Orenitram (treprostinil tablets) reduced clinical worsening and slowed disease progression in people with pulmonary arterial hypertension (PAH) who had recently begun treatment with an alternative approved therapy, a Phase 3 clinical trial has found.
Trial findings were reported in the study, “Combination Therapy with Oral Treprostinil for Pulmonary Arterial Hypertension: A Double-Blind, Placebo-Controlled Study,” published in the American Journal of Respiratory and Critical Care Medicine.
Orenitram, marketed by United Therapeutics, is an approved, extended-release oral formulation of Remodulin (treprostinil injection), which has been shown to improve exercise ability in PAH patients. It works by binding to prostacyclin receptors present on endothelial cells (which line the inner surface of blood vessels), causing them to widen or dilate.
Uptravi (selexipag, marketed by Actelion) is an alternative treatment that also binds to prostacyclin receptors. When Uptravi is used in combination with therapies such as Opsumit (macitentan, also marketed by Actelion) that block the activity of the endothelin receptor and result in blood vessel dilation, it can benefit PAH patients.
While oral Orenitram has been shown to improve patients’ exercise capacity, its effect on other clinical outcomes in combination with other PAH therapies has not been properly assessed.
A team of researchers at 152 centers across 23 countries carried out a Phase 3 trial (NCT01560624), called FREEDOM EV, to test the effects of oral Orenitram compared with placebo in PAH patients who had recently began treatment with a different approved oral therapy.
The team recruited 690 PAH patients between the ages of 18 and 75 who were able to walk at least 150 meters (about 500 feet) in six minutes, determined using the six-minute walk distance (6MWD) test, at the initial screening visit. All participants were using an approved oral monotherapy between 30 and 90 days before the start of the trial.
Oral monotherapy treatments included: endothelin receptor inhibitors, such as Opsumit, Letairis (ambrisentan, marketed by Gilead in the U.S.), and Tracleer (bosentan, marketed by Actelion); therapies that stimulate soluble guanosine cyclase causing blood vessel dilation, such as Adempas (riociguat, marketed by Bayer); and phosphodiesterase type 5 (PDE5) inhibitors, such as Revatio (sildenafil, marketed by Pfizer) and Adcirca (tadalafil; marketed by United Therapeutics in the U.S.).
Of the patients selected, 346 were given Orenitram, and 344 a placebo. Patients in the treatment group initially took 0.125 mg of Orenitram three times a day (spaced carefully every six to eight hours with food), then increasing doses in 0.125 mg increments for the first four weeks, followed by 0.25 mg increments up to a maximum dose of 12 mg three times a day.
Researchers met with participants in the fourth, eighth, and 12th weeks, and then at 12-week intervals throughout the study for clinical assessments, including the 6MWD, the Borg dyspnea score (a measure of breathing ability), plasma N-terminal pro-brain natriuretic peptide levels, or NT-proBNP (a marker of heart damage), and WHO functional class.
The main goal of the study was to assess clinical worsening, which was defined as death from any cause, hospitalization due to PAH, disease progression, starting inhaled or infused therapies, or a general unsatisfactory long-term clinical response.
Results showed that 90 (26%) participants in the Orenitram group experienced a clinical worsening event, compared with 124 (36%) of those treated with a placebo.
Orenitram was also found to delay clinical worsening events by a median of nine weeks, compared with placebo. A significant change in clinical worsening events between the two groups occurred during the 24th week, mainly due to a reduction in disease progression in the Orenitram group.
The Orenitram group had a higher mortality risk at the beginning of the study, but the risk decreased between weeks 12 and 60.
The plasma NT-proBNP levels in those taking Orenitram decreased significantly, and there was a significant improvement in WHO functional class from assessments done during week 12 to week 48, compared with those in the placebo group.
In the 24th week, those taking Orenitram increased their 6MWD by 16 meters (about 52 feet), while those treated with a placebo only increased theirs by 8 meters (26 feet). Patient-reported Borg dyspnea scores assessed at the end of each walk test also improved in patients taking Orenitram from week 12 to week 48.
“Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal-pro-brain natriuretic peptide, all favored oral treprostinil treatment at week 24 and beyond,” the researchers wrote.
The most common side effects of treatment included headache, diarrhea, flushing, nausea, and vomiting. More participants in the Orenitram group (18.8%) discontinued treatment due to adverse events, compared with the placebo group (4.1%). Treatment discontinuation was more common before the 24th week among those receiving Orenitram at a median dose of 1.4 mg, three times a day.
The study showed “oral treprostinil [Orenitram] administered three times daily to a relatively homogenous [similar] group of participants with PAH who were taking oral monotherapy reduced the likelihood of clinical worsening due to disease progression,” the researchers said.