A Double-blind (Sponsor Unblinded) Study to Investigate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of Repeat Dosing of GSK2646264 in Cutaneous Lupus Erythematosus Patients

This study is designed to examine safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effect of repeat dosing of GSK2646264 in patients with subacute and chronic cutaneous lupus erythematosus (CLE) lesions and in acute CLE like lesions induced by photoprovocation (PV).
Current study is two group study. In Group A, Patients with fewer than two active lesions will be enrolled and exposed to photoprovocation (PV) for 3 consecutive days. Patients that develop PV lesions at any time during this period, as determined by the local investigative team, will receive 1% strength GSK2646264 on 1 lesion and placebo on 1 lesion daily and either 1% strength GSK2646264 or placebo on an area of uninvolved skin, for skin pharmacokinetic (PK) of study drug, for 28 days.
In Group B, Patients that have a minimum of 2 active existing CLE lesions as determined by the investigators will be enrolled into group B and have one lesion treated with 1% GSK2646264 and 1 lesion with placebo.
A completed patient will be defined as a subject who receives at least 25 days of study drug and completes the end of treatment biopsy (at day 28) and assessment. Thereafter patients will be followed for 28 days in Group A only or until complete resolution of induced PV lesions, as determined by the investigator.

开始日期2017-01-13

申办/合作机构

GSK Plc

NCT02424799 / Completed临床1期

A Randomised Double Blind (Sponsor Unblinded), Single and Repeat Ascending Dose First Time in Human Study in Healthy Subjects, Cold Urticaria and Chronic Spontaneous Urticaria Subjects to Investigate Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of GSK2646264

This First Time in Human (FTIH) study, which will be performed in three parts, is designed to investigate the safety, local tolerability, pharmacokinetics and pharmacodynamics after single and repeat topical applications of up to 2 strengths of GSK2646264 and corresponding placebo within the same subject, in healthy adult subjects (Part A), subjects with cold urticaria (CU, Part B) and subjects with chronic spontaneous urticaria (CsU, Part C). The study will also measure short term effects of GSK2646264 on the number and size of weals in subjects with CsU, and in healthy subjects and subjects with CU following provocation tests.

开始日期2014-11-17

申办/合作机构

GSK Plc

100 项与 GSK-2646264 相关的临床结果

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100 项与 GSK-2646264 相关的转化医学

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100 项与 GSK-2646264 相关的专利（医药）

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项与 GSK-2646264 相关的文献（医药）

2021-12-01·British journal of clinical pharmacology2区 · 医学

Effects of a topical treatment with spleen tyrosine kinase inhibitor in healthy subjects and patients with cold urticaria or chronic spontaneous urticaria: Results of a phase 1a/b randomised double‐blind placebo‐controlled study

2区 · 医学

Article

作者: Ratia, Nirav ; Walker, Alexandra ; Metz, Martin ; Perry, Hayley ; Grattan, Clive ; Maurer, Marcus ; Gisbert, Sophie ; Williams, Nicola ; Dewit, Odile ; Dickson, Marion C.

Aims:

To explore the safety, tolerability, pharmacokinetics and pharmacodynamics (PD) of GSK2646264 using skin challenge models.

Methods:

Healthy volunteers (HV) with a positive allergen skin prick test received GSK2646264 (0.5% or 1% ww) and placebo creams on up to 10% body surface area (BSA). Cold (ColdU) or chronic spontaneous (CSU) urticaria patients received 1% GSK2646264 or placebo on up to 10% BSA. PD assessments included weal characteristics after skin allergen challenge, critical temperature threshold (CTT) in ColdU patients and defined area urticaria activity score in CSU patients.

Results:

Thirty‐four patients were randomised (17 HV, 12 ColdU, 5 CSU). Topical application of GSK2646264 and placebo was well tolerated. Systemic pharmacokinetics (AUC [0–24] h*ng/mL) was similar between HVs (Geomean 97.9 [%CV 37]) and ColdU patients (Geomean 68.2 [%CV 14; 3.5% BSA] or 167 [%CV 120; 10% BSA]). Whilst in HVs a similar reduction in skin allergen challenge weal area was observed following 3 applications of GSK2646264 and placebo, a trend towards a greater reduction was seen in ColdU with GSK2646264 compared to placebo. A clinically meaningful reduction in CTT, in ColdU patients treated with GSK2646264, was observed in 4 of 9 patients, who demonstrated either a complete inhibition of ColdU to ≤4°C (n = 2) or partial response (reduction by >4°C, n = 2). Due to the small number of CSU patients recruited, no meaningful conclusions could be drawn from the defined area urticaria activity score PD endpoint.

Conclusion:

This Phase 1/1b study confirms that GSK2646264 cream applied topically penetrates the skin and some reduction in CTT was observed.(NCT02424799)

2021-11-01·Experimental dermatology3区 · 医学

Safety, pharmacokinetics and pharmacodynamics of a topical SYK inhibitor in cutaneous lupus erythematosus: A double‐blind Phase Ib study

3区 · 医学

Article

作者: Hoang, Bao ; Williams, Nicola ; Nevin, Katherine ; Worm, Margitta ; Carnarius, Heike ; Erwig, Lars ; Ratia, Nirav ; Dickson, Marion ; Schneider‐Merck, Tanja ; Walker, Alex ; Gisbert, Sophie ; Wenzel, Joerg ; Foster, Katie

Abstract:

The immunoregulator spleen tyrosine kinase (SYK) is upregulated in cutaneous lupus erythematosus (CLE). This double‐blind, multicentre, Phase Ib study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of the selective SYK inhibitor GSK2646264 in active CLE lesions. Two lesions from each participant (n = 11) were each randomized to topical application of 1% (w/w) GSK2646264 or placebo for 28 days; all participants received GSK2646264 and placebo. The primary endpoint was safety and tolerability of GSK2646264, assessed by adverse event incidence and a skin tolerability test. Secondary endpoints included change from baseline in clinical activity and mRNA expression of interferon‐related genes in skin biopsies. Levels of several immune cell markers were evaluated over time. Eight (73%) participants experienced ≥ 1 adverse event (all mild in intensity), and maximal dermal response was similar for GSK2646264 and placebo. The expression of several interferon‐related genes, including CXCL10 and OAS1, showed modest decreases from baseline after 28 days of treatment with GSK2646264 compared with placebo. Similar findings were observed for CD3 + T cell and CD11c + dendritic cell levels; however, overall clinical activity remained unchanged with GSK2646264 vs. placebo. Further studies are warranted to assess SYK inhibitors as potential treatment for CLE.

2019-04-01·British journal of pharmacology2区 · 医学

GSK2646264, a spleen tyrosine kinase inhibitor, attenuates the release of histamine in ex vivo human skin

2区 · 医学

Article

作者: Barker, Mike ; Dickson, Marion C. ; Hooper‐Greenhill, Edward ; Skov, Per S. ; Falkencrone, Sidsel ; Ramirez Molina, Cesar

Background and Purpose:

Chronic spontaneous urticaria presents as a heterogeneous syndrome characterised by wheals, angioedema, or both for greater than 6 weeks. Spleen tyrosine kinase mediates allergen‐induced mast cell degranulation via the IgE signalling pathway, a central component of wheal formation and inflammation. In this study, we investigated the effects of perfused or topically administered GSK2646264 on IgE‐mediated histamine release from mast cells in an ex vivo human skin model.

Experimental Approach:

Using a novel SkiP device, ex vivo human skin from mastectomy surgeries was challenged with anti‐IgE, complement 5a (C5a), and buffer to induce histamine release from skin mast cells. Histamine was collected via microdialysis fibres and measured fluorometrically. GSK2646264 was delivered via perfusion either using microdialysis fibres or topically in a cream. Drug concentrations in the skin were measured by LC–MS, and a pharmacokinetic/ pharmacodynamic (PK/PD) relationship developed.

Key Results:

Perfused GSK2646264 significantly inhibited anti‐IgE (but not C5a)‐induced histamine release in a concentration‐dependent manner. The 0.5, 1, and 3% cream delivered GSK2646264 to the dermis above the IC90 and dose‐dependently attenuated anti‐IgE‐induced histamine release.

Conclusions and Implications:

GSK2646264 administered topically or direct to the dermis blocked histamine release from in situ skin mast cells. A PK/PD relationship curve suggests that dermal concentrations above 6.8 μM should lead to approximately 90% inhibition of histamine release from skin mast cells following activation of the Fc fragment of IgE receptor 1a, implicating a potential use for the compound in skin mast cell diseases such as urticaria.

100 项与 GSK-2646264 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
皮肤红斑狼疮	临床1期	德国	GSK Plc	2017-01-13
慢性荨麻疹	临床1期	德国	GSK Plc	2014-11-17
慢性荨麻疹	临床1期	英国	GSK Plc	2014-11-17
家族性寒冷性荨麻疹	临床1期	德国	GSK Plc	2014-11-17
家族性寒冷性荨麻疹	临床1期	英国	GSK Plc	2014-11-17