Journal of the American College of Cardiology
`33 2010 by the American College of Cardiology Foundation
`Published by Elsevier Inc.
`
`Vol. 55. No. 18, 2010
`ISSN 0?35-IU‘3W$36.00
`doi:loleijachDIUDLUET
`
`Addition of Inhaled Treprostinil to Oral
`
`Therapy for Pulmonary Arterial Hypertension
`
`A Randomized Controlled Clinical Trial
`
`Vallerie V. McLaughlin, MD,* Raymond L. Benza, MD,’I‘ Lewis J. Rubin, MD,:[:
`Richard N. Channick, MDA: Robert Voswinckcl, MD,§ Victor F. Tapson, MD,”
`
`Ivan M. Robbins, MD,1l Horst Olschewski, MD,# Melvyn Rubenfire, MD,‘ Werner Seeger, MD§
`
`Arm Areal", Michigan; Pirrréurgii, Penmyivam'a; La folio, Cch'fcmic; Giersen, Germany;
`Der-cam, North Carolina; Narbnii’i’e, Tennessee; and Graz, Azania
`
`Objectives
`
`Background
`
`Methods
`
`Results
`
`This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension (PAH) pa-
`tients receiving therapy with either bosentan or sildenafil.
`
`There is no cure for PAH, despite effective treatments, and outcomes remain suboptimal. The addition of in-
`haled treprostinil, a long-acting prostacyclin analog. might be a safe and effective treatment addition to other
`PAH-specific oral therapies.
`
`Two hundred thirty-five PAH patients with New York Heart Association (NYHA) functional class III (98%) or IV
`symptoms and a 6-min walk distance (GMWD) of 200 to 450 m while treated with hosentan (70%) or sildenafil
`were randomized to inhaled treprostinil (up to 54 pg) or inhaled placebo 4 times daily. The primary end point
`was peak BMWD at :12 weeks. Secondary end points included time to clinical worsening, Borg Dyspnea Score,
`NYHA functional class, 12-week trough BMWD. 6-week peak GMWD. quality of life. and PAH signs and symo
`toms. The biomarker N-terminal pro-brain natriuretic peptide (NT-proBN P) was assessed.
`
`Twenty-three patients withdrew trom the study prematurely (13 treprostlnll. 10 placebo). The Hodges-Lehmann
`between—treatment median difference in change from baseline in peak SMWD was 19 rn at week 6 (p = 0.0001)
`and 20 m at week 12 (p = 0.0004). Hodges-Lehmann between-treatment median difference in change from base
`line in trough BMWD at week 12 was 14 m (p = 0.0066). Quality of life measures and NT-proBNP Improved on active
`therapy. There were no improvements in other secondary and pointsI including time to clinical worsening, Borg Dys-
`pnea Score, NYHA functional class. and PAH signs and symptoms. Inhaled treprcstinil was safe and well-tolerated.
`
`Conclusions
`
`This trial demonstrates that. among PAH patients who remain symptomatic on bcsentan or sildenafil, inhaled
`treprostinil improves exercise capacity and quality of life and is safe and well-tolerated. (TRIUMPH I: Double
`Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in
`Patients With Severe Pulmonary Arterial Hypertension; NCT00147199)
`(J Am Coll Cardiol 2010;55:1915—22)
`© 2010 by the American College of Cardiology Foundation
`
`
`
`
`
`
`From the 'Universiry of Michigan Health System. Ann Arbor, Michigan;
`TAIIcgheny General Hospital, Pittsburgh, Pennsylvania; 42University of Calit'ornin
`at San Diego, LaJoIIa, California; §Universiry of Gicsscn Lung Center, Gicsscn,
`Germany; "Duke University Medical Center, Durham, North Carolina; 1Vandcr—
`bilt University School of Medicine, Nashville, Tennessee; and the #Mcdicn]
`University of Graz. Graz, Austria. This reseru'ch was filnded by United Theml'mmirs
`Corporation. Dr. McLaughlin has sewed as cenailtantr'slxstker for Ame-lion i’liannaeculimls,
`Gilead Sciences, and Pfizer; and has received mania grants From .l'ictclion Pharn‘laocutimis.
`Pings-wt, Filmer, and United Therapeutifi Corp. Dr. Berra has reached research grants From
`United Thempeufim Cmp., Gilead Sdemrs, Actclion Pharmaceuticals, hing Rx, Inc, and
`Pfizer. Dr. Rubin has served as mmdmnnfinvcstippmr for and has shock ownership in United
`Theraflzufics Com. Dr. Channidt has served as ormsulmtl’spealner for and received research
`grants fi‘Um Aachen T’I'larrnat‘ctllictds, Gilmd Selma, Pfizer. and United Thrown-cs Corp.
`Dr. Tapson has sen-ed as consull‘mti’stmker for Actol'lon Plumnaceuticals, Gilead sciences.
`Lung Rx, Inc, United 'I'Iiempeutiis Corp" and Lilly; and has received mat-arch giants fium
`
`(Mellon Phnnnacmltials, Gilead Sciences, [Jung Rx. Inc; and United Thmapcutics Corp. Ur.
`Robbins has sencd as mnnrlrmc’nmker lbr Acmlicn Pharmimeutimis, Gilead Sciences,
`United Therapeutics Corn. and Lung Rx. Inc; and has received maid! grants fimr Gilead
`Sciences, Amelia] Plinnnacc'ufials, Pfizer, United 'Iltemrmtics Corp, and lung Rx. Inc. Dr.
`Olschewski has sum-d as consultant fix Buyer Sdiu'ing AG, GlamSmithKline, Myogcn, and
`Navarris; as a speaker firr Solving, Amlion Phan‘naocutimls, Enqrsivc, MW Pfimcr, and
`Unirhcr, and has receivcd research grants from Deutsche Forschungsgemeinsclmft,
`Osterrcichische Nationalhank, and European Union Framework 5 and 6 and pharma-
`ceutical grants fimn Schcring AG, Unitlicr, Actclion I‘hannaccut-icals and Eng-give. Dr,
`Rubcnfire has received research grants from Adelion Pharmaceuticals, United
`'I‘hcrapcutics Corp. and Pfizer. Dr. Sccgcr has served as consulmntfspcnkcr for Lung
`RX. Ind, and has patents with United Therapeutics Corp. (U5020080200449Al,
`W'000200?134292A3).
`Manuscript received July 21. 2009; revised manuscript received December 17.
`2009, accepted January 4, 2010.
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01622
`
`UNITED THERAPEUTICS, EX. 2095
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`Page 1 of 11
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`

`

`1916
`
`Melanghin at at.
`Inhaled Treproslinil for PAH
`
`JACC Vol. 55. No. 18. 2010
`May 4, 2010:1915-22
`
`Abbreviations
`and Acronyms
`
`6MWD = 6-rnln walk
`Ilslanoe
`CI = confidence Interval
`
`eCMI'l = extended
`Cochran-ManteI-floenszel
`
`IN. = Hodges-Lehmann
`MLWHF = Minnesota
`IJvlng with Heart Fallure
`NT-proBNP = N-tennlnal
`pro-brain mtriuretlo peptide
`mun = New York Heart
`Association
`
`PAH = pulmonaryI Medal
`hypertenelon
`was = WIleoxon rank sum
`
`Over the past 15 years, agents
`from 3 therapeutic classes have
`been investigated and are now
`widely used for the treatment of
`pulmonary arterial hypertension
`(PAH), a rare disease character-
`ized by progressive elevation in
`pulmonary artery pressure, pul—
`monary vascular resistance, and
`ultimately, right ventricular fail-
`ure (1,2). Prostaeyclins (epopro-
`stenol, treprostinil, and iloprost),
`endothelin receptor antagonists
`(bosentan, ambrisentan, and sitax-
`sentan), and phosphodiesterase in—
`hibitors (sildenafil, tadalafil) have
`
`been evaluated in PAH patients,
`on the basis of known pathobio—
`logical mechanisms of action, and
`have demonstrated improvements in symptoms, exercise
`tolerance, and in some studies, hemodynamic status, over
`the short term (3-9). There is no cure for PAH, despite
`these treatment options, and longer-term outcomes in PAH
`have been suboptimal. The concept of combining agents
`targeting different pathways in an attempt
`to improve
`outcomes is an area of active investigation, given the
`availability of agents from 3 distinct therapeutic categories.
`To date, 4 randomized placebo-controlled trials of combi-
`nation therapy are completed, with mixed results (10—13).
`Treprostinil is a tricyclic benzindene prostacyclin analog,
`with pharmacologic actions similar to those ofepoprostenol.
`It is stable at room temperature and has an elimination
`half-life of 4.6 h (14). In a randomized, placebo-controlled
`trial, treprostinil administered subcutaneously improved ex-
`ercise capacity and hemodynamic status in PAH patients
`(4). Two small investigator—initiated open label studies have
`suggested clinical benefit with treprostinil administered
`intravenously (15,16). Although clinically effective, subcu-
`taneous and intravenous administration of treprostinil
`might be associated with adverse effects including infusion
`site pain and blood stream infections, respectively (17,18).
`Initial open label studies with inhaled treprostinil have
`demonstrated favorable effects in terms of exercise capacity
`and hemodynamic status (19,20). In this study (TRIUMPH
`[TReprostinil Sodium Inhalation Used in the Management
`of Pulmonary Arterial HypertensionD, we assessed the
`efficacy and safety of inhaled treprostinil or placebo in PAH
`patients receiving therapy with either bosentan or sildenafil.
`
`Methods
`
`randomized, placebo-controlled,
`This was a 12-week,
`double—blind, multiccnter study in patients with PAH who
`were receiving a stable dose of bosentan or sildenafil for 3
`months before study initiation. The study was sponsored by
`United Therapeutics Corporation. Following institutional
`
`review board approval at each participating institution, all
`patients pr0vided written informed consent before any
`study-related assessments.
`Eligible patients were between the ages of 18 and 75 years
`with a confirmed diagnosis of idiopathic or familial PAH or
`PAH associated with collagen vascular disease, human
`immunodeficiency virus infection, or anorexigen use. Pa-
`tients were New York Heart Association (NYT-IA) func—
`tional class III or IV severity with a baseline 6—min walk
`distance (6MWD) between 200 and 450 m and were
`receiving bosentan 125 mg daily or any prescribed dose of
`sildenafil, 220 mg tid, for at least 3 months before study
`entry. Additionally, women of child-bearing potential were
`required to practice an acceptable method of birth control.
`Patients were considered ineligible for study participation
`if they: were pregnant or nursing; were diagnosed with any
`acute or chronic illness other than those associated with
`
`PAH (collagen vascular disease, human immunodeficiency
`virus, or anorexigen use); had received any investigational
`medications, prostanoids, or phosphodiesterase inhibitors
`other than sildenafil within 30 days; or had changed or
`discontinued any PAH medication within 3 months.
`Before randomization, patients were trained on proper
`nebulizer technique with the OPTINEB device (Nebu-Tec,
`Elsenfeld, Germany). Patients were randomized (1 of 1) to
`receive either inhaled treprostinil sodium or placebo 4 times
`daily in combination with bosentan or sildenafil. At the
`discretion of the study investigator, patients initiated ther-
`apy at 3 breaths (13 |u.g)/inhalation. If clinically tolerated,
`the dosing was to be increased over the first 2 weeks to reach
`a maximum of 9 breaths (54 pg) at each of the 4 daily doses.
`Patients were contacted by study personnel via telephone to
`assess patient tolerance to study drug, adverse events, and to
`up-titrate study drug dosing as tolerated.
`Baseline, Week 6, and Week 12 assessments included
`
`physical exam including PAH signs and symptoms and vital
`signs, NYHA fianctional classification, 6MWD, Borg Dys-
`pnea score (immediately after 6MWD), and clinical labo-
`ratory parameters including: urine pregnancy screening,
`blood chemistries, hematology, coagulation times, and
`N—terminal pro—brain natriuretic peptide (NT—proBNP).
`Additionally, at baseline and week 12, the following assess—
`ments were conducted: complete medical history including
`concomitant medications, pulmonary function tests, chest
`radiography, and completion of the Minnesota Living with
`Heart Failure (MLWHF) questionnaire. Adverse events
`were obtained throughout the study.
`The primary end point was 6MWD measured at peak,
`defined as within 10 to 60 min after treprostinil inhalation
`at week 12. Secondary end points included time to clinical
`worsening, defined as death, transplantation, hospital stay
`due to worsening PAH, or initiation of additional approved
`PAH—specific therapy, Borg Dyspnea Score, NYHA func—
`tional class, trough 6 MWD at week 12 (obtained at least
`4 h after study drug administration), peak 6MWD at Week
`6, quality of life as measured by the MLWHF question-
`
`UNITED THERAPEUTICS, EX. 2095
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`WATSON LABORATORIES V. UNITED TH ERAPEUTICS, |PR2017—01622
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`
`

`

`JACC Vol. 55. N0. 18, 2010
`May 4. 2010:1915-22
`
`McLaughlin ef al.
`Inhaled Trepresiinil [or PAH
`
`1917
`
`patients, 115 were randomized to treprostinil and 120 were
`randomized to placebo (Fig. 1). Twenty-three patients
`withdrew from the study prematurely, 13 (9 bosentan, 4
`sildenafil) in the treprostinil group and 10 (8 bosentan, 2
`sildenafil) in the placebo group. The mean dose of study
`drug was 50 i 10 pig in the inhaled treprostinil group and
`52 i 7 pig in the inhaled placebo group.
`Eflicacy outcomes. o—MlN WALK. The 6MWD results are
`presented in Figures 2 and 3. The peak 6MWD within—
`treatment median changes from baseline were 21.6 m
`(interquartile range: —8.0 to 54.0 m) and 3.0 m (inter-
`quartile range: —26.0 to 31.5 tn) for inhaled treprostinil
`and placebo groups, respectively, with an H-L between-
`treatment median difference of 20 m at week 12 (95%
`confidence interval [CI]: 8.0 to 32.8, p[eCMH] = 0.0004,
`p[WRS] = 0.0016). The H—L between—treatment median
`diiference in change in peak 6MWD was 19 m (95% CI: 8.5
`to 28.3, p[eCMH] = 0.0001, p[VVRS] = 0.0004) at Week
`6, and for the change in trough 6MWD it was 14 m (95%
`CI: 4 to 24.8, p[eCMH] = 0.0066, p[VVRS] = 0.0040) at
`week 12. Patients in the lowest quartile for baseline 6MWD
`(204 to 302 m, n = 59) had the greatest treatment effect in
`change in 6MWD by week 12, with an H—L between-
`treatment median difference of 49 m (95% CI: 23.7 to 78.2,
`p[eCMH] = 0.0003, p[VVRS] = 0.0007). As demonstrated
`in Figure 3, 60 patients receiving inhaled treprostinil (52%)
`experienced an improved 6MWD of 20 m or greater, with
`36 patients (31%) improving by at
`least 50 m. Patients
`receiving background bosentan therapy experienced an H—L
`between—treatment median difference in change in peak
`6MWD of 22 m (95% CI: 10.0 to 34.0, p[eCMH] =
`0.0001, p[VVRS] = 0.0004) and 25 m (95% CI: 10.2 to
`40.0) p[eCMH] = 0.0002, p[VVRS] = 0.0009) at weeks 6
`and 12, respectively. Patients taking sildenafil background
`therapy had an H—L between—treatment median difference
`
`Table 1
`
`Patient Demographic Data
`
`Placebo
`inhaled "IE
` Characterls‘llc [n = 1.15] {n = 120] p \l'alue
`
`
`
`Age. yrs
`55 {20-75)
`52 (13-75)
`0.056
`Male-{female
`22,193
`22.398
`0.88
`PAH etlology
`lPM-l or familial
`CVD
`other
`Background PAH therapy
`Bosentan
`Slldenafil
`Time on background therapy. weeks
`0.62
`90 2 75
`99 t 79
`Besentan
`0.44
`i"? I 69
`65 t 60
`Slldenafil
`0.62
`1.1.822
`11.273
`Baseline NYHA “wa
`
`
`
`346 I 63 351 1 69Baseline 6MWD, m 0.50
`
`64 {56)
`40 {35)
`11 {9]
`
`77 {67)
`se (33)
`
`67 (56)
`37 (31)
`16(13)
`
`83 (73)
`32 :27)
`
`0.60
`
`0.29
`
`naire, and PAH signs and symptoms. The NT—pro BNP
`was included as an ancillary assessment. All 6MWD assess-
`ments were planned at 3 to 5 h after bosentan dosing or 30
`to 120 min after sildenafil dosing.
`Statistics. This study had 90% power to detect a 35—m
`difi‘erence (75-m SD) between treatment groups in peak
`6MWD change from Baseline at week 12 with at least 200
`patients enrolled with power calculations in PASS software
`(Microsoft, Redmond, Washington) and a nonparametric
`(Mann-Whitney) adjustment to a 2-sample t test. This
`assumed SD was somewhat larger than that estimated from
`the trial data (66.8 m), suggesting that the true power is
`P9096. For 6MWD variables including peak and trough, a
`nonparametric analysis of c0variance was performed on all
`randomized patients. The effect of inhaled treprostinil
`versus placebo on 6MWD was tested with nonparametric
`analysis of covariance within the framework of extended
`Cochran—Mantel—Haenszel (eCMH) test (21,22). Specifi—
`cally, a Cochran—Mantel—Haensael mean score test was used
`on the standardized ranks of the residuals from an ordinary
`least squares regression with change in 6MWD at week 12
`as a linear function of etiology (as a categorical variable) and
`baseline 6MWD (as a continuous variable). Etiology and
`baseline 6MWD were chosen as covariates for this analysis,
`due to their demonstrated prognostic power in various
`previously conducted PAH trials. For confirmatory pur—
`poses, the eEect of inhaled treprostinil versus placebo on
`6MWD was further tested with the Wilcoxon rank sum
`
`test. The median difference between treatment
`(VVRS)
`groups was determined by the Hodges—Lehmann (H—L)
`between-treatment median difference. Imputation was used
`for missing data with worst rank for death, addition of PAH
`therapy during the trial or discontinuation due to disease
`progression,
`last rank carried forward for other missing
`values if a post—baseline assessment was performed, or the
`mean of placebo ranks if there was no post—baseline
`assessment.
`
`All secondary variables was evaluated by comparing the
`difference between baseline and week 12. The difference
`
`between treatment groups for baseline and secondary vari-
`ables was evaluated with either a chi—square test
`(for
`dichotomous data) or WRS test (for ordinal or continuous
`data).
`
`The safety of inhaled treprostinil was evaluated by com-
`paring adverse experiences in the 2 treatment groups with
`regard to frequency,
`intensity, seriousness, and causality.
`Changes in hematology, clinical chemistries, coagulation,
`chest radiography, lung function tests, and vital signs from
`baseline were also assessed between treatment groups.
`
`Results
`
`Demographic data. Two hundred thirty—five patients with
`a mean age of 54 years (range 18 to 75 years) were enrolled
`at 31 centers between June 2005 and July 2007. Patient
`demographic data are described in Table 1. Of the 235
`
`Values are mean (range). n. n [96). or mean ‘* 5D.
`6MWD = min walk distance; {ND = collagen vascular disease: IPA“ = idiopathic pulmonaryI
`arterial hypertension; NM = New York Heart Association functional class: PAH = pulmonary
`arterial hypertension; ‘I'RE = treprosthll.
`
`UNITED THERAPEUTICS, EX. 2095
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`Page 3 of 11
`
`

`

`1918
`
`McLaughlin et a1.
`Inhaled Treproslinil for PAH
`
`IACC ‘i'GI. 55. N0. 18. 2010
`May 4‘ 2010:1915-22
`
`
`
`Overview of Patients Entered into the Trial
`
`Randomized (N=235)
`
`\ A
`
`llocated to receive placebo (N=120)
`
`/
`Allocated to receive inhaled Treprostinil (N=115)
`
`Received the allocated Intervention (N=115)
`
`Received the allocated Intervention (N=120)
`
`Lost to Follow—op (N=I])
`Discontinued the Intervention (N=13)
`°
`Three patients with worsening PAH
`°
`Seven patients wilh Adverse Events
`'
`Three patients withdrew consent
`
`Lost to Follow—up (N=0)
`Discontinued the Intervention {N=lll)
`'
`One palient died
`'
`Four patients with Adverse Events
`'
`Five patients withdrew consent
`
`
`
`Analyzed l‘or El‘fieaey, Intent to Treat (N=l15)
`
`Analyzed l‘or Emeaey, Intent to Treat (N=l20]
`
`Analyzed for Safety (N=115)
`
`Analyzed for Safety (N=12ll)
`
`Patient Disposition
`
`
`
`A total of 235 patients were randomized into the study—115 to treprostinil and 120 to placebo. All randomized patients received investigational
`treprostinilfplaeebo. There were 13 premature discontinuations in the treprostinil group and 10 in the placebo group. PAH —- pulmonary arten'al hypertension.
`
`
`
`
`in change in peak 6MVVD at weeks 6 and 12 0f11 and 9 m,
`respectively (p = NS).
`
`SECONDARY END POINTS. There was no difference in time
`
`between—treatment median difference of —4 in the global
`score (p = 0.027] and —2 in the physical score (p = 0.037),
`for patients receiving inhaled trcprostinil.
`
`to clinical worsening between treatment groups (Table 2).
`There was no change in Borg Dyspnea Score, NYHA
`functional classification, and PAH signs and symptoms
`from baseline to week 12 compared with placebo. Quality of
`life as assessed by the MLWHF questionnaire had an H-L
`
`
`ANCILLARY END POINT. The NT-proBNP results are pre-
`sented in Figure 4. One hundred fifty—five patients provided
`pro-BNP results at baseline and week 12. Median baseline
`NT—proBNP levels were 593 pg/ml (n = 73) and 670 pg/ml
`(n : 82] in the treprostinil and placebo groups, respectively.
`
`
`
`
`
`
`MBEI‘S
`
`U10
`A01
`
`ChangefromBaseline>DefinedValue
`
`(meters)
`was:0
`
`Percentage of Patients
`
`
`lInhaled Treprostinil l Placebo I
`
`
`
`
`
`
`m cm... .. 5m
`Primary end point. change in peak 6min walk distance (SMWD) for patient
`receiving background sildenafil (ruled bars), background hosentan [dotted
`harsl. and the entire population (said bars}. There was a plaeeoooorrected
`improvement of 20 m at 12 weeks in the total population. Results presented
`as Hodgestehman between-treatment median difference.
`
`
`
`GMWD Improvements
`
`Distribution of the percentage of patients who achieved specific improvements
`in 6mm walk distance (6MWD) at 12 weeks. For example, 31% of patients tak-
`ing inhaled treprostinil and 12% of patients taking inhaled placebo had an
`improvement in 6MWD of >50 m at 12 weeks.
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01622
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`Page 4 of 11
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`

`

`JACC Vol. 55. No. 18. 2010
`MayI 4. 2010:1915-22
`
`McLaughlin et al.
`Inhaled Trepmslinil for Phil
`
`1919
`
`Table 2
`
`Clinical Worsening Events
`
`Treatment
`
`Inhaled TRE
`Placebo
`
`Extent pl Clinical Worsening
`(n = 115)
`[n = 120}
`No clinical womenlng
`11.149?)
`114 (95]
`Clinical meaning
`4 (3)
`5 (5)
`Death
`0 i0)
`1 (<1)
`Transplantation
`O (0}
`O (0)
`PAH hospital stay
`4 (3}
`5 (4)
`
`0 IO)Initiation of approved PAH therapy 0 I0)
`
`
`Values shown are n {9a}.
`PAH
`pulmonary arterial hypertension: TRE
`
`treprostinil.
`
`Table 3 Adverse Events Occurring In
`210% of Patients Receiving Inhaled TRE
`
`Treatment
`MW Bruits Occurring
`
`Inhaled TRE (n = 115)In 23% of‘i'RE Patients Placebo (n = 120)
`
`Cough
`62 I54}
`35 [291*
`Headache
`47 (41}
`27 [231*
`Nausea
`22 (19}
`13 (1.1)
`Dizziness
`20(11'}
`18 [15]
`Flushing
`17 (15}
`:I. [<1}*
`Threat irritation
`16 (14)
`10 (a)
`Pharyngolaryngeal pain
`13 (11}
`T (6)
`
`Diarrhea 9 (B) 11:10)
`
`
`The NT-proBNP within treatment median changes from
`baseline were —57 pg/ml (interquartile range: —396.0 to
`34.0) and 40 pg/ml (interquartile range: —93.0 to 288.0) for
`inhaled treprostinil and placebo group, respectively, with an
`H—L between—treatment median difference in change from
`baseline in NT—proBNP levels of —187 pg/ml {95% CI:
`—333 to —64.0, p = 0.0014) at week 12. The H-L
`between-treatment median difemnce in change from base-
`line was —159 pg/ml (95% CI: —299 to —64.0, p = 0.0003)
`at week 6.
`
`Safety. There were no clinically significant changes in
`pulmonary function tests, chest radiography, or clinical
`laboratory parameters, including: blood chemistries, hema—
`tology, and coagulation times between treatment groups.
`Seventy-five (72%) patients receiving inhaled treprostinil
`and 96 (87%) receiving placebo obtained the maximum dose
`of 9 breaths (54 pg) 4 times daily. The average time to
`maximum dose was approximately 3 weeks in both treat-
`ment groups.
`Adverse events are summarized in Table 3. The most
`
`common adverse event was cough, which occurred in 54%
`of patients receiving inhaled treprostinil as compared with
`
`Values shown are n (96]. 'p r; 0.05.
`TRE = trepmeilnil
`
`29% of patients receiving placebo. There were 11 serious
`adverse events reported in the inhaled treprostinil group,
`including 3 events of worsening pulmonary hypertension, 2
`events of syncope, and 1 event of each of the following:
`anemia, abdominal pain, diabetes mellitus, diarrhea, gastric
`ulcer, and right ventricular failure.
`Twenty—three patients prematurely discontinued the study.
`In the placebo group, 1 patient died, 4withdrew due to adverse
`events, and 5 patients withdrew consent; of these patients, 8
`were receiving background bosentan. In the inhaled treprostinil
`group, 3 patients discontinued due to worsening pulmonary
`hypertension, 7 withdrew due to adverse events, and 3
`withdrew consent; of these patients, 9 were receiving back-
`ground bosentan.
`
`In this study, PAH patients with NYHA functional class III
`or IV symptoms and a 6MVVD of 200 to 450 III while
`receiving oral monotherapy with either boscntan or silde—
`nafil were randomized to receive either inhaled treprostinil
`or placebo. The primary end point of change from baseline
`in 6MWD at week 12 had an H—L between—treatment
`
`median difference of 20 m (p = 0.0004). Additionally, the
`change in 6MWD improved as early as week 6 (H—L
`median difference of 19 m, p = 0.0001) and was sustained
`at trough at week 12 (14 m, p = 0.0066). The importance
`of sustained efiects at trough is notable, because this is the
`first such observation with a prostanoid given on an inter—
`mittent basis. The improvement in 6MWD was greatest in
`those in the lowest quartile for baseline 6MWD (49 m, p =
`0.0003). This observation of greatest benefit in the most
`severely compromised patients studied was also made in the
`pivotal trial with subcutaneous treprostinil but is contrary to
`the recent study evaluating the addition of sildenafil in those
`symptomatic while receiving epoprostenol (4,12). The im-
`provement noted in these advanced but not end—stage
`patients with inhaled treprostinil suggests that such patients
`still have capacity to improve with inhaled prostanoid
`therapy.
`
`UNITED THERAPEUTICS, EX. 2095
`
`
`
`Baseline(pain'IL)
`
`from s'3aa‘aass3s
`Pro-EN?MedlanChange
`
`
`
`llnhaled TRE I Placebo
`
`
`
`
`
`W:
`Plambo: median = 690 (n = 87)
`
`Inhaled TRE: median = 596 (n = 73) Inhaled TRE: n'iedi'an = 602 (n = 86]
`
`W:
`Phoebe: median = era (n = 82)
`
`NT—proBhlP Changes
`
`Median change from baseline in Nstenninal pro brain natriuretio peptide INT?
`proBNP} at week 6 and week 12. Samples were available for 155 patients at
`week 12. TRE = treprostinil.
`
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR2017—01622
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`1920
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`flelauglllin at al.
`Inhaled 'I’repmstinil for PM!
`
`JACC Vol. 55. Ne. 18, 2010
`Mayr 4. 2010:1915-22
`
`Other observations, although not pro—specified analyses,
`are worthy of comment. Twelve percent of the patients
`randomized to placebo experienced an improvement
`in
`6MWD of more than 50 tn at week 12, stressing the
`importance of placebo—controlled trials for PAH in which
`the 6MWD is an end point. The improvement in 6MWD
`was greater for patients receiving bosentan therapy com-
`pared with sildenafil
`therapy, although the number of
`patients taking sildcnafil was smaller, and this comparison
`was not an objective of this study. Although this improve-
`ment in 6MWD is perhaps a function of sample size and
`varying sildenafil close, this observation is surprising, par—
`ticularly in light of the potential synergy between the cyclic
`adenosine monophosphate and cyclic guanosine monophos-
`phate pathways and prior clinical reports with sildenafil and
`prostanoids in both observational and controlled clinical
`trials (12,23-25). More formal study of the combination of
`inhaled treprostinil and oral sildenafil in an appropriately
`powered trial would be informative.
`The overall clinical worsening event rate in the study was
`low—only 10 total events. Clinical assessments, including
`the 6MWD and NT—pro BNP, were static over the 12—
`week course of this trial in the placebo group, reflecting the
`relative stability of this group over a short 12-week period,
`potentially a function of the background therapy with
`bosentan or sildenafil. Although the definition of time to
`clinical worsening has varied from trial
`to trial,
`it has
`fiinctioned as an important morbidity and mortality type
`end point in PAH trials. However, as clinical investigation
`in PAH evolves, it is likely that trials will include those who
`are less ill and already receiving PAH-specific therapy,
`potentially resulting in low event rates as seen in the current
`study. Trials of longer duration, ostensibly end point-driven
`trials, might be the future direction of this field.
`There were significant improvements in the secondary
`end point of quality of life as assessed by the MLWHF
`questionnaire and the ancillary end point of NT-pro BNP.
`Plasma NT—pro BNP concentrations correlate with hemo-
`dynamic severity and prognosis in PAH (26-28). The
`improvement in NT-pro BNP with inhaled treprostinil in
`this study was consistent with the improvements noted in
`the placebo—controlled study of ambrisentan in PAH, the
`only other placebo-controlled trial that has evaluated NT-
`pro BNP as an end point. The consistent NT-pro BNP in
`the patients randomized to placebo is compelling and
`suggests clinical stability over 12 weeks in this group of
`patients treated with bosentan or sildenafil. Reductions in
`NT-pro BNP in patients treated with inhaled treprostinil
`therapy for PAH might reflect a beneficial effect on right
`ventricular function and, in turn, prognosis.
`Inhaled treprostinil was safe and well-tolerated. The most
`common adverse event was cough, which occurred in 54%
`and 29% of the treprostinil and placebo groups, respectively.
`Other commonly reported adverse events included head—
`ache, nausea, dizziness, and flushing—all common side
`effects of prostanoid therapy.
`
`This study compares favorably to other placebo—
`controlled combination therapy trials.
`In the first ever
`placebo-controlled trial of combination therapy, Humbert
`et al. (10) evaluated bosentan versus placebo in 33 patients
`initiating intravenous epoprostenol (upfront combination
`therapy). There were improvements in functional class,
`6MWD, and hemodynamic status in both groups, but no
`difference between the groups. Although this is an
`important study, due in part to the small sample size and
`study design, the practical implications of this study are
`limited.
`
`Evaluating the addition of inhaled iloprost versus placebo
`in PAH patients who remain symptomatic while taking
`bosentan has been the objective of 2 randomized placebo-
`controlled trials. In 1, there was an improvement in post—
`inhalation and pre—inhalation mean 6MWD of 26 m (p =
`0.051) and 19 m (p = 0.14), respectively, as well as in
`improvement in time to clinical worsening (p = 0.0219)
`(11). The other trial
`that evaluated the addition of
`
`iloprost or placebo to bosentan was terminated prema-
`turely after a futility analysis predicted failure at
`the
`predetermined sample size of 36 patients/group (13).
`Although the study design of these 2 studies parallel
`current clinical practices, their application to contempo-
`rary treatment is limited by the small sample size and the
`contradictory results. In comparison,
`the well—powered
`current study demonstrates an eEect on exercise capacity
`as measured by the 6MWD both pre- and post-
`inhalation at the conclusion of the study at 12 weeks and
`after inhalation as early as 6 weeks. On a practical note,
`there is a patient-perceived advantage in the ease of
`delivery with inhaled treprostinil compared with inhaled
`iloprost, which is administered 6 to 9 times/day with each
`inhalation requiring on average 10 to 15 min.
`In the largest placebo—controlled study of combination
`therapy to date, Simonneau et al. (12) evaluated the addition
`of sildenafil (target dose 80 mg tid) or placebo in 267 PAH
`patients who remained Symptomatic with a 6MWD of 100
`to 450 m while taking a stable dose of intravenous epopro—
`stenol for at least 3 months. These investigators reported an
`improvement in the placebo—adjusted mean 6MWD at 16
`weeks of 28.8 m (p = 0.0002) as well as improvements in
`pulmonary artery pressure, cardiac output, and time to
`clinical worsening. Contrary to that of the current study, the
`treatment benefit in terms of 6MWD was less impressive
`for the patients with a lower baseline 6MWD. Again, given
`the trial design, the practical implications of this study in
`the current
`treatment paradigm, when many patients
`commence treatment with oral agents, is limited. Addi—
`tionally, most patients were treated with sildenafil at a
`dose of 80 mg tid, above the currently approved dose of
`20 mg tid.
`Compared with the other completed combination ther—
`apy trials, the current study is highly relevant in terms of
`study design, adding a nonparenteral prostanoid in patients
`receiving initial oral therapy for PAH. Prostanoids have
`
`UNITED THERAPEUTICS, EX. 2095
`
`WATSON LABORATORIES v. UNITED THERAPEUTICS, IPR2017—01622
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`JACC Vol. 55. No. 18, 2010
`May 4, 2010:1915-22
`
`Mclaughlin er al.
`Inhaled Trepmdinil or m
`
`1921
`
`long been recognized as effective agents for the treatment of
`PAH. The complicated delivery system and potential side
`eEects associated with parenteral prostanoids have deterred
`some patients and caregivers from instituting this effective
`class of agents early. The ease of delivery of inhaled
`treprostinil, combined with the clinical benefits as demon-
`strated here, might expand the prostanoid treatment options
`for PAH patients.
`Of note, all combination therapy trials completed to date
`are of short duration (12 to 16 weeks) with a primary end
`point of 6MWD. The absolute magnitude of placebo-
`corrected change in 6MWD in these trials is typically less
`than many of the studies of monotherapy in treatment-naive
`patients. It is possible that the potential for further vasodi-
`lation and antiremodeling with our current agents is blunted
`after a patient is exposed for some length of time to an agent
`of another class. This underscores the importan