Clinical Trials

* On December 23, 2015, Actelion announced that the New England Journal of Medicine (NEJM) has published the results of the oral, selective IP prostacyclin receptor agonist, selexipag, in patients with pulmonary arterial hypertension (PAH). The NEJM paper presents the results of the GRIPHON study, a multicenter, Phase III study in which 1,156 patients, 79.6% of whom were already treated for PAH at baseline, received either placebo or selexipag for a median of 63.7 weeks and 70.7 weeks respectively. The patients' dose was adjusted weekly until the individualized maximum tolerated dose was achieved (ranging from 200 micrograms twice daily to 1,600 micrograms twice daily).
In GRIPHON, the risk of the primary composite endpoint of death from any cause or complication related to PAH up to the end of the treatment period was reduced by 40% (p<0.001) with selexipag compared to placebo. The treatment effect was driven by hospitalization and disease progression, which accounted for 81.9% of the primary endpoint events. The benefit of selexipag was consistent across pre-specified patient sub-groups such as PAH classification, WHO functional class and use of medication for PAH, which included patients receiving an ERA and a PDE-5 inhibitor at baseline (n = 376; 32.5%).
The adverse events observed with selexipag were consistent with those typically observed for prostacyclin therapies, including headache, diarrhea, nausea, and jaw pain. These adverse events were typically mild to moderate in severity. Overall, 7.1% of placebo-treated patients and 14.3% of selexipag-treated patients prematurely discontinued treatment due to adverse events.
In this event-driven, Phase III study, 1,156 patients with pulmonary arterial hypertension were randomized to receive placebo or selexipag in individualized doses (maximum 1,600 micrograms twice daily). Stable use of an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, or both was allowed at enrollment. The primary outcome measure was a composite of death or complication related to PAH up to the end of treatment period.
A primary end point event occurred in 397 patients (41.6% placebo, 27.0% selexipag). The hazard ratio for selexipag versus placebo was 0.60 (99% CI, 0.46 to 0.78; P<0.001). Disease progression and hospitalization accounted for 81.9% of events. The effect of selexipag on the primary end point was similar in patients not receiving treatment and already receiving treatment for the disease, including a combination of two therapies.
Overall, 41 (7.1%) patients in the placebo group and 82 (14.3%) in the selexipag group prematurely discontinued treatment due to an adverse event. The most frequent adverse events leading to treatment discontinuation in the selexipag group (>1% difference between selexipag and placebo) were headache (3.3%), diarrhea (2.3%), and nausea (1.7%). Hyperthyroidism occurred in eight selexipag-treated patients and led to treatment discontinuation in one patient. No serious adverse events were reported more frequently (>1% difference between selexipag and placebo) in the selexipag group. Adverse events associated with prostacyclin occurred more frequent during the dose-adjustment phase, where they were used to define the individualized maximum tolerated dose.
(Sitbon O et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015; 373:2522-33.)

* On October 22, 2015, Actelion announced that further key data from the pivotal Phase III GRIPHON study with the investigational drug selexipag (Uptravi®) will be shared through a poster presentation at the American College of Chest Physicians' CHEST Congress in Montréal, Canada. The poster, titled 'Individualized dosing of selexipag based on tolerability in the GRIPHON study shows consistent efficacy and safety in patients with pulmonary arterial hypertension' will be presented by Dr Richard Channick from Massachusetts General Hospital, Boston, USA (abstract).

* On August 27, 2015, Actelion announced that key data from the pivotal Phase III GRIPHON study with selexipag (Uptravi®) will be shared during a 'best poster session' at the European Society of Cardiology (ESC) Congress in London, UK. The poster presentation, titled ‘Effect of selexipag on long-term outcomes in patients with pulmonary arterial hypertension (PAH) receiving one, two or no PAH therapies at baseline: results from the GRIPHON study’ will be part of the 'Best posters in pulmonary hypertension treatment strategies' session with a focussed discussion with the lead author, Prof Dr Irene Lang from the Medical University of Vienna, Vienna, Austria, at 15.30 on 30 August (Abstract: P2365).

* On March 15, 2015, Actelion announced that key long-term outcome data from the pivotal selexipag (Uptravi®) Phase III GRIPHON study were shared during an oral presentation at the American College of Cardiology (ACC) Congress in San Diego, US. The presentation highlighted that the investigational drug selexipag significantly reduced the risk of a morbidity/mortality event by 40% versus placebo (p<0.0001) in patients with pulmonary arterial hypertension (PAH). The presentation was given by Vallerie McLaughlin M.D., Director of the Pulmonary Hypertension Program in the Division of Cardiovascular Medicine at the University of Michigan, United States and Steering Committee member of the GRIPHON study. In this pivotal, double-blind, placebo-controlled, event-driven trial, 1,156 patients suffering from PAH were randomized 1:1 to placebo or selexipag. Patients were treated for up to 4.3 years, with median exposure to study treatment of 63.1 weeks for patients on placebo (n=582), and 70.6 weeks for patients on selexipag (n=574). At enrolment, 80% of patients were already receiving therapy for PAH, with 15% receiving endothelin receptor antagonist (ERA) monotherapy, 32% receiving phosphodiesterase-5 inhibitor (PDE-5i) monotherapy and 33% receiving a combination of both an ERA and a PDE-5i. At baseline, 47% of patients were in WHO Functional Class I/II and 53% in Functional Class III/IV.

CONSISTENT KEY SUBGROUP FINDINGS: The reduction in risk of a morbidity/mortality event was consistent across key subgroups; age, gender, PAH etiology, baseline WHO Functional Class and irrespective of background therapy, including patients receiving selexipag on top of a combination of both an ERA and a PDE-5i.

DOSING IN GRIPHON: Titrating selexipag to an individualized maintenance dose based on tolerability was effective in achieving long-term outcome benefits across the tested dose range. The dosing in GRIPHON was initiated at 200 micrograms (mcg) twice daily (b.i.d) and increased weekly in steps of 200 mcg up to a maximum of 1600 mcg b.i.d. After titrating to the highest tolerated dose, the benefit was consistent across the pre-specified low- (200, 400 mcg b.i.d), medium- (600, 800, 1'000 mcg b.i.d) and high-maintenance (1'200, 1'400, 1'600 mcg b.i.d) dose groups.
SIX-MINUTE WALK DISTANCE: Treatment with selexipag also led to a statistically significant increase in six-minute walk distance (6MWD) at week 26 of 12 meters in the entire patient population (p=0.0027), with an improvement of 34 meters in PAH-treatment-naïve patients (p=0.0002).
SAFETY AND TOLERABILITY: Tolerability of selexipag in GRIPHON was consistent with therapies targeting the prostacyclin pathway. Adverse reactions occurring more frequently (>5%) on selexipag compared to placebo, over the course of the study, were headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing.
Over the course of the study, the proportion of patients discontinuing treatment due to adverse events, without a morbidity or mortality event, was 14% on selexipag and 7% on placebo.
Further data from the GRIPHON study will be shared through scientific publication.

* On March 2, 2015, Actelion announced that key data from the pivotal Phase III selexipag (Uptravi®) study will be shared during an oral presentation at the American College of Cardiology (ACC) Congress in San Diego, US. The oral presentation, entitled 'Effect of selexipag on morbidity/mortality in pulmonary arterial hypertension: results of the GRIPHON study' will be given by Professor Vallerie McLaughlin of the University of Michigan Health System Division of Cardiovascular Medicine in Ann Arbor.

* On June 16, 2014, Actelion announced the top-line results of the pivotal Phase III GRIPHON study in 1,156 patients with pulmonary arterial hypertension (PAH) with selexipag. Initial analysis shows that the event-driven outcome study has met its primary efficacy endpoint with high statistical significance. Selexipag decreased the risk of a morbidity/mortality event versus placebo by 39% (p<0.0001). Efficacy observed was consistent across the key subgroups; age, gender, WHO Functional Class, PAH etiology and background PAH therapy. Patients were treated for up to 4.3 years. The overall tolerability profile of selexipag in GRIPHON was consistent with prostacyclin therapies. Detailed study results will be made available through scientific disclosure at upcoming congresses and in peer reviewed publications. Uptitration of selexipag allows each patient's maintenance dose to be individualized based on tolerability. Dosing in GRIPHON was initiated at 200 micrograms (mcg) bid and increased in steps of 200 mcg twice daily up to a maximum of 1600 mcg twice daily. The most common adverse events in GRIPHON that occurred with higher frequency on selexipag than placebo were in-line with those known in prostacyclin therapies; headache, diarrhea, nausea, jaw pain, vomiting, pain in extremity, myalgia, nasopharyngitis and flushing. The proportion of patients discontinuing treatment due to adverse events was 14 percent on selexipag and 7 percent on placebo.