Benefits of Orenitram for PAH Patients Detailed in New Data

United Therapeutics’ Orenitram (treprostinil) improves heart function and lowers risk status in people with pulmonary arterial hypertension (PAH) who had begun treatment with another approved therapy, new data from a Phase 3 clinical trial show.

Moreover, compared with Actelion’s Uptravi (selexipag), treatment with Orenitram was linked to significantly lower healthcare costs, by a mean of $75,183, according to a retrospective analysis of U.S. health insurance claims from 256 PAH patients.

“We are pleased to share these additional data, which we believe distinguishes Orenitram in the oral prostacyclin drug class, and strengthens its value proposition to physicians, payers and patients,” Michael Benkowitz, president and chief operating officer of United Therapeutics, said in a press release.

Orenitram is an approved, extended-release oral formulation of treprostinil injection (sold as Remodulin, also by United Therapeutics). Orenitram was shown to improve exercise capacity in PAH patients when given alone (as a monotherapy). 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, thus lowering blood pressure.

Whether Orenitram offers additional clinical benefits besides improving patients’ exercise capacity in combination with other PAH therapies is unknown.

The randomized, placebo-controlled, multicenter Phase 3b FREEDOM EV trial (NCT01560624) was designed to test the effects of oral Orenitram compared with a placebo in PAH patients who were already receiving an approved oral monotherapy 30 to 90 days before the start of the trial.

It recruited a total of 690 PAH patients (from 18 to 75 years old) who were able to walk at least 150 meters (about 500 feet) in six minutes, determined using the six-minute walk test (6MWT), at the initial screening visit.

Of the 690 patients, 346 were given increasing doses of Orenitram — from 0.125 mg three times a day up to a maximum dose of 12 mg three times a day. The other 344 patients received a placebo treatment (control group).

Results after 24 weeks showed that 26% of patients (90 patients) given Orenitram experienced a clinical worsening event, compared with 36% (124 patients) in the placebo group. Moreover, Orenitram delayed clinical worsening events by a median of nine weeks, compared with placebo.

Clinical worsening 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. In this case, a reduction in clinical worsening risk with Orenitram treatment was largely driven by a roughly 61% decrease in the risk of disease progression compared with placebo.

A group of 61 patients (75% women) participated in a sub-study to evaluate their heart function — using right heart catheterization — at the start of the trial and at 24 weeks. Right heart catheterization, a standard diagnostic test in PAH, uses a catheter passed into a vein in the neck or groin to measure the pressure in the heart and lungs.

By the end of the study, patients were receiving Orenitram at a median dose of 5.5 mg three times a day.

Most of the participants (85%) had been treated with phosphodiesterase type 5 (PDE5) inhibitors (such as Revatio by Pfizer and Adcirca marketed by United Therapeutics in the U.S.) or soluble guanylate cyclase stimulators (like Bayer’s Adempas); and the other 15% with endothelin receptor inhibitors (such as Opsumit and Tracleer, both marketed by Actelion, and Letairis marketed by Gilead in the U.S.).

Results showed that treatment with Orenitram led to a 20% decrease in the resistance to blood flow in arteries that supply blood to the lungs — a parameter called pulmonary vascular resistance — compared with a 1% drop in the placebo group, a statistically significant difference. This resulted in a 21% reduction in the pulmonary vascular resistance index, which measures blood flow in relation to a person’s body size.

These changes were accompanied by a significant increase (19%) in blood pumped by the heart (a parameter called cardiac output), and an overall increase of 17% in the cardiac index (a measure of heart performance relative to the size of the body).

No differences were seen between Orenitram and placebo groups in other heart-related parameters, including mean right atrial pressure, pulmonary artery wedge pressure, pulmonary artery pressure, or heart rate.

Part of these findings were previously presented in a talk, titled “Treatment with oral treprostinil improves hemodynamics in participants with PAH,” at the Pulmonary Vascular Research Institute 14th Annual World Congress on Peripheral Vascular Disease, held earlier this year in Lima, Peru.

Additional clinical parameters evaluated in the FREEDOM EV trial included plasma N-terminal pro-brain natriuretic peptide levels, or NT-proBNP (a marker of heart damage), WHO functional class, and the noninvasive French risk assessment, which identifies patients maintaining or achieving a very low risk status. Orenitram-treated patients had a statistically significant lower risk by 60 weeks than those on placebo, a group with an already low risk at the start of the trial.

A new post-hoc analysis of FREEDOM-EV looked at the impact of Orenitram on another risk score, the REVEAL 2.0 risk score (RRS), which ranges from one (lowest risk) to 20 (highest risk).

At the start of the trial, patients were classified as low risk (score of zero to six) — 53% in the Orenitram group and 61% in the placebo — at intermediate risk (score of seven or eight) – 26% on Orenitram vs. 21% on placebo — and at high risk (score of nine or higher), 21% of the Orenitram group vs. 18% of those on placebo.

The mean RRS scores at the start of the trial showed a difference, with the Orenitram group scoring 6.3 and the placebo group 5.83. The distribution of RRS, however, showed no statistically significant difference between groups.

The analysis showed that by 36 weeks, the mean score of those given Orenitram decreased by 0.61, while in the placebo group, it decreased by 0.01, which was a statistically significant difference.

Further analysis evaluated the results of the FREEDOM-EV trial after being adjusted according to the patient’s risk at the start of the trial. The new analysis revealed that after adjusting by the French noninvasive risk score, Orenitram decreased the risk of clinical worsening by 39% compared with placebo, and by 33% when adjusted to the RRS.

Overall, the risk scores obtained “indicate that risk status was improved in [Orenitram-treated] participants compared to placebo by two different risk score methodologies,” the researchers wrote in an abstract titled “An analysis of FREEDOM-EV using the French noninvasive and REVEAL 2.0 risk stratification criteria.”

Furthermore, “risk scores appear to be a convenient and robust stratification tool,” they wrote in another abstract titled “The impact of stratification by baseline pulmonary arterial hypertension risk score – analysis from the FREEDOM-EV study.”

Researchers had planned to present the results summarized in the two abstracts at the American Thoracic Society 2020 International Conference in May, but the meeting has been canceled due to the COVID-19 pandemic.

“FREEDOM-EV demonstrated that Orenitram treatment not only delays disease progression, but also leads to durable improvement in clinically relevant components of risk, including six-minute walk distance, NT-proBNP, and functional class,” said Andrew Nelsen, head of global medical affairs at United Therapeutics. “These additional analyses, coupled with the hemodynamic improvements, should bolster PAH physician confidence in treatment.”

Finally, United Therapeutics also reported on results from a study, published in the journal Drugs – Real World Outcomes, based on a retrospective analysis of data from U.S. health insurance claims for 256 patients with PAH treated with either Orenitram (130 patients) or Uptravi (selexipag, marketed by Actelion; 126 patients). Uptravi is an alternative treatment that also acts on prostacyclin receptors.

The study is titled, “Medication Adherence and Healthcare Costs Among Patients with Pulmonary Arterial Hypertension Treated with Oral Prostacyclins: A Retrospective Cohort Study.”

The analysis looked at patient adherence and persistence to treatment and rates of hospitalizations as well as healthcare costs over six months. Treatment discontinuation was defined by a gap of either 30 or more days, or 60 or more days, and was measured using the medication possession ratio (MPR; the percentage of time a patient has access to medication) and the proportion of days covered (PDC; the proportion of days covered by prescription claims for the medication).

Results revealed that the mean MPR was significantly higher for patients given Orenitram. However, additional parameters, including the proportion of patients with an 80% or higher mean MPR or mean PDC between groups showed no significant differences, suggesting a similar treatment adherence and persistence.

In addition, no differences were seen for hospitalizations (for both all-cause and due to PAH), length of hospital stay, or visits to the emergency room.

Treatment with Uptravi was, however, more costly — by a mean of $73,680 — than Orenitram, representing a 51.4% increase in costs. Orenitram primarily was linked to lower pharmacy costs.

Uptravi was linked to 66.9% higher PAH-related mean total healthcare costs — a mean difference of $75,183 — over Orenitram.