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First-in-human SAD & MAD trials for MW151, a novel Alzheimer's disease drug candidate that attenuates proinflammatory cytokine dysregulation

人类首例 SAD

基本信息

批准号：
10061521
负责人：
LINDA J VAN ELDIK
金额：
$ 119.36万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10061521
关键词：
Address Adult Age Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Amyloid beta-Protein Animal Model Animals Anti-Inflammatory Agents Arts Attenuated Award Bioavailable Brain Canis familiaris Cardiovascular system Central Nervous System Diseases Characteristics Chemicals Clinical Clinical Investigator Clinical Protocols Clinical Trials Coenzyme A Data Development Disease Disease Progression Dose Drug Kinetics Elderly Exhibits Formulation Functional disorder Funding Future Homeostasis Human Immunosuppression Impaired cognition Individual Inflammation Inflammatory Injury Intravenous Investigational Drugs Maximum Tolerated Dose Measures Metabolic Modeling Nerve Degeneration Neurodegenerative Disorders Neuroglia Oral Outcome Pamphlets Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Pharmacology and Toxicology Phase Phase I Clinical Trials Phase Ib Clinical Trial Plasma Population Predisposition Public Health Rattus Risk Route Safety Synapses Testing Therapeutic Toxicology analog base clinical development cohort cytokine design dose information drug candidate effective therapy first-in-human genotoxicity healthy volunteer neuroinflammation novel novel therapeutic intervention phase 1 study physical property pre-clinical preclinical development prevent respiratory restoration safety study small molecule stressor success volunteer

项目摘要

ABSTRACT There are no approved disease-modifying drugs to prevent, delay, or slow disease progression of Alzheimer's disease (AD) and related dementias. The overwhelming majority of AD clinical trials targeted the beta-amyloid pathway with disappointingly ineffective outcomes in >99% of the studies. Therefore, there is an urgent need to diversify the portfolio of disease modifying approaches that are distinct from prior art. Our unbiased discovery strategy for the campaign described here focused on targeting a particular form of dysregulated inflammation, injurious proinflammatory cytokine overproduction in the brain, that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. We seek funding for the required phase 1 clinical safety studies of MW01-2-151SRM (=MW151). MW151 is a novel, CNS-penetrant, orally bioavailable, small molecule candidate that selectively suppresses stressor-induced proinflammatory cytokine overproduction. MW151 ameliorates synaptic damage and cognitive impairment at low doses in diverse animal models where proinflammatory cytokine dysregulation is established as a contributor to disease progression. MW151 has no liabilities in investigational new drug (IND)-enabling safety pharmacology and toxicology tests such as respiratory and cardiovascular safety pharmacology, rat and dog 28-day repeat administration toxicology, and genotoxicity. The low risk aspect of MW151 safety is reinforced by an analog developed for the demanding intravenous route of administration and its progression through phase 1a and promising status in phase 1b. We hypothesize that MW151 will be a successful oral candidate for future treatment of individuals with MCI/AD. This application seeks to progress through the required first-in-human (FIH) safety clinical trials. Our specific aims are: Aim 1: Conduct a first-in-human (FIH) phase 1a single ascending dose (SAD) study. This study will determine safety and tolerability, maximum tolerated dose, and pharmacokinetics (PK) of MW151 in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 2a clinical trials. Aim 2: Conduct a phase 1b multiple ascending dose (MAD) study of MW151. This study will determine safety and tolerability, maximum tolerated dose, and PK of MW151 in healthy adult volunteers. In addition, a cohort of elderly healthy subjects and exploratory PD inflammatory cytokine endpoints in CSF will be included. Aim 3: Prepare clinical protocol and investigators brochure for a future phase 2a clinical trial of MW151 in early AD. Based on the outcomes of the proposed phase 1 studies, we will design a phase 2a trial and prepare the documents required. This will allow immediate progress to future FIP studies for AD. Overall, MW151 represents a unique opportunity for development as a first-in-class disease-modifying therapeutic.

摘要