ORIGINAL RESEARCH ARTICLE
`
`Cardiovascular
`Therapeutics
`
`Inhaled lloprost to Inhaled Treprostinil in
`Rapid Transition from
`Patients with Pulmonary Arterial Hypertension
`
`,2 Zeenat Safdar,3 Raymond L. Benza,‘1 Richard N. Channick,5 Erika
`Robert C. Bourge,1 Victor F. Tapson
`B. Rosenzweig" Shelley Shapiro} R.
`James White,8 Christopher Shane McSwain,9 Stephen Karl
`Gotzkowsky,9 Andrew C. Nelsen9 & Lewis J. Rubin1o
`
`1 University of Alabama at Birmingham, Birmingham, AL, USA
`2 Duke University Medical Center, Durham, NC, USA
`3 Baylor College of Medicine, Houston, TX, USA
`4 Allegheny General Hospital, Pittsburgh, PA, USA
`5 Massachusetts General Hospital, Boston, MA, USA
`6 Columbia Presbyterian Medical Center, New York, NY, USA
`It David Geffen UCLA School of Medicine, Greater Los Angeles VA Healthcare System, Los Angeles. CA, USA
`8 University of Rochester Medical Center, Rochester, NY, USA
`9 United Therapeutics Corp, Research Triangle Park, NC, USA
`10 UCSD Medical Center, San Diego. CA, USA
`
`Keywords
`Iloprost; Inhaled; Pulmonary arterial
`hypertension; Quality of life; Treprostinil.
`
`Correspondence
`Robert C. Bourge, MD, The University of
`Alabama at Birmingham, 311 THT, 1900
`University Blvd, Birmingham, AL 35294, USA.
`Tel_: +205-934—3624;
`Fax: +205-9?5-5150;
`E-mail: bbourge@uab.edu
`
`Clinical Trial Registration: NCT00741819
`
`dOi:10.1111l1?55-5922_12008
`
`SUMMARY
`
`Background: [nhaled treprostinil is a prostacyclin analog approved for the treatment of
`pulmonary arterial hypertension [PAH] that may provide a more. convenient treatment
`option for patients receiving inhaled iloprost while maintaining the. clinical benefit of
`inhaled prostacyclin therapy. Aims: 111 this open-label safety study. 73 PAH patients were
`enrolled with primarily World Health Organization Class II (56%} or 111 {42%) symptoms.
`At baseline. most patients [93%) were receiving 5 pg of iloprost per dose but 33% of
`patients reported a dosing frequency below the labeled rate of 6—9 times daily. Patients initi-
`ated inhaled treprostinil at 3 breaths fourtintes daily (qid) at the immediate next scheduled
`iloprost dose. The primary objective was to assess the safety of rapid transition from iloprost
`to inhaled treprostinil: clinical status and quality of life were also assessed. Results: Most
`patients [84%) achieved the target treprostinil dose of 9 breaths qid and remained on study
`until transition to commercial therapy (89%). The lnost frequent adverse events {AEs} were
`cough (”HP/o), headache (44%), and nausea (30%}. and five patients prematurely discon-
`tinued study drug due to AE [n = 3). disease progression (11 = I). or death {11 = I). At week
`12, the time spent on daily treatment activities was reduced compared to baseline, with a
`mean total savings of 1.4 h per day. Improvements were also observed at week 12 for enmin
`walk distance (+160: P < 0.001]. N~tenninal proAB-type natriuretic peptide (—74 pgimlg
`P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains
`P < 0001). Conclusions: Pulmonary arterial hypertension patients can be safely transi-
`tioned from inhaled iloprost to inhaled treprostinil while tttaintaining clinical status.
`
`Introduction
`
`Pulmonary arterial hypertension tf’AH) is a rare. life-threatening
`disease of the pulmonary vasculature characterized by a progres-
`sive increase in pulmonary vascular resistance. and ultimately,
`right ventricular failure [1]. Prostacyclin analogs mimic the effects
`of prostacyclin. alt endogenous prostaglandin. to cause vasodila-
`tion of the pulmonary arterial bed and inhibition of platelet
`aggregation. and the therapeutic benefits of these therapies for
`the treatlnent of PAH are well established [2—?]. Due to relatively
`
`short in viva half-lives. proslacyclin analogs have been historically
`administered by either continuous intravenous or subcutaneous
`infusion. As such. the use of these therapies is complex and often
`challenging to administer [2]. In recent years. inhaled prostacy-
`clin analogs have emerged as attractive treatment options for PAH
`patients requiring prostacyclin therapy due to their relatively low
`incidence of systemic side effects. their ease of use compared to
`the parenteral therapies. and their ability to deliver vasodilatory
`effects directly to the lung vasculature reducing intrapulmonary
`shunting (WQ mismatch)
`[28—11].
`In fact,
`the prostacyclin
`
`38 Cardiovascular Therapeutics 31 120131 38—44
`
`© 2012 Blackwell Publishing Ltd
`
`UNITED THERAPEUTICS, EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS, |PR201?—01621
`Page 1 of 7
`
`

`

`RC. Bourge et at.
`
`Rapid Transition to Inhaled Treprostinil
`
`analogs iloprost (Ventavisw. Actelion Pharmaceuticals Ltd. Allsch-
`wil. Switzerland) and treprostinil (Tyvasow. United Therapeutics
`Corp. Research Triangle Park. NC. USA) are both approved in the
`USA as inhaled therapies for the treatment of PAH [12.13].
`While the mechanism of action of iloprost and treprostinil is
`similar.
`the in viva pharmacokinetics {PK}. and thus indicated
`treatment regimens, are different, Due to its relatively short half-
`life (20—30 min}. the recommended administration schedule for
`inhaled iloprost is 6—9 doses (inhalations) per day with a mini-
`mum of 2 h between doses and a target maintenance dose of 5 pg
`per administration [12]. Conversely, with an elimination half-life
`of approximately 4.5 h, the recommended dosing of inhaled tre-
`prostinil
`is four times per day (qid) with approximately 4 h
`between doses and a target ntaintenance dose of 9 breaths per
`treatment session [[3]. Given the more favorable administration
`schedule of inhaled treprostinil compared to inhaled iloprost. the
`objective of this study was to investigate the safety. efficacy. and
`quality of life (QoL} after rapid transition from inhaled iloprost
`therapy to inhaled treprostinil therapy in PAH patients.
`
`Methods
`
`Study Design
`
`This study was a multicenter. prospective, open-label safety
`evaluation in PAH patients receiving stable iloprost therapy. The
`study was
`sponsored by United Therapeutics Corporation.
`Following institutional review board approval, all patients pro-
`vided informed consent before any study-related assessments.
`
`Study Population
`
`Eligible patients were between the age of 18 and 75 years with a
`diagnosis of idiopathiclhereditary PAH. PAH associated with colla-
`gen vascular disease or human immunodeficiency virus, or PAH
`associated with unrepaired or repaired congenital systemic-to-
`pulmonary shunt (repaired 2 5 years). Patients were required to
`have a baseline tit-min walk distance {fiMWD} of 2250 m and be
`receiving a stable dose of iloprost for at least 30 days prior to base-
`line. For patients receiving endothelin receptor antagonist (ERA)
`or PDE-S inhibitor background therapy, a stable dose for those
`medications was required for 30 days prior to baseline. Women of
`childbearing potential were required to practice an acceptable
`method of birth control. Patients were considered ineligible if they
`were pregnant or nursing: had left-sided heart disease (World
`Health Organization [WHO] Group 2] or significant parenchymal
`lung disease (WHO Group 3}; were receiving any investigational
`medication: or if they had changed or discontinued any PAH med-
`ication within 30 days.
`
`Study Drug
`
`Following completion of all baseline study assessments. patients
`discontinued iloprost therapy during the baseline visit and initi-
`ated inhaled treprostinil at 3 breaths {a pgfbreath] qid. The initial
`dose of inhaled treprostinil occurred in the investigator clinic at
`the time of the patients' next scheduled dose of inhaled iloprost.
`The suggested treprostinil dose titration was an increase of one
`additional breath per dosing session every 3 days with a goal of 9
`breaths qid within the [irst 3 weeks of treatment, If clinically indi-
`cated. investigators were allowed to increase to a maximum of 12
`breaths qid. Prior to initiation of study drug patients were trained
`on proper utilization of the OPTINEB06 device {Nebu-Tec, Elsen-
`feld, Germany}.
`
`Study Assessments
`
`Baseline. week 6. week 12. and month 12 assessments included a
`physical examination. vital signs. GMWD (EDI: immediately fol-
`lowing GMWD], WHO functional class. the Cambridge Pulmonary
`Hypertension Outcome Review {CAMPHOR} questionnaire [14].
`and clinical
`laboratory parameters including urine pregnancy
`screening, blood chemistries. hematology, coagulation times, and
`N-terminal probrain natriuretic peptide {NT-proBNP). All 6MWD
`and SDI assessments were conducted at peak drug concentrations
`[10—30 min postiloprost at baseline;
`[0—60 min post-treprostinil
`during treatment phase). Additionally, the drug administration
`activities questionnaire and the treatment satisfaction question-
`naire for medicine [TSQMJ [15] were conducted at baseline and
`week 12: the patient impression of change {PIC} assessment was
`conducted at week 12. For the drug administration activities ques-
`tionnaire. patients were asked to provide information related to
`the daily administration and time requirements of inhaled iloprost
`(baseline) and inhaled treprostinil (week 12]. In support of this
`analysis. patients were also given the option of completing a T-day
`drug administration activities diary that recorded all time spent
`with the drug andlor device for the 7 days before baseline {on
`iloprost] and for the 7 days before week 12 assessments (on tre-
`prostinil.) Adverse events {AEs}.
`including incidence. severity.
`and relatedness to study drug. were monitored throughout the
`study as were any changes in concomitant medications,
`For analysis of inhaled treprostinil PK. blood samples were col-
`lected 10 min prior to dosing and 5. 10. 15. 20. 30. 45. 60. 90.
`180, 270. and 360 min after dosing. Patients were eligible for PK
`analysis if they had been receiving inhaled treprostinil for at least
`30 days and if they had been on a stable dose for at least 3 days.
`Plasma concentrations of treprostinil were determined using a
`validated method as described previously [16].
`
`Data Analysis
`
`Study Obiectives
`
`The primary study objective was to evaluate the acute and long-
`term safety of inhaled treprostinil therapy following rapid transi-
`tion from inhaIed iloprost therapy. Secondary objectives were to
`evaluate the effect ofinhaled treprostinil on 6MWD, Borg dyspnea
`index (not). plasma NT-proBNP, WHO functional class, and QoL
`in a group of previously stable iloprost patients.
`
`Numeric endpoints for postbaseline assessments were compared
`to baseline using a Wilcoxon signed rank test. and statistical signif-
`icance was set at P < 0.05, Data are presented as observed case
`with no imputation for missing data. Analysis of secondary end-
`points was descriptive in nature with no formal hypothesis testing.
`Statistical analysis was performed using SAS‘” software, version
`9.2 (SAS Institute Inc.. Cary. NC, USA). The database and all
`
`CC) 2012 Biackwell Publishing Ltd
`
`Cardiovascular Therapeutics 3‘] {20t3} 38—44 39
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS. IF’R201 7—01621
`Page 2 of 7
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`

`

`Rapid Transition to Inhaled Treprostinil
`
`RC. Bourge et 01.
`
`statistical outputs were retained by the sponsor. United Therapeu-
`tics Corporation. All authors had access to the data to enable con-
`[irmation oi the findings. The authors assume full responsibility
`for the completeness and accuracy of the content of the manu-
`script.
`
`Results
`
`Patient Demographics and Disposition
`
`Seventy-three patients were enrolled between December 2008
`and December 2009 with a mean age of 49 years (range: 18—?4),
`Patients were predominantly female [78%) with idiopathic.l
`hereditary PAH [48%) and WHO functional class Illlll (5614291)}
`Symptoms (Table 1}, Median baseline 6MWD was 3?8 m [inter-
`quartile range [IQR]: 330—452}; median baseline plasma NT-proB-
`NP concentration was 626 pgtlmL (IQR: 222—1 331]}. Most patients
`(59%]: were receiving triple therapy tie, ERA, PDE-S inhibitor,
`and iloprost}.
`Baseline iloprost usage is shown in Table 2. All patients were
`using the l-neb AAD‘” System (Philips Respironics, Pittsburg, PA,
`USA]. and most patients (93%) were receiving 5.0 pg of iloprost
`per dose. Twenty-eight patients {38%} reported using iloprost less
`than the labeled irequency of 6—9 inhalations per day [Table 2).
`Seventy patients {96%) completed the week 12 assessments. Eight
`(11%} patients eventually discontinued the study drug due to AE
`(n = 3). withdrawn consent {n = 3]. disease progression [rt = l).
`and death {n = 1) (Table 3}. The majority of patients (n = 65)
`continued to receive treatment until the study was terminated by
`
`Table 1 Baseline characteristics
`
`
`
` Characteristic N = 73
`
`Age, year
`Female
`PAH etiology
`Idiopathic or hereditary
`Collagen vascular disease
`Other“
`Background PAH therapy
`ERA only
`PDE-5 inhibitor only
`Both
`None
`WHO functional class
`I
`ll
`Ill
`IV
`ouwo, m
`NT—proBNP, pgrmL
`
`49 {ls-T4}
`5? [78]:
`
`35 I48]:
`16 1221
`22 [31]}
`
`t9 lzol
`8 [11}
`43 [59}
`3 {41
`
`[1]
`1
`41 [56}
`31 [42}
`0 ii]!
`3?8 [330—452]
`626 {222—1330}
`
`Table 2 Inhaled prostacyclin dosing
`
`CharaCtEristiI:
`
`Baseline iloprost usage
`Dose
`
`2.5 pg
`5,0 pg
`Frequency
`<ox day
`2 6x day
`Inhaled treprostinil dosing
`Week 12 Dose
`<9 breaths
`2 9 breaths
`Were 9 breaths achieved?
`No
`Yes
`Time to reach 9 breaths In = 61]
`
`N 2 ?3
`
`5 [7]
`68 [93}
`
`28 [33]
`45 [62]
`
`19 [26]
`54 [74]
`
`12 [1 6]
`61 l84l
`18 [L22]
`
`Values are n [it] and median [interquartile range] days.
`
`Table 3 Summary of discontinuations and adverse events [AEsl
`
`CharactE‘ristic
`
`Discontinued ioveralll
`AE
`Withdrawn consent
`Disease progression
`Death
`AEs [any event!
`Cough
`Headache
`Nausea
`Chest discomfort
`Flushing
`Nasopharyngitis
`Upper respiratory tract infection
`Dizziness
`Palpitations
`Throat irritation
`Fatigue
`Oropharyngeal pain
`Productive cough
`
`N = 73
`
`3 [1 11
`3 i4:
`3 [4!
`1
`[1:
`1
`[1:
`21 [9?!
`54 {741
`32 {441
`22 [30]
`12 (to:
`11 [151
`11 [15]
`11 [151
`10 [141
`9 [12]
`9 [12]
`8 [l 11
`i" [10]
`7 (10!
`
`Values are n is}. Includes AEs occurring in at
`Mean exposure 32.4 weeks (range: 04—560}.
`
`least 10% of patients.
`
`the sponsor [mean exposure = 32.4 weeks; range, 11.4—56.0}, at
`which point most patients transitioned to commercial therapy.
`
`Values are mean [range] for age and median [interquartile range} for
`oMWD and NT-proBNP. All other values are n IX}. PAH, pulmonary arte
`rial hypertension; ERA, endothelin receptor antagonist; PDE-5, phospho—
`diesterase type 5; WHO, World Health Organization; olVlWD, o—min walk
`distance; NT—proBNP, N-terminal pro-B-type natriuretic peptide. aOther
`PAH Etiology includes HIV infection in = 31. repaired congenital shunt
`in = 4}. and unrepaireci congenital shunt In = 15}.
`
`Dosing and Acute Tolerability
`
`inhaled treprostinil achieved was
`The mean [2:SDJ dose of
`8.8 t 2.4, 8.9 i 2.4. 9.3 t 2.0. and 9.2 d: 1.4 breaths qid for week
`6, week 12, month 6, and month 12, respectively. Most patients
`(84%) achieved the target dose of 9 breaths within approximately
`18 days (Table 2]. Analysis of AEs with onset during the lirst day
`of study drug dosing [cough [25%]: headache [1195]] and with
`
`40 Cardiovascular Therapeutics 31 [2013] 38-«14
`
`© 2012 Eiackwell Publishing Ltd
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS. IF’R201 7—01621
`Page 3 of 7
`
`

`

`R.C. Bourge er of.
`
`Rapid Transition to Inhaled Treprostinil
`
`onset during the first 5 days of study drug dosing {cough [38%].
`headache [27%] and nausea [8%]) was consistent with inhaled
`prostacyclin therapy and did not reveal any evidence of acute
`decompensation. There was one AE leading to discontinuation of
`study drug during the first 5 days of dosing that the individual
`investigator deemed “reasonably attributable" to study drug [psy-
`chotic disorder [day 3]},
`
`Safety
`
`The most frequent AEs with inhaled treprostinil included cough
`(74%]. headache (44%}, and nausea {30%) (Table 3). Most AEs
`were mild or moderate in intensity: severe AEs were reported in
`21 (29%} patients. Fifteen serious adverse events {SAEs} were
`reported in 10 ( 14%} patients, including two events each of poeti-
`monia and worsening pulmonary hypertension. Most SAEs (10
`|67%|} were considered by the investigator to be "not reasonably
`attributable” to study drug. Three (4%} patients prematurely dis-
`continued study drug due to an AB. including two events of dysp-
`nea and one event each of chest pain, cough, dysphonia, fluid
`retention, myocardial
`infarction, pulmonary hypertension, and
`psychotic disorder. One patient died during the course of the study
`due to disease progression {study day = 125), Although there
`were occasional transient changes in individual laboratory param-
`eters during the study, there were no clinically significant, treat-
`ment-related changes in laboratory parameters following the
`transition to inhaled treprostinil.
`
`Efficacy
`
`The median {IQR} change from baseline in 6MWD was increased
`at both week 6 [+9.5 In [—14 to 35]: n = 710:.D = 0.008} and week
`12 (+160 m [—8 to 39]; n = 68; P < 0.001}, and this treatment
`effect appeared to be maintained through month 12 for patients
`with long-term data {Table 4}. 6M W1) improvements were associ-
`ated with maintained or improved BDI values (Table 4). Com-
`pared with baseline, median (IQR) plasma concentrations of
`NT-proBNP were reduced at week 6 {—80 pglmL [—376 to 501:
`rt = 69; P < 0.001} and week 12 (—74 pgme [—339 to 371:
`n = 68: P: 0.001} and tended to be lower at month 12 for
`patients with long-term data (Table 4). WHO functional class was
`maintained or improved for the majority of patients at each
`postbaseline time point, with 96% of patients demonstrating
`
`maintained or improved functional status at both week 12 and
`month 12 (Table 4). Consistent with these changes in WHO func-
`tional class. clinical symptoms of PAH were also maintained or
`improved in the majority of patients.
`
`Quality of Life
`
`The transition from iloprost to inhaled treprostinil reduced the
`titne spent on daily treatment activities. with a 68% (P< 0.001}
`reduction in total time including reduced time spent gathering
`supplies (—48%; P = 0.004). preparing the treatment system
`(—30%: P = 0,007}, inhalation (—80%; P< 0,001}, and cleaning
`the treatment system (—77%: P< 0.001} {Figure I]. Across
`patients, the transition to inhaled treprostinil resulted in a mean
`total
`time saved of 1.4 h per day (39.1 min [week 12] vs.
`123.). min [haseline]}, Treatment administration questionnaire
`data for the overall study population were supported by detailed,
`7-day diary data (n = 16} that indicated a similar direction and
`magnitude of change in treatment administration times.
`Improvements were observed for all domains of CAMPHOR at
`each assessment time, with the exception ofthe activity domain at
`month 12 (Figure 2A}. CAMPHOR improvements tended to he
`maximal by week 6 and were largely maintained through 1 year
`for patients with long-term data, Analysis of the treatment satis-
`faction questionnaire (TSQMJ for week 12 revealed improve-
`ments in effectiveness. convenience, and global satisfaction, with
`no change in side effects [Figure 2B}. PIC data for week 12 versus
`baseline (n = 6?] indicated that the majority of patients felt that
`their symptoms of PAH were much or somewhat better (38%;
`P < 0.001) and that the time spent on treatment administration
`was much or somewhat
`less (91%; P< 0.001}. Overall. 94%
`(P < 0.001} of patients were much more or more satisfied with
`inhaled treprostinil therapy.
`
`Pharmacekinetics
`
`Pharmacokinetics data were obtained in a cohort of 17 patients.
`The PK subpopulation was primarily female (82 %} and Caucasian
`(94%}. with a mean age of 51 years (range: 18—74}. For patients
`receiving 9 breaths {54 ,1th of inhaled treprostinil qid {n = 11},
`the geometric mean Cum was 1015.3 pghnL with a high variabil-
`ity estimate [% coefficient of variation} of 118%. For AUCILHF
`the geometric mean was 993.6 h*pg!mL [151 ‘16} {Figure 3].
`
`Table 4 Change from baseline in 6MWD, NT—proBNP, and WHO functional class
`
`
`
`Week 12 Month 6Week 6 Month 12
`
`
`
`
`
`snwo, ma
`BDI"
`NT-proBNP, pgmeb
`WHO functional class
`
`Improved
`Maintained
`Worsened
`
`9.5 1—14 to 351'1
`—0.54 (0201‘
`—80 [—33% to 501e
`
`115.0 {—8 to 391e
`—0.os 10.221“
`44 (—339 to 371“
`
`2601—21 to 511”
`—0.51 10.210“
`
`27.0 1—7 to 541“
`—1.06 10.3131‘1
`—111 [—345 to 931'“
`
`4 [0]
`61 1871
`5 l7]
`
`0 [9]
`6018?!
`3 [41
`
`11 [19]
`45 [73}
`2 131
`
`it 129)
`16 1671
`1 14)
`
`Values presented as median linterquartile range}, mean {SE}, or n [it]. 6MWD, 6-min walk distance: 1301, berg dyspnea index; NT—proBNP, N—terminal
`proB—type natriuretic peptide. a6111111111) and B01 data for n = ?0 [week 6}, n = 68 {week 12}, n = 55 [month 6:, and n = 23 [month 12}. bNT-proBNP
`data for n = 69 {week 6}, n = 68 {week 12}, and n = 241month 12}. cF' < 0.05. “P < 0.01. 9P < 0001. ns, not significant.
`
`(<21 2012 Blackwell Publishing Ltd
`
`cardiovasCular Therapeutics 31 [2013} 38—44
`
`41
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS. IF’R201 7—01621
`Page 4 of 7
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`

`

`Rapid Transition to Inhaled Treprostinil
`
`R.C. Bourge et at.
`
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`Figure 1 Time spent on daily treatment activities. The mean {iSEJ time
`spent on each activity {minidayi
`is presented for baseline {iioprosc
`n = 70: and week 12 {inhaled treprostinil; n = at]. 3i3 < 0.001; bP < 0.01.
`
`Figure 3 Mean {4:50} plasma treprostinil concentration versus time
`following administration of 54 pg of inhaled treprostinil [n = 11]. Values
`are pgrmL.
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`Discussion
`
`While inhaled iloprost provides an alternative to parenteral pros-
`tacyclin therapy, the relatively short half-life of the compound
`requires a frequent dosing schedule potentially limiting compli-
`ance and perhaps efficacy. Given the potential administration
`advantages of inhaled treprostinil with respect to dosing fre-
`quency and duration.
`this study examined the effects of rapid
`transition from inhaled ifoprost
`to inhaled treprostinil
`in PAH
`patients. Overall. the results demonstrate that this transition was
`safe and well tolerated with no apparent loss of clinical status.
`Common AEs reported were similar to those observed previ-
`ously in the placebo-controlled trial for treprostinil and consis-
`tent with either the route of administration {cough and throat
`irritation]: or well-known effects of prostacyclin therapy {head-
`ache, nausea, flushing. and dizziness} [8.10.17], The AE profile
`observed in the first few days after the transition was similar
`to that observed for the overall study period with no evidence
`of acute deterioration immediately following the transition to
`inhaled treprostinil. Overall, most AEs were mild to moderate
`in intensity and did not
`result
`in discontinuation of study
`drug.
`Overall, the transition from inhaled ilopmst to inhaled treprosti-
`nil resulted in a time savings of approximately 1.4 h per day. The
`data suggest that these time savings may have contributed to
`enhanced overall treatment satisfaction {'I'SQM}, improved QoL
`(CAMPHOR), and a favorable PIC. While changes in 6MWD,
`NT-proBNP. and WHO functional class are well-established mea-
`sures of PAH treatment efficacy, questionnaire-based analysis of
`QoL and treatment satisfaction following a switch in therapy have
`not been extensively investigated [18—20]. Given the relative lack
`of studies employing these patient-reported metrics in a PAH
`population, the minimal important difference for each, and thus
`the clinical relevance of these findings. is unknown. Despite this
`limitation, the magnitude of change in CAMPHOR and TSQM
`following the transition to inhaled treprostinil compares favorably
`to that previously observed in both PAH and non-PAH popula-
`tions121—ZSI.
`Despite being clinically stable on study entry, 38% of patients
`reported iloprost usage below the labeled dose. Therefore,
`
`Figure 2 Cambridge pulmonary hypertension outcome review ICAM
`PHOR] and treatment satisfaction questionnaire for medicine [TSQM}. (A:
`Mean [iSEi CAMPHOR scores presented for baseline tiloprost; n = r2],
`week 6 (inhaled treprostinil; n = 6?], week 12 {inhaled treprostinil;
`n = an,
`and month 12
`{inhaled treprostinil;
`n = 24).
`aP < 0.001;
`bP < 0.05; "snot significant.
`{B} The mean ELSE] TSQM score for each
`category is presented for baseline [iloprost n = F2] and week 12 {inhaled
`treprostinil; n = eel. ‘P < 0.001.
`
`42 Cardiovascular Therapeutics 31 l2013] 33—44
`
`(0 2012 Blackwell Publishing Ltd
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IF’R201 7—01621
`Page 5 of 7
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`

`R.C. Bourge er of.
`
`Rapid Transition to Inhaled Treprostinil
`
`observed improvements in secondary endpoints such as ISMWD
`artd NT-proBNP likely reflect compliance with the labeled dosing
`frequency rather than specific differences between the molecules.
`Together, these data suggest that the treatment administration
`advantages of treprostinil may have allowed for more study
`patients to better reach their target prostacyclin exposure. Impor-
`tantly, a higher concentration of inhaled iloprost (20 Jttglme) was
`approved for use during the course of this trial, with a goal of
`reducing treatment time [12]. In fact. in a retrospective analysis of
`RESPIRE registry patients {n = II}, the 20 pgimL iloprost concen-
`tration reduced treatment time by 56% [26]. While it is unknown
`how many patients in this study were receiving this higher ilo-
`prost concentration at baseline, it
`is possible that had this treat-
`ment option been available at the start of the study. the patient-
`reported differences in treatment administration time seen in this
`study would have been reduced.
`This study provides the first analysis of the PK of inhaled tre-
`prostinil in PAH patients following titration to the recommended
`maintenance dose of 54 pg qid. While the sample size is limited,
`the observed values
`for
`t3“m (1015 pgme) and AUCm.“
`(994 h‘pgrmL} are consistent with those previously observed in
`healthy volunteers and PAH patients [13.2123]. Based on the
`Cum observed in this study,
`the peak plasma concentration
`achieved with 54 pg qid of inhaled treprostinil in PAH patients is
`roughly comparable to the steady-state plasma levels seen with
`continuous infusion (subcutaneous or intravenous) of 10 ngikgl‘
`min in healthy volunteers [16].
`
`Limitations
`
`The conclusions drawn from this study are limited by the fact
`that this was an open-label trial with no placebo or active com-
`parator; however, a blinded trial would have partially defeated
`the rationale of this observational study. which was to assess the
`safety and tolerability of transition from a l3 to 9 times daily ther-
`apy to a qid therapy. In addition to these requisite differences in
`therapy administration frequency. differences in nebulizer device
`also prevented the implementation of a blinded study design.
`This open-label design may have increased the chances of en roll-
`ing patients who were dissatisfied with their current
`iloprost
`therapy (i.e.. selection bias}.
`It
`is unknown whether patients
`receiving the higher iloprost concentration at baseline would
`have demonstrated similar changes in treatment administration
`time, QoL. and efficacy. Given that patients were transitioned to
`inhaled treprostinil at baseline, there was no collection of safety
`data while patients were receiving iloprost, thus preventing any
`direct comparison of the relative safety profiles across the two
`therapies. Patient-reported QoL and treatment administration
`time questionnaire data are inherently subjective, and the mini-
`mally important difference for these metrics has not been estab-
`lished for PAH patients. As such. the clinical relevance of the
`observed changes is unknown and the data should be interpreted
`with caution. Long-term data beyond week 12 are limited by a
`relatively small sample size and may be affected by a completer
`bias that would not account for patients who may have discon-
`tinued the trial for reasons such as treatment dissatisfaction.
`
`Given these concerns, interpretations of data beyond week 12
`should be limited.
`
`Conclusions
`
`In summary, these data indicate that rapid transition from inhaled
`iloprost to inhaled treprostinil in PAH patients is safe with no
`apparent
`loss of clinical efficacy. These data suggest
`that
`the
`administration advantages of inhaled treprostinil allowed for a
`redttction in total treatment preparation and administration times
`per day that may have resulted in increased dosing compliance,
`more appropriate prostacyclin exposures, and possibly enhanced
`therapeutic benefit.
`
`Acknowledgments
`
`All authors were involved with the conception, design, acquisi-
`Iion,ana1ysis. interpretation of data, andlor critical revision of the
`manuscript. The authors thank the investigators. coordinators.
`and other support staff from all of the centers that participated in
`this study, without whom this work would not have been possi-
`ble. The authors acknowledge Strategic Pharma Solutions and
`Brooke Harrison. PhD. for their technical expertise in the develop-
`ment of this manuscript.
`
`Conflict of Interest
`
`R.C.B. serves on the Scientific Advisory Board and Speaker's
`Bureau for United Therapeutics and has received research grant
`support from Actelion, Bayer, CardioMEMS. Gilead Sciences.
`Medtronic, Novartis, Pfizer, and United Therapeutics. V.F.T.
`serves on the Scientific Advisory Board and provides consulting
`and lecturing services for Actelion, Bayer, Gilead Sciences,
`GlaxoSmithKline, Pfizer, United Therapeutics, and Novartis and
`has received research grants from Actelion. Bayer. Gilead Sci-
`ences. GlaxoSmithKline, United Therapeutics. and Novartis. 2.5.
`has served on the Advisory Board and Speaker’s Bureau for
`United Therapeutics. Actelion and Gilead Sciences and is a
`consultant
`for United Therapeutics, Actelion and Gilead Sci-
`ences. R.L.B. has received grant support from United Therapeu-
`tics, Gilead Sciences. Lung Rx, Bayer, and Novartis and has
`received honorarium from Actelion, Gilead Sciences, United
`Therapeutics, and GlaxoSmithKIine. R.N.C.
`is a consultant for
`Actelion Pharmaceuticals and United Therapeutics and has
`received research funding from Actelion and Bayer. E.B.R. has
`received honoraria for consultation at Scientilic Advisory Board
`meetings from United Therapeutics and Actelion and has also
`received support
`for
`research from United Therapeutics and
`Actelion. 5.5. has received grant support from Gilead Sciences.
`United Therapeutics, Bayer, Actelion, Medtronics. and Novartis
`and has provided consulting and Speaker’s Bureau services for
`Gilead Sciences, United Therapeutics, Actelion, and Novartis.
`R.J.W. has served as a paid consultant to the sponsor and has
`received research funding to participate in ntulticenter clinical
`trials with this study's sponsor
`(United Therapeutics]. Lilly:r
`ICOS. Gilead
`Sciences.
`and Actelion. R.J.W.
`also
`has
`investigator-initiated research support from United Therapeutics
`and Gilead. R.J.W. does not have equity interest
`in any
`pharmaceutical company, and his paid consulting activities are
`fully disclosed and supervised by the University of Rochester
`Conflict of interest Committee. C.S.M.. S.K.G.. and A.C.N. are
`
`ts“) 2012 Blackwell Publishing Ltd
`
`CardiovasCular Therapeutics 31 [2013: 38—44 43
`
`UNITED THERAPEUTICS, EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IF’R201 7—01621
`Page 6 of 7
`
`

`

`Rapid Transition to Inhaled Treprostinil
`
`RC. Bourge et al.
`
`employees of the sponsor, United Therapeutics. L.J.R. has been
`a consultant and investigator for Actelion and United Therapeu-
`
`tics and serves on the Scientific Advisory Board for United Ther-
`apeutics.
`
`References
`
`2.
`
`1. McLaughlin W. Archer 5L. Badesch DB. el al.
`ACCFIAHA 2009 experl ('nnsensus dncumenl
`on pulmonary hypertension a report of the
`American College of Cardiology Ftlundalinn
`Task Force on Expert Consensus Documents
`and the American Heart Association developed
`in collaboration with the American College oi
`Chest Physicians; American Thoracic Society.
`Inc: and the Pulmonary Hypertension
`Association. J Am Coil Cardin?! 2009;53:573—
`16l9.
`lladesch I‘ll}. Melaughlin W, Delcmix M, et at.
`Proslanoid Iherapy ior pulmnnary arterial
`hypertension. J Am Coll Cardin! 2004;43:565—6] 5.
`3. Barst RJ. Rubin u. Long WA, et al. A
`comparison oi cnntinuous intravenous
`epnprostenol {prostaeyclin} with mnvenlional
`lherapy {or primary pulmnnary hypertension.
`The Primary Pulmonary Hyperlension Sludy
`Group. N Eng! J Med 1996334296402.
`4. Humhert M. Morrell NW. Archer SI... et al.
`Cellular and molecular pathnhiology oi
`pulmonary arterial hypertension. J Am Coll
`Cordial 2004M}: 1 35—245.
`5. HumIJerl M. Sitbnn 0. Sinionneau G. Treatment
`oi pulmon