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, subsequent to an IND to be filed by 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 α3β4 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 α4β2 nAChR. However, several aspects of nicotine dependence in humans, particularly poor abstinence rates and frequent relapse, are poorly addressed by current pharmacotherapy, 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 α3β4 subtype is strongly correlated with several aspects of nicotine dependence and that polymorphisms in the genes for the α3, α5 and β4 nAChRs, are associated with heavy smoking, inability to quit, and increased sensitivity to nicotine during abstinence. Supporting these genetic findings, functional activation of β4 nAChR was shown to restore a ‘stop’ signal on nicotine reward, suggesting an intriguing explanation for the remarkable efficacy of Astraea’s α3β4-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 α3β4-selective drug candidate from the α4β2- 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 preIND 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, and 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 a relapse and improving abstinence rates.
