ITI-007 for schizophrenia

In schizophrenia, controlling residual symptoms, negative symptoms (e.g. social withdrawal, flattened affect and depression), diminished quality of life and functional impairment remains a challenge with limited treatment options.

First generation antipsychotics cause extrapyramidal side effects and movement disorders while second-generation APDs lead to weight gain and metabolic alterations. Consequently, there is a tremendous unmet medical need in disease management.

ITI-007, a new molecular entity, is a high-affinity antagonist at the serotonin 2A (5-HT2A) receptor with lower affinity for D2 receptors, among other targets. It has a sixty-fold separation between its affinity for 5-HT2A receptors and D2 receptors, much wider than other antipsychotics.

Finding effective AND safe treatments for schizophrenia remains a huge challenge.

Methods

335 people were randomised (1:1:1:1) to receive ITI-007 (60 mg, 120 mg), placebo or 4 mg risperidone once in the morning for 4 weeks after discontinuing their existing antipsychotic therapy. This was a double-blind, placebo controlled, parallel phase II study in people with schizophrenia experiencing an acute exacerbation of psychosis.

Treatment naïve and treatment resistant patients were excluded.

Baseline and weekly assessment with the Positive and Negative Syndrome Scale (PANSS) evaluated participants during the study, total PANSS change after 4 weeks was the primary end point.

Phase II clinical trials evaluate whether the drug in question has any biological activity or effect.

Results

Efficacy

ITI-007 60 mg significantly improved total PANSS to day 28, compared with placebo (change −13.2 points vs. −7.4 points; p = .017). The effect size of 0.4 is in the range of other antipsychotics (Turner et al, 2012)
Risperidone showed similar efficacy to ITI-007 60 mg
ITI-007 120 mg was similar to placebo
Total PANSS improvement with ITI-007 60 mg was driven by an improvement in positive symptoms and general psychopathology
For the group as a whole, negative symptoms improved with 60 mg ITI-007, but not significantly
Risperidone and 120 mg ITI-007 did not improve negative symptoms.

ITI-007 60 mg was similar to risperidone and superior to placebo, but ITI-007 120 mg was no better than placebo.

Negative and depression symptom subgroups

Approximately a third of the patients showed prominent negative symptoms at baseline. An exploratory subgroup analysis showed 60 mg ITI-007 reduced the severity of PANSS negative symptoms (effect size = 0.34). This was not replicated by risperidone. The change in negative symptoms was independent of improvements in positive symptoms, depression or extrapyramidal side effects.

PANSS-derived prosocial factor in the 60 mg ITI-007 group significantly (p < 0.001) improved prosocial behaviour. Risperidone was also significantly effective here but with a smaller effect size. Improvement in the PANSS-derived prosocial factor reflects an improvement of symptoms related to emotional and social withdrawal and suspiciousness, it is a cluster of symptoms corresponding to social function.

Safety

Of 335 subjects, 81% completed the study and very few patients were lost to follow-up after discharge from the inpatient unit, providing a study completion rate of 74%. There were no serious adverse events with ITI-007. Five patients discontinued study treatment due to an adverse event (two on ITI-007; dry mouth and worsening of schizophrenia).

The relative risk of any treatment-emergent adverse event for 60 mg ITI-007 was similar to placebo but higher for 120 mg ITI-007 (p = 0.024). The most frequent adverse event reported in the study was somnolence/sedation (placebo = 13%, 60 mg ITI-007 = 17%, risperidone = 21% and 120 mg ITI-007 = 33%). ITI-007 was not associated with extrapyramidal symptoms. Median weight gain (change from screening at day −7 to day 28) was about 1 kg for patients on placebo, 60 mg ITI-007 or 120 mg ITI-007 and about 2.5 kg for patients on risperidone. ITI-007 lacks significant activity at many receptors (e.g., H1, muscarinic, serotonin 2C) that are blamed for antipsychotic side effects (i.e., clinically significant sleep induction, cognitive impairment, weight gain).

Compared to risperidone, ITI-007 showed statistically significantly lower prolactin levels, fasting glucose, total cholesterol and triglycerides than risperidone (p<0.05 for all comparisons). Levels remained low while on ITI-007 but increased when switched to other antipsychotics. ITI-007 at both doses did not prolong corrected QT intervals and did not cause sustained heart rate elevations.

ITI-007 achieves this by being a presynaptic partial agonist and postsynaptic antagonist with functional mesolimbic/mesocortical selectivity. This allows for functional blockade of dopamine without increasing dopamine turnover and corresponds to antipsychotic efficacy without motor side effects (Snyder et al, 2015).

We still await a treatment for schizophrenia that has superior efficacy to clozapine with fewer adverse effects.

Commentary

The authors speculate that the lack of therapeutic efficacy of the 120 mg dose was due to a higher frequency of somnolence/sedation, which could have affected patients’ behaviour and obscured therapeutic effects. Although unlikely, it is also possible that varying receptor affinities occurring at the higher (120 mg) dose alters ITI-007’s therapeutic activity.

Considering this is a phase II trial it presents a number of interesting findings. I am looking forward to results from larger phase III trials where ITI-007 is given for longer periods and where negative symptoms are the primary outcome measured.

The advent of a new chemical entity with unique pharmacological properties and potential in ameliorating negative symptoms is quite exciting, especially when considering ITI-007’s comparable efficacy to risperidone and its favourable safety profile.

Considering all of the positive outcomes, one must still consider the evidence with caution as the groups were small and the subgroups even more so. One phase III trial to assess its antipsychotic efficacy was completed in September 2015 (NCT02282761). It enrolled 450 participants and had 3 treatment arms. Of great interest were the study’s arms of ITI-007; 60mg and 40mg per day (the third being placebo). The higher dose of 120mg seems to have been discarded.

Two more phase III trials are ongoing in SZ (NCT02469155) and bipolar depression (NCT02600494). The first is due for completion this year while the latter in December 2017. Considering all of these clinical trials compare ITI-007 to placebo or risperidone, it would be interesting to see how its place in therapy develops. Thus far it has been shown to be useful in managing positive symptoms and it has a very favourable short-term side effect profile with potential to help patients in many other aspects.

The study adhered to the CASP checklist for randomised controlled trials (PDF).