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

Award Number: U01DA047791
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2022

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DEVELOPMENT OF A NOVEL DRUG CANDIDATE WITH A FIRST-in-CLASS MECHANISM FOR SMOKING CESSATION, RELAPSE and ABSTINENCE - 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 option for quitting and sustaining long-term abstinence.


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: 2024 ( Subtotal = $0 )
2024	2020	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	3	11/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	3	6/20/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $646,565 )
2020	2020	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	001	3	7/24/2020	NON-COMPETING CONTINUATION	$646,565
2020	2019	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	2	7/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $646,565

Issue Date FY: 2019 ( Subtotal = $2,158,836 )
2019	2019	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	001	2	7/30/2019	NON-COMPETING CONTINUATION	$2,158,836
2019	2018	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	1	10/23/2018	NEW	$0
														Subtotal = $2,158,836

Issue Date FY: 2018 ( Subtotal = $1,141,152 )
2018	2018	ASTRAEA THERAPEUTICS LLC	20170 SEA GULL WAY	SARATOGA	CA	95070	SANTA CLARA	USA	Drug Use and Addiction Research Programs	000	1	9/19/2018	NEW	$1,141,152
														Subtotal = $1,141,152

Grand Total All Awards = $3,946,553

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

Award Number: U01DA047791

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/30/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2022

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