SUMMARY

• In the phase 3 SERAPHIN trial with a safety population of 741 patients with pulmonary arterial hypertension (PAH; randomized 1:1:1), the incidence rates of elevated liver aminotransferases (aspartate aminotransferase [AST] and/or alanine aminotransferase [ALT] >3 × upper limit of normal [ULN]) were similar across groups receiving placebo, macitentan 3 mg, or OPSUMIT.¹ Frequency of hepatic abnormalities in SERAPHIN and hepatic safety data in the SERAPHIN open-label extension (OLE) are also reported below.
• In the OPsumit^® USers Registry (OPUS) and OPsumit^® Historical Users (OrPHeUS) combined study, the incidence rates per 100 person-years (PYs) of ≥1 hepatic adverse event (HAE) and ≥1 hepatic adverse event of special interest (HAESI) were 0.07 (95% confidence interval [CI], 0.07-0.08) and 0.04 (95% CI, 0.04-0.05), respectively, in the overall follow-up set and 0.07 (95% CI, 0.06-0.08) and 0.04 (95% CI, 0.04-0.05), respectively, in the PAH follow-up set.²
• Accumulated safety data from several studies in a variety of unapproved indications (DUAL-1, DUAL-2, MERIT-1, MAESTRO, MELODY-1, MUSIC, Study 201 and PORTICO), were analyzed for reports of adverse events (AEs) denoting liver function abnormalities or laboratory abnormalities. The data are summarized in this letter.^3-10
• A pharmacovigilance study which evaluated the potential association between endothelin receptor antagonists (ERAs) and drug-induced liver injury events using Food and Drug Administration Adverse Event Reporting System (FAERS) data, identified a disproportionality analysis signal for drug-induced liver injury in patients treated with OPSUMIT, which included hepatic failure, cholestatic injury, and serious drug-related hepatic disorders with a reporting odds ratio (ROR) of 1.64 (95% CI, 1.39-1.94), 1.62 (95% CI, 1.43-1.83), and 1.40 (95% CI, 1.29-1.51), respectively.¹¹
• In a retrospective study that evaluated the association between different (ERA; and different ERA combination regimens) and liver injury using the FAERS data, of the 3581 reports of liver injury, 578 cases were suspected of OPSUMIT use (ROR, 1.00; 95% CI, 0.92-1.090).¹²

CLINICAL DATA

SERAPHIN

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. Overall, 742 patients ≥12 years of age were randomized 1:1:1 to receive placebo (n=250), macitentan 3 mg (n=250), or OPSUMIT 10 mg (n=242); mean treatment duration was 85.3, 99.5, and 103.9 weeks, respectively.¹

Patients who had idiopathic or heritable PAH or PAH related to connective-tissue disease, repaired congenital systemic to pulmonary shunts, human immunodeficiency virus, or drug use or toxin exposure were eligible.¹ Select exclusion criteria included AST and/or ALT >1.5 × ULN or moderate to severe hepatic impairment (i.e., Child-Pugh Class B or C).¹³

One patient randomly assigned to placebo did not receive study drug and was excluded from the safety analysis.¹ Incidence rates of elevated liver aminotransferases (AST or ALT >3 × ULN) were similar across all groups. Hepatic safety data in SERAPHIN are described in the Table: Incidence of Hepatic Laboratory Abnormalities in the SERAPHIN Trial below.

Please refer to the Figure: Time to First Appearance of AST or ALT >3 × ULN in SERAPHIN below for the time to first appearance of AST or ALT >3 × ULN in SERAPHIN.

Table: Frequency and Intensity of AEs and Serious Adverse Events (SAEs) Denoting Liver Function Abnormalities (Including Unrelated to Study Drug), Including AEs Leading to Discontinuation and Deaths, as Reported in SERAPHIN up to end of treatment (EOT) + 28 Days; All Treated Set provides safety data from SERAPHIN relating to AEs denoting liver function abnormalities. Frequency of treatment-emergent liver laboratory abnormalities in the SERAPHIN study is reported in Table: Frequency of Treatment-Emergent Liver Laboratory Abnormalities in the SERAPHIN Study up to EOT + 28 Days; All Treated Set.

Open-Label Extension

SERAPHIN OLE was a long-term, multicenter, single-arm, noncomparative, OLE study that evaluated the long-term safety and tolerability of OPSUMIT. Eligible patients had either completed the double-blind treatment in SERAPHIN without experiencing a primary endpoint event or experienced a morbidity event during the SERAPHIN study. Of the 742 patients randomized in SERAPHIN, 550 (74.1%) were enrolled in SERAPHIN OLE (OLE safety set), including 182 (33.1%) patients originally randomized to OPSUMIT. The median (min, max) exposure to OPSUMIT from first intake of OPSUMIT in SERAPHIN OLE to end of treatment was 40.1 (0.1, 130.5) months.¹⁶ Hepatic safety data is reported in Table: Incidence of Liver Function Abnormalities in SERAPHIN OLE.

OPUS and OrPHeUS

OPUS was a prospective, multicenter, long-term, observational drug registry in the United States (US). OrPHeUS was a retrospective, multicenter, US medical chart review. These studies enrolled patients who newly initiated OPSUMIT (October 2013-June 2020 for OPUS and OrPHeUS combined). Patients enrolled in OPUS were not allowed to participate in OrPHeUS.²

As of June 2020, there were 5654 new users of OPSUMIT in the combined OPUS/OrPHeUS population (enrolled set); 5650/5654 patients had follow-up data (overall follow-up set), and 4626/5650 had a diagnosis of PAH (PAH follow-up set). The median (quartile [Q]1-Q3) and total exposure of OPSUMIT were 13.6 (4.8-28.0) months and 8322 PY, respectively, for the overall follow-up set and 14.5 (5.2-29.0) months and 7044 PY, respectively, for the PAH follow-up set.²

The incidence rates per 100 PYs of ≥1 HAE and ≥1 HAESI were 0.07 (95% CI, 0.07-0.08) and 0.04 (95% CI, 0.04-0.05), respectively, in the overall follow-up set and 0.07 (95% CI, 0.06-0.08) and 0.04 (95% CI, 0.04-0.05), respectively, in the PAH follow-up set. Increased blood bilirubin was the most common HAE and HAESI in the overall and PAH follow-up sets.² Hepatic safety information is summarized in the Table: Hepatic Safety in the Overall and PAH Follow-up Sets below.

Other Randomized, Placebo-Controlled, Clinical Studies With OPSUMIT in Non-PAH Indications

Safety data were analyzed for information regarding the reporting frequency of AEs denoting liver function abnormalities or laboratory abnormalities during randomized, double-blind, placebo-controlled studies with OPSUMIT. These included the pivotal SERAPHIN study investigating OPSUMIT for the treatment of symptomatic PAH, and several additional studies with OPSUMIT in a variety of unapproved therapeutic indications (DUAL-1, DUAL-2, MAESTRO, MERIT-1, MELODY-1, MUSIC, Study 201 and PORTICO). Information about the design of these studies and treatment exposure in each study arm is provided in Table: Randomized, Double-blind, Placebo-Controlled Studies With OPSUMIT in Adult Patients, while relevant safety information from these studies is described in the following sections.

Table: Frequency of AEs Denoting Liver Function Abnormalities, as Reported in Placebo-Controlled, Randomized Studies With OPSUMIT in Non-PAH Indications; All Safety Set provides safety data relating to AEs denoting liver laboratory abnormalities from the other placebo-controlled studies investigating OPSUMIT in a variety of therapeutic indications (DUAL-1, DUAL-2, MAESTRO, MERIT-1, MELODY-1, MUSIC, Study 201 and PORTICO). Frequency of treatment-emergent liver laboratory abnormalities in the above-mentioned studies is also reported in the subsequent tables below.

Real-World Evidence

Gu et al (2024)¹¹ conducted a comprehensive pharmacovigilance study that evaluated the potential association between ERAs and drug-induced liver injury events based on FAERS data between January 2004 and December 2022.

For OPSUMIT, a disproportionality analysis signal was identified for drug-induced liver injury, which included hepatic failure, cholestatic injury, and serious drug-related hepatic disorders with a ROR of 1.64 (95% CI, 1.39-1.94), 1.62 (95% CI, 1.43-1.83), and 1.40 (95% CI, 1.29-1.51), respectively.

Dong et al (2023)¹² conducted a retrospective study that evaluated the association between different ERAs (and different ERA combination regimens) and liver injury using the FAERS data from January 2004 to December 2022.

Of the 3581 reports of liver injury, 578 cases were suspected of OPSUMIT use (ROR [95% CI], 1.00 [0.92-1.09]; proportional reporting ratio, 1.00; information component, 0.00; empirical Bayesian geometric mean, 1.00).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 November 2024.