Mattingly et al. BMC Psychiatry
`
`https://doiorg/10.1186/s12888 020 02523 1
`
`(2020) 20:199
`
`BMC Psychiatry
`
` RESEARCH ARTICLE
`Open Access
`Switching to Lurasidone following 12
`®
`monthsof treatment with Risperidone:
`“
`results of a 6-month, open-label study
`Greg W.Mattingly’, Peter M. Haddad*3*°, Michael Tocco®, Jane Xu®, Debra Phillips®, Andrei Pikalov® and
`Antony Loebel®
`
`Keywords: Lurasidone, Antipsychotic agents, Schizophrenia, Adverse effects, Weight, Metabolic, Lipids, Prolactin
`
`Abstract
`
`Background:Patients with a diagnosis of schizophrenia are at an increased risk for developing metabolic syndrome,
`which is associated with greater cardiovascular morbidity and mortality. Treatment with some commonly used
`antipsychotic medications may increase the risk of developing metabolic syndrome. The aim of the study was to
`evaluate the safety of lurasidone in patients who continued lurasidone or switched from risperidone to lurasidone. A
`secondary aim was assessmentof the effect of long term lurasidone on the Positive and Negative SyndromeScale
`(PANSS).
`Methods: The treatment sample in the current study consisted of clinically stable patients with schizophrenia
`(N= 223) who had completed a 12 month, double blind study of lurasidone vs. risperidone. In the current
`extension study, all patients received 6 months of open label treatment with lurasidone, either continuing
`lurasidone assigned during the preceding doubleblind trial, or switching from double blind risperidone to
`lurasidone. Safety and tolerability parameters included body weight, prolactin, and metabolic laboratory tests.
`Results: Six months of OL treatment with lurasidone was generally well tolerated, with a low incidence of parkinsonism
`(4.5%) and akathisia (3.1%). Overall, few adverse events were rated as severe (4.9%), and discontinuation due to an adverse
`event was low in the lurasidone continuation vs. risperidone switch groups (3.7% vs. 6.9%). In the lurasidone continuation
`versus risperidone switch groups, change from OL baseline to 6 month endpoint (observed case) was observed in mean
`body weight (— 0.6 vs. 26 kg), median total cholesterol (— 4.0 vs. + 4.5 mg/dL), triglycerides (— 4.5 vs. 5.5 mg/dL), glucose (0.0
`vs. 3.0 mg/dL) and prolactin (males, +0.15 vs. 112 ng/mL; females, + 1.3 vs. 308 ng/mL). Improvement in PANSS total score
`was maintained, from OL baseline to endpointin the continuation vs. switch groups (+ 1.0 vs. 1.0; OC).
`Conclusions: |n this 6 month extension study, lurasidone treatment was generally well tolerated and associated with
`minimal effects on weight, metabolic parameters, and prolactin levels. Patients who switched from risperidone to lurasidone
`experienced reductions in weight, metabolic parameters and prolactin levels commensurate with increases in these safety
`parameters experienced during the previous 12 monthsof treatment with risperidone.
`Trial registration: ClinicalTrials.gov NCT00641745 (Date of Registration: March 24, 2008).
`
`* Correspondence: paladinmed@gmail.com
`SSunovion Pharmaceuticals Inc, Fort Lee, NJ, 84 Waterford Dr, Marlborough,
`MA 01752, USA
`Full list of authorinformationis available at the end of the article
`
`© The Author(s). 2020 Open Access This artide is licensed under a Creative Commons Attribution 4.0 Intemational License,
`which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give
`appropriate credit to the original author(s) and the source, providealink to the Creative Commons licence, and indicate if
`changes were made. The images or other third party material in this artide are indudedin the article's Creative Commons
`licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons
`licence and yourintended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain
`permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
`The Creative Commons Public Domain Dedication waiver (http.//creativecommons.org/publicdomain/zero/1.0/) applies to the
`data made available in this article, unless otherwise stated in a cedit line to the data.
`
`1
`
`Exhibit 2087
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`Mattingly et al. BMC Psychiatry (2020) 20:199
`
`Page 2 of 13
`
`Background
`Non-response to treatment with an initial antipsychotic
`occurs in at least 50% of patients with first episode
`schizophrenia and increases as the illness becomes more
`chronic and recurrent [1, 2]. The recommended next-
`step treatment option in non-responders is switching to
`an alternative antipsychotic [3, 4]. In addition to lack of
`efficacy, problems with safety or tolerability frequently
`necessitate switching antipsychotics [5].
`Lurasidone is an atypical antipsychotic agent that has
`demonstrated efficacy in short-term [6–9] and long-term
`studies [10–12] of patients with schizophrenia, with a
`safety profile indicating minimal effects on weight, meta-
`bolic parameters, and prolactin [13, 14].
`Previously, the effectiveness of switching patients with
`schizophrenia or schizoaffective disorder to lurasidone
`using 3 different dosing strategies has been evaluated
`[15]. At the time of the switch, patients were in a non-
`acute phase of their illness and were being treated with a
`wide range of typical or atypical antipsychotics. This 6-
`week study demonstrated that switching patients to lura-
`sidone was associated with good efficacy and tolerability
`and low rates of treatment failure (8%), regardless of
`switching strategy (rapid or slow titration of lurasidone).
`Initial improvement in weight and lipids was observed
`after 6 weeks of treatment. In a 6-month, open-label
`extension of this study, improvements in efficacy on lur-
`asidone were maintained, with minimal long-term effects
`on weight, metabolic parameters, and prolactin [16].
`The effect on safety parameters of switching patients
`with schizophrenia from olanzapine to lurasidone has
`also been evaluated in a 6-month, open-label extension
`study in which patients who completed 6 weeks of
`double-blind, placebo-controlled treatment with olanza-
`pine or lurasidone were switched to 6 months of open-
`lurasidone 40–120 mg/d [17]. At 6-month end-
`label
`point, switching from olanzapine to lurasidone resulted
`in clinically meaningful (≥7%) reduction in weight in
`29.0% of patients; and median reduction in lipid parame-
`ters, including total cholesterol (− 15.0 mg/dL) and tri-
`glycerides (− 28.0 mg/dL).
`We now report results of an open-label extension study
`in which patients with schizophrenia who completed a
`double-blind, 12-month study of lurasidone versus risperi-
`done [18] either continued lurasidone or switched from
`risperidone to lurasidone for an additional 6 months of
`open-label treatment. Notable safety results for lurasidone
`vs. risperidone at endpoint of the initial double-blind
`study included: mean reduction in weight (− 1.0 vs. + 1.5
`kg) and waist circumference (− 0.6 vs. + 1.6 cm); smaller
`mean increases in prolactin for females (+ 34.9 vs. 53.3 ng/
`mL) but similar increases for males (13.5 vs. 14.1 ng/mL).
`The primary objective of this study was to evaluate the
`long-term safety, tolerability and overall effectiveness of
`
`lurasidone in both the continuation and risperidone
`switch groups.
`
`Methods
`Study design
`Detailed methods for the initial 12-month, double-blind
`study have been previously reported [18]. Briefly, clinic-
`ally stable outpatients, ages 18–75 years, with a diagnosis
`of schizophrenia or schizoaffective disorder, were ran-
`domly assigned in a 2:1 ratio to receive lurasidone (flex-
`ibly dosed, 40–120 mg/d) or risperidone (flexibly dosed,
`2–6 mg/d). Study completers were eligible to continue
`into the current 6-month, open-label extension study
`that was conducted from March 2009 to January 2011 at
`sites in the United States (n = 40), South Africa (n = 7),
`Argentina (n = 5), Chile (n = 5), Brazil (n = 4), Croatia
`(n = 3), Thailand (n = 3), and Israel (n = 1). To maintain
`the double-blind in the initial 12-month study, all
`patients entering the current open-label study received
`3 days of single-blind placebo washout followed by 7
`days of lurasidone 80 mg/d. After 7 days, the lurasidone
`dose could be titrated, based on the judgment of the in-
`vestigator, in the range of 40–120 mg/d.
`The study was conducted in accordance with the Good
`Clinical Practice Guidelines of the International Confer-
`ence on Harmonisation and with the ethical principles
`of the Declaration of Helsinki. The study was approved
`by an institutional review board or independent ethics
`committee at each study site, and all patients provided
`written informed consent prior to initiation of study
`procedures. No important changes in study design or
`methodology were made after the study was initiated.
`
`Assessments
`Assessment visits occurred at baseline of the open-label
`extension study and monthly thereafter. Adverse events
`were based on patient self-report in response to an
`open-ended question or were based on investigator
`observation of changes in the patient during examin-
`ation. Movement disorder symptoms were evaluated
`with the Simpson-Angus Scale (SAS)
`[19], Barnes
`Akathisia Rating Scale (BARS)
`[20], and Abnormal
`Involuntary Movement Scale (AIMS) [21]. Safety assess-
`ments
`included
`laboratory
`tests
`(chemistry
`and
`hematology panels, lipid panel, glycosylated hemoglobin
`[HbA1c], bone alkaline phosphatase, N-telopeptide,
`osteocalcin, parathyroid hormone, prolactin, and testos-
`terone), electrocardiograms (ECG), physical examina-
`tions, and vital sign measurements.
`In a subset of
`patients (at selected US sites), bone mineral density
`assessments were performed (BMD, using dual-energy
`x-ray absorptiometry [DXA]). T-scores were calculated
`([patient’s BMD – mean BMD of sex-matched young
`adults] / 1-SD of young adults), and standard criteria
`
`2
`
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`

`Mattingly et al. BMC Psychiatry
`
`(2020) 20:199
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`Page 3 of 13
`
`were used to determine BMD category (normal vs.
`osteopenia vs. osteoporosis) [22]. Ophthalmologic exam-
`inations, including dilated funduscopic andslit lamp eye
`examinations, were also performed.
`Efficacy was assessed using the Positive and Negative
`Syndrome Scale (PANSS) [23], Clinical Global Impres-
`sion, Severity scale [21], and the Montgomery-Asberg
`Depression Rating Scale (MADRS)
`[24]. Training and
`certification of raters at each investigational site on study
`assessments was provided prior to initiation of the
`double-blind study.
`
`Statistical analysis
`The primary safety analysis population consisted ofall
`patients who received at least one dose of lurasidone
`during the 6-month open-label extension study. All
`safety and efficacy outcomes were pre-specified and were
`analyzed for the overall treatment sample, and for 2
`patient subgroups: patients who received lurasidone in
`the double-blind study, and patients who received risper-
`idone in the double-blind study. Change scores werecal-
`culated from double-blind baseline to open-label study
`endpoint and from open-label baseline to open-label
`study endpoint (month 6). Observed cases (OC) andlast
`observation carried forward (LOCF-endpoint) analyses
`were performed.
`
`Results
`Patient disposition and study treatment
`Of the 236 patients who completed the initial 12-month
`double-blind study, 223 (94.5%) continued into the current
`open-label extension study. Overall, 90.1% of patients com-
`pleted at least 3 months of open-label treatmentwith lurasi-
`done, and 174/223 (78.0%) completed 6months of
`treatment. Reasons for premature discontinuation included
`adverse events (11/223; 4.9%), withdrew consent (11/223;
`4.9%), lost to follow-up (10/223; 4.5%), insufficient clinical
`response (8/223; 3.6%), and miscellaneous other reasons (9/
`223; 4.0%). Figure 1 summarizes patient disposition for the
`two pre-specified patient subgroups (based on double-blind
`treatment assignment in theinitial double-blind study.
`Patient characteristics were similar at open-label base-
`line in both the lurasidone continuation subgroup, and
`the risperidone-to-lurasidone switch subgroup (Table 1).
`The mean daily dose of lurasidone during open-label ex-
`tension was 81.1 mg. Twenty-nine percent of patients
`(n =65) received at least one concomitant medication,
`most commonly anxiolytics (22%), hypnotics/sedatives
`(18%), antidepressants (15%), and anticholinergics (13%).
`
`Safety
`Adverse events
`The most commonly reported adverse events were head-
`ache (6.3%), psychotic disorder (5.4%), and parkinsonism
`
`
`
`
`
`Double-blind Study
`12 Months
`
`Randomized to
`lurasidone
`N= 427
`
`Randomized to
`risperidone
`N = 202
`
`Completed
`double-blind study
`n= 147
`
`Completed
`double-blind study
`n=89
`
`Open-label Study
`6 Months
`
`Continued on
`lurasidone in open-label
`study (LUR-LUR)
`n= 136
`
`Switched to lurasidone
`in open-label study
`(RIS-LUR)
`n=87
`
`Discontinued open-label study, n(%)
`Withdrew consent
`Insufficient clinical response
`Adverse event
`Lost to follow-up
`Administrative
`
`Protocolviolation
`
`)
`
`27 (19.
`
`Protocol violation
`
`22 (25.3)
`(4.6)
`3.4
`35
`6.9
`5.7
`1.1
`3.4
`
`13
`
`Discontinued open-label study, n (%)
`Withdrew consent
`Insufficientclinical response
`Adverse event
`Lost to follow-up
`Administrative
`
`Completed
`open-label study
`= 65 (74.7%)
`
`Completed
`
`open-label study
`
`= 109 (80.1%)
`
`L Fig. 1 Patient Disposition. LUR = lurasidone; RIS = risperidone; DB: double blind; OLE: open label extension
`
`

`

`Mattingly et al. BMC Psychiatry (2020) 20:199
`
`Page 4 of 13
`
`(4.5%; Table 2), with minimal differences between the
`lurasidone continuation versus risperidone switch groups.
`For both groups combined, a total of 11 patients (4.9%)
`experienced an adverse event rated as severe; and 10
`patients (4.5%) experienced a serious adverse event, con-
`sisting of schizophrenia (n = 3), psychotic disorder (n = 3),
`ankle fracture (n = 1),
`lung carcinoma (n = 1), possible
`seizure (n = 1), attempted suicide (n = 1; patient recovered
`and completed the study), and a completed suicide (n = 1;
`on open-label day 22 in a patient who had previously
`received 12 months of double-blind lurasidone, and who
`was experiencing recurrent psychotic symptoms).
`
`Extrapyramidal symptoms
`In the combined patient groups, the proportion who
`reported an extrapyramidal
`symptom (EPS)-related
`adverse event during the extension study was 7.6%, and
`the proportion with akathisia was 3.1%. EPS-related
`adverse events reported in more than 1 patient were
`parkinsonism (4.5%) and dystonia (1.3%). The incidence
`of an EPS-related adverse event was similar in the lurasi-
`done continuation versus risperidone switch groups
`(Table 2). No patient discontinued due to an EPS-
`related adverse event or akathisia. Mean change from
`open-label baseline to study endpoint (LOCF) was 0.0
`on the Simpson-Angus Scale, 0.0 on the Barnes Akathi-
`sia Rating Scale global clinical assessment of akathisia,
`and + 0.3 on the Abnormal Involuntary Movement Scale
`total score.
`
`Table 1 Patient Characteristics (Open-Label Baseline, Safety
`Population)
`Characteristic
`Male, n (%)
`
`LUR LURa (N = 136) RIS LURb (N = 87)
`102 (75.0)
`58 (66.7)
`
`Age, mean (SD), y
`
`43.9 (10.7)
`
`42.8 (10.8)
`
`Race, n (%)
`
`White
`
`Black
`
`Asian
`
`Other
`
`50 (36.8)
`
`67 (49.3)
`
`6 (4.4)
`
`13 (9.6)
`
`Ethnicity, Hispanic/Latino, n (%)
`
`36 (26.5)
`
`Duration of illness, mean (SD), y 16.9 (10.7)
`≥4 hospitalizations, n (%)
`
`30 (22.1)
`
`PANSS total score, mean (SD)
`
`55.4 (13.6)
`
`CGI S score, mean (SD)
`
`2.8 (0.8)
`
`39 (44.8)
`
`40 (46.0)
`
`1 (1.1)
`
`7 (8.0)
`
`25 (28.7)
`
`17.6 (11.9)
`
`25 (28.8)
`
`55.5 (11.2)
`
`2.9 (0.8)
`
`4.3 (4.4)
`5.1 (5.6)
`MADRS score, mean (SD)
`CGI S Clinical Global Impression Severity Scale, LUR lurasidone, MADRS
`Montgomery Åsberg Depression Rating Scale, PANSS Positive and Negative
`Syndrome Scale, RIS risperidone, SD standard deviation
`a Patients who received lurasidone in both double blind and
`open label studies
`b Patients who received risperidone during the double blind study and were
`switched to lurasidone in the open label study
`
`Table 2 Adverse Events Reported in ≥2% of Patients During
`Open-Label Treatment With Lurasidone
`Adverse Event, n (%)
`
`LUR LURa
`(N = 136)
`80 (58.8)
`
`RIS LURb
`(N = 87)
`51 (58.6)
`
`≥1 adverse event
`
`Headache
`
`Psychotic disorder
`
`Parkinsonism
`
`Anxiety
`
`Blood creatine phosphokinase increased
`
`Insomnia
`
`Nasopharyngitis
`
`Akathisia
`
`Somnolence
`
`Influenza
`
`Nausea
`
`Upper respiratory infection
`
`Vomiting
`
`Back pain
`
`Decreased appetite
`
`7 (5.1)
`
`6 (4.4)
`
`5 (3.7)
`
`2 (1.5)
`
`5 (3.7)
`
`3 (2.2)
`
`5 (3.7)
`
`5 (3.7)
`
`5 (3.7)
`
`6 (4.4)
`
`3 (2.2)
`
`6 (4.4)
`
`3 (2.2)
`
`2 (1.5)
`
`3 (2.2)
`
`7 (8.0)
`
`6 (6.9)
`
`5 (5.7)
`
`6 (6.9)
`
`3 (3.4)
`
`5 (5.7)
`
`3 (3.4)
`
`2 (2.3)
`
`2 (2.3)
`
`1 (1.1)
`
`3 (3.4)
`
`0 (0)
`
`3 (3.4)
`
`3 (3.4)
`
`2 (2.3)
`
`Weight decreased
`LUR lurasidone, RIS risperidone
`a Patients who received lurasidone in both double blind and
`open label studies
`b Patients who received risperidone during the double blind study and were
`switched to lurasidone in the open label study
`
`4 (2.9)
`
`1 (1.1)
`
`Body weight, BMI, waist circumference
`Mean weight, BMI, and waist circumference were
`reduced, from double-blind to open-label baseline,
`in
`patients who received 12 months of treatment with lura-
`sidone (− 1.1 kg, − 0.55 kg/m2, and − 0.4 cm,
`respect-
`ively), and were increased in patients who received 12
`months of treatment with risperidone (+ 2.4 kg, + 2.1 kg/
`m2, + 2.8 cm, respectively; Table 3; Fig. 2).
`Mean changes
`in mean weight, BMI, and waist
`circumference at 6-month open-label endpoint
`(OC
`analysis) were minimal
`in the lurasidone continuation
`subgroup; in contrast, notable reductions were observed
`in the subgroup that switched from risperidone to lurasi-
`done (− 2.9 kg, − 1.0 kg/m2, − 1.6 cm, respectively; [OC]);
`and the proportion of patients who experienced ≥7%
`weight loss was 19.7%; Table 3).
`
`Metabolic parameters
`Median total cholesterol, triglycerides, and glucose were
`reduced,
`from double-blind to open-label baseline,
`in
`patients who received 12 months of treatment with lurasi-
`done (− 8.5 mg/dL, − 13.0 mg/dL, − 1.0 mg/dL, respectively);
`and in patients who received 12 months of treatment with
`risperidone, median triglycerides and glucose were minimally
`increased (+ 1.0 mg/dL, + 3.0 mg/dL, respectively), while total
`
`4
`
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`

`Mattingly et al. BMC Psychiatry (2020) 20:199
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`Page 5 of 13
`
`Table 3 Change From Double-blind Baseline in Safety Parameters After 12-months of Treatment With Lurasidone or Risperidone,
`Followed by 6-months of Open-label Treatment With Lurasidone (OC analysis)
`Parameter
`Weight, kg
`
`LUR LUR
`n = 109a
`
`RIS LUR
`n = 66a
`
`DB Baseline mean (SD)
`
`Mean change to OL Baseline (after 12 mo DB Tx)
`
`Mean change from OL Baseline to Month 6 OL
`≥ 7% weight increase from DB Baseline, %
`≥ 7% weight decrease from DB Baseline, %
`≥ 7% weight increase from OL Baseline, %
`≥ 7% weight decrease from OL Baseline, %
`Body mass index, kg/m2
`
`DB Baseline mean (SD)
`
`Mean change to OL Baseline (after 12 mo DB Tx)
`
`Mean change from OL Baseline to Month 6 OL
`
`Waist circumference, cm
`
`DB Baseline mean (SD)
`
`Mean change to OL Baseline (after 12 mo DB Tx)
`
`Mean change from OL Baseline to Month 6 OL
`
`Total cholesterol, mg/dL
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Triglycerides, mg/dL
`
`DB Baseline mean (SD)
`
`81.1 (18.25)
`
`82.9 (18.65)
`
`1.1
`
`0.6
`
`12.8
`
`28.4
`
`1.8
`
`6.4
`
`n = 109
`
`27.7 (5.3)
`
`0.55
`
`0.2
`
`n = 104
`
`93.8 (14.1)
`
`0.4
`
`0.9
`
`n = 108
`
`196.4 (45.4)
`
`8.5
`
`4.0
`
`n = 108
`
`127.5 (57.7)
`
`+ 2.4
`
`2.9
`
`13.6
`
`18.2
`
`3.0
`
`19.7
`
`n = 66
`
`28.8 (5.6)
`
`+ 2.1
`
`1.0
`
`n = 62
`
`97.5 (14.3)
`
`+ 2.8
`
`1.6
`
`n = 64
`
`188.0 (49.0)
`
`9.0
`
`+ 4.5
`
`n = 64
`
`125.5 (88.8)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Glucose, mg/dL
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Hemoglobin A1c, %
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Bone alkaline phosphatase, mcg/L
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`N telopeptide (urine), nmol BCE/mmol creatinine
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Osteocalcin, ng/mL
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`13.0
`
`4.5
`
`n = 105
`
`95.1 (14.5)
`
`1.0
`
`0.0
`
`n = 103
`
`5.7 (0.4)
`
`0.0
`
`0.0
`
`n = 106
`
`13.6 (5.2)
`
`0.9
`
`+ 1.5
`
`n = 104
`
`41.2 (120.3)
`
`+ 1.5
`
`1.0
`
`n = 104
`
`5.25 (3.38)
`
`0.85
`
`+ 1.0
`
`5.5
`
`n = 63
`
`94.6 (13.7)
`
`+ 3.0
`
`3.0
`
`n = 63
`
`5.6 (0.4)
`
`0.0
`
`0.0
`
`n = 61
`
`13.9 (4.3)
`
`0.3
`
`0
`
`n = 62
`
`37.0 (35.8)
`
`4.0
`
`+ 0.5
`
`n = 61
`
`5.70 (4.36)
`
`1.0
`
`5
`
`

`

`Mattingly et al. BMC Psychiatry (2020) 20:199
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`Page 6 of 13
`
`Table 3 Change From Double-blind Baseline in Safety Parameters After 12-months of Treatment With Lurasidone or Risperidone,
`Followed by 6-months of Open-label Treatment With Lurasidone (OC analysis) (Continued)
`Parameter
`LUR LUR
`Median change from OL Baseline to Month 6 OL
`0
`
`RIS LUR
`0
`
`Parathyroid hormone, pg/mL
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Prolactin, ng/mL, males
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Prolactin, ng/mL, females
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Testosterone, total, ng/dL, males
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`Median change from OL Baseline to Month 6 OL
`
`Testosterone, free, pg/mL, males
`
`DB Baseline mean (SD)
`
`Median change to OL Baseline (after 12 mo DB Tx)
`
`n = 105
`
`38.6 (17.4)
`
`0
`
`+ 2.0
`
`n = 84
`
`7.7 (6.7)
`
`0.6
`
`+ 0.15
`
`n = 24
`
`20.0 (24.7)
`
`0.75
`
`+ 1.3
`
`n = 84
`
`498.1 (198.4)
`
`+ 24.9
`
`23.5
`
`n = 84
`
`10.3 (5.5)
`
`0.015
`
`1.06
`Median change from OL Baseline to Month 6 OL
`BCE bone collagen equivalent, LUR lurasidone, RIS risperidone, DB double blind, OL open label, SD standard deviation, OC observed case
`a Results presented are an observed case analysis of the number of patients available with test results at Month 18
`
`n = 61
`
`43.2 (27.8)
`
`2.0
`
`+ 4.0
`
`n = 43
`
`10.2 (6.5)
`
`+ 12.8
`
`11.2
`
`n = 21
`
`18.6 (40.8)
`
`+ 35.2
`
`30.8
`
`n = 42
`
`481.3 (231.5)
`
`103.0
`
`+ 43.5
`
`n = 40
`
`9.6 (6.2)
`
`1.405
`
`0.095
`
`cholesterol was reduced (− 9.0 mg/dL; Table 3). Median
`hemoglobin A1c levels were unchanged at double-blind
`endpoint in both treatment groups.
`In the lurasidone continuation group, minimal changes
`were observed at 6-month open-label endpoint in median
`total cholesterol, triglycerides, glucose, and hemoglobin
`A1c (Table 3). In the risperidone switch group, small
`reductions were observed in triglycerides and glucose
`from open-label baseline to 6-month endpoint (− 5.5 mg/
`dL, − 3.0 mg/dL, respectively; OC); while total cholesterol
`increased (+ 4.5 mg/dL; Table 3). Median hemoglobin A1c
`levels were unchanged from open-label baseline to 6-
`month endpoint in both patient groups.
`
`Prolactin
`Median change in prolactin were notably different, from
`double-blind to open-label baseline, after 12 months of
`double-blind treatment with lurasidone and risperidone
`in both men (− 0.6 ng/mL vs. + 12.8 ng/mL), and women
`(− 0.75 ng/mL vs. + 35.2 ng/mL).
`In the lurasidone
`continuation group, median change in prolactin was
`minimal, from open-label baseline to 6-month endpoint
`(OC analysis), for men (+ 0.15 ng/mL) and women (+
`
`in the risperidone switch group notable
`1.3 ng/mL);
`reductions were observed after 6 months of treatment
`with lurasidone for men (− 11.2 ng/mL) and women (−
`30.8 ng/mL; Table 3; Fig. 3a and b). No galactorrhea,
`amenorrhea or gynecomastia were observed in patients
`treated with open-label lurasidone.
`
`Bone turnover markers and bone mineral density
`As summarized in Table 3, minimal changes were
`observed in markers of bone turnover (bone alkaline
`phosphatase, osteocalcin, bone collagen equivalents, and
`urinary N-telopeptide) for both lurasidone and risperidone
`during 12 months of double-blind treatment, and during
`6 months of open-label treatment with lurasidone.
`In a subset of patients at US sites, bone mineral
`density (BMD) was assessed by dual-energy x-ray ab-
`sorptiometry [DXA]. Based on DXA assessments, no
`loss of bone mineral density was observed during 6
`months of open-label treatment with lurasidone in ei-
`ther the lurasidone continuation group (n = 46) or the
`risperidone switch group (n = 27). Median percent
`change in BMD, from open-label baseline to 6-month
`endpoint
`(OC) was
`+ 0.4% in
`the
`lurasidone
`
`6
`
`

`

`Mattingly et al. BMC Psychiatry
`
`(2020) 20:199
`
`Page 7 of 13
`
`—*=LUR-LUR (n = 136)" = RIS (n = 87)*F
`
`== RIS-LUR (n = 87)*
`
`12-month
`double-blind
`study
`
`=O
`
`bx==
`2=
`x)
`
`s£o0ca=o
`
`
`
`Oco
`
`Oo
`=
`
`3
`Double-blind
`Baseline
`
`Open-label
`Baseline
`
`Month
`1
`
`Month
`2
`
`Month
`3
`
`Month
`4
`
`Month
`5
`
`Month
`6
`
`LOCF
`endpoint
`
`Fig. 2 Median Change in Weight From Double Blind Baseline Through 6 Months of Open Label! Treatment With Lurasidone, by Treatment Assignment in the
`Double Blind Study. LUR = lurasidone; RIS = risperidone. “Subgroup entering open label extension; 6 month completer analysis: LUR LUR, n= 109; RIS LUR,
`n= 66. ‘Patients in the RIS LUR groupreceived risperidone in the 12 month, double blind study
`
`continuation group (m= 31) and 1.5% in the risperi-
`done switch group (n=13). For the combined treat-
`ment groups, 4/44 patients (9.1%) experienced a gain,
`from open-label baseline to 6-month endpoint,
`in
`lumbar spine BMD resulting in a shift in BMD cat-
`egory from osteoporosis to osteopenia, or from osteo-
`penia to normal. A gain in lumbar spine BMD was
`more common in patients switched from risperidone
`to lurasidone (15.4% [2/13]) compared with patients
`continuing lurasidone (6.5% [2/31]). No patient expe-
`rienced a loss in BMD.
`
`Electrocardiographic parameters
`There were noclinically meaningful changes in mean
`ECG parameters during 6 months of open-label treatment
`with lurasidone. One patient had a QTcF >500 msec at
`the month 3 assessment, which represented a >60-msec
`increase from open-label baseline; at the next assessment,
`the patient had a QTcF <450 msec with a QTcF change
`score < 60 msec.
`
`Physical examination andvital signs
`There were no clinically meaningful changes in vital
`signs (heart rate, systolic and diastolic blood pressure,
`body temperature) during open-label
`treatment with
`lurasidone.
`In the subset of patients (n =57) with an ophthalmo-
`logic assessment that included dilated funduscopic and
`slit
`lamp eye examinations,
`there were no clinically
`significant
`treatment-emergent abnormalities
`in any
`ophthalmologic parameter.
`
`Efficacy
`Patients (per protocol) were clinically stable at entry
`into the double-blind study (mean baseline PANSS
`
`total score of 65.1). At open-label baseline, after com-
`pletion of 12months of treatment with lurasidone or
`risperidone, patients showed improvement in PANSS
`total score (- 8.7 and - 8.3, respectively). Improvementin
`PANSStotal score was maintained during 6 months of
`treatment with lurasidone (mean [95%-CI] change from
`OL baseline to LOCF-endpoint, +1.0 [-0.1, +2.2]).
`Improvement was maintained on the PANSStotal score
`in both the lurasidone continuation group (+ 1.0 [- 0.5, +
`2.6]) and in the risperidone switch group (+ 1.0 [- 0.9, +
`2.8]; LOCF-endpointanalysis; Fig. 4). Mean improvement
`on the CGI-S was also maintained during 6 months of
`open-label treatment, both in the lurasidone continuation
`group (0.0 [-0.1, +0.2]) and in the risperidone switch
`group (0.0 [-0.1, +0.1]; LOCF-endpoint analysis of
`change from open-label baseline).
`At double-blind baseline, mean MADRS scores were
`similar for patients randomized to lurasidone andrisper-
`idone (6.8 and 6.9, respectively). After completion of 12
`months of double-blind treatment with lurasidone or
`risperidone, mean change scores were-1.7 and- 2.6,
`respectively. Mean improvement on the CGI-S was
`maintained during 6 months of open-label
`treatment,
`both in the lurasidone continuation group (+ 0.2 [- 0.6,
`+1.0]) and in the risperidone switch group (+ 1.0 [0.1,
`2.0]; LOCF-endpoint analysis of change from open-label
`baseline).
`
`Discussion
`Patients with schizophrenia who completed a previously
`reported [18] 12-month, double-blind,
`flexible-dose
`study of lurasidone versus
`risperidone,
`received 6
`months of additional open-label lurasidone treatment,
`with patients in the double-blind risperidone group
`switching to lurasidone. At the end of the initial 12-
`
`

`

`Mattingly et al. BMC Psychiatry
`
`(2020) 20:199
`
`Page 8 of 13
`
`
`
`MedianProlactinLevelng/mL)
`
`
`
`
`
`12-month
`double-blind
`study
`
`e—LUR-LUR (n= 102)"
`-™-RIS-LUR (n = 58)*
`
` =<m=RIS (n = 58)**
`
`0
`Double-blind
`Baseline
`
`Open-label
`Baseline
`
`Month
`1
`
`LOCF
`endpoint
`
`—*—LUR-LUR (n= 34)*—=mRIS (n = 29)*t
`=—™—RIS-LUR (n = 58)*
`
`
`
`
`
`
`
`
`
`MedianProlactinLevelng/mL)
`
`Double-blind
`Baseline
`
`Open-label
`Baseline
`
`Month
`1
`
`Month
`3
`
`Month
`6
`
`LOCF
`endpoint
`
`Fig. 3 Median Changein Prolactin From Double Blind Baseline Through 6 Months of Open Label Treatment With Lurasidone, by Treatment
`Assignmentin the Double Blind Study. 3 A. Males, LUR =lurasidone; RIS = risperidone. “Subgroupentering openlabel extension; 6 month completer
`analysis: LUR LUR, n= 102; RIS LUR, n= 68. ‘Patients in the RIS LUR groupreceived risperidone in the 12 month, double blind study. 3 B. Females.
`LUR= lurasidone;RIS = risperidone. “Subgroup entering open label extension; 6 month completer analysis: LUR LUR, n = 34; RIS LUR, n= 29. ‘Patients in
`the RIS LUR groupreceived risperidone in the 12 month, doubleblind study
`
`month, double-blind phase, treatment with risperidone
`was associated with statistically significant
`increases
`compared to lurasidone in weight, BMI, waist circumfer-
`ence, prolactin levels, glucose, and insulin [18]. After 6
`months of treatment in the current extension study,
`patients who switched from risperidone to lurasidone
`demonstrated consistent improvement in these safety
`parameters, with reductions
`in weight, BMI, waist
`circumference, glucose, and prolactin levels.
`The patient group treated with lurasidone during the
`initial
`12-month
`study
`demonstrated
`consistent
`improvement from double-blind baseline in weight,
`BMI, glycemic indices, and metabolic parameters. Small
`but consistent additional improvement was noted in
`
`these parameters during the current 6 months of exten-
`sion phase treatment with lurasidone.
`The weight and metabolic results of the current study
`are consistent with findings reported from previouslura-
`sidone studies in which long-term treatment with lurasi-
`done was associated with minimal effects on weight,
`BMI, waist circumference, glycemic indices, and lipid
`parameters [10-—12, 16, 17, 25, 26].
`The current results are also consistent with two
`previously reported lurasidone switch studies. In the
`first study patients who weretreated for 6 weeks with
`olanzapine showed clinically meaningful
`reductions
`in
`weight, waist circumference, and selected metabolic parame-
`ters after switching to 6 months of treatment with lurasidone
`
`

`

`Mattingly et al. BMC Psychiatry
`
`(2020) 20:199
`
`Page 9 of 13
`
`12-month
`double-blind
`study
`
`—LUR-LUR (n = 136)*
`“mRIS-LUR (n = 87)*
`
` =<m=RIS (n = 87)*t
`
`29°°”
`
`a2-w
`
`
`
`nnw
`Zz
`&coOa
`
`=
`
`Double-blind
`Baseline
`
`Open-label
`Baseline
`
`Month
`1
`
`3
`
`Month
`6
`
`LOCF
`endpoint
`
`Fig. 4 Mean PANSS Total Score From Double Blind Baseline Through 6 Months of Open Label Treatment With Lurasidone, by Treatment
`Assignmentin the Double Blind Study. LUR =lurasidone; PANSS = Positive and Negative SyndromeScale;RIS = risperidone. “Subgroup entering
`openlabel extension; 6 month completer analysis: LUR LUR, n = 115; RIS LUR, n= 71. ‘Patients in the RIS LUR groupreceived risperidone in the
`12 month, double blind study
`
`[17]. In the second study [15] patients (N= 240) with a diag-
`nosis of schizophrenia who were stable on treatment with a
`range of typical and atypical (eg. olanzapine, quetiapine,
`risperidone) antipsychotics were switched to lurasidone, 40—
`120 mg/d. After 6 weeks of open-label treatment with lurasi-
`done, improvement in weight and lipid parameters were
`observed. In a 6-month, open-label extension of this study,
`improvements in efficacy on lurasidone were maintained,
`with minimal long-term effects on weight, metabolic param-
`eters, and prolactin [17].
`Amongpatients in the initial double-blind phase of
`the current study, treatment with risperidone was asso-
`ciated with notable increases in prolactin levels, with
`commensurate reduction in prolactin in males (- 11.2
`ng/mL) and females
`(-30.8ng/mL)
`following the
`switch to lurasidone. Previous systematic reviews and
`meta-analyses h