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

Study Overview
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Brief Summary
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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.

Official Title
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A Multicentre, Randomised, Double-blind (Sponsor-unblinded), Placebo-controlled, Repeat Dose Study to Investigate the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2982772 in Subjects With Active Plaque-type Psoriasis

Conditions
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Psoriasis

Intervention / Treatment
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* Drug: GSK2982772
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GSK2982772 receivers in Cohort 1<br>Randomized subjects will receive GSK2982772 BID (approximately 12 hours apart) via oral route for 84 days. | Drug: GSK2982772<br>* GSK2982772 will be supplied as a white to almost white, round, film coated 30 mg oral tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.<br>|
| Placebo Comparator: Placebo receivers in Cohort 1<br>Randomized subjects will receive placebo BID via oral route for 84 days. | Drug: Placebo<br>* Matching placebo will be supplied as a white to almost white, round film coated tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.<br>|
| Experimental: GSK2982772 receivers in Cohort 2<br>Randomized subjects will receive GSK2982772 TID (approximately 8 hours apart) via oral route for 84 days | Drug: GSK2982772<br>* GSK2982772 will be supplied as a white to almost white, round, film coated 30 mg oral tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.<br>|
| Placebo Comparator: Placebo receivers in Cohort 2<br>Randomized subjects will receive placebo TID via oral route for 84 days. | Drug: Placebo<br>* Matching placebo will be supplied as a white to almost white, round film coated tablets; two tablets to be taken in the morning and two in the evening, as directed for Cohort 1 and for Cohort 2 two tablets to be taken three times daily as directed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, is associated with liver injury and impaired liver function or any other situations as per medical or scientific judgment. Safety Population comprised of all participants who received at least one dose of study treatment. | Up to Day 116 | 
| Number of Participants With Worst-case Post-Baseline Clinical Chemistry Results by Potential Clinical Importance (PCI) Criteria | Blood samples were collected for analysis of clinical chemistry parameters. Clinical concern ranges were >=2x Upper Limit of Normal (ULN) units per liter (U/L) for alanine aminotransferase (ALT), <30 millimoles per liter (mmol/L) for albumin, >=2x ULN U/L for alkaline phosphatase, >=2x ULN U/L for aspartate aminotransferase (AST), <2 or >2.75 mmol/L for Calcium, >44.2 mmol/L for Creatinine, <3 or >9 mmol/L for Glucose, <3 or>5.5 mmol/L for Potassium, <130 or >150 mmol/L for Sodium, and >=1.5xULN micromoles per liter for total bilirubin. Participants were counted in worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (example given [e.g.], High to High), or whose value became normal, were recorded in To Normal or No Change category. Participants were counted twice if they had values that changed 'To Low' and 'To High', Baseline is defined as the latest pre-dose assessment. | Up to Day 116 | 
| Number of Participants With Worst-case Post-Baseline Hematology Results by PCI Criteria | Blood samples were collected for analysis of hematology parameters. Clinical concern ranges were >0.54 calculated as proportion of red blood cells in blood for Hematocrit, >180 grams per liter for Hemoglobin, <0.8 x10^9 cells per liter for Lymphocytes, <1.5 x10^9 cells per liter for Neutrophil count, <100 or >550 x10^9 cells per liter for Platelet count and <3 or >20 x10^9 cells per liter White Blood Cell count. Participants were counted in the worst case category that their value changes to (Low, Normal or High), unless there is no change in their category. Participants whose value category was unchanged (e.g., High to High), or whose value became normal, are recorded in the To Normal or No Change category. Participants were counted twice if they had values that changed 'To Low' and 'To High'. Baseline is defined as the latest pre-dose assessment. | Up to Day 116 | 
| Change From Baseline in Urine Potential of Hydrogen (pH) | Urine samples were collected for measurement of urine pH at indicated time points. pH is a measure of hydrogen ion concentration and used to determine the acidity or alkalinity of urine. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value. | Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 43, Day 85 and Follow-up (Day 116) | 
| Change From Baseline in Urine Specific Gravity | Urine samples were collected to analyze specific gravity of urine. Specific gravity, is a measure of urine concentration and is measured using a chemical test. Specific gravity measurements provide a comparison of the amount of substances dissolved in urine as compared to pure water. If there were no solutes present, the specific gravity of urine would be 1.000 the same as pure water. Specific gravity between 1.002 and 1.035 could be considered as normal. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value. | Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 43, Day 85 and Follow-up (Day 116) | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Blood pressure was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value. | Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116) | 
| Change From Baseline in Heart Rate | Heart rate was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value. | Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116) | 
| Change From Baseline in Respiratory Rate | Respiratory rate was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value. | Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116) | 
| Change From Baseline in Body Temperature | Body temperature was measured at indicated time points in supine or semi-supine position after 5 minutes rest. Baseline is defined as the latest pre-dose assessment. Change from Baseline is defined as any post-dose visit value minus Baseline value. | Baseline (Pre-dose on Day 1), Day 8, Day 15, Day 29, Day 43, Day 57, Day 71, Day 85 and Follow-up (Day 116) | 
| Number of Participants With Any Time Post-Baseline Results for Electrocardiogram Findings | Single 12-lead electrocardiograms were obtained at indicated time points during the study using an electrocardiogram machine that automatically calculates the heart rate and measures PR, QRS, QT, QT interval corrected for heart rate (QTc) using Bazett's formula (QTcB) intervals and QTc using Fridericia's formula (QTcF). The abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Baseline is defined as the latest pre-dose assessment. Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. The number of participants with normal and abnormal electrocardiogram findings at any time post-Baseline visit has been presented. | Up to Day 116 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentrations of GSK2982772 at Days 43 and 85 | Blood samples were collected for pharmacokinetic analysis of GSK2982772 following 60 mg BID and 60 mg TID dose at indicated time points. The pharmacokinetic analysis was performed using non-compartmental methods. The analysis was based on Pharmacokinetic Population which comprised of participants in the 'Safety' Population for whom a pharmacokinetic sample was obtained and analyzed. | Day 43 (Pre-dose) and Day 85 | 
| Post-dose Plasma Concentrations of GSK2982772 on Days 1 and 43 | Blood samples were collected for pharmacokinetic analysis of GSK2982772 following 60 mg BID and 60 mg TID dose at indicated time points. The pharmacokinetic analysis was performed using non-compartmental methods. | 1, 2, 4 and 6 Hours Post-dose on Days 1 and 43 | 
| Adjusted Mean Percentage Change in Histopathological Scoring of Psoriatic Lesional Biopsy Following Administration of GSK2982772 | A target lesion for biopsy was identified on the trunk or extremities at indicated time points. The manual cell counting performed on stained tissue section was referred as histopathological scoring of psoriatic lesions. Histologic assessment included measurement of Cluster of differentiation 11 (CD11+), CD161+, CD3+ and Elastase. Baseline is defined as the latest pre-dose assessment. Percentage change from Baseline was determined from the back-calculation of the log ratio to Baseline. Data for all the listed biomarkers from skin biopsy has been presented for two skin types; dermis and epidermis at Day 43. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses. NA indicates that data was not available as geometric coefficient of variation could not be calculated for single participant. | Baseline (Pre-dose on Day 1) and Day 43 | 
| Adjusted Mean Percentage Change in Histopathological Scoring of Psoriatic Lesional Biopsy: Epidermis Thickness | A target lesion for biopsy was identified on the trunk or extremities at indicated time points. The manual cell counting performed on stained tissue section was referred as histopathological scoring of psoriatic lesions. Histologic assessment included measurement of epidermis thickness. Baseline is defined as the latest pre-dose assessment. Percentage change from Baseline was determined from the back-calculation of the log ratio to Baseline. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses. | Baseline (Pre-dose on Day 1) and Day 43 | 
| Number of Participants With Changes in Keratin 16 (K16) Histopathological Scoring in Psoriatic Lesional Biopsies | A target lesion for biopsy was identified on the trunk or extremities at indicated time points. The manual cell counting performed on stained tissue section was referred as histopathological scoring of psoriatic lesions. Histologic assessment included measurement of K16 as keratin expression. Baseline is defined as the latest pre-dose assessment. Results for K16 were categorized as, negative to positive, no change and positive to negative at Day 43. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses. | Baseline (Pre-dose on Day 1) and Day 43 | 
| Messenger Ribonucleic Acid (mRNA) Expression of Inflammatory Gene Transcripts in Psoriatic Lesional Biopsies Following Administration of GSK2982772 | A target lesion for biopsy was identified on the trunk or extremities at indicated time points. mRNA expression of inflammatory markers and tissue healing were assessed. Data has been presented for inflammatory gene transcripts including interferon gamma, interleukin 10, interleukin 17A, interleukin 21, interleukin 22, interleukin 23 subunit alpha, interleukin 4 and tumor necrosis factor. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all biomarker analyses. | Day 1 and Day 43 | 
| Percentage Change From Baseline Psoriatic Lesion Severity Sum (PLSS) Scores in the Index Lesion Following Administration of GSK2982772 | Two plaques were selected, one for clinical assessment (index plaque) and one for biopsy. Each lesion was evaluated for 3 components: erythema, induration, and scaling. Each component was given a score using a scale ranging from 0 (no symptom) to 4 (very marked) with increasing score reflecting increased lesion severity. The PLSS is the sum of the erythema, scaling and plaque thickness scores. The total PLSS score ranged from 0 (no symptom) to 12 (very marked). Each lesion must have a PLSS score of >=5. Baseline is defined as the latest pre-dose assessment. Percentage change from Baseline was determined from the back-calculation of the log ratio to Baseline. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all efficacy analyses. | Baseline (Pre-dose on Day 1) and Days 15, 29, 43, 57, 71, 85 | 
| Actual PLSS Scores in the Index Psoriatic Lesion Following Administration of GSK2982772 | Two plaques were selected one for clinical assessment (index plaque) and one for biopsy. Each lesion was evaluated for 3 components: erythema, induration, and scaling. Each component was given a score using a scale ranging from 0 (no symptom) to 4 (very marked) with increasing score reflecting increased lesion severity. The PLSS is the sum of the erythema, scaling and plaque thickness scores. The total PLSS score ranged from 0 (no symptom) to 12 (very marked). Each lesion must have a PLSS score of >=5. Due to major Baseline imbalances in psoriasis Baseline characteristics between the BID and TID groups, placebo BID and placebo TID arms were reported separately for all efficacy analyses. | Days 1, 15, 29, 43, 57, 71 and 85 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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psoriasis, tolerability, GSK2982772, RIP1 kinase inhibitor, safety