Lumateperone for Schizophrenia

Out of the Pipeline Lumateperone for schizophrenia Jonathan M. Meyer, MD ntipsychotic nonadherence is a Table 1 This novel oral known contributor to relapse risk Fast facts about lumateperone antipsychotic’s among patients with schizophrenia.1 favorable A Brand name: Caplyta Because relapse episodes may be associated Class: Oral atypical antipsychotic tolerability with antipsychotic treatment resistance, this profile may must be avoided as much as possible by Indication: Adults with schizophrenia appropriate medication selection.2 Adverse Approval date: December 20, 2019 promote improved effect burden is an important factor lead- Availability date: March 31, 2020 adherence ing to oral antipsychotic nonadherence, Manufacturer: Intra-Cellular Therapies, Inc., with patient-derived data indicating that New York, NY extrapyramidal symptoms (EPS) (odds ratio Dosing forms: 42-mg oral capsule (taken with food). Note: This is equivalent to the [OR] 0.57, P = .0007), sedation/cognitive 60-mg dose of lumateperone tosylate used adverse effects (OR 0.70, P = .033), prolac- in clinical trials tin/endocrine effects (OR 0.69, P = .0342), Recommended dosage for schizophrenia: and metabolic adverse effects (OR 0.64, 42 mg/d with food. Avoid use with moderate or strong cytochrome P450 3A4 (CYP 3A4) P = .0079) are all significantly related to inhibitors or CYP 3A4 inducers or in patients 3 lower rates of adherence. With this in mind, with moderate or severe hepatic impairment successive generations of antipsychotics as defined by Child-Pugh Criteria (Child-Pugh have been released, with fewer tolerability B or C). These are not contraindications issues present than seen with earlier compounds.1,4 Although these newer second- generation antipsychotics (SGAs) have not proven more effective for schizophrenia lower affinity for dopamine D2 receptors than those first marketed in the 1990s, they (Ki 32 nM), along with low affinity for alpha generally possess lower rates of EPS, hyper- 1-adrenergic receptors (Ki 73 nM), and mus- prolactinemia, anticholinergic and anti- carinic and histaminergic receptors (Ki > 100 histaminic properties, metabolic adverse nM).6,7 However, there are some distinguish- effects, and orthostasis.5 This improved ing features: the ratio of 5HT2A receptor adverse effect profile will hopefully increase affinity to D2 affinity is 60, greater than that the chances of antipsychotic acceptance in of other SGAs such as risperidone (12), patients with schizophrenia, and thereby Dr. Meyer is a Psychopharmacology Consultant, California Department promote improved adherence. of State Hospitals, Sacramento, California; Clinical Professor of Lumateperone (Caplyta) is a novel oral Psychiatry, University of California, San Diego, La Jolla, California; and Deputy Editor of CURRENT PSYCHIATRY. antipsychotic approved for the treatment of Disclosure adult patients with schizophrenia (Table 1). It In the past 12 months, Dr. Meyer has received speaking or advising possesses some properties seen with other fees from Acadia Pharmaceuticals, Alkermes, Allergan (now Abbvie), Intra-Cellular Therapies, Janssen Pharmaceutica, Neurocrine, Otsuka SGAs, including high affinity for sero- America, Inc., Sunovion Pharmaceuticals, and Teva Pharmaceutical Current Psychiatry tonin 5HT2A receptors (Ki 0.54 nM) and Industries Ltd. Vol. 19, No. 2 33 Out of the Pipeline Figure Dopamine D2 receptor occupancy over 24 hours at steady state in patients with schizophrenia after an oral dose of lumateperone 42 mg 100 80 60 Clinical Point eceptor occupancy 40 Lumateperone’s ratio of 5HT2A receptor affinity to D2 affinity 20 % Striatal D2 r is 60, greater than that of other SGAs 0 1 hour 3 to 4 hours 7.5 hours 24 to 27 hours Source: Reference 9 olanzapine (12.4) or aripiprazole (0.18)8; at that lumateperone does not increase pre- steady state, the D2 occupancy remains <40% synaptic dopamine release, indicating that (Figure) and the corresponding rates of EPS/ it possesses agonist properties at the pre- akathisia were only 6.7% for lumateperone vs synaptic D2 short receptor.10 That property 6.3% for placebo in short-term clinical trials.7,9 may explain how lumateperone functions as an antipsychotic despite low levels of D2 How it works receptor occupancy.10 A unique aspect of lumateperone’s phar- Another hypothesis is based on our macology may relate to differential actions understanding of pimavanserin’s pharma- at presynaptic and postsynaptic dopamine cology. Pimavanserin is a selective 5HT2A D2 receptors. Other antipsychotics possess antagonist FDA-approved for the treatment comparable antagonist (or partial agonist) of Parkinson’s disease psychosis (PDP), properties at postsynaptic D2 receptors (the with extremely high receptor affinity (Ki D2 long isoform) and the presynaptic auto- 0.087 nM) and no appreciable binding at receptor (the D2 short isoform). By block- dopamine receptors.5 Pimavanserin not ing the presynaptic autoreceptor, feedback only treats PDP, but is being evaluated in Discuss this article at inhibition on dopamine release is removed; clinical trials for dementia-related psycho- www.facebook.com/ therefore, the required higher levels of post- sis, and has positive data for augmenting MDedgePsychiatry synaptic D2 receptor occupancy needed for antipsychotics when there is a low level of effective antipsychotic action (eg, 60% to D2 blockade.11,12 In a controlled trial, pima- 80% for antagonists, and 83% to 100% for vanserin added to risperidone, 2 mg/d, was partial agonists) may be a product of the as effective as risperidone, 6 mg/d, illus- need to oppose this increased presynaptic trating the point that near-saturation of the Current Psychiatry 34 February 2020 release of dopamine. In vitro assays show 5HT2A receptor can increase antipsychotic Out of the Pipeline efficacy when dopamine blockade is rela- but “differences in side-effects are more tively low. For risperidone, 2 mg/d, the marked.”18 expected D2 occupancy is only 60%.13 Until novel mechanisms are discovered Lumateperone also has moderate bind- that increase schizophrenia response rates, ing affinity for serotonin transporters the availability of newer antipsychot- (SERT) (Ki 33 nM). Serotonin transporter ics with more favorable tolerability pro- occupancy at the dose approved for schizo- files presents clinicians and patients with phrenia (42 mg/d) is approximately 30%,14 added options when adverse effects inter- below the ≥80% SERT occupancy seen with fere with prior treatment. In all phases of selective serotonin reuptake inhibitor (SSRI) the adult schizophrenia trial program for antidepressants; nevertheless, there is evi- luma teperone, 811 patients received short- dence for antidepressant effects seen in pre- term (4- to 6-week) exposure (dose range: clinical assays, schizophrenia studies, and 14 to 84 mg/d), while 329 had ≥6 months Clinical Point 8,15,16 phase III trials for bipolar depression. exposure and 108 had ≥1 year of expo- The efficacy of It is hypothesized that near-saturation of sure to the 42-mg/d dose. In these stud- the 5HT2A receptor might act synergisti- ies, there was no single adverse reaction lumateperone has cally with the modest extent of 5HT reup- leading to discontinuation that occurred been established in take inhibition to promote downstream at a rate >2%. The only adverse events that 2 pivotal, double- effects associated with effective antidepres- occurred at rates ≥5% and more than twice blind, placebo- sant treatments.8 In vivo data also showed the rate of placebo were somnolence/seda- controlled trials phosphorylation of N-methyl-d-aspartate tion (lumateperone 24%, placebo 10%), and receptor subunits and glycogen synthase dry mouth (lumateperone 6%, placebo 2%). kinase 3 beta (GSK3B), properties that could Nausea was present in 9% of the lumateper- impact cognition or negative symptoms in one group compared with 5% for placebo.7 patients with schizophrenia.8 In the short-term studies, the combined rate of EPS and akathisia was 6.7% for lumatep- Clinical implications erone and 6.3% for placebo.7 This difference Nonadherence with oral antipsychotics translates to a number needed to harm of among patients with schizophrenia is often 250 for these neurologic adverse effects. The related to adverse effects.17 The SGAs mar- functional impact of lumateperone’s gluta- keted since 2000 generally have lower rates matergic mechanisms is not well character- of sedation and metabolic and/or endocrine ized within the schizophrenia population, adverse events than earlier compounds, yet but the antidepressant potential has been each has limitations: studied for patients with bipolar depres- • asenapine: sedation and weight gain sion, with 1 positive phase III trial.19 • the partial agonists (aripiprazole, brex- piprazole, cariprazine): akathisia Efficacy in adults with schizophrenia. • lurasidone: dose-dependent EPS and The efficacy of lumateperone has been akathisia established in 2 pivotal, double-blind, • iloperidone: orthostasis.18 placebo-controlled trials. The first was a Ziprasidone is an exception, because it 4-week, phase II trial (Study 005) in which had low rates of most adverse effects in 335 adults age 18 to 55 with an acute exac- schizophrenia trials, but the need to take it erbation of schizophrenia were random- twice daily with a 500 kcal meal hampers ized in a 1:1:1:1 manner to lumateperone, its use. A meta-analysis of 32 oral antipsy- 42 mg/d (60 mg of lumateperone tosylate), chotics, including first-generation agents, luma teperone, 84 mg/d (120

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