O R I G I N A L R ES E A R C H A R T IC L E
`
`Rapid Transition from Inhaled Iloprost to Inhaled Treprostinil in
`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,6 Shelley Shapiro,7 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
`7 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.: +205-934-3624;
`Fax: +205-975-5150;
`E-mail: bbourge@uab.edu
`
`Clinical Trial Registration: NCT00741819.
`
`doi: 10.1111/1755-5922.12008
`
`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 prostacyclin therapy. Aims: In this open-label safety study, 73 PAH patients were
`enrolled with primarily World Health Organization Class II (56%) or III (42%) symptoms.
`At baseline, most patients (93%) were receiving 5 lg of iloprost per dose but 38% of
`patients reported a dosing frequency below the labeled rate of 6–9 times daily. Patients initi-
`ated inhaled treprostinil at 3 breaths four times 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 most 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 = 1), or death (n = 1). 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 6-min
`
`walk distance (+16.0; P < 0.001), N-terminal pro-B-type natriuretic peptide (74 pg/mL;
`P = 0.001), and the Cambridge Pulmonary Hypertension Outcome Review (all domains
`P < 0.001). 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 prostaglandin, 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 [2–7]. Due to relatively
`
`short in vivo half-lives, prostacyclin 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 (V/Q mismatch) [2,8–11].
`In fact,
`the prostacyclin
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`R.C. Bourge et al.
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`Rapid Transition to Inhaled Treprostinil
`
`®
`analogs iloprost (Ventavis
`, Actelion Pharmaceuticals Ltd, Allsch-
`®
`, United Therapeutics
`wil, Switzerland) and treprostinil (Tyvaso
`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 vivo 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 lg
`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
`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 idiopathic/hereditary 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  5 years). Patients were required to
`have a baseline 6-min walk distance (6MWD) of  250 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-5 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 (6 lg/breath) 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
`®
`device (Nebu-Tec, Elsen-
`on proper utilization of the OPTINEB
`feld, Germany).
`
`Study Assessments
`
`Baseline, week 6, week 12, and month 12 assessments included a
`physical examination, vital signs, 6MWD (BDI; immediately fol-
`lowing 6MWD), 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 BDI assessments were conducted at peak drug concentrations
`(10–30 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 drug and/or 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 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 6MWD, 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.
`®
`software, version
`Statistical analysis was performed using SAS
`9.2 (SAS Institute Inc., Cary, NC, USA). The database and all
`
`ª 2012 Blackwell Publishing Ltd
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`Rapid Transition to Inhaled Treprostinil
`
`R.C. Bourge et al.
`
`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 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: 18–74).
`Patients were predominantly female (78%) with idiopathic/
`hereditary PAH (48%) and WHO functional class II/III (56/42%)
`symptoms (Table 1). Median baseline 6MWD was 378 m (inter-
`quartile range [IQR]: 330–452); median baseline plasma NT-proB-
`NP concentration was 626 pg/mL (IQR: 222–1330). Most patients
`(59%) were receiving triple therapy (i.e., ERA, PDE-5 inhibitor,
`and iloprost).
`Baseline iloprost usage is shown in Table 2. All patients were
`®
`System (Philips Respironics, Pittsburg, PA,
`using the I-neb AAD
`USA), and most patients (93%) were receiving 5.0 lg of iloprost
`per dose. Twenty-eight patients (38%) reported using iloprost less
`than the labeled frequency 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 (n = 1),
`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
`
`Age, year
`Female
`PAH etiology
`Idiopathic or hereditary
`Collagen vascular disease
`Othera
`Background PAH therapy
`ERA only
`PDE-5 inhibitor only
`Both
`None
`WHO functional class
`I
`II
`III
`IV
`6MWD, m
`NT-proBNP, pg/mL
`
`N = 73
`
`49 (18–74)
`57 (78)
`
`35 (48)
`16 (22)
`22 (30)
`
`19 (26)
`8 (11)
`43 (59)
`3 (4)
`
`1 (1)
`41 (56)
`31 (42)
`0 (0)
`378 (330–452)
`626 (222–1330)
`
`Table 2 Inhaled prostacyclin dosing
`
`Characteristic
`
`Baseline iloprost usage
`Dose
`2.5 µg
`5.0 µg
`Frequency
`<69 day
` 69 day
`
`Inhaled treprostinil dosing
`Week 12 Dose
`<9 breaths
` 9 breaths
`
`Were 9 breaths achieved?
`No
`Yes
`Time to reach 9 breaths (n = 61)
`
`Values are n (%) and median (interquartile range) days.
`
`N = 73
`
`5 (7)
`68 (93)
`
`28 (38)
`45 (62)
`
`19 (26)
`54 (74)
`
`12 (16)
`61 (84)
`18 (7–22)
`
`Table 3 Summary of discontinuations and adverse events (AEs)
`
`Characteristic
`
`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 cough
`
`N = 73
`
`8 (11)
`3 (4)
`3 (4)
`1 (1)
`1 (1)
`71 (97)
`54 (74)
`32 (44)
`22 (30)
`12 (16)
`11 (15)
`11 (15)
`11 (15)
`10 (14)
`9 (12)
`9 (12)
`8 (11)
`7 (10)
`7 (10)
`
`Values are n (%). Includes AEs occurring in at least 10% of patients.
`Mean exposure 32.4 weeks (range: 0.4–56.0).
`
`the sponsor (mean exposure = 32.4 weeks; range, 0.4–56.0), at
`which point most patients transitioned to commercial therapy.
`
`Values are mean (range) for age and median (interquartile range) for
`6MWD and NT-proBNP. All other values are n (%). PAH, pulmonary arte-
`rial hypertension; ERA, endothelin receptor antagonist; PDE-5, phospho-
`diesterase type 5; WHO, World Health Organization; 6MWD, 6-min walk
`distance; NT-proBNP, N-terminal pro-B-type natriuretic peptide. aOther
`PAH Etiology includes HIV infection (n = 3), repaired congenital shunt
`(n = 4), and unrepaired congenital shunt (n = 15).
`
`Dosing and Acute Tolerability
`
`The mean (±SD) dose of
`inhaled treprostinil achieved was
`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
`18 days (Table 2). Analysis of AEs with onset during the first day
`of study drug dosing (cough [25%]; headache [11%]) and with
`
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`R.C. Bourge et al.
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`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 pneu-
`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 AE, 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 m [14 to 35]; n = 70; P = 0.008) and week
`12 (+16.0 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). 6MWD 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 pg/mL [376 to 50];
`n = 69; P < 0.001) and week 12 (74 pg/mL [339 to 37];
`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
`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 1). 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.
`123.2 min [baseline]). 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 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 effectiveness, convenience, and global satisfaction, with
`no change in side effects (Figure 2B). PIC data for week 12 versus
`baseline (n = 67) indicated that the majority of patients felt that
`their symptoms of PAH were much or somewhat better (73%;
`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.
`
`Pharmacokinetics
`
`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 lg) of inhaled treprostinil qid (n = 11),
`the geometric mean Cmax was 1015.3 pg/mL with a high variabil-
`ity estimate (% coefficient of variation) of 118%. For AUC(0-τ),
`the geometric mean was 993.6 h*pg/mL (151%) (Figure 3).
`
`Table 4 Change from baseline in 6MWD, NT-proBNP, and WHO functional class
`
`6MWD, ma
`BDIa
`NT-proBNP, pg/mLb
`WHO functional class
`Improved
`Maintained
`Worsened
`
`Week 6
`
`9.5 (14 to 35)d
`0.54 (0.20)c
`80 (376 to 50)e
`
`4 (6)
`61 (87)
`5 (7)
`
`Week 12
`
`16.0 (8 to 39)e
`0.66 (0.22)d
`74 (339 to 37)d
`
`6 (9)
`60 (87)
`3 (4)
`
`Month 6
`
`26.0 (3 to 51)e
`0.51 (0.27)ns
`
`11 (19)
`45 (78)
`2 (3)
`
`Month 12
`
`27.0 (7 to 54)d
`1.06 (0.36)d
`111 (345 to 93)ns
`
`7 (29)
`16 (67)
`1 (4)
`
`Values presented as median (interquartile range), mean (SE), or n (%). 6MWD, 6-min walk distance; BDI, borg dyspnea index; NT-proBNP, N-terminal
`pro-B-type natriuretic peptide. a6MWD and BDI data for n = 70 (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). cP < 0.05. dP < 0.01. eP < 0.001. ns, not significant.
`
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`Rapid Transition to Inhaled Treprostinil
`
`R.C. Bourge et al.
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`Figure 1 Time spent on daily treatment activities. The mean (±SE) time
`spent on each activity (min/day)
`is presented for baseline (iloprost;
`n = 70) and week 12 (inhaled treprostinil; n = 61). aP < 0.001; bP < 0.01.
`
`Figure 3 Mean (±SD) plasma treprostinil concentration versus time
`following administration of 54 lg of inhaled treprostinil (n = 11). Values
`are pg/mL.
`
`(A)
`
`(B)
`
`Figure 2 Cambridge pulmonary hypertension outcome review (CAM
`PHOR) and treatment satisfaction questionnaire for medicine (TSQM). (A)
`Mean (±SE) CAMPHOR scores presented for baseline (iloprost; n = 72),
`week 6 (inhaled treprostinil; n = 67), week 12 (inhaled treprostinil;
`aP < 0.001;
`n = 67), and month 12 (inhaled treprostinil; n = 24).
`bP < 0.05; nsnot significant. (B) The mean (±SE) TSQM score for each
`category is presented for baseline (iloprost; n = 72) and week 12 (inhaled
`treprostinil; n = 66). aP < 0.001.
`
`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 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 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 iloprost 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 (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 [21–25].
`Despite being clinically stable on study entry, 38% of patients
`reported iloprost usage below the labeled dose. Therefore,
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`R.C. Bourge et al.
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`Rapid Transition to Inhaled Treprostinil
`
`observed improvements in secondary endpoints such as 6MWD
`and 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 lg/mL) 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 = 11), the 20 lg/mL 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 lg qid. While the sample size is limited,
`(1015 pg/mL) and AUC(0-τ)
`the observed values
`for Cmax
`(994 h*pg/mL) are consistent with those previously observed in
`healthy volunteers and PAH patients [13,27,28]. Based on the
`Cmax observed in this study, the peak plasma concentration
`achieved with 54 µg 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 ng/kg/
`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 6 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 enroll-
`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
`reduction 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-
`tion, analysis, interpretation of data, and/or 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. Z.S.
`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 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 honoraria for consultation at Scientific Advisory Board
`meetings from United Therapeutics and Actelion and has also
`received support
`for research from United Therapeutics and
`Actelion. S.S. 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 multicenter clinical
`trials with this study’s sponsor (United Therapeutics), Lilly/
`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
`
`ª 2012 Blackwell Publishing Ltd
`
`Cardiovascular Therapeutics 31 (2013) 38–44 43
`
`IPR2021-00406
`United Therapeutics EX2035
`Page 6 of 7
`
`

`

`Rapid Transition to Inhaled Treprostinil
`
`R.C. 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.
`
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