Latuda (Lurasidone HCl) Receives 2 New
`Indications for Use in Bipolar Depression as
`Monotherapy and as Adjunctive Therapy
`with Lithium or Valproate
`
`By Loretta Fala, Medical Writer
`
`ipolar disorder is a disruptive, long-termillness as-
`sociated with mood swings ranging from the lows
`of depression to the highs of mania, and in some
`cases, symptoms of depression and mania at the same
`time (ie, mixed episodes).'! The symptoms of bipolar
`disorder may vary from person to person. Mood swings
`associated with bipolar disorder have the potential to
`cause substantial difficulties in relationships, work, or
`school. Moreover, manic episodes can be severe and, in
`some cases, even harmful.'
`According to the National Institute of Mental Health,
`an estimated 2.6%of the US adult population—approx-
`imately 5.7 million people—areaffected bybipolar disor-
`der.’ The median age ofonset for bipolar disorder is 25
`years.’ According to the Centers for Disease Control and
`Prevention, in 2011, patients with bipolar disorder had a
`39.1% inpatient hospitalization rate compared with a
`4.5%rate for patients with other behavioral healthcare
`diagnoses.’ Overall, bipolar disorder is the most expen-
`sive behavioral health diagnosis, attributed mostly to
`indirect costs, including lost productivity, absenteeism,
`and presenteeism (ie, attending work while sick).
`The comorbid conditions associated with bipolardis-
`order include anxiety, substance abuse, panic disorder,
`andeating disorders, among others. The risk ofsuicideis
`increased in patients with bipolar disorder, particularly
`in those who also have anxiety and substance abuse.*
`The total economic burden ofbipolar disorder, in-
`cluding direct and indirect costs, in the United States
`was estimated to be $45 billion in 19915° A 2009 anal-
`ysis estimatedthat the totalcosts ofbipolar disorder were
`dramatically higher, totaling $151 billion in direct and
`indirect costs.’ Of this total, bipolar I disorder accounted
`for $30.7 billion, and bipolar I] disorder accounted for
`$120.3 billion.’
`Bipolar disorder requires lifelong treatment, which
`may include medication, psychological counseling or
`therapy, and education and support groups.! The aim of
`initial treatment is to balance moods immediately, and
`once symptomsare stabilized, maintenance therapyis
`
`used to manage bipolar disorder on a long-term basis.
`Failure to adhere to maintenance treatment increases
`the risk for relapse and the escalation of minor mood
`changesinto full-blown episodes of mania or depression.!
`Early diagnosis and management may help to improve
`outcomes for patients and to reduce associated health-
`care costs.
`
`Medications used to treat bipolar disorder include
`lichium, anticonvulsants, antipsychotics, antidepres-
`sants, benzodiazepines, and a combination ofolanzapine
`and fluoxetine. These agents have class-specitic adverse
`effects. Finding an appropriate treatment for an individ-
`ual patient generally involves a trial-and-error approach
`and an adjustment to a new medication. [n addition,
`some medications can take weeks or even months to
`manifest the full therapeutic effect.!
`“Patients with bipolar disorder spend the majority of
`their symptomatic time in the depressed phase of the
`illness. This phase most commonly results in impaired
`function, a remarkable decrease in quality of life and may
`lead to increased risk for attempted suicide,” said Joseph
`Calabrese, MD, Professor of Psychiatry and Director of
`the MoodDisorders Program, University Hospitals Case
`Medical Center, Case Western Reserve University,
`Cleveland, OH. “Unfortunately, there are very few treat-
`mentsspecifically approvedto treat the symptomsofbi-
`polar depression, which represents a very large unmet
`medical need for patients and their families.”
`
`A NewAtypical Antipsychotic Agent for the
`Treatment of Bipolar Depression
`In June 2013, lurasidone hydrochloride (HCI; Latuda;
`Sunovion Pharmaceuticals), an oral atypical antipsy-
`chotic, was approved by the US Food and Drug Admin-
`istration (FDA) for 2 newindications—as monotherapy,
`andas adjunctive therapy withlithium or with valproate
`tor the treatmentofadult patients with major depressive
`episodes associated with bipolar I disorder (bipolar de-
`pression). Latuda was previously approved by the FDA in
`2010 for the treatment ofpatients with schizophrenia.®
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`Vol 7 | Special Feature | March 2014
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`1
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`Exhibit 2057
`Slayback v. Sumitomo
`IPR2020-01053
`
`Exhibit 2057
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`
`
`
`
`
`Lurasidone HCI Monotherapy: Primary Efficacy Results
`
`IE'e)[2 for Studies in Depressive Episodes Associated with
`Bipolar | Disorder (MADRS Scores)
`Primary efficacy measure: MADRS
`Placebo-
`subtracted
`LS mean
`
`
`Treatment
`Mean baseline
`change from difference*
`
`group
`score (SD)
`baseline (SE)
`(95% CI)
`
`
`
`
`Lurasidone HCl
`-15.4 (0.8)
`4.6
`30.3 (5)
`(20-60mgdaily)”|
`(4.9 to -2.3)
`
`
`-154(08) 46
`Lurasidone HCI
`30.6 (4.9)
`(80-120mgdaily)|
`(6.9 to ~2.3) :
`—
`Placebo
`30.5 (5)
`-10.7 (0.8)
`
` HCl, hydrochloride; LS,least-squares; MADRS, Montgomery-Asberg
`
`Difference (drug minus placebo) in LS mean change from baseline.
`‘Treatment groupsignificantly superior to placebo.
`NOTE:BipolarI disorderis also referred to as bipolar depression.
`Clindicates confidence interval, unadjusted for multiple comparisons;
`
`Depression Rating Scale; SD, standard deviation; SE, standard error.
`Source: Latuda (lurasidone hydrochloride) tablets prescribing
`information; 2013.
`
`tration with food substantially increases the absorption of
`lurasidone HCI. Lurasidone HClis available as tablets in
`20-mg, 40-mg, 60-mg, 80-mg, and 120-mg strengths.®
`In patients with moderate and severe renal
`impair-
`ment, the recommendedstarting dose of lurasidone HCl
`is 20 mg daily, and the maximum recommended doseis
`80 mg daily. In patients with moderate and severe hepat-
`ic impairment, the recommendedstarting dose is 20 mg
`daily. The maximum recommended dose is 80 mg daily
`for patients with moderate hepatic impairment and 40
`mgdaily for patients with severe hepatic impairment.*
`With the concomitant use of a moderate cytochrome
`(CY) P3A4 inhibitor (eg, diltiazem), the dose of lurasi-
`done HCI should be reducedto halfofthe original dose
`level. The recommendedstarting dose is 20 mg daily,
`and the maximum recommendeddose is 80 mg daily.
`With the concomitant use of a moderate CYP3A4
`inducer, it may be necessary to increase the dose of
`lurasidone HCI.
`Lurasidone HCI should not be used concomitantly
`with a strong CYP3A4inducer(eg, rifampin, avasimibe,
`St John’s wort, phenytoin, carbamazepine). Grapefruit
`and grapefruit juice should be avoided by patients taking
`lurasidone HCI,because the juice mayinhibit the CYP3A4
`enzyme andalter the concentrations of lurasidone HCL.*
`
`Clinical Studies
`Lurasidone HCl as Monotherapy
`The efficacy of lurasidone HCl as monotherapy was
`demonstrated in a 6-week, randomized, double-blind, pla-
`cebo-controlled trial of 485 adult patients who met the
`Diagnostic and Statistical Manual ofMental Disorders, Fourth
`Edition, Text Revision (DSM-IV-TR) criteria for major de-
`pressive episodes associated with bipolar | disorder, with or
`without rapid cycling, and without psychotic features.®
`These patients ranged in age from 18 to 74 years, with a
`mean age of 41.5 years. The patients were randomized to
`receive 1 of2 flexible-dose ranges oflurasidone HCI (20-
`60 mg daily or 80-120 mg daily) or to placebo.
`The Montgomery-Asberg Depression Rating Scale
`(MADRS), a 10-item clinician-rated scale with total
`scores ranging from |
`(no depressive features) to 60
`(maximum score), was usedas the primary rating instru-
`ment to measure depressive symptomsin this study. The
`primary end point was the change from baseline in
`MADRSscore at week 6. The Clinical Global Impres-
`sion-Bipolar-Severity ofIllness scale (CGI-BP-S), a cli-
`nician-rated scale that measures the patient’s current
`illness state on a 7-point scale, with a higher score asso-
`ciated with greater illness severity, served as the second-
`ary rating instrument.®
`lurasidone HCl was
`trial,
`Based on this clinical
`found to be superior to placebo for the low-dose range
`
`The approval of lurasidone HCI was supported by 2
`clinical trials, one that evaluated its efficacy as mono-
`therapy, and another that evaluatedits efficacy as ad-
`junctive therapy in adults with depressive episodes asso-
`ciated with bipolar depression.*”
`
`Mechanism of Action
`The mechanism ofaction of lurasidone HC! for the
`treatment of bipolar depression and schizophrenia is
`unknown. Its efficacy may be mediated through a com-
`bination of central dopamine D, and serotonin type 2
`(5-HT,,) receptor antagonism. Lurasidone HCl is an
`antagonist with high affinity binding at the D, recep-
`tors and the 5-HT serotonin receptors 5-HT2, and
`5-HT?receptors.*
`In short-term, placebo-controlled trials of patients
`with bipolar depression and schizophrenia, no postbase-
`line QT prolongations exceeding 500 msec were report-
`ed in patients treated with lurasidone HCI orplacebo.*
`
`Dosing
`For the treatment of bipolar depression, the recom-
`mendedstarting oral dose of lurasidone HCl as monother-
`apy or as adjunctive therapy with either lithium or val-
`proate is 20 mgdaily, with no dose titration required; the
`recommendeddose for lurasidone HCI is 20 mg daily to
`120 medaily.’ The maximum recommended dose of lu-
`rasidone HCl, as monotherapy or as adjunctive therapy
`with lithium or valproate, is 120 mg daily. Lurasidone HCl
`should be taken with food(at least 350 calories): adminis-
`
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`

`
`
` Lurasidone HCI Adjunctive Therapy with Lithium or Valproate:
`Le|')'-374 Primary Efficacy Results for Studies in Depressive Episodes
`
`Associated with Bipolar | Disorder (MADRS Scores)
`
`
`
`Primaryefficacy measure: MADRS
`Placebo-
`
`
`subtracted
`LS mean
`Meanbaseline
`change from difference*
`
`Treatment group
`score (SD)
`(95% CI)
`baseline (SE)
`
`
`
`
`
`
`Lurasidone HCL
`30.6 (5.3)
`-17.1 (0.9)
`3.6
`(20-120 mg daily)* +
`lithium or valproate
`Placebo + lithium
`or valproate
`
`(-6 to-1.1) 30.8 (4.8)
`
`-13.5 (0.9)
`
`
` ‘Difference (drug minus placebo) in LS mean change from baseline.
`‘Treatment groupstatistically significantly superior to placebo.
`NOTE:BipolarI disorderis also referred to as bipolar depression.
`
`Clindicates confidence interval, unadjusted for multiple comparisons;
`
`HCI, hydrochloride; LS, least-squares; MADRS, Montgomery-Asberg
`
`Depression Rating Scale; SD, standard deviation; SE, standard error.
`
`Source: Latuda (lurasidone hydrochloride) tablets prescribing
`information; 2013.
`
`
`
`
`
`(20-60 mg daily) and the high-dose range (80-120 mg
`daily) in reducing the MADRS and CGI-BP-Sscores at
`week 6 (Table 1). The high-dose range did not show
`additional efhcacy, on average, comparedwith the low-
`dose range.
`
`Lurasidone HCl as Adjunctive Therapy with
`Lithium or Valproate
`Theefficacy of lurasidone HCIas an adjunctive ther-
`apy with lithium or valproate was demonstrated in a
`6-week, randomized, double-blind, placebo-controlled
`trial of 340 adult patients who met the DSM-IV-TRcri-
`teria for major depressive episodes associated with bipo-
`lar | disorder, with or withoutrapid cycling, and without
`psychotic features. These patients ranged in age from 18
`to 72 years, with a mean age of 41.7 years. Patients who
`remained symptomatic after treatment with lithium or
`valproate were randomized to receive lurasidone HClat
`flexible doses of 20 mg to 120 mg daily, or to placebo.*
`To assess depressive symptoms in this study,
`the
`MADRSwasusedas the primary rating instrument. The
`primary end point was the change from baseline in
`MADRSscore at week 6. The key secondary instrument
`was the CGI-BP-Sscale. In this study, lurasidone HCl as
`an adjunctive therapy with lithium or valproate was
`superior to placebo at reducing MADRS and CGI-BP-S
`scores at week 6 (Table 2).*
`
`Safety
`The most frequently observed adverse reactions(inci-
`dence 25% andatleast twice the rate for placebo) asso-
`ciatedwiththe use oflurasidone HCl as monotherapyfor
`bipolar depression (daily doses ranging from 20-120 mg)
`reported in clinical trials were akathisia, extrapyramidal
`symptoms(ie, bradykinesia, cogwheel rigidity, drooling,
`dystonia, extrapyramidaldisorder, glabellar reflex abnor-
`mal, hypokinesia, muscle rigidity, oculogyric crisis, oro-
`mandibular dystonia, Parkinsonism, psychomotor tetar-
`dation, tongue spasm, torticollis, tremor, and trismus),
`somnolence, nausea, vomiting, diarrhea, and anxiety.
`At daily doses ranging from 20 mg to 120 mg as ad-
`junctive therapy with lithium or valproate for bipolar
`depression, the most frequent adverse reactions (inci-
`dence 25% andatleast twice the rate of placebo) were
`akathisia and somnolence.®
`
`Contraindications
`Lurasidone HC]is contraindicated in patients with a
`knownhypersensitivity to lurasidone HCl or any compo-
`nents in the formulation. Other contraindications for
`lurasidone HCl include concomitant use with a strong
`CYP3A4 inhibitor
`(eg, ketoconazole) or a strong
`CYP3A4 inducer (eg, rifampin).8
`
`Warnings and Precautions
`Boxed warning. The prescribing information for lu-
`rasidone HCl includes a boxed warningstating that el-
`derly patients with dementia-telated psychosis who are
`treated with antipsychotic drugs have an increased risk
`of death. Lurasidone HClis not approved for the treat-
`ment of patients with dementia-related psychosis. The
`boxed warningalsostates that there is an increased risk
`of suicidal thinking andsuicidal behavior in children,
`adolescents, and young adults taking antidepressants,
`and patients should be monitored for worsening and
`emergence ofsuicidal thoughts and behaviors when tak-
`ing lurasidone HCI.§
`Neuroleptic malignant syndrome (NMS). NMSis a
`potentially fatal symptom complex that has been report-
`ed with the use of antipsychotic drugs, including lurasi-
`done HCl. The management of NMS should include
`immediate discontinuation of lurasidone HCI or other
`antipsychotic drugs not essential to concurrent therapy.
`Patients should be monitored carefully.*
`Tardive dyskinesia. |f signs and symptomsoftardive
`dyskinesia appear in a patient taking lurasidone HCl,
`drug discontinuation should be considered if clinically
`appropriate. However, some patients may require treat-
`ment with lurasidone HCI despite the presence oftar-
`dive dyskinesia.
`Metabolic changes. Atypical antipsychotic drugs
`have been associated with metabolic changes, including
`hyperglycemia, dyslipidemia, and weight gain, that may
`increase cardiovascular and cerebrovascular risk. Pa-
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`tients should be monitored for symptoms of hypergly-
`cemia, including polydipsia, polyuria, polyphagia, and
`weakness. Glucose should be monitored regularly in pa-
`tients with diabetes or whoare at risk for diabetes. Un-
`desirable alterations in lipids have been observedin pa-
`tients treated with atypical antipsychotics. Weight gain
`has been observed with the use of atypical antipsychot-
`ics. The clinical monitoring of weight is recommended.
`Hyperprolactinemia. Prolactin elevations may occur
`with use of lurasidone HCI and other dopamine D, re-
`ceptor antagonists.
`Leukopenia, neutropenia, and agranulocytosis.
`Complete blood counts should be performed in patients
`with a preexisting low white bloodcell count ora histo-
`ry ofleukopenia or neutropenia. If a clinically significant
`decline in white blood cells occurs in the absence of
`other causative factors, the discontinuation of lurasidone
`HCIshould be considered.
`
`The approval of lurasidone HC! for bipolar
`depression adds a new treatment option for
`patients suffering from this seriousillness.
`
`Orthostatic hypotension and syncope. Dizziness,
`tachycardia or bradycardia, and syncope may occur
`with theuse of lurasidone HCI, especially early in treat-
`ment. In patients with known cardiovascular or cere-
`brovascular disease, and in antipsychotic-naive pa-
`tients, a lower starting dose and slower titration should
`be considered.®
`
`Use in Specific Populations
`Pregnancy. Lurasidone HCl should only be used
`during pregnancy if the potential benefit justifies the
`potential risk.§
`Nursing mothers. Lurasidone HCI should be discon-
`tinued by nursing mothers or nursing should be discon-
`tinued while taking lurasidone HCl. The risk of drug
`discontinuation to the mother should be considered.®
`
`Conclusion
`Bipolar depressionis a lifelong illness associated with
`serious morbidity and a heavy economic toll. In June
`2013, the FDA approved 2 new indications for the oral
`atypical antipsychotic lurasidone HCI for the treatment
`of depressive episodes associated with bipolar depression;
`the drug was approved as monotherapy, and as adjunc-
`tive therapy with lithium or valproate. Previously, this
`drug was approved by the FDA for the treatment of
`schizophrenia in 2010. The approvalof lurasidone HC!
`for bipolar depression adds a new treatment option for
`patients suffering from this serious illness.
`In 2 trials, lurasidone HCl demonstratedsignificant
`improvements in depressive symptoms after 6 weeks
`compared with placebo, as monotherapy, and as adjune-
`tive therapy withlithium or valproate, in patients with
`depressive episodes associated with bipolar depression.
`In clinical trials of patients with bipolar depression,
`the most commonadverse reactions in patients receiv-
`ing lurasidone HCI as monotherapy were akathisia, ex-
`trapyramidal symptoms, somnolence, nausea, vomiting,
`diarrhea, and anxiety. In patients receiving lurasidone
`HCl as adjunctive therapy with lithium or valproate,
`the most common adverse reactions were akathisia and
`somnolence. i
`
`References
`1. Mayo Clinic staff. Diseases and conditions: bipolar disorder. January 18, 2012.
`www.mayoclinic.comphealth/bipolar-disorder/D$00356. Accessed August 26, 2013.
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`ica. www.nimh.nih gov/health/publications/the-numbers-count-mental-disorders-
`in-america/index.shuml+ Bipolar. Accessed August 27, 2013.
`3. Centers for Disease Control and Prevention. Burden of mental illness. Updated July
`1, 2011. www.cde.gov/mentalheal th/basics/burden.htm. Accessed August 28, 2013.
`4. Sagman D, Tohen M. Comorbidityin bipolar disorder. March 23, 2009. Psychiatr
`Times. www.psychiatrictimes.com/bipolar-disorder/comorbidity-bipolar-disorder/page/
`O/1!_EXT_4pageNumber=3&_EXT_4comsorteof. Accessed August 28, 2013.
`5. Hirschfeld RM, Vomik LA.Bipolar disorder—costs and comorbidity. Am] Manag
`Care. 2005;11(3 suppl ):S85-S90.
`6. Wyatt RJ, Henter |. An economic evaluation of manic-depressive illness—1991.
`Soc Psychiatry Psychiatr Epidemiol. 1995;30:213-219.
`7. Dilsaver SC. Anestimate of the minimum economic burden of bipolar | andII
`disorders in the United States: 2009. J Affect Disord. 2011;129:79-83.
`8. Latuda (lurasidone hydrochloride) tablets [prescribing information]. Marlborough,
`MA:Sunovion Pharmaceuticals Inc; July 2013.
`9. Lowes R. Lurasidone approved for bipolar depression. Medscape. July 1, 2013. www.
`medscape.com/viewarticle/S07204. Accessed August 26, 2013.
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