- Orenitram demonstrated improvement in hemodynamic parameters and risk status, important indicators of long-term outcomes in PAH patients, in presentations at recent scientific conferences

- Separately, total PAH-related patient healthcare costs are 67% higher for selexipag in article published in Drugs - Real World Outcomes

SILVER SPRING, Md. and RESEARCH TRIANGLE PARK, N.C., April 23, 2020 /PRNewswire/ -- United Therapeutics Corporation (Nasdaq: UTHR) today detailed recent publications on Orenitram® (treprostinil) Extended-Release Tablets, which provide additional evidence of the beneficial treatment effect in patients with pulmonary arterial hypertension (PAH).

Orenitram was originally approved by the U.S. Food and Drug Administration (FDA) in 2013, with a label indicating that it improves PAH patients' exercise capacity when used as a monotherapy. As a result of the FREEDOM-EV clinical study, the labeling was updated by the FDA in October 2019 to indicate that Orenitram delays disease progression when used in conjunction with an oral background PAH therapy.

The recent publications add further to the evidence showing the benefits of treatments with Orenitram in PAH patients:

• Data from the FREEDOM-EV hemodynamic sub-study showing that Orenitram significantly improved key hemodynamic parameters, including pulmonary vascular resistance (20% reduction), cardiac output (19% increase), and cardiac index (17% increase), at a median week 24 dose of 5.5 mg three times daily were recently presented at the Pulmonary Vascular Research Institute (PVRI) 14th Annual World Congress on Peripheral Vascular Disease (PVD).1
• Analyses of the FREEDOM-EV study showing that Orenitram significantly improved patient risk status assessed by two different methodologies (REVEAL 2.0 and French noninvasive), which can be predictor of clinical worsening and survival, were accepted for presentation at the American Thoracic Society (ATS) 2020 International Conference.2,3
• A retrospective database analysis of U.S. health insurance claims concluding that treatment with selexipag was associated with 67% higher PAH-related patient healthcare costs compared to Orenitram despite similar adherence, persistence, and rate of PAH-related hospitalizations was recently published in the journal Drugs – Real World Outcomes.4,5,6 (Comparison of products does not imply clinical comparisons of safety or efficacy.)

"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, PharmD, United Therapeutics' Head of Global Medical Affairs. "These additional analyses, coupled with the hemodynamic improvements, should bolster PAH physician confidence in treatment."

"Data from the FREEDOM-EV study have resonated well with PAH providers and payers," said Michael Benkowitz, President and Chief Operating Officer of United Therapeutics. "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. We appreciate the investigators and patients who participated in these studies."

Newly published data are summarized below. Please refer to the respective publications for further information.

Significant Impact on Hemodynamics – Data from the FREEDOM-EV Study

FREEDOM-EV was a phase III, international, multi-center, randomized, double-blind, placebo- controlled, event-driven study of Orenitram in patients with PAH receiving background oral monotherapy (N=690).7,8 Orenitram decreased the risk of adjudicated clinical worsening events by 25% compared to placebo (hazard ratio: 0.75; p=0.039). These results were largely driven by a 61% decrease in the risk of disease progression compared to placebo (hazard ratio: 0.39; p=0.0002).

The hemodynamic sub-study included 61 patients who volunteered for right heart catheterization at baseline and study Week 24.1,9 Patients were predominantly female (75%) and received background phosphodiesterase type 5 inhibitor, soluble guanylate cyclase stimulator (85%), or endothelin receptor antagonist (15%) therapy.

At Week 24, the median (interquartile range) Orenitram dose achieved was 5.5 (3.5, 6) mg three times daily (TID). Treatment with Orenitram resulted in significant changes in hemodynamic parameters at Week 24, including a:

• 20% reduction in pulmonary vascular resistance (PVR; p=0.0241);
• 21% reduction in pulmonary vascular resistance index (PVRI; p=0.0295);
• 19% increase in cardiac output (CO; p=0.0051);
• 17% increase in cardiac index (CI; p=0.0128); and
• 13% increase in stroke volume (SV; p=0.043).

There were no significant changes in other hemodynamic parameters, including mean right atrial pressure (RAPm), pulmonary artery wedge pressure (PAWPm), pulmonary artery pressure (PAPm), or heart rate (HR) between the Orenitram and placebo groups. Data set are represented in the table below.

The most common adverse reactions reported were consistent with the parent study and included headache, diarrhea, flushing, nausea, and vomiting.

Data are limited by the relatively small sample size compared to the parent study (61 patients v. 690 patients). Authors note that baseline patient characteristics were similar; however, median Orenitram dose achieved was higher in hemodynamic sub-study patients (5.5 mg TID vs. 3.56 mg TID, overall).

Significant Impact on Risk – Data from the FREEDOM-EV Study

Orenitram demonstrated a robust impact on key measures of disease status in the FREEDOM-EV study, including functional class, NT-proBNP levels, and French noninvasive risk profile.7,8 Those treated with Orenitram exhibited a statistically significant improvement in French noninvasive risk profile compared to placebo through study Week 60. This is of particular note, as despite seemingly balanced characteristics, placebo-assigned participants were found to be at lower risk at baseline (p=0.002).

Thus, a post-hoc analysis of FREEDOM-EV was performed to determine the impact of Orenitram on the REVEAL 2.0 risk score (RRS).2 At baseline, 53%, 26%, and 21% of Orenitram subjects were in low (score 0-6), intermediate (score 7-8), and high-risk (score ≥9) categories, respectively, compared with 61%, 21%, and 18% of placebo subjects, respectively. The baseline RRS distribution was not statistically different between groups (p=0.0831), although mean scores between the groups were (6.3 Orenitram vs. 5.83 placebo; p=0.0107). Compared to baseline, there was a statistically significant improvement in RRS category in those treated with Orenitram compared to placebo through Week 36 (see figure, beyond Week 36 not presented). At Week 36, the mean RRS in participants treated with Orenitram decreased by 0.61, compared to a decrease of 0.01 in participants treated with placebo (mean difference: -0.599; p=0.002). 

To further assess the impact of the imbalance in patient risk in FREEDOM-EV, primary endpoint results were alternatively adjusted by baseline risk score.3 That is, the primary endpoint was corrected for the imbalance in baseline patient risk. Adjusting the primary endpoint analyses by baseline risk score magnified the treatment effect already observed in the pre-specified analysis (a 25% reduction in clinical worsening with Orenitram; hazard ratio: 0.75; p=0.039). Adjusting by the French noninvasive methodology, Orenitram was found to decrease the risk of clinical worsening events by 39% compared to placebo (hazard ratio: 0.61; p=0.0006). Adjusting by RRS (as a continuous variable), Orenitram decreased the risk of clinical worsening events by 33% compared to placed (hazard ratio: 0.67; p=0.0047).

The authors comment that risk scores appear to be a robust stratification tool and may be more sensitive for detecting treatment effects than traditional stratification factors.

Assessment of patient risk status via French noninvasive methodology was prespecified as an exploratory analysis in the FREEDOM-EV statistical analysis plan. Additional evaluations on patient risk were conducted post-hoc and should be regarded with appropriate caution.

Cost Effectiveness – Data from a U.S. Health Insurance Claims Study

A total of 256 patients with PAH receiving oral prostacyclin therapy were included in this retrospective database analysis (130 Orenitram and 126 selexipag patients).4,5,6 Various outcomes were evaluated over a six-month follow-up period, including adherence to treatment, persistence on treatment, all-cause and PAH-related hospitalizations, as well as healthcare costs.

Adherence, persistence, and hospitalization outcomes were comparable between patient groups. Treatment adherence was measured using the medication possession ratio (MPR) and the proportion of days covered (PDC). Mean MPR was higher for Orenitram patients (p=0.039), but there were no significant differences in the proportion of patients with ≥80% mean MPR, mean PDC, or ≥80% PDC between groups. Also, there was no significant difference between groups in the proportion of patients persistent on treatment, when discontinuation was defined as a gap in treatment of either ≥30 or ≥60 days. Mean number of all-cause outpatient visits was higher with Orenitram (p