Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Repeat Doses of GSK2982772 in Subjects With Psoriasis

This is the first study with GSK2982772, a receptor-interacting protein-1 (RIP1) kinase inhibitor, in subjects with active plaque-type psoriasis (PsO). The primary objective will be to investigate the safety and tolerability of repeat oral doses of GSK2982772 60 milligram (mg) twice daily (BID) for 84 days in Cohort 1 and 60 mg thrice daily (TID) for 84 days in Cohort 2. In addition, a number of experimental and clinical endpoints will be employed to obtain information on the pharmacokinetics, pharmacodynamics, and efficacy in subjects with active PsO. There will be two Cohorts of subjects. In Cohort 1 after a screening period of up to 30 days, approximately 30 subjects will be randomized to receive either GSK2982772 60 mg BID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). In Cohort 2 after a screening period of up to 30 days, approximately 24 subjects will be randomized to receive either GSK2982772 60 mg TID or placebo for 84 days (12 Weeks), followed by a follow-up period (28 days). The total duration of participation is approximately 20 Weeks from screening to the last study visit.


Eligibility Criteria:
Inclusion Criteria:

* Between 18 and 75 years of age inclusive, at the time of signing the informed consent.
* Subjects who do not have any medical conditions, other than active plaque-type psoriasis, that in the opinion of the Investigator put the subject at unacceptable risk or interfere with study assessments or integrity of the data. All medical conditions must be stable for the duration of the study.
* Presence of active chronic plaque-type psoriasis as determined by the Investigator for at least 6 months (confirmed by the subject or medical record) before first dose of study treatment (Day 1).
* Subject has psoriasis plaques involving Body Surface Area \>=3% assessed at screening and before dosing on Day 1.
* Physician Global Assessment \>=3.
* Subject must agree to avoid prolonged exposure to natural sunlight, tanning beds or phototherapy devices for the duration of the study
* Subject has at least two stable plaques assessed at screening and before dosing on Day 1:

Both must be of a suitable size (\>=3 centimeter \[cm\] by 3 cm) and one in a site suitable for repeat biopsy, and one in a site suitable for index lesion PLSS scoring.

Both plaques must have a PLSS lesional score \>=2 for the induration component (moderate or above), \>=1 for erythema and scaling with a total score of \>=5.

The biopsy lesion must not be on the face, groin, scalp, knees, elbows, or on the palmar/plantar surfaces of the hands/feet, and must be shielded from natural light with clothing.

* Subject is naive to any biologic therapies for psoriasis, OR has had previous exposure to a single anti- TNF biologic agent in the context of a previous clinical trial. The anti-TNF biologic agent must have been discontinued more than 8 weeks prior to screening visit (12 Weeks or 5 half lives whichever is longer from first dose).
* A body mass index within the range of 18.5-35 kilogram per meter square (kg)/m\^2 (inclusive).
* Male and Female subjects:

Males: Male subjects with female partners of child bearing potential must comply with the pre specified contraception requirements.

Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum or urine human chorionic gonadotropin test), not lactating, and is either of non-reproductive potential or reproductive potential. If of reproductive potential, then the subject should agree to follow one of the options listed per GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential from 30 days prior to the first dose and until 30 days after the last dose of study medication The Investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.

* Capable of giving signed informed consent

Exclusion Criteria:

* Subjects with clinically overt concurrent psoriatic arthritis who are receiving chronic disease-modifying anti-rheumatic medications therapy (other than non-steroidal anti-inflammatory drug), as judged by the Investigator.
* Has nonplaque forms of psoriasis (e.g. erythrodermic, guttate, or pustular), as judged by the Investigator.
* Has current drug-induced psoriasis (e.g., a new onset of psoriasis or an exacerbation from beta blockers, calcium channel blockers, or lithium).
* Subject with current history of Suicidal Ideation Behaviour as measured using the Columbia Suicide Severity Rating Scale or a history of attempted suicide.
* An active infection, or a history of infections as follows:

Hospitalization for treatment of infection within 60 days before first dose (Day 1).

Currently on any suppressive therapy for a chronic infection (such as pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypical mycobacteria).

Use of parenteral (intravenous or intramuscular) antibiotics (antibacterials, antivirals, antifungals, or antiparasitic agents) within 60 days before first dose.

A history of opportunistic infections within 1 year of screening (e.g. pneumocystis jirovecii, cytomegalovirus, pneumonitis, aspergillosis). This does not include infections that may occur in immunocompetent individuals, such as fungal nail infections or vaginal candidiasis, unless it is of an unusual severity or recurrent nature.

Recurrent or chronic infection or other active infection that, in the opinion of the Investigator might cause this study to be detrimental to the subject.

History of tuberculosis (TB), irrespective of treatment status. A positive diagnostic TB test at screening defined as a positive QuantiFERON-TB Gold test or T-spot test.

In cases where the QuantiFERON or T-spot test is indeterminate, the subject may have the test repeated once, but they will not be eligible for the study unless the second test is negative.

In cases where the QuantiFERON or T-spot test is positive, but a locally-read follow up chest X-ray, shows no evidence of current or previous pulmonary tuberculosis, the subject may be eligible for the study at the discretion of the Investigator and medical monitor.

* ECG for heart rate QTc \>450 milliseconds (msec) or QTc \>480 msec in subjects with bundle branch block.
* Alanine aminotransferase \>2×upper limit of normal (ULN) and bilirubin \>1.5×ULN (isolated bilirubin \>1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) at screening.
* 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 renal disease or estimated glomerular filtrate rate by Chronic Kidney Disease Epidemiology Collaboration equation \<60 mL/min/1.73 m\^2.
* Hereditary or acquired immunodeficiency disorder, including immunoglobulin deficiency.
* A major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant.
* A planned surgical procedure that, in the opinion of the Investigator, makes the subject unsuitable for the study.
* A history of malignant neoplasm within the last 5 years, except for adequately treated cancers of the skin (basal or squamous cell carcinoma) or carcinoma in situ of the uterine cervix that has been fully treated and shows no evidence of recurrence.
* A history of hypertrophic scarring or keloid formation, or known allergy to lidocaine or other local anaesthetics.
* The subject has received treatment with the specified therapies listed in the protocol, or changes to those treatments, within the specified timeframe.

Other medications (including vitamins, herbal and dietary supplements) will be considered on a case-by-case basis, and will be allowed if in the opinion of the Investigator the medication will not interfere with the study procedures or compromise subject safety.

* History of alcohol or drug abuse that would interfere with the ability to comply with the study.
* Subject intends to sunbathe or use a tanning device (sun bed or solarium) within 14 days prior to Day 1 and until completion of the follow up visit (Day 112).
* History of sensitivity to any of the study treatments, or components thereof or a history of drug or other allergy that, in the opinion of the Investigator or Medical Monitor, contraindicates their participation.
* Received a live or attenuated vaccine within 30 days of randomization OR plan to receive a vaccination during the study until completion of the follow-up visit.
* The subject has participated in a clinical trial and has received an investigational product within 30 days or 5 half-lives, whichever is longer before the first dose of study medication, or plans to take part in another clinical trial at the same time as participating in this clinical trial. Subjects who were randomized into Cohort 1 are not eligible to be re-randomized into Cohort 2.
* Hemoglobin \<11 g/deciliter (dL); hematocrit \<30%, white blood cell count =\<3,000/millimeter (mm)\^3 (\<=3.0×10\^9/L) ; platelet count \<=100,000/microliter (µL) (\<=100 × 10\^9/L); absolute neutrophil count \<=1.5×10\^9/L at the screening visit.
* 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. As potential for and magnitude of immunosuppression with this compound is unknown, subjects with presence of hepatitis B core antibody (HBcAb) should be excluded. Subjects positive for HBsAg and/or positive for anti-HBcAb (regardless of anti-HBs antibody status) are excluded.
* A positive serology for human immunodeficiency virus 1 or 2 at screening.
* Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 3 months.
* Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day