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Using in-vivo Real-time Biosensor to Evaluate Prodrugs Designed to Prolong Therapeutic Effects for Smoking Cessation.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DA056334-01A1
Agency Tracking Number: R41DA056334
Amount: $318,605.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIDA
Solicitation Number: PA21-262
Timeline
Solicitation Year: 2021
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-04-01
Award End Date (Contract End Date): 2023-12-31
Small Business Information
11760 SUNRISE VALLEY DR APT 615
Reston, VA 20191-1429
United States
DUNS: 118135125
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: Yes
Principal Investigator
 PETER LEE
 (202) 556-1971
 peter@spacerx.xyz
Business Contact
 PETER LEE
Phone: (202) 556-1971
Email: peter@spacerx.xyz
Research Institution
 UNIVERSITY OF PENNSYLVANIA
 
3451 WALNUT STREET
PHILADELPHIA, PA 19104-6205
United States

 Nonprofit College or University
Abstract

ABSTRACT
Developing drugs that target the central nervous system (CNS) is hampered by an inability to perform direct in
vivo preclinical measurements. Here, we propose to identify an optimal smoking cessation drug candidate by
monitoring how our newly synthesized prodrugs alter real-time brain dopamine responses to nicotine.
Varenicline (CHANTIX®) is the leading FDA-approved oral medication for smoking cessation. However, only
22% of patients maintain abstinence for 52 weeks following varenicline treatment1 and 67% of patients stop
treatment prematurely2, suggesting that therapies with better patient compliance are needed. To address this
need, we recently developed extended-release prodrugs that are designed to improve the pharmacokinetic
properties of varenicline. Varenicline reduces nicotine craving and use by dual action: first providing a transient
increase in dopamine levels and subsequently by blocking the dopamine response to nicotine3-5. These
changes aim to stabilize dopamine signaling in the brain to achieve two goals: (1) reduce the side effects of
transiently dopamine increases and (2) prolong the duration with which the drug reduces the reward value of
nicotine. In this Phase I grant, we will use an in vivo dopamine biosensor to evaluate real-time dopamine levels
in the striatum (a reward center in the brain) following administration of our novel prodrugs. We will establish
an in vivo relationship between brain efficacy (as defined by dopamine release) and drug levels in circulation.
These studies will allow us to screen for prodrugs that have optimal efficacy for altering both the level and
duration of dopamine response, which we use as a biomarker for predicting efficacy for smoking cessation.
The primary hypothesis of this Phase I grant is that a prodrug that stabilizes the initial dopamine release in the
striatum while also more efficiently blocking subsequent dopamine responses to nicotine will be more effective
than varenicline at decreasing IV self-administration of nicotine. We will test this hypothesis by: 1) establishing
pharmacokinetics for each prodrug relative to varenicline; 2) measuring striatal dopamine levels using real-time
in vivo biosensors to determine how different exposure curves affect dopamine response; and 3) assessing
behavioral changes in response to the prodrugs using a well-established nicotine addiction model. Our initial
pilot data demonstrate that, in comparison to varenicline, our prodrugs favorably alter the dopamine release
profile in the striatum. Thus, our prodrug approach changes the physiological function of the reward system
and may be a better drug for clinical use. Importantly, the core technology used in this grant to develop
improved smoking cessation drugs can be utilized more broadly as a general pharmacodynamic assay for
CNS drug development. Therefore, this research will provide a platform for drug discovery using in vivo real-
time methodologies. SpaceRx has extensive experience making varenicline analogs and prodrugs, and real-
time biosensing and measuring neural activity dynamics is a core technology of the Betley laboratory, making
our team ideally suited to test our hypothesis to successfully develop novel smoking cessation drugs.

* Information listed above is at the time of submission. *

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