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
Condition: Psoriasis
MeSH terms: Psoriasis
Intervention: GSK2831781; Placebo
Intervention description: 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.; Commercial saline solution administered by IV over approximately 2 hours
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double (Participant, Investigator)
Enrollment: 67.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Tuberculin Purified Protein Derivative; Delayed Type Hypersensitivity; Biopsy; Induration; First time in human; T-cells; LAG-3; safety; GSK2831781; psoriasis

Summary:

      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).
    

Eligibility criteria:

        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.