SERAPHIN trial: Long-term efficacy
The long-term efficacy and safety of OPSUMIT® (macitentan) were investigated in the pivotal SERAPHIN trial across a broad range of patients with pulmonary arterial hypertension (PAH).
Study design and composite primary endpoint
The SERAPHIN trial was a multicentre, double-blind, randomised, placebo-controlled, parallel-group, event-driven, Phase 3 trial that assessed the efficacy and safety of OPSUMIT®. The primary endpoint in SERAPHIN was a composite endpoint of time to first morbidity or mortality event, up to end of treatment.
Adapted from Pulido et al. 2013
*All events adjudicated by a blinded clinical events committee.
Patient population
The SERAPHIN trial assessed the efficacy and safety of OPSUMIT® across a broad range of patients with PAH.
Adapted from Pulido et al. 2013
*Patients may be on more than one background therapy.
‡1 patient was in FC I, 14 patients in FC IV.
§Other aetiologies included drug- or toxin-induced PAH (3%) and HIV-PAH (1%).
#Patients with repaired congenital systemic-to-pulmonary shunts.
Long-term efficacy with OPSUMIT®
Evidence for the long-term efficacy of OPSUMIT® is based on SERAPHIN primary endpoint data showing a significant reduction in the risk of a morbidity-mortality* event vs placebo in patients with pulmonary arterial hypertension (PAH).
In the SERAPHIN trial, OPSUMIT® significantly reduced the risk of a morbidity-mortality event* by 45% vs placebo.
Adapted from Pulido et al. 2013
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
With OPSUMIT®, patients were half as likely to be hospitalised due to PAH compared with placebo.
Adapted from Channick et al. 2015
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
OPSUMIT® is the only endothelin receptor antagonist (ERA) to demonstrate a long-term survival benefit at 7 years, with over 60% of patients still alive in the open-label extension of the SERAPHIN trial.‡
Adapted from Souza et al. 2017 and OPSUMIT® PI
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
‡182 patients randomised to OPSUMIT® in the double-blind SERAPHIN trial continued on OPSUMIT® in the open-label extension. This included mainly FC II–III patients with IPAH/HPAH or PAH associated with CTD, CHD, HIV or drugs/toxins; 64% of patients were on background therapy at baseline, with 62% on a PDE-5i and 6% on an oral or inhaled prostanoid. Survival was estimated by the Kaplan-Meier method.
Efficacious in a broad range of patients with PAH
The treatment effect of OPSUMIT® on the risk of a morbidity-mortality* event vs placebo was consistent across subgroups of different pulmonary arterial hypertension (PAH) aetiologies, World Health Organization (WHO) functional classes (FC), and both incident and prevalent patients.
PAH aetiology
Consistent with the primary endpoint in the overall population in SERAPHIN, OPSUMIT® reduced the risk of a morbidity-mortality event* vs placebo in a broad range of patients with PAH, including those with connective tissue disease (CTD)-associated PAH and those with congenital heart disease (CHD)-associated PAH.‡
Adapted from OPSUMIT® PI and Pulido et al. 2013
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
‡Patients with repaired congenital systemic-to-pulmonary shunts.
WHO FC
In the SERAPHIN trial, OPSUMIT® showed a consistent beneficial treatment effect across WHO FC subgroups, reducing the risk of a morbidity-mortality* event vs placebo in both patients with baseline WHO FC I/II PAH and those with baseline WHO FC III/IV PAH.
Adapted from Channick et al. 2014
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
Incident and prevalent PAH
OPSUMIT® reduced the risk of a morbidity-mortality event* vs placebo in treatment-naïve patients with incident PAH (diagnosed 6 months prior to enrolment) and with prevalent PAH (diagnosed >6 months prior to enrolment).‡
There was also a significant reduction in the risk of morbidity-mortality* with OPSUMIT® vs placebo in incident and prevalent PAH patients who were treatment-naïve or already receiving therapy.§
Adapted from Simonneau et al. 2015
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
‡Enrolled patients were classified by time from diagnosis to enrolment as incident (≤6 months; n=110) or prevalent (>6 months; n=157).
§Morbidity-mortality risk reduction vs placebo in incident PAH patients: 57% (HR 0.43, 95% CI: 0.25–0.73; p=0.001); prevalent PAH patients: 41% (HR 0.59, 95% CI: 0.42–0.84; p=0.003).
OPSUMIT® as monotherapy and in combination therapy
In the SERAPHIN trial, OPSUMIT® reduced the risk of a morbidity-mortality event* vs placebo as both monotherapy and in combination therapy in patients with pulmonary arterial hypertension (PAH).
In the SERAPHIN trial, treatment with OPSUMIT® in patients not receiving background PAH therapy at baseline resulted in a 55% reduction in the risk of a morbidity-mortality event* vs placebo.
Adapted from Pulido et al. 2013
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
OPSUMIT® reduced the risk of a morbidity-mortality event* by 38% vs placebo in patients receiving background therapy with a phosphodiesterase type-5 inhibitor (PDE-5i) or an oral or inhaled prostanoid at baseline.‡
Adapted from Pulido et al. 2013
*As measured by a composite primary morbidity-mortality endpoint. Results were driven by a decrease in PAH worsening and do not apply to mortality on its own.
‡61% of patients were on a PDE-5i and 5% were on an oral/inhaled prostanoid.
OPSUMIT® improves multiple risk criteria
Compared with placebo, OPSUMIT® improved four key prognostic risk factors associated with pulmonary arterial hypertension (PAH) in the SERAPHIN trial: six minute walk distance (6MWD), World Health Organization (WHO) functional class (FC), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac index.
6MWD*
WHO FC*
NT-proBNP‡
(SERAPHIN haemodynamic sub-study)
Cardiac index‡
(SERAPHIN haemodynamic sub-study)
Adapted from Pulido et al. 2013 and Galiè et al. 2017
*In SERAPHIN, 64% of patients received OPSUMIT® in combination with other PAH-specific therapy.
‡In the SERAPHIN haemodynamic sub-study, 49% of patients received OPSUMIT® in combination with other PAH-specific therapy.
Effect of OPSUMIT® on health-related quality of life
SERAPHIN is the first clinical trial to demonstrate a significant health-related quality of life (HRQoL) benefit of a pulmonary arterial hypertension (PAH)-targeted therapy in 7 out of 8 domains in the 36-Item Short Form (SF-36) survey. By Month 6, patients treated with OPSUMIT® had significantly improved SF-36 and physical and mental component summary (PCS and MCS) scores vs placebo (p<0.05). OPSUMIT® also reduced the risk of a ≥3-point HRQoL deterioration vs placebo until end of treatment (p=0.0173).
Adapted from Mehta et al. 2017
PF, physical functioning; RP, role-physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role-emotional; MH, mental health
*Statistically significant difference vs placebo (p<0.05).
Continue reading
OPSUMIT® has a well-characterised and generally manageable safety profile.
Component not published? componentType is undefined.
Component not published? componentType is undefined.
CI, confidence interval; CHD, congenital heart disease; CTD, connective tissue disease; ERA, endothelin receptor antagonist; FC, functional class; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial hypertension; HR, hazard ratio; HRQoL, health-related quality of life; IPAH, idiopathic pulmonary arterial hypertension; IV, intravenous; MCS, mental component summary; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAH, pulmonary arterial hypertension; PCS, physical component summary; PDE-5i, phosphodiesterase type-5 inhibitor; SC, subcutaneous; SF-36, 36-Item Short-Form Survey; 6MWD, 6-minute walk distance; WHO, World Health Organization
CP-220224 ∣ June 2021
OPSUMIT® PRESCRIBING INFORMATION AND ADVERSE EVENT REPORTING
