Lumateperone The functional profile of a novel modulator of serotonin, dopamine and glutamate neurotransmission Schizophrenia is a major neuropsychiatric disorder that affects over 1 % of the world’s population. It is characterized by the experience of hallucinations and delusions, referred to as “positive” symptoms, and by a variety of other symptoms, including decreased social function and speech, flat affect, disorganized thought, and low motivation, referred to as “negative” symptoms. The treatment of schizophrenia was revolutionized 60 years ago with the introduction of Chlorpromazine, the prototype of the class of medications, retroactively noted as firstgeneration antipsychotics or typical antipsychotic medications. These drugs are primarily characterized by thei high-affinity antagonism at the dopamine D2 receptor. Typical antipsychotic drugs are effective treatments for reducing positive symptoms in many patients. Owing to their potent D2 receptor antagonism within the nigrostriatal motor system, their utility is limited by severe motor abnormalities including acute parkinsonian movement deficits and dystonia, referred to generally as extrapyramidal motor syndromes (EPS), and drug-induced tardive dyskinesia. The rediscovery of clozapine in 1989 heralded the initial era of secondgeneration antipsychotics or atypical antipsychotics. In general, second-generation antipsychotics have lower D2 affinity, along with high serotonin 5-HT2A antagonist affinity. These atypical drugs offer an improved tollerability and side-effect profile and with particular regard to EPS. Unfortunately, entusiasm for the newer generation of antipsychotic medications has been tempered by the emergence of other severe and often debilitating side effects, including a liability for profound weight gain, an increased incidence of type II diabetes, cognitive impairment, sedation, orthostatic hypotension and loss of bladder control. The side effects appear to be associated with non-selective interactions of these medications with receptors that are unrelated to antipsychotic efficacy, including serotoninergic 5HT2C, histaminergic H1, alpha-adrenergic and muscarinic receptors. Other than clozapine, no mechanistically novel drug has been developed that has been game-changing in the treatment of schizophrenia. In addition to a potential tradeoff between safety and efficacy, D2 antagosnists, including second-generation antipsychotics, are not fully effective for all patients and schizophrenia symptom dimensions, indicating the need for alternative treatments. Lumateperone Lumateperone (lumateperone tosylate, IT-007) is a mechanistically novel agent for schizophrenia. The mechanism of action of Lumateperone is unique because it simulneously modulates serotonin, dopamine, and glutamate neurotransmission, the key neurotransmitters implicated in serious mental illness. Specifically, lumateperone acts as a potent serotonin 5HT2A receptor antagonist, a dopamine D2 receptor presynaptic partial agonist and postsynaptic antagonist, a D1 receptor-dependent modulator of glutamate, and a serotonin re-uptake inhibitor (SERT). Receptor Binding Profile Analysis Binding activity at a variety of receptor targets, including recombinant human serotonin receptors and rat dopamine D2 and human recombinant dopamine D4 receptors, was measured in vitro using standard radioligand displacement methods to determine affinity. Functional activity of ITI-007 at 5-HT2A receptors was studied by measuring serotonin-mediated increases in calcium fluorescence and confirmed by phosphatidylinositol (PI) turnover in cells expressing the 5HT2A receptor. Functional activity at D2 receptors was measured as blockade of dopamine-induced inhibition of forskolin-stimulated (10 μM) cAMP accumulation in cells expressing human recombinant D2-short receptor Receptor binding affinity of ITI-007 as measured by radioligand displacement in comparison antipsychotic drugs. Lumateperone hasassays a wider separation with between A potent ITI-007 for the 5-HT2A with a itsbinding affinityaffinity for D2ofand 5-HT2A receptors, subclassratio of of serotonin receptors comparable D2 to 5-HT2A affinity of 60:1. Byto contrast, currentrisperidone antipsychoticand medications olanzapine have a ratio of approximately of 12:1. This separation of serotonergic and dopaminergic activities is unprecedented among the currently used antipsychotic medications, including risperidone (ratio of 12fold), olanzapine (12.4-fold). ITI-007 possesses a high selectivity (i.e., >2,000-fold) for 5HT2A receptors relative to histamine H1 receptors. The compound also displays a high selectivity for 5-HT2A, relative to 5-HT2C receptors (~320-fold 5-HT2A/5-HT2C binding ratio) Effect on phosphorylation of TH Phosphorylation of tyrosine hydroxylase (TH), which is localized in presynaptic terminals of dopamine neurons in striatum, is a functional indicator of antipsychotic drugs potential to disrupt striatal dopamine metabolism/ to perturb presynaptic dopamine synthesis in striatum The typical antipsychotics, haloperidol, and atypical antipsychotics which possess high-affinity D2 receptor antagonist activity, such as risperidone and olanzapine, were found to significantly increase TH phosphorylation In contrast, ITI-007, administered at a dose level (3 mg/kg, p.o.) above the IC50 for blockade of DAMPH hyperactivity had no significant effect on phosphorylation at S40, showing a biochemical response at this site similar to that of aripiprazole and clozapine Effect on dopamine neurotransmission The effects of ITI-007 on striatal dopamine neurotransmission were monitored by measurement of levels of dopamine (DA), 3,4dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) either after acute or chronic admnistration. Acute or chronic administration of haloperidol or risperidone resulted in significant increases in the metabolism of dopamine, as measured by elevated DOPAC/DA and HVA/DA ratios Aripiprazole had a small effect on DOPAC/DA and HVA/DA ratios. ITI-007, administered at three dose levels representing a ~10-fold range encompassing the effective dose level for blockade of D-AMPH hyperactivity, had no significant effect on the DOPAC/DA or HVA/DA ratio, relative to vehicle control, measured after either acute or chronic administration. Effect of acute (2 h) or chronic (21 day) daily treatment with haloperidol, risperidone, aripiprazole, or ITI-007 on HVA/DA and DOPAC/DA ratios in rat striatal tissue Measurement of forelimb catalepsy in mice In order to assess the potential of IT-007 to elicite striatal motor side effects was evaluated using mouse forelimb catalepsy model. Forelimb catalepsy was measured using the bar grip test. Mice receiving IT-007 did not exhibit significant forelimb catalepsy, compared with vehicle control mice. In contrast, mice receiving oral administration of haloperidol exhibited profound forelimb catalepsy at each time point measured. IT-007 (Lumateperone) had no effect on presynaptic dopamine measures, including dopamine turnover, TH phosphorylation. The absence of functional effects on multiple measures of striatal dopamine neurotrasmission indicate that IT-007 also may act as a partial agonist at presynaptic dopamine D2 receptors. Preferential effects on mesocortical /mesolimbic pathways The ability of IT-007 to increase extracellular levels of dopamine in the medial prefrontal cortex was compared with the striatum using in vivo microdialysis. Dopamine and DOPAC levels were measured simultanwously in rats prepared with microdialysis probes in both the mPFC and striatum In summary, ITI-007 preferentially increased DA efflux in the mPFC compared with striatum Effect on GluN2B receptor phosphorilation state in nucleus accumbens Glutamate neurotransmission, mediated through NMDA-type receptors, is deficient in schizophrenia patients. Subanesthetic doses of NMDA receptor antagonists, like ketamine, induce psychotomimetic symptoms in humans. Thus, an increase of NMDA receptor activity would be expected to reduce psychosis. IT-007 increased tyrosine 1472 phosphorilation of mesolimbic GluN2B-type NMDA receptors in vivo, a modification that is known to direct GluN2b trafficking increasing synaptic NMDA activity. The data support the concept that IT-007 exerts molecular effects in the nucleus accumbens promoting glutamatergic neurotransmission. Cmax 1-2 h, SS 5 days Pharmacokinects variable Extensive metabolism: UGT1A4, UGT2B15, aldoketoreductase (AKR)1C1, AKR1B10, AKR1C4, CYP3A4, UGT1A1, CYP2C8 and CYP1A2 Coadministration of lumateperone with CYP3A4 inducers should be avoided since coadministration decreases the exposure of lumateperone. Coadministration of lumateperone with moderate or strong CYP3A4 inhibitors increases lumateperone exposure, which may increase the risk of toxicity. Coadministration of lumateperone with UGT inhibitors should be avoided since coadministration may increase the exposure of lumateperone and/or its metabolites. Although Positive and Negative Syndrome Scale total scoredouble-blind, phase III trial. The efficacy of lumateperone in patients the with acute schizophrenia was demonstrated in a randomized, multicentre, In this study, 450 patients reduction aged 18–60 years receiveof lumateperone tosylate 60 or 40 mg of were 15.6 randomized in the to42mg lumateperone group was(equivalent to 42 or 28 mg, respectively, of the active moiety lumateperone) placebo once daily for 4 weeks. numerically andorstatistically different from the reduction in the this relatively placebo effect Syndrome affectedScale the(PANSS) total score versus The primary endpoint wasplacebo the changegroup, from baseline to day 28 in high the Positive and Negative effect size in this study. placebo. In the prespecifiedultimate modified intentionto-treat analysis (n = 435), the least squares (LS) mean change from baseline in the PANSS total score at day 28 was − 14.5 in the lumateperone 42 mg once daily group compared with − 10.3 in the placebo group (LS mean difference − 4.2; p = 0.02). The treatment effect in the lumateperone 28 mg once daily group (vs placebo) was not statistically significant (LS mean difference − 2.6). At day 28, significant (p < 0.05) improvements versus placebo were also observed with lumateperone 42 mg once daily on the PANSS positive symptom and general psychopathology subscales, and in psychosocial function as measured by the PANSS-derived prosocial factor score and the Personal and Social Performance (PSP) scale. Results From a 12-Month Open-label Safety Study of Lumateperone (ITI-007) in Patients with Stable Symptoms of Schizophrenia Christoph U. Correll, MD1; Kimberly E Vanover, PhD2; Suresh Durgam, MD2; Robert Davis, PhD2; William Rowe, MSN2; Sharon Mates, PhD2; and Andrew Satlin, MD In the 1-year open-label study, 107 patients had completed 1 year of treatment. Only 4 treatment-emergent adverse event (TEAEs) occurred in ≥5% of patients (weight decrease, dry mouth, headache and diarrhea); the majority of AEs were mild or moderate in intensity. Most metabolic parameters and mean prolactin levels decreased from SOC baseline, as did mean body weight and BMI. Based on AE reporting and EPS/motor symptom scales, lumateperone treatment was associated with minimal EPS risk. Lumateperone 42mg treatment was associated with significant reductions in PANSS Total score from baseline, with continuing PANSS improvement throughout the study. In patients with moderateto- severe depression symptoms at baseline (CDSS>5), mean CDSS scores decreased from 7.4 (baseline) to 3.1 (Day 300); 60% of patients met Calgary Depression Scale (CDSS) ( the most widely used scale for assessing depression in schizophrenia) response criteria (50% improvement from baseline) by Day 75 and this response rate was maintained through day 300. Similar magnitude of CDSS improvement was seen regardless of concurrent antidepressant therapy. Results From Subgroups of Patients With Negative and Depression Symptoms Approximately a third of the patients met the criteria for prominent negative symptoms at baseline and were included in an exploratory a priori specified subgroup analysis of treatment effects on negative symptoms in this acutely exacerbated population. In this subgroup, 60 mg ITI-007 reduced the severity of symptoms as reflected by the PANSS negative symptoms subscale (ES 5 .34). In contrast, the improvement in negative symptoms with risperidone was minimally less than that with placebo (ES 5 2.02). Thirteen percent of patients met the criteria of comorbid symptoms of depression at baseline and were included in this subgroup analysis. ITI-007 60 mg significantly reduced the total PANSS score and the CDSS score in this subgroup with an ES of approximately 1 on both measures, while risperidone showed substantially smaller ESs. First, schizophrenia is an illness that typically requires long-term treatment with antipsychotics. The ongoing long-term studies results will be crucial. Second, as noted by the study authors, only the 42-mg dose has separated from placebo in published studies. Neither a lower (28 mg) nor a higher (84 mg) dose has demonstrated efficacy. This finding creates an as yet unexplained narrow therapeutic window. Third, lumateperone does not appear to offer unique efficacy about negative symptoms. Finally, it is also an open question whether lumateperone has equivalent or greater efficacy to the most effective drugs or whether it is a more metabolically friendly but modestly efficacious antipsychotic.
