ITI-214 Safe With Signs of Efficacy in Phase 1/2 Parkinson Disease Study

October 23, 2018

ITI-214 showed favorable safety with early signs of improvement in motor symptoms for patients with Parkinson disease

Robert A. Riesenberg, MD

Treatment with ITI-214 showed a favorable safety profile with early signs of improvement in motor symptoms for patients with Parkinson disease, according to findings from a phase 1/2 study presented at the 2018 ANA Annual Meeting.

In the trial, treatment was given for 7 days across a variety of doses, with adverse events (AEs) increasing with the dose. Overall, a treatment-emergent AE was experienced by 20% of patients in the placebo group compared with 46.7% with ITI-214. Most events were mild and there were no serious adverse events. Although still early, there were signs of improvement in on-time without dyskinesia, Unified Parkinson’s Disease Rating Scale (UPDRS), and Unified Dyskinesia Rating Score (UDysRS) with ITI-214.

“Improvement in motor symptoms and reduction in motor complications (eg, reduced dyskinesias) were noted with ITI-214 treatment,” principal investigator Robert A. Riesenberg, MD, from Atlanta Center for Medical Research, said in a statement. “Several subjects with profound motor impairments improved dramatically while taking ITI-214, only to have these symptoms re-emerge after cessation of ITI-214 treatment.”

ITI-214 is an inhibitor of phosphodiesterase 1 (PDE1), which is a calcium dependent enzyme that breaks down cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Inhibition of PDE1, which is only active in the presence of intracellular calcium, could reinstate the cAMP and cGMP intracellular signaling pathways.

The phase 1/2 trial enrolled 40 patients, with 30 in the ITI-214 arm and 10 in the placebo group. Patients in the investigational arm received ITI-214 at 1 mg, 3 mg, 10 mg, 30 mg, or 90 mg, with 8 patients enrolled at each dose. The mean age of patients in the ITI-214 group was 68.3 years, and two-thirds were male. A quarter of patients were on concomitant carbidopa plus levodopa and 14% were on a dopamine agonist.

Treatment with ITI-214 reduced the UPDRS part III score from approximately 30 at baseline to about 26 by day 7. Patients were followed for 30 days, with scores beginning to increase again after treatment with the PDE1 inhibitor was stopped. A drop in UPDRS part III from around 32.5 to 27.5 was seen in the placebo group.

By day 7, significantly more patients had a UDysRS score of 0 with ITI-214 compared with the placebo group. At day 7, scores in the ITI-214 arm ranged from 0 to 15, with a quarter of patients having a score of 0. Scores stayed approximately the same from baseline to day 7 in the placebo group.

On-time without dyskinesias increased by slightly more than 1 hour in the ITI-214 group compared with a decline of nearly 1 hour in the placebo arm. The clinical impression of severity index for Parkinson disease (CISI-PD) scores dropped from baseline to day 7 in the ITI-214 group but stayed the same in the placebo arm. At baseline, the CISI-PD score was over 1.1 in the ITI-214 group compared with approximately 0.7 at day 7.

The most frequently reported treatment-emergent AEs with ITI-214 were dizziness (16.7%), hypotension (13.3%), and somnolence (10%). There were reductions in blood pressure and heart rate noted in the trial, but no dose reductions or changes were needed. There were no clinically significant changes in ECG parameters and no other clinically significant findings.

“In this trial, once-daily ITI-214 for 7 days was shown to be safe and generally well tolerated across a broad range of doses from 1 mg to 90 mg in subjects currently maintained on dopamine replacement therapy,” study author Daniel Todd Laskowitz, MD, from Duke University School of Medicine, said in a statement.

A later stage clinical trial is planned for ITI-214, based on findings from the phase 1/2 study, which is still enrolling participants (NCT03257046). Intra-Cellular Therapies, the company developing the therapy, noted that additional findings from the study would be presented at an upcoming meeting. In addition to Parkinson disease, the treatment is also being assessed for patients with heart failure (NCT03387215).

Davis R, Riesenberg RA, Laskowitz DT, et al. A Phase I/II Clinical Study of ITI-214, a Novel Phosphodiesterase I Inhibitor, for the Treatment of Motor and Non-Motor Symptoms of Parkinson’s Disease. Presented at: 143rd American Neurological Association Annual Meeting; Atlanta, Georgia, October 21 to 23, 2018. Abstract M217.