Efficacy and Safety of Inhaled Iloprost in Japanese Patients With Pulmonary Arterial Hypertension　– Insights From the IBUKI and AIR Studies –

Abstract

Background: Inhaled iloprost is approved for pulmonary arterial hypertension (PAH) in many countries. IBUKI was a phase III, non-randomized, open-label study of the efficacy and safety of inhaled iloprost in Japanese patients with PAH.

Methods and Results: Adults with PAH who were treatment-naïve or administered endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 inhibitors (PDE5-Is) and in NYHA/WHO functional class (FC) III/IV had inhaled iloprost (2.5 µg, increased to 5.0 µg if tolerated) 6–9 times daily for 12 weeks. Eligible patients entered a 40-week extension phase. Endpoints included change from baseline to week 12 in pulmonary vascular resistance (PVR; primary endpoint), other efficacy parameters, and safety. Data were compared with new subgroup analyses of treatment-naïve Western PAH patients from the global phase III AIR study. 27 patients received iloprost: 89% were treated with an ERA and/or PDE5-I; 70% with both. At week 12, PVR improved from baseline by –124 dyn·sec·cm⁻⁵ (95% CI, –177 to –72) and 6-min walking distance increased by 36.0 m (95% CI, 14.9 to 57.1). NYHA/WHO FC improved in 62%; none worsened. Common drug-related adverse events were headache (37%) and cough (15%); 1 patient experienced hypotension; none reported syncope or hemoptysis. There were no deaths and no unexpected long-term safety findings. AIR PAH subgroup analyses showed similar results.

Conclusions: Inhaled iloprost appeared effective and safe in Japanese PAH patients, including ERA- and PDE5-I-treated patients, consistent with findings of the AIR PAH subpopulation and previous iloprost studies.

Pulmonary arterial hypertension (PAH) is a serious, chronic disease characterized by increased pulmonary vascular resistance (PVR) caused by progressive vascular remodeling that leads to right heart failure and death.^1–6 Despite advances in the treatment of PAH, mortality rates remain high at 14%, 31%, and 39% at 1, 3, and 5 years, respectively.⁷

Recommended pharmacological treatment options for PAH comprise 4 distinct drug classes with different mechanisms of action: prostacyclin analogs, endothelin receptor antagonists (ERAs), phosphodiesterase type 5 inhibitors (PDE5-Is), and soluble guanylate cyclase stimulators.^2,8,9

In PAH, the prostacyclin analogs exert their therapeutic effects by promoting direct arterial vasodilation and inhibiting platelet aggregation, by increasing intracellular levels of cyclic adenosine monophosphate. As a synthetic prostacyclin, intravenous epoprostenol has been approved in many countries, including Japan, having shown high efficacy in the treatment of PAH. It is, however, associated with frequent systemic adverse drug reactions and requires an indwelling central venous catheter, increasing the risk of serious complications such as sepsis and thrombosis. In Japan, beraprost is uniquely approved as an oral prostacyclin analog and widely prescribed to patients with relatively mild PAH.

Inhaled administration has a number of inherent advantages over intravenous infusion of prostacyclin analog therapy for PAH, notably the potential for selective delivery of the drug to the pulmonary circulation, and the relative ease of use compared with intravenous treatment. Iloprost is a stable prostacyclin analog that has long been approved for the treatment of PAH in the United States¹⁰ and Europe,¹¹ which can be administered via a number of routes including inhalation.^2,12 Treatment with inhaled iloprost has previously shown consistent efficacy and safety in patients with PAH in World Health Organization (WHO) functional class (FC) III/IV when used as monotherapy in the global phase III AIR (Aerosolized Iloprost Randomized) study¹³ and as add-on therapy to ERAs in the phase II STEP (Safety and pilot efficacy Trial in combination with bosentan for Evaluation in Pulmonary arterial hypertension study).¹⁴

The majority of studies of inhaled iloprost in PAH have been conducted in predominantly North American and Western European Caucasian populations. The phase III IBUKI (Iloprost Bridging study in Japanese patients with pUlmonary arterial hypertension for evaluation of PVR and pharmacoKInetics) study was therefore conducted to further assess the efficacy, safety, and pharmacokinetics of inhaled iloprost in Japanese patients with PAH, the majority of whom were being treated with both an ERA and a PDE5-I. Here we present data from the initial 12-week study and the 40-week extension phase of IBUKI, alongside a subgroup analysis of treatment-naïve Western PAH patients from the AIR study.

Methods

IBUKI Study

Study Design and Patients The IBUKI study (NCT01469169) was a non-randomized, open-label, single-arm study of patients with PAH conducted at 18 centers in Japan. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines, and local ethics committee approval was obtained at each study site. All patients gave written informed consent.

The study consisted of an initial 12-week treatment period followed by a 40-week extension period. During the 12-week treatment period, patients received iloprost inhalation 2.5 or 5.0 µg, 6 times daily: upon waking, at bedtime, and a further 4 times at ≥2-h intervals. Extra inhalations at ≥2-h intervals to a maximum of 9 times daily were allowed if required. Treatment was initiated at a dose of 2.5 μg, and increased to 5.0 μg at the second dose 2 h later, according to individual need and tolerability. If 5.0 μg was not tolerated, the next dose could be reduced to 2.5 μg, and if intolerance persisted, treatment was discontinued. Patients maintained this “optimized” dose throughout the 12-week treatment period. Patients who completed this period were eligible for entry into the 40-week extension period, where they were maintained on the same dose of iloprost, if possible. Inhaled iloprost was delivered via the I-neb Adaptive Aerosol Delivery (AAD) system (Philips Respironics (UK) Ltd). The particle size and fine particle fraction of aerosol delivered by the I-neb AAD system is suitable for delivery to the lung by nebulization. Appropriate administration of a single inhalation dose of iloprost 2.5 or 5.0 μg was achieved by using a drug solution chamber of each dose. In addition, the I-neb AAD technology analyzes the patient’s breathing pattern and adjusts the delivered dose for each breath, providing drug delivery during inspiration and avoiding aerosol waste during expiration.^15,16

Adults aged 18–75 years with symptomatic idiopathic PAH (IPAH), heritable PAH (HPAH), drug- or toxin-induced PAH, PAH associated with connective tissue diseases, or PAH associated with congenital heart disease, surgically corrected or repaired for more than 1 year were eligible for inclusion. Patients were required to be in New York Heart Association (NYHA)/WHO FC III or IV, and have a cardiac catheterization result at screening consistent with mean pulmonary artery pressure (mPAP) at rest >25 mmHg, pulmonary arterial wedge pressure (PAWP) or left ventricular end-diastolic pressure ≤15 mmHg, and PVR ≥240 dyn·sec·cm⁻⁵, or PVR ≥400 dyn·sec·cm⁻⁵ if treated with both an ERA and a PDE5-I. Patients with a baseline 6-min walking distance (6MWD) <100 or >500 m, and those with any clinically relevant medical condition that would compromise the evaluation of efficacy and/or safety of the study drug were excluded. Treatment with an ERA and/or PDE5-I was permitted if initiated ≥12 weeks prior to enrollment and at a stable dose for ≥8 weeks. Other prostacyclins or prostacyclin analogs, prostaglandins, prednisone >20 mg/day or equivalent, oral immunosuppressive drugs (unstable dose), intravenous immunosuppressive drugs, or any other non-specific chronic or investigational treatments for PAH were not permitted.

Outcome Measures Hemodynamic measurements by catheterization were performed at the week 12 visit pre-inhalation, and 5, 15, and 30 min after inhalation. The primary endpoint was change in PVR from baseline to week 12, post-inhalation. Secondary efficacy endpoints included changes in hemodynamic parameters, 6MWD, NYHA/WHO FC, N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) levels, Borg category ratio (CR) 10 score, and quality of life measured by the EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) and Living with Pulmonary Hypertension (LPH) questionnaire. Time to clinical worsening, mortality, and need for heart/lung transplantation were also secondary endpoints. Safety was assessed through the recording of adverse events (AEs) coded by the Medical Dictionary for Regulatory Activities (MedDRA) version 16.1 for the 12-week analysis and MedDRA version 17.1 for the 52-week analysis.

Treatment compliance was assessed throughout the study, and defined as administration of between 6 and 9 inhalations per day for ≥75% of days between each visit and for the whole 12-week treatment period.

For pharmacokinetic analysis, blood samples were collected at the week 12 visit prior to and 0, 5, 15, 30, 60, and 90 min after inhalation. Plasma iloprost concentrations were measured using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters, calculated from the iloprost plasma concentration-time profile, included area under the curve, maximum concentration (C_max), time to C_max (T_max), and terminal half-life.

Statistical Analysis Because of the exploratory nature of the study, no formal statistical test was planned, and all variables were analyzed descriptively. Efficacy and safety analyses included all patients who received at least 1 dose of study medication; efficacy analyses also required at least 1 post-baseline PVR measurement, defined as the full analysis population. Results are presented as mean±SD unless otherwise stated. The 2-sided 95% confidence interval (CI) of the mean change from baseline to week 12 was estimated using 1-sample t-statistics. The minimum PVR measured at 5, 15, or 30 min after the end of inhalation was taken as the designated “best” post-baseline PVR measurement.

AIR Study-PAH Subgroup Analysis

Detailed methods of the AIR study have been published previously.¹³ In brief, patients with primary pulmonary hypertension (PH) and selected forms of non-primary PH based on the classification system in place at the time of the study (ie, appetite suppressant-associated PH, scleroderma-associated PH, or chronic thromboembolic PH (CTEPH)), and in NYHA FC III or IV were enrolled in the AIR study. Patients were randomly assigned to receive either placebo or inhaled iloprost 2.5 or 5.0 µg 6 or 9 times daily, with an overnight break for up to 12 weeks. The AIR study included a composite primary endpoint consisting of ≥10% increase in 6MWD and improvement in the NYHA FC in the absence of clinical deterioration or death during the 12 weeks.

A post hoc PAH subgroup analysis of the AIR intention-to-treat population was conducted to exclude patients with CTEPH, which is now recognized as a separate entity from PAH under the revised clinical classification system. As the PAH subgroup analyses were exploratory, statistical tests were not conducted.

AEs were coded initially in AIR by the Hoechst adverse reaction terminology system version 2.3; however, for consistency with the IBUKI study, AEs were re-coded by MedDRA version 16.1 for the 12-week PAH subgroup analysis.

Results

IBUKI Study

Patients Of the 34 patients screened, 27 received at least 1 dose of inhaled iloprost, and 23 completed the initial 12-week study period; of these, 21 had post-baseline PVR at week 12. Twenty-two patients entered the long-term extension phase, of whom 17 continued to week 52. Baseline characteristics are shown in Table 1. Patients were all in NYHA/WHO FC III and the majority were female (96%), had a diagnosis of IPAH/HPAH (74%), and had been treated with both an ERA and a PDE5-I (70%). Only 11% of patients were treatment-naïve.

Table 1. Baseline Characteristics of Patients Included in the IBUKI Study (Safety Analysis Population) and in the AIR PAH Subgroup (ITT Population)

Characteristic	IBUKI study	AIR PAH subgroup
	Iloprost (n=27)	Iloprost (n=68)	Placebo (n=78)
Age, years	46.4±15.5	48.7±14.1	51.8±12.0
Female, n (%)	26 (96)	45 (66)	54 (69)
Dana point classification of PAH, n (%)
IPAH/HPAH	20 (74)	51 (75)	51 (65)
CTD	5 (19)	13 (19)	22 (28)
Other PAH	2 (7)	4 (6)	5 (6)
NYHA/WHO FC, n (%)
III	27 (100)	40 (59)	46 (59)
IV	0	28 (41)	32 (41)
6MWD, m	396±72.2	336±98.0	315±93.7
PVR, dyn·sec·cm−5	614±355	1,008±393*	1,048±523†
Pretreatment status, n (%)
Treatment-naïve	3 (11)	68 (100)	78 (100)
Treated with ERA	3 (11)	0	0
Treated with PDE5-I	2 (7)	0	0
Treated with ERA and PDE5-I	19 (70)	0	0

Data are mean±SD unless otherwise stated. *n=64, ^†n=74. 6MWD, indicates 6-min walking distance; CTD, connective tissue disease; ERA, endothelin receptor antagonist; HPAH, heritable PAH; IPAH, idiopathic PAH; ITT, intention-to-treat; NYHA/WHO FC, New York Heart Association/World Health Organization functional class; PAH, pulmonary arterial hypertension; PDE5-I, phosphodiesterase type 5 inhibitor; PVR, pulmonary vascular resistance; SD, standard deviation.

During the 12-week treatment period, compliance was 96.3% overall. During this period, the frequency of inhalations averaged 6.27±0.57 times per day, and the average daily dose and the duration of iloprost treatment were 28.3±7.07 µg and 78.4±22.2 days, respectively.

Pharmacokinetics of Iloprost Iloprost was rapidly absorbed, with a T_max of 0.09–0.15 h after the start of inhalation, and rapidly eliminated from plasma, with a half-life of 0.14–0.15 h at a dose of 2.5 or 5.0 μg. The area under the curve of iloprost at doses of 2.5 and 5.0 μg was 25.0 and 45.9 ng·h/L, respectively, with geometric mean C_max values of 56.7 and 101 ng/L, respectively.

Efficacy in Initial 12-Week Study Changes from baseline to week 12 in hemodynamic parameters, including the primary endpoint of PVR, are summarized in Table 2. At 12 weeks, the best change from baseline in PVR was –124±115 dyn·sec·cm⁻⁵ (95% CI, –177 to –71.8; Figure 1A), and in PVR index was –195±179 dyn·sec·cm⁻⁵·m² (95% CI, –276 to –113). A decrease in mPAP and a small increase in cardiac output (CO) were observed, with a best change from baseline to week 12 of –6.75±5.50 mmHg and +0.62±1.31 L/min, respectively. No clinically notable changes were observed in PAWP, mean right atrial pressure, or mixed venous oxygen saturation. Mean arterial pressure and systemic vascular resistance were below baseline at all post-inhalation time points at week 12.

Table 2. Hemodynamic Parameters at Baseline and at Week 12 Before and After Inhalation of Iloprost in the IBUKI Study (Full Analysis Population)

	Week −2∼0	Mean change from baseline at week 12 (95% CI)
	Baselinea	Pre-inhalationb	Post-inhalation
			5 min	15 min	30 min	Bestc
PVR, dyn·sec·cm−5	602±269	−7.04 (−64.7 to 50.6)	−109 (−159 to −59.1)	−73.1 (−127 to −19.0)	−60.3 (−108 to −12.5)	−124 (−177 to −71.8)
PVRI, dyn·sec·cm−5·m2	927±442	−12.4 (−100 to 75.4)	−173 (−251 to −94.0)	−117 (−196 to −37.1)	−93.5 (−165 to −22.0)	−195 (−276 to −113)
mPAP, mmHg	43.6±12.0	0.14 (−3.00 to 3.29)	−4.49 (−6.69 to −2.30)	−4.63 (−6.77 to −2.50)	−5.25 (−7.91 to −2.60)	−6.75 (−9.25 to −4.24)
CO, L/min	5.18±1.65	0.15 (−0.17 to 0.47)	0.50 (0.00 to 1.01)	0.05 (−0.39 to 0.48)	0.01 (−0.60 to 0.63)	0.62 (0.02 to 1.22)
mRAP, mmHg	4.86±3.38	−0.24 (−1.66 to 1.18)	−0.57 (−2.11 to 0.97)	−0.33 (−1.87 to 1.20)	−0.67 (−2.20 to 0.87)	–
PAWP, mmHg	7.8±3.3	0.1 (−1.6 to 1.8)	0.7 (−1.1 to 2.5)	0.3 (−1.3 to 1.9)	−0.3 (−2.0 to 1.4)	–
MAP, mmHg	82.9±11.8	−3.16 (−7.30 to 0.98)	−5.41 (−10.1 to −0.74)	−5.08 (−8.12 to −2.04)	−5.57 (−9.15 to −1.99)	–
SvO2, %	69.6±6.39	−1.73 (−4.71 to 1.26)	−1.21 (−4.57 to 2.15)	−2.18 (−5.74 to 1.39)	−2.71 (−6.16 to 0.73)	–
SVR, dyn·sec·cm−5	1,313±453	−57.3 (−182 to 67.5)	−149 (−297 to −0.79)	−64.7 (−202 to 72.8)	−43.3 (−185 to 98.0)	–

All baseline values are mean±SD. ^aBaseline value measured at the start of the IBUKI study. ^bPre-inhalation values correspond to trough levels, whereas post-inhalation values correspond to peak drug effect. ^cLowest value among 5-, 15-, and 30-min time popints post-dose (best) for mPAP and highest value for CO. CI, confidence interval; CO, cardiac output; MAP, mean arterial pressure; mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; PAWP, pulmonary arterial wedge pressure; PVRI, PVR index; SvO₂, mixed venous oxygen saturation; SVR, systemic vascular resistance. Other abbreviation as in Table 1.

Figure 1.

Changes in pulmonary vascular resistance from baseline to week 12 in (A) the IBUKI 12-week study* and (B) the AIR PAH subgroup^†. *Best change for full analysis population and subgroup treated with both ERA and PDE5-I. ^†ITT population with PAH. Best refers to lowest value among 5-, 15-, and 30-min time points post-inhalation. In the AIR study, a single inhalation of iloprost was given to all the subjects in the placebo group at week 12 for catheter testing in order to evaluate the acute drug effect of the inhalation; therefore, in AIR PAH, the pre-inhalation PVR values were used for the placebo group. ERA, endothelin receptor antagonist; ITT, intent-to-treat; PAH, pulmonary arterial hypertension; PDE5-I, phosphodiesterase type 5 inhibitor; PVR, pulmonary vascular resistance; SD, standard deviation.

Improvements from baseline to week 12 were also noted for the secondary efficacy variables 6MWD, which increased by 36.0±46.4 m (95% CI, 14.9 to 57.1), and NYHA/WHO FC, for which 62% of patients improved (Figures 2A,B). At week 12, small changes from baseline were observed in NT-proBNP levels (–11.2±115 pg/ml), while Borg CR 10 score remained relatively unchanged.

Figure 2.

(A) Change from baseline to week 12 post-inhalation in 6MWD and (B) percentage of patients with improved/stabilized/worsened NYHA/WHO FC in the IBUKI 12-week study and the AIR PAH subgroup*. *ITT population with PAH. 6MWD, 6-min walking distance; ERA, endothelin receptor antagonist; ITT, intent-to-treat; NYHA/WHO FC, New York Heart Association/World Health Organization functional class; PAH, pulmonary arterial hypertension; PDE5-I, phosphodiesterase type 5 inhibitor.

In the quality of life analyses, there was no apparent change from baseline to week 12 in either EQ-5D descriptive health profile or LPH total score. Values at baseline and week 12 were 0.83±0.12 and 0.86±0.14, respectively, for EQ-5D and 17.6±10.9 and 15.4±13.1, respectively, for LPH total score. However, the EQ-5D visual analog scale appeared to deteriorate over this period, decreasing from 80.1±11.3 at baseline to 69.6±23.2 at week 12.

Efficacy in Long-Term Extension The improvements in 6MWD observed at week 12 were maintained during the long-term extension period; the mean change from baseline at week 52 was +36.7±35.0 m.

At week 52, NYHA/WHO FC had improved in 7 patients (41.2%) and stabilized in 10 subjects (58.8%); no patients experienced worsening of NYHA/WHO FC.

None of the patients in either the initial 12-week treatment period or the long-term extension experienced clinical worsening, needed heart/lung transplantation, or died.

PAH Subgroup Analysis From the AIR 12-Week Study

Baseline characteristics of the 146 patients included in the AIR PAH subgroup analysis are shown in Table 1. The majority of patients were female and had IPAH/HPAH. All were treatment-naïve. Overall, 59% of the PAH subgroup population were in NYHA FC III, the remainder being in NYHA FC IV.

At week 12, 19% of iloprost recipients and 4% of placebo recipients in the AIR PAH subgroup met the primary endpoint of ≥10% increase in 6MWD and improvement in NYHA FC in the absence of clinical deterioration or death.

Over the 12-week study period, PVR decreased by –244±292 dyn·sec·cm⁻⁵ post-inhalation in the iloprost group, but increased by +113±354 dyn·sec·cm⁻⁵ pre-inhalation in the placebo group (note: a single inhalation of iloprost was given to all the subjects in the placebo group at week 12 for catheter testing, in order to evaluate the acute drug effect of the inhalation; therefore, in AIR PAH, the pre-inhalation PVR values were used for the placebo group) (Figure 1B, Table 3). 6MWD improved by 31.3±75.9 m in the iloprost group, but decreased by 8.78±79.4 m in the placebo group. In the iloprost group, 26% of patients had an improvement in NYHA FC, compared with 9% of patients in the placebo group (Figure 2, Table 3).

Table 3. Main 12-Week Efficacy Results by Baseline Background Treatment From the IBUKI, AIR PAH Subgroup, and STEP¹¹ Studies

	IBUKI study	AIR PAH subgroup		STEP study
	Subgroup of patients on background therapy with ERA+PDE5-I	Treatment-naïve patients		Patients on background therapy with ERA
	Iloprost (n=15)	Iloprost (n=50)	Placebo (n=61)	Iloprost (n=28)	Placebo (n=26)
PVR, dyn·sec·cm−5 (vs. baseline)
Mean±SD change*	−127±108	−244±292	113±354†	−164±223	81±267
% change	−21	−23	+9†	−20	+7
6MWD, m (vs. baseline)	n=15	n=64	n=65	n=31	n=32
Mean±SD change	34.2±22.2	31.3±75.9	−8.8±79.4	30.4±60.0	4.1±61.4
NYHA/WHO FC, n (%) change‡	n=15	n=65	n=67	n=32	n=33
Improved	9 (60)	17 (26)	6 (9)	11 (34)	2 (6)
Stabilized	6 (40)	44 (68)	53 (79)	20 (63)	30 (91)
Worsened	0	4 (6)	8 (12)	0	1 (3)
Unknown	0	0	0	1 (3)	0

*Changes in PVR were the optimal value (best) post-inhalation in IBUKI, the value shortly after inhalation in AIR PAH, and the value at 15 min after inhalation in STEP. ^†In the AIR study, a single inhalation of iloprost was given to all the subjects in the placebo group at week 12 for catheter testing in order to evaluate the acute drug effect of the inhalation; therefore, in AIR PAH, the pre-inhalation PVR values were used. ^‡Subjects with at least 1 class improvement in NYHA/WHO FC at week 12 were considered “improved” and those with at least 1 class deterioration were regarded as “worsened”. Abbreviations as in Table 1.

Safety in the IBUKI Study and AIR PAH Subgroup

Safety data for the initial 12-week treatment period in IBUKI and the AIR PAH subgroup are shown in Table 4. In IBUKI, among any AEs, 74% of patients had AEs related to study drug, including headache (37%), cough (15%), abdominal discomfort, blood pressure (BP) decreased, dizziness, flushing, and hot flush (11% for each). All AEs were mild-to-moderate and the discontinuation rate because of AEs was low (<10%). For the AEs of special interest, only 1 patient had hypotension and no patients reported syncope or hemoptysis; 2 patients reported serious AEs: 1 case of acute myocardial infarction not related to study drug, and the other study drug-related headache, neither of which resulted in discontinuation. There were no deaths. Pre-inhalation systolic and diastolic BP values were similar at all visits after day 1; any decreases in BP occurred immediately after inhalation and returned close to pre-inhalation values within 15 min. No notable change in mean oxygen saturation level was seen between pre-inhalation and post-inhalation assessments.

Table 4. Safety Over 12 Weeks in Patients With PAH From the IBUKI (Safety Analysis Population) and AIR (Safety Analysis With PAH) Studies

Patients with AEs, n (%)	IBUKI study	AIR PAH subgroup
	Iloprost (n=27)	Iloprost (n=68)	Placebo (n=78)
Any AE	25 (93)	63 (93)	70 (90)
Study drug-related AEs	20 (74)	50 (74)	53 (68)
Discontinuation because of AEs	2 (7)	3 (4)	5 (6)
Any SAEs	2 (7)	19 (28)	18 (23)
Study drug-related SAEs	1 (4)	8 (12)	4 (5)
Deaths	0	1 (1)	3 (4)
Common (>10% of patients receiving iloprost) treatment emergency AEs*
Cough	5 (19)	25 (37)	26 (33)
Headache	10 (37)	23 (34)	21 (27)
Flushing	3 (11)	16 (24)	11 (14)
Nasopharyngitis	3 (11)	10 (15)	6 (8)
Pain in jaw	1 (4)	9 (13)	7 (9)
Diarrhea	3 (11)	8 (12)	11 (14)
Nausea	2 (7)	8 (12)	8 (10)
Edema peripheral	0	8 (12)	12 (15)
Chest pain	0	7 (10)	6 (8)
Back pain	1 (4)	7 (10)	2 (3)
Syncope	0	7 (10)	5 (6)
Dizziness	3 (11)	3 (4)	9 (12)
Blood pressure decreased	3 (11)	2 (3)	1 (1)
Hot flush	3 (11)	3 (4)	2 (3)
Abdominal discomfort	3 (11)	1 (1)	1 (1)

*Coded using MedDRA version 16.1 in the IBUKI study and the AIR PAH subgroup analysis. AE, adverse event; SAE, serious AE. Other abbreviation as in Table 1.

The safety profile of long-term iloprost inhalation observed in the 40-week extension period of IBUKI was similar to that seen in the initial 12-week study period.

In the PAH subgroup analysis of the 12-week AIR study, AEs occurred at a similar frequency in the iloprost and placebo groups (Table 4). Among any AEs, the most common drug-related AEs in the iloprost group were cough (32%), headache (31%), flushing (24%), and jaw pain (13%). Regarding the AEs of special interest, 10% and 6% of patients reported syncope in the iloprost and placebo groups, respectively, 9% and 6% reported hypotension, and 3% and 1% reported hemoptysis. No relevant changes in mean BP values were observed, with only slight decreases detected in mean systolic BP and diastolic BP after inhalation of iloprost. Over the 12 weeks, serious AEs were reported by 28% of patients in the iloprost group and 23% of patients in the placebo group, the most common being syncope (7% and 1%, respectively), worsening PAH (4% and 3%), dyspnea (3% and 4%), and pneumonia (3% and 0%). Syncope generally occurred 2–9 h after the last inhalation when the trough of the acute hemodynamic effect of iloprost was assumed. Four deaths were reported in the AIR PAH subgroup during the 12-week randomized phase: 1 in the iloprost group from acute decompensated cor pulmonale that was considered unrelated to the study drug, and 3 in the placebo group.

Discussion

IBUKI is the first trial to evaluate the efficacy and safety of inhaled iloprost in a Japanese population of PAH patients, the majority of whom had been treated with both an ERA and a PDE5-I. Over the initial 12-week treatment period, improvements were noted in PVR, several other hemodynamic parameters, NYHA/WHO FC, and 6MWD. Inhaled iloprost was well tolerated throughout the full 52-week study period, and had an AE profile similar to that of the prostanoid class, and typically related to the vasodilatory action of the drug.

Two previous 12-week, randomized, double-blind trials, conducted in primarily Western Caucasian populations, and 1 long-term open-label, randomized study have shown consistent efficacy and safety of inhaled iloprost in patients with PAH.^13,14,17

In the AIR study (n=203) in treatment-naïve patients, inhaled iloprost monotherapy significantly improved the clinically important composite endpoint of ≥10% improvement in 6MWD and improved NYHA FC without deterioration in clinical condition compared with placebo. Inhaled iloprost also significantly improved a number of secondary endpoints, including 6MWD, NYHA FC, and hemodynamic parameters.¹³ In a long-term phase II study of 63 patients with IPAH or other forms of PH, inhaled iloprost therapy led to improvements in exercise capacity, functional capacity, and hemodynamic parameters, and an estimated 2-year survival rate of 85%.¹⁷ In both studies, iloprost was well tolerated and the AE profile was typical of prostanoid therapy.^13,17

The STEP study evaluated iloprost as an add-on to bosentan therapy in 67 patients with PAH (of whom 55% had IPAH).¹⁴ Iloprost improved NYHA FC and time to clinical deterioration. The authors concluded that the addition of inhaled iloprost to background bosentan therapy was safe and effective for patients with PAH.

To determine whether the clinical benefits of iloprost treatment in PAH are consistent in Japanese and non-Japanese patients, the efficacy data from IBUKI are presented alongside those from the AIR PAH subgroup and STEP studies. In general, the efficacy findings in the subgroup of patients treated with both an ERA and a PDE5-I during the IBUKI study were consistent with those seen in AIR and STEP (Table 3); in all 3 studies, iloprost improved hemodynamic parameters and functional and exercise capacity in patients with PAH. In each study, improvements in PVR of approximately 20% and in 6MWD of >30 m were noted with iloprost treatment over the 12-week period, and of the long-term patients over 90% achieved improved or stabilized their NYHA FC. Thus, inhaled iloprost appears to be effective as monotherapy and as an add-on to background therapy (ie, as add-on to an ERA or an ERA plus a PDE5-I) in patients with PAH, the effects being consistent in Japanese and Western populations.

In addition, with respect to the chronic hemodynamic effects of inhaled iloprost treatment (measured at trough level before inhalation), PVR was stabilized (mean change of –7 dyn·sec·cm⁻⁵), while a notable improvement in post-inhalation PVR at peak drug effect was observed at week 12 in the IBUKI study (Table 2). A similar chronic effect (at trough level) was observed in the iloprost group at week 12 of the AIR study (mean change of –9 dyn·sec·cm⁻⁵). In contrast, PVR had worsened in the AIR placebo group at week 12 (mean change of +96 dyn·sec·cm⁻⁵), which should be taken into account when considering the chronic effect of iloprost treatment (at trough level).¹³ In the AIR study, the acute hemodynamic effect after a single inhalation of iloprost at week 12 did not differ between the iloprost and placebo groups.¹³ Thus, the improvement in post-inhalation PVR (at peak drug effect) with iloprost appeared to be sustained over the 12-week treatment period, without development of drug tolerance.

The limitations of the IBUKI study include its relatively small sample size and single-arm design, reflecting the fact that PAH is an orphan disease and the number of Japanese subjects is limited. Also, when looking across the 3 studies, differences in study designs and patient populations need to be taken into consideration. The most notable difference between the studies is in background PAH therapy: AIR was conducted in treatment-naïve patients, STEP in patients treated with an ERA, and IBUKI in patients who had mostly (70%) been on treatment with both an ERA and a PDE5-I. The latter is a common clinical practice in Japan, and possibly contributed to the relatively lower baseline PVR of patients in IBUKI (Table 1). As a result, the change from baseline in PVR in the IBUKI study of –124 dyn·sec·cm⁻⁵ appeared relatively low compared with that seen in AIR and STEP; however, the mean percent change in PVR was similar among the 3 studies (–21.7% in IBUKI, –23.2% in the AIR overall population and –19.7% in STEP). The AIR PAH subgroup also included a substantial proportion (41%) of patients in NYHA FC IV, compared with STEP and IBUKI, which included 5% and 0% of patients, respectively, in FC IV. In general, baseline values for mean PVR and mPAP tended to be higher and CO lower in the AIR PAH subgroup than in IBUKI and STEP,¹⁴ most likely reflecting the fact that the AIR study was conducted in treatment-naïve patients in NYHA classes III and IV. Baseline mean 6MWD also tended to be higher in IBUKI than in either STEP¹⁴ or the AIR PAH subgroup (396 m vs. 335 m and 325 m, respectively).

The differences in baseline parameters and background therapies in the IBUKI, AIR, and STEP studies likely reflect the evolution of the standard of care over time, as evidence for the benefits of combination therapy has increased since the first PAH-specific drug became available.^9,18 However, the optimal treatment algorithms for patients with different types of PAH are yet to be determined. The findings of the IBUKI study may hold particular relevance in this current treatment era of combination therapy for PAH; considering the dynamics of the treatment paradigm, it is noteworthy that the efficacy and safety of iloprost were seen consistently, not only across different geographic regions, but also in patients with different treatment backgrounds. In Japan, combination therapy with an ERA and a PDE5-I is a recognized treatment option;¹⁸ based on the findings of the IBUKI study, iloprost may provide an additional and effective treatment option in patients already receiving an ERA-PDE5-I combination.

In conclusion, Japanese patients with PAH, mostly on background treatment with both an ERA and a PDE5-I, demonstrated clinical improvements with inhaled iloprost and no unexpected safety signals compared with the safety profile already reported for inhaled iloprost.

Acknowledgments

We thank Yo Hoshino, Bayer Yakuhin Ltd, and Christian Meier, Bayer Pharma AG, for providing scientific input. Editorial assistance was provided by Adelphi Communications Ltd, supported by Bayer Pharma AG.

Disclosures

T. Satoh reports receiving remuneration (eg, lecture fees) and research funding from Actelion Pharmaceuticals Ltd. Nobuhiro Tahara reports receiving lecture fees from Actelion Pharmaceuticals Japan Ltd. H.O. reports receiving remuneration (eg, lecture fees) from Actelion, Bayer, and Boehringer, research funding from Actelion and Boehringer, and travel expenses etc, from Actelion, Bayer, Gilead, GSK, Novartis, Pfizer, AstraZeneca, Boehringer, Chiesi, Menarini, and Roche; he reports that his spouse has received research funding from Bayer. S.N. is an employee of Bayer Pharma AG, and M.M. and Y.M. are employees of Bayer Yakuhin Ltd; they each report receiving an annual income, remuneration and travel expenses within the framework of their employment, without separate remuneration. The other authors report no conflicts.

References

• 1.    Dai  Z,  Sugimura  K,  Fukumoto  Y,  Tatebe  S,  Miura  Y,  Nochioka  K, et al. Visualization of complete regression of pulmonary arterial remodeling on optical coherence tomography in a patient with pulmonary arterial hypertension. Circ J 2014; 78: 2771–2773.
• 2.    Galiè  N,  Humbert  M,  Vachiery  JL,  Gibbs  S,  Lang  I,  Torbicki  A, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46: 903–975.
• 3.    Matsubara  H,  Ogawa  A. Treatment of idiopathic/hereditary pulmonary arterial hypertension. J Cardiol 2014; 64: 243–249.
• 4.    Montani  D,  Gunther  S,  Dorfmuller  P,  Perros  F,  Girerd  B,  Garcia  G, et al. Pulmonary arterial hypertension. Orphanet J Rare Dis 2013; 8: 97.
• 5.    Nergui  S,  Fukumoto  Y,  Do.e  Z,  Nakajima  S,  Shimizu  T,  Ikeda  S, et al. Role of endothelial nitric oxide synthase and collagen metabolism in right ventricular remodeling due to pulmonary hypertension. Circ J 2014; 78: 1465–1474.
• 6.    Schermuly  RT,  Ghofrani  HA,  Wilkins  MR,  Grimminger  F. Mechanisms of disease: Pulmonary arterial hypertension. Nat Rev Cardiol 2011; 8: 443–455.
• 7.    Farber  HW,  Miller  DP,  Poms  AD,  Badesch  DB,  Frost  AE,  Muros-Le  RE, et al. Five-year outcomes of patients enrolled in the REVEAL registry. Chest 2015; 148: 1043–1054.
• 8.    Badesch  DB,  Abman  SH,  Simonneau  G,  Rubin  LJ,  McLaughlin  VV. Medical therapy for pulmonary arterial hypertension: Updated ACCP evidence-based clinical practice guidelines. Chest 2007; 131: 1917–1928.
• 9.    Galiè  N,  Corris  PA,  Frost  A,  Girgis  RE,  Granton  J,  Jing  ZC, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62: D60–D72.
• 10.   Ventavis US Label. 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021779s0091bl.pdf (accessed July 13, 2015).
• 11.   European Medicines Agency. Find medicine: Ventavis – iloprost. 2015. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000474/human_med_001133.jsp&mid=WC0b01ac058001d124 (accessed July 13, 2015).
• 12.    Olschewski  H,  Walmrath  D,  Schermuly  R,  Ghofrani  A,  Grimminger  F,  Seeger  W. Aerosolized prostacyclin and iloprost in severe pulmonary hypertension. Ann Intern Med 1996; 124: 820–824.
• 13.    Olschewski  H,  Simonneau  G,  Galiè  N,  Higenbottam  T,  Naeije  R,  Rubin  LJ, et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322–329.
• 14.    McLaughlin  VV,  Oudiz  RJ,  Frost  A,  Tapson  VF,  Murali  S,  Channick  RN, et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med 2006; 174: 1257–1263.
• 15.    Dhand  R. Intelligent nebulizers in the age of the Internet: The I-neb Adaptive Aerosol Delivery (AAD) system. J Aerosol Med Pulm Drug Deliv 2010; 23(Suppl 1): iii–v.
• 16.    Hardaker  LE,  Hatley  RH. In vitro characterization of the I-neb Adaptive Aerosol Delivery (AAD) system. J Aerosol Med Pulm Drug Deliv 2010; 23(Suppl 1): S-11–S-20.
• 17.    Olschewski  H,  Hoeper  MM,  Behr  J,  Ewert  R,  Meyer  A,  Borst  MM, et al. Long-term therapy with inhaled iloprost in patients with pulmonary hypertension. Respir Med 2010; 104: 731–740.
• 18.   Japanese Circulation Society. Guidelines for treatment of pulmonary hypertension. 2012. https://www.j-circ.or.jp/guideline/pdf/JCS2012_nakanishi_h.pdf (accessed March 4, 2016).