Efficacy and Safety of Lumateperone

for Treatment of Schizophrenia

 Introduction
• Schizophrenia is a frequently chronic and debilitating
disorder that affects approximately 1% of the general
population.

• It is characterized by psychotic symptoms, cognitive

impairment and negative symptoms
 Introduction

• Psychotic (positive) symptoms include delusions,

hallucinations, and disordered thinking. These symptoms
are accompanied by cognitive impairment (abnormalities
in thinking, reasoning, attention, memory, and perception),
impaired insight and judgment,

• negative symptoms including loss of motivation (avolition),

loss of emotional range (restricted affect), a decrease in
spontaneous speech (poverty of speech) , anhedonia (lack
of sexual pleasure) and social isolation
 Introduction
• What are problems associated with old treatment ?
• 1-current antipsychotic therapy is often effective for
improving positive symptoms associated with
schizophrenia efficacy is limited for negative symptoms,
cognitive impairment, and social functioning.
• 2-current treatments are associated with substantial
adverse effects, including motor impairments, prolactin
abnormalities, weight gain, metabolic disturbances, and
cardiovascular risk factors.
• 3-these effects add to the already increased morbidity and
mortality associated with schizophrenia.
 Introduction
• What is the mechanism of lumateperone ?
• Lumateperone(lumateperonetosylate, ITI-007) is a
mechanistically novel investigational agent for
schizophrenia.

• The mechanism of action of lumateperone is unique

because it simultaneously modulates serotonin,
dopamine, and glutamate neurotransmission, the key
neurotransmitters implicated in serious mental illness.
 Introduction
continue

• Specifically, lumateperone acts as a potent serotonin 5-

HT2A receptor antagonist, a dopamine D2 receptor
presynaptic partial agonist and postsynaptic antagonist,
aD1 receptor–dependent modulator of glutamate, and
a serotonin reuptake inhibitor.
• In addition, lumateperone lacks interaction with off-
target receptors that may contribute to the adverse
effects of other antipsychotic drugs.
 Introduction
• What is the pharmacokinetic of novel antipsychotic
drug?
• Lumateperone is rapidly absorbed, with an effective half-
life of 13 to 21 hours for lumateperone and metabolites,
supporting once-daily administration.
• What are the difference between novel antipsychotic
drug and old one ?
• 1- first generation act only on dopamine
neurotransmitter and second generation in addition to
dopamine , act on serotonin .
• 2- lower incidence of side effects.
 Introduction
• In December 2019,
• lumateperone received its first global approval in the USA
for the treatment of schizophrenia in adults.

• The drug is also under clinical development for bipolar

depression, behavioural disorders associated with
dementia and Alzheimer’s disease, sleep maintenance
insomnia and major depressive disorders
 Introduction
• The recommended dosage of lumateperone is 42 mg
administered orally once daily with food.

• Lumateperone carries a boxed warning stating that

elderly patients with dementia-related psychosis are at
an increased risk of death; the drug is not approved for
the treatment of dementia-related psychosis
 Methods
• When and where are curried this study?
• This randomized clinical trial was conducted from
November 13, 2014, to July 20, 2015.

• Data analysis was performed from August 13 to

September 15, 2015.

• Patients were recruited at 12 US clinical sites and

admitted to an inpatient research unit for a screening
period of 2 to7days before randomization .
 Methods
• All participating patients provided written informed
consent, and data were deidentified.

• The trial followed the Consolidated Standards of

Reporting Trials (CONSORT) reporting guideline.
 Methods
• Patient selection
• Eligible participants were aged 18 to 60 years and had a
clinical diagnosis of schizophrenia according to the DSM-
5.

• Patients were included if they were experiencing an acute

exacerbation of psychosis, defined as a total score on the
Brief Psychiatric Rating Scale15 of 40 or higher and the
patients should have onset of the acute episode within 4
weeks of screening.
 Methods
• Patients were required to have a score of 4 or higher, indicating
moderate to severe disease severity, on the Clinical Global
Impression–Severity of Illness (CGI-S) at screening and baseline.

• Patients had to have a previous response to antipsychotic therapy

• Severity of illness was confirmed at baseline by a Positive and

Negative Syndrome Scale (PANSS) total score of 70 or higher,
indicating moderate to extreme symptoms of schizophrenia.

• Design , intervention and randomization were illustrated in the

following follow chart and patient disposition
 Methods
• Measures and Procedures
• 1-the PANSS total score vs placebo
• 2-the CGI-S score
• 3-the PANSS positive, negative, and general
psychopathology subscales,
• 4-the Personal and Social Performance (PSP) scale,
 Methods
• 5-Safetywasassessedby treatment-emergent adverse
events (TEAEs), modified physical examinations, 12-lead
(ECGs), vital signs, and clinical laboratory tests

• Selected safety end points (fasting total cholesterol,

high-density lipoprotein cholesterol, low-density
lipoprotein cholesterol, glucose, insulin, triglycerides,
and prolactin levels) for treatment groups were
compared with placebo using MMRM

• measured only twice during the study (once at screening

or baseline and once after baseline).
 Methods
• 6-Motor tolerability and safety were assessed by the
Simpson-Angus Scale,
• 7-Barnes Akathisia Rating Scale,24 and Abnormal
Involuntary Movement Scale.
• 8-Suicidality was evaluated by the Columbia Suicide
Severity Rating Scale.
• These measures were assessed weekly by remote
structured clinical interviews conducted via secure
videoconferencing (MedAvante Inc).
• Highly trained centralized raters, independent of the
study sites and blinded to treatment and study visit, were
used to minimize baseline score inflation
 Methods
• 5. female subjects must be of non-childbearing

• 6. subject must be able to provide informed consent, where the

subject are fluent and literate in a language spoken by the
Investigator and staff;

• 7. subject must be willing to be hospitalized for the duration of the

inpatient period of the study, and willing to comply with all
Investigator and staff instructions.
 Methods
• Statistical analysis
• In each treatment arm, 132 patients were expected to
have evaluable data.
• The study was designed to have 90% power to
demonstrate an effect size of0.4.
• The treatment effect on the primary efficacy end point
was evaluated using a mixed-effects model for repeated
measures (MMRM).
• .
 Methods
• Statistical analysis
• All prespecified efficacy analyses were performed for
a prespecified modified intent-to-treat analysis set,
which includes all randomized patients who received
at least 1 dose of study medication and had a valid
baseline and at least 1 valid post dose assessment.

• SAS statistical software, version 9.4 or higher (SAS

Institute Inc) was used for the statistical analyses
 Results
• Baseline demographic and clinical characteristics
were similar across groups as shown in the
following table
Results
 Results
• Efficacy
• Treatment with 42 mg of lumateperone demonstrated a
statistically significant improvement in change from
baseline to day 28 inPANSS total score vs placebo
• Statistically significant differences from placebo in the
PANSS total score were observed at the day 8 assessment
and continued through the day 28 assessment with 42 mg
of lumateperone .
• Interaction analyses suggested consistent treatment
effects for demographic subgroups of race (black vs not
black), ethnicity (Hispanic/Latino vs not Hispanic/Latino),
age (≤40 vs >40 years), and sex for the comparison of
42mg of lumateperone vs placebo in PANSS total score.
 Results
• Individuals in the 42 mg of lumateperone group also met
the key secondary end point with a statistically significant
change in CGI-S score from baseline to day 28 vs placebo

• there was no significant difference between the 28mg of

lumateperone group and the placebo group for the
primary end point, the groups significantly differed on
CGI-S
 Results
• with 42 and 28mg of lumateperone significantly
improved the PANSS positive subscale score from
baseline to day 28 compared with placebo
• Statistically significant improvements vs placebo were
observed with 42mg of lumateperone in the general
psychopathology subscale score and in psychosocial
function.
 Results
• Safety
• Treatment-emergent adverse events occurred in 97
patients (64.7%) in the 42mg of lumateperone group, 85
(56.7%) in the 28 mg of lumateperone group, and 75
(50.3%) in the placebo group.
• TheTEAEs occurring in either lumateperone group in
5%or more of patients and more than 2 times the rate in
the placebo group
 Result
• Two patients experienced severe-intensity TEAEs and
discontinued treatment: orthostatic hypotension in the
42 mg of lumateperone group) and convulsions in the
28mg of lumateperone group; this patient had
preexisting risk factors and relevant medical history
regarding seizure

• All other TEAEs were mild or moderate in intensity.

 Result
• Safty
• No serious and unexpected drug reactions were reported
during the study
• There was no increase in suicidal ideation or behavior with
lumateperone at either dose as measured by TEAEs or the
Columbia Suicide Severity Rating Scale
• No extrapyramidal symptoms (EPS)–related TEAEs
occurred in 5%ormore of patients in any treatment arm
• There were no significant mean changes in metabolic
parameters frombaseline to day 28 compared with
placebo
 Discussion

• Treatment with 42 mg of lumateperone compared with

placebo significantly improved symptoms in patients
with acute exacerbation of schizophrenia without
causing many of the adverse effects commonly observed
with currently available antipsychotics
• Treatment with 42 mg of lumateperone significantly
improved symptoms, with significant reductions
beginning at the first week and maintained throughout
treatment.
 Discussion
• A responder analysis indicated that 54 patients (36.5%)
who received A higher dose (84mg) of lumateperone
(equivalent to 120 mg of lumateperone tosylate) was
not effective in a previous study
 Discussion
• patients treated with 28 mg of lumateperone did not
have a statistically significant decrease in the PANSS
total score, decreases on the PANSS positive symptom
subscale and on the CGI-S outperformed placebo,
establishing a dose-response curve for the efficacy of
lumateperone.
• Improvements in psychosocial function were suggested
by significant improvements assessed by the siterated
PSP and the centrally rated PANSS-derived prosocial
factor, which was previously identified via factor analysis
in patients with schizophrenia and mood disorders and
has been used to assess other antipsychotics.
 Dicussion
• Given the high burden of schizophrenia, including risk of
EPS, parkinsonism and akathisia, hyperprolactinemia,
weight gain, dyslipidemia, diabetes, and cardiovascular
diseases tolerability and safety issues associated with
many antipsychotics lead to non adherence

• In this study, treatment with lumateperone demonstrated

a safety profile similar to placebo, confirming results
observed in a previous clinical trial.
 Discussion
• Antipsychotics are, in general, associated with risk of
seizure, however, the specific risks associated with
lumateperone could not be determined from this study
because patients that develop seizure with a history of
seizure from beginning of the study .

• The adverse events in the lumateperone groups that

occurred at a clinically meaningful rate were sedation,
somnolence, fatigue, and constipation, which all were
predominantly mild.
 • Conclusions
• The unique pharmacologic mechanisms of
lumateperone seem to confer antipsychotic efficacy with
favorable safety and tolerability.

• The efficacy and safety profiles of lumateperone may

differ in important ways from existing treatments for
patients with schizophrenia.
Thanks for all