Clinical Trials

* On September 10, 2013, Actelion has announced that morbidity and mortality data from the SERAPHIN study was shared during an oral presentation at the European Respiratory Society Annual Congress 2013 in Barcelona, Spain. The presentation highlighted that the investigational drug macitentan (Opsumit®) from Actelion significantly reduced the risk of morbidity and mortality events in patients with pulmonary arterial hypertension (PAH). The presentation from Professor Hossein-Ardeschir Ghofrani of the University Hospital Giessen, Giessen, Germany, focused on key efficacy data for macitentan from the recent landmark SERAPHIN trial. Professor Ghofrani presented data showing the primary endpoint of the study, time from treatment initiation to first morbidity or mortality event. Initially he showed the results of a 45% reduction in the risk of morbidity/mortality events for macitentan 10mg versus placebo (p<0.0001) in the 742 patients taking part in the largest ever trial in PAH. Professor Ghofrani then went on to note that the effect seen early in the study, was sustained throughout the study and was observed regardless of baseline WHO functional class or background PAH therapy.

The SERAPHIN study also demonstrated a significant treatment effect for macitentan 10mg in its secondary outcome measures and compared with placebo, a higher proportion of macitentan- treated patients had nasopharyngitis, headache, and anemia. One patient in each treatment group discontinued due to anemia. Professor Ghofrani presented data showing that the reduction in risk of hospitalization for PAH and death due to PAH associated with macitentan 10mg treatment versus placebo was 50% (p<0.0001) and that all-cause mortality was reduced by 36% (p=ns).

* On September 2, 2013, Actelion has announced that new data for macitentan (Opsumit®) from the landmark SERAPHIN study was presented at the European Society of Cardiology Annual Congress 2013 in Amsterdam, the Netherlands. The presentations from leading experts in the field shared the latest findings on the impact of macitentan on exercise capacity, long term outcome and cardiopulmonary hemodynamics.

6MWD and long-term outcomes: In an oral presentation, Dr Nazzareno Galiè from the Institute of Cardiology, University of Bologna, Bologna, Italy presented data evaluating the association between 6MWD, a measure of exercise capacity and the long-term outcome measured with the endpoint of PAH-related death or hospitalization in the SERAPHIN study. Dr Galiè first shared that macitentan 10mg provided sustained long-term improvements in 6-minute walk distance (6MWD) versus placebo over 12 months (+25.4m, p<0.0001) and then discussed how 6MWD values at both baseline and month 6 were prognostic of long-term outcomes. Finally he showed data to demonstrate that changes in 6MWD from baseline to Month 6 were not associated with PAH-related death or hospitalization risk, raising important questions about the link between functional improvements and long term treatment success. Dr Galiè commented about data presented at the ESC Congress 2013, "The SERAPHIN study is the first event-driven outcome trial in PAH to evaluate the association between 6MWD and long-term outcomes. These data confirm the efficacy of macitentan in improving the functional abilities of patients with PAH, as well as to significantly improve patient outcome.

Dr Galiè added; "While our findings show that the absolute 6MWD value at baseline is prognostic, there is no clear relationship between the change in 6MWD from baseline and long-term treatment outcomes. The study results confirm that while the change in 6MWD is a useful marker of functional improvement, it is not an appropriate measure when looking to understand the impact of treatment on long-term morbidity and mortality. This observation reinforces the importance of selecting appropriate outcome measures when investigating new treatment options for our patients."

Hemodynamic effects of macitentan: Further evidence of the efficacy of macitentan was provided in a second oral presentation, when Dr Adam Torbicki of the Department of Pulmonary Circulation and Thromboembolic Diseases, Center of Postgraduate Medical Education, ECZ-Otwock, Poland, discussed the results of a substudy of SERAPHIN that investigated the impact of macitentan on cardiopulmonary hemodynamics in pulmonary arterial hypertension. Dr Torbicki commented; "Macitentan significantly improved hemodynamic parameters overall in PAH patients in the SERAPHIN study. Furthermore, in our substudy, consistent improvements in pulmonary vascular resistance (PVR) and cardiac index (CI) were achieved with macitentan irrespective of background PAH therapy or baseline WHO functional class."

Professor Marion Delcroix of Gasthuisberg University Hospital, Leuven, Belgium will present a poster entitled 'Is 6-minute walk distance (6MWD) associated with long-term outcomes in pulmonary arterial hypertension (PAH)? Results from SERAPHIN'.

Professor Olivier Sitbon of the Hôpital Universitaire de Bicêtre, Université Paris-Sud, Paris, France will present a poster on the 'Effect of macitentan on haemodynamics in SERAPHIN, a randomised controlled trial in pulmonary arterial hypertension (PAH)'.

Professor Pavel Jansa of Charles University, Prague, Czech Republic will present the poster 'Impact of macitentan on the health-related quality of life (HRQoL) in pulmonary arterial hypertension (PAH): results from a long-term randomised controlled trial'.

Consistent secondary endpoint findings
The study also demonstrated that macitentan reduces the risk of death due to PAH or hospitalization for PAH, one of the secondary endpoints of the study, by 33 percent (3 mg, p=0.0146) and 50 percent (10 mg, p<0.0001) as compared to placebo. In addition, the evaluation of survival, while not statistically significant, showed that macitentan 10 mg reduced the risk of all-cause mortality by 36 percent  (p=0.2037). Patients treated with macitentan 10 mg once a day also experienced a clinically relevant functional improvement, as shown by the baseline adjusted, placebo corrected mean increase in 6-minute walking distance measured at month 6 (secondary endpoint) by 23 meters (p=0.007) with a more pronounced treatment effect in patients in WHO Functional Class III/IV at baseline (+37 meters; p=0.009).
Safety and tolerability
Macitentan in this patient population was well tolerated. The overall incidence of adverse events reported and treatment discontinuations due to adverse events in patients was similar across all groups. The incidence of serious adverse events was lower in patients treated with macitentan as compared to placebo with 52 percent and 45 percent of patients in the macitentan 3 mg and 10 mg groups, respectively, who experienced serious adverse events, and 55 % of patients in the placebo group. The most frequent adverse events associated with the use of macitentan are nasopharyngitis, headache and anemia. Elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal were observed in 4.5 percent of patients receiving placebo, in 3.6 percent of patients on 3 mg of macitentan and in 3.4 percent of patients on 10 mg of macitentan. In addition, no difference was observed between macitentan and placebo on fluid retention (edema).
A decrease in hemoglobin - reported as an adverse event - was observed more frequently on macitentan than placebo, with no difference in treatment discontinuation between groups. On 22nd October 2012 Actelion announced that it had submitted a new drug application to the Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) in patients with pulmonary arterial hypertension.
* On April 30, 2012,  Actelion has announced  that initial analysis indicates that the pivotal, long-term, event-driven study SERAPHIN with macitentan, a novel dual endothelin receptor antagonist, in 742 patients suffering from pulmonary arterial hypertension (PAH) and treated for up to three and a half years, has met its primary endpoint. Macitentan, at both the 3 mg and 10 mg dose, decreased the risk of a morbidity/mortality event over the treatment period versus placebo. This risk was reduced by 45 percent in the 10 mg dose group (p<0.0001). At 3 mg, the observed risk reduction was 30 percent (p=0.0108). Treatment with macitentan in the SERAPHIN study was well tolerated.Secondary efficacy endpoints, including change from baseline to month 6 in six-minute walk-distance, change from baseline to month 6 in WHO functional class and time - over the whole treatment period - to either death due to PAH or hospitalization due to PAH, also showed a dose-dependent effect (pThe safety set comprised 741 patients (randomized 1:1:1), who received at least one dose of study treatment. Mean exposure to study treatment was 85.3 weeks for placebo patients (n=249), 99.5 weeks for patients on 3 mg (n=250) and 103.9 weeks for patients on 10 mg (n=242).  Macitentan in this patient population was well tolerated. The number of adverse events reported and patients discontinuing treatment due to adverse events was similar across all groups. Elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal were observed in 4.5 percent of patients receiving placebo, in 3.6 percent of patients on 3 mg of macitentan and in 3.4 percent of patients on 10 mg of macitentan. In addition, no difference was observed between macitentan and placebo on fluid retention (edema).  A decrease in hemoglobin - reported as an adverse event - was observed more frequently on macitentan than placebo, with no difference in treatment discontinuation between groups. Submission of the registration dossier to Health Authorities worldwide is expectedby the fourth quarter of 2012. Macitentan has been granted orphan status on September 2011 in Europe.