OPSUMIT - Reports of Peripheral Edema

SUMMARY

• Peripheral edema is a known clinical consequence of pulmonary arterial hypertension (PAH) and worsening PAH, and it is also a known effect of endothelin receptor antagonists (ERAs).¹
• In the SERAPHIN study in PAH, 45/249 (18.1%) patients receiving placebo, 40/250 (16%) patients receiving macitentan 3 mg, and 44/242 (18.2%) patients receiving OPSUMIT reported peripheral edema.¹
• Peripheral edema was reported as an adverse event (AE) in the MERIT-1 study in inoperable chronic thromboembolic pulmonary hypertension (CTEPH), the MAESTRO study in Eisenmenger syndrome, PORTICO study in portopulmonary hypertension, the MELODY-1 study in combined pre- and post-capillary pulmonary hypertension (CpcPH), the DUAL-1 and DUAL-2 studies in systemic sclerosis (SSc), and the MUSIC study in idiopathic pulmonary fibrosis.^2-7
• Peripheral edema was reported as an AE in the OPUS/OrPHeUS registry consisting of patients with PAH newly initiating OPSUMIT and as an AE of special interest (n/N=3/467) in a real-world study that evaluated the safety and effectiveness of OPSUMIT in patients with PAH.^8,9
• Additional citations pertaining to this topic are included in the REFERENCES section for your review.^10-20
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

CLINICAL DATA

Pivotal Trial

SERAPHIN in PAH

The Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) study was a multicenter, double-blind, randomized, placebo-controlled, event driven phase 3 study to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic PAH. Patients ≥12 years of age (N=742) were randomized 1:1:1 to receive OPSUMIT, macitentan 3 mg, or placebo once daily. The mean duration of study treatment was 103.9, 99.5, and 85.3 weeks for patients who received OPSUMIT, macitentan 3 mg, and placebo, respectively.¹

In SERAPHIN, peripheral edema was reported with similar incidences across the macitentan and placebo treatment groups.¹ Altogether, 45/249 (18.1%) patients receiving placebo, 40/250 (16%) receiving macitentan 3 mg, and 44/242 (18.2%) receiving OPSUMIT experienced peripheral edema. Furthermore, 2 patients (0.8%) in the placebo group and no patients in the macitentan 3 mg and OPSUMIT groups reported severe peripheral edema.²¹ The incidence of peripheral edema by severity during SERAPHIN is summarized in Table: Incidence of Peripheral Edema by Severity in SERAPHIN below.

Peripheral Edema AEs by Subgroup

Evaluation of peripheral edema in the PAH population by subgroups (sex, age, World Health Organization [WHO] functional class (FC) at baseline, PAH etiology, clinical signs and symptoms of right heart failure at baseline, PAH therapy at baseline, race, and geographic location) indicated that although the incidences varied across the subgroups, there was little indication of a clinically relevant effect of macitentan treatment on the basis of a difference compared with placebo treatment (macitentan vs placebo) or macitentan dose.²¹

In patients with WHO FC I/II at baseline, the incidence of peripheral edema was higher in the OPSUMIT group (22.3%) than in the macitentan 3 mg (11.6%) and placebo (14.6%) groups. However, in patients with WHO FC III/IV at baseline, the incidence of peripheral edema was lower with OPSUMIT (14%) compared with macitentan 3 mg (21.4%) and placebo (21.8%).²¹

In elderly patients (≥65 years), the incidence of peripheral edema was higher in the macitentan groups (30.3% and 25.9% in the macitentan 3 mg and OPSUMIT groups, respectively) than in the placebo group (18.2%). In patients aged 18-64 years, the incidence in the placebo group was similar to that in the elderly patients (18.7%), but the incidence in the macitentan groups was lower (14.3% and 17.7% with macitentan 3 mg and OPSUMIT, respectively).²¹

Other Clinical Studies

MERIT-1 in CTEPH

MERIT-1 was a phase 2, double-blind, randomized, placebo-controlled trial to assess macitentan in 80 patients with CTEPH adjudicated as inoperable. Eighty patients were randomized 1:1 to receive OPSUMIT daily (n=40) or placebo (n=40). The incidence of peripheral edema was higher in the OPSUMIT group (23%) than the placebo group (10%).²

MAESTRO in Eisenmenger Syndrome

MAESTRO was a multicenter, double-blind, randomized, placebo-controlled, 16-week, phase 3 study to assess the efficacy, safety, and tolerability of OPSUMIT in patients with Eisenmenger syndrome. Two hundred and twenty-six patients were randomized 1:1 to receive OPSUMIT (n=114) or placebo (n=112) once daily. Eight patients (7%) in the OPSUMIT group and 6 (5.4%) in the placebo group had at least 1 AE related to edema and fluid overload.³

PORTICO in  Portopulmonary Hypertension

PORTICO was a randomized, double-blind, placebo-controlled, prospective, multicenter, 12week study to assess the safety and efficacy of OPSUMIT in patients with portopulmonary hypertension. Patients were randomized to OPSUMIT (n=43) or placebo (n=42). The incidence of peripheral edema was higher in the OPSUMIT group (n=11; 26%) than the placebo group (n=5; 12%).⁴

MELODY-1 in CpcPH

MELODY-1 was a multicenter, double-blind, randomized, placebo-controlled, 12-week, phase 2 study to evaluate the safety and tolerability of OPSUMIT in patients with CpcPH due to left ventricular dysfunction. Sixty-three patients were randomized 1:1 to receive OPSUMIT (n=31) or placebo (n=32) once daily. Eight (25.8%) patients in the OPSUMIT group and 6 (18.8%) in the placebo group had at least 1 AE related to edema and fluid overload.⁵

DUAL-1 and DUAL-2 in SSc

DUAL-1 and DUAL-2 were phase 3 prospective, randomized, placebo-controlled, doubleblind, multicenter, parallel-group studies to assess the efficacy, safety, and tolerability of macitentan in patients with ischemic digital ulcers associated with SSc. In DUAL-1, a total of 289 patients were randomized 1:1:1 to receive daily macitentan 3 mg (n=95), OPSUMIT (n=97), or placebo (n=97). Similarly, in DUAL-2, a total of 265 patients were randomized 1:1:1 to receive daily macitentan 3 mg (n=88), OPSUMIT (n=88), or placebo (n=89). The overall incidence of peripheral edema reported in the DUAL-1 and DUAL-2 studies are summarized in Table: Incidence of Peripheral Edema by Severity in DUAL-1 and DUAL-2 below.⁶

MUSIC in Idiopathic Pulmonary Fibrosis

The Macitentan USe in an Idiopathic pulmonary fibrosis Clinical (MUSIC) study was a prospective, randomized, double-blind, multicenter, parallel-group, placebo-controlled phase 2 proof of concept study. In total, 178 patients were randomized 2:1 to daily OPSUMIT (n=119) or placebo (n=59). The incidence of peripheral edema was higher in the OPSUMIT group (11.8%) than in the placebo group (6.8%).⁷

Study 201 in Essential Hypertension

Study 201 was a multicenter, randomized, placebo- and active-controlled phase 2 study in 379 patients with essential hypertension. Patients were randomized 1:1:1:1:1 to receive macitentan 0.3 mg (n=63), macitentan 1 mg (n=66), macitentan 3 mg (n=61), OPSUMIT (n=62), enalapril (n=65) or placebo (n=62). In Study 201, no fluid retention or peripheral edema AEs were reported in any of the patients receiving macitentan.²¹

Real-World Evidence

The OPUS registry (NCT02126943) and the OrPHeUS chart review (NCT03197688) provided real-world data for patients with PAH newly initiating OPSUMIT.^9,18-20 McLaughlin et al (2022)⁹ included patients from the OPUS and OrPHeUS registries, which were patients who initiated OPSUMIT from April 2014-June 2020 and October 2013March 2017, respectively. There was a total of 5654 enrolled patients from the OPUS and OrPHeUS registries combined (2670 and 2984 patients from OPUS and OrPHeUS, respectively). Four patients didn’t have follow-up data; therefore, the overall follow-up set was 5650 patients. In OPUS, 283/2667 (10.6%) of patients experienced peripheral edema during the observation period (from initiation of OPSUMIT to the end of study, death, loss of follow-up, consent withdrawal, or date of OPSUMIT discontinuation+30 days). No AE reporting (with the exception of hepatic AEs) was conducted in OrPHeUS due to the retrospective design.

Jung et al (2023)⁸ conducted a prospective, multi-center, real-world, observational study that evaluated the safety and effectiveness of OPSUMIT in adult patients with PAH at 50 medical centers in Korea. Of the 474 enrolled patients, 467 were included in the safety analysis. Of the 467 patients, 344 were female, and the mean (±standard deviation [SD]) age at enrollment was 48.5 (±15.8) years. Overall, 3 (0.64%) patients reported peripheral edema (considered as an AE of special interest) in this study.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 25 September 2025.