A First in Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Intravenous (IV) Dose of GSK2831781 in Healthy Volunteers and Patients With Plaque Psoriasis

Phase 1CompletedNCT02195349

GlaxoSmithKline67 enrolled

Overview

This study is a phase I, randomised, double blind (sponsor unblinded), placebo-controlled, single ascending dose study GSK2831781 administered by IV. GSK2831781 is a humanized Antibody Dependent Cell Cytotoxicity (ADCC) enhanced monoclonal afucosylated antibody that is specific to the Lymphocyte Activation Gene-3 (LAG-3) protein. This is the first administration of GSK2831781 in humans and will evaluate in two parts the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of single IV doses of GSK2831781 administered to healthy subjects previously vaccinated with Bacillus Calmette Guérin (BCG) (Part A delayed type hypersensitivity \[DTH\] cohorts) and patients with plaque psoriasis (Part B). The inclusion of DTH and psoriasis subjects to explore the mechanism in biopsies and clinical response endpoints in these populations, as well as investigate systemic biomarkers will provide useful information prior to conducting studies in other immune-inflammatory disease which will involve more invasive tissue biopsies. Measuring the pharmacology of GSK2831781 using the depletion of LAG-3+ T-cells in skin biopsies from Tuberculin Purified Protein Derivative (PPD) skin challenge and lesional skin biopsies from patients with psoriasis, will be helpful in understanding of the dose response relationship, which will be important for designing future studies in immuno-inflammatory diseases, including psoriasis. Approximately 67 subjects will be enrolled to complete dosing and critical assessments. The subject numbers will be split to approximately 40 healthy subjects (Part A) and 27 patients with psoriasis (Part B).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Interventions

GSK2831781BIOLOGICAL

GSK2831781 (100 milligram (mg)/mL) and its dilutions (Diluent - 0.9 percent saline solution containing 0.015 percent Polysorbate 80) as clear or opalescent, colourless, yellow to brown liquid solution administered by IV over approximately 2 hours.

PlaceboBIOLOGICAL

Commercial saline solution administered by IV over approximately 2 hours

Eligibility

Sex: ALLMin age: 18 YearsMax age: 75 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Part A males aged between 18 and 65 years of age and Part B males and females aged between 18 and 75 years of age inclusive, at the time of signing the informed consent * Part A: A body weight \<=120 kilogram (kg) and Body mass index (BMI) within the range 19-32 kg/square meter (m\^2) (inclusive), Part B: BMI within range 19-35 kg/m\^2 (inclusive). * Alanine aminotransferase (ALT), alkaline phosphatase and bilirubin \<=1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35 percent) * Based on single or averaged Electrocardiogram QT interval corrected for heart rate (QTc) values of triplicate Electrocardiogram (ECGs) obtained over a brief recording period: Electrocardiogram QT interval corrected for heart rate using Fridericia's formula (QTcF) \<450 milliseconds (msec) * Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form For Part A study subjects only * Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and 12-lead ECGs. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator in consultation with the Glaxosmithkline (GSK) Medical Monitor, if required, agree and document that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures Delayed type hypersensitivity (DTH) cohorts only * Subjects with a history of Bacillus Calmette Guérin (BCG) vaccination as evidence by either: A BCG scar and verbal confirmation of BCG vaccination ; Or documented medical history of a BCG vaccination with or without a BCG scar * Subjects with a history of current vaccination for Tetanus, diphtheria, measles, pertussis, mumps and rubella For Part B study subjects only * Subject has psoriasis covering Body Surface Area (BSA) \>=3 percent as assessed at Screening and Day-1 * Subject has had a confirmed diagnosis of chronic plaque-type psoriasis (without recent documented flare within 30 days prior to screening) for at least 6 months * Subject has at least 2 stable plaques assessed at Screening and Day -1. One of a suitable size and in a site suitable for repeat biopsy, and one for index lesion Plaque Lesional Severity Score (PLSS) scoring. Both must have a PLSS lesional score of \>=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 or scalp and must be protected from the sun * A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin (hCG) test at screening and negative urine hCG test at Day -1 for Females of Reproductive Potential \[FRP\]), not lactating, and at least one of the given conditions applies: Non-reproductive potential defined as pre-menopausal females with a documented tubal ligation; or documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; or hysterectomy; or documented bilateral oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause (refer to laboratory reference ranges for confirmatory levels)\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to use a barrier method (male condom or female diaphragm) plus to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP from 28 days prior to the first dose of study medication and until completion of the follow-up visit. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. The investigator or designee should remind the subjects of the need to comply with these requirements approximately monthly, either at study visits or by telephone call until the follow-up visit. Exclusion Criteria: * Received live vaccine (s) attenuated or recombinant within 4 weeks of Day 1 or plan to receive a live vaccination during the study until follow-up * Subjects from a high risk area of the world for tuberculosis or have history of tuberculosis or have close family members with confirmed Mycobacterium tuberculosis (MTB) infection or positive at screening by Quantiferon testing * Subject is unable to abstain from travelling to areas with high endemic rates of infectious diseases until the end of the follow up period * A medical history of severe allergic reaction, angio-edema, anaphylaxis or immunodeficiency * Subjects with neutrophil results below the normal range at screening and baseline * Subjects with any clinical, even mild, Gastrointestinal (GI) upset such as, but not limited to, diarrhea or abdominal cramping during the previous week before dosing, as well as history of more chronic GI upset, e.g. Irritable Bowel Syndrome (IBS) * Current evidence of ongoing or acute infection within 3 months prior to the first dose of study drug, such as: Serious local infection (e.g. cellulitis, abscess); Systemic infection \[e.g. pneumonia, septicaemia, Tuberculosis (TB)\] * Subjects who test positive for pre-existing ADA to GSK2831781 at screening. * History of malignancy, except for basal cell or squamous cell carcinoma, or in situ cervical carcinoma that has been fully treated and shows no evidence of recurrence * Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) * History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8gram (g) of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits * History of sensitivity to any of the study medications or Tuberculin Purified Protein Derivative (PPD) challenge agent, or components thereof or a history of drug (or Immunoglobulin G therapeutic antibodies) or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation * A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening * A positive pre-study drug/alcohol screen * A positive test for Human Immunodeficiency Virus (HIV) antibody * Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period * The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 3 months, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) * Exposure to more than four new chemical entities within 12 months prior to the first dosing day * Subjects with an aspartate aminotransferase and/or gamma glutamyltransferase level above the upper limit of normal at screening and/or baseline will be excluded For Part A study subjects only * Use of prescription drugs or non-prescription drugs, if in the opinion of the investigator (in consultation with the GSK medical monitor), the medication will interfere with the study procedures or compromise subject safety * Subjects must not currently be taking any of the following: topical steroids on the arms, oral or systemic steroids or any other immune-modulators (the washout period will be determined, on a case by case basis, by the investigator in consultation with the GSK medical monitor) * Subjects with an aspartate aminotransferase and/or gamma glutamyltransferase level above the upper limit of normal at screening and/or baseline will be excluded. For Part A (only cohorts with DTH challenge) study subjects only: * Use of nicotine patches on the arm at screening that would interfere with the injection sites * Presence of tattoos, naevi or other skin abnormalities such as keloids (or a history of keloids) that may, in the opinion of the investigator, interfere with DTH assessments * Subjects participating, within seven days of screening, in recreational sun-bathing, or the use of a sun-bed, on the area of the skin from the wrist to the shoulder (inclusive) For Part B study subjects only: * History of significant cardiac, endocrinologic, haematologic, pulmonary, metabolic, renal, hepatic, immunologic (excluding psoriasis and psoriatic arthritis), urologic, neurologic, dermatologic (except psoriasis), psychiatric or gastrointestinal conditions that, in the opinion of the investigator and/or GSK medical monitor, places the subject at unacceptable risk * Clinically significant abnormalities of laboratory assessments (not related to disease) as judged by the investigator and/or GSK medical monitor * All systemic psoriasis medications, including psoralen long-wave ultraviolet radiation treatments, or other systemic immunosuppressives, are not allowed within 5 half lives prior to Day-1 (Methotrexate and cyclosporin are not allowed within 8 weeks of Day -1; Psoralen long-wave Ultraviolet (UV) is not allowed within 4 weeks of Day-1). Subjects should not be included if the investigator considers that the subject is at high risk of requiring rescue with prohibited medication for duration of study up to follow-up. This assessment should be based on current disease activity or a history of frequent and/or severe flares requiring systemic immunosuppression. * The use of single treatment phototherapy (ultraviolet B or self treatment with tanning beds) is not allowed within 14 days prior to Day -1 * The use of topical therapies for psoriasis are not allowed with 7 days prior to Day-1 on the index lesion or biopsy plaque * Previous treatment with anti- Tumour necrosis factor (TNF)/ Interleukin (IL)-12/IL-23 or any other monoclonal antibodies is not allowed within 12 weeks prior to Day-1 * Patients that require narrow therapeutic index medications from Screening to Follow-up * Vulnerable subjects (e.g. person kept in detention) * Subjects who are not able to understand and communicate in the native language of the country where the study is conducted. * Subjects who work for the Sponsor or CRO.

Locations (3)

GSK Investigational Site

Bonn, North Rhine-Westphalia, Germany

GSK Investigational Site

Berlin, Germany

GSK Investigational Site

London, United Kingdom

Outcomes

Primary Outcomes

Number of Participants With Hematology Abnormalities of Potential Clinical Importance (PCI)

Hematology parameters with PCI ranges: hematocrit (high: \>0.54 percentage of red blood cells), hemoglobin (high: \>180 grams per liter \[g/L\]), lymphocytes (low: \<0.8\*giga cells per liter \[10\^9/L\]), neutrophil count (low: \<1.5\*10\^9/L), platelet count (low: \<100\*10\^9/L and high: \>550\*10\^9/L), and while blood cell count (low: \<3\*10\^9/L and high: \>20\*10\^9/L) for healthy volunteers and psoriasis participants. Safety population consisted of all randomized participants who received at least one dose of study treatment. Only those participants for which at least one value of PCI was reported are summarized.

Time frame: Up to 307 days

Number of Participants With Clinical Chemistry Abnormalities of PCI

Clinical chemistry parameters and their potential clinical concern values: albumin (low: \<30 millimoles per liter \[mmol/L\]), calcium (low: \<2 mmol/L, high: \>2.75 mmol/L), creatinine (high: \>44.2 mmol/L), glucose (low: \<3 mmol/L, high: \>9 mmol/L), magnesium (low: \<0.5 mmol/L, high: \>1.23 mmol/L), phosphorus (low: \<0.8 mmol/L, high: \>1.6 mmol/L), potassium (low: \<3 mmol/L, high: \>5.5 mmol/L), sodium (low: \<130 mmol/L, high: \>150 mmol/L), and total carbon dioxide (CO2) (low: \<18 mmol/L, high: \>32 mmol/L). Number of participants with clinical chemistry of PCI are presented.

Time frame: Up to 307 days

Number of Participants With Vital Signs of PCI

Vital signs included heart rate, systolic and diastolic blood pressure and body temperature were performed with the participant in a semi-supine position after the participant had rested for at least 5 minutes. The PCI range for heart rate (low: \<40 beats per minute \[BPM\] and high: \>110 BPM), systolic blood pressure (low: \<85 and high: \>160 millimeter of mercury \[mmHg\]), diastolic blood pressure (low: \<45 mmHg and high: \>100 mmHg) and body temperature (low: \<35 degree Celsius and high: \>37.5 degree Celsius). Number of participants with vital signs of PCI are presented.

Time frame: Up to 307 days

Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) of PCI

Triplicate ECG was measured in a semi-supine position after 5 minutes rest. A single 12-lead ECG was obtained by using an ECG machine that automatically calculates heart rate and measured PR, QRS, QT, and Fridericia's formula (QTcF) intervals. The PCI ranges for QTc Interval (high: \>450 millisecond \[msec\]), PR Interval (low: \<110 msec and high: \>220 msec) and QRS Interval (low: \<75 msec and high: \>110 msec). Number of participants with ECG values of PCI are presented.

Time frame: Up to 307 days

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (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 study treatment. A SAE is defined as any untoward medical occurrence that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect and other important medical events judged by the investigator that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition.

Time frame: Up to 307 days

Change From Baseline in Interleukin (IL)-6, IL-8, Interferon-gamma, and Tumor Necrosis Factor (TNF) Alpha

IL-6, IL-8, interferon-gamma and TNF alpha were assessed at indicated time points. Baseline was considered as the latest pre-dose assessment with a non-missing value for Baseline (Day 1, pre-dose). Change from Baseline was calculated as post-Baseline value minus Baseline value.

Time frame: Baseline, 6, 12, 24 and 48 hours post-dose

Number of Participants With Abnormal Values on Urinalysis by Dipstick in Placebo Healthy Volunteers

Urine samples were collected at indicated time points to analyze parameters including glucose, protein, blood, leucocytes, nitrites and ketones by dipstick. Urine dipstick tests were either read as qualitative concentrations as Negative, Trace, 1+ (low concentrations present), 2+ (moderate concentrations present), 3+ (high concentrations present) and 4+ (very high concentrations present); or as semi quantitative cell counts or concentrations (0, 0.25, 0.5, 1.5,5, 7, 9, 10, 25, 50, 150, 250) where units depend on the test performed; (cells/micro liter for blood and leucocytes; mmol/L for glucose and ketones; g/L for protein), and Negative (not detected) or Positive (detected) for nitrites. For each methodology, abnormal results were defined as those that were not 'Negative' or 'Trace'. Only categories with abnormal urinalysis values are presented.

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 191

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.0003 mg/kg (ADA-ve)

Time frame: 6, 12, 72, 168 hours, Day 15 and 29

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.0015 mg/kg (ADA-ve)

Time frame: 6, 12, 72, 168 hours, Days 15, 29 and 43

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.0075 mg/kg (ADA-ve)

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57 and 85

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.04 mg/kg (ADA-ve)

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 147

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.15 mg/kg (ADA-ve)

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 219

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.15 mg/kg (ADA+ve)

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 191

Number of Participants With Abnormal Values on Urinalysis by Dipstick for Psoriasis Placebo

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 307

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.5 mg/kg

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 237

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 1.5 mg/kg

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 277

Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 5 mg/kg

Time frame: 6, 12, 72, 168 hours, Days 15, 22, 29, 43, 57, 85, 121 and 307

Secondary Outcomes

Change From Baseline (PPD First Challenge) of Induration Diameter From Re-challenge at 3 Days Post-dose

The induration diameter by challenge site is defined as the average of the two skin response test values (vertical and horizontal) at each challenge site. A challenge site is defined by skin response (SR) directionality (upper/lower) and SR laterality (left/right). Four categories considered were as follows: left upper, right upper, left lower and right lower. Baseline was considered as Day -26. Change from Baseline was calculated as post-Baseline value minus Baseline value. Data is presented for DTH participants.

Time frame: Baseline, Days 4, 8, 15 and 22 post-dose

Duration of Induration in the Re-challenge for DTH

The duration of induration was the time (in days) to achieve an overall induration less than 6 mm from the time of the PPD re-challenge post-dose. Duration of induration was calculated as: PPD re-challenge post-dose up to the last available induration measurement. Data is presented for DTH participants.

Time frame: Up to 28 days post-dose

Change From Baseline (PPD First Challenge) of Lymphocyte Activation Gene-3 (LAG-3)+ Cells in Biopsies of Re-challenged Skin at 3 Days Post-dose

A punch biopsy was taken from one of the challenge sites. Cells in biopsies of re-challenged skin were measured by immunohistochemistry (IHC) and the LAG-3+ cells characterized and counted. Baseline was considered as Day -26 for this outcome measure. Change from Baseline was calculated as post-Baseline value minus Baseline value. Data is presented for DTH participants.

Time frame: Baseline and 72 hours post-dose

Change From Baseline in LAG-3+ Cells in Lesional Biopsies in Psoriasis Participants at Day 29

A punch biopsy was taken from active leading edge of the lesion. Cells in lesional biopsies of skin were measured by IHC and count the LAG-3+ cells. The regions of interest for LAG3+ were located in epidermis and dermis. Baseline was considered as the latest pre-dose assessment with a non-missing value for Day -1. Change from Baseline was calculated as post-Baseline value minus Baseline value.

Time frame: Baseline and Day 29

Area Under the Plasma Time Curve From Zero to Infinity (AUC[0-infinity]) of GSK2831781 0.0003 mg/kg (ADA-ve)

Data from ClinicalTrials.gov

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Blood samples were collected at specified time points for GSK2831781 in plasma. Pharmacokinetic (PK) population consisted of all participants in the Safety Population who had at least 1 non-missing PK assessment.

Time frame: Pre-dose, 1, 2, 4, 6, 8, 12 and 24 hours post-dose

AUC(0-infinity) for GSK2831781 0.0015 mg/kg (ADA-ve)