Optimization Of Tissue Targeting Properties Of Macitentan, A New Dual Endothelin Receptor Antagonist, Improves Its Efficacy In A Rat Model Of Pulmonary Fibrosis Associated With Pulmonary Arterial Hypertension

Iglarz, Marc; Landskroner, Kyle; Wanner, Daniel; Rey, Markus; Hess, Patrick; Clozel, Martine

doi:10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a6445

Cited by 11 publications

(19 citation statements)

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“…Macitentan, a novel dual ERA, has been shown to prevent the development of lung fibrosis in a rat model of bleomycin-induced pulmonary fibrosis [11]. To investigate the efficacy and safety of macitentan in subjects with IPF, the prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled, phase II, proof-of-concept Macitentan USe in an Idiopathic Pulmonary Fibrosis Clinical (MUSIC) trial (NCT00903331) was designed.…”

Section: Introductionmentioning

confidence: 99%

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Raghu¹,

Million-Rousseau²,

Morganti³

et al. 2013

Eur Respir J

237

149

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Idiopathic pulmonary fibrosis is a progressive, fatal disease. This prospective, randomised, double-blind, multicentre, parallel-group, placebo-controlled phase II trial (NCT00903331) investigated the efficacy and safety of the endothelin receptor antagonist macitentan in idiopathic pulmonary fibrosis.Eligible subjects were adults with idiopathic pulmonary fibrosis of ,3 years duration and a histological pattern of usual interstitial pneumonia on surgical lung biopsy. The primary objective was to demonstrate that macitentan (10 mg once daily) positively affected forced vital capacity versus placebo.Using a centralised system, 178 subjects were randomised (2:1) to macitentan (n5119) or placebo (n559). The median change from baseline up to month 12 in forced vital capacity was -0.20 L in the macitentan arm and -0.20 L in the placebo arm. Overall, no differences between treatments were observed in pulmonary function tests or time to disease worsening or death. Median exposures to macitentan and placebo were 14.5 months and 15.0 months, respectively. Alanine and/or aspartate aminotransferase elevations over three times upper limit of normal arose in 3.4% of macitentan-treated subjects and 5.1% of placebo recipients.In conclusion, the primary objective was not met. Long-term exposure to macitentan was well tolerated with a similar, low incidence of elevated hepatic aminotransferases in each treatment group. @ERSpublications Long-term exposure to macitentan was well tolerated in IPF in a trial that did not meet its primary end-point

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Section: Introductionmentioning

confidence: 99%

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Raghu¹,

Million-Rousseau²,

Morganti³

et al. 2013

Eur Respir J

237

149

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“…This supposition is supported by the results from an experimental rat model of pulmonary fibrosis. In this study, micro-autoradiographs indicating the localisation of each drug demonstrated greater tissue penetration with macitentan compared with bosentan [16].…”

Section: The Et Pathwaymentioning

confidence: 52%

“…Macitentan was shown to be more efficacious than bosentan in reducing the development of pulmonary fibrosis and right ventricular hypertrophy in the rat model of pulmonary fibrosis associated with PAH [16]. In addition, a study using the deoxycorticosterone acetone-salt rat model of hypertension investigated the effect of acute oral macitentan versus bosentan administration on mean arterial pressure.…”

Section: The Et Pathwaymentioning

confidence: 99%

Pathways in pulmonary arterial hypertension: the future is here

Sitbon

Morrell

2012

European Respiratory Review

103

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It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways.However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options.This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

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“…Macitentan, a novel dual endothelin receptor antagonist, has been proposed to prevent the development of lung fibrosis in a bleomycin-induced rat model of fibrosis [20]. In this RCT, subjects were randomized to macitentan (n = 119) or placebo (n = 59) [21].…”

Section: Recent Significant Clinical Trials (2010 Onwards)mentioning

confidence: 99%

Idiopathic Pulmonary Fibrosis: Recent Trials and Current Drug Therapy

Jones

Fletcher²,

Richeldi³

2013

Respiration

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Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with increasing incidence; the median survival is only 35 months and as yet no therapy has been proven to prolong survival. Recent unexpected randomised controlled trial (RCT) results and the conflicting evaluations of drug efficacy by regulatory agencies when considering the approval of pirfenidone have emphasised that we remain in the first stages of both our understanding of disease-relevant therapeutic targets and in our ability to investigate these putative targets with well-designed RCT. Three phase III trials are, however, anticipated to report results in 2014 and there is cautious optimism that we may be entering an era of mechanism-based anti-fibrotic therapies proven by large RCT to modify disease progression. We must now address how to practically translate these therapies safely and with maximal efficacy from a homogenous RCT population to the ‘real-life' heterogeneous population of patients with IPF. The role of a formal multi-disciplinary team meeting in a specialist centre with expertise in IPF is key to this. New methodological and ethical research challenges will arise as we enter an era of potential combination therapy; standardized, robust RCT design will be central to meeting these challenges if we are to enable ongoing progress in our aim of increasing both the length and quality of life of patients with IPF.

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Optimization Of Tissue Targeting Properties Of Macitentan, A New Dual Endothelin Receptor Antagonist, Improves Its Efficacy In A Rat Model Of Pulmonary Fibrosis Associated With Pulmonary Arterial Hypertension

Cited by 11 publications

References 0 publications

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial

Pathways in pulmonary arterial hypertension: the future is here

Idiopathic Pulmonary Fibrosis: Recent Trials and Current Drug Therapy

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