SUMMARY

• The phase 3 SERAPHIN trial was conducted to evaluate the long-term safety and efficacy of OPSUMIT in patients with symptomatic pulmonary arterial hypertension (PAH). In this event-driven study, OPSUMIT significantly reduced the risk of a morbidity/mortality event by 45% compared with placebo. Adverse reactions more frequent on OPSUMIT than on placebo by ≥3% were anemia, bronchitis, headache, and nasopharyngitis.¹
• At baseline, 224 patients (30.5%) were classified as PAH-connective tissue disease (CTD) in SERAPHIN. A subgroup analysis showed that the treatment effect of OPSUMIT was consistent with the overall PAH study population among the PAH-CTD patients.^1,3
• The OPsumit^® USers Registry (OPUS) and OPsumit^® Historical USers cohort study (OrPHeUS) combined data sets showed that the clinical outcomes and safety profile of patients with PAH-CTD treated with OPSUMIT were generally consistent with those of patients with idiopathic/heritable PAH (I/HPAH) treated with OPSUMIT.^4,5 Of the 1192 patients with PAH-CTD, 34.8%, 49.9%, and 15.3% of patients received OPSUMIT as monotherapy, double therapy, and triple therapy at treatment initiation, respectively.⁴
• One retrospective study and 1 retrospective claims-based analysis that provide information on OPSUMIT use in patients with PAH-CTD are summarized below.^6,7
• Additional information for review is provided under the REFERENCES section.⁸

CLINICAL DATA

SERAPHIN Study in PAH

The Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) trial 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.^1,2 The study design is presented in Figure: Study Design.

Please visit http://www.clinicaltrials.gov">http://www.clinicaltrials.gov">http://www.clinicaltrials.gov

Efficacy

OPSUMIT decreased the risk of a morbidity/mortality event vs placebo (risk reduction) by 45% (hazard ratio [HR]=0.55; 97.5% confidence interval [CI], 0.39 to 0.76; P<0.001). The beneficial effect of OPSUMIT was primarily attributable to a reduction in clinical worsening events (deterioration in 6-minute walk distance [6MWD] and worsening of PAH symptoms and need for additional PAH treatment), with death and prostanoid initiation representing fewer events.¹

Safety

One patient randomly assigned to placebo did not receive study drug and was excluded from the safety analysis. Mean exposure to study treatment was 85.3 weeks and 103.9 weeks in the placebo and OPSUMIT groups, respectively. Incidence rates of elevated liver aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] >3×upper limit of normal) and peripheral edema were similar across all groups. Adverse reactions more frequent on OPSUMIT than on placebo by ≥3% were anemia, bronchitis, headache, and nasopharyngitis. The number of patients discontinuing treatment due to adverse events (AEs) was 31 (12.4%) and 26 (10.7%) in the placebo and OPSUMIT groups, respectively. Three patients, 1 in each group, discontinued due to anemia.¹

Subgroup Analysis of Patients With PAH-CTD From the SERAPHIN Study

A total of 224 patients with PAH-CTD were enrolled in SERAPHIN (n=81 placebo, n=70 macitentan 3 mg, n=73 OPSUMIT),¹ with scleroderma as the most frequent CTD subtype observed at baseline (see Table: Summary of PAH-CTD Patients at Baseline).^1,3 Consistent with the overall PAH study population (interaction test indicated no heterogeneity; P=0.84), OPSUMIT decreased the risk of a morbidity/mortality event vs placebo (risk reduction) by 42% (HR=0.58; 95% CI, 0.33 to 1.02) among patients with PAH-CTD (see Figure: Effect of OPSUMIT on the Primary Outcome Composite Endpoint of Morbidity or Mortality by PAH Etiology).²

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 finished in June 2020. Patients were excluded if they were enrolled in an ongoing clinical trial. OrPHeUS was a retrospective, multicenter, US medical center chart review (NCT03197688).⁴ OrPHeUS included patients who newly initiated OPSUMIT between October 2013 and December 2016 (inclusive) with individual patient data recorded up to March 2017.⁵ Patients who were enrolled in a clinical trial involving OPSUMIT, and those who were enrolled in OPUS were not allowed to participate in OrPHeUS.⁴

As of June 2020, OPUS/OrPHeUS had 4626 patients with PAH with follow-up data, of whom 2498 patients had I/HPAH and 1192 patients had PAH-CTD, including 708 patients with systemic sclerosis (SSc), 159 patients with systemic lupus erythematosus (SLE) and 124 patients with mixed CTD (MCTD; Table: Demographics and Baseline Characteristics at OPSUMIT Initiation).⁴

Treatment Patterns

Of the 1192 patients with PAH-CTD, 34.8%, 49.9%, and 15.3% of patients received OPSUMIT as monotherapy, double therapy, and triple therapy at treatment initiation, respectively. At 1 and 2 years, patients with PAH-CTD were more likely to escalate from monotherapy to combo therapy, and from double to triple therapy, compared to patients with I/HPAH (see Figure: Treatment regimen at OPSUMIT initiation, 6 and 12 months after OPSUMIT initiation).⁴

Treatment Regimen at OPSUMIT Initiation and at 6 and 12 Months After OPSUMIT Initiation⁴

Safety and Tolerability

Among patients with I/HPAH, 434 (17.4%) and 5 (0.2%) patients discontinued OPSUMIT due to nonhepatic and hepatic AEs (HAE), respectively. Similarly, among patients with PAHCTD, 194 (16.3%) and 7 (0.6%) patients discontinued OPSUMIT due to nonhepatic and HAEs, respectively (see Table: OPSUMIT Discontinuation and AEs).⁴

Hospitalization and Survival

The 1- and 3-year Kaplan-Meier (KM) survival estimates, respectively, for the I/HPAH group were 90.5% (95% confidence limit [CL], 89.1-91.7) and 75.7% (95% CL, 73.1-78.2) and PAH-CTD group were 90.6% (95% CL, 88.6-92.3) and 74.3% (95% CL, 70.5-77.7). Similar KM survival estimates were observed at 1 year for patients with SSc-PAH 89.8% (95% CL, 86.9-92.0), SLE-PAH 92.5% (95% CL, 86.4-95.9), and MCTD-PAH 93.8% (95% CL,
86.7-97.2). Patients with SLE-PAH had the highest survival at 3 years (84.7; 95% CL,
74.7-91.0; see Table: Hospitalization and Survival).⁴

Retrospective Studies

Song et al (2024)⁶ conducted a retrospective study that evaluated the efficacy and safety of OPSUMIT in patients with PAH-CTD. Of the 32 PAH-CTD patients included in the study, 9 were on OPSUMIT monotherapy (female, n=6; mean age, 46.44 years) and 23 on OPSUMIT plus sildenafil combination therapy (female, n=20; mean age, 41.65 years). At 0 and
24 weeks, 6MWD, N-terminal pro-brain natriuretic peptide (NT-proBNP), systolic pulmonary artery pressure (sPAP), tricuspid regurgitation pressure gradient (TRPG), and tricuspid annular plane systolic excursion revealed a statistically significant difference in the macitentan monotherapy group (P<0.05). No statistically significant differences were observed in right ventricular diameter (RVD), right atrial diameter (RAD), ascending aortic root inner diameter (AAO), and left ventricular end-diastolic diameter (LVEDd) at week 0 and 24. Similarly, among the OPSUMIT combined with sildenafil treatment group, 6MWD, NT-proBNP, LVEDd, sPAP and TRPG showed statistically significant differences (P<0.001) between 0 and 24 weeks. Additionally, the 2 treatment groups did not show any statistically significant differences in the safety parameters (ALT, AST, serum creatinine, and hemoglobin) between baseline and 24 weeks (P>0.05).

Real-World Evidence

Sargent et al (2023)⁷ conducted a retrospective claims-based analysis between October 1, 2015, and September 30, 2021, to assess the real-world treatment patterns among adult patients with PAH-CTD. Patients were categorized into 2 cohorts: PAH-CTD, n=728; PAH, n=4023. The mean follow-up durations were 18.8 and 19.6 months, respectively. The most common first treatment regimens (a treatment regimen was defined as all PAH agents observed within 60 days of the first PAH-related agent observed) for both cohorts were sildenafil (PAH-CTD, 38.7%; PAH, 51.5%), tadalafil (10.0%; 9.4%), and OPSUMIT (8.1%; 5.4%) as monotherapy. These were also the most frequently used agents in any of the first 3 treatment regimens. Combination therapy was more frequent in PAH-CTD vs the PAH cohort (any regimen, 40.9% vs 27.2%; first treatment regimen, 26.9% vs 18.5%; second, 52.8% vs 42.0%; third, 55.2% vs 48.5%).

Limitations of the study:

• Patients may have been misclassified in a given cohort due to inaccuracies in the health insurance claims data, including diagnosis codes and treatments received.
• Treatment patterns were observed based on prescription fills from pharmacy claims but does not imply that the medication was actually taken. The study included medications for which insurance claim was submitted. Medications received through patient support programs without a record in an insurance claim were not captured.
• The study results might not be generalizable to patients without health insurance or those with insurance plans other than commercial ones. Differences observed in the treatment pattern might be partly explained by the differences in patient characteristics between cohorts such as disease severity and hemodynamics.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 May 2024.