SUMMARY

• The efficacy, safety, and tolerability of OPSUMIT in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) was evaluated in a multicenter, double-blind (DB), randomized, parallel-group, placebo-controlled, phase 2 study (MERIT-1). In MERIT-1, the treatment effect of OPSUMIT compared with placebo after 16 weeks was a significant 19% reduction in pulmonary vascular resistance (PVR; ratio of geometric means, 0.81; 95% confidence interval [CI], 0.70-0.95; P=0.0098). OPSUMIT was well tolerated in this study population and safety was consistent with the known safety profile for OPSUMIT from previous clinical studies.¹
• Long-term safety, tolerability, and efficacy of OPSUMIT in patients with inoperable CTEPH was evaluated in a multicenter, single-arm, open-label extension (OLE), phase 2 study (MERIT-2). Most frequent adverse events (AEs) were worsening of pulmonary hypertension, decreased hemoglobin and upper respiratory tract infection. The mean (standard deviation [SD]) change in the 6-minute walk distance (6MWD) from baseline in MERIT-1 to 6 and 36 months in MERIT-2 was 38.5 (52.75) m and 32.1 (76.59) m, respectively.²
• A combined analysis of the OPUS and OrPHeUS real-world data sets described the treatment patterns and safety profiles of 163 CTEPH patients and 4286 pulmonary arterial hypertension (PAH) patients that were treated with OPSUMIT.³
• A company sponsored trial (UMBRELLA) examined the use of OPSUMIT in CTEPH. Please visit ClinicalTrials.gov for more information.⁴
• The phase 3 MACiTEPH study evaluating macitentan 75 mg in patients with CTEPH was stopped due to futility. The decision to stop the trial was made in accordance with a recommendation by the study’s independent data monitoring committee following a pre-planned interim analysis. No new safety signals were observed.⁵
• Additionally, 3 case reports are not summarized within this document but are included in the references.^6-8

CLINICAL DATA

Macitentan in thE tReatment of Inoperable chronic Thromboembolic pulmonary hypertension (MERIT-1)

MERIT-1 was a prospective, multicenter, DB, randomized, parallel-group, placebo-controlled, phase 2 study assessing the efficacy, safety, and tolerability of OPSUMIT in patients with inoperable CTEPH.¹ The study design of MERIT-1 and its OLE (MERIT-2) are presented in Figure: MERIT-1 and MERIT-2 Study Design.

Exploratory endpoints included change from baseline to weeks 8 and 16 in 6MWD, N-terminal pro b-type natriuretic peptide (NT-proBNP) at week 24 expressed as a percentage of the baseline value and change from baseline to week 16 in other hemodynamic parameters, as well as the time to pulmonary hypertension-related disease progression.¹

Study Results

Overall, 186 patients were screened for study eligibility and 80 inoperable CTEPH patients were randomized 1:1 to receive either OPSUMIT once daily or placebo. The baseline characteristics of the patients were balanced between the treatment groups (Table: Baseline Characteristics). Most patients were in World Health Organization (WHO) Functional Class (FC) III and were receiving PAH-specific therapy. Of the patients who received PAH medications at baseline, the median duration of treatment was 4.6 months (interquartile range [IQR] 3.0-13.8) in the OPSUMIT group and 6.9 months (IQR 3.8-15.4) in the placebo group.¹

Primary Endpoint

After 16 weeks, the geometric mean PVR at rest decreased to 71.5% (95% CI, 63.5-80.4) of the baseline value in the OPSUMIT group, corresponding to a mean decrease from baseline of 255 dyn∙sec/cm⁵, and decreased to 87.6% (95% CI, 79.0-97.2) of the baseline value in the placebo group, corresponding to a mean decrease from baseline of 82 dyn·sec/cm⁵. The treatment effect was a significant 19% reduction in PVR with OPSUMIT compared with placebo (ratio of geometric means, 0.81;(95% CI, 0.70-0.95; P=0.0098; Figure: Primary Endpoint of PVR at Week 16). The treatment effect with respect to the primary endpoint was consistent across all prespecified subgroups, including patients receiving background PAH-specific therapy at baseline (Figure: Effect of OPSUMIT on the Primary Endpoint by Pre-specified Subgroups).¹

Secondary Endpoints

After 24 weeks of treatment, the mean (SD) change in 6MWD from baseline was an increase of 35 m (52.52) in the OPSUMIT group and 1 m (83.24) in the placebo group. The 6MWD least squares mean difference at week 24 was 34.0 m between OPSUMIT and placebo (95% CI, 2.9-65.2; P=0.033; Figure: Mean Change From Baseline in 6MWD). Patients on baseline PAH therapy had a 6MWD treatment effect of 32.4 m (95% CI, -7.0 to 71.7) while those without baseline PAH therapy had a treatment effect of 37.8 m (95% CI, -‍19.7 to 95.4; P_interaction=0.88). The least-squares mean difference for OPSUMIT versus placebo was 15.2 m (95% CI, -4.9 to 35.3, P=0.14) at week 8, 18.3 m (95% CI, -‍8.1 to 44.7, P=0.17) at week 16, and 34.0 m (95% CI, 2.9-65.2; P=0.033) at week 24. No significant difference was seen in the Borg dyspnea index between treatment groups at week 24 (least-square means difference: -0.39; 95% CI, -1.21 to 0.43; P=0.35).¹

Exploratory Endpoints

As the difference in Borg dyspnea index was not a significant secondary endpoint, the change in WHO FC at week 24 was treated as an exploratory endpoint. At week 24, 3 (7.5%) of placebo-treated patients and 0 OPSUMIT-treated patients experienced worsening in WHO FC (odds ratio [OR] 0.21; 95% CI, <0.001-1.46; P=0.096).¹

By week 24, 95.0% (95% CI, 81.5-98.7) of patients receiving OPSUMIT and 87.5% (95% CI, 72.5-94.6) of patients receiving placebo were free from pulmonary hypertension-related disease progression (P=0.085). Overall, 2 (5%) patients in the OPSUMIT group and 7 (18%) patients in the placebo group had pulmonary hypertension-related disease progression events.¹

Safety

The most frequent adverse events (AEs) are shown in Table: AEs in MERIT-1. Serious adverse events (SAEs) were reported in 3 (8%) patients treated with OPSUMIT and in 7 (18%) patients given placebo. The SAEs reported in the OPSUMIT group were acute right ventricular failure, peripheral edema, and weight increase, each reported in 1 (3%) of 40 patients. There were no observed elevations in the concentrations of alanine aminotransferase (ALT) or aspartate aminotransferase (AST). Two patients (5%), both in the placebo group, died during the study. The reasons were reported as right ventricular failure and hemorrhagic stroke.¹

OLE Study (MERIT-2)

Study Design

Patients who completed the 24-week MERIT-1 study entered MERIT-2. MERIT-2 was a multicenter, single-arm, OLE, phase 2 study, in which all patients received OPSUMIT treatment once daily (with or without food); it was performed to assess the long-term safety, tolerability, and efficacy of OPSUMIT in patients with inoperable CTEPH (Figure: MERIT-1 and MERIT-2 Study Design). Patients could receive OPSUMIT until the patient, investigator, or sponsor decided to discontinue treatment.²

Study Results

Of the 80 patients randomized in MERIT-1, 36 who received placebo and 40 who received OPSUMIT entered MERIT-2 (N=76). The data for MERIT-2 were collected between February 3, 2015, and March 21, 2022. Four MERIT-1 placebo patients did not enter MERIT-2; 1 patient died, 1 patient was lost to follow-up, and 2 patients discontinued due to physician decision.²

Overall, 26 of 76 patients completed 24 weeks of study treatment in MERIT-2. Thirty-one (40.8%) patients prematurely discontinued study treatment due to 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%).²

The patient population was predominantly female (63.2%) and white (64.5%), with a mean (SD) age of 57.8 (13.99) years at the start of MERIT-1. Most patients were enrolled at sites in Eastern Europe (46.1%) and Asia (35.5%). At the start of MERIT-2, 65.8% of patients were on ≥1 concomitant PAH-specific therapy, with the most common being a phosphodiesterase-5 inhibitor (PDE-5i; sildenafil, 35 [46.1%] or tadalafil, 13 [17.1%]). Additionally, 5 (6.6%) patients received riociguat and 2 (2.6%) patients received iloprost.²

Safety and Tolerability

Safety and Tolerability of OPSUMIT in MERIT‑2

The most common AEs are shown in Table: AEs and Exposure in MERIT-2. The most common SAE was balloon pulmonary angioplasty (n=10, 13.2%), which occurred between 14 and 64 months after MERIT-2 baseline. Nine (11.8%) patients experienced at least 1 AE that led to discontinuation of the study drug. Edema and fluid retention, anemia/decrease of hemoglobin, hepatic events, and hypotension were the AEs of special interest reported in 22 (28.9%), 22 (28.9%), 15 (19.7%), and 12 (15.8%) patients, respectively. There were 14 (18.4%) treatment-emergent deaths reported during the OL period; however, none were related to OPSUMIT. Cardiac disorder (n=7; 9.2%) was the most frequently reported cause of death.²

Safety and Tolerability of OPSUMIT in Patients Who Received OPSUMIT in MERIT‑1 and MERIT‑2

The median (quartile [Q] 1, Q3) duration of OPSUMIT treatment for patients in the long-term (DB/OL) OPSUMIT subgroup (n=40) was 50.4 (31.5, 69.7) months. Overall, 35% of patients received study treatment for ≥60 months. Forty (100%) patients experienced ≥1 treatment-emergent AE, and 26 (65%) patients experienced ≥1 treatment-emergent SAE. AEs reported in this subgroup were consistent with those reported in the OL group. Edema and fluid retention, anemia/decrease of hemoglobin, hepatic events, and hypotension were the common AEs reported in 20 (50.0%), 12 (30.0%), 9 (22.5%), and 9 (22.5%) patients, respectively. Eight (20%) deaths were reported, with cardiac disorder (n=5; 12.5%) being the most frequently reported cause of death. None of the treatment-emergent deaths were associated with OPSUMIT.²

Efficacy

The mean (SD) change in 6MWD in MERIT-2 open-label (OL) OPSUMIT patients is presented in the figure below: 6MWD From Start of OL OPSUMIT Treatment for the Merit-2 OL OPSUMIT Analysis Sets. The mean (SD) change in 6MWD from baseline in MERIT-1 to 6 and 36 months in MERIT-2 was 38.5 (52.75) m and 32.1 (76.59) m, respectively. Most patients (60.5%) in the “All patients MERIT-2 OL OPSUMIT” group were in WHO FC III at MERIT-2 baseline; this either remained unchanged or improved at month 6 (83.3% and 12.5%, respectively) and 36 (80.0% and 18.2%, respectively) for most patients. Similar results were observed in the long-term (DB/OL) OPSUMIT subgroup.²

OPUS and OrPHeUS Real-World Data Sets

The OPsumit^® USers (OPUS) Registry was a prospective, multicenter, long-term, observational drug registry in the United States (US; NCT02126943); conducted between April 2014 and June 2020. Patients were excluded if they were enrolled in an ongoing clinical trial.¹¹

The OPsumit^® Historical USers cohort (OrPHeUS) was a retrospective, multicenter, US medical center chart review (NCT03197688). OrPHeUS included patients who newly initiated OPSUMIT between October 2013 and December 2016 (inclusive) with individual patient data recorded up to March 2017. Patients who were enrolled in a clinical trial involving OPSUMIT, and those who were enrolled in OPUS were not allowed to participate in OrPHeUS ¹¹

Both the OPUS Registry and the OrPHeUS study included patients with CTEPH. Data from the combined OPUS and OrPHeUS CTEPH populations provide an opportunity to describe the clinical characteristics, treatment patterns, hepatic safety, and survival in CTEPH patients newly treated with OPSUMIT.³

Study Design

The present analyses were based on the combined OPUS and OrPHeUS data sets with the data cut-off of April 2019 for OPUS, and data observation period between October 2013 and March 2017 (inclusive) for OrPHeUS. The analysis included CTEPH and PAH patients with follow-up data. In OPUS, AEs including hepatic adverse events (HAEs), were collected via the electronic case report form. The Independent Liver Safety Data Review Board (ILSDRB) reviewed and assessed all case reports of hepatic adverse events of special interest (HAESI). In OrPHeUS, HAEs and HAESIs were identified from data in the medical charts and pharmacovigilance reporting and reviewing by the ILSDRB.³

Study Results

As of April 2019, the combined OPUS and OrPHeUS population included 163 CTEPH and 4286 PAH patients with follow-up data. Demographics and characteristics for the CTEPH and PAH populations at OPSUMIT initiation are described in Table: Demographics and baseline characteristics at OPSUMIT initiation.³

Treatment Patterns

Median (Q1-Q3) exposure time to OPSUMIT in the CTEPH population was 14 (3-30) months at data cut-off. Eighty-seven (53.4%) CTEPH patients had an exposure time of >12 months and 66 (40.5%) had an exposure time of >18 months. Median (Q1-Q3) exposure time to OPSUMIT in the PAH population was 14 (5-28) months at data cut-off. Combination therapy at OPSUMIT initiation in the CTEPH and PAH populations is shown in Table: PAH therapy at OPSUMIT initiation in the CTEPH and PAH populations.³

Safety, tolerability, survival, and hospitalization

In the CTEPH arm, 60 (36.8%) patients discontinued OPSUMIT treatment of which 26 (16%) patients and 0 (0%) patients discontinued due to an AE or HAE, respectively. Twenty-nine (17.8%) patients discontinued not due to an AE/HAE while 5 (3.1%) patients were missing a reason for discontinuation. Twelve (7.4%) and 9 (5.5%) patients were reported as having ≥1 HAE and ≥1 HAESI, respectively while there was 1 (0.6%) patient reported having ALT/AST ≥3 times the upper limit of normal (ULN) and 1 (0.6%) patient with ALT/AST ≥3 times the ULN and total bilirubin ≥2 times the ULN. In the CTEPH population, the Kaplan-Meier (KM) survival estimate (95% CI) was 95.2% (88.8-98.0) at 1 year and 90.9% (82.2, 95.5) at 2 years. In the PAH population, the KM survival estimate (95% CI) was 92.9% (91.9-93.7) at 1 year and 85.6% (84.1-87.0) at 2 years. Hospitalizations and death in the CTEPH and PAH populations are provided in Table: Hospitalizations and Deaths.³

Extended Follow-up Data From OPUS/OrPHeUS

A publication is available that reported the extended follow-up data for the combined OPUS/OrPHeUS population from April 2014 to June 2022. The study consisted of 5650 new users of OPSUMIT with follow-up data (overall follow-up set), of whom 192 and 4626 (PAH follow-up set) patients were prescribed OPSUMIT for the treatment of CTEPH and PAH, respectively. The publication reported the efficacy and safety data pertaining to the overall and PAH follow-up sets; however, results specific to the CTEPH population were not reported in the publication.¹¹

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 02 August 2024.