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).[1]
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.[1]
Adapted from Pulido et al. 2013[1]
*All events adjudicated by a blinded clinical events committee.[1]
Patient population
The SERAPHIN trial assessed the efficacy and safety of OPSUMIT® across a broad range of patients with PAH.[1]
Adapted from Pulido et al. 2013[1]
*Patients may be on more than one background therapy.[1]
‡1 patient was in FC I, 14 patients in FC IV.[1]
§Other aetiologies included drug- or toxin-induced PAH (3%) and HIV-PAH (1%).[1]
#Patients with repaired congenital systemic-to-pulmonary shunts.[1]
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).[1]
In the SERAPHIN trial, OPSUMIT® significantly reduced the risk of a morbidity-mortality event* by 45% vs placebo.[1]
Adapted from Pulido et al. 2013[1]
*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.[1]
With OPSUMIT®, patients were half as likely to be hospitalised due to PAH compared with placebo.[2]
Adapted from Channick et al. 2015[2]
*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.[1]
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.‡[3][4]
Adapted from Souza et al. 2017[3] and OPSUMIT® PI[4]
*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.[1]
‡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.[3]
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.[1][4][5][6][7]
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.‡[1][4][5]
Adapted from OPSUMIT® PI[4] and Pulido et al. 2013[5]
*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.[1]
‡Patients with repaired congenital systemic-to-pulmonary shunts.[1]
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.[6]
Adapted from Channick et al. 2014[6]
*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.[6]
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).‡[7]
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.§[7]
Adapted from Simonneau et al. 2015[7]
*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.[7]
‡Enrolled patients were classified by time from diagnosis to enrolment as incident (≤6 months; n=110) or prevalent (>6 months; n=157).[7]
§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).[7]
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).[1][5]
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.[5]
Adapted from Pulido et al. 2013[5]
*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.[1]
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.‡[5]
Adapted from Pulido et al. 2013[5]
*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.[1]
‡61% of patients were on a PDE-5i and 5% were on an oral/inhaled prostanoid.[1]
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.[1][5][8]
6MWD*[5]
WHO FC*[1]
NT-proBNP‡[8]
(SERAPHIN haemodynamic sub-study)
Cardiac index‡[8]
(SERAPHIN haemodynamic sub-study)
Adapted from Pulido et al. 2013[1][5] and Galiè et al. 2017[8]
*In SERAPHIN, 64% of patients received OPSUMIT® in combination with other PAH-specific therapy.[1]
‡In the SERAPHIN haemodynamic sub-study, 49% of patients received OPSUMIT® in combination with other PAH-specific therapy.[8]
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).[9]
Adapted from Mehta et al. 2017[9]
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).[9]
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OPSUMIT® has a well-characterised and generally manageable safety profile.[1][10]
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
