Brexpiprazole is a new atypical antipsychotic approved for the treatment of schizophrenia and as an adjunctive therapy for major depressive disorder. A randomized controlled trial found brexpiprazole 4 mg to be effective for acute schizophrenia based on improvement in PANSS scores compared to placebo. Brexpiprazole was generally well-tolerated with mild to moderate adverse effects. While it shows potential, the study had limitations such as no active comparator and excluded certain patient populations. More research is still needed to determine brexpiprazole's efficacy and safety compared to other antipsychotics.

1. Brexpiprazole (Rexulti ®)
in antipsychotic therapy
Nina Chacko
Pharm.D. Candidate, Class of 2017
Ernest Mario School of Pharmacy
Rutgers, the State University of New Jersey

2. Objectives
• Define schizophrenia disease state and
pathophysiology
• Review current therapies available
• Examine brexpiprazole as a new therapy option
• Evaluate Beacon trial and determine clinical use
of brexpiprazole

3. Schizophrenia
• Neurodevelopmental disorder with genetic and
environmental components
• Worldwide prevalence: 1%
• Onset: late teens or early adulthood
• Risk increases with family relation
• 10% if related first-degree
• 40% if child of 2 schizophrenic parents
Meyer JM, et al. Goodman and Gillman’s; 2011

4. Symptoms
Positive Negative Cognitive
• Hallucinations
• Delusions
• Disorganized speech
• Disorganized/agitate
d behavior
• Apathy
• Avolition
• Anhedonia
• Alogia
• Impaired attention
• Impaired working
memory
• Impaired executive
function
Crimson M, et al. Pharmacotherapy, A physiologic approach; 2014

5. Pathophysiology

6. Pathophysiology:
Serotonin
• Structural similarities between hallucinogens and
serotonin
• Serotonergic receptors present on dopamine
neurons
• Stimulation lowers dopamine release
Crimson M, et al. Pharmacotherapy, A physiologic approach; 2014

7. DSM-V Criteria for Diagnosis
• 2 or more of the following, present for a significant portion of
1 month. At least one must be 1, 2, or 3:
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly disorganized or catatonic behavior
5. Negative symptoms (avoltion or less emotional expression)
• Decreased level of functioning
• Continuous signs for 6 months
• Rule out schizoaffective disorder, major depressive
disorder, or substance abuse
American Psychiatric Association. Diagnostic and Statistical Manual of
Mental Disorders. 5th ed. Arlington, VA: American Psychiatric
Association; 2013

8. Current Therapy Options
• First generation (typical) antipsychotics
• Chlorpromazine
• Haloperidol
• Mechanism: D2 receptor antagonists
• Most effective against positive symptoms
• Ineffective against negative symptoms
• Side effects: Extrapyramidal symptoms
• Akathisia
• Tardive dyskinesia
Crimson M, et al. Pharmacotherapy, A physiologic approach; 2014

9. Current Therapy Options
• Second generation (atypical) antipsychotics
• Risperidone
• Clozapine
• Aripiprazole
• Higher affinity for serotonin receptors than dopamine
receptors
• More effective against negative symptoms, as well as
positive
• Side effects: weight gain, metabolic abnormalities
Crimson M, et al. Pharmacotherapy, A physiologic approach; 2014

10. Brexpiprazole
• Otsuka Pharmaceuticals
• Indication: Monotherapy for
schizophrenia and adjunctive
therapy to treat major
depressive disorder (MDD)
• Serotonin-Dopamine Activity
Modulator (SDAM)
• 5HT1A partial agonist
• D2 partial agonist
• 5HT2A and α1B/2C antagonist
• Dose: Available orally in 0.25,
0.5 1, 2, 3, 4 mg tablets
Rexulti ® [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Co.; 2015

11. Pharmacokinetics
• Peak concentration in 4 hours; 95% bioavailable
• Highly plasma protein bound (>99%)
• Not affected by hepatic or renal impairment
• Mainly by CYP3A4 and CYP2D6
• Inactive metabolite (DM-3411)
• <1% excreted in urine unchanged
• <14% excreted in feces unchanged
• Half-life=91 hours
Rexulti ® [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Co.; 2015

12. Warnings/Precautions
• Increased mortality in elderly patients with dementia-related psychosis. Rexulti is
NOT approved for patients with dementia related psychosis
• Suicidal thoughts and behaviors in children, teenagers, and young adults
• Cerebrovascular Adverse reactions (stroke) in elderly patients with dementia-
related psychosis
• Neuroleptic Malignant Syndrome (NMS)
• Tardive Dyskinesia
• Metabolic changes
• Leukopenia, neutropenia, agranulocytosis
• Orthostatic Hypotension and Syncope
• Seizures
• Body Temperature Dysregulation
• Dysphagia
• Potential for Cognitive/Motor Impairment
Rexulti ® [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Co.; 2015

13. Brexpiprazole vs.
Aripiprazole
• Mechanism of Action:
• D2 partial agonist
• 5HT1A partial agonist
• 5HT2A antagonist
• Approved July 2015
• Less affinity for D2
receptor  less EPS
• Mechanism of Action:
• D2 partial agonist
• 5HT1A partial agonist
• 5HT2A antagonist
• Approved 2002
• More affinity for D2
receptor  more EPS
Maeda K J Pharmacol Exp Ther. 2014;350(3):589-604.

14. A multicenter, randomized, double-blind,
controlled phase 3 trial of fixed-dose
brexpiprazole for the treatment of adults with
acute schizophrenia (BEACON trial)
Kane JM, Skuban A, Ouyang J, et al.
Funded by: Otsuka Pharmaceutical Development &
Commercialization Inc. and H. Lundbeck A/S

15. Objective and Trial Design
• Objective: To analyze the efficacy, safety, and
tolerance of brexpiprazole versus placebo in
patients with acute schizophrenia
• Trial Design: Randomized, double-blind, placebo-
controlled, Phase 3 trial
• Patients from 64 study centers in 8 countries
• July 2011-January 2014
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

16. Study Population
Inclusion Criteria Exclusion Criteria
• 18-65 years old with a current
schizophrenia diagnosis,
experiencing acute
exacerbation of psychotic
symptoms and noticeable
deterioration of usual function
• Patients who benefit from
hospitalization or continued
hospitalization for an acute
relapse at trial entry, and had
history of relapse and/or
symptom exacerbation without
antipsychotic treatment
• Patients with first episode of
schizophrenia
• Clinically significant tardive dyskinesia
• Severe akathisia
• History of substance abuse within past
180 days
• A DSM-IV-TR diagnosis that is not
schizophrenia
• Received electroconvulsive therapy 60
days before screening or study drug in
any other previous trial
• Concomitant medications:
oral/immediate release intramuscular
antipsychotics, depot/long-acting
injectable antipsychotics,
antidepressants, mood stabilizers,
benzodiazepines, psychotropic agents,
ramelteon, non-benzodiazepine sleep
aids, antihistamines (except cetirizine
and loratadine), varenicline, vitamins,
nutritional supplements, herbal
preparations, CYP2D6 inhibitors,
CYP3A4 inhibitors/inducers,
investigational agentsJ.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

17. Methods
• Patients split into 4 randomized groups
• Brexpiprazole 1 mg
• Brexpiprazole 2 mg
• Brexpiprazole 4 mg
• Placebo
• Given once daily orally for 6 weeks
• Followed up 30 days after last dose for safety
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

18. Outcomes
• Primary: Change from baseline to 6 weeks in
Positive and Negative Syndrome Scale (PANSS)
• Key Secondary: Change from baseline to week 6
in Clinical Global Impressions-Severity (CGI-S)
• Other secondary: Personal and Social Performance
scale (PSP), PANSS positive and negative
subscales, PANSS excited component (PEC) and
Marder Factor scores, Clinical Global Impressions-
Improvement (CGI-I) score at week 6, response rate,
and discontinuation rate for lack of efficacy
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

19. Statistical Analysis
• Endpoints measured with mixed model for repeated
analysis
• Differences between placebo and average effect of
brexpiprazole 2 and 4 mg tested for statistical significance
• If average effect was significant, placebo compared to
brexpiprazole 2 and 4 mg individually
• If both were significant, secondary endpoints were tested
• Least squares (LS) mean used for PANSS difference
from baseline to week 6
• Cochran-Mantel-Haenszel row mean score test for
response rate and discontinuation due to lack of
efficacy (secondary endpoints)
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

20. Brexpiprazole
Placebo
(n=184)
1 mg
(n=120)
2 mg
(n=186)
4 mg (n=184)
Demographics
Age (years), mean (SD) 39.3
(10.8)
39.1
(11.9)
36.9
(10.9)
38.6 (11.0)
BMI (kg/m2), mean (SD) 26.6 (5.6) 26.7 (5.8) 26.3 (6.1) 27.1 (6.6)
Male, n (%) 111 (60.3) 77 (64.2) 122 (65.6) 113 (61.4)
Race, n (%)
Caucasian 110 (59.8) 75 (62.5) 118 (63.4) 104 (56.5)
Black/African American 45 (24.5) 26 (21.7) 41 (22.0) 50 (27.2)
Other 29 (25.7) 19 (15.9) 27 (14.6) 30 (10.3)
Clinical characteristics
Age at 1st diagnosis (years), mean (SD) 25.6 (8.9) 26.3 (9.2) 25.2 (7.5) 25.5 (7.1)
Duration of current episode (weeks), mean
(SD)
2.6 (2.8) 2.4 (2.8) 2.7 (3.0) 2.3 (2.2)
PANSS, mean (SD)
Total score 94.8
(13.0)
93.3
(12.8)
96.3
(12.8)
95.1 (12.5)
Positive subscale score 26.0 (4.6) 24.9 (4.3) 24.9 (4.3) 24.9 (4.4)
Negative subscale score 24.0 (5.3) 23.3 (5.4) 24.1 (5.2) 23.9 (5.0)
CGI-S score, mean (SD) 4.9 (0.6) 4.9 (0.7) 5 (0.7) 4.9 (0.6)
PSP scale score, mean (SD) 43.7 45.5 43.7 44.7 (11.1)

21. Baseline Characteristics
• 1005 patients screened, 674 randomized to double-blind treatment
• 458 completed study
• 81/120 brexpiprazole 1 mg
• 129/186 brexpiprazole 2 mg
• 130/184 brexpiprazole 4 mg
• 118/184 placebo
• Reasons for dropout
• Withdrawal of consent to participate (12.5%)
• Lack of efficacy (9.8%)
• Occurrence of adverse effects (8.5%)
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

22. Results
• LS mean PANSS score difference from baseline
to week 6
• Placebo vs. average effect of Brexpiprazole 2 mg
and 4 mg = -4.78, p=0.0093
• Placebo vs. Brexpiprazole 2 mg: -3.08, p=0.1448
• Placebo vs. Brexpipraozle 4 mg: -6.47, p=0.0022
• Secondary endpoints not formally tested
• Trends to Brexpiprazole 4 mg being more statistically
significant
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

23. Adverse Effects
• 395 (58.6%) patients reported at least 1 or more
treatment-emergent adverse effect (TEAE)
• More than 95% of brexpiprazole groups reported
TEAEs as mild to moderate
• Serious TEAEs and discontinuation due to
underlying schizophrenia
• Moderate weight gain, increase in creatine
phosphokinase were most significant
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

24. Author’s Conclusions
• Brexpiprazole 4 mg is effective and well-tolerated
for acute schizophrenia
• Confirmed results of another Phase 3 trial
(VECTOR trial)
• Recognized limitations
• No active comparator
• Excluding patients with extreme symptoms
J.M. Kane et al. / Schizophrenia Research 164 (2015) 127–135

25. Study Critique
• Strengths
• Randomized, double-
blinded
• Multi-centered in
different countries
• 458 participants
• Well-tolerated adverse
effects
• Limitations
• No active control
• “Stepwise” analysis
• Excluded populations
with multiple
comorbidities
• Making long-term
claims from a 2.5 year
trial

26. Conclusion
• Efficacy: Brexpiprazole is effective when tested
against placebo, but unknown against active
agent
• Safety: Well-tolerated, milder side effects
• Cost: Not enough information available
• I would not recommend Brexpiprazole (Rexulti ®)
to be added to the formulary for the treatment of
schizophrenia.

27. Questions?

28. References
American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013
Crismon M, Argo TR, Buckley PF. Chapter 50. Schizophrenia. In: DiPiro JT, Talbert RL,
Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic
Approach, 9e. New York, NY: McGraw-Hill; 2014.
Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled
phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute
schizophrenia. Schizophr Res. 2015;164(1-3):127-35.
Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: in vitro and in vivo
characterization of a novel serotonin-dopamine activity modulator. J Pharmacol Exp Ther.
2014;350(3):589-604.
Meyer JM. Chapter 16. Pharmacotherapy of Psychosis and Mania. In: Brunton LL,
Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of
Therapeutics, 12e. New York, NY: McGraw-Hill; 2011
Rexulti ® [package insert]. Tokyo, Japan: Otsuka Pharmaceutical Co.; 2015