# DEVELOPMENT OF A NOVEL DRUG CANDIDATE WITH A FIRST-in-CLASS MECHANISM FOR SMOKING CESSATION, RELAPSE and ABSTINENCE

> **NIH NIH U01** · ASTRAEA THERAPEUTICS, LLC · 2020 · $646,565

## Abstract

ABSTRACT
 This application, in response to PAR-18-219 `Grand Opportunity in Medications Development for
Substance-use Disorders', proposes to advance the IND-enabling development of a novel small-molecule drug
candidate with a novel first-in-class mechanism as pharmacotherapy for smoking cessation, relapse prevention
and longterm abstinence. Relapse to smoking is very common after initial abstinence with pharmacotherapy
and represents a major clinical challenge. 24-week abstinence rates for all three available pharmacotherapies
is still poor and averages only 22% for varenicline, 16% for bupropion, and 16% for nicotine replacement
therapies, compared to 9% for placebo. These poor abstinence rates with current pharmacotherapies are
inadequate for overall tobacco harm reduction, given that tobacco use still remains the leading preventable
cause of death and morbidity in the developed world. Despite the clear need and possible high impact, there
have been no new pharmacotherapy approved for smoking cessation for over a decade since varenicline's
approval. There is a crucial need for new approaches and new pharmacotherapy that reduce craving and
relapse and can promote sustained abstinence. This application aims to advance the IND development of a
novel pharmacotherapeutic with a new first-in-class mechanism for relapse prevention and smoking cessation,
that has shown distinctive preclinical efficacy in decreasing cue-induced, stress-induced and nicotine-induced
relapse and nicotine self-administration. The lead drug candidate is a new molecular entity targeting a new
pharmacological mechanism, the α3β4 nicotinic acetylcholine receptor (nAChR). The α3β4 nAChR clearly
plays a role in nicotine dependence and drug relapse mechanisms, and genome-wide association studies in a
large population of smokers reveal that polymorphisms in the genes encoding the α3, β4 and α5 subunits of
the nAChR are linked to increases in risk for nicotine dependence and inability to quit. The lead candidate
proposed for development is selected from a novel series of highly potent and selective α3β4 nAChR ligands,
which to our knowledge, are some of the most selective α3β4 nAChR ligands reported. Importantly, their
excellent in vivo efficacy for blocking reinstatement of nicotine seeking (a model of relapse), strongly suggests
that targeting the α3β4 nAChR may provide a superior profile over existing treatments, particularly for
improving longterm abstinence and preventing relapse. We have completed several preclinical toxicology and
DMPK studies that confirm the suitability of the lead candidate for IND-enabling studies. We propose to
continue the development and file an IND to enable the assessment of the safety and efficacy of this first-in-
class mechanism in human clinical trials. With our results thus far, we anticipate that we will be able to
advance the future clinical development of this drug candidate into a successful smoking cessation medication
and a safe effective...

## Key facts

- **NIH application ID:** 9985784
- **Project number:** 5U01DA047791-03
- **Recipient organization:** ASTRAEA THERAPEUTICS, LLC
- **Principal Investigator:** Nurulain T Zaveri
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $646,565
- **Award type:** 5
- **Project period:** 2018-09-30 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985784

## Citation

> US National Institutes of Health, RePORTER application 9985784, DEVELOPMENT OF A NOVEL DRUG CANDIDATE WITH A FIRST-in-CLASS MECHANISM FOR SMOKING CESSATION, RELAPSE and ABSTINENCE (5U01DA047791-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985784. Licensed CC0.

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