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-B-type natriuretic peptide (NT-proBNP), change in 6-minute walk distance (6MWD), and hospitalization for worsening heart failure (HF).¹
• The percent of patients with at least 1 adverse event (AE) was 74.2% in the OPSUMIT group and 59.4% in the placebo group.¹
• SERENADE was an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study that evaluated the safety and tolerability of OPSUMIT in patients with HF with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD). Recruitment was terminated in December 2019 due to slow enrollment. The median (quartile [Q]1-Q3) change in NT-proBNP from baseline to week 24 was +9 (-272 to +306) pg/mL and +35 (-330 to +444) pg/mL in the OPSUMIT and placebo groups, respectively (geometric mean ratio, 1; 90% CI, 0.9-1.2; 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 1 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 HF.¹

Patients with World Health Organization (WHO) Group 2 pulmonary hypertension over 18 years old with chronic HF 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 HF 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 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 HF 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

AEs from the MELODY-1 study are summarized in Table: AEs 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 an international, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 2b study that evaluated the safety and tolerability of OPSUMIT in patients with HFpEF and PVD.²

Adult patients (aged ≥18 years) with the following criteria were included in the study: signs or symptoms of HF requiring treatment with ≥1 class of oral diuretic; NYHA FC II or III; LVEF ≥40%; evidence of LV hypertrophy or left atrial enlargement on screening echocardiography; elevated plasma NT-proBNP or BNP within 3 months of screening; and evidence of PVD. Patients were subjected to a 4-week single-blind placebo run-in period (to ensure clinical stability), followed by a 5-week single-blind OPSUMIT run-in period (to exclude patients with fluid retention) and finally randomized to receive the double-blind treatment for up to 52 weeks.²

The primary endpoint was change in NT-proBNP from baseline to week 24. Secondary endpoints included changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score and accelerometer-assessed proportion of time spent in light to vigorous physical activity (LVPA) (>100 activity counts per minute) from baseline to week 24 and time to a worsening HF event during 52 weeks of follow-up. Safety endpoints (from randomization to 30 days after treatment discontinuation) were also assessed.²

Study Results

The target of 300 patients was not reached due to slow enrollment; recruitment was prematurely terminated in December 2019. A total of 142 patients were randomized (OPSUMIT, n=71; placebo, n=71) and the baseline characteristics were well balanced between the treatment groups (see Table: Select Baseline Characteristics).²

The median (range) treatment duration, irrespective of interruptions, was 42 (4–61) weeks and 41 (3–60) weeks for the OPSUMIT and placebo groups, respectively.²

The median (Q1-Q3) change in NT-proBNP from baseline to week 24 was +9 (-272 to +306) pg/mL and +35 (-330 to +444) pg/mL in the OPSUMIT and placebo groups, respectively. The geometric mean (median) percentage at week 24 was 108.4 (102) in the OPSUMIT group and 106.3 (105) in the placebo group. There was no statistically significant difference between the groups; the geometric mean ratio (OPSUMIT over placebo) at week 24 was 1 (90% CI, 0.9-1.2), P=0.79.²

There was no statistically significant difference between OPSUMIT and placebo for any secondary endpoints. The least squares mean treatment difference for KCCQ score and proportion of time spent in LVPA between OPSUMIT and placebo was -3.5 (standard error, 2.8; 90% CI, -8.2 to +1.2; P=0.22) and -0.02 (standard error, 0.02; 90% CI, -0.05 to +0.02; P=0.37), respectively. Overall, only 30 patients treated with OPSUMIT and 31 with placebo had evaluable LVPA data due to poor compliance. At a median follow-up duration of 362 days, the worsening HF events in the OPSUMIT and placebo groups were 20 and 13, respectively (HR, 1.48; 90% CI, 0.83-2.67; P=0.24).²

For information regarding safety, see Table: Safety in the Double-Blind Treatment Period (Safety Analysis Set).²

Patients who completed the double-blind study were eligible to participate in the SERENADE open-label extension (OLE) study that assessed the long-term safety and tolerability of OPSUMIT in patients with HFpEF and PVD (n=91; OPSUMIT, n=46; placebo, n=45). The median (range) treatment duration in the OLE study was 56 (0–126) weeks. Serious adverse events (SAE) were reported in 49 (53.8%) patients, with congestive cardiac failure (6.6%), RV failure (5.5%), and acute kidney injury being the most frequently reported SAEs. Adverse events (AE) of special interest were anemia (14.3%), fluid retention/edema (13.2%), and hepatic AEs of special interest (5.5%). AEs leading to treatment discontinuation occurred in 25 (27.5%) patients, with congestive cardiac failure (3.3%) and RV failure (3.3%) being the most frequently reported AEs. Eleven patients died during the open-label study. The OLE was prematurely terminated.² Please refer to the supplementary material for more information on SERENADE-OLE.³

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 20 March 2025.