Single-blind, Randomised, Placebo-controlled Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Repeat Doses of GSK2647544 and Its Potential Pharmacokinetic Interaction With Simvastatin in Healthy Volunteers

GSK2647544 is an orally available, selective inhibitor of Lp PLA2 that is being developed for the treatment of Alzheimer's disease. The current study is a single-blind, randomised, placebo-controlled, 4-cohort study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of repeat doses of GSK2647544. Cohorts 1, 2 and 3 will evaluate escalating doses of GSK2647544 in young healthy volunteers for 7 days, 7 days, and 14 days, respectively. Cohort 4 will evaluate repeat doses of GSK2647544 in healthy elderly volunteers for 14 days. Additionally, Cohorts 1 and 3 will include an assessment of potential drug-drug interaction with simvastatin to examine CYP3A4 inhibition by GSK2647544.

开始日期2013-11-22

申办/合作机构

GSK Plc

NCT01924858 / Terminated临床1期

An Open Label Positron Emission Tomography (PET) Study to Investigate the Brain Biodistribution of 18F-GSK2647544 in Healthy Subjects

This is an open label, PET study in healthy male subjects to determine if GSK2647544 is able to cross the blood-brain-barrier. The study will use GSK2647544 radiolabelled with fluorine-18 ([18F] GSK2647544) to determine the ratio of the concentration of the compound in tissue to that in plasma at equilibrium, expressed as the PET volume of distribution (VT). The study will consist of at least four visits; 2 screening visits, scanning day and follow-up. On Day 1 (scanning day) the subject will receive a single oral dose of GSK2647544 (100 mg) followed approximately 2 hours later by a single intravenous (IV) infusion of [18F]-GSK2647544 and a dynamic PET scan. Arterial and venous blood sampling will be used to determine the plasma kinetics of [18F]-GSK2647544 and unlabeled GSK2647544. In addition, each subject will undergo a structural magnetic resonance imaging (MRI) scan of the brain to aid in the definition of neuroanatomy. The dose of GSK2647544 was selected based on the review of the safety, tolerability, pharmacokinetics (PK), and pharmacodynamic (PD) data obtained in the first time in human (FTIH) study.

开始日期2013-08-19

申办/合作机构

GSK Plc

NCT01702467 / Completed临床1期

A Single-Blind, Randomized, Placebo-Controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single, Oral Escalating Doses of GSK2647544 in Healthy Volunteers

The current study will examine the safety, tolerability, plasma pharmacokinetics (PK), and plasma pharmacodynamics (PD) of single-doses of GSK2647544.The study will be conducted as a randomized, single-blind, placebo controlled, 4-way crossover single oral ascending dose design in 2 independent cohorts, eight healthy male subjects in each of the cohorts. Each potential subject will undergo Screening visit, Treatment Phase and Follow-up visit.

开始日期2012-10-19

申办/合作机构

GSK Plc

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100 项与 GSK-2647544 相关的转化医学

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项与 GSK-2647544 相关的文献（医药）

2017-02-01·Molecular imaging and biology3区 · 医学

Investigation of the Brain Biodistribution of the Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitor [18F]GSK2647544 in Healthy Male Subjects

3区 · 医学

Article

作者: Buraglio, Mauro ; Lewis, Yvonne ; Rabiner, Eugenii A ; Passchier, Jan ; Guan, Chenbing ; Wu, Kai ; Fong, Regan ; Huiban, Mickael ; Coello, Christopher ; Shabbir, Shaila ; Xu, Yanmei ; Lockhart, Andrew ; Brown, Andrew P

PURPOSE:

GSK2647544 is a potent and specific inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), which was in development as a potential treatment for Alzheimer's disease (AD). In order to refine therapeutic dose predictions and confirm brain penetration, a radiolabelled form of the inhibitor, [¹⁸F]GSK2647544, was manufactured for use in a positron emission tomography (PET) biodistribution study.

PROCEDURES:

[¹⁸F]GSK2647544 was produced using a novel, copper iodide (Cu(I)) mediated, [¹⁸F]trifluoromethylation methodology. Healthy male subjects (n = 4, age range 34-42) received an oral dose of unlabelled GSK2647544 (100 mg) and after 2 h an intravenous (iv) injection of [¹⁸F]GSK2647544 (average injected activity and mass were 106 ± 47 MBq and 179 ± 55 μg, respectively) followed by dynamic PET scans for 120 min. Defined regions of interest (ROI) throughout the brain were used to obtain regional time-activity curves (TACs) and compartmental modelling analysis used to estimate the primary outcome measure, whole brain volume of distribution (V_T). Secondary PK and safety endpoints were also recorded.

RESULTS:

PET dynamic data were successfully obtained from all four subjects and there were no clinically significant variations of the safety endpoints. Inspection of the TACs indicated a relatively homogenous uptake of [¹⁸F]GSK2647544 across all the ROIs examined. The mean whole brain V_T was 0.56 (95 % CI, 0.41-0.72). Secondary PK parameters, C_max (geometric mean) and T_max (median), were 354 ng/ml and 1.4 h, respectively. Metabolism of GSK2647544 was relatively consistent across subjects, with 20-40 % of the parent compound [¹⁸F]GSK2647544 present after 120 min.

CONCLUSIONS:

The study provides evidence that GSK2647544 is able to cross the blood brain barrier in healthy male subjects leading to a measurable brain exposure. The administered doses of GSK2647544 were well tolerated. Exploratory modelling suggested that a twice-daily dose of 102 mg, at steady state, would provide ~80 % trough inhibition of brain Lp-PLA₂ activity.

TRIAL REGISTRATION:

Clintrials.gov: NCT01924858.

2016-12-01·International journal of clinical pharmacology and therapeutics

Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of GSK2647544 in healthy volunteers

Article

作者: Xu, Yanmei ; Guiney, William ; Yao, Xiaozhou ; Fong, Regan ; Xu, Jianfeng ; Gray, Frank ; Wu, Kai ; Lockhart, Andrew

OBJECTIVE:

To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor).

METHODS:

Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2.

RESULTS:

Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively.

CONCLUSIONS:

GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2. .

项与 GSK-2647544 相关的新闻（医药）

2022-06-01

·BioSpace

SciNeuro Pharmaceuticals Announces a License and Option Agreement with GSK to Progress Development of Novel Therapies for CNS Diseases

SHANGHAI and ROCKVILLE, Md., June 1, 2022 /PRNewswire/ -- SciNeuro Pharmaceuticals (SciNeuro), a leader in the discovery and development of innovative therapeutics for the treatment of CNS diseases, today announced the execution of an exclusive, worldwide license and option agreement with GlaxoSmithKline (GSK). The agreement focuses on inhibitors of Lp-PLA2, an enzyme that has been implicated in the pathogenesis of neurodegenerative diseases. Clinical findings suggest that inhibition of Lp-PLA2 activity may improve cognitive function in subjects with Alzheimer's disease.1 Under the agreement, SciNeuro will receive a worldwide license to intellectual property covering certain GSK Lp-PLA2 inhibitors and will be responsible for their further development through clinical proof-of-concept (PoC). Following the completion of the PoC studies, GSK has the option to reclaim rights to the compounds in all territories excluding Greater China, which SciNeuro would retain, under pre-agreed terms for subsequent development and commercialization. SciNeuro will pay an upfront fee, near-term and downstream milestones, and royalties to GSK. If GSK exercises its option, SciNeuro will receive an option exercise fee, downstream milestones, and royalty payments from GSK. In addition, GSK will have a right to purchase equity in SciNeuro. "We are excited to further the development of these novel Lp-PLA2 inhibitors. Given the critical role of Lp-PLA2 in CNS integrity and the demonstrated human pharmacology of Lp-PLA2 inhibition, we look forward to evaluating the clinical benefit of these Lp-PLA2 inhibitors in the treatment of CNS diseases," said Min Li, Ph.D., Founder and CEO of SciNeuro Pharmaceuticals. "We are pleased to enter into this agreement with SciNeuro that allows us to assess the clinical potential of these Lp-PLA2 inhibitors by leveraging SciNeuro's early development expertise in CNS disease," said John Lepore, M.D., SVP and Head of Research, at GSK. "This agreement enables us to focus on progressing our own internal assets, while maintaining pipeline optionality for the development of these Lp-PLA2 inhibitors in the future." About SciNeuro Pharmaceuticals SciNeuro Pharmaceuticals is an innovation-driven, neuroscience-focused biopharmaceutical company with an established pipeline of novel therapeutic candidates to address neurodegenerative and other CNS diseases. The company focuses on targets that are supported by human biology and which play a critical role in regulating foundation biology, to achieve better probability of success in clinical development. SciNeuro is committed to delivering medicines that can make a difference to improve the lives of patients around the world, transforming scientific discoveries into groundbreaking therapies. To learn more, visit . SciNeuro Media Contact: Jessie Yang, jessie.yang@scineuro.com 1 Maher-Edwards G, De'Ath J, Barnett C, Lavrov A, Lockhart A. A 24-week study to evaluate the effect of rilapladib on cognition and cerebrospinal fluid biomarkers of Alzheimer's disease. Alzheimers Dement (N Y). 2015;1(2):131-140.

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