TRITON Phase 3b Study Results Presented at the European Society of Cardiology Congress
While the primary endpoint was not met, exploratory analysis suggests a signal of reduced risk of disease progression of initial triple oral combination therapy vs initial double oral therapy for Pulmonary Arterial Hypertension (PAH) patients
In the TRITON trial, both the initial triple oral therapy and initial double oral therapy arms demonstrated reductions in the primary endpoint, pulmonary vascular resistance, of 54 percent and 52 percent respectively, with no statistical difference observed between both groups.1 Improvements were observed in six-minute walk distance,1 N-terminal pro-brain natriuretic peptide (NT-proBNP) and clinical variables at week 26 in patients who were treated with either initial triple oral or initial double oral combination therapy, with no difference between treatment regimens.2
However, initial triple oral therapy was associated with a 41 percent reduction in the risk of first disease progression event compared to initial oral double therapy at an average follow up of 77.6 and 75.8 weeks, respectively.1 Sixteen initial disease progression events were observed in patients taking initial triple oral therapy, and 27 events were observed in patients taking initial double oral therapy (hazard ratio 0.59; 95 percent confidence interval [CI]; 0.32, 1.09).3 Two patients died in the initial triple therapy group (1.7 percent) compared to nine (7.1 percent) in the initial double therapy group up to the end of the main observation period (hazard ratio 0.23; 95 percent CI 0.05, 1.04). These results are not statistically significant and should be interpreted as exploratory considering the primary endpoint was not met.1,3
The nature of reported adverse events (AEs) were consistent with the known safety profiles of the study medications.1,4,5
“While the study’s primary endpoint was not met, we observed a signal of reduced risk of disease progression in the initial triple oral combination therapy group as compared to the initial double oral therapy group,” said Nazzareno Galiè*, Full Professor of Cardiology at the
The efficacy and safety of selexipag has been demonstrated in PAH previously in the pivotal GRIPHON trial, which showed that, compared with placebo, selexipag demonstrated a 40 percent risk reduction in disease progression as captured by the primary composite end point of morbidity and mortality.4,6 Consistent results were seen when selexipag was added to double oral therapy (an endothelin receptor antagonist [ERA] plus a phosphodiesterase type-5 inhibitor [PDE-5i]), compared to double oral therapy alone.7
“Data from the TRITON and pivotal GRIPHON studies reinforce the role of selexipag in the escalation of therapy on top of double oral therapy with an ERA and PDE-5i. These studies reaffirm Janssen’s commitment to innovation and the scientific advancement of PAH treatment and care,” said Alessandro Maresta, M.D., Vice President and Head of Medical Affairs at
* Prof. Galiè has received research support from
About the TRITON Study1,2,3
TRITON (NCT02558231) is a multicentre, double-blind, placebo-controlled, Phase 3b study, that randomised 1:1 newly diagnosed, treatment-naïve, PAH patients to initial triple oral or initial double oral combination therapy. Macitentan and tadalafil were initiated at randomisation, selexipag/placebo at day 15 (uptitrated until week 12). Efficacy and safety were assessed in a blinded manner and all patients were followed until the end of the observation period (until the last patient randomised completed the week 26 visit; median follow-up time approximately 17 months). The primary endpoint was change in PVR at week 26, expressed as ratio of baseline. Secondary endpoints, tested hierarchically, included change in six-minute walk distance and NT-proBNP at week 26, time to disease progression (centrally adjudicated) from randomisation until the end of observation period plus seven days, and absence of worsening WHO functional class at week 26. Safety was reported up to end of observation period. The trial enrolled 247 patients.
Selexipag is an oral selective prostacyclin IP receptor agonist approved by the
The efficacy of selexipag in PAH was established in GRIPHON (Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial HypertensiON), the largest randomised, controlled trial ever conducted in PAH patients. This double-blind, multicentre study aimed to evaluate the long-term efficacy and safety of oral selexipag and included almost 400 patients who were already receiving double combination PAH treatment. The study provided the first randomised, controlled evidence for triple oral combination therapy in PAH. Selexipag was shown to delay disease progression and significantly reduce the risk of hospitalisation compared with placebo, as well as improving exercise capacity.6 Overall, the most common adverse events in the selexipag group were consistent with the known side effects of prostacyclin, including headache, diarrhoea, nausea, and jaw pain.6
Important Safety Information
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Macitentan is an oral endothelin receptor antagonist (ERA) approved by the
The efficacy of macitentan in PAH was established in SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome), a long-term event-driven study in PAH patients with predominantly WHO FC II-III symptoms treated for an average of two years.5 SERAPHIN was the largest and longest clinical study conducted at that time, and the first completed study that demonstrated long-term outcomes with a composite morbidity and mortality primary endpoint.5,8 Compared with placebo, macitentan significantly reduced the risk of the first occurrence of a morbidity or mortality event (the primary endpoint).5 Macitentan also reduced the risk of PAH-related death and hospitalisation, as well as significantly improving WHO FC and health-related quality of life versus placebo.9,10 Overall, the most common adverse events frequently associated with macitentan than placebo were headache, nasopharyngitis and anaemia.11
Important Safety Information
About Pulmonary Arterial Hypertension (PAH)
PAH is a specific form of pulmonary hypertension (PH) that causes the walls of the pulmonary arteries (blood vessels leading from the right side of the heart to the lungs) to become thick and stiff, narrowing the space for blood to flow, and causing an increased blood pressure to develop within the lungs. PAH is a serious, progressive disease with a variety of aetiologies and has a major impact on patients' functioning as well as their physical, psychological and social wellbeing. There is currently no cure for PH and it is often fatal.12,13,14 However, the last decade has seen significant advances in the understanding of the pathophysiology of PAH, transforming the prognosis for PAH patients from symptomatic improvements in exercise tolerance 10 years ago, to delayed disease progression today.
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Cautions Concerning Forward-looking Statements
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995 regarding UPTRAVI® (selexipag) and OPSUMIT® (macitentan). The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of
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Galié N, et al. Long-term outcomes in newly diagnosed pulmonary arterial hypertension (PAH) patients receiving initial triple oral combination therapy: Insights from the randomised controlled TRITON study.
European Society of Cardiology Congress. 31 August – 1 September 2020. Virtual.
- Chin K, et al. Efficacy and Safety of Initial Triple Oral Versus Initial Double Oral Combination Therapy in Patients with Newly Diagnosed Pulmonary Arterial Hypertension (PAH): Results of the Randomized Controlled TRITON Study. Am J Respir Crit Care Med 2020;201:A2928.
N. Long-term outcomes in newly diagnosed pulmonary arterial hypertension (PAH) patients receiving initial triple oral combination therapy: Insights from the randomised controlled TRITON study. Presented at European Society of Cardiology Congress. 29 August – 1 September 2020. Virtual.
UPTRAVI® (selexipag) Summary of Product Characteristics.
Janssen-Cilag International NV. July 2019.
OPSUMIT® (macitentan) Summary of Product Characteristics.
Janssen-Cilag International NV. April 2020.
- Sitbon O, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med2015;373(26):2522–33.
- Coghlan J, et al. Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study. Am J Cardiovasc Drugs 2018; 18: 37–47.
- Said, K. Macitentan in pulmonary arterial hypertension: The SERAPHIN trial. Glob Cardiol Sci Pract 2014; 2:26–30.
- Channick RN, et al. Effect of Macitentan on Hospitalizations. Results from the SERAPHIN Trial. JACC Heart Fail 2015; 3:1-8.
- Mehta S, et al. Macitentan Improves Health-Related Quality of Life for Patients With Pulmonary Arterial Hypertension. Results From the Randomized Controlled SERAPHIN Trial. Chest 2017; 151:106-18.
- Pulido T, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369:809-18.
- Vachiéry JL, et al. Challenges in the diagnosis and treatment of pulmonary arterial hypertension.Eur Respir Rev2012; 21:313-20.
Galiè N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.
Eur Heart J2016;37:67-119.
- Hoeper MG, et al. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev 2014; 23:450-7.
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