Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction

Information

  • Research Project
  • 10231218
  • ApplicationId
    10231218
  • Core Project Number
    U01DA051077
  • Full Project Number
    5U01DA051077-02
  • Serial Number
    051077
  • FOA Number
    PAR-18-219
  • Sub Project Id
  • Project Start Date
    8/15/2020 - 3 years ago
  • Project End Date
    7/31/2023 - 10 months ago
  • Program Officer Name
    RAMEY, TANYA S
  • Budget Start Date
    8/1/2021 - 2 years ago
  • Budget End Date
    7/31/2022 - a year ago
  • Fiscal Year
    2021
  • Support Year
    02
  • Suffix
  • Award Notice Date
    8/10/2021 - 2 years ago

Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction

PROJECT SUMMARY This application entitled ?Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction? is in response to PAR-18-219 ?Grand Opportunity in Medications Development for Substance-Use Disorders (U01 Clinical Trial Optional)?. This application represents the continuation of our current work under the U01 DA041731 funded from 9/1/2017 through 5/31/2020 entitled ?Preclinical Studies for the Development of Selective mGlu2 Positive Allosteric Modulators to Treat Substance Abuse Disorders?. Cigarette smoking, attributable primarily to the addictive properties of nicotine, is one of the largest preventable causes of disease and death in the US. Metabotropic glutamate receptor subtype 2 (mGlu2) receptor positive allosteric modulators (PAMs) represent an innovative strategy to treat nicotine addiction. Medications that activate mGlu2 receptors can be effective via a dual mechanism by a) reversing the acute effects of nicotine, thus decreasing drug reinforcement, and b) restoring glutamatergic function to normal levels, thus preventing relapse to drug use. Our lead drug candidate, SBI-0069330, is a potent and selective mGlu2 PAM with excellent drug-like properties including oral bioavailability, brain penetration, and metabolic stability. Importantly, SBI-0069330 reduces nicotine self-administration and cue-induced nicotine reinstatement in rats without affecting natural food reward. In addition, SBI-0069330 has been shown to be well-tolerated and safe in 14-day toxicology studies in rats and dogs. We are on track to complete the data package to support SBI-0069330 as a clinical candidate under the current U01 DA041731 grant by May 31, 2020. The overall objective of this grant application is to advance SBI- 0069330 into the clinic and determine its safety, tolerability and pharmacokinetic (PK) profile in healthy human subjects. The specific aims of this proposal are: (1) Complete the investigational new drug (IND) application for SBI-0069330, submit for Food and Drug Administration (FDA) review, and obtain allowance for human testing; (2) Manufacture drug product with a formulation suitable for human dosing in Phase 1 clinical studies; (3) Complete Phase 1 clinical studies in healthy volunteers and determine the safety, tolerability, and PK profile of SBI-0069330 in humans and (4) Complete CMC development and toxicology testing to support a future 12-week Phase 2A clinical efficacy trial. We have assembled a multidisciplinary team of investigators who have the depth and breadth of knowledge and experience to achieve these milestones. This team has been collaborating fruitfully and effectively with the team of Jane Acri and David White at NIDA under the current U01 DA041731 grant. The infrastructure required to undertake the proposed work is fully established and operational. We have also manufactured sufficient active pharmaceutical ingredient (API) of SBI-0069330 that can be readily formulated into drug product and used for dosing in the Phase 1 clinical studies without delay after acceptance of the IND application. Achievement of the indicated milestones will produce a clinical compound ready for a Phase 2A proof-of-concept efficacy study for nicotine addiction.

IC Name
NATIONAL INSTITUTE ON DRUG ABUSE
  • Activity
    U01
  • Administering IC
    DA
  • Application Type
    5
  • Direct Cost Amount
    3287817
  • Indirect Cost Amount
    867037
  • Total Cost
    4154854
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    279
  • Ed Inst. Type
  • Funding ICs
    NIDA:4154854\
  • Funding Mechanism
    Non-SBIR/STTR RPGs
  • Study Section
    ZDA1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
  • Organization Department
  • Organization DUNS
    020520466
  • Organization City
    LA JOLLA
  • Organization State
    CA
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    920371005
  • Organization District
    UNITED STATES