Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients　― A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study ―

Abstract

Background: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH).

Methods and Results: This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was −104±191 dyn·s/cm⁵, whereas that in the placebo group was 26±180 dyn·s/cm⁵. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as −130±189 dyn·s/cm⁵ (P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index.

Conclusions: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667])

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease with a poor prognosis. The pulmonary artery is chronically obstructed, which causes abnormalities of the pulmonary circulation, resulting in increased pulmonary arterial pressure and pulmonary vascular resistance (PVR), and leading to right heart failure. The mechanism of onset involves a transition from recurrent/latent acute pulmonary thromboembolism to CTEPH.^1,2 Histopathological investigations have revealed that vascular lesions of the pulmonary arterioles in CTEPH are similar to those observed in pulmonary arterial hypertension (PAH). Thromboembolism triggers secondary pulmonary arteriole remodeling, which is suggested to lead to increased PVR.^3–5

Editorial p 1691

To treat CTEPH, the organized clot is first extracted with the intima and then pulmonary endarterectomy (PEA) is conducted.^4,6–10 For patients who cannot undergo PEA or who develop remnant or recurrent pulmonary hypertension after PEA, balloon pulmonary angioplasty (BPA) is considered and performed.^4,11 Clinical evidence on BPA has been accumulating,¹¹ and pulmonary vasodilators indicated for PAH are also being used in CTEPH. However, the only drug approved for CTEPH is the soluble guanylate cyclase stimulator, riociguat. To date, only a few randomized comparative control studies verifying the effectiveness of pulmonary vasodilators for CTEPH have been conducted,^5,12–14 so further improvements in pulmonary vasodilators as a treatment method for CTEPH are desired.

Selexipag is an orally available selective prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This characteristic is exhibited by high selectivity of MRE-269, its active metabolite, for the IP receptor.^15,16 In a placebo-controlled double-blind international Phase III study of selexipag (GRIPHON) with PAH patients, the risk of morbidity/mortality events was reduced by 40%.¹⁷ Moreover, in an open-label uncontrolled clinical study of selexipag with Japanese PAH patients,¹⁸ pulmonary hemodynamics, exercise tolerance, symptoms, and pro-B-type natriuretic peptide (NT-proBNP) were improved after 16 weeks of treatment. With regard to safety, the incidence of prostacyclin-related adverse drug reactions (ADRs) such as headache, diarrhea and pain in jaw was high, so the results were similar to the existing safety profile. Furthermore, no safety issues were identified. As a result, the efficacy and tolerability of selexipag in Japanese PAH patients were confirmed.¹⁸

In the present study, we conducted a placebo-controlled, double-blind Phase II study with Japanese CTEPH patients to examine the efficacy and safety of selexipag for CTEPH.

Methods

Selection of Patients

We selected Japanese patients (age, 20–75 years) who had undergone a pulmonary ventilation/perfusion scan and pulmonary angiography within 2 years prior to screening for this study entry, which revealed areas of deficient pulmonary blood flow, and thus a diagnosis of CTEPH. The NYHA/WHO functional class was II–IV. Pulmonary hemodynamics during rest, as determined with a right heart catheter test within 60 days of the start of selexipag or placebo treatment, was set as the baseline. Mean pulmonary artery pressure (mPAP) was to be ≥25 mmHg, pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure were to be <15 mmHg, and resting PVR >400 dyn·s/cm⁵. Patients who were pregnant, had a total lung capacity <60% of the predicted TLC value, Child-Pugh class B or C, and those who underwent PEA within 180 days before initiation of study drug administration were excluded. In addition, patients who received prostacyclin (PGI₂) and/or its derivatives 4 weeks (1 week for beraprost sodium) prior to treatment with the investigational drug were excluded. The effective anticoagulant dose had to be administered throughout the study from 90 days before treatment initiation. Concomitant use could be with a phosphodiesterase-5 (PDE5) inhibitor, a pulmonary vasodilator, or an endothelin-receptor antagonist (ERA). However, patients newly administered such treatment at 90 days prior to treatment with the investigational drug were excluded. Concomitant use of a certain dose of a calcium antagonist from 90 days before treatment with the investigational drug was allowed.

This study was conducted according to the ethical principles set by the institutional human ethics committees (of the participating facilities or regions) and the Helsinki Declaration. The study design was approved by the Chiba University Hospital’s Institutional Review Board. All subjects gave written informed consent prior to being enrolled.

Study Design

This study was a Phase II randomized, double-blind, placebo-controlled parallel-group comparison study. Briefly, patients were randomized in a 3:1 ratio to either the selexipag group or placebo group. A sample size of 32 was the maximum number of patients expected to be enrolled within the randomization period. Within 8 weeks of the baseline visit, treatment was initiated with selexipag 100 μg twice daily, titrated to 800 μg with a minimum interval of 3 days. Thereafter, the dose was titrated up to 800 μg at increments of 200 μg if tolerability was acceptable, with reference to the Phase IIa study for PAH conducted in Europe. The maximum tolerated dose was selected for each subject within 5 weeks of treatment. Thereafter, treatment was continued for 17 weeks with the maintenance dose for at least 4 weeks (Figure 1). Based on a previous clinical study of selexipag, the maximum dose for this study was selected to be 800 μg twice daily.¹⁹ Pulmonary hemodynamics were evaluated with the Swan-Ganz catheter method while the patient was recumbent. The indirect Fick or thermodilution method was used to calculate cardiac output (CO), and the same procedure was used for each patient during the study. Cardiac index was calculated as CO/body surface area. PVR was calculated from the transpulmonary pressure and CO [PVR = 80(mPAP − PAWP) / CO].

Figure 1.

Schematic of the study design. The fastest attainable dose titration schedule is presented. A total of 100 μg of the study drug was administered twice daily and titrated according to individual tolerance. Dose reduction and re-uptitration were allowed. For doses >600 μg, the patients had to remain in the hospital for at least 3 days and 2 nights from the time of titration.

Pulmonary hemodynamics and 6-min walk distance (6MWD), which were the efficacy endpoints, were measured at 17 weeks after administration of the study drug began. NT-pro-BNP was measured at each visit up until 17 weeks. Death and CTEPH-related hospitalization were evaluated up to 17 weeks from baseline. Subjects’ symptoms were evaluated at each visit according to the NYHA/WHO functional class. For safety and tolerance, ADRs, clinical test values, vital signs, and ECG were recorded at each visit. Patients who completed this study could participate in the long-term extended administration study.

Statistical Analysis

The primary endpoint (PVR) and the secondary endpoints (other pulmonary hemodynamics measurement values [mPAP, cardiac index, mean right atrial pressure (mRAP), mixed venous oxygen saturation (SvO₂)], 6MWD, and NT-pro-BNP level) at week 17 were compared with values obtained at baseline in the Per-Protocol Set (PPS) group using the Wilcoxon rank sum test in the selexipag and placebo groups. Death or CTEPH-related hospitalization was analyzed in the All-treated Set (ATS) group, and the safety evaluation variables were analyzed in the Safety Set group. Subjects without week 17 PVR data were excluded from the PPS analysis. Significant difference was defined as a P<0.05 (2-tailed test). All analyses were performed with SAS (version 9.2; Cary, NC, USA).

Results

Patients

Between 2010 and 2012, 34 (10 male, 24 female) subjects were recruited from 18 institutions. Their demographic characteristics at baseline are presented in Table 1. Patients who could not undergo PEA because of organized peripheral thrombus, those with persistent or recurrent pulmonary hypertension after PEA and those at high risk (complications, elderly etc.) or could not undergo PEA for other reasons were enrolled as subjects. All judgements and diagnoses were performed by the principal investigator or a sub-investigator at each trial site. Additionally, a member of an independent central evaluation committee comprised of PEA experts also reviewed the process to ensure that the allocation of each patient to these predefined categories was justified. At baseline, the NYHA/WHO functional class was mainly II or III. For the disease classification, PEA was not indicated for most patients because they had a distal organized thrombus. At baseline, approximately half of the patients were receiving an ERA or PDE5 inhibitor and their doses were unchanged during treatment with the investigational drug. The remaining half of the patients received selexipag alone. The distribution of the maintenance doses is shown in Table 2.

Table 1. Patients’ Baseline Characteristics (All-Treated Set)

	Placebo (n=9)	Selexipag (n=25)
Sex [n (%)]
Male	2 (22.2%)	8 (32.0%)
Female	7 (77.8%)	17 (68.0%)
Age (years)
Mean±SD	60±5	58±15
Median (min, max)	61 (52, 67)	63 (28, 75)
6-min walk distance (m)
Mean±SD	355±114	378±77
Median (min, max)	373 (118, 475)	370 (193, 581)
NYHA/WHO functional class
I	0 (0.0%)	0 (0.0%)
II	5 (55.6%)	13 (52.0%)
III	3 (33.3%)	11 (44.0%)
IV	1 (11.1%)	1 (4.0%)
Disease class [n (%)]
PEA not indicated because of distal organized thrombus	6 (66.7%)	19 (76.0%)
Persistent or recurrent pulmonary hypertension after PEA	1 (11.1%)	3 (12.0%)
High-risk case (complications, elderly etc.) or PEA could not be performed for other reasons	2 (22.2%)	3 (12.0%)
Concomitant use of pulmonary vasodilator [n (%)]
Present	5 (55.6%)	13 (52.0%)
PDE5 inhibitor	1 (11.1%)	5 (20.0%)
ERA	4 (44.4%)	8 (32.0%)
None	4 (44.4%)	12 (48.0%)
Time since diagnosis (years)
Mean±SD	3.5±4.6	3.8±3.9

ERA, endothelin-receptor antagonist; NYHA/WHO, New York Heart Association/World Health Organization; PDE-5, phosphodiesterase type 5; PEA, pulmonary endarterectomy; SD, standard deviation.

Table 2. Dose Distribution (Per-Protocol Set)

	Placebo (n=7)	Selexipag (n=21)
Final maintenance dose (μg/day)
0	7	0
200	0	0
400	0	1
600	0	1
800	0	0
1,000	0	4
1,200	0	4
1,400	0	2
1,600	0	9

Of the 25 patients in the selexipag group, 4 (1 did not adhere to the exclusion criteria; 3 had PVR not in accordance with the protocol), and of the 9 patients in the placebo group, 2 (1 missing week 17 data and discontinued participation in the study; and 1 PVR not in accordance with the protocol) were excluded from the PPS (Figure 2).

Figure 2.

Analysis set. Of the patients who discontinued treatment, only those with stable administration for at least 4 weeks were included in the per-protocol set (PPS).

Efficacy

The changes in PVR from baseline to week 17 are shown in Figure 3, and the outline of changes in the pulmonary hemodynamic variables and other efficacy endpoints are presented in Table 3. Additionally, the changes in PVR based on the status of concomitant use of a pulmonary vasodilator are shown in Table 4. In the selexipag group, PVR (mean±SD) decreased from 700±302 dyn·s/cm⁵ to 596±266 dyn·s/cm⁵ after 17 weeks (95% confidence interval [CI]: −191, −17 dyn·s/cm⁵, P=0.0266, Wilcoxon signed rank test). In the placebo group, PVR increased from 756±303 dyn·s/cm⁵ to 782±391 dyn·s/cm⁵ (95% CI: −140, 192 dyn·s/cm⁵, P=0.8125, Wilcoxon signed rank test). Based on these values, treatment efficacy was −130±189 dyn·s/cm⁵ (95% CI: −299, 39 dyn·s/cm⁵, P=0.1553, Wilcoxon rank sum test) after 17 weeks of selexipag treatment. In the selexipag group that did not concomitantly receive pulmonary vasodilator, PVR (mean±SD) decreased from 625±220 dyn·s/cm⁵ to 567±267 dyn·s/cm⁵ after 17 weeks of treatment, but in the placebo group, it increased from 755±366 dyn·s/cm⁵ to 926±437 dyn·s/cm⁵. After 17 weeks of selexipag treatment, treatment efficacy was −229±122 dyn·s/cm⁵ (P=0.0364, Wilcoxon rank sum test) in the group that did not concomitantly receive a pulmonary vasodilator.

Figure 3.

Change in pulmonary vascular resistance from baseline to week 17. Data are presented as mean±SD. Mean change from baseline to 17 weeks of treatment was −104 dyn·s/cm⁵ (95% confidence interval: −191, −17 dyn·s/cm⁵) in the selexipag group and 26 dyn·s/cm⁵ (95% confidence interval: −140, 192 dyn·s/cm⁵) in the placebo group.

Table 3. Changes in Pulmonary Hemodynamic Variables, 6MWD, NT-Pro BNP, and NYHA/WHO Functional Class (Per-Protocol Set)

	Placebo (n=7)			Selexipag (n=21)			Treatment effect	P value
	Baseline	Week 17	Change	Baseline	Week 17	Change
PVR (dyn·s/cm5)	756±303 (400, 1,131)	782±391 (337, 1,376)	26±180 (−247, 245)	700±302 (400, 1,631)	596±266 (247, 1,143)	−104±191 (−593, 171)	−130±189	0.1553*
CI (L/min/m2)	2.5±0.8 (1.6, 3.9)	2.2±0.4 (1.7, 2.7)	−0.3±0.8 (−1.5, 1.1)	2.4±0.5 (1.6, 3.1)	2.6±0.7 (1.8, 4.4)	0.2±0.6 (−0.6, 1.9)	0.5±0.6	0.0798*
mPAP (mmHg)	41.6±8.5 (33.0, 54.0)	39.0±11.0 (25.0, 51.0)	−2.6±4.2 (−8.0, 4.0)	41.1±11.7 (25.0, 63.0)	38.2±10.7 (24.0, 57.0)	−2.9±−6.4 (−19.0, 5.0)	−0.3±6.0	0.9273*
TPR (dyn·s/cm5)	963±383 (514, 1,407)	986±439 (526, 1,600)	23±247 (−453, 241)	887±328 (513, 1,908)	781±273 (353, 1,303)	−107±224 (−762, 219)	−129±230	0.1129*
mRAP (mmHg)	5.1±3.3 (2.0, 12.0)	5.9±4.2 (1.0, 12.0)	0.7±2.1 (−2.0, 4.0)	5.4±3.3 (1.0, 13.0)	6.0±5.9 (1.0, 29.0)	0.6±4.7 (−10.0, 16.0)	−0.1±4.3	0.8270*
SvO2 (%)	65.1±10.6 (52.5, 81.2)	64.3±11.9 (47.2, 79.0)	−0.8±2.9 (−5.3, 3.6)	66.4±7.5 (49.1, 80.2)	64.5±7.8 (49.1, 76.8)	−1.9±6.0 (−11.2, 11.8)	−1.1±5.4	0.4046*
6MWD (m)	344±121 (118, 470)	371±85 (225, 487)	27±49 (−16, 107)	376±81 (193, 581)	395±64 (292, 575)	19±55 (−160, 118)	−9±54	0.7656*
NT-pro BNP (pg/mL)	1,231±1,601 (13, 4,492)	1,109±1,383 (29, 3,219)	−122±888 (−1,678, 1,322)	402±490 (9, 1,758)	572±1,029 (23, 3,501)	170±651 (−260, 2,360)	293±713	0.8358*
NYHA/WHO functional class (n)	I: 0	I: 0	Improved: 1	I: 0	I: 0	Improved: 3	Relative risk Proportion improved: 1.00 Proportion deteriorated: –	Proportion improved: 1.0000 Proportion deteriorated: –**
	II: 3	II: 3		II: 11	II: 14
	III: 3	III: 4	Deteriorated: 0	III: 10	III: 7	Deteriorated: 0
	VI: 1	VI: 0		VI: 0	VI: 0

Data are presented as mean±SD (min, max). *P value determined using Wilcoxon rank sum test. **P value determined using Fisher’s exact test. 6MWD, 6-min walk distance; CI, cardiac index; mPAP, mean pulmonary artery pressure; mRAP, mean right atrial pressure; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; PVR, pulmonary vascular resistance; SvO₂, mixed venous oxygen saturation; TPR, total pulmonary resistance.

Table 4. Change in PVR According to Pulmonary Vasodilator Use (Per-Protocol Set)

Status of concomitant therapy	Treatment group	Timing	n	Mean±SD Min~Max	Treatment effect	P value*
Present	Placebo	Baseline	4	756±306 (416, 1,059)	−56±212	0.8615
		Week 17		673±377 (337, 1,185)
		Change		−83±156 (−247, 126)
	Selexipag	Baseline	12	757±350 (440, 1,631)
		Week 17		618±275 (276, 1,143)
		Change		−139±225 (−593, 153)
Absent	Placebo	Baseline	3	755±366 (400, 1,131)	−229±122	0.0364
		Week 17		926±437 (503, 1,376)
		Change		171±71 (103, 245)
	Selexipag	Baseline	9	625±220 (400, 1,046)
		Week 17		567±267 (247, 1,086)
		Change		−57±132 (−228, 171)

Data are presented as mean±SD (min, max). *P value determined using the Wilcoxon rank sum test.

Similar to PVR, total pulmonary resistance (TPR) (mean±SD) decreased. Moreover, treatment efficacy was −129±230 dyn·s/cm⁵ (P=0.1129, Wilcoxon rank sum test) and the cardiac index (mean±SD) increased from 2.4±0.5 L/min/m² to 2.6±0.7 L/min/m² after 17 weeks in the selexipag group. Conversely, in the placebo group, cardiac index decreased from 2.5±0.8 L/min/m² to 2.2±0.4 L/min/m². Treatment efficacy after 17 weeks of selexipag treatment was 0.5±0.6 L/min/m² (P=0.0798, Wilcoxon rank sum test). An evident treatment effect due to selexipag was not demonstrated according to the pulmonary hemodynamic variables, 6MWD or NT-proBNP. In the selexipag group that did not concomitantly receive pulmonary vasodilator, 6MWD (mean±SD) changed from 389±102 m to 417±81 m after 17 weeks of treatment, and in the placebo group, it changed from 414±62 m to 419±77 m. After 17 weeks of selexipag treatment, treatment efficacy was 23±33 m (P=0.3500, Wilcoxon rank sum test) in the group that did not concomitantly receive pulmonary vasodilator. The NYHA/WHO functional class at the start of the study was class II for 11 patients and class III for 10 patients in the selexipag group, and class II for 3 patients, class III for 3, and class IV for 1 patient in the placebo group. After 17 weeks of selexipag treatment, 3 patients (14.3%, 95% CI: 3.0–36.3%) had improved their functional class. Throughout the study, none of the patients exhibited any deterioration in NYHA/WHO functional class. During the study, there was 1 death in the selexipag group in the ATS.

Safety

Serious adverse events occurred in 2 patients (8.0%) in the selexipag group. Dissemination intravascular coagulation occurred after 117 days, followed by congestive heart failure and stress-induced cardiomyopathy, leading to the patient’s death 14 days later. Congestive heart failure and stress-induced cardiomyopathy were considered to be occurred because of deterioration in CTEPH by the investigator, but a causal relationship with the investigational drug could not be ruled out. Discontinuation did not occur due to other ADRs. In another patient, right ventricular failure occurred after 71 days of treatment, which led to a decrease in the selexipag dose administered. Symptoms occurred after titration of the selexipag dose and the patient recovered 8 days after reducing the dose of the drug. As a result, a correlation with the investigational drug could not be ruled out. ADRs (excluding those without a causal relationship) occurred in 22 (88.0%) of 25 patients in the selexipag group and 6 (66.7%) of the 9 patients in the placebo group. The ADRs that occurred at a rate ≥10% in the selexipag group were headache (56.0%), diarrhea (56.0%), pain in jaw (36.0%), myalgia (28.0%), hot flush (20.0%), malaise and flushing (16.0%), and nausea and arthralgia (12.0%). These reactions were generally observed when prostacyclin was administered and most patients improved or recovered with symptomatic treatment without discontinuation of the study drug. In the placebo group, headache (33.3%), diarrhea (22.2%), flushing, and arthralgia (11.1%) were observed. The adverse events that occurred at a rate ≥10% in both groups are presented in Table 5.

Table 5. Adverse Events (AEs) Related to Selexipag Usage (Safety Set)

	Placebo (n=9)		Selexipag (n=25)
	Patients (%)	No. of events	Patients (%)	No. of events
Total patients with ≥1 AE	6 (66.7%)	18	22 (88.0%)	102
Headache	3 (33.3%)	4	14 (56.0%)	17
Diarrhoea	2 (22.2%)	3	10 (40.0%)	13
Pain in Jaw	–	–	9 (36.0%)	10
Myalgia	–	–	7 (28.0%)	8
Hot flush	–	–	5 (20.0%)	5
Malaise	–	–	4 (16.0%)	5
Flushing	1 (11.1%)	1	4 (16.0%)	4
Nausea	–	–	3 (12.0%)	4
Arthralgia	1 (11.1%)	1	3 (12.0%)	3

AEs (related to selexipag) with a frequency of at least 10.0% were extracted.

In both groups, there were no abnormal clinical test values, blood pressure, pulse rate, or ECG results that could be considered as a clinical problem.

Based on these findings, the administration of the maximum dose of selexipag (800 μg) twice daily was tolerated by the patients.

Discussion

In this study, after 17 weeks of selexipag administration, the decrease in PVR, which was the primary endpoint, tended to be high in the selexipag group compared with the placebo group, but the difference in each group was not significant. The difference was identified as significant in the group that did not receive combination treatment with a pulmonary vasodilator, although the number of subjects in this group was low. Administering a selexipag dose up to 800 μg was safe and was adequately tolerated by these CTEPH patients.

Surgical treatment (i.e., PEA), which removes the organized blood thrombus from the pulmonary artery, is the first-choice treatment for CTEPH,⁴ but for patients who cannot undergo PEA, drug therapy with a pulmonary vasodilator or treatment with BPA is performed. Riociguat is the only drug approved for CTEPH that has been adjudicated as inoperable or for patients with persistent/recurrent pulmonary hypertension after PEA.²⁰ Pulmonary vasodilators other than riociguat have been reported to improve pulmonary hemodynamics and/or 6MWD in past clinical studies,^5,21–24 but are ineligible for insurance coverage in Japan.

In the present study, the primary endpoint was PVR. Many studies have demonstrated that a decrease in PVR through treatment of CTEPH leads to improved prognosis.^22–28 In an observational study, Skoro-Sajer et al²² subcutaneously administered treprostinil for 12 months to 25 CTEPH patients who could not undergo PEA. They found a change from baseline of −116±325 dyn·s/cm⁵ in PVR, which indicated a significant improvement (P=0.01). The 5-year survival was 16% in the control group (n=31) and 53% in the treprostinil group, thereby demonstrating a significant improvement (P=0.02). Those findings suggest that a decrease ≥100 dyn·s/cm⁵ in PVR owing to treatment intervention in CTEPH patients leads to improved survival prognosis.

A significant improvement in PVR was not observed in the selexipag group compared with the placebo group in our study. However, comparing the pre- and post-treatment data in the selexipag group, a significant improvement in PVR was observed, thus demonstrating that selexipag improved PVR in CTEPH patients, with subsequent potential improvement in survival prognosis. The ratio of the geometric mean for the change in PVR due to selexipag treatment was 83.4%, a finding similar to that obtained in other clinical studies.^20,21,29 In addition, an improvement trend in PVR was observed in patients treated with the combination of ERA or PDE5 inhibitor. These findings suggest that selexipag alone and combined with another pulmonary vasodilator might be effective in CTEPH patients. Because this study was conducted before riociguat was approved for market entry, no patient was treated with a combination of selexipag and riociguat. Moreover, none of the recruited patients had a history of BPA. Therefore, the efficacy of selexipag in CTEPH patients treated with riociguat, as well as in those with a history of BPA is a future topic of investigation.

In CHEST-1 study, a Phase III study in which the efficacy and safety profile of riociguat in patients with CTEPH were investigated, the 6MWD significantly improved in the riociguat group compared with placebo group, but patients who received the pulmonary vasodilator concomitantly were not allowed to participate in the study.²⁰ In the current study, an evident treatment effect due to selexipag was not demonstrated according to the 6MWD, but it, as well as PVR, tended to be improved in the selexipag group that did not receive combination treatment with a pulmonary vasodilator as compared with the placebo group. Several improvements in the pathological conditions in patients were demonstrated, such as pulmonary hemodynamics, including PVR and the 6MWD, even among those administered the placebo. Although the cause of this result is unclear, the concomitant use of a pulmonary vasodilator at baseline may have had to the effect. In fact, the dose of bosentan was increased in 42.9% (3/7) of patients in the placebo group within 90 days before the start of treatment with the investigational drug. Thus, a stratified analysis was performed to derive the status of concomitant use of a pulmonary vasodilator at baseline. Based on our findings, when a pulmonary vasodilator was concomitantly administered, the PVR (mean±SD) achieved after 17 weeks of treatment in the placebo group decreased from 756±306 dyn·s/cm⁵ to 673±377 dyn·s/cm⁵, and the change from baseline to week 17 was −83±156 dyn·s/cm⁵. In addition, when a pulmonary vasodilator was concomitantly administered, the 6MWD (mean±SD) achieved after 17 weeks of treatment in the placebo group changed from 292±134 m to 336±81 m, and the change from baseline to week 17 was 44±61 m. As the number of patients examined was low, a future investigation is warranted. For the group that did not concomitantly use a pulmonary vasodilator, the decrease in PVR and the change in 6MWD in the selexipag group was high compared with the placebo group. Therefore, similar to riociguat, selexipag might become a first-choice drug.

Regarding safety, the incidence of adverse events caused by PGI₂ drugs was high, but serious adverse events were few, and most were mild or moderate. We did not identify any adverse events related to hypertension or thyroid dysfunction. Based on these findings, administering a selexipag dose up to 800μg was safe and adequately tolerated by CTEPH patients.

In this study, several patients had few adverse events and did not respond to the administered treatment, even when the 800 µg dose was administered. The upper limit of the dose was 800 μg, a value that is half the upper limit of the PAH dose that has gained market approval. In a recent comparison of PAH patients with adverse drug reactions due to selexipag with those without any ADRs, treatment efficacy was found to be higher in those with prostacyclin-associated ADRs.³⁰ These findings suggest that 1,600 μg twice daily is the maximum maintenance dose and treatment efficacy should be confirmed, even for CTEPH patients, in future studies.

The pharmacodynamics of selexipag and MRE-269 in CTEPH patients were similar to those in healthy adult males and PAH patients. Such findings suggests that selexipag can be administered to patients receiving other oral pulmonary vasodilators and experience no adverse events.

The results of pulmonary hemodynamics, exercise tolerance and tolerability obtained in this study are considered to warrant further investigation in a Phase III study.

Study Limitations

The number of subjects was set as the maximum number of patients that could be recruited in Japan, not the number of patients required to demonstrate the usefulness of selexipag in terms of efficacy endpoints with a statistical significance. The study had a short duration and the maximum dose was one-half of that approved for PAH treatment. Further, no patient was administered concomitant treatment with riociguat, and none had a history of BPA. Thus, the study population was not identical to those who are treated according to the present treatment algorithm and clinical settings.

Conclusions

Selexipag was administered to Japanese CTEPH patients for the first time, showing tolerability and an acceptable safety profile. In addition, it showed an improvement in the pulmonary dynamics of CTEPH patients who could not undergo PEA and of CTEPH patients with persistent or recurrent pulmonary hypertension after PEA. However, the decrease in PVR, which was the primary endpoint, was not significantly different between the selexipag and placebo groups. A Phase III study (JapicCTI-163279) in Japanese patients with CTEPH is underway, the findings of which are anticipated.

Acknowledgments

Statistical analysis and medical writing were supported by Nippon Shinyaku and Actelion Pharmaceuticals Japan. The authors express their sincere gratitude to sub-investigators and clinical coordinators, as well as Editage (www.editage.jp) for English language editing. The study was funded by Nippon Shinyaku and Actelion Pharmaceutical Japan. The sponsors were involved in the study design and in the collection, analysis, and interpretation of data.

Data Availability

The de-identified participant data will not be shared.

Disclosures

N. Tanabe received remuneration from Nippon Shinyaku, Actelion Pharmaceuticals Japan, Bayer Yakuhin and DAIICHI SANKYO, and scholarship funds from Nippon Shinyaku. He belongs to the endowed department by Actelion Pharmaceuticals Japan. H. Matsubara received remuneration from Nippon Shinyaku, Actelion Pharmaceuticals Japan, Pfizer Japan, Bayer Yakuhin, United Therapeutics Corporation, AOP Orphan Pharmaceuticals AG and Grupo Ferrer Internacional, S.A., and research funds from Nippon Shinyaku. N. Nakanishi has no conflicts of interest. N. Tahara received remuneration from Actelion Pharmaceuticals Japan and Pfizer Japan. S. Ikeda received remuneration from Nippon Shinyaku and Actelion Pharmaceuticals Japan. T. Kishi received remuneration from Eli Lilly Japan and Astellas Pharma, and research funds from Astellas Pharma. T. Satoh received remuneration from Nippon Shinyaku, Actelion Pharmaceuticals Japan, Bayer Yakuhin, Mochida Pharmaceutical and Astellas Pharma, and scholarship funds from Nippon Shinyaku and Mochida Pharmaceutical. K. Hirata received research funding from Actelion Pharmaceuticals Japan and Glaxo Smith Kline, and scholarship funds from Nippon Shinyaku and Bayer Yakuhin. T. Inoue received remuneration from Bayer Yakuhin and Mochida Pharmaceutical, and research funds from Bayer Yakuhin, EPS Corporation and EP-CRSU. He also received scholarship funds from Abbott Vascular Japan, SHIONOGI, DAIICHI SANKYO, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Teijin Healthcare Limited, TEIJIN PHARMA, Terumo Corporation, Nippon Boehringer Ingelheim, MEDTRONIC JAPAN and UNION TOOL. H. Kimura belongs to the endowed department by Actelion Pharmaceuticals Japan. Y. Okano and O. Okazaki have no conflicts of interest. M. Sata received remuneration from Bayer Yakuhin and Astellas Pharma, and scholarship funds from Bayer Yakuhin and Astellas Pharma. I. Tsujino received research funds from Actelion Pharmaceuticals Japan, and scholarship funds from Actelion Pharmaceuticals Japan. S. Ueno has no conflicts of interest. N. Yamada received remuneration from Pfizer Japan and Bayer Yakuhin. A. Yao and T. Kuriyama have no conflicts of interest.

K. Fukuda, K. Hirata, T. Inoue, and M. Sata are members of Circulation Journal’ Editorial Team.

IRB Information

This study was approved by Chiba University Hospital’s Institutional Review Board, Chiba, Japan (reference no. 021027). The institutional review boards of each participating institution approved the study protocol.

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