ABOUT MACITENTAN

Macitentan is an orally available endothelin receptor antagonist (ERA) that resulted from a tailored drug discovery process in Actelion’s laboratories.

Macitentan (Opsumit®) is currently approved for the treatment of pulmonary arterial hypertension (PAH), a chronic, life-threatening disorder which severely compromises the function of the lungs and heart. The product is commercially available in over 35 markets, including the US (since November 2013), Germany (since January 2014) and Japan (since June 2015). The registration process for other countries is ongoing.

CURRENT STATUS

Macitentan is currently being further evaluated in multiple studies to expanding the clinical utility of this important product in PAH and beyond.

MERIT (MERIT; Macitentan in thE tReatment of Inoperable chronic Thromboembolic pulmonary hypertension) is a Phase II prospective, randomized, placebo-controlled, double-blind, multi-center, parallel-group study to assess the efficacy, safety and tolerability of 10 mg macitentan in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).

In MERIT, 80 inoperable patients were randomized in a 1:1 ratio into 2 treatment groups (macitentan 10 mg or placebo) over a 24 week treatment period. The study started in August 2014 and was completed in September 2016. Patients with symptomatic PH in WHO Functional Class (FC) III or IV at baseline were allowed to receive PH background therapy throughout the study, including PDE-5 inhibitors or oral/inhaled prostanoids. All patients included into the study underwent independent operability assessment based on local or central adjudication committees.

After 16 weeks the treatment effect was a significant 16% reduction in pulmonary vascular resistance (PVR) with macitentan compared with placebo (95% CL: −30%, −1%; p=0.04 intention-to-treat (ITT)). The efficacy observed was consistent across all sub-groups, included patients receiving background PH specific therapy at baseline (61%), including PDE-5 inhibitors (59%). Mean PVR decreased from baseline in both macitentan and placebo groups (geometric mean percent ratios of Week 16/baseline 73.0% and 87.2%, respectively).

The study also showed a significant positive effect of macitentan compared to placebo on exercise capacity. After 24 weeks of treatment, the mean change in 6-minute walk distance (6-MWD) from baseline was an increase of 35 meters (m) in macitentan and 1 m in placebo. The 6-MWD least-squares mean difference at Week 24 was 34.0 meters between macitentan and placebo (95% CL: 2.9, 65.2 m; p=0.03).

Macitentan was well tolerated in this patient population and safety was in general consistent with the known safety profile for macitentan from previous clinical studies. The most frequently reported adverse events that occurred with higher frequency on macitentan vs. placebo were peripheral edema (22.5% vs. 10.0%) and events related to anemia (17.5% vs. 2.5%). Hemoglobin decreases were observed in both macitentan and placebo groups and in only one subject in each group hemoglobin values decreased below 100 g/L during the study.

MAESTRO (MAcitentan in Eisenmenger Syndrome To RestOre exercise capacity) is a Phase III multi-center, double-blind, randomized, placebo-controlled, parallel-group study to evaluate the effects of macitentan on exercise capacity in patients with Eisenmenger Syndrome. This study is ongoing, with approximately 220 subjects to be randomized in a 1:1 ratio into 2 treatment groups (macitentan 10 mg or placebo) over a 16 week treatment period.

PORTICO (PORtopulmonary Hypertension Treatment wIth maCitentan ─ a randOmized Clinical Trial) is a randomized, double-blind, placebo-controlled, prospective, multicenter, parallel group Phase IV study to assess the safety and efficacy of macitentan in patients with portopulmonary hypertension (PoPH). The primary objective of the study is to evaluate the effect of 10 mg macitentan on pulmonary vascular resistance (PVR) as compared to placebo. Secondary objectives include the evaluation of the effect of macitentan as compared to placebo on exercise capacity and WHO functional class, as well as the evaluation of the safety and tolerability of macitentan in patients with PoPH.

RUBATO is a Phase III prospective, multi-center, double-blind, placebo-controlled parallel group study is to assess the efficacy and safety of macitentan in stable Fontan-palliated adolescents and adults. The primary objective is to assess the effect of macitentan 10 mg as compared to placebo on exercise capacity through cardiopulmonary exercise testing (peak VO2).  Secondary objectives include the evaluation of the safety and tolerability of macitentan as compared to placebo in stable Fontan-palliated patients. The duration of the study is expected to be approximately 28 months; the start is planned for mid-2017.

TOMORROW (pediaTric use Of Macitentan tO delay disease pRogRessiOn in PAH Worldwide) is a multicenter, controlled, randomized, open-label event-driven study to assess the efficacy, safety and pharmacokinetics of a pediatric formulation of macitentan versus standard of care in children with PAH. The study will enroll children between the age of 1 month and 18 years in more than 20 countries and is expected to last up to 6 years.

AVAILABLE CLINICAL DATA

Macitentan has been studied in SERAPHIN, a multicenter, double-blind, placebo-controlled, parallel-group, event-driven, Phase III outcome study in 742 patients with symptomatic PAH, who were randomized to three treatment groups (placebo [N = 250], 3 mg [N = 250] or 10 mg [N = 242] of macitentan once daily), to assess the long-term effect on morbidity or mortality.

Treatment with macitentan 10 mg resulted in a 45% risk reduction (hazard ratio [HR] 0.55; 97.5% CI: 0.39 to 0.76; logrank p < 0.0001) of the composite morbidity-mortality endpoint up to end of treatment (EOT) when compared to placebo. The treatment effect was established early and was sustained. In patients already on background therapy for PAH treatment with macitentan 10 mg resulted in a 38% risk reduction (HR 0.62; 97.5% CI: 0.43 to 0.8; logrank p=0.0094) of the composite morbidity-mortality endpoint compared to placebo.

The risk of PAH related death or hospitalization for PAH up to EOT was reduced by 50% (HR 0.50; 97.5% CI: 0.34 to 0.75; logrank p < 0.0001) in patients receiving macitentan 10 mg (50 events) compared to placebo.

Efficacy of macitentan 10 mg on the primary endpoint was consistent across subgroups of age, sex, ethnic origin, geographical region, aetiology, by monotherapy or in combination with another PAH therapy and by WHO FC (I/II and III/IV).

The most commonly reported adverse drug reactions are nasopharyngitis (14.0%), headache (13.6%) and anaemia (13.2%, see section 4.4). The majority of adverse reactions are mild to moderate in intensity.

MILESTONES

2013 – Opsumit approved by the EU Commission
2013 – Opsumit approved by the US FDA
2012 – SERAPHIN outcome study meets its primary endpoint
2007 – Initiation of Phase III SERAPHIN study in PAH patients
2005 – Initiation of Phase II dose ranging study
2004 – Entry-into-man
2003 – Selection of macitentan for initiation of preclinical studies

KEY SCIENTIFIC LITERATURE

Pulido T et al. N Engl J Med 2013;369:809-18.

Iglarz M. et al. J Pharmacol Exp Ther. 2008;327(3):736-45.

Iglarz M et al. Am J Respir Crit Care Med 2011;183:A6445.

Sidharta PN et al. Eur J Clin Pharmacol 2011;67(10):977-84.

Bruderer S et al. AAPS J 2012; 14(1):68-78.

 

Clinical Trial Supply Coordinator, Technical operations 

 

"I enjoy working for Actelion because it has a culture of innovation and creativity."