Opsumit Shows Promise for Portopulmonary Hypertension in Phase 4 Trial
Treatment for 12 weeks with Actelion Pharmaceuticals’ Opsumit (macitentan) significantly improved blood vessels’ resistance in patients with portopulmonary hypertension without causing further damage to the liver, data from the PORTICO Phase 4 trial show.
The study, “Macitentan for the treatment of portopulmonary hypertension (PORTICO): a multicentre, randomised, double-blind, placebo-controlled, phase 4 trial” was published in the journal Lancet Respiratory Medicine.
Portopulmonary hypertension (POPH) is a condition characterized by pulmonary arterial hypertension (PAH) together with elevated pressure in the portal vein — the vein responsible for directing blood from parts of the gastrointestinal tract to the liver.
POPH is a common complication of advanced liver disease; while liver transplant is the most effective treatment strategy, severe PAH is a contraindication for this procedure as it reduces its chances of success and worsens the overall prognosis.
This means that it is necessary to first treat PAH in these patients so that they can undergo a liver transplant. However, few studies have explored the efficacy of anti-PAH therapies in POPH.
In the Phase 4 PORTICO (NCT02382016) study, researchers evaluated the safety and efficacy of Opsumit in POPH patients.
Opsumit is an oral therapy approved in the U.S. and Europe for treatment of PAH symptoms and to slow the progression of disease. It works by reducing the contraction and narrowing of blood vessels, which can help reduce their resistance to blood flow, and lower blood pressure in the lungs.
The PORTICO trial randomized 85 patients (older than 18) with symptomatic POPH to receive either 10 mg of Opsumit (43 patients) daily, or a placebo (42 patients) for 12 weeks. This was followed by a 12-week open-label period where all eligible patients — 91% and 98% in the Opsumit and placebo groups, respectively — were given Opsumit.
Results showed that after 12 weeks of Opsumit treatment, POPH patients had a significant reduction in pulmonary vascular resistance (by 35%), and in mean pulmonary arterial pressure (mPAP).
The treatment also increased the patients’ cardiac index, compared to those treated with a placebo. The cardiac index measures the amount of blood ejected by the heart in a unit of time divided by the body surface area.
There were no changes in blood pressure of the right atrium of the heart, nor in the levels of NT-proBNP (a marker of right heart dysfunction) between the two groups. Also, no significant differences in disease severity or in the six-minute walk distance test (which assesses exercise capacity and endurance) were found between the two groups.
Of note, liver function and the pressure in the liver’s main blood vessel did not worsen with Opsumit treatment.
However, the team observed some secondary effects associated with Opsumit. The most frequent adverse effect was peripheral edema (swelling in the hands and lower legs), seen in 26% of Opsumit-treated patients, compared to 12% in the placebo group. Additional side effects included headache and bronchitis.
In total, 21% of Opsumit-treated patients reported at least one serious adverse effect, compared to 14% in the placebo group. Among Opsumit-treated patients, four stopped treatment because of adverse events, namely hypersensitivity, inflammation in the lungs’ tiny air sacs (alveoli), worsening of PAH, or anemia.
In the open-label phase, 30% of patients receiving Opsumit had at least one serious adverse effect, and 12% discontinued the treatment because of side effects.
Overall, the results show that “treatment with [Opsumit] in patients with portopulmonary hypertension resulted in improvement in pulmonary vascular resistance, without leading to further adverse liver conditions in patients with mildly or moderately impaired liver function,” researchers stated.
“Although no functional improvements were seen over this timescale, the findings from this study indicate that macitentan might be a therapeutic option in patients with portopulmonary hypertension,” the team concluded.