Dataset Information

First-in-human assessment of PRX002, an anti-?-synuclein monoclonal antibody, in healthy volunteers.

ABSTRACT: ?-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets ?-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce ?-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human ?-synuclein transgenic mice.This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study assessed the impact of PRX002 administered to 40 healthy participants in 5 ascending-dose cohorts (n?=?8/cohort) in which participants were randomly assigned to receive a single intravenous infusion of study drug (0.3, 1, 3, 10, or 30?mg/kg; n?=?6/cohort) or placebo (n?=?2/cohort).PRX002 demonstrated favorable safety, tolerability, and pharmacokinetic profiles at all doses tested, with no immunogenicity. No serious adverse events, discontinuations as a result of adverse events, or dose-limiting toxicities were reported. Serum PRX002 exposure was dose proportional; the average terminal half-life across all doses was 18.2 days. A significant dose-dependent reduction in free serum ?-synuclein (unbound to PRX002) was apparent within 1 hour after PRX002 administration, whereas total ?-synuclein (free plus bound) increased dose-dependently, presumably because of the expected change in kinetics following antibody binding.This study demonstrates that serum ?-synuclein can be safely modulated in a dose-dependent manner after single intravenous infusions of an anti-?-synuclein antibody. These findings support continued development of PRX002, including further characterization of its safety, tolerability, pharmacokinetics, and pharmacodynamic effects in the central nervous system in patients with Parkinson's disease. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

SUBMITTER: Schenk DB

PROVIDER: S-EPMC5324684 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.

Schenk Dale B DB Koller Martin M Ness Daniel K DK Griffith Sue G SG Grundman Michael M Zago Wagner W Soto Jay J Atiee George G Ostrowitzki Susanne S Kinney Gene G GG

Movement disorders : official journal of the Movement Disorder Society 20161125 2

<h4>Background</h4>α-Synuclein is a major component of pathologic inclusions that characterize Parkinson's disease. PRX002 is an antibody that targets α-synuclein, and its murine parent antibody 9E4 has been shown in preclinical studies to reduce α-synuclein pathology and to protect against cognitive and motor deteriorations and progressive neurodegeneration in human α-synuclein transgenic mice.<h4>Methods</h4>This first-in-human, randomized, double-blind, placebo-controlled, phase 1 study asses ...[more]

PMID: 27886407

Similar Datasets

Project description:AimsGlucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial.MethodsHealthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose-lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges.ResultsREGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC0-90 minutes ) by 80% to 90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups.ConclusionREGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.

Project description:IntroductionNerve growth factor plays a key role in the pathology of osteoarthritis (OA) related chronic pain. The aim of these studies was to evaluate the safety, tolerability, pharmacokinetics, and clinical response of AMG 403, a human anti-nerve growth factor monoclonal antibody, in healthy volunteers and subjects with knee OA.MethodsTwo phase I, randomized, placebo-controlled, double-blind studies were conducted. The single-ascending dose study randomized healthy volunteers (n = 48) 3:1 to receive AMG 403 (1, 3, 10, or 30 mg intravenously; or 10 or 30 mg subcutaneously; n = 8 per group) or placebo. The multiple-ascending dose study randomized knee OA subjects (n = 18) 3:1 to receive AMG 403 (3, 10, or 20 mg subcutaneously once monthly for four doses) or placebo. Safety, tolerability, and pharmacokinetics (PK) were assessed for both studies. Patient's and physician's disease assessments and total WOMAC score were determined in knee OA subjects.ResultsAMG 403 appeared to be well-tolerated after single and multiple doses, except for subject-reported hyperesthesia, pain, and paresthesia (mild to moderate severity). These treatment-emergent neurosensory events showed evidence of reversibility and a possible dose-dependence. Three serious adverse events were reported in AMG 403 treated subjects, but were not considered treatment related. AMG 403 PK was linear with an estimated half-life of 19.6 to 25.8 days. After multiple doses, AMG 403 PK showed modest accumulation (≤2.4-fold increase) in systemic exposure. Knee OA diagnosis, body weight, and anti-drug antibody development did not appear to affect AMG 403 PK. Patient's and physician's disease assessments and total WOMAC score showed improvement in AMG 403 treated knee OA subjects compared with placebo.ConclusionsAMG 403 was generally safe and well-tolerated in both healthy volunteers and knee OA patients, and exhibited linear pharmacokinetics. Preliminary clinical efficacy was observed in knee OA subjects.Trial registrationClinicalTrials.gov NCT02348879 . Registered 23 December 2014. Clintrials.gov NCT02318407 . Registered 2 December 2014.

Dataset Information

First-in-human assessment of PRX002, an anti-?-synuclein monoclonal antibody, in healthy volunteers.

Publications

First-in-human assessment of PRX002, an anti-α-synuclein monoclonal antibody, in healthy volunteers.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets