Long-Term Safety and Efficacy of Macitentan in Inoperable Chronic Thromboembolic Pulmonary Hypertension: Results from MERIT and its Open-Label Extension
verfasst von:
Nick H. Kim, Andrea M. D’Armini, Luke S. Howard, David P. Jenkins, Zhi-Cheng Jing, Eckhard Mayer, Liliya Chamitava, Gabriela Lack, Hany Rofael, Maria Solonets, Hossein-Ardeschir Ghofrani
Evidence for use of pulmonary arterial hypertension targeted-therapies in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is limited. In MERIT-1, the endothelin receptor antagonist macitentan improved hemodynamic and functional parameters versus placebo in patients with inoperable CTEPH over a 24-week double-blind (DB) period. Its open-label (OL) extension study (MERIT-2) provides long-term safety/efficacy data.
Methods
MERIT-2 (NCT02060721) was a multicenter, single-arm, OL, phase 2 extension study of MERIT-1. Patients completing MERIT-1 were eligible to receive 10 mg macitentan once-daily in MERIT-2. Safety and efficacy (6-min walk distance [6MWD] and change in World Health Organization functional class [WHO FC]) were assessed in all patients in MERIT-2 regardless of treatment received in DB (All patients MERIT-2 OL macitentan 10 mg group) and the subgroup of patients receiving DB macitentan in MERIT-1 (Long-term [DB/OL] macitentan 10 mg subgroup).
Results
Of the 80 patients randomized in MERIT-1, 76 entered MERIT-2 (All patients MERIT-2 OL macitentan 10 mg group): 40 who received DB macitentan (DB-macitentan patients) and 36 DB placebo (DB-placebo patients). Median (interquartile range) macitentan exposure in the All patients MERIT-2 OL macitentan 10 mg group was 45.5 (26.0, 66.1) months. During the OL period, treatment-emergent adverse events (AE) were reported in 72 (94.7%) patients; most frequent were worsening of pulmonary hypertension (19.7%), decreased hemoglobin (18.4%) and upper respiratory tract infection (15.8%). Fourteen (18.4%) patients died; none were assessed as macitentan-related. At Month 6 post-OL baseline, mean (standard deviation) change in 6MWD was − 0.4 m (43.62) for DB-macitentan patients and 10.7 m (45.63) for DB-placebo patients; the majority had unchanged (83.3%) or improved (12.5%) WHO FC. Safety/efficacy analyses were consistent in the Long-term (DB/OL) macitentan 10 mg subgroup.
Conclusion
These analyses provide long-term safety/efficacy data in patients with inoperable CTEPH treated with macitentan. No unexpected safety findings occurred; reported AEs were consistent with the known safety profile of macitentan. At 6 months post-OL baseline, DB-placebo patients modestly improved 6MWD; DB-macitentan patients maintained improvements observed in MERIT-1. WHO FC was largely unchanged.
Prior presentation: Data were presented in part as a poster at ATS, Dallas, Texas, May 2019 (Howard et al. Am J Respir Crit Care Med 2019; 199:A6068).
Key Summary Points
Why carry out this study?
Evidence for use of pulmonary arterial hypertension targeted-therapies in patients with chronic thromboembolic pulmonary hypertension (CTEPH) is limited.
Improvements in hemodynamics and functional parameters in patients with inoperable CTEPH following treatment with the endothelin receptor antagonist macitentan were demonstrated in the phase 2 MERIT-1 study; its open-label (OL) extension study (MERIT-2) presents long term safety and efficacy data for these patients.
What did the study ask?
MERIT-2 collected long-term safety and efficacy data (change in 6-min walk distance [6MWD] and World Health Organization functional class [WHO FC]) in patients who received macitentan from the start of MERIT-2 (All patients MERIT-2 OL macitentan 10 mg group) and in the subgroup of patients who received double blind (DB) macitentan in MERIT-1 (Long-term [DB/OL] macitentan 10 mg subgroup).
What were the study outcomes/conclusions?
Adverse events reported in the study were in line with the known safety profile of macitentan and disease under study; the most frequent were worsening of pulmonary hypertension, decreased hemoglobin and upper respiratory tract infection.
After 6 months of OL macitentan treatment, patients who received DB placebo in MERIT-1 showed modest improvements in 6MWD and patients who received DB macitentan in MERIT 1 maintained their previously observed improvements; WHO FC remained unchanged for most patients.
What was learned from the study?
Long-term macitentan use in patients with inoperable CTEPH did not result in any unexpected safety findings; the nature of observed safety events was consistent with the known profile of macitentan and the underlying disease.
These long-term data confirm the positive findings for 6MWD and stable WHO FC in patients receiving macitentan during the 24-week double blind period of MERIT-1.
Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare and progressive form of pulmonary hypertension (PH), characterized by macroscopic and microscopic changes in the pulmonary vasculature resulting in increased pulmonary vascular resistance (PVR), right ventricular failure and eventually death [1‐3]. Surgical removal of thromboembolic obstructions with pulmonary endarterectomy is the recommended treatment for CTEPH [4‐6], however, for some patients the location of the lesions makes them ineligible for this treatment. Balloon pulmonary angioplasty (BPA) is an emerging alternative treatment for otherwise inoperable patients [7, 8].
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The remodelling of the pulmonary microvasculature observed in CTEPH (World Health Organization [WHO] Group 4 PH) is similar to that of pulmonary arterial hypertension (PAH; WHO Group 1 PH) [2, 9], therefore, medical therapies for PAH have been investigated for the management of inoperable CTEPH. However, current recommendations for their use in patients with CTEPH are based on the results of a limited number of randomized controlled trials [10‐12]. Macitentan is an oral, dual-action endothelin receptor antagonist (ERA), approved for long-term use in patients with PAH to reduce the risks of disease progression and hospitalization for PAH [13‐15]. The phase 2 MERIT-1 study assessed the efficacy and safety of macitentan 10 mg versus placebo in 80 patients with inoperable CTEPH [16]. By Week 24, the primary endpoint of reduced PVR and the secondary endpoint of an improvement in 6-min walk distance (6MWD) were met, with clinically significant improvements observed in macitentan-treated patients. Overall, macitentan was well tolerated in patients with CTEPH during the MERIT-1 study and the presented safety/tolerability profiles were consistent with that observed in patients with PAH.
This analysis (MERIT-2) of the open-label (OL) extension period of MERIT-1 presents long-term safety and efficacy data for the use of macitentan 10 mg in patients with inoperable CTEPH beyond the 24 weeks of treatment in the MERIT-1 study.
Methods
Study Design
MERIT-1 (NCT02021292) was a 24-week, multicenter, double-blind (DB), randomized, parallel-group, placebo-controlled phase 2 study which aimed to evaluate the effect of macitentan 10 mg versus placebo on PVR (primary endpoint) and exercise capacity (6MWD, key secondary endpoint) over a period of 24 weeks in patients with inoperable CTEPH [16]; safety and tolerability were also monitored. Data were collected between April 3, 2014–March 17, 2016.
MERIT-2 (NCT02060721) was a multicenter, single-arm, OL, phase 2 extension study to assess the long-term safety and tolerability of macitentan 10 mg in patients with inoperable CTEPH. Patients who completed the 24 weeks of MERIT-1 entered MERIT-2 and received OL treatment with macitentan 10 mg, while remaining blind to their previous study treatment (macitentan 10 mg or placebo) (Figure S1).
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Patients received macitentan 10 mg as a once-daily oral administration with or without food until patient, investigator or sponsor decided to discontinue the study treatment. A post-treatment safety follow-up period of 30 days followed permanent discontinuation of study treatment. The safety follow-up/end of study visit performed at the end of this period corresponded to the end of the MERIT-2 study for an individual patient, unless they were enrolled in a post-trial access program or the UMBRELLA study (mUlticentre, single-arM, open-laBel, long-teRm safety study with macitEntan in patients with puLmonary arterial hypertension previousLy treated with mAcitentan in clinical studies; NCT03422328). For such patients, the end of study was the end of treatment.
Ethical Approval
Data were collected in MERIT-1 and MERIT-2 in accordance with the Good Clinical Practice guidelines and Declaration of Helsinki. The study protocol was approved by the institutional review board, or independent ethics committee at each participating site and patients gave full written consent for their participation and use of their data for publication. The Scientific Committee, composed of external experts in CTEPH with experience in clinical studies, were involved in the study design and provided guidance on both MERIT-1 and MERIT-2. An Independent Liver Safety Data Review Board provided assessment and advice regarding serious hepatic adverse events of special interest (AESI). The list of study sites, investigators and ethical committees are included in Supplementary Methods 1.
Patient Population
Patient eligibility criteria for the MERIT-1 study have been described previously [16]. Patients aged 18–80 years old with a confirmed diagnosis of inoperable CTEPH, in WHO functional class (FC) II − IV, who completed the full 24 weeks of MERIT-1 were eligible to be enrolled in MERIT-2. Patients were not enrolled in MERIT-2 if they had hemoglobin < 100 g/L, serum aspartate aminotransferase and/or alanine aminotransferase > 3 × upper limit of normal and systolic blood pressure < 90 mmHg at the time of planned transition to MERIT-2, or had discontinued DB study treatment in MERIT-1. Permitted background therapies were phosphodiesterase-5 inhibitors, oral or inhaled prostacyclin analogues and the soluble guanylate cyclase stimulator riociguat (the latter was permitted in MERIT-2 only as riociguat was not approved/available at the start of MERIT-1). Patients were excluded in cases of treatment with strong cytochrome P450 3A4 inducers or another ERA.
Assessments
Safety assessments included adverse events (AEs), serious AEs (SAEs), AESIs and marked laboratory abnormalities. Preferred Terms included under the AESI grouped terms of hepatic events, edema and fluid retention, anemia and decrease of hemoglobin, and hypotension are listed in Supplementary Methods 2. Efficacy assessments (exercise capacity measured by 6MWD and WHO FC) were performed at enrollment, at each 6-monthly visit and at end of treatment.
Statistical Analyses
All analyses were descriptive. Two observation periods were defined, the first commencing at enrollment into MERIT-2 and the second commencing at enrollment into MERIT-1. For analyses with a MERIT-2 baseline (defined as the time of entry into MERIT-2), three analysis sets were described (Fig. S2): the All patients MERIT-2 OL macitentan 10 mg group comprised all patients enrolled into the MERIT-2 study (N = 76); two subgroups were additionally defined according to the treatment received during MERIT-1 and included patients previously on placebo (n = 36; MERIT-2 OL macitentan 10 mg-DB-placebo patients) and those previously on macitentan 10 mg (n = 40; MERIT-2 OL macitentan 10 mg-DB-macitentan patients). The Long-term [DB/OL] macitentan 10 mg subgroup comprised patients enrolled in the MERIT-2 study who received macitentan 10 mg during the MERIT-1 study (n = 40) (Fig. S2). For analyses performed with this dataset, baseline was defined as the time of entry into MERIT-1.
Safety analyses included treatment-emergent AEs, AEs leading to premature discontinuation of study treatment, SAEs, AESIs, laboratory parameters, and deaths. Efficacy analyses included change from baseline in 6MWD and the proportion of patients with worsened, improved, or unchanged WHO FC.
Results
Patient Characteristics
A total of 80 patients (DB-placebo patients n = 40; DB-macitentan patients n = 40) from 16 countries were randomized in the MERIT-1 study, 77 of whom completed the study. Of these, 76 patients (DB-placebo patients n = 36; DB-macitentan patients n = 40) continued into the MERIT-2 study and were treated with OL macitentan 10 mg (Fig. 1). Data were collected in MERIT-2 between February 3rd 2015 and March 21st 2022.
Fig. 1
Patient disposition. *Data from 19/23 patients from China were excluded from the analyses after the cut-off date of October 17, 2019; serious adverse events, pregnancies and deaths continued to be reported. In total, 38 (50.0%) patients completed the study: 12 (15.8%) completed the safety follow-up/end of study visit and 26 (34.2%) were enrolled in a post-trial access program or the UMBRELLA study. There were 19 (25%) patients who prematurely discontinued the study for the following reasons: 14 (18.4%) died (6 DB-placebo, 8 DB-macitentan), 2 (2.6%) due to physician decision (1 DB-placebo, 1 DB-macitentan), 2 (2.6%) due to patient decision (1 DB-placebo, 1 DB-macitentan), 1 (1.3%; DB-macitentan) was lost to follow-up. Two of the patients who had ‘death’ as reason of premature discontinuation of study stopped treatment due to ‘physician decision’. 19 (25%) Chinese patients were ongoing at the cut-off date and were excluded from the analyses. DB double-blind, OL open-label
×
In early 2020, during the course of the study, a potential issue with China’s Human Genetic Resources updated regulations [17] was identified (further details provided in Supplementary Methods 3). To ensure compliance with data export rules, information in the clinical database collected after 17 October 2019 from Chinese patients were excluded from the final analysis, however SAEs, pregnancies and deaths were reported to the global safety database.
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Of the 76 patients in MERIT-2, 26 (34.2%) completed 24 weeks of study treatment. There were 31 (40.8%) patients who prematurely discontinued study treatment for the following reasons: death (n = 12; 15.8%), physician decision (n = 10, 13.2%), patient decision (n = 8; 10.5%) and loss to follow-up (n = 1; 1.3%). Nineteen (25.0%) Chinese patients were ongoing at the 17 October 2019 data cut-off and were excluded from the analyses as of this date (Fig. 1). A post hoc sensitivity analysis of safety excluding patients ongoing at Chinese sites after the cut-off date was performed and results are presented in Tables S1–S4. There were 38 (50.0%) patients who completed the study, 19 (25.0%) who discontinued and 19 (25.0%) who were study-ongoing at data cut-off date (Chinese patients); reasons for study discontinuations are outlined in Fig. 1.
Patients were predominantly female (63.2%) and white (64.5%); the mean (standard deviation [SD]) age at the start of MERIT-1 was 57.8 (13.99) years (Table 1). The majority of patients were enrolled at sites in Eastern Europe (46.1%) and Asia (35.5%). The proportion of patients on at least one concomitant PAH-specific therapy at the start of MERIT-2 was 65.8%, the most common being a phosphodiesterase-5 inhibitor: sildenafil (n = 35; 46.1%) or tadalafil (n = 13; 17.1%). In addition, 5 patients (6.6%) were receiving riociguat and 2 (2.6%) patients were receiving iloprost.
Table 1
Demographics and clinical characteristics at MERIT-1 baseline for patients who entered MERIT-2
Characteristic
Observation commencing from MERIT-2 enrollment
Observation commencing from MERIT-1 enrollment
MERIT-2 OL macitentan 10 mg group
All patients
N = 76
DB-placebo patients
N = 36
DB-macitentan patients
N = 40
Long-term (DB/OL) macitentan 10 mg subgroup
N = 40a
Female,n (%)
48 (63.2)
22 (61.1)
26 (65.0)
26 (65.0)
Age, years, mean (SD)
57.8 (13.99)
57.4 (14.16)
58.2 (14.00)
58.2 (14.00)
Time since CTEPH diagnosis, years, mean (SD)
1.5 (2.21)
1.3 (2.04)
1.7 (2.36)
1.7 (2.36)
Race,n (%)
White
49 (64.5)
24 (66.7)
25 (62.5)
25 (62.5)
Asian
27 (35.5)
12 (33.3)
15 (37.5)
15 (37.5)
Geographical region,n (%)
Eastern Europe
35 (46.1)
18 (50.0)
17 (42.5)
17 (42.5)
Asia
27 (35.5)
12 (33.3)
15 (37.5)
15 (37.5)
Western Europe
12 (15.8)
5 (13.9)
7 (17.5)
7 (17.5)
Latin America
2 (2.6)
1 (2.8)
1 (2.5)
1 (2.5)
Six-minute walk distance, m, mean (SD)
352.6 (81.73)
352.0 (75.52)
353.0 (87.90)
353.0 (87.90)
WHO FC,n (%)
II
17 (22.4)
5 (13.9)
12 (30.0)
12 (30.0)
III
58 (76.3)
30 (83.3)
28 (70.0)
28 (70.0)
IV
1 (1.3)
1 (2.8)
0 (0.0)
0 (0.0)
Pulmonary vascular resistance, dyn.s/cm5, mean (SD)
941.3 (411.02)
954.7 (448.38)
929.2 (379.65)
934.4 (393.64)
Baseline characteristics for patients entering MERIT-2 were as recorded at the start of the MERIT-1 study
CTEPH chronic thromboembolic pulmonary hypertension, DB double-blind, OL open-label, SD standard deviation, WHO FC World Health Organization functional class
Safety and Tolerability of Macitentan 10 mg in MERIT-2
For the All patients MERIT-2 OL macitentan 10 mg group (N = 76), the median (interquartile range [Q1, Q3]) duration of OL macitentan treatment was 45.5 (26.0, 66.1) months and over a third of patients (35.5%) received study treatment for at least 60 months. The median (Q1, Q3) duration of treatment was similar between the DB-placebo (46.6 [31.1, 67.4]) and DB-macitentan patient subgroups (44.8 [26.0, 64.1]; Table 2).
Table 2
Safety and exposure
Observation commencing from MERIT-2 enrollment
Observation commencing from MERIT-1 enrollment
MERIT-2 OL macitentan 10 mg group
All patients
N = 76
DB-placebo patients
N = 36
DB-macitentan patients
N = 40
Long-term (DB/OL) macitentan 10 mg subgroup
N = 40
Exposurea, months, median (Q1, Q3)
45.5 (26.0, 66.1)
46.6 (31.1, 67.4)
44.8 (26.0, 64.1)
50.4 (31.5, 69.7)
Patient with ≥ 1 adverse events,n (%)
Adverse event
72 (94.7)
34 (94.4)
38 (95.0)
40 (100)
Serious adverse event
44 (57.9)
19 (52.8)
25 (62.5)
26 (65.0)
Adverse event leading to treatment discontinuation
9 (11.8)
4 (11.1)
5 (12.5)
5 (12.5)
Most frequent adverse eventsb,n (%)
Worsening of pulmonary hypertension
15 (19.7)
7 (19.4)
8 (20.0)
8 (20.0)
Decreased hemoglobin
14 (18.4)
7 (19.4)
7 (17.5)
11 (27.5)
Upper respiratory tract infection
12 (15.8)
4 (11.1)
8 (20.0)
10 (25.0)
Peripheral edema
11 (14.5)
5 (13.9)
6 (15.0)
15 (37.5)
Anemia
10 (13.2)
8 (22.2)
2 (5.0)
3 (7.5)
Bronchitis
9 (11.8)
5 (13.9)
4 (10.0)
4 (10.0)
Cough
9 (11.8)
5 (13.9)
4 (10.0)
6 (15.0)
Nasopharyngitis
9 (11.8)
5 (13.9)
4 (10.0)
4 (10.0)
Dizziness
8 (10.5)
3 (8.3)
5 (12.5)
7 (17.5)
Cardiac failure
8 (10.5)
3 (8.3)
5 (12.5)
6 (15.0)
Dyspnea
8 (10.5)
3 (8.3)
5 (12.5)
6 (15.0)
Arterial angioplastyc
7 (9.2)
3 (8.3)
4 (10.0)
4 (10.0)
Back pain
7 (9.2)
5 (13.9)
2 (5.0)
2 (5.0)
Cataract
7 (9.2)
4 (11.1)
3 (7.5)
3 (7.5)
Diarrhea
7 (9.2)
5 (13.9)
2 (5.0)
3 (7.5)
Headache
7 (9.2)
5 (13.9)
2 (5.0)
3 (7.5)
Urinary tract infection
7 (9.2)
3 (8.3)
4 (10.0)
6 (15.0)
Pneumonia
7 (9.2)
3 (8.3)
4 (10.0)
4 (10.0)
Syncope
7 (9.2)
1 (2.8)
6 (15.0)
6 (15.0)
Decreased weight
7 (9.2)
6 (16.7)
1 (2.5)
2 (5.0)
Arthralgia
6 (7.9)
5 (13.9)
1 (2.5)
2 (5.0)
Increased C-reactive protein
6 (7.9)
2 (5.6)
4 (10.0)
4 (10.0)
Pain in extremity
6 (7.9)
2 (5.6)
4 (10.0)
6 (15.0)
Right ventricular failure
6 (7.9)
1 (2.8)
5 (12.5)
6 (15.0)
Osteoarthritis
5 (6.6)
4 (11.1)
1 (2.5)
1 (2.5)
Pyrexia
5 (6.6)
1 (2.8)
4 (10.0)
4 (10.0)
Deaths, n (%)
14 (18.4)
6 (16.7)
8 (20.0)
8 (20.0)
Treatment emergent periods were defined as follows: MERIT-2 OL macitentan 10 mg group: Treatment start date in MERIT-2 OL, up to 30 days after end of treatment in MERIT-2 OL; Long-term (DB/OL) macitentan 10 mg subgroup: Start of macitentan in MERIT-1 DB, up to 30 days after end of treatment in MERIT-2 OL
DB double-blind, OL open-label, Q1, Q3 interquartile range
aFor OL datasets, exposure refers to OL exposure to macitentan 10 mg; for DB/OL dataset, exposure refers to cumulative DB/OL exposure to macitentan 10 mg
bAdverse events ≥ 10% in any group, by Preferred Term
cTerm refers to balloon pulmonary angioplasty
During the OL period, 72 (94.7%) patients experienced at least one treatment-emergent AE and 44 (57.9%) at least one treatment-emergent SAE (Table 2 and Table S2a). The most frequently reported AEs were worsening of pulmonary hypertension (n = 15; 19.7%), decreased hemoglobin (n = 14; 18.4%) and upper respiratory tract infection (n = 12; 15.8%) (Table 2). The most frequent SAEs were BPA (combined Preferred Terms of arterial angioplasty or angioplasty: n = 10; 13.2%; this procedure was reported as an SAE due to the requirement for hospitalization), worsening of pulmonary hypertension (n = 6; 7.9%) and right ventricular failure (n = 5; 6.6%) (Table S2a). All reported BPA procedures occurred between months 14 and 64 post-MERIT-2 baseline. Two patients had drug-related SAEs: one patient experienced hypotension and one patient hematuria.
AESIs of edema and fluid retention, anemia/decrease of hemoglobin, hepatic events and hypotension were reported in 22 (28.9%), 22 (28.9%), 15 (19.7%) and 12 (15.8%) patients, respectively (Table 3). Nine (11.8%) patients experienced an AE leading to premature treatment discontinuation; further details are provided in Table S3a. No notable changes in clinical laboratory parameters were observed over the course of the study.
Table 3
Adverse events of special interest
Observation commencing from MERIT-2 enrollment
Observation commencing from MERIT-1 enrollment
MERIT-2 OL macitentan 10 mg group
All patients
N = 76
DB-placebo patients
N = 36
DB-macitentan patients
N = 40
Long-term (DB/OL) macitentan 10 mg
subgroup
N = 40
Edema and fluid retentiona,n (%)
22 (28.9)
9 (25.0)
13 (32.5)
20 (50.0)
Incidence rate – per 100 person-year (95% CI)
9.1 (6.0, 13.9)
7.7 (4.0, 14.7)
10.6 (6.1, 18.2)
19.8 (12.8, 30.7)
Anemia/hemoglobin decreaseb,n (%)
22 (28.9)
14 (38.9)
8 (20.0)
12 (30.0)
Incidence rate – per 100 person-year (95% CI)
9.4 (6.2, 14.3)
13.1 (7.8, 22.1)
6.3 (3.2, 12.7)
9.2 (5.3, 16.3)
Hepatic eventsc,n (%)
15 (19.7)
6 (16.7)
9 (22.5)
9 (22.5)
Incidence rate – per 100 person-year (95% CI)
5.8 (3.5, 9.6)
4.6 (2.1, 10.2)
6.9 (3.6, 13.3)
6.2 (3.2, 12.0)
Hypotensiond, n (%)
12 (15.8)
3 (8.3)
9 (22.5)
9 (22.5)
Incidence rate – per 100 person-year (95% CI)
4.6 (2.6, 8.0)
2.3 (0.7, 7.0)
6.9 (3.6, 13.3)
6.1 (3.2, 11.7)
Treatment emergent periods were defined as follows: MERIT-2 OL macitentan 10 mg group: Treatment start date in MERIT-2 OL, up to 30 days after end of treatment in MERIT-2 OL; Long-term (DB/OL) macitentan 10 mg subgroup: Start of macitentan in MERIT-1 DB, up to 30 days after end of treatment in MERIT-2 OL
AE adverse event, AESI AE of special interest, CI confidence interval, DB double-blind, OL open-label, Q1, Q3 interquartile range
aDuring the OL period, reported as serious in one DB-macitentan patient (day of AE onset: 1477), no listed AESIs led to premature study drug discontinuation; one additional serious AESI reported during the DB period for the Long-term (DB/OL) macitentan 10 mg subgroup
bDuring the OL period, reported as serious in 1 DB-macitentan patient (day of AE onset: 1358); AESIs leading to premature study drug discontinuation listed in 2 patients (1 DB-macitentan and 1 DB-placebo, (day of AE onset 1083 and 37, respectively)
cDuring the OL period, reported as serious in 1 DB-macitentan patient (day of AE onset: 1377); AESI leading to premature study drug discontinuation listed in 1 patient (DB-placebo; day of AE onset: 2101); the most common hepatic AESI experienced in ≥ 5% of patients was increased bilirubin (All patients MERIT-2 OL macitentan 10 mg group n = 5; 6.6%; Long-term (DB/OL) macitentan 10 mg subgroup n = 3; 7.5%)
dReported as serious in 1 DB-macitentan patient (day of AE onset: 500); no listed AESIs led to premature study drug discontinuation
Fourteen (18.4%) patients died during the OL period; causes of death are detailed in Table S4a. The most frequently reported causes of death were cardiac disorders (n = 7; 9.2%). All deaths were treatment-emergent and none were assessed to be related to macitentan by the investigator.
Safety and Tolerability of Macitentan 10 mg in Patients Who Received Macitentan in MERIT-1 and MERIT-2
For patients in the Long-term (DB/OL) macitentan 10 mg subgroup (N = 40), the median (Q1, Q3) duration of macitentan treatment was 50.4 (31.5, 69.7) months, with 35.0% of patients receiving study treatment for at least 60 months.
During the DB/OL period, 40 (100%) patients in the long-term macitentan 10 mg subgroup experienced at least one treatment-emergent AE and 26 (65.0%) experienced at least one treatment-emergent SAE (Table 2, Table S2a). The nature of reported AEs was consistent with the OL group (Table 2, Table S2a) and the known profile of the drug [14, 15]. AESIs of edema and fluid retention, anemia/decrease of hemoglobin, hepatic events and hypotension were reported in 20 (50.0%), 12 (30.0%), 9 (22.5%) and 9 (22.5%) patients, respectively (Table 3).
Eight patients (20.0%) in the Long-term (DB/OL) macitentan 10 mg subgroup died during the OL period, with the most frequently reported causes of death being cardiac disorders (n = 5; 12.5%) (Table S4a). All deaths were treatment-emergent and none were assessed to be related to macitentan by the investigator.
Sensitivity Analyses
Results for the post hoc sensitivity analyses for safety, conducted with the Chinese patients ongoing at the data cut-off removed, were generally consistent with the main analyses for both the All patients MERIT-2 OL macitentan 10 mg group (N = 57) and the Long-term (DB/OL) macitentan 10 mg subgroup (N = 30) (Tables S1–S4).
Impact of COVID-19
The COVID-19 pandemic started in early 2020, affecting the last 2 years of data collection for the MERIT-2 study. Guidance was provided to investigators for managing study-related procedures during the pandemic as part of a protocol amendment. Impact of COVID-19 on MERIT-2 was judged to be minimal. Major COVID-19-related impact on data collection included missing laboratory test results in 29 (38.2%) patients and late safety follow-up or end of study visits in 5 (6.6%) participants from the All patients MERIT-2 OL macitentan 10 mg treatment group. COVID-19-related treatment emergent AEs were observed in 7 (9.2%) patients and 1 (1.3%) patient presented with a serious COVID-19-related treatment emergent AE (COVID-19 pneumonia). No COVID-19-related AEs led to premature discontinuation of study treatment and no deaths occurred due to COVID-19 infection.
Efficacy
For the All patients MERIT-2 OL macitentan 10 mg group, the mean (SD) 6MWD at MERIT-2 baseline was 379.4 m (87.05); this was 388.0 m (83.31) in DB-macitentan patients and 369.9 m (91.25) in DB-placebo patients. The mean (SD) change in 6MWD from MERIT-2 baseline to Months 6 and 36 were 4.9 m (44.60) and 11.0 m (60.02) overall, − 0.4 m (43.62) and − 0.3 m (69.22) for DB-macitentan patients, and 10.7 m (45.63) and 23.2 m (46.55) for DB-placebo patients, respectively (Fig. 2). For patients in the Long-term (DB/OL) macitentan 10 mg subgroup, the mean (SD) 6MWD at MERIT-1 baseline was 353.0 m (87.90). The mean (SD) change in 6MWD from MERIT-1 baseline to MERIT-2 Months 6 and 36 was 38.5 m (52.75) and 32.1 m (76.59).
Fig. 2
6MWD from start of open-label macitentan treatment for the MERIT-2 OL macitentan 10 mg analysis sets. 6MWD (graph): Mean ± SE; Change in 6MWD (table): Mean ± SD. Baseline value is the last non-missing assessment obtained prior or equal to the start of macitentan 10 mg in MERIT-2 OL. Data from 19/23 patients from China were excluded from the analyses after the cut-off date of October 17, 2019. 6MWD six-minute walk distance, DB double-blind, OL open-label, SD standard deviation, SE standard error
×
For the All patients MERIT-2 OL macitentan 10 mg group, the majority of patients (60.5%) were in WHO FC III at MERIT-2 baseline. For most patients, this remained unchanged or improved at Month 6 (83.3% and 12.5%, respectively) and at Month 36 (80.0% and 18.2%, respectively) (Table 4). Results were similar for patients in the Long-term (DB/OL) macitentan 10 mg subgroup (Table 4).
Table 4
WHO FC status
Observation commencing from MERIT-2 enrollment
Observation commencing from MERIT-1 enrollment
MERIT-2 OL macitentan 10 mg group
All patients
N = 76
DB-placebo patients
N = 36
DB-macitentan patients
N = 40
Long-term (DB/OL) macitentan 10 mg
subgroup
N = 40
Baseline WHO FCa, n (%)
I
4 (5.3)
1 (2.8)
3 (7.5)
0
II
25 (32.9)
10 (27.8)
15 (37.5)
12 (30.0)
III
46 (60.5)
24 (66.7)
22 (55.0)
28 (70.0)
IV
1 (1.3)
1 (2.8)
0
0
OL Month 6, n
72
33
39
39
Worsened, n (%)
3 (4.2)
0
3 (7.7)
1 (2.6)
Unchanged, n (%)
60 (83.3)
29 (87.9)
31 (79.5)
26 (66.7)
Improved, n (%)
9 (12.5)
4 (12.1)
5 (12.8)
12 (30.8)
OL Month 12, n
68
32
36
36
Worsened, n (%)
3 (4.4)
0
3 (8.3)
1 (2.8)
Unchanged, n (%)
55 (80.9)
27 (84.4)
28 (77.8)
25 (69.4)
Improved, n (%)
10 (14.7)
5 (15.6)
5 (13.9)
10 (27.8)
OL Month 36, n
55
27
28
28
Worsened, n (%)
1 (1.8)
0
1 (3.6)
0
Unchanged, n (%)
44 (80.0)
20 (74.1)
24 (85.7)
20 (71.4)
Improved, n (%)
10 (18.2)
7 (25.9)
3 (10.7)
8 (28.6)
DB double-blind, OL open-label, WHO FC World Health Organization functional class
aMERIT-2 OL macitentan 10 mg group baseline value is the last non-missing assessment obtained prior or equal to the start of macitentan in MERIT-2 OL. Long-term (DB/OL) macitentan 10 mg subgroup baseline value is the value from the last non-missing assessment obtained prior to, i.e., before or on the day of randomization in MERIT-1 DB
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Discussion
These analyses of MERIT-1 [16] and its OL extension study (MERIT-2) provide valuable long-term data in patients with CTEPH treated with macitentan 10 mg, with over a third of patients receiving treatment for at least 60 months. Insights into safety and efficacy were gained using two partially overlapping groups: patients who received macitentan 10 mg in MERIT-2, regardless of their treatment assignment in MERIT-1 (All patients OL macitentan 10 mg group) and those who received macitentan 10 mg in both the MERIT-1 DB and MERIT-2 OL periods (Long-term [DB/OL] macitentan 10 mg subgroup).
Compared to other CTEPH patient populations, either in contemporary registries [18‐20] or earlier clinical trials [10‐12], patients enrolling in MERIT-1 tended to be younger, with higher baseline PVR and 6MWD levels and a similar proportion of patients in WHO FC III/IV [18, 19]. The proportion of deaths occurring during MERIT-2 was similar to the 3-year survival (80%) seen in patients with inoperable CTEPH in the United States CTEPH registry [18].
Safety results from these analyses echo the initial findings from patients with CTEPH in the MERIT-1 study [16], and are similar in nature to those reported in patients with PAH treated with macitentan in long-term clinical trials [21, 22] and in a real-world clinical setting [23]. There were no new safety findings for macitentan 10 mg identified from this analysis and overall, the nature of adverse events was generally consistent with the known safety profile of macitentan [14, 15]. The proportion of patients experiencing AESIs in both the All patients MERIT-2 OL macitentan 10 mg group and the Long-term (DB/OL) macitentan 10 mg subgroup was slightly higher than that observed previously with macitentan use in patients with PAH [22, 24]. However, the events were mostly non-serious and few led to treatment discontinuation. The length of the exposure periods and small patient population in MERIT-2 should be taken into account when interpreting these results. A higher incidence of the AESI of anemia/decreased hemoglobin was observed during OL treatment in DB-placebo versus DB-macitentan patients. Such an observation is not unexpected, as this is a known adverse effect of macitentan, which usually stabilizes over time [14, 15]. The incidence of AESIs was slightly higher for the Long-term (DB/OL) macitentan 10 mg subgroup versus the MERIT-2 OL macitentan 10 mg group, in particular for AESIs of edema and fluid retention. This is also not unexpected given the longer exposure period.
In terms of efficacy, long-term improvements in 6MWD were observed for patients in the MERIT-2 OL macitentan 10 mg group who were allocated to macitentan during MERIT-1 (DB-macitentan subgroup), as the initial improvements observed from baseline in MERIT-1 (mean [SD] change: 35.0 m [52.52] [16]) were maintained up to Month 36 in MERIT-2. Patients in the DB-placebo subgroup demonstrated an improved 6MWD at 6 months post baseline in the OL (mean [SD] change 10.7 m [45.63]), confirming the positive findings observed for participants who received macitentan 10 mg for the same time period in the MERIT-1 study. These changes observed in the DB-placebo subgroup generally persisted over time. Over 12 months in MERIT-2, most patients’ WHO FC status improved or remained unchanged compared with baseline; consistent with MERIT-1 [16], more patients improved rather than worsened.
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There were 10 (13.2%) patients who had BPA procedures carried out during MERIT-2. No BPAs were reported in the first year of the OL study and are therefore unlikely to have impacted the efficacy results. The proportion of BPAs reported in MERIT-2 is reflective of both the time the study was conducted and the location of the study sites. Data from the Worldwide CTEPH Registry [19], collected around a similar time period (2015–2019), suggest that approximately 20% of patients were considered candidates for BPA. However, the majority of these were performed in Western Europe and Japan whereas in MERIT-2, the majority of patients were from Eastern Europe and China. In the United States CTEPH registry, collecting data between 2015 and 2019, only 5% of patients underwent BPA [25], demonstrating global differences in the availability of BPA at the time.
There are limitations associated with these analyses. The sample size was small (N = 76) with high dropout rates, and this was further impacted by the required reduction in data collection for 19 Chinese patients. However, sensitivity analyses excluding these patients were consistent with the main analyses. Data from this study are uncontrolled and descriptive in nature and aside from safety analyses, all results should be considered exploratory. These are limitations inherent to OL extension study design. Finally, no hemodynamic (PVR) or N-terminal pro-brain natriuretic peptide data were available for the OL period.
Conclusions
These analyses of MERIT-1 and MERIT-2 provide long-term safety and efficacy data in patients with inoperable CTEPH treated with macitentan 10 mg. No new safety findings for macitentan 10 mg were identified and overall, the nature of adverse events reported was consistent with the known safety profile of macitentan. Patients in the DB-macitentan subgroup maintained the improvements in 6MWD seen during MERIT-1 and patients in the DB-placebo subgroup demonstrated an improved 6MWD at 6 months post baseline, confirming the positive findings observed for participants who received macitentan 10 mg for the same time period in the MERIT-1 study.
Acknowledgements
We thank the participants of this study.
Medical Writing, Editorial, and Other Assistance
Medical writing assistance was provided by Kate Horne PhD and Laura Corbett PhD of eluSCIdate Ltd (Meggen, Switzerland) and was funded by Actelion Pharmaceuticals Ltd, a Johnson & Johnson Company. Clinical evaluation of hepatic safety was performed by the Independent Liver Safety Data Review Board: Willis Maddrey MD (chairperson), Paul Watkins MD, and James Freston, MD.
Declarations
Conflict of Interest
Nick H Kim served as a Scientific Committee member for Johnson & Johnson; received research grants/support from Enzyvant and Lung Biotechnology; received consultant fees from Johnson & Johnson, Bayer, Merck, United Therapeutics, Gossamer Bio, Pulnovo and Polarean; and received speaker fees from Johnson & Johnson, Bayer and Merck. Andrea M D'Armini has received fees for organising Masters-level courses, lecture fees and writing assistance from Merck and AOP health; and fees for serving on Scientific Committees from Johnson & Johnson. Luke S Howard has received consultancy fees from Ferrer, Johnson & Johnson and Morphic; fees for serving on Scientific Committees/advisory boards from Gossamer Bio, Apollo Therapeutics, Altavant, MSD and Johnson & Johnson; honoraria for lectures from Johnson & Johnson, MSD, Aerovate and Ferrer; fees for expert testimony from Johnson & Johnson; travel support from Johnson & Johnson and Gossamer Bio; received institutional grant support from MSD and holds stock in Circular, ATXA Therapeutics, iOWNA, Calibre Biometrics and OneWelbeck Clinic. David P Jenkins has received fees for serving on a Scientific Committee for Johnson & Johnson and lecture fees from Bayer. Zhi-Cheng Jing has received consultancy fees, lecture fees and fees for serving on a Scientific Committee from Johnson & Johnson, Bayer, GlaxoSmithKline, Lee’s Pharmaceuticals, and Pfizer; fees for serving on an adjudication committee from Johnson & Johnson; and grant support from Johnson & Johnson, Bayer, GlaxoSmithKline, Pfizer, The National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1–002), and The National Key Research and Development Program of China (No. 2016YFC0901502). Current affiliation: Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China. Eckhard Mayer has received consultancy fees from Johnson & Johnson, Bayer and Merck; lecture fees from Johnson & Johnson, Bayer and Merck; and fees for serving on a Scientific Committee for Johnson & Johnson. Liliya Chamitava, was an employee of Johnson & Johnson at the time of the study. Current affiliation: Valos S.r.L, Genova, Italy. Gabriela Lack, Hany Rofael and Maria Solonets are employees of Johnson & Johnson. Hossein-Ardeschir Ghofrani has received fees for serving as a board member for AbbVie, Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; consultancy fees and fees for serving on a Scientific Committee for Johnson & Johnson, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; lecture fees from Johnson & Johnson, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and grant support from Johnson & Johnson, Bayer, Novartis, and Pfizer.
Ethical Approval
Data were collected in MERIT-1 and MERIT-2 in accordance with the Good Clinical Practice guidelines and Declaration of Helsinki. The study protocol was approved by the institutional review board, or independent ethics committee at each participating site and patients gave full written consent for their participation and use of their data for publication. The Scientific Committee, composed of external experts in CTEPH with experience in clinical studies, were involved in the study design and provided guidance on both MERIT-1 and MERIT-2. An Independent Liver Safety Data Review Board provided assessment and advice regarding serious hepatic adverse events of special interest (AESI). The list of study sites, investigators and ethical committees are included in Supplementary Methods 1.
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