Once-Daily, Single-Tablet Combination Therapy of Macitentan, Tadalafil in the Management of Patients With PAH

There is currently no cure for patients with pulmonary arterial hypertension (PAH). Medications and procedures can help slow the progression of the disease, and treatment options vary from patient to patient.

Based on findings from the Phase 3 A DUE study,¹ Janssen Research & Development, LLC, recently submitted a New Drug Application (NDA) to the FDA seeking approval of an investigational once-daily, single-tablet combination therapy of macitentan and tadalafil (M/T STCT) for the long-term treatment of adults with WHO functional class (FC) II or III PAH. Filing preparations in Europe and other countries are underway.

Consulant360 reached out to James F. List, MD, PhD, Global Therapeutic Area Head, whose team oversees a portfolio of programs including Pulmonary Hypertension at Janssen Research & Development, LLC, to explain the A DUE study.

Consultant360: Please provide an overview of the A DUE study.

James F. List, MD, PhD: The Phase 3 A DUE study was a double-blind, randomized, active-controlled, multi-center, adaptive parallel-group study designed to compare the efficacy and safety of a single-tablet combination therapy of M/T STCT vs macitentan and tadalafil monotherapies in patients with PAH.

A total of 187 adult PAH patients 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 3 months, were enrolled in the study.

The primary endpoint in A DUE was pulmonary vascular resistance (PVR), measured 16 weeks following initiation of treatment, expressed as the ratio of geometric means to baseline compared with each monotherapy.

The data were presented during a late-breaking clinical trial presentation at the American College of Cardiology’s 72nd Annual Scientific Session & Expo Together with World Heart Federation’s World Congress of Cardiology.

C360: What were the findings from the study?

Dr List: A DUE met the primary endpoint and demonstrated that the M/T STCT significantly and markedly improved blood flow through pulmonary blood vessels, also known as pulmonary hemodynamics, vs macitentan and tadalafil monotherapies.

Additionally, although the A DUE study was not powered to demonstrate a benefit on exercise capacity, a trend for clinically relevant improvement in 6-minute walk distance (6MWD) was observed (did not reach statistical significance).

The safety profile of M/T STCT was consistent with the safety profiles of the individual components, macitentan and tadalafil, and no new safety observations were made during the study period.

C360: How might these findings impact clinical practice and what is the importance of the recent NDA to the FDA for the approval of single-tablet combination therapy of M/T STCT for the long-term treatment of adult patients with PAH?

Dr List: PAH is a rare, progressive, and life-threatening blood vessel disorder characterized by the constriction of small pulmonary arteries and elevated blood pressure in the pulmonary circulation that eventually leads to right heart failure.

Clinical evidence has shown that initial combination therapy targeting multiple PAH-specific pathways improves functional and long‑term outcomes compared with monotherapy. However, registry and real-world data suggest that many patients are not initiated to or not escalated to combination therapy in a timely manner. Moreover, patients with PAH generally must take multiple pills as part of their daily regimen and no single-tablet combination is currently available.

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

A single-tablet combination has the potential to be an important new option for helping physicians optimize disease management with the potential to enhance convenience and help improve adherence to therapy and outcomes.

C360: What is the mechanism of action in M/T STCT?

Dr List: M/T STCT is an investigational single-tablet combination therapy that combines the ERA, macitentan, and the PDE5i, tadalafil, for improvement in pulmonary hemodynamics.

C360: What is the benefit of multiple treatment options for patients with pulmonary arterial hypertension?

Dr List: While there is no cure for PAH, treatment can help improve symptoms and slow disease progression. Treatment options for patients with PAH often include foundational medicines and add-on therapies that are individualized based on disease severity and any underlying conditions.

Since people with PAH are often prescribed numerous medicines to manage their condition, the potential to offer a single-tablet combination of two guideline-recommended therapies could not only decrease pill burden but may also help improve the patient treatment experience and clinical outcomes. If approved, Janssen’s comprehensive PAH portfolio has the potential to cover all guidelines-recommended treatment pathways.

C360: What would you say is next for research on the treatment of patients with PAH?

Dr List: Our goal is to transform PAH into a manageable condition so patients can lead a full life. We are working on accelerating diagnosis and to elevate the standards of care along the treatment journey. In addition, our discovery efforts are focusing on addressing the underlying disease to further optimize treatment and one day, potentially, provide a cure.

Reference:

1. Late-breaking phase 3 A DUE data show investigational single tablet combination therapy of macitentan and tadalafil significantly improves pulmonary hemodynamics versus monotherapy in patients with pulmonary arterial hypertension (PAH). News Release. Janssen Research & Development, LLC. March 6, 2023. Accessed June 30, 2023. https://www.janssen.com/late-breaking-phase-3-due-data-show-investigational-single-tablet-combination-therapy-macitentan-and 

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