The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1475 Volume 56 August 17, 2015 IN THIS ISSUE Alirocumab (Praluent) to Lower LDL-Cholesterol p 113 Palbociclib (Ibrance) for Metastatic Breast Cancer p 115 Brexpiprazole (Rexulti) for Schizophrenia and Depression .p 116 In Memoriam p 118 Panobinostat (Farydak) for Multiple Myeloma online only Lenvatinib (Lenvima) for Thyroid Cancer .online only Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1475 Volume 56 ▶ August 17, 2015 Take CME Exams ALSO IN THIS ISSUE Palbociclib (Ibrance) for Metastatic Breast Cancer p 115 Brexpiprazole (Rexulti) for Schizophrenia and Depression .p 116 In Memoriam p 118 Panobinostat (Farydak) for Multiple Myeloma online only Lenvatinib (Lenvima) for Thyroid Cancer .online only Alirocumab (Praluent) to Lower LDL-Cholesterol The FDA has approved the subcutaneously injected PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor alirocumab (Praluent – Sanofi/Regeneron) as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol (LDL-C) It was not approved for general use in statin-intolerant patients Alirocumab is the first PCSK9 inhibitor to be approved in the US Evolocumab (Repatha – Amgen), another PCSK9 inhibitor, was recently approved in Europe and has been recommended for approval for the same indications in the US by an FDA Advisory Committee Pronunciation Key Alirocumab: al i rok' ue mab Praluent: prahl' u ent MECHANISM OF ACTION — PCSK9 binds to LDL receptors on hepatocytes, promoting receptor degradation, preventing LDL-C clearance from blood, and increasing serum concentrations of LDL-C Alirocumab is a human monoclonal antibody that targets PCSK9, prevents it from binding to LDL receptors, and increases hepatic uptake of LDL-C Table Pharmacology Class Formulation PCSK9 inhibitor 75, 150 mg/mL preservative-free solution in single-use pen or prefilled syringe Route Subcutaneous injection Tmax 3-7 days Metabolism Probably degradation to small peptides and amino acids Elimination Low concentrations: saturable binding to PCSK9 Higher concentrations: nonsaturable proteolysis Half-life (terminal) 12 days with statin coadministration NEW GUIDELINES — The American College of Cardiology and the American Heart Association no longer recommend using specific cholesterol targets in the treatment of hyperlipidemia They now recommend high-intensity statin therapy (e.g., atorvastatin 40-80 mg), which generally results in LDL-C reductions of ≥50%, for patients with clinical atherosclerotic cardiovascular disease.1 The National Lipid Association has recommended use of statins to achieve LDL-C reductions of ≥50% in patients with familial hypercholesterolemia.2 CLINICAL STUDIES — Results of randomized, double-blind clinical trials comparing alirocumab 75-150 mg injected subcutaneously every weeks to oral ezetimibe 10 mg/day or placebo in patients already taking maximally tolerated statin therapy are summarized in Table Table Some Alirocumab Clinical Trials Trial Population COMBO I1 (n=316) COMBO II2 (n=720) FH I3 (n=486) FH II3 (n=249) High CV Risk High CV Risk HeFH HeFH Mean LDL-C Treatment Arms Change at 24 Weeks Alirocumab Placebo Alirocumab Ezetimibe Alirocumab Placebo Alirocumab Placebo -48.2% -2.3% -50.6% -20.7% -48.8% +9.1% -48.7% +2.8% CV = cardiovascular; HeFH = heterozygous familial hypercholesterolemia DJ Kereiakes et al Am Heart J 2015; 169:906 CP Cannon et al Eur Heart J 2015; 36:1186 Summarized in the FDA Clinical Review A randomized, double-blind trial (LONG TERM) in 2341 patients at high risk for cardiovascular events because of HeFH, established coronary heart disease, or known coronary disease risk factors and with LDL-C levels ≥70 mg/dL despite treatment with maximally tolerated statin 113 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 57 (1475) ® August 17, 2015 Table Some Drugs for Hypercholesterolemia Drug Cholesterol Absorption Inhibitor Ezetimibe – Zetia (Merck) HMG-CoA Reductase Inhibitors Atorvastatin – generic Lipitor (Pfizer) Fluvastatin – generic Lescol (Novartis) extended-release – Lescol XL Lovastatin – generic extended-release – Altoprev (Covis) Formulations Usual Adult Dosage 10 mg tabs 10 mg PO once/d 10, 20, 40, 80 mg tabs Initial: 10-20 mg PO once/d Max: 80 mg PO once/d Initial: 40 mg PO bid Max: 40 mg PO bid 80 mg PO once/d Initial: 20 mg PO once/d Max: 80 mg PO once/d2 Initial: 20 mg PO once/d Max: 60 mg PO once/d Initial: mg PO once/d Max: mg PO once/d Initial: 40 mg PO once/d3 Max: 80 mg PO once/d Initial: 10-20 mg PO once/d4,5 Max: 40 mg PO once/d6 Initial: 10-20 mg PO once/d7 Max: 40 mg PO once/d8,9 20, 40 mg caps 80 mg ER tabs 10, 20, 40 mg tabs 20, 40, 60 mg ER tabs Pitavastatin – Livalo (Kowa) 1, 2, mg tabs Pravastatin – generic Pravachol (BMS) Rosuvastatin – Crestor (AstraZeneca) 10, 20, 40, 80 mg tabs Simvastatin – generic Zocor (Merck) PCSK9 Inhibitor Alirocumab – Praluent (Sanofi/Regeneron) 5, 10, 20, 40 mg tabs 5, 10, 20, 40, 80 mg tabs 75, 150 mg/mL single-use pens, prefilled syringes Initial: 75 mg SC q2 wks Max: 150 mg SC q2 wks Cost1 $236.50 9.50 190.70 105.30 153.00 233.70 10.10 546.70 189.30 20.10 169.70 216.10 3.50 123.50 1120.00 ER = extended release; SC = subcutaneously Approximate WAC for 30 days’ treatment at the lowest initial dose WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Or 40 mg bid Patients with significant renal impairment should start with 10 mg/d Higher concentrations of rosuvastatin have been reported in Asian patients; an intial dosage of mg once/d is recommended Patients with severe renal impairment not on hemodialysis should begin with mg and not exceed 10 mg/d Maximum dose in Asian patients is 20 mg/d (E Lee et al Clin Pharmacol 2005; 78:330) Patients with severe renal impairment should begin with mg/d Patients taking 80 mg/d for ≥12 months without evidence of myopathy can continue at this dosage The maximum daily dose of simvastatin should be 10 mg if taken with diltiazem (Cardizem), verapamil (Calan), or dronedarone (Multaq) and 20 mg if taken with amlodipine (Norvasc), ranolazine (Ranexa), or amiodarone (Cordarone) therapy compared alirocumab 150 mg with placebo, both injected subcutaneously every weeks for 78 weeks The mean change in LDL-C at 24 weeks (the primary endpoint) was -61.0% with the active drug and +0.8% with placebo At 78 weeks of treatment, the mean change was -52.4% with alirocumab and +3.6% with placebo A post-hoc analysis found that major cardiovascular events occurred in 1.7% of patients treated with alirocumab and in 3.3% of those treated with placebo (p=0.002).3 In an unpublished, randomized, double-blind trial (HIGH FH, summarized in the package insert) in 107 patients with HeFH who had baseline LDL-C levels ≥160 mg/dL despite taking maximally tolerated statin therapy, the mean reduction in LDL-C at 24 weeks (the primary endpoint) was significantly greater with alirocumab 150 mg given every weeks than with placebo (-43% vs -7%) Two randomized, double-blind trials in a total of 660 high-risk patients taking atorvastatin 20 or 40 mg/day (OPTIONS I) or rosuvastatin 10 or 20 mg/day (OPTIONS II, summarized in the FDA clinical review) found that 114 adding biweekly 75-mg doses of alirocumab reduced LDL-C significantly more than adding ezetimibe, doubling the dose of the statin, or (in OPTIONS I) switching from atorvastatin to a maximally tolerated dose of rosuvastatin.4 ADVERSE EFFECTS — Most clinical trials of alirocumab found no significant differences in adverse events between the active drug and placebo In the 78week trial, patients injected with alirocumab were significantly more likely to experience injection-site reactions (5.9% vs 4.2% with placebo) and myalgia (5.4% vs 2.9% with placebo) Neurocognitive events including amnesia, memory impairment, and confusion occurred in some patients with use of alirocumab.1 Hypersensitivity reactions, including some that required hospitalization, have also occurred PREGNANCY — Monoclonal antibodies are unlikely to cross the placenta in the first trimester, but may so subsequently Animal studies found that alirocumab injections had no adverse effects on the fetus The drug has not been studied in pregnant women The Medical Letter ® DOSAGE AND ADMINISTRATION — The recommended starting dosage of alirocumab is 75 mg injected subcutaneously into the thigh, abdomen, or upper arm every weeks It can be increased to a maximum of 150 mg if necessary The injection site should be rotated with each use If a dose is missed, it should be administered only if the next dose is scheduled to be given at least days later LDL-C levels should be measured within 4-8 weeks after starting therapy with alirocumab or changing the dose Alirocumab is supplied in prefilled pens or glass syringes containing 75 or 150 mg of the drug in mL of solution Dosage units must be refrigerated, but should be allowed to warm to room temperature for 30-40 minutes before injection The drug should be discarded if exposed to room-temperature conditions for ≥24 hours, or if the solution is discolored or contains visible particulates CONCLUSION — The PCSK9 inhibitor alirocumab (Praluent) given by subcutaneous injection every ▶ Palbociclib (Ibrance) for Metastatic Breast Cancer Palbociclib (Ibrance – Pfizer), an oral cyclin-dependent kinase inhibitor, has been approved by the FDA for use in combination with the aromatase inhibitor letrozole (Femara, and generics) for first-line treatment of postmenopausal women with estrogen receptor (ER)positive, human epidermal growth factor receptor (HER2)-negative metastatic breast cancer It is the first cyclin-dependent kinase inhibitor to become available in the US Pronunciation Key Palbociclib: pal” boe sye’ klib Ibrance: eye’ brans STANDARD TREATMENT — The American Society of Clinical Oncology (ASCO) recommends that postmenopausal women with ER-positive, HER2-negative metastatic breast cancer be offered hormone therapy (preferably an aromatase inhibitor) as standard firstline treatment.1,2 These patients often well for many years with hormone therapy alone; how to identify a target population that could benefit from the addition of other drugs is unclear.3 MECHANISM OF ACTION — Cyclin-dependent kinases and regulate the G1/S phase transition within the cell cycle This pathway may be hyperactivated in some malignancies, including estrogen-dependent breast cancer Palbociclib inhibits CDK and 6, which blocks progression of the cell cycle and results in cell cycle arrest or senescence.4 Vol 57 (1475) August 17, 2015 weeks can further lower LDL-cholesterol levels by 40% or more in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease already taking maximally tolerated doses of a statin Limited post-hoc data suggest that it may decrease the incidence of cardiovascular events as well The long-term efficacy and safety of alirocumab are unknown, and it is expensive ■ NJ Stone et al 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines J Am Coll Cardiol 2014; 63:2889 JG Robinson et al Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia J Clin Lipidol 2011; 5(3 Suppl):S18 JG Robinson et al Efficacy and safety of alirocumab in reducing lipids and cardiovascular events N Engl J Med 2015; 372:1489 H Bays et al Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial J Clin Endocrinol Metab 2015 June (epub) Table Pharmacology Class CDK and inhibitor Formulation 75, 100, 125 mg capsules Route Oral Tmax 6-12 hours Metabolism Primarily by CYP3A and sulfotransferase SULT2A1 Elimination (healthy subjects) Feces (~74%); urine (~18%) Half-life (cancer patients) ~29 hours CLINICAL STUDIES — Approval of palbociclib was based on an open-label trial (PALOMA-1/TRIO-18) that randomized 165 postmenopausal women with ER-positive, HER2-negative advanced breast cancer to letrozole 2.5 mg once daily for 28 days alone or with palbociclib 125 mg once daily added on days 1-21 of a 28-day treatment cycle Median progression-free survival, the primary endpoint, was significantly longer in patients taking letrozole plus palbociclib than in those taking letrozole alone (20.2 vs 10.2 months).5 A randomized, double-blind trial (PALOMA3) in 521 women with ER-positive, HER2-negative advanced breast cancer previously treated with hormonal therapy found that palbociclib 125 mg/day for weeks every 28 days plus the estrogen receptor antagonist fulvestrant (Faslodex) 500 mg IM every 14 days for the first injections and then every 28 days significantly increased median progression-free survival compared to fulvestrant alone (9.2 vs 3.8 months).6 115 The Medical Letter ® ADVERSE EFFECTS — Grade and neutropenia occurred in 48% and 6%, respectively, of patients taking palbociclib plus letrozole Grade neutropenia occurred in 1% of those taking letrozole alone No cases of febrile neutropenia were reported during the first clinical trial; in the second trial, 0.6% of patients treated with palbociclib developed febrile neutropenia Grade leukopenia occurred in 19% of those taking both drugs compared to none of those taking letrozole alone Pulmonary embolism, fatigue, upper respiratory infection, nausea, stomatitis, anemia, thrombocytopenia, peripheral neuropathy, and epistaxis have also been reported in patients taking palbociclib DRUG INTERACTIONS — Palbociclib is a substrate of CYP3A; concurrent administration of strong CYP3A inhibitors or moderate or strong CYP3A inducers is not recommended.7 DOSAGE, ADMINISTRATION, AND COST — The recommended starting dosage of palbociclib is 125 mg once daily with food for 21 days, followed by days off Patients treated with the drug should also take letrozole 2.5 mg once daily on all 28 days Blood counts should be monitored before starting therapy, at the beginning of each treatment cycle, and on day 14 of the first cycles Both drugs should be continued until disease progression occurs The labeling specifies a number of dosage adjustments that should be made if adverse effects occur The daily dose of palbociclib should be reduced to 75 mg if coadministered with a strong CYP3A inhibitor The cost of palbociclib for one 28-day treatment cycle is $9850.8 CONCLUSION — Palbociclib (Ibrance), the first cyclindependent kinase and inhibitor to be approved in the US, markedly extended median progression-free survival when added to either letrozole (Femara, and generics) or fulvestrant (Faslodex) in women with estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER2)-negative advanced breast cancer Serious adverse effects such as grade 3-4 neutropenia and grade leukopenia can occur The drug's effect on overall survival remains to be determined How to identify patients whose prognosis would justify the additional cost and toxicity of palbociclib is unclear ■ AH Partridge et al Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer : American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 2014; 32:3307 Aromatase inhibitors for adjuvant treatment of postmenopausal breast cancer Med Lett Drugs Ther 2011; 53:47 LA Carey and CM Perou Palbociclib–taking breast-cancer cells out of gear N Engl J Med 2015; 373:273 116 August 17, 2015 Vol 57 (1475) CG Murphy and MN Dickler The role of CDK4/6 inhibition in breast cancer Oncologist 2015; 20:483 RS Finn et al The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase study Lancet Oncol 2015; 16:25 NC Turner et al Palbociclib in hormone-receptor-positive advanced breast cancer N Engl J Med 2015; 373:209 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy ▶ Brexpiprazole (Rexulti) for Schizophrenia and Depression The FDA has approved the oral, once-daily, secondgeneration antipsychotic brexpiprazole (Rexulti – Otsuka/Lundbeck) for treatment of schizophrenia and as an adjunct to antidepressants for treatment of major depressive disorder (MDD) Aripiprazole (Abilify), a structurally similar second-generation antipsychotic also comarketed by Otsuka (with BMS), recently became available generically Pronunciation Key Brexpiprazole: breks pip' zole Rexulti: recks ul' tee STANDARD TREATMENT – Schizophrenia - Secondgeneration antipsychotics are not clearly more effective than first-generation drugs, but they have a much lower risk of tardive dyskinesia Clozapine (Clozaril, and others) is the most effective secondgeneration antipsychotic drug, but it is usually reserved for refractory disease because of its potential for serious toxicity Olanzapine (Zyprexa, and generics) appears to have slight advantages over some other drugs in efficacy, but its metabolic adverse effects may be unacceptable for long-term use Patients who not respond to one antipsychotic may respond to another Long-acting injectable antipsychotics may be useful when adherence is a problem.1 Table Pharmacology Class Second-generation antipsychotic Mechanism of action Dopamine (D2) and serotonin (5-HT1A ) partial agonist; 5-HT2A antagonist Formulation 0.25, 0.5, 1, 2, 3, mg tablets Route Oral Tmax Within hours Metabolism Primarily hepatic by CYP3A4 and 2D6 Elimination Feces (46%); urine (25%) Half-life (terminal) 91 hours The Medical Letter Vol 57 (1475) ® August 17, 2015 Table Some Oral Second-Generation Antipsychotics Drug Aripiprazole – generic Abilify (BMS/Otsuka) Asenapine – Saphris (Forest) Brexpiprazole – Rexulti (Otsuka/Lundbeck) Clozapine5 – generic Clozaril (Novartis) orally disintegrating – generic FazaClo (Jazz) suspension – Versacloz (Jazz) Iloperidone – Fanapt (Novartis) Lurasidone – Latuda (Sunovion) Olanzapine3 – generic Zyprexa (Lilly) orally disintegrating – generic Zyprexa Zydis Paliperidone3 – Invega (Janssen) Quetiapine – generic Seroquel (AstraZeneca) extended-release – Seroquel XR Risperidone3 – generic Risperdal (Janssen) orally disintegrating – generic Risperdal M-TAB Ziprasidone – generic Geodon3 (Pfizer) Some Available Oral Formulations Usual Adult Maintenance Dosage in Schizophrenia1 Usual Adult Maintenance Dosage in MDD1 2, 5, 10, 15, 20, 30 mg tabs 10-30 mg once/d 2-15 mg once/d 2.5, 5, 10 mg sublingual tabs 0.25, 0.5, 1, 2, 3, mg tabs 25, 50, 100, 200 mg tabs 25, 100 mg tabs 12.5, 25, 100, 150, 200 mg ODT 5-10 mg bid 2-4 mg once/d 100-300 mg tid 50 mg/mL susp 1, 2, 4, 6, 8, 10, 12 mg tabs 20, 40, 60, 80, 120 mg tabs 2.5, 5, 7.5, 10, 15, 20 mg tabs 6-12 mg bid 40-160 mg once/d 10-20 mg once/d 5, 10, 15, 20 mg ODT 1.5, 3, 6, mg ER tabs 25, 50, 100, 200, 300, 400 mg tabs 50, 150, 200, 300, 400 mg ER tabs 0.25, 0.5, 1, 2, 3, 4, mg tabs; mg/mL soln 0.25, 0.5, 1, 2, 3, mg ODT 0.5, 1, 2, 3, mg ODT 20, 40, 60, 80 mg caps 6-12 mg once/d 300-800 mg/d in or divided doses 400-800 mg once/d 4-8 mg/d in or doses 40-100 mg bid Cost2 $765.00 892.00 See footnote 833.00 mg once/d 865.50 See footnote 217.50 1125.80 588.60 1321.20 1321.50 See footnote 1035.60 See footnote 838.80 See footnote 26.40 553.20 202.70 582.60 See footnote 849.90 See footnote 40.30 600.00 150-300 mg once/d 694.70 mg/d in or 25.60 650.00 doses7 369.70 780.00 See footnote 171.00 804.50 MDD = major depressive disorder; ODT = orally disintegrating tablets; ER = extended-release As an adjunct to antidepressant therapy Approximate WAC for 30 days’ treatment at the lowest usual maintenance dosage in schizophrenia WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly August 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drugpricing-policy Also available parenterally Not FDA-approved for adjunctive treatment of MDD Clozapine is associated with seizures and agranulocytosis and should be reserved for patients with schizophrenia who fail to respond to other drugs A fixed-dose combination of olanzapine and fluoxetine (Symbyax - Lilly) is FDA-approved for use in treatment-resistant depression The usual dosage in adults is one 6/25 mg or 12/50 mg olanzapine/fluoxetine capsule every evening The WAC for a 30-day supply of 6/25 mg capsules is $402.30 Risperidone is used for adjunctive treatment of MDD by some clinicians, but is not FDA-approved for this indication MDD – A selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac, and generics), a serotonin-norepinephrine reuptake inhibitor (SNRI) such as venlafaxine (Effexor, and generics), bupropion (Wellbutrin XL, and others), or mirtazapine (Remeron, and generics) could be used for first-line treatment of major depression Most clinicians begin with an SSRI When an adequate trial of an SSRI produces little to no response, another antidepressant can be tried, or two antidepressants from different classes can be combined Augmentation with antipsychotic drugs may be helpful when the response to antidepressant agents is inadequate, but adverse effects such as weight gain or extrapyramidal symptoms can occur.1 CLINICAL STUDIES – Schizophrenia - Brexpiprazole was compared to placebo in two 6-week, randomized, double-blind trials in a total of 1076 adults 18-65 years old with schizophrenia The primary endpoint in both studies was mean improvement at weeks in scores on the 181-point Positive and Negative Syndrome Scale (PANSS) In one study, mean improvements in PANSS scores were significantly greater with both mg/day (20.7 points) and mg/day (19.7 points) than with placebo (12.0 points).2 In the other study, improvement was significantly greater with mg/ day (20.0 points), but not with mg/day (16.6 points), compared to placebo (13.5 points).3 MDD - In two unpublished, 6-week, double-blind trials (summarized in the package insert), a total of 980 adults 18-65 years old with MDD that had not responded adequately to prior antidepressant therapy were randomized to receive brexpiprazole or placebo as an adjunct to an SSRI or SNRI The primary endpoint in both studies was mean improvement at weeks in scores on the clinician-rated 61-point Montgomery-Asberg Depression Rating Scale (MADRS) In one study, mean improvements in MADRS scores were significantly greater with brexpiprazole mg/day than with placebo (8.4 vs 5.2 points) In the other study, improvement was numerically greater with brexpiprazole mg/day and mg/day than with placebo (8.3 and 7.6 vs 6.3 points), but statistical significance was not achieved (p=0.033 for mg/day vs placebo; superiority criteria required p