Lumateperone (INN) (developmental code names ITI-007, ITI-722) is an investigational atypical antipsychotic which is currently under development by Intra-Cellular Therapies, licensed from Bristol-Myers Squibb, for the treatment of schizophrenia. It is also being developed by Intra-Cellular Therapies for the treatment of bipolar disorder, depression, and sleep and behavioral disturbance in dementia, autism, and other neuropsychiatric disorders. As of September 2015, lumateperone has passed the first of two phase III clinical trials for schizophrenia.
Relative to presently-available antipsychotics, lumateperone possesses a unique and novel mechanism of action. It acts as a 5-HT2A receptor antagonist (Ki = 0.54 nM), a partial agonist of presynaptic D2 receptors and an antagonist of postsynaptic D2 receptors (Ki = 32 nM), and a SERT blocker (Ki = 61 nM). It also possesses affinity for the D1 receptor (Ki = 52 nM) and weak affinity for the α1A- and α1B-adrenergic receptors (Ki = 173 nM at α1) and D4 receptor. Lumateperone does not significantly bind to the 5-HT2B, 5-HT2C, H1, or mACh receptors.
Lumateperone shows a 60-fold difference in its affinities for the 5-HT2A and D2 receptors, which is far greater than that of most or all existing atypical antipsychotics, such as risperidone (12-fold), olanzapine (12.4-fold), and aripiprazole (0.18-fold). It is thought that this property may improve the effectiveness and reduce the side effect profile of lumateperone relative to currently-available antipsychotics, a hypothesis which is supported by the observation of minimal catalepsy in mice treated with the drug. Moreover, it has been expressed that this property could result in full occupancy and blockade of the 5-HT2A at low doses, with dose-dependent adjustable modulation of the D2 receptor, as well as the SERT, possible with increasing doses, which would uniquely allow for clinical optimization of efficacy and side effect incidence.
Unlike most current antipsychotics, such as haloperidol, risperidone, and olanzapine, lumateperone does not disrupt striatal dopamine signaling, a property which is likely due to partial agonism of presynaptic D2 receptors. In accordance, similarly to aripiprazole, which is also a partial agonist of presynaptic D2 receptors, lumateperone showed no striatum-based motor side effects (i.e., catalepsy) in animals.
In phase II clinical trials, lumateperone showed statistically-significant efficacy in improvement of psychosis at a dose of 60 mg daily. In addition, it distinguished itself from its comparator risperidone in reducing negative symptoms, including improvement in social function, as well as in alleviating depressive symptoms in schizophrenia patients with comorbid depression, whereas risperidone had no effect. Lumateperone also distinguished itself from risperidone in that it produced little or no weight gain, did not negatively affect metabolic parameters (i.e., insulin, glucose, triglyceride, and cholesterol levels), did not increase prolactin levels, and did not show a rate of the side effect of akathisia that differed from placebo. In addition, lumateperone did not produce any changes in cardiovascular function, such as QTc prolongation, and unlike risperidone, it did not produce a measurable increase heart rate. Due to its favorable influence on metabolic parameters, it was concluded that lumateperone, unlike many other available antipsychotics such as risperidone, may not cause an increase in the risk of diabetes or cardiovascular disease, and hence may prove to be a significant improvement relative to many existing antipsychotic drugs in terms of long-term safety and tolerability.
Lumateperone, at a dose of 60 mg per day, was not found to be associated with any statistically significant treatment-emergent side effects relative to placebo. At a dose of 120 mg daily, the most frequent adverse effect observed was sedation/somnolence, reported by 32.5% of patients. There was no evidence of extrapyramidal symptoms or increase in suicidal ideation or behavior.