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Out of the Pipeline

Brexpiprazole for and as adjunct for major depressive disorder

Leslie Citrome, MD, MPH

rexpiprazole, FDA-approved in Table 1 A pharmacodynamic July 2015 to treat schizophrenia and Fast facts about brexpiprazole profile unlike other as an adjunct for major depressive B Brand name: Rexulti disorder (MDD) (Table 1), has shown effi- means that cacy in 2 phase-III acute trials for each Class: Atypical brexpiprazole might indication.1-6 Although brexpiprazole is Indications: Schizophrenia and adjunctive therapy for major depressive disorder a D2 , it differs be better tolerated FDA approval date: July 10, 2015 from , the other available D2 partial agonist, because it is more potent Availability date: August 2015 at 5-HT1A and 5-HT2A recep- Manufacturer: Otsuka America Pharmaceutical, Inc., and tors and displays less intrinsic activity at 7 Dosing forms: 0.25 mg, 0.5 mg, 1 mg, 2 mg, D2 receptors, which could mean better 3 mg, and 4 mg tablets tolerability. Recommended dosage: 2 to 4 mg/d (schizophrenia) and 2 mg/d (major depressive Clinical implications disorder) Schizophrenia is heterogeneous, and indi- vidual response and tolerability to anti- psychotics vary greatly8; therefore, new drug options are useful. For MDD, before How it works the availability of brexpiprazole, only In addition to a subnanomolar binding affin- 3 antipsychotics were FDA-approved for ity (Ki < 1 nM) to dopamine D2 receptors as adjunctive use with ther- a partial agonist, brexpiprazole also exhib- apy9; brexpiprazole represents another its similar binding affinities for serotonin agent for patients whose depressive symp- 5-HT1A (partial agonist), 5-HT2A (antago- toms persist after standard antidepressant nist), and α1B (antagonist) and treatment. α2C (antagonist) receptors.7 Variables that limit the use of antipsy- Brexpiprazole also has high affinity chotics include extrapyramidal symptoms (Ki < 5 nM) for dopamine D3 (partial ago- (EPS), , sedation/somnolence, weight gain, metabolic abnormalities, and Dr. Citrome is Clinical Professor of Psychiatry and Behavioral Sciences, hyperprolactinemia. If post-marketing New York Medical College, Valhalla, New York, and a member of the Current Psychiatry editorial board. studies and clinical experience confirm Disclosure that brexpiprazole has an overall favor- Dr. Citrome is a consultant to Alexza Pharmaceuticals, Alkermes, able side-effect profile regarding these Allergan, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum Pharmaceuticals, Genentech, Janssen, Jazz tolerability obstacles, brexpiprazole Pharmaceuticals, Lundbeck, Merck, Medivation, Mylan, Novartis, would potentially have advantages over Noven, Otsuka, Pfizer, Reckitt Benckiser, Reviva, Shire, Sunovion, Takeda, Teva, and Valeant Pharmaceuticals; and is a speaker for some other available agents, including Allergan, AstraZeneca, Janssen, Jazz Pharmaceuticals, Lundbeck, Current Psychiatry aripiprazole. Merck, Novartis, Otsuka, Pfizer, Shire, Sunovion, Takeda, and Teva. Vol. 14, No. 10 73 Out of the Pipeline

nist), serotonin 5-HT2B (antagonist), and trials conducted in adults, 2 studies each for 5-HT7 (antagonist), and at adrenergic α1A each disorder.1-6 These studies are described (antagonist) and α1D (antagonist) recep- in Table 2.2-5 tors. Brexpiprazole has moderate affinity for H1 receptors (Ki = 19 nM, antago- Schizophrenia. The primary outcome nist), and low affinity for muscarinic M1 measure for the acute schizophrenia trials receptors (Ki > 1000 nM, antagonist). was change on the Positive and Negative Brexpiprazole’s pharmacodynamic pro- Syndrome Scale (PANSS) total scores from file differs from other available antipsy- baseline to 6-week endpoint. Statistically chotics, including aripiprazole. Whether significant reductions in PANSS total score this translates to meaningful differences in were observed for brexpiprazole dos- efficacy and tolerability will depend on the ages of 2 mg/d and 4 mg/d in one study,2 Clinical Point outcomes of specifically designed clinical and 4 mg/d in another study.3 Responder At 91 hours, the half- trials as well as “real-world” experience. rates also were measured, with response Animal models have suggested amelio- defined as a reduction of ≥30% from base- life of brexpiprazole ration of schizophrenia-like behavior, line in PANSS total score or a Clinical Global is relatively long: depression-like behavior, and anxiety-like Impressions-Improvement score of 1 (very A steady-state behavior with brexipiprazole.6 much improved) or 2 (much improved).2,3 concentration is Pooling together the available data for the recommended target dosage of brexpipra- attained in 2 weeks At 91 hours, brexpiprazole’s half-life is rel- zole for schizophrenia (2 to 4 mg/d) from atively long; a steady-state concentration the 2 phase-III studies, 45.5% of patients therefore is attained in approximately​ responded to the drug, compared with 31% 2 weeks.1 In the phase-III clinical trials, brex- for the pooled placebo groups, yielding piprazole was titrated to target dosages, and a number needed to treat (NNT) of 7 therefore the product label recommends the (95% CI, 5-12).6 same. Brexpiprazole can be administered Although not described in product label- with or without food. ing, a phase-III 52-week maintenance study In a study of brexpiprazole , after demonstrated brexpiprazole’s efficacy in a single oral dose of [14C]-labeled brexpip- preventing exacerbation of psychotic symp- razole, approximately 25% and 46% of the toms and impending relapse in patients administered radioactivity was recovered in with schizophrenia.10 Time from randomiza- urine and feces, respectively. Less than 1% tion to exacerbation of psychotic symptoms of unchanged brexpiprazole was excreted in or impending relapse showed a beneficial the urine, and approximately 14% of the oral effect with brexpiprazole compared with dose was recovered unchanged in the feces. placebo (log-rank test: hazard ratio = 0.292, Exposure, as measured by maximum con- P < .0001). Significantly fewer patients in centration and area under the concentration the brexpiprazole group relapsed compared curve, is dose proportional. with placebo (13.5% vs 38.5%, P < .0001), Metabolism of brexpiprazole is mediated resulting in a NNT of 4 (95% CI, 3-8). principally by cytochrome P450 (CYP) 3A4 Discuss this article at and CYP2D6. Based on in vitro data, brex- Major depressive disorder. The primary www.facebook.com/ piprazole shows little or no inhibition of outcome measure for the acute MDD stud- CurrentPsychiatry CYP450 isozymes. ies was change in Montgomery-Åsberg Depression Rating Scale (MADRS) scores Efficacy from baseline to 6-week endpoint of the ran- FDA approval for brexpiprazole for schizo- domized treatment phase. All patients were phrenia and for adjunctive use in MDD was required to have a history of inadequate Current Psychiatry 74 October 2015 based on 4 phase-III pivotal acute clinical response to 1 to 3 treatment trials of standard Out of the Pipeline

Table 2 Pivotal randomized, double-blind, placebo-controlled phase-III trials of brexpiprazole ClinicalTrials. Length Brexpiprazole gov identifier (weeks) N dosage (mg/d) Comments Schizophrenia NCT01396421 6 636 0.25, 2, 4 • Published as Correll et al, 20152 • Positive study for brexpiprazole, 2 mg/d and 4 mg/d • In groups receiving 2 or 4 mg of brexpiprazole, dosing began at 1 mg/d and was titrated to 2 mg/d on Day 5 and 4 mg/d on Day 8 Clinical Point NCT01393613 6 674 1, 2, 4 • Published as Kane et al, 20153 The phase-III • Positive study for brexpiprazole, 4 mg/d • In groups receiving 2 or 4 mg of studies showed brexpiprazole, dosing began at 1 mg/d positive results for and was titrated to 2 mg/d on Day 5 and 4 mg/d on Day 8 brexpiprazole, 2 mg/d Major depressive disorder (adjunctive to antidepressant treatment) and 3 mg/d, with NCT01360632 14 677 1, 3 • Published as Thase et al, 20154 change in MADRS (randomized • Positive study for brexpiprazole, 3 mg/d phase: superior to placebo • Dosing of brexpiprazole was either 6 weeks) 0.5 mg/d for the first week, followed by 1.0 mg/d for the remainder of the trial, or 0.5 mg/d for the first week, followed by 1 mg/d for the second week, followed by 3 mg/d for the remainder of the trial NCT01360645 14 379 2 • Published as Thase et al, 20155 (randomized • Positive study for brexpiprazole, 2 mg/d phase: • Dosing of brexpiprazole was 0.5 mg/d for 6 weeks) the first week, followed by 1 mg/d for the second week, followed by 2 mg/d for the remainder of the trial

for their current depressive baseline to endpoint superior to that episode. In addition, patients entered the observed with placebo.4,5 randomized phase only if they had an inad- When examining treatment response, equate response to antidepressant therapy defined as a reduction of ≥50% in MADRS during an 8-week prospective treatment trial total score from baseline, NNT vs placebo of standard antidepressant treatment plus for response were 12 at all dosages tested, single-blind placebo. however, NNT vs placebo for remission Participants who responded adequately to (defined as MADRS total score ≤10 and ≥50% the antidepressant in the prospective single- improvement from baseline) ranged from 17 blind phase were not randomized, but to 31 and were not statistically significant.6 instead continued on antidepressant treat- When the results for brexpiprazole, 1 mg/d, ment plus single-blind placebo for 6 weeks. 2 mg/d, and 3 mg/d, from the 2 phase-III tri- The phase-III studies showed positive als are pooled together, 23.2% of the patients results for brexpiprazole, 2 mg/d and receiving brexpiprazole were responders, Current Psychiatry 3 mg/d, with change in MADRS from vs 14.5% for placebo, yielding a NNT of 12 Vol. 14, No. 10 75 Out of the Pipeline

(95% CI, 8-26); 14.4% of the brexpiprazole- Contraindications treated patients met remission criteria, vs The only absolute contraindication for 9.6% for placebo, resulting in a NNT of 21 brexpiprazole is known hypersensitivity (95% CI, 12-138).6 to brexpiprazole or any of its components. Reactions have included rash, facial swell- Tolerability ing, urticaria, and anaphylaxis.1 Overall tolerability can be evaluated by As with all antipsychotics and antipsy- examining the percentage of patients who chotics with an indication for a depressive discontinued the clinical trials because of disorder: an adverse event (AE). In the acute schizo- • there is a bolded boxed warning in the phrenia double-blind trials for the recom- product label regarding increased mortality mended dosage range of 2 to 4 mg, the in geriatric patients with dementia-related Clinical Point discontinuation rates were lower overall psychosis. Brexpiprazole is not approved In schizophrenia trials, for patients receiving brexpiprazole com- for treating patients with dementia-related pared with placebo.2,3 In the acute MDD psychosis the discontinuation trials, 32.6% of brexpiprazole-treated • there is a bolded boxed warning in the rates were lower for patients and 10.7% of placebo-treated product label about suicidal thoughts and patients receiving patients discontinued because of AEs,4,5 behaviors in patients age ≤24. The safety and brexpiprazole yielding a number needed to harm (NNH) efficacy of brexpiprazole have not been estab- of 53 (95% CI, 30-235).6 lished in pediatric patients. compared with The most commonly encountered AEs placebo for MDD (incidence ≥5% and at least twice Dosing the rate for placebo) were akathisia (8.6% vs Schizophrenia. The recommended starting 1.7% for brexpiprazole vs placebo, and dose- dosage for brexpiprazole for schizophrenia related) and weight gain (6.7% vs 1.9%),1 is 1 mg/d on Days 1 to 4. Brexpiprazole can with NNH values of 15 (95% CI, 11-23), and be titrated to 2 mg/d on Day 5 through Day 22 (95% CI, 15-42), respectively.6 The most 7, then to 4 mg/d on Day 8 based on the commonly encountered AE for schizophre- patient’s response and ability to tolerate the nia (incidence ≥4% and at least twice the rate medication. The recommended target dos- for placebo) was weight gain (4% vs 2%),1 age is 2 to 4 mg/d with a maximum recom- with a NNH of 50 (95% CI, 26-1773).6 mended daily dosage of 4 mg. Of note, rates of akathisia in the schizo- phrenia trials were 5.5% for brexpiprazole Major depressive disorder. The recom- and 4.6% for placebo,1 yielding a non- mended starting dosage for brexpiprazole statistically significant NNH of 112.6 In a as adjunctive treatment for MDD is 0.5 mg 6-week exploratory study,11 the incidence or 1 mg/d. Brexpiprazole can be titrated of EPS-related AEs including akathisia was to 1 mg/d, then up to the target dosage of lower for brexpiprazole-treated patients 2 mg/d, with dosage increases occurring (14.1%) compared with those receiving at weekly intervals based on the patient’s aripiprazole (30.3%), for a NNT advan- clinical response and ability to tolerate the tage for brexpiprazole of 7 (not statistically agent, with a maximum recommended dos- significant). age of 3 mg/d. Short-term weight gain appears modest; however, outliers with an increase of ≥7% of Other considerations. For patients with body weight were evident in open-label long- moderate to severe hepatic impairment, or term safety studies.1,6 Effects on glucose and moderate, severe, or end-stage renal impair- lipids were small. Minimal effects on prolac- ment, the maximum recommended dosage tin were observed, and no clinically relevant is 3 mg/d for patients with schizophrenia, Current Psychiatry 76 October 2015 effects on the QT interval were evident. and 2 mg/d for patients with MDD. Out of the Pipeline

In general, dosage adjustments are rec- ommended in patients who are known Related Resources CYP2D6 poor metabolizers and in those • Citrome L. Brexpiprazole: a new dopamine D2 receptor par- tial agonist for the treatment of schizophrenia and major de- taking concomitant CYP3A4 inhibitors pressive disorder. Drugs Today (Barc). 2015;51(7):397-414. or CYP2D6 inhibitors or strong CYP3A4 • Citrome L, Stensbøl TB, Maeda K. The preclinical profile of inducers1: brexpiprazole: what is its clinical relevance for the treat- ment of psychiatric disorders? Expert Rev Neurother. In • for strong CYP2D6 or CYP3A4 inhibi- press. tors, administer one-half the usual dosage Drug Brand Names • for strong/moderate CYP2D6 with Aripiprazole • Abilify • Prozac strong/moderate CYP3A4 inhibitors, Brexpiprazole • Rexulti • Paxil administer a one-quarter of the usual dosage • for known CYP2D6 poor metabolizers Clinical Point taking strong/moderate CYP3A4 inhibitors, No dosage adjustment for brexpiprazole No dosage also administer a one-quarter of the usual is required on the basis of sex, race or eth- adjustment for dosage nicity, or smoking status. Although clinical • for strong CYP3A4 inducers, double studies did not include patients age ≥65, the brexpiprazole is the usual dosage and further adjust based on product label recommends that in general, required on clinical response. dose selection for a geriatric patient should the basis of sex, In clinical trials for MDD, brexpiprazole be cautious, usually starting at the low end race or ethnicity, or dosage was not adjusted for strong CYP2D6 of the dosing range, reflecting the greater inhibitors (eg, paroxetine, fluoxetine). frequency of decreased hepatic, renal, and smoking status Therefore, CYP considerations are already cardiac function, concomitant diseases, and factored into general dosing recommenda- other drug therapy. tions and brexpiprazole could be adminis- tered without dosage adjustment in patients References 1. Rexulti [package insert]. Rockville, MD: Otsuka; 2015. with MDD; however, under these circum- 2. Correll CU, Skuban A, Ouyang J, et al. Efficacy and safety stances, it would be prudent to start brexpip- of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. razole at 0.5 mg, which, although “on-label,” Am J Psychiatry. 2015;172(9):870-880. represents a low starting dosage. (Whenever 3. Kane JM, Skuban A, Ouyang J, et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed- 2 drugs are co-administered and 1 agent has dose brexpiprazole for the treatment of adults with acute the ability to disturb the metabolism of the schizophrenia. Schizophr Res. 2015;164(1-3):127-135. other, using smaller increments to the target 4. Thase ME, Youakim JM, Skuban A, et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive dosage and possibly waiting longer between disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study [published dosage adjustments could help avoid poten- online August 4, 2015]. J Clin Psychiatry. doi: 10.4088/ tial drug–drug interactions.) JCP.14m09689. continued

Bottom Line Brexpiprazole, an , is FDA-approved for schizophrenia and as an adjunct to antidepressants in major depressive disorder. For both indications, brexpiprazole demonstrated positive results compared with placebo in phase-III trials. Brexpiprazole is more potent at serotonin 5-HT1A and 5-HT2A receptors and displays less intrinsic activity at D2 receptors than aripiprazole, which could mean Current Psychiatry that the drug may be better-tolerated. Vol. 14, No. 10 77 Out of the Pipeline

5. Thase ME, Youakim JM, Skuban A, et al. Efficacy and safety should drive decision-making. Expert Opin Pharmacother. of adjunctive brexpiprazole 2 mg in major depressive 2009;10(12):1917-1928. disorder: a phase 3, randomized, placebo-controlled study 9. Citrome L. Adjunctive aripiprazole, , or in patients with inadequate response to antidepressants for major depressive disorder: an analysis of number needed [published online August 4, 2015]. J Clin Psychiatry. doi: to treat, number needed to harm, and likelihood to be helped 10.4088/JCP.14m09688. or harmed. Postgrad Med. 2010;122(4):39-48. 6. Citrome L. Brexpiprazole for schizophrenia and as adjunct 10. Hobart M, Ouyang J, Forbes A, et al. Efficacy and safety for major depressive disorder: a systematic review of of brexpiprazole (OPC-34712) as maintenance treatment the efficacy and safety profile for this newly approved in adults with schizophrenia: a randomized, double-blind, antipsychotic—what is the number needed to treat, number placebo-controlled study. Poster presented at: the American needed to harm and likelihood to be helped or harmed? Int Society of Clinical Psychopharmacology Annual Meeting; J Clin Pract. 2015;69(9):978-997. June 22 to 25, 2015; Miami, FL. 7. Maeda K, Sugino H, Akazawa H, et al. Brexpiprazole I: 11. Citrome L, Ota A, Nagamizu K, Perry P, et al. The effect in vitro and in vivo characterization of a novel serotonin- of brexpiprazole (OPC‐34712) versus aripiprazole in adult dopamine activity modulator. J Pharmacol Exp Ther. patients with acute schizophrenia: an exploratory study. 2014;350(3):589-604. Poster presented at: the Society of Biological Psychiatry 8. Volavka J, Citrome L. Oral antipsychotics for the treatment Annual Scientific Meeting and Convention; May 15, 2015; of schizophrenia: heterogeneity in efficacy and tolerability Toronto, Ontario, Canada.

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Current Psychiatry 78 October 2015