MAA submitted to the European Medicines Agency for approval of single tablet combination therapy of macitentan and tadalafil for treatment of pulmonary arterial hypertension – Jansen Pharmaceuticals

The Janssen Pharmaceutical Companies of Johnson & Johnson announced the submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMA) seeking approval of a single tablet combination therapy of macitentan 10 mg and tadalafil 40 mg (M/T STCT) for the long-term treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) in adult patients of WHO functional class (FC) II-III.

The application is based on data from the Phase III A DUE study , which demonstrated that the M/T STCT significantly improved pulmonary haemodynamics (blood flow through pulmonary blood vessels) versus macitentan and tadalafil monotherapies in patients with PAH.

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

“The ESC/ERS guidelines recommend double and triple combination therapy which means that PAH patients may increasingly face more complex treatment regimens, with some taking many pills each day to manage their condition and any potential comorbidities,“ said Tamara Werner-Kiechle, M.D., EMEA Therapeutic Area Lead Neuroscience and Pulmonary Hypertension, Janssen-Cilag GmbH. “A single tablet combination could be an important new option for people living with PAH with the potential to enhance convenience and help improve adherence and outcomes. We look forward to working with the EMA to bring this combination therapy to those in need of new options, as soon as possible.”

The Phase III A DUE study (AC-077-A301) was designed to compare the efficacy and safety profile of M/T STCT versus macitentan and tadalafil monotherapies in patients with PAH. The data were presented as a Late-Breaking Clinical Trial presentation during the American College of Cardiology’s (ACC) 72nd Annual Scientific Session & Expo Together With World Heart Federation’s World Congress of Cardiology, in New Orleans on 6 March 2023. The study met its co-primary endpoint, demonstrating marked pulmonary haemodynamic improvement as shown by the highly statistically significant, consistent and robust pulmonary vascular resistance (PVR) reduction in participants treated with M/T STCT compared to both monotherapies at 16 weeks. PVR change with M/T STCT (n=70, -45 percent change from baseline) was significantly greater versus macitentan (n=35, -23 percent PVR change from baseline) at week 16 (treatment effect: 29 percent reduction; 95 percent confidence limit [CL]: -18 percent, -39 percent; p<0.0001). PVR change with M/T STCT (n=86, -44 percent change from baseline) was also significantly greater versus tadalafil (n=44, -22 percent change from baseline) at week 16 (treatment effect: 28 percent reduction; 95 percent CL: -20 percent, -36 percent; p<0.0001).

Although the A DUE study was not powered to demonstrate a benefit on exercise capacity, there was a positive trend for clinically relevant improvement in 6-minute walk distance (6MWD) in favour of M/T STCT versus both monotherapies as the key secondary endpoint.

The safety profile of M/T STCT was consistent with the known safety profiles of of the individual components, macitentan and tadalafil, and no new safety observations were made. The most common adverse events were headache, oedema, anaemia, haemoglobin decrease, and hypotension. The open label arm of the A DUE study is still ongoing.

The application to the EMA follows a New Drug Application submitted to the FDA in May 2023 seeking approval of single tablet combination therapy of macitentan and tadalafil for the treatment of patients with PAH.