SUMMARY

• There was a phase 3 study and an open-label extension to the study investigating the effect of OPSUMIT in patients with Eisenmenger syndrome (ES): MAESTRO and MAESTRO-OL.¹
• OPSUMIT did not show an improvement over placebo on the primary endpoint of change from baseline to week 16 in 6-minute walk distance (6MWD) in patients with ES. OPSUMIT was well-tolerated in this study population and safety was generally consistent with the known safety profile for OPSUMIT from previous clinical studies.¹
• The OPsumit USers (OPUS) and OPsumit Historical USers (OrPHeUS) combined data sets provide additional insight into real-world use of OPSUMIT in patients with pulmonary arterial hypertension (PAH) associated with congenital heart disease (PAHCHD), including ES.² 
• Additional studies and case reports are available for review in the References.^3-11

CLINICAL DATA

MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity (MAESTRO)

MAESTRO was a multicenter, double-blind, randomized, placebo-controlled, 16-week, phase 3 study to evaluate the effects of OPSUMIT on exercise capacity in patients with ES. Patients were randomized 1:1 to receive placebo or OPSUMIT once daily for 16 weeks. The primary endpoint was change from baseline to week 16 in 6MWD. Secondary endpoints included change from baseline to week 16 in World Health Organization (WHO) functional class (FC) and Borg Dyspnea index. Exploratory endpoints included N-terminal pro b-type natriuretic peptide (NT-proBNP) level at end of treatment (EOT) and change in oxygen saturation (SpO₂) from baseline to week 16. Safety endpoints included evaluation of adverse events (AEs), laboratory abnormalities, and decreases in SpO₂ >10% at rest. Additionally, a hemodynamic substudy was performed at select specialized centers looking at additional exploratory hemodynamic endpoints.¹

Select inclusion criteria included male and female patients with ES aged ≥12 years of age including patients with Down syndrome and those with anatomically classified complex cardiac defects (excluding conotruncal defects, which refer to ventricular outflow tract anomalies such as tetralogy of Fallot, truncus arteriosus or transposition of great arteries). Enrollment in the hemodynamic substudy was restricted to patients aged ≥18 years, with ES and simple atrial septal defects or ventricular septal defects, without Down syndrome. ES was established by echocardiography showing a large or nonrestrictive open congenital defect at atrial, ventricular or arterial level (isolated defect or in combination) and righttoleft shunt or bidirectional shunt with prevalent right-to-left direction. Other inclusion criteria included resting SpO₂ ≤90% and >70%, mean pulmonary arterial pressure (mPAP) >25 mmHg, pulmonary artery wedge pressure (PAWP) or left ventricular end diastolic pressure (LVEDP) ≤15 mmHg, pulmonary vascular resistance (PVR) ≥800 dyn⋅sec⋅cm^-5, WHO FC II to IV, and 6MWD of 50 to 450 m.¹

Patients were excluded from the study if they had significant left ventricular dysfunction (ejection fraction <45%), previously recognized moderate-to-severe lung disease, conotruncal heart defects, severe tricuspid regurgitation or greater than mild tricuspid stenosis, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3×upper limit of normal (ULN), iron deficiency (serum ferritin <10 mcg/L), treatment by phlebotomy within 1 month prior to randomization, and treatment with endothelin receptor antagonists (ERAs) or prostanoids within 1 month prior to randomization. In the hemodynamic substudy, patients with certain congenital heart lesions where estimation of PVR was not readily possible or reproducible with standard techniques, were excluded.¹

Results

Baseline Characteristics

Overall, 226 patients were enrolled in the study (placebo, n=112; OPSUMIT, n=114) and 39 patients participated in the hemodynamic substudy (placebo, n=19; OPSUMIT, n=20). Baseline characteristics of the study population are summarized in Table: Baseline Characteristics.¹

Primary Endpoint

After 16 weeks of treatment, the 6MWD increased from baseline by a mean ± standard deviation (SD) of 18.3±84.4 m in the OPSUMIT group and 19.7±53.0 m in the placebo group. The 6MWD least-squares mean difference at week 16 was -4.7 m between OPSUMIT and placebo (95% confidence limit [CL], -22.8 to 13.5; P=0.612). The proportion of patients with an improvement in 6MWD at week 16 (change from baseline >0 m) was 72.8% in the OPSUMIT group and 65.2% in the placebo group. The difference in exercise capacity between treatment groups was consistent in prespecified subgroups (location of cardiac defect, WHO FC, geographical region, phosphodiesterase type 5 inhibitor (PDE-5i) at baseline and Down syndrome status). Post hoc analyses showed that the difference between treatment groups was also consistent regardless of simple or complex cardiac defects and gender. A post hoc analysis also showed that the treatment effect was similar for patients with and without a hemoglobin decrease of ≥2 g/dL from baseline to EOT.¹

Secondary and Exploratory Endpoints

WHO FC from baseline to week 16 improved in 8.8% of patients in the OPSUMIT group and 14.3% in the placebo group, odds ratio 0.53 (95% CL, 0.23-1.24). Worsening of WHO FC was reported for 1 patient in each treatment arm. There were no observed relevant trends in Borg dyspnea index between the OPSUMIT and placebo groups.¹

At EOT, the geometric mean NT-proBNP level increased to 109.2% (95% CL, 96.5-123.6) of the baseline value in the placebo group and decreased to 88.7% (95% CL, 80.0-98.3) of the baseline value in the OPSUMIT group (ratio of geometric means, 0.80; 95% CL, 0.68-0.94). The placebo-corrected mean treatment effect of OPSUMIT on SpO₂ at rest was 0.8% (95% CL, -0.3 to 2.0). Additionally, the placebo-corrected treatment effect on SpO₂ immediately after 6MWD was 2.0% (95% CL, -0.7 to 4.7).¹

Hemodynamic Substudy

The geometric mean pulmonary vascular resistance index (PVRi) at week 16 decreased to 85.3% of the baseline value in the OPSUMIT group and increased to 101.1% of the baseline value in the placebo group (ratio of geometric means, 0.87; 95% CL, 0.73-1.03). At week 16, the mean±SD systemic vascular resistance index decreased from baseline by 376±910.4 dyn∙sec/cm⁵/m² in the OPSUMIT group and increased 11±1119.1 dyn∙sec/cm⁵/m² in the placebo group (least-squares mean difference, -‍410 dyn∙sec/cm⁵/m²; 95% CL, -953 to 133). There were no differences between the treatment groups for any of the other cardiac hemodynamic parameters.¹

A post hoc analysis of 6MWD for patients in the hemodynamic substudy showed a mean increase from baseline to week 16 of 34.1 m in the OPSUMIT group and 3.5 m in the placebo group (least-squares mean difference, 24.9 m; 95% CL, -9.1 to 59.0). The proportion of patients in the substudy with an improvement in 6MWD at week 16 (change from baseline >0 m) was 85.0% in the OPSUMIT group and 57.9% in the placebo group.¹

Safety

An overview of common AEs and other laboratory findings of interest are found in Table: AEs and Laboratory Findings of Interest. Two patients (1.8%) in each group discontinued the study treatment due to an AE. Treatment serious adverse events (SAEs) were reported in 7 patients (6.1%) in the OPSUMIT group and 2 patients (1.8%) in the placebo group. Eight patients were hospitalized due to SAEs: 6 in the OPSUMIT group (1 for a nervous system disorder, 3 for cardiac disorders, and 2 for infection) and 2 in the placebo group (both for cardiac disorders). One patient died in the OPSUMIT group due to respiratory failure and was considered unrelated to the study treatment.¹

MAESTRO-OL

Two hundred seventeen patients (97% of the patients who completed the double-blind study) entered the open-label extension study and 202 patients had an assessment at month 6 (data collected up to June 07, 2017). Patients who received double-blind placebo followed by open-label OPSUMIT (n=102) had a mean±SD improvement in 6MWD of 27.1±43.4 m. The improvement was maintained at month 12 with a mean±SD increase of 24.5±55.6 m from the open label baseline. Patients who received double-blind OPSUMIT followed by open-label OPSUMIT (n=100) had a mean±SD improvement in 6MWD of 6.0±55.8 m from baseline in the open-label extension to month 12.¹

Information From the OPUS/OrPHeUS Data Sets in PAH

OPUS was a prospective, multicenter, long-term, observational drug registry in the United States (US; NCT02126943), conducted between April 2014 and June 2020.²  Patients were excluded if they were enrolled in an ongoing clinical trial. 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.^2,12 Patients who were enrolled in a clinical trial involving OPSUMIT, and those who were enrolled in OPUS were not allowed to participate in OrPHeUS. The data from OPUS and OrPHeUS were combined to describe the baseline characteristics, treatment patterns, hospitalizations, survival, and safety in patients with PAH-CHD who were treated with OPSUMIT.² 

The combined OPUS/OrPHeUS had 4626 PAH patients, of whom 4459 were prescribed OPSUMIT only for PAH. A total of 2498 (56%) patients had idiopathic/heritable PAH (I/HPAH) and 272 (6.1%) had PAH-CHD which included 80 patients with ES, 82 with left to right shunts, and 92 with small/coincidental CHD. Results specific to ES patients are discussed below.²

Baseline and Functional Characteristics

The majority of patients in the ES subgroup were female (70%) with a median (Q1-Q3) age of 42 (33-54) years and were White (70%).² Other baseline and functional characteristics are presented in Table: Baseline Characteristics at OPSUMIT Initiation in Overall PAH-CHD Group and ES Subgroup.

Hemodynamic Parameters

At OPSUMIT initiation, patients with ES had the highest median (Q1-Q3) mPAP of 58 (50-78) mmHg and PVR of 8.8 (4.1-14.2) woods unit.² 

Treatment Patterns

Of the 80 patients with ES, 33.8% received monotherapy, 51.3% received double therapy, and 15% received triple therapy at OPSUMIT initiation. The proportion of patients receiving mono, double, and triple therapy at 6 months (N=63) after OPSUMIT initiation were 20.6%, 58.7%, and 20.6%, respectively, and the proportion of patients at 12 months (N=53) after OPSUMIT initiation were 18.9%, 64.2%, and 17%, respectively. A total of 66.3% of patients with ES were treated with other PAH therapies prior to OPSUMIT initiation.² 

Exposure and Discontinuations

Across all the PAH-CHD subgroups, the discontinuations were similar.²  The discontinuations and Kaplan-Meier (KM) estimates of OPSUMIT discontinuations at 1 and 2 years for overall PAH-CHD patients and ES subgroup are presented in Table: OPSUMIT Exposure and Discontinuations for Overall PAH-CHD Group and ES Subgroup.

Safety and Tolerability

The proportion of patients with ≥1 AE was similar across the PAH-CHD subgroups. Among the ES subgroup, 8.8% experienced ≥1 hepatic AE and 5% experienced ≥1 hepatic AE of special interest.²  The AEs in overall PAH-CHD patients and the ES subgroup are summarized in the table: AEs in OPUS only in Overall PAH-CHD Group and ES Subgroup.

AEs in OPUS only in Overall PAH-CHD Group and ES Subgroup² 

Hospitalizations and Survival

The hospitalization and deaths for overall PAH-CHD population and ES subgroup are presented in the table: Hospitalizations and Deaths.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 17 May 2024.