Phase 1
Completed N=67
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
Source: ClinicalTrials.gov NCT02195349 ↗Enrolled (actual)
67
Serious AEs
1.5%
Results posted
Aug 2019
Primary outcomePrimary: Number of Participants With Hematology Abnormalities of Potential Clinical Importance (PCI) — 3; 0; 0; 0 Participants
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).
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Hematology Abnormalities of Potential Clinical Importance (PCI) |
3; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Clinical Chemistry Abnormalities of PCI |
1; 0; 0; 1; 1; 1 | — |
| PRIMARY Number of Participants With Vital Signs of PCI |
1; 0; 0; 1; 0; 0 | — |
| PRIMARY Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) of PCI |
2; 0; 0; 0; 0; 1 | — |
| PRIMARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |
8; 0; 0; 5; 6; 3 | — |
| PRIMARY Change From Baseline in Interleukin (IL)-6, IL-8, Interferon-gamma, and Tumor Necrosis Factor (TNF) Alpha |
2.889; 1.430; 0.000; 0.258; 1.025; 4.305 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick in Placebo Healthy Volunteers |
2; 2; 1; 1; 4; 1 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.0003 mg/kg (ADA-ve) |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.0015 mg/kg (ADA-ve) |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.0075 mg/kg (ADA-ve) |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.04 mg/kg (ADA-ve) |
1; 0; 0; 0; 1; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.15 mg/kg (ADA-ve) |
4; 0; 0; 0; 3; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.15 mg/kg (ADA+ve) |
4; 0; 0; 0; 4; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for Psoriasis Placebo |
1; 4; 0; 2; 0; 1 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 0.5 mg/kg |
0; 2; 1; 0; 0; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 1.5 mg/kg |
0; 4; 0; 1; 1; 0 | — |
| PRIMARY Number of Participants With Abnormal Values on Urinalysis by Dipstick for GSK2831781 5 mg/kg |
0; 5; 0; 0; 0; 0 | — |
| SECONDARY Change From Baseline (PPD First Challenge) of Induration Diameter From Re-challenge at 3 Days Post-dose |
3.167; 6.500; 2.000; 6.500; 0.300; 2.167 | — |
| SECONDARY Duration of Induration in the Re-challenge for DTH |
20.0; 20.0 | — |
| SECONDARY 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 |
15.3; 19.7 | — |
| SECONDARY Change From Baseline in LAG-3+ Cells in Lesional Biopsies in Psoriasis Participants at Day 29 |
2.7; -2.5; 0.3; -2.5; -1.2; -9.8 | — |
| SECONDARY Area Under the Plasma Time Curve From Zero to Infinity (AUC[0-infinity]) of GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY AUC(0-infinity) for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC[0-t]) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY AUC(0-t) for GSK2831781 0.0015 mg/kg (ADA-ve) |
0.0060 | — |
| SECONDARY AUC(0-t) for GSK2831781 0.0075 mg/kg (ADA-ve) |
1.3497 | — |
| SECONDARY AUC(0-t) for GSK2831781 0.04 mg/kg (ADA-ve) |
23.6008 | — |
| SECONDARY AUC(0-t) for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
168.3458; 238.1434 | — |
| SECONDARY AUC(0-t) for GSK2831781 0.5 mg/kg |
1187.8496 | — |
| SECONDARY AUC(0-t) for GSK2831781 1.5 mg/kg |
8493.7344 | — |
| SECONDARY AUC(0-t) for GSK2831781 5 mg/kg |
40599.8938 | — |
| SECONDARY Area Under the Concentration-time Curve From Zero (Pre-dose) to Week 4 (AUC[0-Week 4]) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 0.0015 mg/kg (ADA-ve) |
NA | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 0.0075 mg/kg (ADA-ve) |
NA | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 0.04 mg/kg (ADA-ve) |
NA | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
NA; NA | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 0.5 mg/kg |
NA | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 1.5 mg/kg |
NA | — |
| SECONDARY AUC(0-Week 4) for GSK2831781 5 mg/kg |
NA | — |
| SECONDARY Percentage of AUC(0-infinity) Obtained by Extrapolation (%AUCex) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY %AUCex for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY %AUCex for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY %AUCex for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY %AUCex for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY %AUCex for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY %AUCex for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY %AUCex for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Maximum Observed Concentration (Cmax) for GSK2831781 0.0003 mg/kg (ADA-ve) |
NA | — |
| SECONDARY Cmax for GSK2831781 0.0015 mg/kg (ADA-ve) |
0.0127 | — |
| SECONDARY Cmax for GSK2831781 0.0075 mg/kg (ADA-ve) |
0.1523 | — |
| SECONDARY Cmax for GSK2831781 0.04 mg/kg (ADA-ve) |
0.8196 | — |
| SECONDARY Cmax for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
3.0047; 3.4255 | — |
| SECONDARY Cmax for GSK2831781 0.5 mg/kg |
8.4810 | — |
| SECONDARY Cmax for GSK2831781 1.5 mg/kg |
41.1481 | — |
| SECONDARY Cmax for GSK2831781 5 mg/kg |
158.8243 | — |
| SECONDARY Time of Occurrence of Cmax (Tmax) for GSK2831781 0.0003 mg/kg (ADA-ve) |
NA | — |
| SECONDARY Tmax for GSK2831781 0.0015 mg/kg (ADA-ve) |
1.950 | — |
| SECONDARY Tmax for GSK2831781 0.0075 mg/kg (ADA-ve) |
1.950 | — |
| SECONDARY Tmax for GSK2831781 0.04 mg/kg (ADA-ve) |
4.025 | — |
| SECONDARY Tmax for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
1.980; 4.990 | — |
| SECONDARY Tmax for GSK2831781 0.5 mg/kg |
3.930 | — |
| SECONDARY Tmax for GSK2831781 1.5 mg/kg |
1.990 | — |
| SECONDARY Tmax for GSK2831781 5 mg/kg |
2.975 | — |
| SECONDARY Time of Last Quantifiable Concentration (Tlast) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY Tlast for GSK2831781 0.0015 mg/kg (ADA-ve) |
1.950 | — |
| SECONDARY Tlast for GSK2831781 0.0075 mg/kg (ADA-ve) |
18.005 | — |
| SECONDARY Tlast for GSK2831781 0.04 mg/kg (ADA-ve) |
72.065 | — |
| SECONDARY Tlast for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
238.750; 288.235 | — |
| SECONDARY Tlast for GSK2831781 0.5 mg/kg |
468.655 | — |
| SECONDARY Tlast for GSK2831781 1.5 mg/kg |
1343.930 | — |
| SECONDARY Tlast for GSK2831781 5 mg/kg |
2016.050 | — |
| SECONDARY Systemic Clearance of Parent Drug (CL) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY CL for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY CL for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY CL for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY CL for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY CL for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY CL for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY CL for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Volume of Distribution at Steady State (Vss) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY Vss for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY Vss for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY Vss for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY Vss for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY Vss for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY Vss for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY Vss for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Mean Residence Time (MRT) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY MRT for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY MRT for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY MRT for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY MRT for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY MRT for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY MRT for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY MRT for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Terminal Elimination Rate (Lambda z) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY Lambda z for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY Lambda z for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY Lambda z for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY Lambda z for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY Lambda z for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY Lambda z for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY Lambda z for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Terminal Phase Half-life (t1/2) for GSK2831781 0.0003 mg/kg (ADA-ve) |
— | — |
| SECONDARY t1/2 for GSK2831781 0.0015 mg/kg (ADA-ve) |
— | — |
| SECONDARY t1/2 for GSK2831781 0.0075 mg/kg (ADA-ve) |
— | — |
| SECONDARY t1/2 for GSK2831781 0.04 mg/kg (ADA-ve) |
— | — |
| SECONDARY t1/2 for GSK2831781 0.15 mg/kg (ADA-ve) and (ADA+ve) |
— | — |
| SECONDARY t1/2 for GSK2831781 0.5 mg/kg |
— | — |
| SECONDARY t1/2 for GSK2831781 1.5 mg/kg |
— | — |
| SECONDARY t1/2 for GSK2831781 5 mg/kg |
— | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 in Healthy Volunteer Placebo |
3; 3; 3; 2; 1 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.0003 mg/kg (ADA-ve) |
0; 0; 0 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.0015 mg/kg (ADA-ve) |
0; 0; 0; 0 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.0075 mg/kg (ADA-ve) |
1; 0; 1; 1 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.04 mg/kg (ADA-ve) |
0; 0; 1; 0; 0 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.15 mg/kg (ADA-ve) |
0; 2; 1; 1; 0 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.15 mg/kg (ADA+ve) |
6; 6; 6; 4; 4 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 Placebo in Psoriasis Participants |
1; 1; 1; 1; 1 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 0.5 mg/kg |
0; 1; 1; 2; 1 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 1.5 mg/kg |
1; 1; 1; 1; 1 | — |
| SECONDARY Number of Participants With Positive ADAs to GSK2831781 5 mg/kg |
0; 0; 0; 1; 1 | — |
| SECONDARY Change From Baseline in Psoriasis Area Severity Index (PASI) Scores |
-0.7; -1.7; -2.4; -2.7; -0.5; -1.8 | — |
| SECONDARY Actual PASI Scores |
10.3; 6.8; 14.1; 9.2; 9.6; 5.1 | — |
| SECONDARY Percentage of Participants Who Achieved >=50 Percent (%) and >=75% Improvement From Baseline in PASI Score |
0; 17; 0; 17; 0; 33 | — |
| SECONDARY Change From Baseline in Plaque Lesional Severity Score (PLSS) Scores for the Index Plaque |
-0.6; -1.3; -1.8; -1.7; -0.2; -2.2 | — |
| SECONDARY Absolute PLSS Scores for the Index Plaque |
7.1; 6.5; 7.7; 6.5; 6.6; 5.2 | — |
| SECONDARY Change From Baseline in Physicians Global Assessment (PGA) Scores in Psoriasis Participants |
-0.1; -0.7; -0.3; -1.0; -0.3; -0.5 | — |
| SECONDARY Absolute PGA Scores in Psoriasis Participants |
4.4; 3.2; 4.8; 4.2; 4.3; 2.5 | — |
| SECONDARY Percentage of Participants in Each PGA Score Category |
0; 0; 0; 0; 0; 17 | — |
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 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin =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 GS
Data sourced from ClinicalTrials.gov (NCT02195349). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.