JANSSEN

Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson, today announced results from the Phase 3b TRITON trial, the first randomised controlled study evaluating the efficacy and safety of initial triple oral combination therapy (UPTRAVI^® [selexipag], OPSUMIT^® [macitentan] and tadalafil) compared to initial double oral combination therapy (placebo, macitentan and tadalafil) in newly diagnosed, treatment-naïve patients with pulmonary arterial hypertension (PAH). Study results were featured as an oral presentation as part of the digital European Society of Cardiology Congress held 29 August – 1 September 2020.

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 Department of Experimental, Diagnostic and Specialty Medicine (DIMES) of the UNIBO. “This signal requires further evaluation to enhance our knowledge in the PAH field.”

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 Actelion Pharmaceuticals Ltd, a Janssen Pharmaceutical Company of Johnson & Johnson. “We will continue to invest in the science and remain committed to transforming PAH into a long-term, manageable condition so that patients can live a normal life.”

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* Prof. Galiè has received research support from Actelion and has served as a paid consultant to the company. Prof. Galiè is not being paid by Actelion for media opportunities.

About the TRITON Study^1,2,3 
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.

About Selexipag 
Selexipag is an oral selective prostacyclin IP receptor agonist approved by the European Medicines Agency (EMA) for the long-term treatment of PAH in adult patients with WHO functional class (FC) II–III, either as combination therapy in patients insufficiently controlled with an endothelin receptor antagonist (ERA) and/or a phosphodiesterase type 5 (PDE-5) inhibitor, or as monotherapy in patients who are not candidates for these therapies. Selexipag, originally discovered and synthesised by Nippon Shinyaku, is the only globally-available oral treatment that works on the prostacyclin pathway with evidence of long-term outcomes.⁴

The efficacy of selexipag in PAH was established in GRIPHON (Prostacyclin (PG I2) R eceptor agonist I n P ulmonary arterial H ypertensiON ), 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 
For complete prescribing information, please visit:
https://www.ema.europa.eu/en/documents/product-information/uptravi-epar-product-information_en.pdf

About Macitentan 
Macitentan is an oral endothelin receptor antagonist (ERA) approved by the European Medicine Agency (EMA) as monotherapy or in combination for the long-term treatment of PAH in adult patients of WHO Functional Class (FC) II to III.⁵

The efficacy of macitentan in PAH was established in SERAPHIN (S tudy with an E ndothelin R eceptor A ntagonist in P ulmonary arterial H ypertension to I mprove cliN ical 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
For complete European Union (EU) prescribing information, please visit: 
https://www.ema.europa.eu/en/documents/product-information/opsumit-epar-product-information_en.pdf

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.

About Actelion 
In June 2017, Actelion became part of the Janssen Pharmaceutical Companies of Johnson & Johnson. Actelion's medicines have helped to expand and strengthen Janssen's portfolio with leading, differentiated in-market medicines and promising late-stage compounds. Janssen has added Pulmonary Hypertension as a therapeutic area of focus to maintain the leadership position Actelion has built in this important disease area.

About the Janssen Pharmaceutical Companies of Johnson & Johnson 
At Janssen, we’re creating a future where disease is a thing of the past. We’re the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular & Metabolism, Immunology, Infectious Diseases & Vaccines, Neuroscience, Oncology, and Pulmonary Hypertension. Learn more at https://www.janssen.com/emea/ . Follow us at https://twitter.com/janssenemea . Actelion Pharmaceuticals Ltd is one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Follow Actelion on Twitter @actelion_com .

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 Actelion Pharmaceuticals Ltd, any of the other Janssen Pharmaceutical Companies and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended December 29, 2019, including in the sections captioned "Cautionary Note Regarding Forward-Looking Statements" and "Item 1A. Risk Factors,” and in the company's most recently filed Quarterly Report on Form 10-Q, and the company's subsequent filings with the Securities and Exchange Commission. Copies of these filings are available online at www.sec.gov , www.jnj.com or on request from Johnson & Johnson. None of the Janssen Pharmaceutical Companies nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.

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References

1. 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.
2. 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.
3. Galié, 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.
4. UPTRAVI^® (selexipag) Summary of Product Characteristics. Janssen-Cilag International NV. July 2019.
5. OPSUMIT^® (macitentan) Summary of Product Characteristics. Janssen-Cilag International NV. April 2020.
6. Sitbon O, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015;373(26):2522–33.
7. 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.
8. Said, K. Macitentan in pulmonary arterial hypertension: The SERAPHIN trial. Glob Cardiol Sci Pract 2014; 2:26–30.
9. Channick RN, et al. Effect of Macitentan on Hospitalizations. Results from the SERAPHIN Trial. JACC Heart Fail 2015; 3:1-8.
10. 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.
11. Pulido T, et al. Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension. N Engl J Med 2013; 369:809-18.
12. Vachiéry JL, et al. Challenges in the diagnosis and treatment of pulmonary arterial hypertension.Eur Respir Rev 2012; 21:313-20.
13. Galiè N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.Eur Heart J 2016;37:67-119.
14. Hoeper MG, et al. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev 2014; 23:450-7.

CP-168836 
August 2020

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