Late-Breaking Phase 3 A DUE Data Show Investigational Single-Tablet Combination Therapy of Macitentan and Tadalafil Significantly Improves Pulmonary Haemodynamics versus Monotherapy in Patients with Pulmonary Arterial Hypertension (PAH)

Study findings presented during the American College of Cardiology’s 72nd Annual Scientific Session & Expo Together With World Heart Federation’s World Congress of Cardiology

European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines recommend initial dual combination therapy with macitentan and tadalafil for PAH patients without cardiopulmonary comorbidities¹

BEERSE, Belgium, 6 March, 2023 – The Janssen Pharmaceutical Companies of Johnson & Johnson today announced results from the Phase 3 A DUE study (NCT03904693), which showed an investigational once-daily, single-tablet combination therapy, also known as fixed-dose combination, of macitentan 10 mg and tadalafil 40 mg (M/T STCT), significantly improved pulmonary haemodynamics (blood flow through pulmonary blood vessels) versus macitentan and tadalafil monotherapies in pulmonary arterial hypertension (PAH) patients with World Health Organization (WHO) functional class (FC) II or III.² The data were presented today as a Late-Breaking Clinical Trial presentation during the American College of Cardiology’s 72^nd Annual Scientific Session & Expo Together With World Heart Federation’s World Congress of Cardiology.

PAH is a rare, progressive and life-threatening blood vessel disorder characterised by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation that eventually leads to right heart failure.³ Recently updated European Society of Cardiology/European Respiratory Society (ESC/ERS) PH guidelines have strengthened recommendations on initial dual combination therapy with macitentan and tadalafil for PAH patients without cardiopulmonary comorbidities.¹ Currently, this requires patients to take multiple pills as no single tablet that combines two or more PAH-specific pathways is available for these patients.

“Targeting different pathways in the treatment of PAH has demonstrated clear clinical benefits, yet current treatment regimens are cumbersome and create a significant pill burden for patients, many of whom take a large number of pills each day to treat their PAH and various comorbidities,” said Kelly Chin, M.D., Professor of Internal Medicine and Director of the Pulmonary Hypertension Program at UT Southwestern Medical Center, and an investigator in the A DUE study.^4,5,6* “The results from this study demonstrate that a single-tablet combination has the potential to support initial dual combination therapy and rapid escalation from monotherapy, which may improve functional outcomes and help close the gap from guideline recommendations to clinical practice.²”

The A DUE study is a double-blind, randomised, active-controlled, multi-centre, adaptive parallel-group study designed to compare the efficacy and safety of investigational M/T STCT versus macitentan and tadalafil monotherapies in patients with PAH.⁷ A total of 187 adult PAH patients from across 148 sites in 19 countries worldwide in WHO FC II or III who were treatment naïve or on a stable dose of an endothelin receptor antagonist (ERA) or a phosphodiesterase type 5 inhibitor (PDE5i) for at least three months, were enrolled in the study.⁷ The primary endpoint is pulmonary vascular resistance (PVR) measured 16 weeks following initiation of treatment expressed as the ratio of geometric means to baseline.⁷

Secondary efficacy outcome measures included change from baseline in exercise capacity as measured by change in 6-minute walk distance (6MWD) at the end of double-blind treatment at week 16 compared to baseline.⁷

Following the double-blind treatment period, patients transitioned to the open-label treatment period for 24 months. Baseline characteristics were balanced across treatment arms except for a higher proportion of WHO FC II patients in the M/T STCT arm and a greater time from diagnosis of PAH in the macitentan arm.⁷

“The guiding light of our PH research is the goal of transforming PAH into a manageable condition, so we’re constantly looking for ways to improve both clinical outcomes and the treatment experience,” said James List, M.D., Ph.D., Global Therapeutic Area Head, Cardiovascular, Metabolism, Retina & Pulmonary Hypertension, Janssen Research & Development, LLC. “A single-tablet combination has the potential to be an important new option for helping physicians optimise disease management with the potential to enhance convenience and help improve adherence and outcomes.⁸”

Key A DUE Study Findings

The A DUE study met its co-primary endpoint, demonstrating marked pulmonary haemodynamic improvement as shown by the highly statistically significant, consistent and robust PVR reduction in participants treated with M/T STCT compared to both monotherapies.² PVR change with M/T STCT (n=70) was significantly greater versus macitentan (n=35, treatment effect: 29 percent; 95 percent confidence limit [CL]: -18 percent, -39 percent; p<0.0001). PVR change with M/T STCT (n=86) was also significantly greater versus tadalafil (n=44, treatment effect: 28 percent; 95 percent CL: -20 percent, -36 percent; p<0.0001).²

Although the A DUE study was not powered to demonstrate a benefit on exercise capacity, there was a clinically relevant improvement in 6MWD.

• At week 16, treatment effect was not statistically significant; however a clinically relevant improvement in 6MWD in favour of M/T STCT versus monotherapies was observed. Adjusted treatment effect in 6MWD, change from baseline, in the M/T STCT (n=70) versus macitentan group (n=35) was 16.04m (CL: -17.0, 49.08; p=0.380) and 25.37m in the M/T STCT (n=86) versus tadalafil group (n=44, CL: -0.93, 51.59; p =0.059).²
• The safety profile of M/T STCT was consistent with the known safety profiles of macitentan and tadalafil monotherapies and no new safety observations were made.²