ITI-214, A Novel Phosphodiesterase I Inhibitor for the Treatment of Parkinson’s Disease: Results from A Phase I/II Clinical Study (P2.8-051)

Objective: Evaluate the safety and tolerability of ITI-214, a potent and selective phosphodiesterase 1 (PDE1) inhibitor, in patients with Parkinson’s disease (PD). Background: Inhibitors of PDE1 block the degradation of the cyclic nucleotides, cAMP and cGMP, potentiating downstream intracellular signaling. The PDE1 inhibitor ITI-214 has shown improvement in motor and non-motor symptoms in rodent models of PD. Additionally, ITI-214 reduced neuroinflammation by regulating microglial function and prevented neurodegeneration in preclinical models. In four Phase I clinical studies in healthy volunteers, ITI-214 was generally well tolerated with a favorable safety profile. Design/Methods: The primary objective of the study is to evaluate the safety and tolerability of ascending doses of ITI-214 in patients who are maintained on stable PD therapy. Secondary objectives are to evaluate the pharmacokinetic profile of ITI-214 and explore its effects on motor and non-motor symptoms. The study was a 7-day Phase I/II randomized, double-blind, placebo-controlled, multiple ascending dose clinical study in patients with mild to moderate PD. Patients were maintained on stable PD therapy. Standard scales were used to assess PD symptoms and biomarkers of disease progression (inflammation) were measured. Results: This Phase I/II clinical trial in patients with PD has been completed with 5 dose cohorts (1, 3, 10, 30, and 90 mg). At these doses, ITI-214 was safe and generally well tolerated. Clinical signals consistent with improvement in motor symptoms of PD and in dyskinesia were observed. Conclusions: Clinical data indicate that ITI-214 is safe and generally well tolerated across a range of doses in patients with mild to moderate PD. Signals of clinical improvement warranting further evaluation were observed. As a selective PDE1 inhibitor, ITI-214 represents a novel approach for the treatment of motor and non-motor symptoms associated with PD. Disclosure: Dr. Davis has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with IntraCellular Therapies. Dr. Riesenberg has nothing to disclose. Dr. Laskowitz has nothing to disclose. Dr. Guptill has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Argen-X, Becton Dickinson, Momenta, and Grifols. Dr. Guptill has received research support from Grifols Foundation, Bioverativ, and Ra Pharmaceuticals. Dr. Sanders has nothing to disclose. Dr. Cooney has nothing to disclose. Dr. Satlin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. O’Brien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Duthiel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Cruz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Hendrick has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Li has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Wennogle has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Glass has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Pinho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Taylor has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Kozauer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Weingart has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Mates has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Snyder has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies. Dr. Vanover has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Intra-Cellular Therapies.