TORONTO (FRONTLINE MEDICAL NEWS) – The experimental antipsychotic ITI-007 was safe and well tolerated, and improved negative symptoms, depression, and overall symptoms in patients with an acute exacerbation episode of schizophrenia in a phase II trial. Importantly, in patients with prominent negative symptoms of schizophrenia and in those with comorbid depression, ITI-007 appeared to be particularly efficacious, in some cases more so than risperidone, and with better tolerability.

“We believe ITI-007’s serotonergic-dopaminergic-glutamatergic pharmacological profile represents a new approach to the treatment of schizophrenia in a single, stand-alone therapy,” reported Kimberly E. Vanover, Ph.D., vice president of clinical development for Intra-Cellular Therapies, the developers of ITI-007. Dr. Vanover reported updated safety and tolerability findings from the ITI-007-005 trial at the annual meeting of the American Psychiatric Association.

The ITI-007-005 trial was a randomized, double-blind, placebo- and active-controlled clinical trial in patients with a current acutely exacerbated episode of schizophrenia. A total of 335 patients were randomly assigned to one of four treatments: either 60 or 120 mg ITI-007, 4 mg risperidone, or placebo. Patients were hospitalized and received study treatment orally once daily in the morning for 28 days. Of those randomized, 311 patients were included in the intent-to-treat (ITT) primary analysis.

Primary endpoint met

The primary endpoint was the mean change from baseline to day 28 on the 30-item Positive and Negative Syndrome Scale ( PANSS ) total score, which measures positive symptoms such as delusions, suspiciousness, and hallucinations; negative symptoms, such as blunted affect, social and emotional withdrawal, and stereotyped thinking; and general psychopathology, such as anxiety, tension, depression, and active social avoidance. Safety and tolerability also were assessed.

The trial met its primary endpoint for the lower dose of ITI-007, with a significant reduction in total PANSS at day 28, compared with placebo. Risperidone also reduced total PANSS to a similar extent as ITI-007 60 mg, but the ITI-007 120 mg dose was not found to be more efficacious than placebo. The results were very similar when only the mean change in the PANSS positive subscale was considered.

“We do not fully understand why the higher dose didn’t separate,” Dr. Vanover reported. One consideration is that at the higher dose, more patients experience somnolence or sedation, the most common adverse event seen with the study drug. Since the drug was given in the morning and the PANSS questionnaire required an interview, it could be that the patients treated with the higher doses scored less well on the test just because they were sleepy. “More studies are needed to determine if the 120 dose could be efficacious if given at night,” as most antipsychotics are, Dr. Vanover said.

Improved negative symptoms

Although as an acute schizophrenia trial, ITI-007-005 was not designed to look just at negative symptoms of schizophrenia, the investigators predefined a subgroup population analysis of patients who had prominent negative symptoms at baseline (defined as a score of 4 or more on at least three negative symptom items on the PANSS at baseline).

While ITI-007 60 mg improved negative symptoms in the overall ITT population, in the subgroup of patients who were exhibiting prominent negative symptoms, the improvement was much greater (effect size, 0.34 vs. 0.19 for ITT population).

Notably, risperidone and 120 mg ITI-007 did not improve negative symptoms in this subgroup or in the overall ITT population.

“What we were able to show in this study is that negative symptoms can improve independently from improvements in positive symptoms with no correlation between these two measures,” Dr. Vanover said. “So, we believe you can get improvements in the primary negative symptoms without it being pseudospecific to the positive symptoms, but this needs to be evaluated in future studies in patients with prominent negative symptoms.

Works in comorbid depression

The investigators also looked at the subgroup of patients with comorbid depression, as this represents a particularly vulnerable population with symptoms across multiple domains.

Although the numbers were small, ITI-007 60 mg showed a “rapid, robust, and statistically significant antipsychotic effect not observed with risperidone,” Dr. Vanover said.

“ITI-007 60 mg also constantly and significantly improved depressive symptoms in this subgroup. We did see a numerical improvement with risperidone, but that effect was variable and did not reach statistical significance.”

“So we believe that this subgroup of patients with schizophrenia and comorbid depression may be particularly sensitive and responsive to ITI-007 treatment.”

Indeed, on the total PANSS score, the percentage improvement seen in the depressed subgroup reached 50%, “which is quite robust,” said Dr. Vanover, as a 30% improvement is generally considered clinically significant.

Metabolic profile proves favorable

ITI-007 was considered safe and well tolerated. The side effect profile seen with the 60-mg dose was not significantly different from placebo.

The most common adverse event was sedation/somnolence, reported in 17% of the 60-mg group and in 13% of the placebo arm. Dr. Vanover stressed, however, that these patients were hospitalized “with not a lot to do, so a lot of people were taking naps.” Sedation or somnolence was reported in 32.5% of the ITI-007 120-mg group.

Importantly, ITI-007 given at the lower 60-mg dose showed no difference from placebo on extrapyramidal symptoms (EPS), akathisia, or prolactin levels. Also, no clinically significant changes were found in cardiovascular function noted (no QTc prolongation or sustained increase in heart rate, as is seen with risperidone), and the drug had a favorable weight gain (“little or none”) and metabolic profile.

Phase III studies ongoing

Two phase III clinical trials of ITI-007 are underway. The first will test a 4-week course of ITI-007 40 mg and 60 mg against placebo in 400 inpatients with acutely exacerbated episodes of schizophrenia. The second study, called ITI-007-302, is again using risperidone as an active control and will randomly assign 500 patients with acutely exacerbated episodes of schizophrenia to a 6-week course of ITI-007 20 mg, 60 mg, placebo, or risperidone 4 mg. The primary outcomes for both studies will be the change in mean PANSS total score from baseline.

ITI-007 is a first-in-class molecule that combines potent serotonin 5-hydroxytryptamine2A–receptor antagonism, dopamine receptor phosphoprotein modulation (DPPM), glutamatergic phosphoprotein modulation, and serotonin reuptake inhibition into a single-drug candidate for the treatment of acute and residual schizophrenia.

At low doses, ITI-007 is a very potent serotonin 5-HT2A–receptor antagonist, Dr. Vanover said. The 5-HT2A–receptor antagonism improves sleep quality, enhances antipsychotic and antidepressant activity, and reduces anxiety and hostility. As the dose of ITI-007 is increased, other pharmacological targets are engaged, including the activation of DPPM effects.

Dr. Vanover is a full-time employee of ITI.