Dataset Information

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study.

ABSTRACT: BACKGROUND:The addition of alirocumab (a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 [PCSK9]) to background statin therapy provides significant incremental low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular event risk reduction. OBJECTIVES:Our objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of alirocumab in healthy Chinese subjects. METHODS:In this double-blind, placebo-controlled, phase I study, 35 Chinese subjects (aged 21-45 years) with baseline LDL-C?>?100 mg/dL (2.59 mmol/L) were randomized to receive a single 1 mL subcutaneous injection of alirocumab 75, 150, or 300 mg, or placebo, and followed up for ~?12 weeks. RESULTS:Treatment-emergent adverse events, most frequently nasal congestion and dry throat, were reported in three of seven or eight subjects in each alirocumab dose group (two of seven in the placebo group). One patient receiving alirocumab 300 mg had a mild local injection-site reaction. No alirocumab recipients demonstrated antidrug antibodies. Maximum alirocumab serum concentrations (6-34 mg/dL) occurred at a median of 3-7 days across the dose groups. Maximum mean LDL-C reductions from baseline were observed on days 8, 15, and 22 with alirocumab 75 (55.3%), 150 (63.7%), and 300 mg (73.7%), respectively. Mean free PCSK9 levels were reduced to below the lower limit of quantification within 4 h of dosing. Total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were reduced with alirocumab. CONCLUSIONS:In Chinese subjects, alirocumab 75, 150, and 300 mg was safe and well-tolerated. Pharmacokinetic/pharmacodynamic parameters, including clinically meaningful reductions in LDL-C and other lipids/lipoproteins, were consistent with data from Japanese and Western populations. Clinicaltrials.gov identifier: NCT02979015.

SUBMITTER: Li H

PROVIDER: S-EPMC7548281 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study.

Li Haiyan H Wei Yudong Y Yang Zhenhua Z Zhang Shuang S Xu Xiuxiu X Shuai Mengmeng M Vitse Olivier O Wu Yiwen Y Baccara-Dinet Marie T MT Zhang Yi Y Li Jianyong J

American journal of cardiovascular drugs : drugs, devices, and other interventions 20201001 5

<h4>Background</h4>The addition of alirocumab (a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 [PCSK9]) to background statin therapy provides significant incremental low-density lipoprotein cholesterol (LDL-C) lowering and cardiovascular event risk reduction.<h4>Objectives</h4>Our objectives were to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of alirocumab in healthy Chinese subjects.<h4>Methods</h4>In this ...[more]

PMID: 32080823

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Project description:IntroductionThis randomized, double-blind, placebo-controlled study in healthy volunteers assessed the safety, tolerability, and pharmacokinetics of single ascending doses of intravenously administered NX210-a linear peptide derived from subcommissural organ-spondin-and explored the effects on blood/urine biomarkers and cerebral activity.MethodsParticipants in five cohorts (n = 8 each) were randomized to receive a single intravenous dose of NX210 (n = 6 each) (0.4, 1.25, 2.5, 5, and 10 mg/kg) or placebo (n = 2 each); in total, 10 and 29 participants received placebo and NX210, respectively. Blood samples were collected for pharmacokinetics within 180 min post dosing. Plasma and urine were collected from participants (cohorts: 2.5, 5, and 10 mg/kg) for biomarker analysis and electroencephalography (EEG) recordings within 48 h post dosing. Safety/tolerability and pharmacokinetic data were assessed before ascending to the next dose.ResultsThe study included 39 participants. All dosages were safe and well tolerated. All treatment-emergent adverse events (n = 17) were of mild severity and resolved spontaneously (except one with unknown outcome). Twelve treatment-emergent adverse events (70.6%) were deemed drug related; seven of those (58.3%) concerned nervous system disorders (dizziness, headache, and somnolence). The pharmacokinetic analysis indicated a short half-life in plasma (6-20 min), high apparent volume of distribution (1870-4120 L), and rapid clearance (7440-16,400 L/h). In plasma, tryptophan and homocysteine showed dose-related increase and decrease, respectively. No drug dose effect was found for the glutamate or glutamine plasma biomarkers. Nevertheless, decreased blood glutamate and increased glutamine were observed in participants treated with NX210 versus placebo. EEG showed a statistically significant decrease in beta and gamma bands and a dose-dependent increasing trend in alpha bands. Pharmacodynamics effects were sustained for several hours (plasma) or 48 h (urine and EEG).ConclusionNX210 is safe and well tolerated and may exert beneficial effects on the central nervous system, particularly in terms of cognitive processing.

Project description:BackgroundAmyloid beta protein (Aβ) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.MethodsDouble-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.ResultsFrom June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.ConclusionsPosiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.Trial registrationNCT02925650 on clinicaltrials.gov (registered on 10-24-2016).

Project description:BackgroundAmyloid beta protein (Aβ) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.MethodsDouble-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) with positive CSF biomarkers were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 hours. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.ResultsFrom June 2017 to December 2021, 19 participants were enrolled, in dose cohorts (6 active: 2 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs placebo groups.ConclusionsPosiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.Trial registrationNCT02925650 on clinicaltrials.gov.

Project description:BACKGROUND:Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, a cytokine essential for the formation, function and survival of osteoclasts. This study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose denosumab (60 and 120 mg) in healthy Chinese volunteers. METHODS:This randomized (3:3:2), single-blind, placebo-controlled study enrolled healthy Chinese volunteers to receive single subcutaneous injection of denosumab 60 mg, 120 mg, or placebo. Study consisted of screening period (up to 21 days), treatment and assessment period (19 weeks), and an end-of-study visit (at week 26). Denosumab pharmacokinetics and pharmacodynamics parameters were estimated using non-compartmental analysis. Safety and tolerability were assessed throughout the study. RESULTS:A total of 63 volunteers received the study treatment and 62 (98.4%) completed the study. Denosumab serum concentrations peaked at around Day 10 with dose-proportional increase from 60 mg to 120 mg. The mean terminal half-life of denosumab 60 mg and 120 mg was 15 days and 26 days, respectively. The serum C-terminal cross-linking telopeptide of type I collagen concentration-time profiles were similar (>80% decrease within 5 days) between denosumab 60 mg and 120 mg groups. The most commonly reported adverse event (AE) was decreased blood calcium levels (denosumab 60 mg, n = 13; denosumab 120 mg, n = 13; placebo, n = 1); however only one volunteer had calcium level below the abnormality value of potential clinical importance and none of the volunteers developed symptoms of hypocalcemia. The majority of AEs were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. No clinically significant findings in vital signs or electrocardiogram were observed. CONCLUSIONS:Both denosumab 60 mg and 120 mg were well tolerated with no new safety concerns identified in healthy Chinese volunteers with similar pharmacokinetics and pharmacodynamics profiles to that of Caucasians. TRIAL REGISTRATION:ClinicalTrial.gov NCT02135640.

Dataset Information

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study.

Publications

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Alirocumab in Healthy Chinese Subjects: A Randomized, Double-Blind, Placebo-Controlled, Ascending Single-Dose Study.

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