ITI-214, A Novel Phosphodiesterase Type I Inhibitor, For The Treatment Of Motor And Non-motor Symptoms Of Parkinson’s Disease (P5.067)

Objective: To evaluate the therapeutic utility of ITI-214 a potent and selective phosphodiesterase type I (PDE1) inhibitor for the treatment of motor and non-motor symptoms of Parkinson’s Disease (PD). Background: Inhibitors of PDE1 block the degradation of the cyclic nucleotides, cAMP and cGMP, potentiating downstream intracellular signaling. The PDE1 enzyme is highly active in pathological states, and our PDE1 inhibitors are designed to reestablish normal function in these disease states. Consequently, PDE1 inhibitors function to reinstate normal signaling for both CNS and non-CNS disorders. ITI-214 is currently being studied in Phase I/II clinical trial in patients with PD. Design/Methods: ITI-214 has been tested in a rodent model of novel object recognition to evaluate cognitive effects. ITI-214 was evaluated behaviorally in the step-down latency test of catalepsy in mice. Anti-parkinsonian effects in mice treated unilaterally with 6-OHDA were evaluated using the cylinder test to assess contralateral limb use. Wakefulness and locomotor activity in mice was measured with telemetry. The Phase 1 program included a single rising dose study in healthy volunteers, a multiple dose 14-day study in healthy volunteers and in patients with schizophrenia, a 7-day at multiple rising doses study, and a bioequivalence study. Results: ITI-214 has shown activity in rodent models of motor and non-motor symptoms in Parkinson’s disease. ITI-214 has been shown to reduced neuroinflammation by regulating microglial function in a number of animal models. In Phase 1 studies, ITI-214 demonstrated a favorable safety profile and was generally well tolerated. Pharmacokinetic evaluation indicated once-a-day dosing. The Phase 1/2 clinical trial design in PD will be presented. Conclusions: ITI-214 represents a novel approach for the treatment of CNS and non-CNS disorders with potential utility in several indications including Parkinson’s disease. The ability of ITI-214 to reduce neuroinflammation by altering microglial function suggests utility in treating neurodegeneration and diseases accompanied by neuronal loss and inflammation. Study Supported by: Intra-Cellular Therapies, Inc Disclosure: Dr. Davis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with IntraCellular Therapies. Dr. Vanover has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with IntraCellular Therapies Inc. Dr. Mates has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intracellular Therapies Inc.