Dataset from A Randomised, Double Blind (Sponsor Unblinded), Placebo-controlled, Single Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a IV Dose of GSK2831781 in Healthy Volunteers and Patients With Plaque Psoriasis

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).

本研究为一项针对GSK2831781的I期、随机、双盲（申办方不设盲）、安慰剂对照的单次递增剂量静脉给药研究。GSK2831781是一种特异性靶向淋巴细胞激活基因3（Lymphocyte Activation Gene-3，LAG-3）蛋白的人源化、抗体依赖性细胞介导的细胞毒性（Antibody Dependent Cell Cytotoxicity，ADCC）增强型去岩藻糖基化单克隆抗体。本研究为GSK2831781的首次人体给药研究，将分为两个部分评估单次静脉给予GSK2831781的安全性、耐受性、药代动力学（pharmacokinetics，PK）、药效动力学（pharmacodynamics，PD）及免疫原性，受试人群分为两类：既往接种过卡介苗（Bacillus Calmette Guérin，BCG）的健康受试者（A部分：延迟型超敏反应[delayed type hypersensitivity，DTH]队列），以及斑块状银屑病患者（B部分）。纳入DTH队列及银屑病患者队列，旨在在上述人群的活检样本与临床应答终点中探索药物作用机制，并考察全身生物标志物，这将为后续在其他免疫炎症性疾病中开展研究（此类研究需实施更具侵入性的组织活检）提供有价值的参考信息。通过结核菌素纯蛋白衍生物（Tuberculin Purified Protein Derivative，PPD）皮肤激发试验的皮肤活检样本，以及银屑病患者的皮损皮肤活检样本中LAG-3阳性T细胞的耗竭情况来评估GSK2831781的药理学作用，将有助于明确其量效关系，这对后续设计针对包括银屑病在内的免疫炎症性疾病的研究具有重要意义。本研究计划纳入约67名受试者以完成给药及关键评估，受试者将分为两组：约40名健康受试者（A部分）与27名斑块状银屑病患者（B部分）。