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Established Efficacy

Clinical Improvement for When Patients Need More1*

FREEDOM-EV Study

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

Dose-response relationship and titratability1,11

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

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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

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

PRIMARY ENDPOINT

Orenitram Is Proven to Delay Disease Progression1

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

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 Risk2,4,5

NT-proBNP
at week 36 vs. placebo‡‡‡

+
m

Average 6MWD improvement
at week 48 vs. placebo

Change in 6MWD was not statistically significant at week 24§§§

%

Improved or maintained WHO FC
at week 24‡‡‡

‡‡‡ 14.7% of patients taking Orenitram improved and 74% maintained WHO FC at week 24 vs. 10.8% improved and 70.9% maintained in the placebo group.

13% more patients taking Orenitram achieved low risk cutoff (NT-proBNP <300 pg/mL) from baseline to week 36.5

§§§ The placebo-adjusted change from baseline in 6MWD at week 24 was +7.5 m (P=0.1411), +12.9 m at week 36 (P=0.0356), and +21.7 m at week 48 (P=0.0015).4

View Transcript

Jean Elwing, MD, discusses the effect of Orenitram on key parameters of risk and overall risk status in FREEDOM-EV.

Higher Doses Achieved Greater Clinical Outcomes10

Reaching the initial target TDD of ≥9 mg achieved greater improvement11

  • 6MWD in FREEDOM-EV: +34 m change from baseline at week 48 with ≥3 mg TID (P<0.01) vs. +5 m with <3 mg TID (P=0.56); prespecified11††††
  • Borg dyspnea in FREEDOM-EV: 43.5% improved from baseline at week 24 with ≥3 mg TID (P=0.0008) vs. 29.6% in <3 mg TID (P=0.59); prespecified11††††

††††Results are compared for participants achieving an Orenitram dose <3 or ≥3 mg TID at week 24 vs. a common placebo group.11

HEMODYNAMIC SUBSTUDY

Orenitram Improved Key Hemodynamics5,6

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

PAC‡‡‡‡

CO‡‡‡‡

CI‡‡‡‡

PVR‡‡‡‡

There were no significant changes to mRAP, mPAP, or mPAWP.5,6

At baseline — PAC: 1.5 mL/mm Hg Orenitram, 1.5 mL/mm Hg placebo; PVR: 581 dynes•sec•cm-5 Orenitram, 653 dynes•sec•cm-5 placebo; CO: 4.9 L/min Orenitram, 4.5 L/min placebo; CI: 2.9 L/min/m2 Orenitram, 2.8 L/min/m2 placebo

Visit the publications library to read about the study

5.5 mg vs. 3.6 mg TID

Higher median dose achieved in the hemodynamic substudy (5.5 mg vs. 3.6 mg TID) vs. parent study by week 245,6§§§§

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

§§§§Excluded from this analysis (n=6) were those patients with missing or mismatched cardiac output estimates (using indirect Fick or thermodilution methodology) at baseline and week 24. Hemodynamic parameters are expressed as geometric means.6

Improved Risk Status3,12

Patients showed improvements in overall risk assessments as early as week 12 and continued through week 84 in:

  • REVEAL Lite 2
  • French Noninvasive Method
  • REVEAL 2.0
  • COMPERA 2.0 ||||||||

|||||||| The use of the French Noninvasive Method risk assessment was a prespecified analysis and REVEAL Lite 2, REVEAL 2.0, and COMPERA were post-hoc risk analyses.3,8

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

Graph showing 4-strata risk status improvement over time
  • 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

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.

IMPORTANT SAFETY INFORMATION FOR ORENITRAM

Contraindications

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

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.

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.

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 at www.orenitram.com or 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. Ramani G, Cassady S, Shen E, et al. Novel dose-response analyses of treprostinil in pulmonary arterial hypertension and its effects on six-minute walk distance and hospitalizations. Pulm Circ. 2020;10(3):2045894020923956. Published 2020 Oct 27. 11. White RJ, Grunig E, Jerjes-Sanchez C, et al. Dose-response relationship of oral treprostinil for secondary endpoints in the FREEDOM-EV study. Poster presented at: European Respiratory Society International Conference; September 27 to October 2 2019; Madrid, Spain. 12. White RJ, Chakinala M, Rischard F, Howell M, Laliberte K, Feldman J. Safety and tolerability of transitioning from parenteral treprostinil to oral treprostinil inpatients with pulmonary arterial hypertension. Presentation.