cardiac disease including clinically significant
 ventricular arrhythmias or long QT syndrome, renal disease where clinically significant
 (minor abnormalities may be permitted base on discussion between investigator and medical
 monitor), respiratory disease or conditions including but not limited to asthma, chronic
 obstructive pulmonary disease (COPD), and bronchiectasis and any current respiratory
 infection (childhood asthma is not an exclusion criterion), sensitivity or severe allergic
 responses to any of the challenge agents or cantharidin, or components thereof or a history
 of drug or other allergy that, in the opinion of the Investigator or GlaxoSmithKline (GSK)
 Medical Monitor, contraindicates their participation; frequent vasovagal syncope, surgery
 requiring general anaesthetic or significant trauma in 3 months leading to study enrolment,
 relevant skin conditions (e.g. recent history of eczema or recurrent eczema, keloid, skin
 allergies, psoriasis, atopic dermatitis, and vitiligo) which in the opinion of the
 investigator could pose safety issues or cause interference with study procedures, sepsis,
 coagulation disorders, peripheral edema, lymphangitis, lymphedema, pleural or pericardial
 effusion, hemorrhage (eg sub-arachnoid) or hemophilia or a related bleeding disorder. -
 History of malignancies e.g. recurrent basal cell carcinoma, hematological malignancy. -
 For subjects receiving cantharidin: Presence on either forearm of tattoos, naevi,
 hypertrophic scars, keloids, hyper- or hypo- pigmentation that may, in the opinion of the
 Investigator, interfere with study assessments. Subjects with very fair skin, very dark
 skin, excessive hair or any skin abnormalities that may, in the opinion of the
 Investigator, interfere with study assessments. - Family history of premature
 cardiovascular disease or long QT syndrome. - QT interval with Fridericia's correction
 (QTcF) > 450 millisecond (msec), based on averaged QTcF values of triplicate ECGs obtained
 over a brief recording period. - Unable or unwilling to refrain from taking prescription or
 non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days
 (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is
 longer) before the start of study treatment until completion of the follow-up visit.
 Paracetamol, at a dose of <= 2 grams per day was permitted for use anytime during the
 study. Other concomitant medications will be considered on case by case basis. - The
 subjects have participated in a clinical trial and received an investigational product
 within the following time period prior to the first dosing day in the study: 30 days; 5
 half-lives or twice the duration of the biological effect of the investigational product
 (whichever is longer) or currently in a study of an investigational device. - Exposure to
 more than four new chemical entities within 12 months prior to the first dosing day. -
 Previous exposure to intravenous lipopolysaccharide (LPS) in a clinical research setting. -
 Alanine transaminase (ALT) >1.5x upper limit of normal (ULN) at screening. - Bilirubin
 >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct
 bilirubin <35%) at screening. - Presence of hepatitis B surface antigen (HBsAg), positive
 hepatitis C antibody test result at screening or within 3 months prior to first dose of
 study treatment. - A positive pre-study drug/alcohol screen at screening. - A positive test
 for human immunodeficiency virus (HIV) antibody at screening. - Persistent clinically
 significant abnormal C-reactive protein (CRP) levels at screening - Persistent clinically
 significant abnormal white cell count (WCC) levels at screening (if clinically significant
 abnormality is detected, WCC can be retested as clinically indicated) - Platelets < 150 x
 10^9 per liter (L) at screening. - Fasted Triglycerides >3.4 millimole per liter (mmol/L)
 at screening. - Fasted Total cholesterol >7.7 mmol/L at screening. - Random glucose > =
 11.1 mmol/L at screening. - Urinary cotinine levels indicative of smoking or history or
 regular use of tobacco- or nicotine-containing products within 3 months prior to screening.
 - History of regular alcohol consumption within 6 months of the study defined as: an
 average weekly intake of >14 units. One unit is equivalent to 8 gram of alcohol: a
 half-pint (approximately 240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25
 mL). - Where participation in the study would result in donation of blood or blood products
 in excess of 500 mL within a 56 day period. - Unable to comply with precautions to minimize
 phototoxicity risk.