Opsumit (macitentan), an oral once-daily therapy developed and marketed by Actelion Pharmaceuticals, is approved to treat the symptoms and help slow the progression of pulmonary arterial hypertension (PAH).
Opsumit is being investigated as a possible treatment for other types of pulmonary hypertension, including chronic thromboembolic pulmonary hypertension (CTEPH) and Eisenmenger syndrome (also known as PAH with congenital heart disease).
How Opsumit works
In PAH, the blood vessels of the lungs (the pulmonary arteries) are severely narrowed, which restricts blood flow through the lungs. This causes increased blood pressure and poorer oxygen transport, among other symptoms, making exercise more difficult.
The arteries narrow due to the contraction of the smooth muscle of the arterial wall, a process called vasoconstriction that is based on signals from proteins called endothelin receptors. When the endothelin type A receptors are activated by binding with the ligand endothelin-1, vasoconstriction is stimulated. In PAH patients, unusually high levels of endothelin-1 and its receptors can lead to an over-activation of the signaling pathway for vasoconstriction.
Opsumit is an endothelin receptor antagonist. It competes with endothelin to bind to the endothelin receptors, so as to prevent, or block, the receptors from activating. As such, it is designed to lessen signaling for vasoconstriction, allowing muscles of the arterials walls to relax. The widening of the blood vessels — known as vasodilatation — can reduce their resistance to blood flow and lower blood pressure in the lungs. Consequently, oxygen transport is better systemwide and patients have greater exercise capacity, including the ability to walk longer distances.
Opsumit in clinical trials
The key clinical trial that demonstrated Opsumit’s efficacy and safety as a potential PAH therapy was the Phase 3 SERAPHIN trial (NCT00660179). Worldwide, it enrolled 752 PAH patients, randomized to receive either a low (3 mg) or high dose (10 mg) of Opsumit or a placebo once daily. Time until a confirmed morbidity (related illness or complication) or mortality event, to surgery, or a to significant worsening of symptoms was the trial primary measure.
Results were initially published in The New England Journal of Medicine and showed that Opsumit significantly improved the time until an morbidity or mortality event. At a median treatment period of 115 weeks, 46.4 percent of patients receiving the placebo experienced such a primary event, compared to 38 percent and 31.4 percent of patients receiving low and high Opsumit doses, respectively.
Further results, published in the scientific journal Chest, demonstrated that Opsumit-treated PAH patients had a significantly improved health-related quality of life and slower rate of disease progression compared to those given placebo. This was measured using the SF-36 physical component summary and mental component summary, a 36-item questionnaire to determine the patient’s physical and emotional quality of life.
A Phase 2 randomized and double-blind clinical trial (NCT02021292), called MERIT-1, assessed Opsumit in 80 patients with inoperable CTEPH at 36 sites in Europe, Asia, and South America. Actelion announced positive results after 16 weeks of treatment, showing that patients receiving Opsumit had significantly reduced mean pulmonary vascular resistance (a measure of the effort required for blood to flow through the lungs) compared to the placebo-treated group.
Opsumit use also significantly improved exercise capacity, measured by the maximum distance walked in six minutes. On average, this distance walked improved by 35 meters after 16 weeks in treated patients, compared to a one-meter improvement in those on placebo. Results of the trial, which concluded in 2016, were published in the journal Lancet Respiratory Medicine.
MERIT-1 was followed by the MERIT-2 study (NCT02060721), a Phase 2 trial assessing the long-term effects of Opsumit, at 10 mg daily, in patients with inoperable CTEPH. MERIT-2 is taking place mostly in Europe and Asia, and is expected to conclude in 2020.
Opsumit was also investigated in a Phase 3 clinical trial (NCT01743001) called MAESTRO as a therapy for Eisenmenger syndrome. This trial, which enrolled 226 patients at 55 locations worldwide, aimed to assess Opsumit’s ability to improve patients exercise capacity after 16 weeks of treatment compared to a placebo. However, it failed to meet its primary endpoint, that of a significant difference between the Opsumit- and placebo-treated groups in the change in distance walked in six minutes, likely due to an unusually high mean improvement of 19.7 meters in the placebo group. Such a placebo-group change is not normally seen in PAH clinical trials. Among Opsumit-treated patients, a mean increase of 18.3 meters in walking distance was recorded.
Other clinical trials have either been completed or are ongoing. One, a Phase 3 clinical trial (NCT02932410), called TOMORROW, aims to assess the safety and efficacy of Opsumit in children with PAH. This trial is currently recruiting up to 300 patients, ages 2 to 17, at 86 locations worldwide — including the U.S., Canada, and much of Europe; information is available by clicking on its identification number.
The most common side effects of Opsumit are anemia, cold-like symptoms, bronchitis, headache, flu, and urinary tract infections.
The U.S. Food and Drug Administration (FDA) approved Opsumit as a PAH therapy in October 2013. This was closely followed by marketing authorization by the European Commission in December 2013.
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