ORIGINAL RESEARCH ARTICLE
`
`Cardiovascular
`Th crap cu rics
`
`Inhaled Iloprost to Inhaled Treprostinil in
`Rapid Transition from
`Patients with Pulmonary Arterial Hypertension
`
`Robert C. Bourge,1 Victor F. Tapson.2 Zeenat Safdar,3 Raymond L. Benza.4 Richard N. Channick.5 Erika
`B. Rosenzweig,° Shelley Shapiro.’ R. James White,8 Christopher Shane McSwain.9 Stephen Karl
`Gotzkowsky,9 Andrew C. Nelsen9 & Lewis J. Rubin10
`
`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
`T 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. M.D., The University of
`Alabama at Birmingham. 311 THT. 1900
`University Blvd. Birmingham, AL 35294. USA.
`Tel.: 1-205-934-3624;
`Fax: +205—9I’5-5150;
`E-mail: bbourge®uabedu
`
`Clinical Trial Registration: NCT00?41819.
`
`doi:10.1111l1?55-5922.12008
`
`SUMMARY
`
`Background: Inhaled 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 prostatyclin therapy. Aims: [n this open—label salety study. 73 PAH patients were
`enrolled with primarily World Health Organization Class II (56%} or III {42%) symptoms.
`Al 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 [our times daily (qid) at the immediate next scheduled
`iloprost dose. The primary objective was to assess the safety of rapid transition front iloprost
`to inhaled treprostinil: clinical status and quality of life were also assessed. Results: Most
`patients {34%) achieved the target treprostinil dose of 9 breaths qid and remained on study
`until transition to commercial therapy {89%). The tnost frequent adverse events {AEs} were
`cough (74%}. headache (44%}. and nausea [30%]. and five patients prematurely discon-
`tinued study drug due to AE [n = 3), disease progression (n = l), or death (n = 1}. At week
`[2, 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 6—min
`walk distance (+160; P < 0.001), N-terrninal pro-B-typc natriuretic peptide (—74 pgt’mL;
`P = 0.001). and the Cambridge Pulmonary Hypertension Outcome Review (all domains
`P‘C 0.00l]. Conclusions: Pulmonary arterial hypertension patients can be safely transi—
`tioned from inhaled iloprost to inhaled treprostinil while maintaining clinical status.
`
`Introduction
`
`Pulmonary arterial hypertension (PAH) 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, an endogenous prostaglai‘idin, to cause vasodila—
`tion of the pulmonary arterial bed and inhibition of platelet
`aggregation. and the therapeutic benefits of these therapies for
`the treatment of PAH are well established |2—?|. Due to relatively
`
`short in vim half—lives, prostacvclin 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 vasculaturie reducing intrapulmonary
`shunting (WQ mismatch]
`[2.8—11|.
`tn lact.
`the prostacyclin
`
`33 Cardiovascular Therapeutics 31 12013J 38—44
`
`(Is) 2012 Blackwell Publishing Ltd
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED TH ERAPEUTICS. IF’R201 7—01622
`Page 1 of 7
`
`

`

`RC. Bourge at at.
`
`Rapid Transition to Inhaied Treprostinil
`
`analogs iloprost thntavis'”. Actelion Pharmaceuticals Ltd. Alisch-
`wil. Switzerland) and treprostinil
`[Tyvasofi‘L 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 thtis indicated
`treatment regimens. are different. Due to its relatively short half—
`life [20 30 min). the recotnmended 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 maintenance dose of 9 breaths per
`treatment session [13]. Given the more favorable administration
`schedttle of inhaled treprostinil compared to inhaled iloprost. the
`objective of this study was to investigate the safety. efficacy. and
`qttality of life (QoL) alter rapid transition from inhaled iloprost
`therapy to inhaled treprostinil therapy in PAH patients.
`
`Methods
`
`Study Design
`
`This study was a multicenler, 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 idiopathicthereditary 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 6-min walk distance (6MWD) 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 binh control. Patients were considered ineligible if they
`were pregnant or nursing: had left-sided heart disease {World
`Health Organization [WHO] Group 2} or significant parenehymal
`lung disease (WHO Group 3): were receiving any investigational
`medication: or if they had changed or discontinued any PAH meti—
`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 (6 ,ttgtbreath} 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 first 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 OPTINEB” device {Nebu—Tec. Elsen—
`feld. Germany).
`
`Study Assessments
`Baseline, week (a. week 12. and month 12 asseSsntents included a
`physical examination, vital signs. 6MWD (EDI; immediately fol—
`lowing 6MWD}. WHO functional class. the Cambridge Pulmonary
`Hypertension Outcome Review (CAMPHORJ questionnaire [14].
`and clinical
`laboratory parameters including urine pregnancy
`screening, blood chemistries. hematology. coagulation times, and
`N-terminal probrain natrittretic peptide (NT-proBNP). All fiMWD
`and 1301 assessments were conducted at peak drug concentrations
`{IO—30 min postiloprost at baseline: 10—60 min post—treprostinil
`during treatment phase). Additionally. the drug administration
`activities questionnaire and the treatment satisfaction question-
`naire for medicine (TSQM) [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 7-day
`drug administration activities diary that recorded all time spent
`with the drttg andlor device for the 7 days before baseline {on
`iloprost) and for the 7 days before week 12 assessments (on tre—
`prostinil.) Adverse events (AEsi,
`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 It} min prior to dosing and 5.
`ll}. 15. 2t}. 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 it 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 Objectives
`
`The primary study objective was to evaluate the acute and long—
`term safety of inhaled treprostinil therapy following rapid transi—
`tion from inhaled iloprost therapy. Secondary objectives were to
`evaluate the effect of inhaled treprostinil on ISMWD. Borg dyspnea
`index [BDI]. 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 SAS0U software, version
`9.2 [SAS Institute lnc.. Cary. NC. USA]. The database and all
`
`© 2012 Blackwell Publishing Ltd
`
`Cardiovascular Therapeutics 31 {2013] 38—44 39
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS. IF’R201 7—01622
`Page 2 of 7
`
`

`

`Rapid Transition to Inhaied Treprostinil
`
`RC. Bourge er oi.
`
`statistical outputs were retained by the sponsor. United Therapeu-
`tics Corporation. All authors had access to the data to enable con-
`firmation of the findings. The authors assume full responsibility
`for the completeness and accuracy of the content of the mantl—
`script.
`
`Results
`
`Patient Demographics and Disposition
`
`Seventy—three patients were enrolled between December 2008
`and December 2009 with a mean age ol 49 years {range: 13—74),
`Patients were predominantly lemale (78%) with idiopathicir
`hereditary PAH (48%) and WHO functional class iii’lll {SoMZ‘l’o}
`symptoms (Table I], Median baseline 6MWD was 373 or (inter—
`quartile range [IQR]: 330 452]: median baseline plasma NT-proB-
`NP concentration was 62.6 pglmL (IQR: 222 [330). Most patients
`(59%) were receiving triple therapy (i.e., ERA, POE—5 inhibitor,
`and iloprost).
`Baseline iloprost usage is shown in Table 2, All patients were
`using the I—neb that]?!flu 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 frequency ol 6 9 inhalations per day {Table 2}.
`Seventy patients (96%) completed the week 12 assessments. Eight
`[11%) patients eventually discontinued the study drug dtie to AE
`(n = 3). withdrawn consent in = 3), disease progression (n = I),
`and death in = 1)
`(Table 3). The majority 01 patients (n = 65)
`continued to receive treatment until the study was terminated by
`
`Table 1 Baseline characteristics
`
`
`
` Characteristic N = 23
`
`Age, year
`Female
`PAH etiology
`Idiopathic or hereditary
`Collagen vascular disease
`Other3
`Background PAH therapy
`ERA only
`PDE—5 inhibitor only
`Both
`None
`WHO functional class
`I
`||
`III
`IV
`GMWD, m
`NT-proBNP, pgimL
`
`49 {18—24:
`5? [TB]
`
`35 {48]
`16 {22]
`22 {30]
`
`19 (26]
`8 {1 1]
`43 {59]
`3 {4!
`
`1 {ll
`41 {56]
`31 {42]
`0 {Di
`373 (330—452)
`626 (222—1330)
`
`Table 2 Inhaled prostacyclin dosing
`
`Characteristic
`
`Baseline iloprost usage
`Dose
`
`2.5 pg
`5.0 pg
`Frequency
`<6>< day
`Zinc day
`Inhaled treprostinil dosing
`Week 12 Dose
`<9 breaths
`2 9 breaths
`Were 9 breaths achieved?
`No
`Yes
`Time to reach 9 breaths {n = 61]
`
`N = 23
`
`5 t?!
`68 [93!
`
`28 [33]
`45 [62!
`
`19 £26!
`54 :24!
`
`12 :16]
`61 [84!
`18 {7—22}
`
`Values are n lit: and median [interquartile range] days.
`
`Table 3 Summary of discontinuations and adverse events IAEsI
`
`
`
` Characteristic N = 23
`
`Discontinued {overall}
`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 caugh
`
`8 [‘I It
`3 [4i
`3 {4!
`1 {1]
`1 ill
`21 {9?}
`54 {74]
`32 {44]
`22 {30]
`12 {16]
`11 {15]
`11 {15]
`11 {15]
`10 {14]
`9 {12]
`9 {12]
`8 i1 1]
`I" {10]
`1’ {10]
`
`Values are n :74}. Includes AEs occurring in at least 10% of patients.
`Mean exposure 32.4 weeks (range: (14—5613].
`
`the sponsor (mean exposure = 32.4 weeks; range. 0.4 56.0). at
`which point most patients transitioned to corn mercial therapy.
`
`Values are mean {range} for age and median (interquartile range: for
`6MWD and NT—proBNP. All other values are n {it}. PAH. pulmonary arte—
`rial hypertension; ERA. endothelin receptor antagonist: PDE-S, phospho—
`diesterase type 5; WHO. World Health Organization: 6MWD. min walk
`distance; NT-proBNP, N-terminal pro-B-tvpe natriuretic peptide. aother
`PAH Etiology includes HIV infection in = 3]. repaired congenital shunt
`{n = 4], and unrepaired congenital shunt [n = 15].
`
`Dosing and Acute Tolerability
`
`
`inhaled treprostinil achieved was
`The mean {:50} dose of
`
`
`
`
`8.8
`2.4. 8.9
`2.4. 9.3
`2.0, and 9.2 :: 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
`l8 days [Table 2). Analysis of AEs with onset during the first day
`of study drug dosing [cough [25%]; headache [11%]} and with
`
`4O Cardiovascular Therapeutics 31 [2013} 38-44
`
`© 2012 Blackwell Publishing Ltd
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS. IF’R201 7—01622
`Page 3 of 7
`
`

`

`R.C. Bourge et oi.
`
`Rapid Transition to Inhaled Treprostinil
`
`onset during tlte first 5 days of study drug dosing tcough [38%].
`headache [27%] and nausea [8°26]: 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 durittg the first 5 days of closing that the individual
`investigator deemed "reasonably attributable" to st tidy drug (psy—
`chotic disorder [day 3]].
`
`Safety
`
`The most frequent ABS with inhaled treprostinil included cough
`[74%). headache (44%). and nausea (30%) tTable 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. includingtwo events each ofpneu-
`monia and worsening pultnonary hypertension. Most SAEs {[0
`[67%]} were considered by the investigator to be ”not reasonably
`attributable" to study drug. Three {4%} patients prematurely dis—
`continued study drtlg due to an AE, including two events of dysp—
`nea and one event each of chest pain. cough. dysphonia. llttid
`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
`trattsitiott to inhaled treprostinil.
`
`Efficacy
`
`The median (10R: change from baseline in GMWD was increased
`at both week 6 {+9.5 n1 |—14to35]:n = 70: P = 0.008) and week
`12 (+161) 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]. oMWD improvements were associ-
`ated with maintained or improved 1301 values {Table 4}. Com—
`pared with baseline. median (IQRJ plasma concentrations of
`NT-proBNP were reduced at week 6 (—80 pgi’mL [—3?6 to 50];
`n = 69: P< 0.001] and week 12 (—74 ngmL [—339 to 37];
`n = 68: P= 0.001) and tended to be lower at month 12 for
`patiettts 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 [2 (Table 4]. Consistent with these changes in WHO func-
`tiottal class, ciinical 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
`time 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 l). Across
`patients. the transition to inhaled treprostinil restllted in a mean
`total
`time saved of 1.4 h per day (39.1 min [week 12] vs.
`I232 mll'l [baseline]). Treatment administration questionnaire
`data for the overall study population were supported by detailed,
`7—day diary data tn = 16) that indicated a similar direction and
`magnitude ofchange in treatment administration times.
`Improvements were observed for all domains of CAMPHOR at
`each assessment time. with the exception of the activity domain at
`month 12 (Figure 2A). CAMPHOR improvements tended to be
`maximal by week 6 and were largely maintained through 1 year
`for patients with long—term data. Analysis of the treatment satis—
`faction questionnaire (TSQM)
`for week 12 revealed improve—
`ments in effec1iveness. convenience. and global satisfaction. with
`no change in side effects (Figure 23]. PIC data for week 12 versus
`baseline {ii = 6?} indicated that the majority of patients felt that
`their symptoms of PAH were much or somewhat better (73%:
`P < 0.00I) and that the time spent on treatment administration
`was much or somewhat
`less (91%: P<0.001}. Overall, 94%
`[P‘s UJJUI) of patients were much more or more satisfied with
`inhaled treprostinil therapy.
`
`Pharmacokinetics
`
`Pharmacokinetics data were obtained in a cohort of 17 patients.
`The PK sttbpopulation was primarily female (82%) and Caucasian
`[94%). with a mean age of 51 years (range: 18—74). For patients
`receiving 9 breaths (54 pg) of inhaled treprostinil qid [n = 11).
`the geometric mean C...“ was [015.3 pglmi. with a high variabil-
`ityr estimate t% coefficient of variation] of 118%. For AUCIMV
`the geometric mean was 993.6 h*pglmL {151%} {Figure 3}.
`
`Table 4 Change from baseline in amwo. NT-proBNP, and WHO functional class
`Week 12 Month 6Week a Month 12
`
`
`
`
`
`
`
`sown, m“
`BDI“
`NT-proBNP, pglme
`WHO functional class
`Improved
`Maintained
`Worsened
`
`9.5 {—14 t0 351d
`—0.54 10.201c
`—80 [—376 to 501‘
`
`4 {6!
`61 [8?]
`5 t7:
`
`16.0 {—8 to 391‘
`—0.66 I022!"
`-74 (—339 to 37]“
`
`6 i9!
`60 t8?)
`3 {4:
`
`26.0 t—3 to 51]3
`—0.51 (0.22)“
`
`27.0 {—7 t0 541d
`—1.06 I036)"
`—l n l—345 to 931'”
`
`11 [191
`45 [78]
`2 (3}
`
`ii [29]
`16 {6?}
`1
`:4:
`
`Values presented as median tinterquartile range}. mean SE}, or n {21.6MWD, o-min walk distance; BDI, borg dyspnea index; NT-proBNP, N-terminal
`pro—B-type natn'uretit: peptide. aéMWD and EDI data for n = 20 [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 = 24 [month 12). ‘P < 0.05. ‘P < 0.01. IEP < 0.001. ns, not significant.
`
`© 2012 Blackwell Publishing Ltd
`
`Cardiovascular Therapeutics 31 [2013: 33PM 41
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IF’R201 7411622
`Page 4 of 7
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`

`

`Rapid Transition to Inhaled Treprostinil
`
`RC. Bourge et oi.
`
`1G0
`
`(pgi’mL)
`Treprostinilconcentration
`
`
`_200
`
`I}
`
`I
`1
`
`r
`2
`
`r
`3
`Time in)
`
`r
`4
`
`r
`5
`
`u
`6
`
`
`
`
`
`
`
`
`
` 60
`
` HumIIIIIISuntannahtumlath-Kymm
`
`§ §
`
`8
`
`‘0
`
`20
`
`0
`
`Gaunt
`luppliu
`
`Propane
`qlbm
`
`huh-lotion
`
`Clean
`
`Total
`
`Figure 1 Time spent on daily treatment activities. The mean {iSEJ time
`spent on each activity {minidayi
`is presented for baseline liioprost;
`n = }'0} and week 12 {Inhaled treprostinil; n = 61]. aP < 0.001; ”P < 0.01.
`
`Figure 3 Mean (i501 plasma treprostinil concentration versus time
`following administration of 54 pg of inhaled treprostinil [n = 11]. Values
`are pgimL.
`
`(A)30
`
`Discussion
`
`
`
`
`‘I'SQHIcon
`
`
`
`
`
`
`
`Mun
`
`Side-mu
`
`Cmnknce
`
`Glob-I
`adulation
`
`E] Baseline I Week 12
`
`Figure 2 Cambridge pulmonary hypertension outcome review [CAM
`PHOR] and treatment satisfaction questionnaire for medicine {TSQM}.
`[All
`Mean (15E: CAMPHDR scores presented for baseline (iloprost; rt = fl],
`week is {inhaled treprostinil; n=6?1_ week 12 :inhaled treprostinil;
`n = 6?},
`and month 12
`:inhaled treprostinil;
`n = 24}.
`aP < 0.001;
`”P < 0.05; "‘not significant.
`{Ell The mean tiSE] TSQM score for each
`category is presented for baseline [iloprost; n = F2} and week 12 [inhaled
`treprostinil; n = 66:. ‘1F" < 0.001.
`
`While inhaled iloprost provides an alternative to parenteral pros-
`taqrclin 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 iloprost
`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 adtttittislration {tough 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 iloprost to inhaled treprosti-
`ni] resulted in a time savings of approximately [.4 h per day. The
`data suggest that these time savings may have contributed to
`enhanced overall treatment satisfaction (TSQM). 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—
`tions[2]—25].
`Despite being clinically stable on study entry. 38% of patients
`reported iloprost usage below the labeled dose. Therefore.
`
`42 Cardiovascular Therapeutics 31 {2013] 38—44
`
`© 2012 Blackwell Publishing Ltd
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IF’R201 7—01622
`Page 5 of 7
`
`

`

`R.C. Bourge at oi.
`
`Rapid Transition to Inhaled Treprostinil
`
`observed improvements in secondary endpoints such as 6MWD
`and NT-proBNP likely reflect compliattce with tlte labeled dosing
`frequency ratlter tltan specific differences between tlte molecules.
`Together. these data suggest
`that the treatment administration
`advatttages of treprostinil may have allowed for more stttdy
`patients to better reach their target prostacyclin exposure. Impor—
`ta ntly, a higher concentration of inhaled iloprost {20 figh‘l‘lL) was
`approved for use during the course of this trial. with a goal of
`reducittg treattnent titne [12]. in fact. in a retrospective analysis of
`RESPIRE registry patients (n = l l), the 20 pgfm]. iloprost concen-
`tration reduced treatment titne by 56% [26]. While it is unknown
`how malty 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
`stttdy would ltave been reduced.
`This study provides the first analysis of the PK of inhaled tre—
`prostinil itt PAH patients following titration to the recommended
`maintenance dose of 54 ,ug qid. While the sample size is limited,
`the observed values
`for Cm,‘
`(1015 pgtmL) and AUCMT,
`[994 h‘pgtmL] are consistent with those previously observed in
`healthy volunteers and PAH patients [13,2128], Based on the
`CW, 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 It) ngikgtr
`mitt itt 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 coni—
`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 6 to 9 times daily ther-
`apy to a qid therapy. In addition to these requisite differences in
`therapy administration frequency. differences in nebttlizer device
`also prevented the implementation of a blinded study design,
`This open—label design may have increased the chances of enroll—
`ittg patients who were dissatisfied with their current
`iloprost
`therapy (i.e.. selection bias].
`[I
`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 00]. 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-
`tintted the trial
`for reasons such as treatment dissatisfaction,
`
`Given these concems.
`should be limited.
`
`interpretations of data beyond week [2
`
`Conclusions
`
`lit summary, these data indicate that rapid transition front 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
`reduction in total treatment preparation and administration times
`per day that may have resulted itt increased dosing compliance,
`more appropriate prostacyclitt exposures. and possibly enhanced
`therapeutic benefit,
`
`Acknowledgments
`All authors were involved with the conception, design, acquisi—
`tion. analysis. interpretation of data. auditor 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 wltotn this work would not have been possi-
`ble. The atttltors acknowledge Strategic Pharma Solutions and
`Brooke Harrison. PhD. for their technical expertise in the develop-
`mettt of this manuscript.
`
`Conflict of Interest
`
`R,C.B. serves on the Scientific Advisory Board and Speaker’s
`Bttreau 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 lectttrittg 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 Tlterapeutics. Actelion and Gilead Sci-
`ences. R.L.B. has received grant suppon from United Therapeu-
`tics, Gilead Sciences, Lung Rx, Bayer. and Novartis and has
`received honorarium from Actelion, Gilead Sciences, United
`Therapeutics, and GlaxoSmithKline, 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 hottoraria for consultation at Scientific 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 Tlterapetttics. Bayer. Actelion. Medtronics. and Novartis
`and has provided consulting attd Speaker’s Bureau services for
`Gilead Sciences, United Therapeutics. Actelion, and Novanis,
`R.J.W. has served as a paid consultant to the sponsor and has
`received research funding to participate in multicenter clinical
`trials with this study's sponsor
`(United Therapeutics}, Lillytr
`ICOS. Gilead
`Sciences.
`and Actelion. R.J.W.
`also
`has
`investigator-initiated research support from United Therapeutics
`and Gilead. R.J.W. does not
`ltave equity interest
`in any
`pharmacetttical 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
`
`© 2012 Blackwell Publishing Ltd
`
`Cardiovascular Therapeutics 31 [2013: 38-44 43
`
`UNITED THERAPEUTICS. EX. 2021
`WATSON LABORATORIES V. UNITED THERAPEUTICS, IF’R201 7—01622
`Page 6 of 7
`
`

`

`Rapid Transition to Inhaled Treprostinil
`
`RC. Bourge oi oi.
`
`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 [or United Titer-
`apeutics.
`
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