The promise of a macitentan-tadalafil polypill
Highlighted in The Journal of the American College of Cardiology, the DUE study focused on a once-daily, single-tablet combination of macitentan (10 mg) and tadalafil (40 mg) for treating PAH. Involving 187 patients with WHO functional class II-III PAH, the study divided them into three groups: 108 received the combination therapy, while 35 and 44 participants were given macitentan and tadalafil monotherapies, respectively.
“A typical patient with pulmonary hypertension may take as many as five to eight pills, sometimes more than once a day,” said Dr. Sean Studer, vice president of medical affairs, at Johnson & Johnson. “Patients with other health conditions may even take more, so it can be a challenge.” Given that reality, “anything that could potentially reduce the pill burden” would be “a welcome addition to the space,” Studer noted.
Canada and Argentina have endorsed macitentan-tadalafil combination in PAH
Already, Canada and Argentina have approved the use of a fixed-dose single-tablet combination of macitentan (10 mg) and tadalafil (40 mg) for patients who had been receiving this combination therapy as separate tablets. In May 2023, J&J filed a New Drug Applications for the macitentan-tadalafil combination therapy for the long-term treatment of pulmonary arterial hypertension (PAH, World Health Organization [WHO] Group 1) in adult patients with WHO functional class (FC) II-III.
The approval targets PAH as defined by WHO Group 1, which specifically involves the arteries in the lungs and heart, and focuses on patients within WHO functional classes II and III. For context, WHO functional class II refers to patients with slight limitations of physical activity, while class III indicates marked limitations as a result of their condition. Functional class I involves minimal or no limitations in physical activity, showing no undue breathlessness or fatigue. Conversely, class IV indicates a severe limitation, with symptoms present even at rest and discomfort increased with any physical activity.
The Phase 3 DUE study observed that certain adverse events (AEs) were more frequent with the M/T FDC. These included events leading to discontinuation, serious AEs, and those of special interest, specifically anemia, hypotension, and edema. “The safety findings were consistent with the two independent components, macitentan and tadalafil,” Studer stated, emphasizing that the adverse events observed were consistent with the use in clinical practice and “what’s been observed with each component over time.”
Evaluating the dual therapy in PAH
The DUE study, recently highlighted in The Journal of the American College of Cardiology, explored the use of once-daily, single-tablet combination therapy of macitentan (10 mg) and tadalafil (40 mg) for PAH. In the study, 187 patients with WHO functional class II-III PAH were randomized into three groups: one receiving the single-tablet combination therapy (108 participants). The two control groups received either macitentan (35 participants) or tadalafil (44 participants) as monotherapies.
Specifically, the study focused on pulmonary vascular resistance (PVR) as the primary outcome, with findings indicating a notable reduction in PVR among patients receiving the combination therapy compared to those on monotherapies. “PVR is an objective and clearly measurable endpoint that you can look at after a fixed period of time,” Studer said. In essence, PVR is a “pragmatic endpoint” that here helped demonstrate the potential benefit of a fixed dose of macitentan and tadalafil. In addition, the use of PVR as an endpoint enabled comparisons with previous trials, allowing for “assessment of the efficacy of a medication or a fixed dose in this case, in a relatively small sample size, with a relatively short observation period.”
The bar chart below illustrates the percentage reduction in Pulmonary Vascular Resistance (PVR) across various treatment groups in the DUE study, as featured in JACC. This data compares the efficacy of two distinct regimens of a single-tablet combination therapy: one being macitentan (10 mg)/tadalafil (40 mg) fixed-dose combination_M (M/T FDC_M), and the other being macitentan (10 mg)/tadalafil (40 mg) fixed-dose combination_T (M/T FDC_T). Also shown are monotherapies of each individual drug – macitentan 10 mg and tadalafil 40 mg.
DUE study highlights enhanced efficacy of macitentan-tadalafil combination
PVR is “a calculated measurement,” Studer noted, requiring a right heart catheterization where clinicians thread sensors, often from the neck or the arm, into the heart to take measurements. These measurements are then used to calculate PVR, which essentially is a measure of how well blood can flow through the pulmonary circulation. Studer noted that PVR has been established not only for diagnostic criteria, but also as a “measure of follow-up points after they’re diagnosed to determine their response to therapy or potential need for additional therapies.”
The DUE study demonstrated that patients with PAH experienced approximately double the reduction in Pulmonary Vascular Resistance (PVR) when treated with a single fixed-dose combination (FDC) tablet of macitentan and tadalafil compared to either drug used as monotherapy. Specifically, the primary endpoint of change in PVR at week 16 as a ratio of baseline indicated a 29% greater reduction for the FDC compared to macitentan alone (–45% vs. –23%; p<0.0001) and a 22% greater reduction compared to tadalafil alone (–44% vs. –22%; p<0.0001).
Macitentan, marketed as Opsumit, has been a strong seller for J&J, driving sales of roughly $1.8 billion in 2021 and 2022.
Emphasizing the significance of the macitentan-tadalafil polypill
In publishing the study, JACC also included an accompanying editorial and a podcast from the journal’s editor-in-chief Dr. Valentin Fuster, editor of The Journal of the American College of Cardiology who supported the clinical relevance of the research in PH/PAH space. “In our view, having a journal with the stature of JACC consider this study and this manuscript worthy of publication was gratifying,” Studer said. This endorsement from JACC, particularly through the accompanying editorial and Fuster’s podcast, not only highlights the study’s significance but also amplifies the broader conversation on advancing treatments in pulmonary hypertension.
In his podcast, Fuster described the medication adherence challenges that PAH poses, which can be especially evident in older patients with multiple cardiopulmonary comorbidities. “I have been working for years on the issue of adherence, and we developed the polypill post-myocardial infarction,” Fuster said in the podcast. “This is to say that in a number of cardiovascular entities, we are going to be using a polypill more and more, and today is an example of what is evolving in patients with pulmonary arterial hypertension.”
Filed Under: Cardiovascular, clinical trials, Drug Discovery, Pulmonology