Stride Velocity 95th Centile Detects Decline in Ambulatory Function Over Shorter Intervals than the 6-Minute Walk Test or North Star Ambulatory Assessment in Duchenne Muscular Dystrophy.

Background: Stride Velocity 95th Centile (SV95C) is the first wearable device-derived clinical outcome assessment (COA) to receive European Medicines Agency (EMA) qualification as a primary endpoint in ambulant patients with Duchenne muscular dystrophy (DMD) aged ≥4 years.

Objective: To compare SV95C-in its first-ever clinical trial application as a secondary endpoint-with established motor function COAs used in the trial (Four-Stair Climb [4SC] velocity, North Star Ambulatory Assessment [NSAA], and Six-Minute Walk Distance [6MWD]).

Methods: SV95C was a secondary endpoint in a subset (n = 47) of participants in the SPITFIRE/WN40227 trial of taldefgrobep alfa, which was discontinued due to lack of clinical benefit.

The Clinical Development of Taldefgrobep Alfa: An Anti-Myostatin Adnectin for the Treatment of Duchenne Muscular Dystrophy.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans.

Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials.

Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression.

Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD.

Design, Setting, And Participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD.

Disease Modification in Alzheimer's Disease: Current Thinking.

Alzheimer's disease (AD) has increasingly been recognized as a huge unmet medical need. Currently, there is no approved drug to cure, prevent, or even slow down the disease. It is imperative to develop disease-modifying treatments for AD to alter the underlying disease progression.

Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results.

Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials.

Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial.

Importance: Antagonism of the postsynaptic metabotropic glutamate subtype 5 receptor is a novel approach to modulate glutamatergic function and has proven efficacy in a number of preclinical behavioral models of depression.

Objective: To evaluate the safety and efficacy of basimglurant modified-release (MR) vs placebo as adjunctive therapy to ongoing antidepressant medication therapy in patients with MDD who had inadequate response within the current episode.

Design, Setting, And Participants: In this phase 2b, double blind, randomized clinical trial of 333 adult patients with a DSM-IV-TR diagnosis of MDD across 59 research clinics globally, patients were assigned to 1 of 2 doses of basimglurant MR (0.

Defining Regions in Multiregional Clinical Trials: An Analytical Approach to Considering Impact of Intrinsic and Extrinsic Factors.

Background: This article describes follow-up work extended from Tanaka et al (2011) in defining the region in multiregional clinical trials (MRCTs). The previous paper advocated a systematic approach to defining regions and recommended the sponsor to think through carefully, prespecify, and justify any regional definitions as well as obtain regulatory concurrence prior to study conduct. Particular attention was advised for intrinsic and extrinsic factors such as race/ethnicity, disease epidemiology, medical practice, and geographic proximity.

Effects of high dose aleglitazar on renal function in patients with type 2 diabetes.

Background: Aleglitazar is a new, balanced dual peroxisome proliferator-activated receptor (PPAR)α/γ agonist designed to optimize lipid and glycemic benefits and minimize PPAR-related adverse effects.

Methods: SESTA R was a 26-week, randomized, double-blind, multicenter study comparing the effects of a supratherapeutic dosage of aleglitazar (600 μg/day) with pioglitazone (45 mg/day) on change in measured GFR (mGFR) in 174 patients with type 2 diabetes and normal to mildly impaired renal function (estimated GFR [eGFR] 60 to 120 ml/min/1.73 m(2)).

Induction pegylated interferon alfa-2a and high dose ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads.

Background & Aims: Patients infected with hepatitis C virus (HCV) genotype 1, body weight ≥85 kg, and high baseline viral load respond poorly to standard doses of pegylated interferon (peginterferon) and ribavirin. We evaluated intensified therapy with peginterferon alfa-2a plus ribavirin.

Methods: This double-blind randomized trial included HCV genotype 1-infected outpatients from hepatology clinics with body weight ≥85 kg and HCV RNA titer ≥400,000 IU/mL.

Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study.

Background: Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar.

Methods: In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with View Article and Find Full Text PDF

Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.

A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT.