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Clinical Improvement for When
Patients Need More1*

Established Clinical Efficacy in FREEDOM-EV1

Orenitram provides clinical intervention for intermediate-risk patients who need improvement of key measures of risk.1-3*

Reduced risk of disease progression1,2

Improved prognostic measures of risk2

Improved key hemodynamic criteria5,6

*2022 guidelines define measures of risk as 6MWD, FC, and NT–proBNP.7

FREEDOM-EV—Assessing the Effect of Orenitram on Time to First Clinical Worsening Event1,2

FREEDOM-EV was an international, multicenter, randomized, double-blind, placebo-controlled, event-driven study.1,2

The key baseline characteristics of patients in FREEDOM-EV1,5,8

44% intermediate-low risk||

23% intermediate-high risk||

79% female

43 years median age

405 m baseline 6MWD (median)

||Patients in FREEDOM-EV included 32% low risk, 44% intermediate-low risk, 23% intermediate-high risk, and 0.4% high risk. Risk was assessed using 6MWD, FC, and NT-proBNP.2,8

Hear from the principal investigator of FREEDOM-EV, R. James White, MD, PhD, who discusses the trial’s key patient characteristics and important outcomes.

Visit the publications library to read the full details of the FREEDOM-EV study >

PRIMARY ENDPOINT

Orenitram Is Proven to Delay Disease Progression1

61%reduced risk of disease progression, resulting in a decreased risk of clinical worsening by 25%1,2¶**

Time to First Clinical Worsening Event (ITT)1

Chart showing the time to clinical worsening events adjusted for number of low-risk criteria at baseline

Reduction in risk of clinical worsening with Orenitram vs placebo (HR=0.75 [95% CI, 0.57-0.99]; P=0.039). Reduction in risk of disease progression with Orenitram vs placebo (HR=0.39 [95% CI, 0.23-0.66]; P=0.0002).1

**Disease progression was defined as a ≥15% decrease in 6MWD and increase in WHO FC, or as a ≥15% decrease in 6MWD and appearance or worsening of symptoms of right heart failure.4

††P value was calculated with log-rank test stratified by background PAH therapy and baseline 6MWD category.2

‡‡Hazard ratio and 95% CI were calculated with proportional hazard model with treatment, background PAH therapy, and baseline 6MWD as explanatory variables.2

39%reduced risk of clinical worsening after accounting for the patients’ actual risk status at baseline2¶¶

¶¶Baseline risk-adjusted data are from a post hoc analysis and should be interpreted with caution.

SECONDARY ENDPOINTS

Orenitram Improved Key Prognostic Measures of Risk—6MWD, NT–proBNP, and WHO FC2,7,10

  • Patients showed an average 6MWD improvement of 22 m—compared with placebo—at week 482,4
    • Although 6MWD change was not statistically significant at 24 weeks, categorical changes in Borg dyspnea score favored Orenitram at all weekly assessments from week 12 to week 482
  • Reduced NT–proBNP—an important indicator of right ventricular dysfunction—by 41% at week 36 compared with placebo5,7
  • 89% of patients improved or maintained FC at week 24, making Orenitram the only oral prostacyclin-class therapy to demonstrate improvements in WHO FC1,2

OVERALL RISK STATUS

Orenitram Provided Long-Term Benefits to Overall Risk Status3

A higher percentage of patients (38%) taking Orenitram improved their COMPERA 4-strata risk status than patients on placebo (26%) through 84 weeks.3¶¶¶

4-Strata Risk Status: Improvement Over Time
Bar graphs showing improvement in 4-strata risk status over time for Orenitram vs placebo
  • Patients in FREEDOM-EV included 32% low risk, 44% intermediate-low risk, 23% intermediate-high risk, and 0.4% high risk8

¶¶¶Data came from a post hoc analysis of FREEDOM-EV data using the COMPERA 4-strata risk assessment. 35% of patients taking Orenitram improved and 53% maintained risk status at week 24 vs 20% improved and 53% maintained with placebo. 38% of patients taking Orenitram improved at week 84 and 56% maintained risk status vs 26% improved and 58% maintained with placebo.3

Jean Elwing, MD, comments on the effect that Orenitram had on several key parameters of risk, as well as overall risk status in the FREEDOM-EV trial.

HEMODYNAMIC SUBSTUDY

Orenitram Improved Key Hemodynamic Criteria—A Leading Indicator of Disease Progression5,6,11

The 24-week substudy included 61 patients from FREEDOM-EV who volunteered for a right heart catheterization at baseline and week 24.6

Patients in the hemodynamic substudy achieved a higher median dose of Orenitram (5.5 mg TID, 95% confidence interval 3.0 mg to 6.0 mg) by week 24 compared with the main FREEDOM-EV study (3.6 mg TID).6

Visit the publications library to read about the study >

Hemodynamic Improvement With Orenitram5,6****
Chart showing hemodynamic improvement with Orenitram
  • 35% increase in PAC††††
  • 20% decrease in PVR††††
  • 19% increase in CO††††
  • 17% increase in CI††††

There were no significant changes to mRAP, mPAP, or mPAWP.6

****P value and % change in the geometric mean were obtained from the analysis of covariance with change from baseline in log-transformed data for each hemodynamic parameter as the dependent variable, treatment as fixed effect, and log-transformed baseline hemodynamic parameter as a covariate.6

††††Percentage reflects change from baseline (PAC, P=0.007; CO, P=0.005; PVR, P=0.02; CI, P=0.01).6

Hear Paul Forfia, MD, discuss the impact of Orenitram on right heart function in the FREEDOM-EV trial.

VITAL STATUS SUBSTUDY

Orenitram Was Associated With a Positive Impact on Survival2‡‡‡‡

In FREEDOM-EV, vital status was collected throughout the study from patients who agreed to be followed, including both patients who discontinued early and who transitioned to the OLE study.2

  • When vital status was collected, cause of death was not specified2
  • Due to the collection of vital status occurring after some participants had exited the study and some investigative sites had closed, vital status was collected for 89% of patients (status unknown for 43 Orenitram and 31 placebo patients)2,4

37% Reduction in Risk of Death vs Placebo at Study Closure (P=0.03)2§§§§

At the time of study closure, 11% of patients in the Orenitram group died vs 17.4% of patients in the placebo group (P=0.03)2

Difference in risk of death was not statistically significant at the end of the randomized treatment period or OLE.2,4|| || || ||

Due to data collection limitations, data must be interpreted cautiously.

Time to Death at Study Closure2,5
Line graph showing risk of death of patients on Orenitram vs placebo at study closure
Summary of Deaths (All Causes)4,5
Time PointOrenitram
n=346
n (%)		Placebo
n=344
n (%)		Cox Hazard Ratio
(95% CI)
P Value (Orenitram-Placebo)		Log-Rank
P Value†††††
Deaths at end of randomized treatment17 (4.9%)18 (5.2%)1 (0.52-1.95) P=0.99P=0.98
Deaths in OLE13 (3.8%)24 (7%)
Deaths in randomized study and OLE‡‡‡‡‡30 (8.7%)42 (12.2%)0.80 (0.50-1.28) P=0.36P=0.43
Deaths in early discontinuation participants8 (2.3%)18 (5.2%)
Total deaths at study closure38 (11%)60 (17.4%)0.63 (0.42-0.95) P=0.03P=0.03

Due to data collection limitations, data must be interpreted cautiously.

‡‡‡‡FREEDOM-EV study closed after the occurrence of approximately 205 adjudicated events.2

§§§§P value was obtained from log-rank test stratified by background PAH therapy and baseline 6MWD category.2

|| || || ||FREEDOM-EV OLE data as of October 2018.

¶¶¶¶P value was calculated with log-rank test stratified by background PAH therapy and baseline 6MWD category.5

*****Hazard ratio, 95% CI, and P value were calculated with proportional hazard model with treatment, background PAH therapy, and baseline 6MWD as explanatory variables.5

†††††P values were calculated with log-rank test stratified by background PAH therapy and baseline 6MWD category.4

‡‡‡‡‡In the Orenitram group, 213 of 346 patients transitioned to the OLE. In the placebo group, 258 of 344 patients transitioned to the OLE.5

Expected Adverse Effects

See the most common adverse effects with Orenitram.

Patient Profiles

See how leading indicators of progression may help you identify patients who are appropriate for Orenitram.

Getting Patients Started

Find out how you may set your patient up for a successful start on Orenitram.

6MWD=6-minute walk distance; AE=adverse effect; CI=cardiac index; CO=cardiac output; ERA=endothelin receptor antagonist; FC=functional class; HR=hazard ratio; ITT=intent-to-treat; MMRM=mixed-effect model repeated measurement; mPAP=mean pulmonary arterial pressure; mPAWP=mean pulmonary arterial wedge pressure; mRAP=mean right atrial pressure; NT-proBNP=N-terminal pro–B-type natriuretic peptide; OLE=open-label extension; PAC=pulmonary arterial compliance; PAH=pulmonary arterial hypertension; PDE-5i=phosphodiesterase type 5 inhibitor; PVR=pulmonary vascular resistance; sGCS=soluble guanylate cyclase stimulator; TID=3 times daily; WHO=World Health Organization.

IMPORTANT SAFETY INFORMATION

Contraindications

  • Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.

Warnings and Precautions

  • Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
  • The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

IMPORTANT SAFETY INFORMATION

Contraindications

  • Avoid use of Orenitram in patients with severe hepatic impairment (Child Pugh Class C) due to increases in systemic exposure.

Warnings and Precautions

  • Abrupt discontinuation or sudden large reductions in dosage of Orenitram may result in worsening of PAH symptoms.
  • The Orenitram tablet shell does not dissolve. In patients with diverticulosis, Orenitram tablets can lodge in a diverticulum.

Adverse Reactions

  • In the 12-week, placebo-controlled, monotherapy study, and an event-driven placebo-controlled, combination therapy study, adverse reactions that occurred at rates at least 5% higher on Orenitram than on placebo included headache, diarrhea, nausea, vomiting, flushing, pain in jaw, pain in extremity, hypokalemia, abdominal discomfort, and upper abdominal pain.

Drug Interactions

  • Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.

Specific Populations

  • Animal reproductive studies with Orenitram have shown an adverse effect on the fetus. There are no adequate and well-controlled studies with Orenitram in pregnant women.
  • It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.
  • Safety and effectiveness of Orenitram in pediatric patients have not been established.
  • Use of Orenitram in patients aged 65 years and over demonstrated slightly higher absolute and relative adverse event rates compared to younger patients. Caution should be used when selecting a dose for geriatric patients.
  • There is a marked increase in the systemic exposure to treprostinil in hepatically impaired patients.

INDICATION

Orenitram is a prostacyclin mimetic indicated for treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to delay disease progression and to improve exercise capacity. The studies that established effectiveness included predominately patients with WHO functional class II-III symptoms and etiologies of idiopathic or heritable PAH (66%) or PAH associated with connective tissue disease (26%).

OREISIhcpOCT19

Please see Full Prescribing Information and Patient Information for Orenitram.

For additional information, call 1-877-UNITHER (1-877-864-8437).

References: 1. Orenitram [package insert]. Research Triangle Park, NC: United Therapeutics Corporation; 2023. 2. White RJ, Jerjes-Sanchez C, Bohns Meyer GM, et al; FREEDOM-EV Investigators. Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial. Am J Respir Crit Care Med. 2020;201(6):707-717. 3. Benza RL, Gomberg-Maitland M, Farber HW, et al. Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension – an analysis of FREEDOM-EV. J Heart Lung Transplant. 2022;41(suppl):1-12. 4. White RJ, Jerjes-Sanchez C, Bohns Meyer GM, et al; FREEDOM-EV Investigators. Combination therapy with oral treprostinil for pulmonary arterial hypertension. A double-blind placebo-controlled clinical trial. Am J Respir Crit Care Med. 2020;201(6)(suppl):E2-E22. 5. Data on file. United Therapeutics Corporation. Research Triangle Park, NC. 6. Khan A, White RJ, Meyer G, et al. Oral treprostinil improves pulmonary vascular compliance in pulmonary arterial hypertension. Respir Med. 2022;193:106744. 7. Humbert M, Kovacs G, Hoeper MM, et al; ESC/ERS Scientific Document Group. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. 8. Benza RL, Gomberg-Maitland M, Farber HW, et al. Contemporary risk scores predict clinical worsening in pulmonary arterial hypertension – an analysis of FREEDOM-EV. J Heart Lung Transplant. 2022;41(11):1572-1580. 9. Boucly A, Weatherald J, Savale L, et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017;50(2):1700889. 10. Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting survival in patients with pulmonary arterial hypertension: the REVEAL risk score calculator 2.0 and comparison with ESC/ERS-based risk assessment strategies. Chest. 2019;156(2):323-337. 11. Milks MW, Sahay S, Benza RL, et al. Risk assessment in patients with pulmonary arterial hypertension in the era of COVID 19 pandemic and the telehealth revolution: state of the art review. J Heart Lung Transplant. 2021;40(3):172-182.