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PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES

Award Number: R44DA033744
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2014
PERIOD OF PERFORMANCE END DATE: 02/28/2018

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PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES - DESCRIPTION (provided by applicant): The goal of the proposed Phase II SBIR is to advance a novel class of alpha3beta4 nicotinic acetylcholine receptor antagonists (new molecular entities), which show excellent in vivo efficacy in blocking nicotine self- administratio and reinstatement of nicotine seeking, towards development as smoking cessation therapy. We have discovered a series of highly potent alpha3beta4 nAChR functional antagonists, all of which have single-digit nanomolar binding affinity and >100-fold target selectivity versus the closely related 42 and 7 nAChR subtypes. In our successful Phase I effort, we showed that three lead compounds from this series not only significantly block nicotine self-administration in rats, at low doses, without effect on food responding, but also block reinstatement of nicotine seeking, an animal model of relapse. The significant efficacy of these selective alpha3beta4 nAChR ligands strongly suggests that alpha3beta4 nAChR functional antagonism' is a promising pharmacological mechanism for smoking cessation pharmacotherapy. We have achieved all of the Aims of our Phase I SBIR and conducted additional studies to support the suitability of this class of compounds for further drug development. We now seek Phase II support to advance an optimized set of lead candidates, through a series of 'de-risking' experiments, with the goal of selecting a 'development candidate' for the proposed indication (smoking cessation). A second goal is to position at least one other compound in our series as backup for the same indication or as a future development candidate for other indications. In Aim 1, we will scale-up (non-GMP) a panel of optimized alpha3beta4 nAChR ligands for preformulation and development activities. In Aim 2, the development candidates will be characterized in a series of ADME studies and PK in two species. In Aim 3, confirmation of oral efficacy of the selected candidates will be determined in a rat model of nicotine self-administration and reinstatement of nicotine-seeking. In Aim 4, we will carry out detailed safety pharmacology and early toxicology studies including GLP cardiovascular safety for dog, functional observational battery and Range-finding toxicology in two species. The desired outcome of this project will be the selection of the most suitable 'development candidate', which will be immediately ready for definitive GLP toxicology studies for an IND submission and advancement as smoking cessation pharmacotherapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2015	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	3	8/28/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	001	3	5/4/2017	SUPPLEMENT FOR EXPANSION	$0
2017	2015	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	3	5/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $5,000 )
2016	2016	ASTRAEA THERAPEUTICS LLC	320 LOGUE AVE	MOUNTAIN VIEW	CA	94043	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	3	5/12/2016	SUPPLEMENT FOR EXPANSION	$5,000
														Subtotal = $5,000

Issue Date FY: 2015 ( Subtotal = $742,129 )
2015	2015	ASTRAEA THERAPEUTICS LLC	320 LOGUE AVE	MOUNTAIN VIEW	CA	94043	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	3	5/6/2015	NON-COMPETING CONTINUATION	$742,129
														Subtotal = $742,129

Issue Date FY: 2014 ( Subtotal = $757,870 )
2014	2014	ASTRAEA THERAPEUTICS LLC	320 LOGUE AVE	MOUNTAIN VIEW	CA	94043	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	2	5/13/2014	COMPETING CONTINUATION	$757,870
														Subtotal = $757,870

Grand Total All Awards = $1,504,999

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PRECLINICAL DEVELOPMENT OF NOVEL SMOKING CESSATION PHARMACOTHERAPIES

Award Number: R44DA033744

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2014

PERIOD OF PERFORMANCE END DATE: 02/28/2018

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