The findings were published in the European Respiratory Journal, in the study, “Initial combination therapy of macitentan and tadalafil in pulmonary arterial hypertension.” The study was funded by Actelion Pharmaceuticals, which markets Opsumit.
Current guidelines indicate that people with comparatively low-risk PAH should be treated first with the combination of an endothelin receptor antagonist (ERA) and a phosphodiesterase type-5 inhibitor (PDE5i). Both are classes of medications that function by prompting blood vessels to relax and widen, thereby lowering blood pressure within the vessels.
Opsumit is an ERA, while Adcirca (marketed by Eli Lilly in Europe and by United Therapeutics in the U.S.) is a PDE5i. Both therapies are approved for the management of PAH; however, the combination had not been studied previously in clinical trials.
OPTIMA (NCT02968901) was a Actelion-sponsored Phase 4 clinical trial that evaluated this treatment combination in people with newly-diagnosed PAH WHO functional class II or III who had not been treated previously.
Participants in the trial were given 10 mg daily Opsumit. Adcirca was given daily starting at a dose of 20 mg, then increasing to 40 mg/day after about one week, with further dose adjustments allowed for tolerability. Participants were treated for 16 weeks, with the option to continue in an extension period.
The study enrolled 46 participants, 44 of whom completed the 16-week study and continued into the extension period. Participants were predominantly female (65.2%) and had class III PAH (78.3%); the mean participants’ age was 57.4 years.
The study’s primary measurement of effectiveness was the change in pulmonary vascular resistance (PVR) after 16 weeks of treatment. PVR is a measurement of how difficult it is for the heart to pump blood to the lungs; it is a common clinical metric to assess PAH. Lower PVR values indicate less difficulty pumping blood (and subsequently less-severe PAH).
Results showed that after 16 weeks of combination treatment, the mean PVR decrease was 47% among participants in OPTIMA, which is a statistically significant change. The majority (87%) experienced a PVR decrease of 30% or greater.
The combination treatment also led to significant improvements in a variety of secondary endpoints (goals). For instance, the average distance participants could walk in six minutes — a common measurement of physical function in ambulatory people — increased by 35.8 meters (about 118 feet).
Mean pulmonary arterial pressure decreased by 7.83 mmHg, and cardiac index (a measure of how much blood the heart can pump) increased by 0.91 L/min/m2 (liters per minute per square meter).
Levels of NT-proBNP, a marker of heart damage, were decreased significantly — by 68%, on average — after 16 weeks of the combination therapy.
Collectively, 29 (63%) participants were deemed to have experienced an improvement in their functional class. The remaining participants had stable disease, and no participant experienced disease worsening over the course of the trial.
The safety profile of Opsumit plus Adcirca was generally consistent with the profiles already known for these medications individually. Almost all (93.5%) participants reported at least one adverse event (side effect), and 13 (28.3%) experienced a serious adverse event.
Adverse events led to treatment discontinuation in three participants, and three participants died during the study for reasons deemed unrelated to the treatment.
“Overall, in the prospective OPTIMA study, initial double combination therapy with macitentan and tadalafil led to a significant improvement, from baseline to week 16, in cardiopulmonary haemodynamics, functional parameters, NT-proBNP and risk profile in newly diagnosed, treatment-naïve patients with PAH,” the researchers concluded.
According to the team, the data “support early use of double oral combination therapy with an ERA and PDE5i to optimally manage PAH.”
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