Latuda (Lurasidone HCI) 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—tenn illness 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—are affected by bipolar disorr
`der.l The median age of onset for bipolar disorder is 25
`years} According to the Centers for Disease Control and
`Prevention. in 201 1, patients with bipolar disorder had a
`39.1% inpatient hospitalization rate compared with a
`4.
`‘34) rate for patients with other behavioral healthcate
`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 bipolar dis—
`order include anxiety. substance abuse. panic disorder.
`and eating disorders, among others. The risk of suicide is
`increased in patients with bipolar disorder, particularly
`in those who also have. anmety and substance abuse.4
`in—
`The total economic burden of bipolar disorder,
`cluding direct and indirect costs, in the United States
`was estimated to be $45 billion in 1991f" A 2009 analr
`ysis estimated that the total costs of bipolar disorder were
`dramatically higher. totaling $151 billion in direct and
`indirect costs.: Of this total. bipolar l disorder accounted
`for $30.7 billion. and bipolar II disorder accounted for
`$120.3 billionf
`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 symptoms are stabilized. maintenance therapy is
`
`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
`changes into full—blown episodes of mania or depression.‘
`Early diagnosis and management may help to improve
`outcomes for patients and to reduce. associated health-
`cate. costs.
`
`Medications used to treat bipolar disorder include
`lithium. anticonvulsants. antipsychotics, antidepres—
`sants, benzodiazepines. and a combination ot’olanzapine
`and fluoxetine. These agents have class-specific 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. In 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 Mood Disorders Program. University Hospitals Case
`Medical Center. Case Western Reserve University.
`Cleveland. OH. “Unfortunately, there are very few treate
`ments specifically approved to treat the symptoms orbi—
`polar depression, which represents a very large unmet
`medical need for patients and their families.”
`
`A New Atypical Antipsychotic Agent for the
`Treatment of Bipolar Depression
`In June 2013. lumsidone hydrochloride (HCl; Latuda;
`Sunovion Pharmaceuticals), an oral atypical antipsy—
`chotic. was approved by the US Food and Drug Admin—
`istration (FDA) for 2 new indications—as monotherapy.
`and as adjunctive therapy with lithium or with valproate
`for the treatment of adult patients with major depressive
`episodes associated with bipolar l disorder (bipolar de—
`pression). Latuda was previously approved by the FDA in
`2010 for the treatment of patients with schizophrenia.“
`
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`Exhibit 2057
`Slayback v. Sumitomo
`|PR2020—01053
`
`Exhibit 2057
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`
`
`
`
`Lurasidone HCI Monotherapy: Primary Efficacy Results
`
`for Studies in Depressive Episodes Associated with
`Bipolar I Disorder (MADRS Scores)
`
`Table 1
`
`
`
`Primary efficacy measure: MADRS
`Placebo—
`subtracted
`LS mean
`Treatment
`Mean baseline
`
`
`change from difference'
`
`group
`score (SD)
`baseline (SE)
`(95% Cl)
`
`Lurasidone HCl
`-l‘5.4 (0.8)
`-4.6
`30.3 (5)
`
`”0—60 meddle: .
`(—639 to —2.3)
`Lurasidone HCl
`—4.6
`
`30.6 (4.9)
`
`"—15.4 (as;
`
`tration with food substantially increases the absorption of
`lurasidone HCl. Lurasidone HCl is available as tablets in
`
`ZU—mg. 40—mg. 60—mg. 80—mg, and lZO—mg strengths.“
`In patients with moderate and severe renal
`impairr
`merit, the recommended starting dose of lurasidone HCl
`is 20 mg daily. and the maximum recommended dose is
`80 mg daily. in patients with moderate and severe hepat'
`ic impairment, the recommended starting dose is 20 mg
`daily. The maximum recommended dose is 80 mg daily
`for patients with moderate hepatic impairment and 40
`mg daily {or patients with severe hepatic impainnent.*
`With the concomitant use of a moderate cytochrome
`(CY) P3A4 inhibitor (eg, diltiazem), the dose of lurasi—
`done HCl should be reduced to halfof the original dose
`level. The recommended starting dose is 20 mg daily,
`and the maximum recommended dose 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 HCl should not be used concomitantly
`with a strong CYP3A4 inducer (cg, rifarnpin. avasimibe.
`St John's wort, phenytoin, carbamazepine). Grapefi'uit
`and grapefruit juice should be avoided by patients taking
`lurasidone HCl, because the juice may inhibit the CYP3A4
`enzyme and alter the concentrations of lurasidone HCl.“
`
`Cliniml Studies
`
`Lurasidone HCl as Monotherapy
`The efficacy of lurasidone HCl as monotherapy was
`demonstrated in a 6-week, randomized. doublerblind, plar
`CCl‘KVCOHUOllCd trial of 485 adult patients who met the
`Diagnostic and Statistical Manual ofMenml Disorders, Fourth
`Edition, Text Revision (DSM’lvaR) criteria for major dee
`pressive episodes associated with bipolar l disorder, with or
`without rapid cycling. and without psychotic features.3
`These patients ranged in age from 18 to 74 years. with a
`mean age. oi‘4l .5 years. The patients were randomized to
`receive 1 of 2 flexible-dose ranges oflurasidone HCl (20—
`60 mg daily or 80—120 mg daily) or to placebo.8
`The Montgomery’Asberg Depression Rating Scale
`(MADRS). a lO-item clinicianrrated scale with total
`scores ranging from 1
`(no depressive features) to 60
`(maximum score), was used as the primary rating insttw
`ment to measure depressive symptoms in this study. The
`primary end point was the change from baseline in
`MADRS score at week 6. The Clinical Global Impres—
`sion—Bipolar’Severity of Illness scale (CGl-BP’S). a die
`nicianvrated scale that measures the patient‘s current
`illness state on a 7—point scale. with a higher score assov
`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 lowdose range
`
`
`
`
`
`(80-129 mg daily)
`
`7 416.7 (as), W ‘7 fl
`30.5) (5’)
`aDifference, (drug minus placebo) in LS mean change from baxline.
`l"Treatment group significantly superior to placebo.
`NOTE: Bipolar l disorder is also referred to as bipolar depression.
`Cl indicates confidence interval, unadjusted for multiple comparisons;
`HCI, hydrochloride; LS, least—squares; MADRS, MontgrmeryAslt-rg
`Depression Rating Scale; SD. standard deviation; SE. standard error.
`Source: Latuda (lurasidone hydrochloride) tablets prescribing
`infonnation; 2013.
`
`The approval of lurasidone HCl was supported by 2
`clinical trials. one that evaluated its efficacy as mono-
`therapy. and another that evaluated its efficacy as ad—
`junctive therapy in adults with depressive episodes asso—
`ciated with bipolar depression.”
`
`Mechanism of Action
`The mechanism of action of lurasidone HCl for the
`
`treatment of bipolar depression and schizophrenia is
`unknown. lts efficacy may be mediated through a com—
`bination of central dopamine D3 and serotonin type 2
`(5-HT2A) receptor antagonim. Lurasidone HCl is an
`antagonist with high affinity binding at the D1 recep—
`tors and the SvHT serotonin receptors S’HTM and
`SrHT7 receptors.8
`In short—term, placeboacontrolled trials of patients
`with bipolar depression and schizophrenia, no postbase’
`line QT prolongations exceeding 500- msec were report-
`ed in patients treated with lurasidone HCl or placebo."
`
`Dosing
`For the treatment of bipolar depression. the recom—
`mended starting oral dose of lurasidone HCl as monother-
`apy or as adjunctive therapy with either lithium or vale
`proate is 20 mg daily. with no dose titration required; the
`recommended dose for lurasidone HCl is 20 mg daily to
`120 mg daily.8 The maximum recommended dose of lu-
`rasidone HCl, as monotherapy or as adj unctive therapy
`with lithium or valproate, is 120 mg daily. Lurasidone HCl
`should be taken with food (at least 350 calories): adminiy
`
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`(20—60 mg daily) and the high-dose range (80—120 mg
`daily) in reducing the MADRS and CGl—BP‘S scores at
`week 6 (Table l). The high—dose range did not show
`additional efficacy. on average. compared with the low
`dose range.8
`
`Lurasidone HCl as Adjunctive Therapy with
`Lithium or Valproate
`The efficacy of lurasidone HCl as an adjunctive therv
`apy with lithium or valproate was demonstrated in a
`6-week. randomized, double-blind, placebocontrolled
`trial of340 adult patients who met the DSM—W'TR cri—
`teria for major depressive episodes associated with bipo-
`lar l disorder. with or without rapid cycling. and without
`psychotic features. These patients ranged in age from 18
`to 72 years, with a mean age of4l.7 years. Patients who
`remained symptomatic after treatment with lithium or
`valproate were randomized to receive lurasidone HCl at
`flexible doses of 20 mg to 120 mg daily. or to placebo.8
`To assess depressive symptoms in this study,
`the
`MADRS was used as the primary rating instrument. The
`primary end point was the change from baseline in
`MADRS score at week 6. The key secondary instrument
`was the CGl-BP‘S scale. In this study. lurasidone HCl as
`an adjunctive therapy with lithium or valproate was
`superior to placebo at reducing MADRS and CleBP—S
`scores at week 6 (Table 2).‘
`
`Safety
`The most frequently observed adverse reactions (inci—
`dence 25% and at least twice the rate for placebo) asso—
`ciated with the use oi'lurasidone HCl as monotherapy for
`bipolar depression (daily doses ranging from 20—120 mg)
`reported in clinical trials were akathisia, extrapyramidal
`symptoms (ie, bradykinesia. cogwheel rigidity, drooling.
`dystonia. extrapyramidal disorder. glabellar reflex abnor‘
`mal. liypokinesia. muscle rigidity. oculogyric crisis. oro—
`mandibular dystonia, Parkinsonism, psychomotor retar—
`dation. tongue spasm. torticollis. tremor. and trismus).
`somnolence. nausea. vomiting. diarrhea, and anxiety.
`At daily doses ranging from 20 mg to 120 mg as adv
`junctivc therapy with lithium or valproate for bipolar
`depression, the most frequent adverse reactions (inciv
`dence 25% and at least twice the rate of placebo) were
`akathisia and somnolence.a
`
`Contraindications
`Lurasidone HCl is contraindicated in patients with a
`known hypersensitivity to lurasidone HCl or any compor
`nenrs in the formulation. Other contraindications for
`lurasidone HCl include concomitant use with a strong
`CYP3A4 inhibitor
`(eg. ketoconazole) or a strong
`CYP3A4 inducer (cg, rifampin).x
`
` Luras'uone HCI Mjmctive Thaapy with Lithium or Vanuate:
`
`
`Table 2 Primary Efim Resinsiorsuidles n Depressive Episodes
`
`Associated with Bipolar! Disorder (MADBS Scores)
`
`Primary efficacy measure: MADRS
`
`
`PlacebOn
`
`
`subtracted
`LS mean
`Mean baseline
`change from difference“
`
`Treatment group
`(95% Cl)
`score (SD)
`baseline (SE)
`
`
`
`
`Lurasidone HCI
`30.6 (5.3)
`-l7.l (0.9)
`-3.6
`
`
`(—6to—l.|)
`(20—120 mg daily)“ +
` 30.8 (4.8)
`lithium or valproate
`Placebo + lithium
`43.5 (0.9.)
`
`or valproate
` aDifference (drug minus placebo) in LS mean change from baseline.
`
`
`l’Treatment group statistically significantly superior to placebo.
`NOTE: Bipolar l disorder is also referred to as bipolar depression.
`
`C1 indicates confidence interval. unadjusted for multiple comparisons;
`
`HCl. liydrrthloride; LS. least—srurares; MADRS. Montgoineiy—Aslrrg
`
`Depression Rating Scale; SD. standard deviation: SE. standard error.
`
`Source: Latuda (lurasidone hydrochloride) tablets prescribing
`
`information; 2013.
`
`
`
`Warnings and Precautions
`Boxed warning. The prescribing information for lu—
`rasidone HCl includes a boxed warning stating that el—
`derly patients with dementiavrelated psychosis who are
`treated with antipsychoric drugs have an increased risk
`of death. Lurasidone HCl is not approved for the treata
`ment of patients with dementia-related psychosis. The
`boxed warning also states that there is an increased risk
`of suicidal thinking and suicidal behavior in children.
`adolescents, and young adults taking antidepressants.
`and patients should be monitored for worsening and
`emergence of suicidal thoughts and behaviors when tak-
`ing lurasidone HCl.“
`Neuroieptic malignant syndrome (NMS). NMS is a
`potentially fatal symptom complex that has been report—
`ed with the use ot‘ antipsychotic drugs, including lurasi—
`done HCl. The management of NMS should include
`immediate discontinuation of lurasidone HCl or other
`
`antipsychotic drugs not essential to concurrent therapy.
`Patients should be monitored carefully."
`Tar-dive dyskinesia. lf signs and symptoms of tardive
`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 HCl despite the presence of tar’
`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 who are at risk for diabetes. Unr
`
`desirable alterations in lipids have been observed in pa—
`tients treated with atypical antipsychotics. Weight pain
`has been observed with the use of atypical antipsychot‘
`ics. The clinical monitoring of weight is recommended.
`Hypcrprolactinemia. Prolactin elevations may occur
`with use of lurasidone HCI and other dopamine I): re—
`ceptor antagonists.
`Leukopenia, neutropenia, and agranulocytosis.
`Complete blood counts should be performed in patients
`with a preexisting low white blood cell count or a 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
`HCI should be considered.
`
`The approval of lurasidone HCl for bipolar
`
`depression adds a new treatment option for
`patients suffering from this serious illness.
`
`Orthostatic hypotension and syncope. Dizziness.
`tachycardia or bradycardia, and syncope may occur
`with the use of lurasidone HCI, especially early in treat‘
`ment. In patients with known cardiovascular or cere—
`brovascular disease, and in antipsychotic‘na'ive pa‘
`tients. a lower starting dose and slower titration should
`be considered.“
`
`Use in Specific Populations
`Pregnancy. Lurasidone HCI 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 discona
`tinued while taking lurasidone HCI. The risk of drug
`discontinuation to the mother should be considered.“
`
`Conclusion
`Bipolar depression is 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 HCl 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 approval of lurasidone HCI
`for bipolar depression adds a new treatment option for
`patients suffering from this serious illness.
`In 2 trials, lurasidone HCI demonstrated significant
`improvements in depressive symptoms after 6 weeks
`compared with placebo, as monotherapy. and as adjuncr
`tive therapy with lithium or valproate, in patients with
`depressive episodes associated with bipolar depression.
`In clinical trials of patients with bipolar depression.
`the most common adverse reactions in patients receiv—
`ing lurasidone HCI as monotherapy were akathisia, CX'
`trapyralnidal symptoms, somnolence, nausea, vomiting,
`diarrhea. and anxiety. In patients receiving lurasidone
`HCI as adjunctive therapy with lithium or valproate.
`the most common adverse reactions were akathisia and
`somnolencc. I
`
`References
`I. Mayo Clinic stall. Diseases and conditions: bipolar disorder. January lb, ZCIZ.
`www.mvocliniccorn/henIdi/bipolnr-disonkr/DSW356. Accessed August 26, 2C1}.
`2. National Institute ochnlal I Icaltl'r. The ”Amber! count: mental disorders in Amcrv
`ica. WWW-llIlllllJllll.:’_\)V]h€dIlII/pulfllelulfiillIC'llulllan'CWII'IIICIIBI'MI‘KXJCB’
`In-HI’lIHICU/illdcxél‘llllll‘ Bipoktr. Accessed August 27. 1C1}.
`3. Centers for Duane Control and Prevention. Burden of mental lIIl'Efi. Updated July
`l. 10] l . wwa.cdc.gov/rncnmlhealth/Iwrcsli‘urdenhtm. Accessed August 26. 20] i.
`4- Sagmari D, 'I'nhen M. Comorbidity in bipolar disorder. March I}, 2009. Psychic"
`limes. wwpsychintnctimes.oorn/bipolar-disorder/eomorbiditybipolar-dirordu/pngef
`C/I l_D(‘l‘_-‘l_1:np,eNumberr 35L_I‘X'I fi4__cormort rd. Accessed August It, ZCI l.
`5. Ilinchfcld RM. Votnilr LA. Bipolar disorder coat: and comorbidity. Am} Mam;
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`6. W'yatt Rl. Ilcmcr I. An economic evaluation of tiiaficdcptcmve illness—I99].
`SOC Psychiatry Psychm Epflitmbl. 1995;3C2213-ZI 9.
`7. Dilsaver SC. An estimate of the minimum economic burden of bipolar I and II
`disorders In the United States: 2W.) Affect ”WEI. ZCI I :IZQJQ-SI.
`8. Luluda (lurasidone hydrochloride) tablets [prescribing infmticnl. Marlborough,
`MA: Sunm-ion I’lmrnuceutrcnl! Inc; _lu|y 2013.
`9. Lowe: R. Lurmidone approved forbipolar depremion. Medmpe. July I. 201 3.www.
`riled-cape.cum/viewartielc/SOHC-I. Accessed August 26, 2C] 3.
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