Primary Endpoint
Adding REXULTI® (brexpiprazole) amplified
antidepressant symptom response vs placebo when taken with an antidepressant

Change in MADRS from Baseline at Week 6 in Adult Patients for Adjunctive
Treatment of MDD (Study 1 and Study 2)1

Change in MADRS from Baseline at Week 6 in Adult Patients for Adjunctive
Treatment of MDD (Study 1 and Study 2)1

Change from Baseline in MADRS Total Score by Study Visit (Week) In
Patients with MDD in Adults (Study 1)1

Change from Baseline in MADRS Total Score by Study Visit (Week) In
Patients with MDD in Adults (Study 1)1

It is unknown if the differences observed at time points earlier than Week 6 represent clinically relevant treatment effects.

Mean MÅDRS before prospective treatment (SD): 31.0 (4.7). Mean MÅDRS after prospective treatment (SD): 27.1 (5.7). Mean MÅDRS at randomization (SD): ADT + placebo (n=178), 27.3 (5.6); ADT + REXULTI 2 mg/day (n=175), 26.9 (5.7).2

MDD study design and efficacy summary

REXULTI was studied in two 6-week, double-blind, placebo-controlled, fixed-dose pivotal trials of adult patients meeting DSM-IV-TR criteria for MDD. After a screening phase of 1-4 weeks, patients entered into an 8-week prospective treatment phase with an SSRI or SNRI (+ single-blind placebo). Subsequently, patients having persistent symptoms without substantial improvement throughout the course of treatment and who met inclusion criteria were randomized to receive adjunctive REXULTI or placebo.3,4

Primary endpoint was the mean change from baseline to Week 6 in the MÅDRS total score in the randomization phase.3,4

In the second pivotal trial, at the 3 mg/day maximum dose, the mean change from baseline (SE) at 6 weeks (randomized phase) was -8.3 (0.5) for ADT + REXULTI (n=213) vs -6.3 (0.5) for ADT + placebo (n=203), and the MÅDRS baseline (SD) for ADT + REXULTI and ADT + placebo was 26.5 (5.3) and 26.5 (5.2), respectively.4

Full study design

REXULTI® (brexpiprazole)—full MDD study design

Full-MDD-study-design
Full-MDD-study-design
1.
1-4 weeks

Screening—patients with partial response to antidepressant treatment entered the clinical trial with1,4:

  • Partial response to 1 to 3 courses of antidepressant treatment in current episode
  • MDD ≥8 weeks’ duration 
     
  • HAM-D17 score ≥18 
  • <50% reduction in symptoms via ATRQ

Study 1 (N=1227), Study 2 (N=2310) 

Group
2.
8 weeks

Prospective phase—clinical investigators initiated a different antidepressant treatment (+ single-blind placebo) at optimal dose and duration to confirm persistent partial response1,4,a

SSRIs

Escitalopram

Sertraline

Paroxetine CR

Fluoxetine

10 or 20 mg/day

100, 150, or 200 mg/day

37.5 or 50 mg/day

20 or 40 mg/day

SNRIs

Duloxetine DR

Venlafaxine XR

40 or 60 mg/day

75, 150, or 225 mg/day

Study 1 (N=826), Study 2 (N=1532)1,4

Group
3.
6 weeks

Randomized double-blind phase—patients with confirmed partial response were randomized to add REXULTI or remain on antidepressant treatment alone (+ placebo)1,4

Study 11 (n=379)

ADT + REXULTI 
2 mg/day (n=175)c

ADT + Placebo
(n=178)c

Study 24,b (n=677)

ADT + REXULTI 
3 mg/day (n=213)c

ADT + Placebo
(n=203)c

Study 1 (N=826), Study 2 (N=1532)1,4

Group
  • Titration—all patients randomized to REXULTI initiated treatment at 0.5 mg/day during Week 1. At Week 2, the REXULTI dose was increased to 1 mg/day and either maintained at 1 mg/day or increased to 2 mg/day or 3 mg/day, based on treatment assignment, from Week 3 onward
  • Primary endpoint—change from baseline to Week 6 in MÅDRS in the randomization phase3,4

MÅDRS
clinician-rated
symptoms5:

  • Apparent sadness
  • Reported sadness
  • Lassitude
  • Inability to feel
  • Inner tension
  • Inner tension
  • Reduced appetite
  • Reduced sleep
  • Concentration difficulties
  • Pessimistic thoughts
  • Suicidal thoughts
  • Pessimistic thoughts
  • Suicidal thoughts

aInclusion criteria for the randomized phase: <50% reduction in HAM-D17 Total Score and ≥14 HAM-D17 score at Week 8 of the prospective phase; <50% reduction in MÅDRS Total Score and Clinical Global Impression-Improvement Score of ≥3 at each scheduled visit of the prospective phase.3,4

bThe efficacy and safety of REXULTI 1 mg/day were also studied in Study 2 (n=211). 

cn values represent efficacy population per final protocol.3,4

ATRQ, Antidepressant Treatment Response Questionnaire; CR, controlled release; DR, delayed release;  HAM-D17, 17-Item Hamilton Depression Rating Scale; MÅDRS, Montgomery-Åsberg Depression Rating Scale; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; XR, extended release.

The efficacy and safety of REXULTI were also studied in patients randomized to receive 1 mg/day in Study 2 (n=211). Results for the ADT + REXULTI 1 mg group for the primary efficacy parameter were not statistically significant when compared with ADT + placebo.4

ADT, antidepressant treatment; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision); MÅDRS, Montgomery-Åsberg Depression Rating Scale; SD, standard deviation; SE, standard error; SNRI, serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor.

Contraindication

In patients with known hypersensitivity to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.

 

Additional Analysis
REXULTI® (brexpiprazole) + ADT separated from ADT + placebo as early as Week 1 and continued to Week 63

The weekly time points prior to Week 6 were not powered for statistical comparison and are descriptive only. Primary endpoint was the mean change from baseline to Week 6 in the MÅDRS total score in the randomization phase.

Mean change from baseline in MÅDRS total scorea,b

madrs-total-score-desktop
madrs-total-score-mob

aBaseline mean MÅDRS scores were 27.3 for ADT + placebo (n=178) and 26.9 for ADT + REXULTI (n=175).

bp values are based on mixed model repeated-measures analysis.

*p=nominal.

ADT, antidepressant treatment; LS, least squares; MÅDRS, Montgomery-Åsberg Depression Rating Scale.

 

Secondary Endpoint
REXULTI® (brexpiprazole) SDS data from a pooled analysis of three 6-week randomized studies in adult patients with MDD

SDS functioning data for adult patients treated with REXULTI + ADT vs ADT + placebo6

SDS data
SDS data

The results require cautious interpretation as the statistical hierarchical testing procedure was terminated after the primary endpoint test.

The key secondary endpoint was change from baseline to Week 6 in SDS mean score across all studies.6

In 2 mg/day or 3 mg/day arms, the mean change in SDS total score from baseline (SE) at Week 6 was -1.43 (0.09) for ADT + REXULTI (N=555) vs -1.03 (0.09) for ADT + placebo (N=564).

 

Sheehan Disability Scale (SDS):
The SDS measures functional disability on 3 items:

  • Work/studies
  • Social life
  • Family life

Patients use visual scales to rate the extent to which each of the 3 items has been disrupted by their symptoms from 0 to 10.7

 

SDS Scale

ADT, antidepressant treatment; LE, latest estimate; LS, least squares; MDD, major depressive disorder; SD, standard deviation; SDS, Sheehan Disability Scale; SE, standard error.

 

Post-hoc analysis
REXULTI® (brexpiprazole) + ADT change in MÅDRS total score in adult patients with MDD—with or without symptoms of anxiety

Using pooled data from 3 similarly designed 6-week randomized studies, including both 2 mg and 3 mg doses, changes were evaluated in MÅDRS total score in patients with MDD—with and without symptoms of anxiety.3,4,8,a,b

Effect on MÅDRS total score in patients with MDD, stratified
by the presence or absence of symptoms of anxiety at baseline:

Patients with MDD with symptoms of anxiety

Patients with symptoms of anxiety vs patients without symptoms of anxiety chart Post-hoc Analysis chart Randomization n 0 - 12 -3 -6 -9 0 6 1 2 3 4 5 W eek Antidepressant + REXULTI 2-3 mg/day (n=287) Antidepressant + placebo (n=282) LS mean (SE) change in MÅDRS total score from randomization

Patients with MDD without symptoms of anxiety

Patients with symptoms of anxiety vs patients without symptoms of anxiety chart Post-hoc Analysis chart 0 6 1 2 3 4 5 Randomization 0 - 12 -3 -6 -9 W eek Antidepressant + REXULTI 2-3 mg/day (n=290) Antidepressant + placebo (n=301)

Effect on MÅDRS total score in patients with MDD, stratified by the presence or absence of symptoms of anxiety at baseline:

Patients with MDD with symptoms of anxiety

patients with symptoms of anxiety vs patients without symptoms of anxiety chart

Patients with MDD without symptoms of anxiety

patients with symptoms of anxiety vs patients without symptoms of anxiety chart

Study limitations: These analyses did not assess the effect of treatment on symptoms of anxiety. Patients with anxiety symptoms had a higher MÅDRS total score at baseline and the effects of anxiety and illness severity on outcomes were not differentiated. Statistical adjustments were not made for multiple comparisons, potentially inflating the type 1 error rate.

Adding REXULTI reduced mean MÅDRS total score by over 2 points in patients with MDD with or without symptoms of anxiety:

  • For patients with symptoms of anxiety, the LS mean change at Week 6 between ADT + REXULTI 2-3 mg/day and ADT + placebo was -2.19 (95% CI: -3.60 to -0.78)8
  • For patients without symptoms of anxiety, the LS mean change at Week 6 between ADT + REXULTI 2-3 mg/day and ADT + placebo was -2.34 (95% CI: -3.58 to -1.10)8

aBaseline demographics and clinical characteristics were similar between treatment subgroups; however, patients with symptoms of anxiety were more likely to be female and have a higher MÅDRS total score at baseline compared with patients without symptoms of anxiety.8

bOf the patients that received an ADT plus REXULTI 2 mg, 3 mg, or placebo, 49% had symptoms of anxiety, defined as a score of ≥7 at baseline on the HAM-D anxiety/somatization factor.8

ADT, antidepressant treatment; CI, confidence interval; HAM-D, Hamilton Rating Scale for Depression; LS, least squares; MÅDRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; SE, standard error.

Important Warning and Precaution for Cerebrovascular Adverse Events, Including Stroke

In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.

Continue exploring REXULTI

Safety Profile ICN

See the safety profile
demonstrated across 2 clinical trials.

Pharmacodynamic ICN

Learn about binding affinities
across neurotransmitter systems.

IMPORTANT SAFETY INFORMATION
and INDICATIONS

 
  • Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults
  • Treatment of schizophrenia in adults and pediatric patients ages 13 years and older
  • Treatment of agitation associated with Alzheimer’s dementia (AAD)
ISI Block Title

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors. The safety and effectiveness of REXULTI have not been established in pediatric patients with MDD.

Contraindication: In patients with known hypersensitivity to brexpiprazole or any of its components. Reactions have included: rash, facial swelling, urticaria and anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. REXULTI is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer’s disease.

Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported in association with administration of antipsychotic drugs, including REXULTI. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of REXULTI, intensive symptomatic treatment, and monitoring.

Tardive Dyskinesia (TD): Risk of TD, and the potential to become irreversible, appear to increase with duration of treatment and total cumulative dose of antipsychotic drugs. TD can develop after relatively brief treatment periods, at low doses, or after discontinuation of treatment. For chronic treatment, use the lowest dose and shortest duration of REXULTI needed to produce a clinical response. If signs and symptoms of TD appear, drug discontinuation should be considered.

Metabolic Changes: Atypical antipsychotic drugs, including REXULTI, have caused metabolic changes including:

  • Hyperglycemia/Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis, hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication and monitor periodically during long-term treatment.
  • Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment.
  • Weight Gain: Weight gain has been observed in patients treated with REXULTI. Monitor weight at baseline and frequently thereafter.

Pathological Gambling and Other Compulsive Behaviors: Intense urges, particularly for gambling, and the inability to control these urges have been reported while taking REXULTI. Other compulsive urges have been reported less frequently. Prescribers should ask patients or their caregivers about the development of new or intense compulsive urges. Consider dose reduction or stopping REXULTI if such urges develop.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in this class. Monitor complete blood count in patients with pre-existing low white blood cell count (WBC)/absolute neutrophil count or history of drug-induced leukopenia/neutropenia. Discontinue REXULTI at the first sign of a clinically significant decline in WBC and in patients with severe neutropenia.

Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. Monitor in patients vulnerable to hypotension, and those with cardiovascular and cerebrovascular diseases.

Falls: Antipsychotics may cause somnolence, postural hypotension, motor, and sensory instability, which may lead to falls causing fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy.

Seizures: REXULTI may cause seizures and should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Body Temperature Dysregulation: Use REXULTI with caution in patients who may experience conditions that increase body temperature (e.g., strenuous exercise, extreme heat, dehydration, or concomitant use with anticholinergics).

Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotics, including REXULTI, and should be used with caution in patients at risk for aspiration.

Potential for Cognitive and Motor Impairment: REXULTI has the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about operating hazardous machinery, including operating motor vehicles, until they are reasonably certain REXULTI does not affect them adversely.

Concomitant Medication: Dosage adjustments are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors or strong CYP3A4 inducers.

Most commonly observed adverse reactions: In clinical trials of adults, the most common adverse reactions were:

  • Major Depressive Disorder (MDD) (adjunctive treatment to antidepressant therapy; ≥5% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased, somnolence, and akathisia.
  • Schizophrenia (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): weight increased. Adverse reactions in patients 13 to 17 years of age were generally similar to those observed in adult patients.
  • Agitation associated with dementia due to Alzheimer’s disease (≥4% incidence and at least twice the rate of placebo for REXULTI vs. placebo): nasopharyngitis and dizziness.

Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy: Adequate and well-controlled studies to assess the risks of REXULTI during pregnancy have not been conducted. REXULTI should be used during pregnancy only if the benefit justifies the risk to the fetus.

Lactation: It is not known if REXULTI is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch).

INDICATIONS

REXULTI is indicated for:

  • Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD) in adults
  • Treatment of schizophrenia in adults and pediatric patients ages 13 years and older
  • Treatment of agitation associated with dementia due to Alzheimer’s disease

Limitations of Use: REXULTI is not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer’s disease

Please see FULL PRESCRIBING INFORMATION, including BOXED WARNING.