A Pilot Proteomic Analysis of Huntington's Disease by Functional Capacity.

The molecular biology of Huntington's Disease (HD) has grown substantially, with pathological considerations extending to genetic modifiers, epigenetic changes, transcriptomics, the proteome, and the metabolome. The metabolome and proteome are especially intriguing in that they most directly reflect the functional state of the cellular environment, which may involve some combination of pathology as well as compensation. We assessed CSF proteomics from eight participants by their functional severity (TFC range 3-13), with 47 proteins having a minimum r-value of 0.

Galantamine-Memantine Combination in the Treatment of Parkinson's Disease Dementia.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson's disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain.

Continuous Levodopa Delivery with an Intraoral Micropump System: An Open-Label Pharmacokinetics and Clinical Study.

Background: Double-blind studies have demonstrated that motor complications in Parkinson's disease (PD) can be reduced with continuous delivery of levodopa. The DopaFuse system is a novel, intraoral micropump that attaches to a retainer and uses a propellant to deliver levodopa/carbidopa (LD/CD) continuously into the mouth.

Objectives: Evaluate the safety, pharmacokinetics, and efficacy of LD/CD delivered via the DopaFuse system compared to treatment with intermittent doses of standard oral LD/CD in PD patients with motor fluctuations.

A Phase I, Randomized, SAD, MAD, and PK Study of Risvodetinib in Older Adults and Parkinson's Disease.

Background: Pre-clinical studies suggest that c-Abl activation may play an important role in the etiology of Parkinson's disease, making c-Abl an important target to evaluate for potential disease-modification.

Objective: To assess safety, tolerability, and pharmacokinetics of the c-Abl inhibitor risvodetinib (IkT-148009) in healthy subjects and participants with Parkinson's disease.

Methods: Part 1 (single ascending dose (SAD)) and Part 2 (7-day multiple ascending dose (MAD)) studies were in healthy volunteers.

An exploratory metabolomic comparison of participants with fast or absent functional progression from 2CARE, a randomized, double-blind clinical trial in Huntington's disease.

Huntington's disease (HD) is increasingly recognized for diverse pathology outside of the nervous system. To describe the biology of HD in relation to functional progression, we previously analyzed the plasma and CSF metabolome in a cross-sectional study of participants who had various degrees of functional impairment. Here, we carried out an exploratory study in plasma from HD individuals over a 3-year time frame to assess whether differences exist between those with fast or absent clinical progression.

Safety, tolerability, and efficacy of NLY01 in early untreated Parkinson's disease: a randomised, double-blind, placebo-controlled trial.

Background: Converging lines of evidence suggest that microglia are relevant to Parkinson's disease pathogenesis, justifying exploration of therapeutic agents thought to attenuate pathogenic microglial function. We sought to test the safety and efficacy of NLY01-a brain-penetrant, pegylated, longer-lasting version of exenatide (a glucagon-like peptide-1 receptor agonist) that is believed to be anti-inflammatory via reduction of microglia activation-in Parkinson's disease.

Methods: We report a 36-week, randomised, double-blind, placebo-controlled study of NLY01 in participants with early untreated Parkinson's disease conducted at 58 movement disorder clinics in the USA.

A Randomized Phase 3 Study Comparing P2B001 to its Components (Low-Dose Extended-Release Rasagiline and Pramipexole) and to Optimized Doses of Marketed Extended-Release Pramipexole in Early Parkinson's Disease.

Background: There remains uncertainty as to the optimal way to initiate therapy for Parkinson's disease (PD) to maximize benefit and minimize adversity.

Objectives: The objective was to determine if P2B001 (a fixed, low-dose, extended-release [ER] combination of pramipexole 0.6 mg and rasagiline 0.

Adaptive clinical trials and master protocols.

Methodologies for randomized, double-blind, placebo-controlled clinical trials continue to develop in concert with evolving scientific and translational knowledge. Adaptive trial designs, in which data generated during the study are used to modify subsequent study activity (i.e.

Cross-sectional analysis of plasma and CSF metabolomic markers in Huntington's disease for participants of varying functional disability: a pilot study.

Huntington's Disease (HD) is a progressive, fatal neurodegenerative condition. While generally considered for its devastating neurological phenotype, disturbances in other organ systems and metabolic pathways outside the brain have attracted attention for possible relevance to HD pathology, potential as therapeutic targets, or use as biomarkers of progression. In addition, it is not established how metabolic changes in the HD brain correlate to progression across the full spectrum of early to late-stage disease.

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability.

Effects of Pridopidine on Functional Capacity in Early-Stage Participants from the PRIDE-HD Study.

Background: No pharmacological treatment has been demonstrated to provide a functional benefit for persons with Huntington's disease (HD). Pridopidine is a sigma-1-receptor agonist shown to have beneficial effects in preclinical models of HD.

Objective: To further explore the effect of pridopidine on Total Functional Capacity (TFC) in the recent double-blind, placebo-controlled PRIDE-HD study.

A New Approach to the Development of Disease-Modifying Therapies for PD; Fighting Another Pandemic.

A disease-modifying therapy that slows disease progression and development of disability is the major unmet need in the treatment of Parkinson's disease. Recent scientific advances suggest many promising and exciting new interventions. However, despite these opportunities, the cost, time and uncertainty of being able to receive an indication as a disease-modifying therapy has caused many pharmaceutical companies to abandon development of potentially disease-modifying drugs.

Additional Safety and Exploratory Efficacy Data at 48 and 60 Months from Open-HART, an Open-Label Extension Study of Pridopidine in Huntington Disease.

Background: Open-HART was an open-label extension of HART, a randomized, double-blind, placebo-controlled study of pridopidine in Huntington disease (HD). Previously, we reported safety and exploratory efficacy data after 36 months of treatment with pridopidine 45 mg twice daily. In the interim, emerging data suggests pridopidine may have neuroprotective effects mediated by sigma-1 receptor agonism.

Baseline Variables Associated with Functional Decline in 2CARE, A Randomized Clinical Trial in Huntington's Disease.

Background: Despite the clearly recognized progressive functional decline of Huntington's disease (HD), detailed investigations of factors associated with the rate of functional progression are limited.

Objective: Understanding factors associated with functional decline through examination of existing HD clinical databases may improve efforts to mitigate it.

Methods: We analyzed data from 2CARE, a randomized clinical trial with up to 5 years of follow-up, to assess potential risk factors for more rapid functional decline in HD.

Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study.

Background: Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability.

Methods: PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA).

Preclinical motor manifestations of Huntington disease.

Huntington disease (HD) is an autosomal-dominant, progressive neurodegenerative condition characterized by multiple movement disorders, psychiatric disturbances, and cognitive decline. As an insidious, progressive disorder, clinical phenoconversion in HD can be quite subtle and difficult to pinpoint. In light of this ambiguity, substantial interest has developed in HD research for biomarker identification, with the intent of establishing specific changes or "stages" of disease progression.

Safety and Exploratory Efficacy at 36 Months in Open-HART, an Open-Label Extension Study of Pridopidine in Huntington's Disease.

Background: Open-HART is an open-label extension of HART, a randomized, placebo-controlled, dose-ranging, parallel-group study.

Objective: To evaluate safety and exploratory efficacy of open-label pridopidine over 36 months in subjects with Huntington's disease (HD).

Methods: Open-HART subjects were treated with pridopidine 45 mg twice daily (BID).

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease.

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD.

Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012.

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity.

Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease.

Design, Setting, And Participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites.