Long-term use of Orenitram led to moderate but durable, and dose dependent, improvements in exercise capacity in pulmonary arterial hypertension (PAH) patients, results from an open-label extension trial show.
These findings were reported in the study “Long term study of oral treprostinil to treat pulmonary arterial hypertension: dosing, tolerability, and pharmacokinetics,” published in the journal Pulmonary Circulation.
However, subcutaneous (under the skin) and intravenous (directly to the blood stream) injections can cause serious side effects, including site pain, bloodstream infection, and thrombosis (blood vessel blockage).
More recently, scientists developed implantable pumps for these therapies to ease the side effects that could limit their use. But their administration can still be complex.
Researchers at United Therapeutics developed Orenitram, an orally available (sustained-release tablet) formulation of treprostinil. [Tyvaso, also marked by United Therapeutics, is an inhaled solution formulation.]
Orenitram is a prostacyclin class therapy that, as with similar agents, is designed to promote blood vessel dilation. First approved in the U.S. in 2002, this therapy has been shown to improve exercise capacity in people with idiopathic or heritable PAH (WHO Group 1), and PAH associated with connective tissue disease.
Potential benefits of Orenitram’s long-term use — at least one year; median of 2.1 years — on walking abilities were explored in the open label FREEDOM-EXT study (NCT01027949).
It enrolled 894 PAH patients (mean age, 48), who had previously participated in one of three Phase 2 (NCT01104870, NCT01477333, and NCT01588405), or three Phase 3 studies (NCT00325442, NCT00887978, and NCT00325403) into Orenitram.
Prior to these trials, 33% of participants had not been treated with any PAH therapy, 39% were on a single background PAH therapy, and 28% were using a combination of an endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 inhibitor (PDE-5i) — mostly, but not exclusively, Tracleer (bosentan) plus Revatio (sildenafil).
During this open-label extension, up to 70% continued treatment with Orenitram for at least 12 months and 367 (41%) started taking at least one other PAH therapy.
After a minimum one year of Orenitram treatment, an overall median improvement in the 6-minute walking distance (6MWD) — a measure of changes in exercise capacity — of 22 meters (about 72 feet) was seen in the 569 patients who completed this trial with baseline data for comparison (baseline here was defined as start of this therapy’s use).
Use of one or more other PAH therapies during the study did not change the patients’ physical capacity.
“This long, prospective data collection provides useful information about oral treprostinil as a treatment option,” the researchers wrote. “For those who remained on therapy with an observed walk, there appeared to be a small but sustained improvement in 6MWD … regardless of background PAH-specific therapy.”
A dose-dependent relationship was also found, with those at the highest dose (>8.5 mg daily) showing a median change of 31 meters in the 6MWD test, compared to 14 meters in the low-dose (≤ 5 mg daily) group.
Most participants, 99%, experienced treatment-related adverse events, as is expected for a prostacyclin class therapy. Those most frequently reported were headache (78%), diarrhea (66%), nausea (56%), flushing (46%), vomiting (38%), and jaw pain (35%).
Side effects led to stopping Orenitram use before the end of one year in 36% of patients; other causes for treatment discontinuation were death (21%) and PAH progression (22%).
Those in treatment groups in the earlier studies and using Orenitram for longer than one year had the opportunity to take the treatment three times a day rather than twice daily.
This regimen improved exposure to the therapy’s active compound, supporting the “hypothesis that improvements in exercise tolerance are dose dependent,” the researchers wrote.
Three times a day use did not result in reports of new or different side effects. Among patients who moved to this regimen, more than 80% reported that the most common side effects experienced (nausea, vomiting, diarrhea, and flushing) were better after the transition.
Overall, patient survival was 94%, 88%, and 82% for participants who remained in the study for 1, 2, and 3 years, respectively.
These results demonstrate that “oral treprostinil [Orenitram] is associated with modest but durable, dose-responsive effects on exercise tolerance for those who remained on therapy at one year in this prospective, uncontrolled study,” the researchers concluded.
Final results are awaited from a recently completed Phase 3 trial, called Freedom-EV, (NCT01560624) assessing Orenitram as an add-on PAH therapy in preventing disease worsening compared to placebo. Preliminary findings, released in August 2018, indicated the Orenitram plus a background therapy could delay time to a first clinical worsening event.