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Signs and Symptoms of Chest Diseases |

Effect of Macitentan on Morbidity and Mortality in Pulmonary Arterial Hypertension (PAH): Results From the SERAPHIN Trial FREE TO VIEW

Lewis Rubin*, MD; Tomás Pulido, MD; Richard Channick, MD; Marion Delcroix, MD; Nazzareno Galie, MD; Hossein-Ardeschir Ghofrani, MD; Pavel Jansa, MD; Franck-Olivier Le Brun, MMSc; Sanjay Mehta, MD; Camilla Mittelholzer, PhD; Loic Perchenet, PhD; B. K. S. Sastry, MD; Olivier Sitbon, MD; Rogerio Souza, MD; Adam Torbicki, MD; Gerald Simonneau, MD
Author and Funding Information

University of California, San Diego, CA


Chest. 2012;142(4_MeetingAbstracts):1026A. doi:10.1378/chest.1456207
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Abstract

SESSION TYPE: Late-Breaking Abstracts

PRESENTED ON: Tuesday, October 23, 2012 at 04:30 PM - 05:45 PM

PURPOSE: Current oral PAH therapies have been approved based on short-term trials with exercise capacity as the primary endpoint. In this event-driven trial, the effect of macitentan, a novel dual endothelin receptor antagonist (ERA) with enhanced tissue penetration, was assessed on a primary endpoint of morbidity and mortality in PAH patients.

METHODS: In this double-blind, placebo-controlled, Phase III, event-driven study, patients (≥12 years) with symptomatic PAH were randomized (1:1:1) to placebo, macitentan 3mg or macitentan 10mg, once daily. Stable background oral or inhaled PAH therapy, other than an ERA, was allowed. The primary endpoint was time from treatment initiation to first morbidity or mortality event in all randomized patients. This composite endpoint, defined as death, atrial septostomy, lung transplantation, initiation of intravenous/subcutaneous prostanoids or worsening of PAH, was blindly and independently adjudicated. Secondary endpoints included the composite of mortality due to PAH or hospitalization for PAH.

RESULTS: 742 patients with PAH were randomized to placebo (n=250), macitentan 3mg (n=250) or macitentan 10mg (n=242); mean treatment duration was 85.3, 99.5 and 103.9 weeks, respectively. Macitentan reduced the risk of occurrence of morbidity and mortality events versus placebo by 30% in the 3mg group (97.5%CI:4-48%;P=0.0108) and 45% in the 10 mg group (97.5%CI:24-61%;P<0.0001). The effect of macitentan on this endpoint was observed irrespective of background PAH therapy (mainly phosphodiesterase type-5 inhibitors); risk reduction for macitentan 3mg and 10mg was 17% (95%CI:-16-41%) and 38% (95%CI:11-57%) in the presence of background PAH therapy and 47% (95%CI:15-66%) and 55% (95%CI:28-72%) in the absence of background PAH therapy. Macitentan 3mg and 10mg also reduced the risk of the secondary endpoint, mortality due to PAH/hospitalization for PAH, by 33% (97.5%CI:3-54%;P=0.0146) and 50% (97.5%CI:25-67%;P<0.0001), respectively. Macitentan was well tolerated, with similar incidences of elevated liver aminotransferases and peripheral edema across all groups. Adverse events more frequently associated with macitentan versus placebo were headache, nasopharyngitis and anemia.

CONCLUSIONS: Macitentan demonstrated a significant effect on the combined endpoint of morbidity and mortality, with a favorable safety profile, in the largest and longest randomized controlled trial of therapy in PAH to date.

CLINICAL IMPLICATIONS: Macitentan has the potential to improve long-term outcomes in PAH patients.

DISCLOSURE: Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Ltd, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Lung LLC, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GeNo

Tomás Pulido: Consultant fee, speaker bureau, advisory committee, etc.: Actelion , Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Lily, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from sources other than industry): National Heart Insitute, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): United Therapeutics

Richard Channick: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion

Marion Delcroix: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Bayer

Nazzareno Galie: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Bayer

Hossein-Ardeschir Ghofrani: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): Ergonex, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Ergonex, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Merck, Consultant fee, speaker bureau, advisory committee, etc.: Novartis

Pavel Jansa: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: AOP Orphan, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Bayer

Franck-Olivier Le Brun: Employee: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion

Sanjay Mehta: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Takeda Nycomed, Grant monies (from sources other than industry): Heart & Stroke Foundation of Ontario/Canada (HSFO/C), Grant monies (from industry related sources): Canadian Institute of Health Research / CIHR, Grant monies (from sources other than industry): Ontario Thoracic Society (OTS), Consultant fee, speaker bureau, advisory committee, etc.: Actelion Pharmaceuticals Canada, Consultant fee, speaker bureau, advisory committee, etc.: Takeda - Nycomed, Consultant fee, speaker bureau, advisory committee, etc.: Boehringer-Ingelheim Canada

Camilla Mittelholzer: Employee: Actelion, Shareholder: Actelion

Loic Perchenet: Employee: Actelion, Shareholder: Actelion

BkS Sastry: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline

Olivier Sitbon: Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): bayer, Grant monies (from industry related sources): Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapuetics, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: United Therapuetics, Consultant fee, speaker bureau, advisory committee, etc.: Bayer

Rogerio Souza: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion

Adam Torbicki: Grant monies (from industry related sources): Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: AOP Orphan Pharmaceutics, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): United Therapeutics, Grant monies (from industry related sources): AOP Orphan Pharmaceutics, Grant monies (from industry related sources): Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bristol Myers Squibb

Gerald Simonneau: Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Novartis

Macitentan is under investigation for the treatment of pulmonary arterial hypertension. SERAPHIN, the Phase 3 study reported here, is the registration trial for macitentan in this indication.

University of California, San Diego, CA

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