Cardiovascular Profile of Valbenazine: Analysis of Pooled Data from Three Randomized, Double-Blind, Placebo-Controlled Trials

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1 Drug Saf (2018) 41: ORIGINAL RESEARCH ARTICLE Cardiovascular Profile of : Aalysis of Pooled Data from Three Radomized, Double-Blid, -Cotrolled Trials Dao Thai-Cuarto 1 Christopher F. O Brie 1 Rolad Jimeez 1 Grace S. Liag 1 Joshua Burke 1 Published olie: 7 December 2017 Ó The Author(s) This article is a ope access publicatio Abstract Itroductio is a ovel vesicular mooamie trasporter 2 ihibitor approved for the treatmet of tardive dyskiesia i adults. Objective Usig data from double-blid, placebo-cotrolled trials, aalyses were coducted to evaluate the cardiovascular effects of oce-daily valbeazie i patiets with a psychiatric disorder who developed tardive dyskiesia after exposure to a dopamie-blockig medicatio. Methods Data were pooled from three 6-week, doubleblid, placebo-cotrolled trials: KINECT (NCT ), KINECT 2 (NCT ), ad KINECT 3 (NCT ). Data from the 42-week valbeazie extesio period of KINECT 3 were also aalyzed. Outcomes of iterest icluded cardiovascular-related treatmet-emerget adverse evets, vital sig measuremets, ad electrocardiogram parameters. Results The pooled safety populatio icluded 400 participats (placebo, = 178; valbeazie 40 mg/day, = 110; valbeazie 80 mg/day, = 112). A history of cardiac disorders was preset i 11.8% of participats, ad 74.3% were takig a cocomitat medicatio with kow potetial for QT prologatio. Mea chages from baselie to week 6 i supie vital sigs ad QTcF (Fridericia correctio) were as follows for placebo, valbeazie 40 mg/day, ad valbeazie 80 mg/day, respectively: systolic blood pressure (0.2, - 2.1, mmhg), diastolic blood pressure (- 0.1, - 1.6, mmhg), heart rate (- 1.7, - 2.2, bpm), QTcF iterval (1.2, 1.1, 2.1 ms); all p[0.05 for valbeazie vs. & Dao Thai-Cuarto dthai@eurocrie.com 1 Neurocrie Bioscieces, Ic., El Camio Real, Sa Diego, CA 92130, USA placebo. No statistically sigificat differeces were observed betwee placebo ad valbeazie i cardiovascular-related, treatmet-emerget adverse evets. No otable additioal effects o cardiovascular outcomes were foud with up to 48 weeks of valbeazie treatmet. Coclusios Results from double-blid, placebo-cotrolled trials showed o apparet differece betwee valbeazie ad placebo o cardiovascular outcomes. No additioal cardiovascular risk was detected durig a loger extesio study with valbeazie. Key Poits Data from cliical trials of valbeazie, which is approved for the treatmet of tardive dyskiesia i adults, were aalyzed to assess the cardiovascular profile of this medicatio. Results idicated that valbeazie had miimal cardiovascular effects i patiets with tardive dyskiesia who had a cocurret psychiatric disorder, the majority of whom were takig cocomitat atipsychotic or atidepressat medicatios. 1 Itroductio I patiets with psychiatric disorders, cardiovascular diseases accout for approximately 20 30% of co-morbid medical diagoses ad 30% of deaths, higher tha i the

2 430 D. Thai-Cuarto et al. geeral populatio [1 5]. Promiet cardiovascular risk factors i patiets with psychiatric disorders iclude obesity, hypertesio, diabetes mellitus, atrial fibrillatio, peripheral vascular disease, hyperlipidemia, ad ischemic heart disease [1, 6, 7]. Direct pathophysiological coectios betwee psychiatric illess ad cardiovascular disease may exist, particularly via the sympathetic ervous system ad the hypothalamic-pituitary axis, both of which are activated by icreased stress, axiety, ad depressio ad are also ivolved i cardiovascular cotrol [1, 3, 8]. Psychiatric illess ad cardiovascular risk may also be idirectly liked through social or behavioral factors such as o-adherece to medical advice or treatmet, social isolatio, smokig, overeatig, ad a sedetary lifestyle [1, 3, 8, 9]. The risk of cardiovascular disease i patiets with psychiatric disorders ca be further complicated by the eed for medicatios associated with adverse effects such as icreased blood pressure, hypotesio, cerebrovascular evets, ad electrocardiogram (ECG) QT prologatio [6, 7]. Cardiovascular warigs ca be foud i the prescribig iformatio for may atipsychotic medicatios (e.g., quetiapie, risperidoe, haloperidol) ad atidepressat medicatios (e.g., citalopram, fluoxetie) [7, 10]. Atipsychotic medicatios have also bee associated with metabolic chages that may affect cardiovascular health, icludig hyperglycemia/diabetes mellitus, dyslipidemia, ad weight gai [6]. Some mechaisms by which these medicatios may affect cardiovascular fuctio iclude io chael blockade (e.g., calcium, sodium, potassium), coductio disturbace or sius ode abormality, vetricular dysfuctio, ad hypotesio [2, 6]. Psychotropic medicatios may also impair cardiovascular fuctio by delayig vetricular repolarizatio, which ca result i a prologed QT iterval ad possible torsades de poites, a upredictable arrhythmia that is difficult to maage [2, 11]. is a ovel vesicular mooamie trasporter 2 ihibitor approved by the US Food ad Drug Admiistratio o 11 April, 2017 for treatig adults with tardive dyskiesia (TD) [12], a movemet disorder associated with exposure to dopamie receptor-blockig agets such as atipsychotic medicatios [13 15]. cliical trials erolled patiets with schizophreia, schizoaffective disorder, or a mood disorder, ad stable doses of cocomitat medicatios (e.g., atipsychotics ad atidepressats) were allowed for psychiatric maagemet [16 18]. was well tolerated i cliical trials, ad the prescribig iformatio for this ew drug (40 80 mg/day, oce-daily dosig) carries o black-box warigs or cotraidicatios as of October 2017 [19]. The label icludes oly two warigs ad precautios: somolece, which ca impair drivig ability; ad possible QT prologatio, with recommeded avoidace i patiets with cogeital log QT sydrome or with arrhythmias associated with a prologed QT iterval [19]. I the curret report, data from three placebo-cotrolled, phase II/III trials ad oe extesio trial were aalyzed to provide more detailed iformatio regardig the cardiovascular profile of valbeazie i patiets with TD ad schizophreia, schizoaffective disorder, or a mood disorder. 2 Methods 2.1 Trial Desig ad Participats The cardiovascular profile of oce-daily valbeazie was assessed usig pooled data from three multiceter, radomized, double-blid, placebo-cotrolled (DBPC) phase II/III trials i adults with TD: KINECT (NCT ) [20], KINECT 2 (NCT ) [16], ad KINECT 3 (NCT ) [17]. I KINECT, participats were radomized to valbeazie 50 mg/day (6 weeks), valbeazie 100 mg/day (2 weeks) the 50 mg/day (4 weeks), or placebo (6 weeks) followed by a 6-week, ope-label phase of valbeazie 50 mg/day. I KINECT 2, participats radomized to valbeazie received a startig dose of 25 mg/day that was escalated icremetally by 25 mg/day every 2 weeks to a maximum of 75 mg/day depedig o cliical respose. I KINECT 3 (phase III trial), participats were radomized to valbeazie 40 mg/day, valbeazie 80 mg/day, or placebo for 6 weeks followed by a blided valbeazie extesio period. Durig the extesio period, participats received up to 42 weeks of treatmet with valbeazie (40 or 80 mg/day, blided dose) followed by a 4-week washout period [18]. The trials icluded me ad wome, aged years, who had a diagosis of schizophreia or schizoaffective disorder, or mood disorder (KINECT 2 ad KINECT 3 oly), i additio to TD as per the Diagostic ad Statistical Maual of Metal Disorders, 4th Editio criteria for at least 3 moths prior to screeig. Participats were required to have moderate or severe TD at screeig, based o a qualitative assessmet of Abormal Ivolutary Movemet Scale videos by exteral reviewers. Participats were also required to be psychiatrically stable, as idicated by a Brief Psychiatric Ratig Scale total score \50. Exclusio criteria for the trials icluded: ay active, cliically sigificat, ad/or ustable medical coditio; kow history of log QT sydrome or cardiac tachyarrhythmia; QTcF (Fridericia correctio) of [450 ms for me or [470 ms for wome; ad the presece of ay cliically sigificat cardiac abormality. Participats requirig a cocomitat medicatio kow to prolog the QT iterval were allowed to participate based o a medical review. Oly idividuals with the capacity to provide

3 Cardiovascular Profile of 431 coset (based o the Uiversity of Califoria, Sa Diego Brief Assessmet of Capacity to Coset) were allowed to participate i the cliical trials. 2.2 Data Aalyses Aalyses were performed usig a pooled safety populatio, defied as all participats from the three DBPC trials who were radomized to treatmet, received oe or more doses of the study drug, ad had oe or more post-baselie safety assessmet. Data were aalyzed for the 6-week DBPC period with participats classified ito three subgroups based o valbeazie dosage: pooled 40 mg/day, which icluded doses of 40 mg (KINECT 3) ad 50 mg (KINECT, KINECT 2); pooled 80 mg/day, which icluded doses of 75 mg (KINECT 2) ad 80 mg (KINECT 3); ad placebo. Aalyses of loger treatmet with valbeazie (40 or 80 mg/day) were coducted usig data from the safety populatio of the valbeazie extesio period of KINECT 3. Outcomes of iterest were treatmet-emerget adverse evets (TEAEs), vital sig measuremets, ad ECG parameters. The icidece of cardiac-related TEAEs was aalyzed by aggregatig the followig cardiac-related MedDRA Ò (Versio 12.0) preferred TEAE terms: cardiac failure, chest pai, ECG QT prologed, myocardial ifarctio, sudde death, ad sycope ad usig the stadardized MedDRA Ò query of torsades de poites/qt prologatio. Additioally, ay preferred term uder the MedDRA Ò system orga class for Cardiac Disorders was icluded for the curret aalysis. The icidece of hypotesio or orthostatic hypotesio TEAEs was aalyzed by aggregatig the followig MedDRA Ò preferred terms: blood pressure decreased, dizziess, dizziess postural, fall, hypotesio, orthostatic hypotesio, orthostatic itolerace, presycope, ad sycope. Vital sig measuremets icluded supie ad orthostatic systolic blood pressure, diastolic blood pressure (DBP), ad heart rate. The mea chages from baselie to week 6 were aalyzed without ay imputatio for missig values. Additioally, orthostatic blood pressure measuremets were aalyzed for potetially cliically sigificat (PCS) values, defied as a decrease from baselie i systolic blood pressure of C 20 mmhg ad a decrease i DBP of C 10 mmhg. Triplicate ECGs with machie-read parameters were used i the valbeazie cliical trials; aalyses were based o the average of triplicate readigs at each study visit. Mea chages from baselie to week 6 i ECG parameters were aalyzed without ay imputatio for missig values. Two sets of categorical summaries for QTcF itervals were performed: (1) umber ad percetage of participats i each treatmet group whose highest reported QTcF value met thresholds of [450, [480, or [500 ms; ad (2) umber ad percetage of participats i each treatmet group whose largest QTcF icrease from baselie met thresholds of [30 or [60 ms. The vital sig ad ECG outcomes described above were also aalyzed i the followig subgroups from the pooled safety populatio: age (\65, C 65 years), sex (me, wome), race (white, black or Africa America, other), body mass idex (\18.5, 18.5 to \25 kg/m 2,25to\30, C 30 kg/m 2 ), kow cardiac history (yes, o), psychiatric diagosis (schizophreia or schizoaffective disorder, mood disorder), atipsychotic medicatio use (atypical oly, typical oly, both, oe), ad use of ay medicatio with a potetial for QT prologatio (yes, o) [21]. Statistical aalyses were coducted for the pooled DBPC studies. Mea chages from baselie (i.e., vital sigs, ECG parameters) were aalyzed usig a aalysis of covariace model that icluded groups, study, ad baselie value as covariates. Categorical outcomes (i.e., TEAEs, PCS vital sigs) were aalyzed usig the Fisher s exact test. For QTc categories, Fisher s exact test was coducted for ay QTc value C 450 ms ad for ay icrease C 30 ms from baselie. No statistical testig was coducted i the subgroups because of small sample sizes. For the KINECT 3 extesio study, o statistical compariso was made betwee valbeazie dose groups because participats were allowed a oe-time dose reductio for tolerability. 3 Results 3.1 Demographics ad Baselie Characteristics The pooled safety populatio icluded 400 participats (placebo, = 178; valbeazie 40 mg/day, = 110; valbeazie 80 mg/day, = 112). Demographics ad baselie characteristics were geerally similar across treatmet groups (Table 1). The mea age i this populatio was 55.8 years, ad the majority of participats were male (57.3%), white (55.5%), aged youger tha 65 years (82.8%), ad had a diagosis of schizophreia or schizoaffective disorder (71.5%). The mea age of TD diagosis was 48.2 years. Of the 400 participats i the pooled safety populatio, 388 (97.0%) had some reported medical history (Table 1). A diagosis of a specific cardiac disorder (per MedDRA Ò SOC) was foud i 47 (11.8%) participats. The most commo terms reported as medical history ([30% of all participats, based o MedDRA Ò preferred term) were hypertesio (53.3%), isomia (35.5%), ad gastroesophageal reflux disease (31.5%). I additio to their curret psychiatric diagosis, oe-quarter of the populatio also reported a history of axiety (25.5%). Of all curret

4 432 D. Thai-Cuarto et al. Table 1 Demographics ad baselie characteristics (pooled safety populatio) ( = 178) 40 mg/day ( = 110) 80 mg/day ( = 112) Age (years) Mea ± SD 55.8 ± ± ± 10.3 \65, (%) 144 (80.9) 95 (86.4) 92 (82.1) C 65, (%) 34 (19.1) 15 (13.6) 20 (17.9) Sex, (%) Me 102 (57.3) 66 (60.0) 61 (54.5) Wome 76 (42.7) 44 (40.0) 51 (45.5) Race, (%) White 95 (53.4) 62 (56.4) 65 (58.0) Black/Africa America 74 (41.6) 42 (38.2) 44 (39.3) Body mass idex (kg/m 2 ) Mea ± SD 28.3 ± ± ± 5.9 \18.5, (%) 2 (1.1) 0 (0) 5 (4.5) 18.5 to \25, (%) 47 (26.4) 29 (26.4) 32 (28.6) 25 to \30, (%) 61 (34.3) 38 (34.5) 32 (28.6) C 30, (%) 68 (38.2) 43 (39.1) 43 (38.4) Age at TD diagosis, mea ± SD (years a ) 48.4 ± ± ± 12.3 AIMS total score, mea ± SD b 9.0 ± ± ± 3.6 Vital sigs, mea ± SD Supie SBP (mmhg) ± ± ± 13.4 Supie DBP (mmhg) 77.1 ± ± ± 8.6 Supie heart rate (bpm) 76.5 ± ± ± 12.0 Orthostatic SBP (mmhg c ) 0.5 ± ± ± 8.5 Orthostatic DBP (mmhg c ) 2.0 ± ± ± 6.1 Orthostatic heart rate (bpm c ) 5.5 ± ± ± 7.3 Electrocardiogram, mea ± SD Heart rate (bpm) 75.2 ± ± ± 13.6 PR iterval (ms) ± ± ± 24.0 QRS duratio (ms) 92.2 ± ± ± 11.6 QTcF iterval (ms) ± ± ± 21.9 Medical history Ay medical history, (%) 172 (96.6) 107 (97.3) 109 (97.3) Ay cardiac disorder, (%) d 20 (11.2) 13 (11.8) 14 (12.5) Coroary artery disease 8 (4.5) 5 (4.5) 3 (2.7) Myocardial ifarctio 4 (2.2) 1 (0.9) 3 (2.7) Cardiac failure cogestive 1 (0.6) 0 (0.0) 3 (2.7) Arrhythmia 2 (1.1) 0 (0.0) 2 (1.8) Chest pai 1 (0.6) 1 (0.9) 0 (0.0) Agia pectoris 3 (1.7) 1 (0.9) 0 (0.0) Cardiac failure 1 (0.6) 0 (0.0) 0 (0.0) Other medical history, (%) e Hypertesio 102 (57.3) 56 (50.9) 55 (49.1) Isomia 61 (34.3) 38 (34.5) 43 (38.4) Gastroesophageal reflux disease 45 (25.3) 43 (39.1) 38 (33.9) Axiety 45 (25.3) 30 (27.3) 27 (24.1) Hypercholesterolemia 34 (19.1) 18 (16.4) 31 (27.7) Depressio 30 (16.9) 23 (20.9) 20 (17.9) Chroic obstructive pulmoary disease 25 (14.0) 19 (17.3) 20 (17.9)

5 Cardiovascular Profile of 433 Table 1 cotiued ( = 178) 40 mg/day ( = 110) 80 mg/day ( = 112) Type 2 diabetes mellitus 32 (18.0) 19 (17.3) 9 (8.0) Drug hypersesitivity 24 (13.5) 20 (18.2) 15 (13.4) Hyperlipidemia 28 (15.7) 15 (13.6) 15 (13.4) Asthma 23 (12.9) 9 (8.2) 20 (17.9) Osteoarthritis 21 (11.8) 16 (14.5) 15 (13.4) Back pai 22 (12.4) 16 (14.5) 14 (12.5) Hypothyroidism 22 (12.4) 12 (10.9) 14 (12.5) Diabetes mellitus 21 (11.8) 9 (8.2) 8 (7.1) Seasoal allergy 12 (6.7) 11 (10.0) 10 (8.9) Drug abuse 11 (6.2) 9 (8.2) 12 (10.7) Hepatitis C 10 (5.6) 11 (10.0) 8 (7.1) Hysterectomy f 19 (25.0) 9 (20.5) 8 (15.7) CYP2D6 geotype, (%) Poor metabolizer 7 (3.9) 8 (7.3) 4 (3.6) Itermediate, extesive, or ultra-rapid 171 (96.1) 101 (91.8) 107 (95.5) metabolizer Not reported 0 (0) 1 (0.9) 1 (0.9) Psychiatric history Primary diagosis, (%) Schizophreia or schizoaffective disorder 134 (75.3) 82 (74.5) 70 (62.5) Mood disorder 44 (24.7) 28 (25.5) 42 (37.5) Duratio of illess, mea ± SD (years) 24.9 ± ± ± 13.0 AIMS Abormal Ivolutary Movemet Scale, CYP cytochrome P450, DBP diastolic blood pressure, SBP systolic blood pressure, TD tardive dyskiesia, SOC system orga class, SD stadard deviatio a Based o available history: placebo, = 138; 40 mg/day, = 85; 80 mg/day, = 82 b Based o available blided cetral rater scores: placebo, = 165; 40 mg/day, = 105; 80 mg/day, = 110 c Orthostatic vital sig measuremets calculated as stadig mius supie values d Table lists all MedDRA Ò preferred terms for the SOC of cardiac disorder that were reported i ay participat regardless of treatmet e Table lists all MedDRA Ò preferred terms reported i C 10% of participats i ay treatmet group f Based o the umber of wome i each treatmet group: placebo, = 76; 40 mg, = 44; 80 mg, = 51 cocomitat medicatios, the most commo classes of drugs were atipsychotic (84.0%), atidepressat (63.8%), ad axiolytic (28.8%) medicatios (Table 2). The majority of participats (74.3%) were takig a cocomitat medicatio with kow potetial to icrease the QT iterval, icludig some atipsychotic medicatios (e.g., risperidoe, aripiprazole, olazapie) ad atidepressat medicatios (e.g., citalopram, mirtazapie). 3.2 Treatmet-Emerget Adverse Evets Few participats i the valbeazie trials had cardiac-related TEAEs, ad o statistically sigificat differece betwee valbeazie ad placebo was foud for ay of these evets (Table 3). Five cardiac-related TEAEs occurred durig the 6-week DBPC period, each reported i oe participat: chest pai (40 mg/day); bradycardia (40 mg/day), blood pressure icreased (80 mg/day), myocardial ifarctio which resulted i death (placebo); ad sudde death as a result of a possible cardiovascular evet i a 73-year-old Africa America ma with multiple cardiac risk factors (80 mg/day) [17]. Both deaths were cosidered urelated (placebo) or ulikely related (80 mg/day) to the study drug. Durig the valbeazie extesio period of KINECT 3, cardiac-related TEAEs that occurred i more tha oe participat were chest pai (40 ad 80 mg/day, = 2 each) ad sycope (40 mg/day, = 3; 80 mg/day, = 1). Cardiac-related TEAEs that led

6 434 D. Thai-Cuarto et al. Table 2 Cocomitat medicatios (pooled safety populatio) Cocomitat medicatio, (%) ( = 178) 40 mg/day ( = 110) 80 mg/day ( = 112) Ay cocomitat medicatio 178 (100.0) 109 (99.1) 112 (100.0) Ay atipsychotic medicatio a 149 (83.7) 98 (89.1) 89 (79.5) Atypical oly 115 (64.6) 73 (66.4) 68 (60.7) Typical or both 34 (19.1) 24 (21.8) 18 (16.1) Quetiapie b 39 (21.9) 31 (28.2) 23 (20.5) Risperidoe b 32 (18.0) 13 (11.8) 19 (17.0) Haloperidol b 15 (8.4) 16 (14.5) 13 (11.6) Aripiprazole b 20 (11.2) 12 (10.9) 15 (13.4) Olazapie b 21 (11.8) 15 (13.6) 10 (8.9) Ziprasidoe b 6 (3.4) 6 (5.5) 11 (9.8) Lithium b 2 (1.1) 6 (5.5) 10 (8.9) Paliperidoe b 3 (1.7) 7 (6.4) 3 (2.7) Lurasidoe 5 (2.8) 6 (5.5) 3 (2.7) Perpheazie b 6 (3.4) 7 (6.4) 2 (1.8) Clozapie b 10 (5.6) 3 (2.7) 3 (2.7) Ay atidepressat medicatio a 111 (62.4) 73 (66.4) 71 (63.4) Trazodoe b 32 (18.0) 26 (23.6) 23 (20.5) Citalopram b 23 (12.9) 16 (14.5) 13 (11.6) Sertralie b 23 (12.9) 13 (11.8) 14 (12.5) Mirtazapie b 12 (6.7) 10 (9.1) 7 (6.3) Buproprio 10 (5.6) 8 (7.3) 8 (7.1) Escitalopram b 5 (2.8) 7 (6.4) 7 (6.3) Duloxetie 6 (3.4) 6 (5.5) 6 (5.4) Fluoxetie b 12 (6.7) 7 (6.4) 4 (3.6) Ay axiolytic medicatio a 49 (27.5) 40 (36.4) 26 (23.2) Lorazepam 18 (10.1) 12 (10.9) 13 (11.6) Hydroxyzie b 14 (7.9) 10 (9.1) 9 (8.0) Alprazolam 7 (3.9) 13 (11.8) 4 (3.6) Buspiroe 6 (3.4) 8 (7.3) 4 (3.6) Cardiovascular medicatios c Lisiopril 46 (25.8) 16 (14.5) 21 (18.8) Amlodipie 24 (13.5) 11 (10.0) 12 (10.7) Hydrochlorothiazide b 10 (5.6) 9 (8.2) 9 (8.0) Metoprolol 10 (5.6) 7 (6.4) 3 (2.7) Losarta 8 (4.5) 3 (2.7) 4 (3.6) Furosemide b 5 (2.8) 3 (2.7) 4 (3.6) Propraolol 4 (2.2) 5 (4.5) 1 (0.9) Ealapril 3 (1.7) 4 (3.6) 1 (0.9) Carvedilol 3 (1.7) 3 (2.7) 0 (0.0) Ateolol 4 (2.2) 0 (0.0) 2 (1.8) Cloidie 3 (1.7) 0 (0.0) 3 (2.7) Nifedipie 2 (1.1) 3 (2.7) 0 (0.0) Diabetes mellitus medicatios d Metformi 43 (24.2) 20 (18.2) 15 (13.4) Isuli glargie 8 (4.5) 4 (3.6) 5 (4.5) Glipizide 4 (2.2) 2 (1.8) 2 (1.8) Sitaglipti 3 (1.7) 4 (3.6) 1 (0.9)

7 Cardiovascular Profile of 435 Table 2 cotiued Cocomitat medicatio, (%) ( = 178) 40 mg/day ( = 110) 80 mg/day ( = 112) Glibeclamide 1 (0.6) 4 (3.6) 1 (0.9) Liraglutide 1 (0.6) 3 (2.7) 1 (0.9) Lipid-modifyig agets e Simvastati 22 (12.4) 9 (8.2) 10 (8.9) Atorvastati 10 (5.6) 9 (8.2) 11 (9.8) Pravastati 9 (5.1) 8 (7.3) 1 (0.9) Rosuvastati 8 (4.5) 4 (3.6) 5 (4.5) Feofibrate 6 (3.4) 4 (3.6) 4 (3.6) Omega-3 fatty acids 4 (2.2) 2 (1.8) 3 (2.7) Gemfibrozil 4 (2.2) 1 (0.9) 2 (1.8) Lovastati 4 (2.2) 1 (0.9) 2 (1.8) Ay medicatio with the potetial to prolog the QT iterval b 130 (73.0) 87 (79.1) 80 (71.4) a Based o specific World Health Orgaizatio Drug Aatomical Therapeutic Chemical Category (i.e., atipsychotics, atidepressats, axiolytics); idividual medicatios iclude all drugs i these categories that were used i C 5% of participats i ay treatmet group b Medicatios with potetial to prolog the QT iterval [21] c Based o multiple drug categories; idividual medicatios iclude all acetylcholiesterase ihibitors, agiotesi atagoists, atiadreergic agets, atiarrhythmic agets, beta blockers, cardiac glycosides, diuretics, potassium-sparig agets, selective calcium chael blockers, ad vasodilators that were used i C 2% of participats i ay treatmet group d Based o multiple drug categories; idividual medicatios iclude all blood glucose-lowerig agets, glycogeolytic hormoes, isulis, ad isuli aalogs that were used i C 2% of participats i ay treatmet group e Based o multiple drug categories; idividual medicatios iclude all lipid-modifyig agets (simple or combiatios) that were used i C 2% of participats i ay treatmet group to discotiuatio from the KINECT 3 valbeazie extesio period were sycope (40 ad 80 mg/day, = 1 each) ad cardiac failure (80 mg/day, = 1). The TEAEs evaluated as potetially related to hypotesio also icluded orthostatic hypotesio, dizziess, ad fall (Table 3). Noe of these TEAEs resulted i discotiuatio from the DBPC trials or the KINECT 3 valbeazie extesio period. 3.3 Vital Sigs Mea values at baselie for supie ad orthostatic vital sig measuremets are show i Table 1. Mea chages from baselie to week 6 (pooled safety populatio) ad week 48 (KINECT 3 extesio safety populatio) i vital sig measuremets were geerally small ad similar across treatmet groups (Table 4). No statistically sigificat differece betwee valbeazie ad placebo was foud i ay week 6 outcome, except for a mea icrease i orthostatic DBP (40 mg/day, 1.3 ± 8.4 mmhg). Durig the 6-week DBPC trials, \5% of participats i all treatmet groups met the PCS criteria for low orthostatic systolic blood pressure (decrease C 20 mmhg: placebo, 3.8%; 40 mg/day, 3.1%; 80 mg/day, 2.0%) ad DBP (decrease C 10 mmhg: placebo, 3.8%; 40 mg/day, 3.1%; 80 mg/day, 3.0%). The rates for icreases i orthostatic heart rates were similar amog treatmet groups (icrease C 15 bpm: placebo, 10.7%; 40 mg/day, 9.4%; 80 mg/day, 15.8%). No statistical differece betwee valbeazie ad placebo was foud i ay of these outcomes. Subgroup aalyses idicated o apparet effects of demographics or other baselie characteristics o vital sigs (data ot show). 3.4 Electrocardiogram Parameters Mea values at baselie for ECG parameters are show i Table 1. Mea chages from baselie to week 6 (pooled safety populatio) ad week 48 (KINECT 3 extesio safety populatio) were geerally small ad ot cosidered cliically importat (Table 5), with o statistically sigificat differece betwee valbeazie ad placebo except for a mea decrease i ECG heart rate (80 mg/day, ± 10.6 bpm). At week 6, mea chages i QTcF were similar across treatmet groups: placebo, 1.3 ms; 40 mg/day, 1.1 ms; 80 mg/day, 2.1 ms; all p[0.05.

8 436 D. Thai-Cuarto et al. Table 3 Treatmet-emerget adverse evets MedDRA Ò preferred term, (%) Double-blid placebo-cotrolled trials (pooled safety populatio) KINECT 3 valbeazie extesio period (safety populatio) ( = 178) 40 mg/day a ( = 110) 80 mg/day a ( = 112) 40 mg/day ( = 97) 80 mg/day ( = 101) Cardiac-related TEAEs b Chest pai 0 (0) 1 (0.9) 0 (0) 2 (2.1) 2 (2.0) Bradycardia 0 (0) 1 (0.9) 0 (0) 0 (0) 0 (0) Blood pressure 0 (0) 0 (0) 1 (0.9) 0 (0) 1 (1.0) icreased Sudde death 0 (0) 0 (0) 1 (0.9) 0 (0) 0 (0) Myocardial 1 (0.6) 0 (0) 0 (0) 0 (0) 0 (0) ifarctio Sycope c 0 (0) 0 (0) 0 (0) 3 (3.1) 1 (1.0) Cardiac failure 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.0) Budle brach block 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.0) left Mitral valve 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.0) icompetece Tricuspid valve 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.0) icompetece Arrhythmia 0 (0) 0 (0) 0 (0) 1 (1.0) 0 (0) supravetricular Coroary artery 0 (0) 0 (0) 0 (0) 1 (1.0) 0 (0) disease Sius tachycardia 0 (0) 0 (0) 0 (0) 1 (1.0) 0 (0) Supravetricular tachycardia 0 (0) 0 (0) 0 (0) 1 (1.0) 0 (0) Hypotesio-related TEAEs d Dizziess 4 (2.2) 2 (1.8) 0 (0) 4 (4.1) 7 (6.9) Fall 0 (0) 2 (1.8) 1 (0.9) 3 (3.1) 2 (2.0) Hypotesio 0 (0) 0 (0) 1 (0.9) 0 (0) 1 (1.0) Orthostatic hypotesio 0 (0) 0 (0) 0 (0) 1 (1.0) 0 (0) SOC system orga class, TEAEs treatmet-emerget adverse evets a No sigificat differece foud betwee valbeazie (40 or 80 mg) ad placebo for ay TEAE preseted i this table b Icludes ay of the aggregated MedDRA Ò preferred terms (cardiac failure, chest pai, electrocardiogram QT prologed, myocardial ifarctio, sudde death, ad sycope), stadardized MedDRA Ò query of torsades de poites/qt prologatio, ad preferred term uder the MedDRA Ò SOC for Cardiac Disorders c Sycope icluded i the aggregated terms for both cardiac-related ad hypotesio-related TEAEs d Icludes ay of the aggregated MedDRA Ò preferred terms for hypotesio or orthostatic hypotesio (blood pressure decreased, dizziess, dizziess postural, fall, hypotesio, orthostatic hypotesio, orthostatic itolerace, presycope, ad sycope) Categorical aalyses showed that although QTcF values exceeded 450 ms i some participats durig the 6-week DBPC period (Table 5), there was o apparet differece betwee placebo ad valbeazie (40 or 80 mg/day). Durig the KINECT 3 valbeazie extesio period, more participats i the 80-mg/day group had a QTcF [450 ms or a QTcF [30 ms icrease from baselie, as compared with the 40-mg/day group (Table 5). However, oly a few participats had a QTcF [480 ms ( = 5), QTcF [500 ms ( = 1), or a QTcF icrease [60 ms ( = 6) at ay poit durig this extesio study, with o apparet differece betwee dose groups. Results from subgroup aalyses idicated o apparet effects of ay baselie characteristic o ECG parameters (data ot show). I the subgroup takig a cocomitat medicatio with kow potetial to prolog the QT iterval, mea QTcF values at baselie ad week 6 were as follows (for placebo, valbeazie 40 mg/day, ad

9 Cardiovascular Profile of 437 Table 4 Mea chages from baselie i supie ad orthostatic vital sig measuremets Vital sig parameter Double-blid placebo-cotrolled trials at week 6 (pooled safety populatio) KINECT 3 valbeazie extesio period at week 48 (safety populatio) 40 mg/day 80 mg/day 40 mg/day 80 mg/day Mea Mea Mea Mea Mea Supie SBP (mmhg) ± ± ± ± ± 15.5 Supie DBP (mmhg) ± ± ± ± ± 10.2 Supie heart rate (bpm) ± ± ± ± ± 11.3 Orthostatic SBP (mmhg) ± ± ± ± ± 8.7 Orthostatic DBP (mmhg) ± ± 8.4 b ± ± ± 10.1 Orthostatic heart rate (bpm) ± ± ± ± ± 7.1 CFB chage from baselie, DBP diastolic blood pressure, umber of participats with available vital assessmet at week 6 (pooled safety populatio) or week 48 (KINECT 3 extesio safety populatio), SBP systolic blood pressure, SD stadard deviatio a Orthostatic vital sig measuremets calculated as stadig mius supie values b p\0.05 vs. placebo Table 5 Electrocardiogram parameters Electrocardiogram parameter Double-blid placebo-cotrolled trials at week 6 (pooled safety populatio) KINECT 3 valbeazie extesio period at week 48 (safety populatio) 40 mg/day 80 mg/day 40 mg/day 80 mg/day Mea Mea Mea Mea Mea Heart rate (bpm) ± ± ± 10.6 a ± ± 12.6 PR iterval (ms) ± ± ± ± ± 14.7 QRS duratio (ms) ± ± ± ± ± 12.6 QTcF iterval (ms) ± ± ± ± ± 18.2 QTcF iterval b 1 (%) 1 (%) 1 (%) 1 (%) 1 (%) [450 ms (6.2) (10.0) (4.5) (13.7) (22.0) [480 ms (1.1) (0) (0) 95 2 (2.1) (3.0) [500 ms (0) (0) (0) 95 0 (0) (1.0) [30 ms icrease (6.2) (2.7) (5.4) (14.7) (24.0) [60 ms icrease (0.6) (0.9) (0) 95 3 (3.2) (3.0) CFB chage from baselie, umber of participats with vital available assessmet at week 6 (pooled safety populatio), week 48 (KINECT 3 extesio safety populatio), or at ay study visit (for all QTcF iterval aalyses), 1 umber of participats who met the QTcF iterval threshold, SD stadard deviatio a p\0.05 vs. placebo b Based o the highest value at ay visit durig double-blid treatmet; participats oly couted oce i each threshold category. No sigificat differece betwee valbeazie (40 or 80 mg) ad placebo for ay QTcF iterval C 450 ms or ay icrease C 30 ms valbeazie 80 mg/day, respectively): baselie (411.2, 414.0, ad ms); week 6 (412.2, 413.7, ad ms). Similar results were foud i the subgroup ot takig a cocomitat QT-prologig medicatio: baselie (414.1, 416.3, ad ms); week 6 (417.9, 418.7, ad ms).

10 438 D. Thai-Cuarto et al. 4 Discussio Aalyses of data from 6-week DBPC trials showed o otable differeces betwee valbeazie (40 or 80 mg/day) ad placebo i the icidece of cardiac- or hypotesiorelated TEAEs, mea chages i vital sig measuremets, cliically relevat chages i orthostatic blood pressure or heart rate (per PCS criteria), or mea chages i ECG parameters. Noe of the DBPC outcomes were statistically sigificat, except for a mea icrease i orthostatic DBP (40 mg/day) ad a mea decrease i ECG heart rate (80 mg/day). However, these chages were ot cosidered cliically relevat because the magitudes were otably smaller tha the correspodig stadard deviatios ad the directios of chage were opposite of what would be expected with orthostatic hypotesio. Mea chages i vital sig measuremets ad ECG parameters durig loger treatmet (i.e., KINECT 3 valbeazie extesio period) were comparable to results from the DBPC trials. Participats i the phase II/III cliical trials had a psychiatric diagosis of schizophreia or schizoaffective disorder, or a mood disorder, ad cocomitat treatmet with atipsychotic ad/or atidepressat medicatios (at stable doses) was allowed for the maagemet of psychiatric disorders. I additio to their curret psychiatric diagosis, 11.8% of participats i the pooled safety populatio reported a prior cardiovascular diagosis or evet (e.g., coroary artery disease, myocardial ifarctio). The medical history of study participats also icluded the followig potetial risk factors for cardiovascular disease: hypertesio (53.3%), hypercholesterolemia (20.8%), hyperlipidemia (14.5%), type 2 diabetes mellitus (15.0%), hypothyroidism (12.0%), ad diabetes mellitus (9.5%). While the cardiovascular risk profile of this study populatio may differ somewhat from a more geeral populatio of patiets with TD, owig to the exclusio of participats with a ustable medical coditio or sigificat cardiac abormality, the characteristics of the study participats erolled icluded co-morbidities ad complicated medicatio requiremets that geerally reflect a real-world patiet populatio. Because orthostatic hypotesio has bee associated with some atipsychotic ad atidepressat medicatios [22], this was a outcome of iterest i the curret aalyses. There were o discerable differeces betwee valbeazie ad placebo with regard to hypotesio-related TEAEs, mea chages i orthostatic vital sig measuremets, or PCS decreases i orthostatic blood pressure or heart rate. The icideces of some TEAEs (e.g., dizziess, fall) were slightly higher i the KINECT 3 valbeazie extesio period tha i the 6-week DBPC trials (Table 3), which may be expected with a loger duratio of observatio o treatmet. The prescribig iformatio for valbeazie does ot iclude ay precautioary statemets regardig orthostatic hypotesio [19]. The prescribig iformatio for valbeazie oly carries two warigs, oe of which is the potetial for QT prologatio. This warig was based o the Food ad Drug Admiistratio s modelig of data from phase I studies. The prescribig iformatio clarifies that the degree of QT prologatio is ot cliically sigificat at plasma cocetratios expected with recommeded dosig. However, dose reductio may be ecessary i certai situatios i which valbeazie exposure may be higher; additioally, avoidig use i patiets with cogeital log QT sydrome or arrhythmias associated with a prologed QT iterval is recommeded [19]. Categorical aalyses of the QTcF iterval for the 6-week DBPC treatmet period showed o clear differece betwee valbeazie ad placebo (Table 5). However, as might be expected i a study of loger duratio (i.e., KINECT 3 extesio, which icluded participats who received up to 48 weeks of valbeazie treatmet), more participats met QTcF iterval categorical criteria at least oce durig treatmet (i.e., QTcF [450 ms, QTcF icrease [30 ms) i this study, but iterpretatio is limited by the lack of a placebo cotrol group. I additio, although the valbeazie trials excluded patiets with a curret QTcF of [450 ms (me) or [470 ms (wome) or a history of QT prologatio, medicatios with a kow potetial for QT prologatio were allowed durig the study based o a case-by-case medical review. I the pooled safety populatio, 74.3% of participats were takig a medicatio with QT prologatio potetial, which icluded some of the atipsychotic ad atidepressat medicatios that were required for psychiatric treatmet. More importatly, results from our subgroup aalyses suggest that the additio of valbeazie to ay of these medicatios did ot appear to exacerbate the risk for a prologed QT iterval. Based o results from drug drug iteractio studies (mauscripts i preparatio), dose adjustmets are recommeded i kow cytochrome P450 (CYP)2D6 poor metabolizers, patiets takig a strog CYP2D6 ihibitor (e.g., paroxetie, fluoxetie, quiidie), ad patiets takig a strog CYP3A4 ihibitor (e.g., itracoazole, ketocoazole, clarithromyci); cocomitat treatmet with strog CYP3A4 iducers is ot recommeded [19]. I the pooled phase II/III cliical trials, oly 4.8% (19/400) of participats were kow poor CYP2D6 metabolizers. Because it is difficult to iterpret results i such a small sample, subgroup aalyses based o CYP2D6 metabolism were ot icluded i this report. Although geotypig for CYP2D6 metabolism is recommeded for patiets requirig higher doses of tetrabeazie (a older vesicular mooamie

11 Cardiovascular Profile of 439 trasporter 2 ihibitor) [23], CYP2D6 geotypig is ot required for valbeazie [19]. The mai limitatios of this report are that the aalyses were coducted post hoc ad that the cliical trials were ot specifically desiged or powered to coduct a statistical assessmet of cardiovascular parameters with valbeazie treatmet; or were the trials desiged to be aalyzed based o the subgroups defied i this report. I additio, adverse evets i cliical trials may be affected by factors such as the baselie health of participats, chages i disease state over the course of treatmet, ad tolerace to treatmet. The curret aalyses were ot adjusted for these factors, although efforts were made to explore the potetial effects of various baselie characteristics o cardiovascular outcomes (i.e., subgroup aalyses). As metioed earlier, exclusio criteria for the cliical trials may limit the geeralizability of the results. However, the data represet a large sample of adults with TD who received valbeazie i additio to their psychiatric medicatios, ad results of the aalyses idicate that valbeazie treatmet cofers miimal cardiovascular risk. Coflicts of iterest Dao Thai-Cuarto, Christopher F. O Brie, Rolad Jimeez, Grace S. Liag, ad Joshua Burke are full-time employees of Neurocrie Bioscieces, Ic. ad have stock/stock optios i the compay. Ethical approval All procedures performed i studies ivolvig huma participats were i accordace with the ethical stadards of the istitutioal ad/or atioal research committee ad with the 1964 Helsiki Declaratio ad its later amedmets or comparable ethical stadards. The trials were also coducted i accordace with Iteratioal Coferece o Harmoizatio Guidelies for Good Cliical Practice, US Code of Federal Regulatios stadards, US Food ad Drug Admiistratio, ad the Health Caada Guidace for Cliical Trial Sposors. Study protocols were approved by istitutioal review boards at participatig ceters. Oly subjects assessed as havig the capacity to provide coset (usig the Uiversity of Califoria, Sa Diego Brief Assessmet of Capacity to Coset) were allowed to participate i the cliical trials. Ope Access This article is distributed uder the terms of the Creative Commos Attributio-NoCommercial 4.0 Iteratioal Licese ( which permits ay ocommercial use, distributio, ad reproductio i ay medium, provided you give appropriate credit to the origial author(s) ad the source, provide a lik to the Creative Commos licese, ad idicate if chages were made. 5 Coclusios The results of aalyses preseted i this report idicate that i DBPC cliical trials, the short-term cardiovascular effects of valbeazie were geerally similar to those of placebo. No uexpected cardiovascular effects were foud i a loger extesio period i which participats received up to 48 weeks of treatmet with valbeazie. Importatly, more tha 70% of participats i the valbeazie studies were takig cocomitat medicatios that have bee associated with icreased cardiovascular risks ad/or QT prologatio, icludig atipsychotic ad atidepressat medicatios eeded to treat primary psychiatric disorders. Post-marketig surveillace, alog with pedig safety data from other loger studies [NCT (12 moths), NCT (18 moths)], will help to further clarify the cardiovascular effects of valbeazie i patiets with TD. I additio, the cardiovascular effects of valbeazie will be evaluated i plaed ad ogoig studies of other movemet disorders (e.g., Tourette sydrome). Ackowledgemets Writig ad editorial assistace was provided by Prescott Medical Commuicatios Group, Ic. (Chicago, IL, USA) with support from Neurocrie Bioscieces, Ic. (Sa Diego, CA, USA). Compliace with Ethical Stadards Fudig This study was sposored by Neurocrie Bioscieces, Ic. (Sa Diego, CA, USA). Refereces 1. Carter P, Ma J, Sagha J, et al. 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