Last updated Nov. 14, 2022, by Teresa Carvalho, MS
Fact-checked by José Lopes, PhD
What is Opsumit for PH?
Opsumit (macitentan), is an oral once-daily therapy used to widen the blood vessels of people with pulmonary arterial hypertension (PAH), slowing disease progression and reducing patients’ risk of being hospitalized.
Opsumit is being investigated as a possible treatment for other types of pulmonary hypertension, including chronic thromboembolic pulmonary hypertension (CTEPH) and PH due to Eisenmenger syndrome — a heart defect that causes irregular blood flow from the heart to the lungs.
The therapy was developed jointly by Actelion Japan and Nippon Shinyaku. Actelion was later acquired by Janssen.
How does Opsumit work?
PAH is in Group I of the World Health Organization (WHO) classification of pulmonary hypertension. In PAH, blood vessels of the lungs (called pulmonary arteries) are narrowed, restricting blood flow through the lungs. This causes increased blood pressure and, among other symptoms, makes 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 endothelin receptors are activated by binding with the ligand endothelin-1, vasoconstriction is stimulated. PAH patients have high levels of endothelin-1.
Opsumit is an endothelin receptor antagonist (ERA). It binds to endothelin receptors, blocking downstream signals and allowing muscles of the arterial walls to relax. By widening the blood vessels — a process known as vasodilation — the therapy can reduce their resistance to blood flow and lower blood pressure in the lungs. Consequently, oxygen transport and exercise capacity improve, enhancing the ability to walk longer distances.
Who can take Opsumit?
The U.S. Food and Drug Administration (FDA) approved Opsumit in 2013, to reduce the risks of disease progression and hospitalization in people with PAH.
This approval was closely followed by marketing authorization in Canada, Europe, and Japan.
Who should not use Opsumit?
Opsumit should not be used in pregnant women as it may cause harm to a developing fetus. Patients who are pregnant or plan to become pregnant should inform their healthcare team. Women who are able to become pregnant should take pregnancy tests before start of treatment, monthly during treatment, and one month after stopping treatment. These women also are recommended to use effective and appropriate birth control methods to avoid pregnancy.
A restricted program called Opsumit Risk Evaluation and Mitigation Strategy (REMS) is available for all women treated with Opsumit.
The therapy also should not be used by people who have had allergic reactions to macitentan or any of the therapy’s components.
How is Opsumit administered?
The recommended dosage is 10 mg, given orally, once daily. Higher doses are not recommended as they have not been studied in PAH patients.
The treatment is available in bi-convex film-coated, round, white tablets of 10 mg, debossed with “10” on both sides. Tablets should not be split, crushed, or chewed. The therapy can be taken with or without food.
Opsumit in clinical trials for PAH
SERAPHIN and SERAPHIN OL trials
The Phase 3 SERAPHIN trial (NCT00660179) enrolled 742 PAH patients worldwide. Participants were randomly assigned to receive either a low (3 mg) or high dose (10 mg) of Opsumit or a placebo once daily. The trial’s primary goal was the time until a confirmed morbidity (including lung transplant and treament with prostanoids), death, or PAH progression.
Results showed Opsumit significantly reduced morbidity or mortality event. At a median treatment period of 115 weeks (about two years), 46.4% of patients receiving the placebo experienced such a primary event, compared to 38% and 31.4% of patients receiving low and high Opsumit doses, respectively.
Further results demonstrated Opsumit-treated PAH patients had significantly improved health-related quality of life.
Participants who completed this trial had the option to enroll in an open-label extension called SERAPHIN OL (NCT00667823). All patients were given Opsumit at the approved dosage of 10 mg/day. The study found survival rates, based on data from all patients receiving 10 mg/day Opsumit in the main parent SERAPHIN study, of 95% after one year of treatment, 84.0% at three years, 73.3% after five years, and 62.6% at seven years. After nine years, the estimated survival was 52.7%.
MERIT-1 and -2 trials
A Phase 2 trial called MERIT-1 (NCT02021292) assessed Opsumit in 80 patients with inoperable CTEPH at 36 sites in Europe, Asia, and Central America. Positive results at 16 weeks of treatment showed 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 group.
Opsumit use also significantly improved exercise capacity, measured by the distance walked in six minutes. On average, this distance improved by 35 meters after 16 weeks in treated patients, compared to a 1-meter improvement in those on placebo.
MERIT-1 was followed by the MERIT-2 study (NCT02060721), a Phase 2 trial that assessed the long-term effects of Opsumit, at 10 mg daily, in patients with inoperable CTEPH. MERIT-2 took place mostly in Europe and Asia, and was concluded in March 2022.
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, primarily aimed to assess Opsumit’s ability to improve exercise capacity after 16 weeks of treatment compared to a placebo.
However, it failed to meet its primary goal, that of a significant difference between the Opsumit and placebo groups in distance walked in six minutes, likely due to an unusually high mean improvement of 19.7 meters in the placebo group. Among Opsumit-treated patients, a mean increase of 18.3 meters in walking distance was recorded.
In a study called POTENT, researchers followed 50 adults with PAH in Saudi Arabia, mostly female, for one year after switching from Tracleer (bosentan) to Opsumit due to inadequate response. The study showed switching from Tracleer to Opsumit improved physical abilities and was generally safe.
A Phase 3 clinical trial called TOMORROW (NCT02932410) aims to assess the safety and efficacy of Opsumit in children with PAH. This worldwide trial is expected to include 300 patients and is planned to conclude in February 2024.
Common side effects of Opsumit
The most common side effects of Opsumit are:
- anemia (red blood deficiency, resulting in reduced oxygen supply to tissues)
- cold-like symptoms
- bronchitis, an inflammation of the lining of the bronchial tubes
- urinary tract infection
Opsumit may cause increased levels of liver enzymes called aminotransferases, a marker of liver toxicity and damage. Patients are recommended to monitor the levels of these enzymes before starting Opsumit and during treatment. Healthcare providers should be informed if any symptom occurs.
Fluid retention may occur not only as an ERA-related side effect but also as a PAH symptom. This issue should be monitored after treatment start. If this symptom gets worse, patients should be assessed to determine if worsening is caused by the treatment or due to an underlying heart failure.
Decreased red blood cell count
Treatment with Opsumit may cause reduced levels of red blood cells and hemoglobin, a protein that carries oxygen in red blood cells. Patients with severe anemia are not recommended to take Opsumit. Hemoglobin levels should be assessed before starting Opsumit and during the treatment.
Liquid accumulation in the lungs
Patients with pulmonary veno-occlusive disease, a rare form of pulmonary hypertension, are at high risk of accumulating fluids in the lungs. If symptoms occur, the treatment should be discontinued.
Reduced sperm count
Decreased sperm count may occur in patients taking Opsumit. It is not known whether this effect is definitive. Male patients should be given advice about potential effects of Opsumit on fertility.
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