SUMMARY

• OPSUMIT has been investigated in a phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group study (MELODY-1) to evaluate the safety and tolerability in patients with combined pre- and post-capillary pulmonary hypertension (CpcPH) due to left ventricular dysfunction (LVD).¹
• The primary endpoint of the study was to evaluate the safety and tolerability based on the proportion of patients experiencing at least one of the following up to end of treatment (EOT): significant fluid retention (defined as an increase in body weight at any time by ≥5%, ≥5 kg from baseline due to fluid overload, or parenteral administration of diuretics) or worsening in New York Heart Association (NYHA) functional class (FC) from baseline.¹
• OPSUMIT had a treatment effect of 10.08% (95% confidence interval [CI], −15.07 to 33.26; P=0.34) versus placebo for the main study endpoint.¹
• No significant change was seen in the exploratory efficacy endpoints, which included evaluation of hemodynamic variables (pulmonary vascular resistance [PVR], mean pulmonary arterial pressure [mPAP], mean right atrial pressure [mRAP], pulmonary arterial wedge pressure [PAWP], total peripheral resistance [TPR], cardiac index, cardiac output, transpulmonary pressure gradient [TPG], diastolic pressure gradient [DPG], and mixed venous oxygen saturation), echocardiographic variables, N-terminal pro-brain natriuretic peptide (NT-proBNP), change in 6-minute walk distance (6MWD), and hospitalization for worsening heart failure.¹
• The percent of patients with at least 1 adverse event was 74.2% in the OPSUMIT group and 59.4% in the placebo group.¹
• SERENADE was a multicenter, double-blind, placebo-controlled, phase 2b study that evaluated the efficacy and safety of OPSUMIT in patients with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD) or right ventricular dysfunction. Recruitment was terminated in December 2019 due to slow enrollment. The primary endpoint was the percent change in NT-proBNP at 24 weeks. The primary and secondary endpoints were not met. The geometric mean ratio of the change in NT-proBNP at 24 weeks was 1.02 (90% CI, 0.88-1.19), P=0.79.²

CLINICAL DATA

Phase 2 Clinical Trials

MELODY-1

The Macitentan in combined prE- and post-capiLlary pulmOnary hypertension due to left ventricular DYsfunction (MELODY-1) study was a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group, 12-week, phase 2 study to evaluate macitentan for the treatment of patients with CpcPH due to LVD. The primary endpoint of the study was to evaluate the safety and tolerability based on the proportion of patients experiencing at least one of the following up to EOT: significant fluid retention (defined as an increase in body weight at any time by ≥5%, ≥5 kg from baseline due to fluid overload, or parenteral administration of diuretics) or worsening in NYHA FC from baseline. The exploratory efficacy endpoints included evaluation of hemodynamic variables (PVR, mPAP, mRAP, PAWP, TPR, cardiac index, cardiac output, TPG, DPG, and mixed venous oxygen saturation), echocardiographic variables, NT-proBNP, change in 6MWD, and hospitalization for worsening heart failure.¹

Patients with World Health Organization (WHO) Group 2 pulmonary hypertension over 18 years old with chronic heart failure with relevant structural heart disease and/or diastolic dysfunction, ejection fraction (EF) ≥30% measured by echocardiography, and in NYHA FC II or III were included in the study. Patients required a 6MWD ≥150 m at screening or randomization and must have met the following right heart catheterization (RHC) criteria: PAWP >15 mmHg and <25 mmHg, mPAP ≥25 mmHg at rest, PVR ≥240 dyn⋅sec/cm⁵, and DPG ≥7 mmHg. Patients also required optimal treatment of left heart failure with a stable dose of oral diuretic(s) for at least 1 week prior to the RHC and up to randomization. Patients with significant unrepaired structural valvular heart disease, pulmonary edema, orthopnea, moderate to severe peripheral edema despite optimal diuretic therapy, uncontrolled heart rate (HR) from atrial fibrillation (>100 bpm), unstable coronary artery disease (CAD), obstructive, restrictive, and infiltrative cardiomyopathies, severe obstructive lung disease, or moderate to severe restrictive lung disease were excluded.¹

Study Results

In MELODY-1, 63 patients were randomized 1:1 to receive either OPSUMIT (n=31) or placebo (n=32) for 12 weeks followed by a 30-day safety follow-up. The baseline characteristics are presented in Table: Baseline Demographics and Disease Characteristics below.¹

Primary Endpoint

Seven patients (22.6%) in the OPSUMIT group and 4 patients (12.5%) in the placebo group experienced the main study endpoint. OPSUMIT had a treatment effect of 10.08% (95% CI, −15.07 to 33.26; P=0.34) versus placebo for the main study endpoint (Table: Significant Fluid Retention or Worsening in NYHA Functional Class). Significant fluid retention occurred on days 10, 12, 28, 29, 57, 57, and 65 in OPSUMIT patients and days 43, 50, and 61 in patients on placebo.¹

Exploratory Efficacy Endpoints

No significant change was seen in OPSUMIT patients compared to placebo patients in percentage of baseline PVR at week 12 (treatment effect 0.93 [95% CI, 0.64-1.36]). No significant changes were seen in other hemodynamic variables (mPAP, mRAP, PAWP, TPR, cardiac index, cardiac output, TPG, DPG, or mixed venous oxygen) or 6MWD from baseline to week 12 compared to placebo (Table: Hemodynamics and Change in 6MWD Treatment Effect at Week 12, OPSUMIT vs. Placebo). A 23% non-significant reduction in NT-proBNP in OPSUMIT patients (n=25) compared to placebo (n=26) from baseline to week 12 was shown (treatment effect 0.77 [95% CI, 0.55-1.08]). Five patients (16.1%) in the OPSUMIT group and 2 (6.3%) in the placebo group were hospitalized for worsening of heart failure up to EOT (treatment difference 9.9% [95% CI, −15.1 to 33.3]). All hospitalizations were associated with the main study endpoint.¹

Safety

Adverse events from the MELODY-1 study are summarized in Table: Adverse Events below. Two deaths considered unrelated to study drug occurred in the OPSUMIT group up to end of study (EOS). One patient died 1 day after receiving the first dose of OPSUMIT due to respiratory failure caused by a bacterial respiratory tract infection and the other patient died 16 days after the 12-week treatment period due to sudden death.¹

SERENADE

SERENADE was a multicenter, double-blind, placebo-controlled, phase 2b study that evaluated the efficacy and safety of OPSUMIT in patients with HFpEF and PVD or right ventricular dysfunction (based on pre-defined echo and/or right heart catheterization parameters). The primary endpoint was the percent change in NT-proBNP at 24 weeks. The secondary endpoints were change from baseline to week 24 in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and accelerometer-assessed proportion of time spent in light to vigorous physical activity (LVPA) (>100 counts per minute), and time to worsening heart failure (HF) up to 52 weeks. Patients with HFpEF and NYHA FC II-III requiring treatment with ≥1 oral diuretic, elevated NT-proBNP (≥200 pg/mL for patients in sinus rhythm or ≥500 pg/mL for patients with atrial fibrillation), left ventricle ejection fraction ≥40%, left atrium enlargement or left ventricular hypertrophy, and PVD were included in the study.²

Study Results

Since the target of 300 patients was not reached, recruitment was terminated in December 2019. A total of 142 patients were randomized (71 patients in the OPSUMIT group and 71 patients in the placebo group).² For information regarding baseline characteristics of the study population, see Table: Baseline Characteristics.

Baseline Characteristics²

The primary and secondary endpoints were not met. The geometric mean ratio of the change in NT-proBNP at 24 weeks was 1.02 (90% CI, 0.88-1.19), P=0.79. The hazard ratio (HR) for time to worsening HF event up to 52 weeks in OPSUMIT vs placebo was 1.48 (90% CI, 0.82-2.67). The least squares mean treatment difference of KCCQ score and proportion of time spent in LVPA between OPSUMIT and placebo was -3.50 (standard error=2.82, P=0.22) and -0.02 (standard error=0.02, P=0.37), respectively. The data regarding the proportion of time spent in LVPA has data missing from 41 and 40 patients in the OPSUMIT and placebo groups, respectively, due to non-compliance.²

For information regarding safety, see Table: Safety (Double-Blind Treatment Period).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 29 March 2024.