In a Phase 3 clinical trial, Opsumit (macitentan) did not meet the study’s primary goal — improved exercise capacity — in patients with pulmonary arterial hypertension (PAH) due to Eisenmenger syndrome, Actelion, the drug’s manufacturer, announced.
Study results, however, will take time to interpret due to a “persistent placebo effect,” a trial researcher said in a press release.
Eisenmenger syndrome is the most advanced form of PAH with congenital heart disease (PAH-CHD). This condition is marked by blood pressure in the lungs that is so high the direction of blood flow is altered — instead of going from the heart to the lungs, it goes from the lungs to the heart. Between the hardening of lung arteries and the unusual blood flow, exercise capacity in these patients is quite limited.
The MAESTRO study (NCT01743001) enrolled 226 patients who either received once-daily treatment with Opsumit (10 mg) — an approved PAH therapy — or placebo. Results showed that, after 16 weeks of treatment, patients taking Opsumit recorded an increase of 18.3 meters in the 6-minute walk distance (6MWD, a measure of exercise capacity) compared to study’s start. But patients on the placebo had an increase of 19.7 meters in the same test.
But among the study’s per-protocol patient population — the 200 people who adhered to all parts of the study (as opposed to the larger intention-to-treat group) — the mean change in 6MWD after 16 weeks was an increase of 30.2 meters in Opsumit patients, and 18.9 meters among those who received placebo, Actelion reported.
“The results of the MAESTRO study are very difficult to interpret,” said Nazzareno Galiè, member of the trial’s Steering Committee, in a press release. “Although the results point towards a benefit of treatment with [Opsumit], we do not see a significant treatment effect on the primary endpoint of exercise capacity as measured in the 6-minute walk test.
“I believe this has been influenced by an unexpected improvement in the placebo arm of the study, which is unusual in a predominantly untreated PAH population. In fact, we have not seen such a persistent placebo effect in the multiple studies published so far in PAH,” he added. “We need to fully analyze the data to understand what could have caused this phenomenon.”
The study also showed that Opsumit induced a 20 percent reduction in the levels of the N-terminal pro b-type natriuretic peptide (a marker of heart activity). A 13 percent reduction in the pulmonary vascular resistance index (PVRi) at 16 weeks of treatment was seen in a hemodynamic sub-group of 39 patients (20 of whom received Opsumit). Compared to study’s start, the PVRi decreased 409.8 dyn.sec/cm5/m2 in the Opsumit group and increased 79.4 dyn.sec/cm5/m2 in the placebo group.
Importantly, Opsumit improved exercise capacity in treated patients in this sub-group, with an increase of 34.1 meters in the 6MWD from study’s start reported, compared to a 3.5-meter improvement in the 19 people on placebo.
“We have seen encouraging results on multiple measures, particularly in the hemodynamic sub-study,” said Guy Braunstein, head of Global Clinical Development at Actelion. Analysis of extended treatment given to all study participants also points to more promising results.
“Preliminary results from the open label extension of the study suggest that patients originally randomized to placebo and subsequently treated with [Opsumit] showed an improvement in exercise capacity after 24 weeks,” Braunstein said. “We must fully understand the results, in particular the reason for the large placebo effect, to know what might be changed so that we can deliver on our commitment to patients with Eisenmenger Syndrome.”
Opsumit was well-tolerated by patients in the MAESTRO trial, with a safety profile consistent with that seen in other studies. The most frequent side effects reported were headache (11.4 percent) and upper respiratory tract infection (9.6 percent). In the treatment group, only seven patients discontinued the treatment due to an adverse side effect, and one patient died due to respiratory failure.
Opsumit is an oral endothelin receptor antagonist for the treatment of PAH that is available in more than 35 countries, including the U.S.