Safety/Toxicology, ADME and CMC Activities to Support the Assessment of the mGlu2 PAM SBP-9330 in a Phase 2 Clinical Study in Smokers

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PROJECT SUMMARY This resubmission application, “Safety/toxicology, ADME and CMC activities to support the assessment of the mGlu2 PAM SBP-9330 in a Phase 2 clinical study in smokers”, is in response to PAR-22-202 and represents the continuation of our current work funded through 07/31/2023 by U01 DA051077 “Clinical development of an mGlu2 positive allosteric modulator to treat nicotine addiction”. Cigarette smoking remains one of the leading causes of death and disease worldwide. Only three types of medications for smoking cessation have been approved by the United States Food and Drug Administration (FDA) (bupropion, varenicline, and nicotine replacement therapy), all of which have poor efficacy and tolerability. Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 2 (mGlu2) decrease nicotine self-administration and cue-induced reinstatement of nicotine seeking in animal models, providing support for mGlu2 as a valid target for the treatment of nicotine addiction. Our investigational drug, the small molecule mGlu2 PAM SBP-9330 (characterized during prior grant U01 DA041731), has recently been evaluated in healthy nonsmokers and smokers in a placebo- controlled, randomized, and double-blind Phase 1 clinical study (NCT04948827). To date, the data for the healthy nonsmokers have been unblinded and analyzed, revealing that SBP-9330 was well tolerated, with no serious adverse events or safety concerns. Human pharmacokinetic data revealed that plasma exposures were nearly dose-proportional, accumulated approximately 2-fold over 14 days of dosing, and were sufficiently high for potential efficacy. These promising data support continuation of the clinical development of SBP-9330.The studies proposed in this grant application are required by the FDA before we can dose SBP-9330 for longer duration in tobacco smokers in a Phase 2 study and beyond. To this end, our Specific Aims are: (1) Perform the preclinical absorption, distribution, metabolism, and excretion (ADME) studies needed to support the Phase 2 clinical development of SBP-9330 in smokers; (2) Perform the preclinical toxicology studies needed to support Phase 2 clinical development of SBP-9330 in smokers; and (3) Perform the Chemistry, Manufacturing, and Controls (CMC) activities needed to support Phase 2 clinical development in smokers. To achieve these Specific Aims, we have retained the same highly experienced and qualified multidisciplinary team of investigators that has collaborated productively during the previous grant (U01 DA041731) and the currently active grant (U01 DA051077). We have also compiled an extensive data package to support the further clinical development of SBP-9330. Achievement of the milestones in this proposal will provide the additional data and drug substance needed to advance SBP-9330 into a Phase 2 proof-of-concept clinical study in smokers. Our team has the depth and breadth of expertise and experience to execute the proposed research plan, as evidenced by the complete and timely achievement of the milestones for both U01 DA041731 and U01 DA051077 in the past six years.