RFA-DA-19-002 Principal Investigator/PD: Vanover, Kimberly E. Project Summary/Abstract Intra-Cellular Therapies Inc (ITI), a clinical-stage biopharmaceutical company, is developing ITI-333, a novel compound with high affinity activity at mu opiate (MOP), 5-HT2A, and D1 receptors. The nonclinical profile of ITI-333 suggests a promising medication, lacking abuse liability, with partial agonist activity at MOP receptors useful for treatment of opiate withdrawal in individuals with Opioid Use Disorders (OUD). ITI is currently completing IND-enabling nonclinical safety, toxicology, pharmacokinetic and manufacturing activities, with the goal of launching Phase 1 human clinical evaluation of ITI-333 in healthy volunteers in Q1 2019. ITI seeks to partner with NIDA in the development of this compound for a novel and safe therapeutic for use in treating OUD, requesting support of clinical development of ITI-333, while committing significant internal funds to a parallel program of non-clinical development and CMC activities in support of the clinical plan. To this end, we submit this application, “Development of ITI-333, a µ-opioid Receptor Partial Agonist and 5HT2A and D1 Receptor Antagonist, for the Treatment of Opioid Use Disorders” to NIDA RFA-DA-19-002, Development of Medications to Prevent and Treat Opioid Use Disorders and Overdose (UG3/UH3). Here, we propose a 2-year UG3 program, including a First-in-Man, single ascending dose (SAD) study (ITI-333-001) to assess the safety, tolerability and pharmacokinetics of ITI-333 in healthy volunteers. The safety, tolerability, and pharmacokinetics of multiple, ascending doses (MAD) of ITI-333 will then be evaluated in a single-center in-patient study (ITI-333-002) with the goal of determining a maximally- tolerated dose (MTD). Both studies will be conducted in collaboration with Clinilabs, a NYC-based CRO. In parallel with the MAD study, we will characterize the in vivo receptor pharmacology of ITI-333 at MOP, 5- HT2A, and D1 receptors in human brain using PET imaging (with Dr. Dean Wong, JHU, ITI-333-003), thereby leveraging our SAD data to clinically validate the mechanism of action of ITI-333 and to inform Phase 2 dose selection. These data will enable us to launch a 3-year UH3 program exploring the human abuse liability (HAL) and functional pharmacology of ITI-333 in collaboration with Dr. Sandra Comer (CUMC), a clinical expert in opioid use and abuse. The HAL study (Phase 2a, ITI-333-004) will characterize the opioid receptor antagonist/partial agonist profile of ITI-333 in humans to explore potential abuse liability in humans. Additional Phase 2 studies will evaluate the in vivo functional pharmacology of ITI-333 in a model of withdrawal precipitation in non-treatment seeking heroin users (ITI-333-005) and in a model of mu-opioid receptor blockade in treatment-seeking heroin users (ITI-333-006). Together, we believe this clinical development plan with inform further development of ITI-333 and the selection of a cogent Phase 3 clinical path toward FDA approval as a medication for the treatment of OUD.

Project Narrative Intra-Cellular Therapies, Inc. (“ITI”), has a biotechnology platform that has enabled discovery of innovative pharmaceutical therapies for CNS disorders based on intracellular signaling. In this project, we propose to develop a novel, small molecule, ITI-333, as a safe, brain-penetrant drug targeting molecular pathways in the brain implicated in the development of opioid-use disorders. Here, we present a clinical development plan designed to advance ITI-333 through human clinical evaluation as a medication for the treatment of opioid withdrawal and relapse and as an aid for the treatment of co-morbid symptoms of depression and anxiety in individuals withdrawing from opioids. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page