U01DA054882

First-in-Human Clinical Development of a Novel Drug Candidate with a First-in-Class Mechanism for Smoking Cessation and Abstinence - Abstract

This application, in response to PAR-19-327 'Grand Opportunity in Medications Development for Substance-Use Disorders', proposes to advance the development of a novel smoking cessation pharmacotherapy into First-in-Human (FIH) Phase 1 and early Phase 2A efficacy clinical trials. This will be done subsequent to an IND to be filed by the end of Q1 of 2021, on our current medication development project U01DA047791.

On this ongoing U01 project, AstraEA Therapeutics advanced the IND-enabling development of a novel small-molecule drug candidate with a first-in-class pharmacological mechanism targeting the A3SS4 nicotinic acetylcholine receptor (nAChR) subtype. Targeting nAChRs, the primary target for nicotine's addictive actions, has proven to be a successful clinical approach for smoking cessation, exemplified by the success of varenicline (ChantixTM), a nAChR partial agonist targeted to the A4SS2 nAChR.

However, several aspects of nicotine dependence in humans, particularly poor abstinence rates and frequent relapse, are poorly addressed by current pharmacotherapy. This is indicated by the fact that fewer than half of smokers motivated to quit are able to do so by the end of treatment, and even fewer can maintain long-term abstinence (high rate of relapse).

Human genetic association studies have shown that other nAChR subtypes, especially the A3SS4 subtype, are strongly correlated with several aspects of nicotine dependence. Polymorphisms in the genes for the A3, A5, and SS4 nAChRs are associated with heavy smoking, inability to quit, and increased sensitivity to nicotine during abstinence. Supporting these genetic findings, functional activation of SS4 nAChR was shown to restore a 'stop' signal on nicotine reward, suggesting an intriguing explanation for the remarkable efficacy of AstraEA's A3SS4-selective partial agonist drug candidate in decreasing nicotine self-administration in rats.

Even more importantly, the significant inhibition of drug-induced, stress-induced, and cue-induced reinstatement of nicotine-seeking (an animal model of relapse) shown by this lead compound at doses lower than those blocking nicotine intake is a novel finding that distinguishes this A3SS4-selective drug candidate from the A4SS2-selective drug varenicline, which is less potent or inactive in blocking reinstatement to nicotine seeking in animal relapse models. This latter efficacy in relapse differentiates AstraEA's novel approach from varenicline and bupropion, which do not block relapse.

We successfully achieved all milestones on our current medication development project and have also completed a pre-IND meeting with the FDA for agreement on our nonclinical definitive tox package to support the proposed clinical development.

The objective of this grant is to advance the clinical development of AT-1082 in Phase 1 single- and multiple-ascending dose (SAD/MAD) FIH trials to assess the safety, tolerability, and pharmacokinetic (PK) profile in humans. Additionally, we aim to conduct an efficient early Phase 2 trial using a crossover procedure that will provide an early readout of medication efficacy for smoking cessation and a go/no-go decision to advance this novel first-in-class candidate to subsequent larger randomized Phase 2 trials.

The project has an experienced drug development team that has successfully advanced this project to IND filing and can support the proposed clinical development. If proven safe, well-tolerated, and efficacious, this drug candidate has the potential for a clinical profile that could possibly be superior to the existing repertoire of smoking cessation medications and can make a real impact on the treatment of nicotine addiction, particularly by reducing the risk of relapse and improving abstinence rates.

Astraea Therapeutics

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

California United States

State-Wide

Grand Opportunity in Medications Development for Substance-Use Disorders (U01 Clinical Trial Optional) (PAR-19-327)

Amendment Since initial award the End Date has been extended from 04/30/24 to 04/30/26 and the total obligations have increased 180% from $2,007,282 to $5,613,363.