Pam Harrison

October 18, 2016

UPDATED October 27, 2016 // WASHINGTON, DC ― The first phase 3 study of an investigational new drug, ITI-007, corroborates findings from an earlier large phase 2b trial in which the first-in-class novel antipsychotic was found to provide rapid and clinically significant reductions in acute psychosis at 4 weeks while having virtually no side effects in comparison with placebo.

The pooled results from the phase 2b and the phase 3 study were presented here at the Institute of Psychiatric Services (IPS): The Mental Health Services 2016 Conference.

However, in a second phase 3 study of the same drug, which was not presented at the meeting, there was no difference in efficacy in comparison with placebo, although the drug was again extremely well tolerated.

"Generally, the dopamine blockers that we have available work in acutely ill patients. In the phase 2b study, the drug behaved like risperidone (Risperdal, Janssen Pharmaceuticals), so ITI-007 was not different from risperidone efficacy-wise," investigator Christoph Correll, MD, professor of psychiatry, Hofstra Northwell School of Medicine, Hempstead, New York, told Medscape Medical News.

"But the uniqueness of this medication is that it actually has placebo-like tolerability except for a bit of sedation, and even in the most recent phase 3 study, where the 60-mg dose of ITI-007 did not separate from placebo, there was again a placebo-level side effect profile and significantly fewer side effects than risperidone."

In the first phase 3 trial (ITI-007-301), a total of 450 patients with an acutely exacerbated episode of schizophrenia were randomly allocated to receive ITI-007 60 mg once a day, or 40 mg once a day, or placebo. No dose titration is necessary with ITI-007.

At baseline, the patients' mean total score on the Positive and Negative Syndrome Scale (PANSS) was 89.8, reflecting marked illness. The mean score on the Clinical Global Impression of Severity of Illness (CGI-S) at baseline was 4.8.

The primary endpoint was the change from baseline on the PANSS total score at day 28 in comparison with placebo.

"At a dose of 60 mg, the drug met the primary endpoint of the study, and separated as early as 1 week from placebo and maintained efficacy at every time point on the PANSS total score (P = .022)," investigators report.

Specifically, the mean change from baseline in the PANSS total score at week 4 was -14.5 points for patients receiving ITI-007 vs -10.3 points for control patients who received placebo.

Efficacy on the same primary endpoint with the 40-mg dose approximated the trajectory of improvement seen with the 60-mg dose, but it did not reach statistical significance.

With both the 40-mg and the 60-mg doses, significant improvement was also seen in clinical global severity of illness score. Prosocial behavior benefits were also observed in this study, with 60 mg significantly separating from placebo on the Personal and Social Performance Scale at 4 weeks.

Eighty-seven percent of patients who received the 60-mg dose of ITI-007 completed the 28-day study compared with 75% of patients who received placebo.

As Dr Correll noted, the high completion rate with the 60-mg dose of ITI-007 speaks to the efficacy and tolerability of this novel agent.

Unique Pharmacology

"The unique pharmacology of this drug represents a novel approach to the treatment of schizophrenia with two studies to date demonstrating efficacy with a reduction in symptoms of acute schizophrenia and benefits in psychosocial function...and ITI-007 also lacks side effects commonly associated with existing treatments," the investigators conclude.

Results from the 4-week phase 2b study of ITI-007 were also presented at the conference. Those results were published earlier this year in Biological Psychiatry.

This study included 335 patients experiencing an acute exacerbation of psychosis. The patients were randomly assigned to ITI-007 (at a dose of either 60 mg or 120 mg), or placebo, or risperidone 4 mg. An acute exacerbation of psychosis was defined as a score of ≥40 on the 18-item Brief Psychiatric Rating Score, with a score of ≥4 on two or more of the positive symptom items.

At the 60-mg dose, patients who received ITI-007 showed significant improvement on the PANSS total score at day 28, at a mean change of -13.2 points vs a mean change of -7.4 points for patients who received placebo.

The lead author of the phase 2b study, Jeffrey Lieberman, MD, chairman, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York City, pointed out that the therapeutic effect of 60-mg ITI-007 on the PANSS total score was comparable to that achieved with risperidone, with an effect size in the range of other effective antipsychotics tested in 4-week clinical trials.

Improvement in total scores on the PANSS was comparable for patients receiving 60 mg of ITI-007 (40%) and for those receiving 4 mg of risperidone (≥30%).

Multiple Potential Indications

Both the 60-mg dose of ITI-007 and risperidone significantly reduced positive symptoms and general psychopathology in comparison with placebo on PANSS subscales as well, Dr Lieberman and colleagues noted.

Indeed, in this study, ITI-007 60 mg demonstrated greater improvement than risperidone in negative symptoms as measured by the PANSS negative subscale, as Dr Correll pointed out.

Dr Correll also pointed out that the lack of separation of 60 mg and 20 mg of ITI-007 from placebo observed in the main efficacy endpoint in the second phase 3 study, known as study 302, may be explained by a very high placebo response in patients who received placebo in the more recent trial.

In study 302, almost 700 acutely psychotic patients were randomly allocated to receive either ITI-007 20 mg, or ITI-007 60 mg, or risperidone 4 mg, or placebo for a total of 6 weeks.

"If you just look at the drug effects, the effect with ITI-007 60 mg was basically the same as it was in the other studies — between a 13.5- and 14.5-point reduction in the PANSS total score," said Dr Correll.

"However, what varied between the three trials was the placebo response, where it was about 7 points in the 2b study, about 10 points in the first phase 3 trial, and over 15 points in the second phase 3 trial. So when you have so much placebo noise around everything, it just makes it hard to interpret this study from an efficacy standpoint," he added.

The other puzzling finding from the second phase 3 study was that risperidone, the active comparator in study 302, was able to rise above the placebo noise, he added.

As Dr Correll explained, this may in part be due to a higher differential dropout rate — approximately 63% of patients who received risperidone completed treatment — and the potential for "functional unblinding," whereby any side effects experienced by participants make it clear to them that they are on an "real drug" for schizophrenia, which can introduce subsequent bias.

Nevertheless, Intra-Cellular Therapies, which is developing ITI-007, is apparently undeterred and has pledged to continue to seek Food and Drug Administration approval for the drug on the basis of the two positive trials to date.

"In my opinion, the company doesn't need to do another study. They have two positive trials, they were both large, adequately controlled, and similarly designed, and the phase 2b study had all the features of a phase 3 trial, and I think that the uniqueness of this medication with its very low side effect profile makes the drug attractive not only for schizophrenia but also for other indications, including bipolar depression and behavioral disturbances in the elderly with dementia, for which the company is already running phase 3 programs," said Dr Correll.

All studies were funded by Intra-Cellular Therapies. Dr Correll has been a consultant and/or advisor to or has received honoraria from Alkermes, Allergan, Forum, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, LB Pharma, Lundbeck, Medavante, Medscape, Neurocrine, Otsuka, Pfizer, ProPhase, Sunovion, Supernus, Takeda, and Teva. He has provided expert testimony for Bristol-Myers Squibb, Janssen, and Otsuka. He has also served on a data safety monitoring board for Lundbeck and Pfizer and has received grant support from Takeda.

Institute of Psychiatric Services (IPS): The Mental Health Services 2016 Conference. Abstracts 18 and 19. Presented October 7, 2016.

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