Janssen Pharmaceutical Companies, a subsidiary of Johnson & Johnson, has announced the submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) for its single-tablet combination therapy containing macitentan 10 mg and tadalafil 40 mg. This combination is intended for the long-term treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) in adult patients classified as WHO functional class (FC) II-III. The application is grounded in the positive outcomes of the Phase 3 A DUE study.
A DUE Study Results
The Phase 3 A DUE study (AC-077-A301) evaluated the efficacy and safety of the macitentan/tadalafil single-tablet combination (M/T STCT) against macitentan and tadalafil monotherapies in PAH patients. The study achieved its co-primary endpoint, demonstrating a statistically significant reduction in pulmonary vascular resistance (PVR) in patients treated with the combination therapy compared to those receiving either monotherapy at 16 weeks. Specifically, PVR decreased by 45 percent from baseline in the M/T STCT group (n=70), versus a 23 percent reduction in the macitentan group (n=35; treatment effect: 29 percent reduction; 95 percent CL: -18 percent, -39 percent; p<0.0001). Similarly, the M/T STCT group (n=86) showed a 44 percent reduction in PVR from baseline, compared to a 22 percent reduction in the tadalafil group (n=44; treatment effect: 28 percent reduction; 95 percent CL: -20 percent, -36 percent; p<0.0001).
While the study was not powered to detect differences in exercise capacity, a positive trend toward clinically relevant improvement in the 6-minute walk distance (6MWD) favored the M/T STCT over the monotherapies as a key secondary endpoint. The safety profile of the combination therapy was consistent with the known safety profiles of macitentan and tadalafil individually, with common adverse events including headache, oedema, anaemia, haemoglobin decrease, and hypotension.
Clinical Significance
Pulmonary arterial hypertension is a rare, progressive, and life-threatening condition characterized by the constriction of small pulmonary arteries, leading to elevated blood pressure in the pulmonary circulation and eventually right heart failure. Updated guidelines from the European Society of Cardiology/European Respiratory Society (ESC/ERS) emphasize initial double combination therapy with macitentan and tadalafil for PAH patients without cardiopulmonary comorbidities. Currently, patients must take multiple pills to target two or more PAH-specific pathways, as no single tablet is available in Europe.
According to Tamara Werner-Kiechle, M.D., EMEA Therapeutic Area Lead Neuroscience and Pulmonary Hypertension, Janssen-Cilag GmbH, the ESC/ERS guidelines recommend double and triple combination therapy, potentially leading to complex treatment regimens with multiple pills daily. A single-tablet combination could offer a more convenient option for PAH patients, potentially improving adherence and outcomes.
About Macitentan and Tadalafil
Macitentan, an endothelin receptor antagonist (ERA), is approved for the long-term treatment of PAH in adult patients of WHO Functional Class (FC) II to III, either as monotherapy or in combination. Tadalafil, a phosphodiesterase-5 (PDE5) inhibitor, is indicated for adults with PAH classified as WHO functional class II and III to improve exercise capacity.
Future Implications
The submission to the EMA follows a New Drug Application submitted to the U.S. Food and Drug Administration (FDA) in May 2023. Approval of the single-tablet combination therapy would provide a new treatment option for PAH patients, potentially simplifying their treatment regimens and improving adherence. Janssen aims to transform PAH into a manageable condition, helping patients lead fuller lives.
