United Therapeutics Announces Top Line Data From the EXPEDITE Study of Remodulin Induction Prior to Orenitram Therapy

A short induction of Remodulin^® (treprostinil) injection allowed study subjects to reach double the typical doses of Orenitram^® (treprostinil) extended-release tablets than patients who did not have a Remodulin induction

SILVER SPRING, Md. & RESEARCH TRIANGLE PARK, N.C.--(BUSINESS WIRE)--United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation, today announced that a preliminary analysis of the EXPEDITE study in patients suffering from World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) demonstrated that 79% of patients in the study achieved an Orenitram (treprostinil) extended-release tablet dose of at least 4 mg three times daily (TID), for a 12 mg total daily dose at 16 weeks, after an up to eight week induction treatment period with Remodulin (treprostinil) injection. Detailed study results will be made available through scientific disclosure at upcoming medical conferences and in peer-reviewed publications.

“The EXPEDITE trial represents a framework to get carefully selected PAH patients on clinically impactful oral doses of a critical class of medication safely and so much more timely,” said John Kingrey, M.D., director of the Pulmonary Hypertension center at INTEGRIS Baptist Medical Center. “I’m so pleased with how my patients did with this approach, as it really did expedite (pun intended!) their path to achieving increased prostacyclin dosages.”

“We’re delighted with the preliminary results from the EXPEDITE study, which provided patients a way to reach efficacious doses in a shorter period of time without having to commit to long-term pump therapy,” said Meredith Broderick, Pharm.D., J.D., Senior Director of Global Medical Affairs at United Therapeutics. “Along with our other phase 4 studies, EXPEDITE demonstrates our commitment to optimize available treatment options in order to help PAH patients better manage their disease.”

In EXPEDITE, patients enrolled in the study achieved a mean total daily Orenitram dose of 16.4 mg at 16 weeks with 79% of study subjects reaching the study’s primary endpoint of a 12 mg total daily dose. Secondary outcome measures included six-minute walk distance (6MWD); the cardiac biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP); WHO functional classification; echocardiography; risk scores; and health related quality of life, as assessed using the emPHasis-10 questionnaire.

A previous real world dosing analysis showed an average Orenitram dose of approximately 6 mg daily after 16 weeks without the induction protocol studied by the EXPEDITE study¹. In addition, scientific literature shows that higher doses of treprostinil have been associated with better outcomes for patients with PAH².

Treatment with Orenitram, three times daily, was well tolerated and the safety profile was consistent with previous Orenitram studies in PAH. In the study, several well-known treprostinil adverse events such as headache, nausea, and vomiting tended to improve after transition to Orenitram from Remodulin.

About the EXPEDITE study
EXPEDITE was a phase 4, multicenter, open-label 16-week study of Remodulin induction followed by oral Orenitram optimization in patients with PAH. Enrollment into the study was completed in May 2022 with a total of 36 patients enrolled. Twenty-nine patients completed the study. Once enrolled, patients were initiated on intravenous or subcutaneous Remodulin in an inpatient or outpatient setting and titrated to a minimum dose of 20 ng/kg/min over two to eight weeks. Patients were then transitioned to Orenitram over one to 21 days in the inpatient or outpatient setting. The primary endpoint was to evaluate the percentage of subjects achieving an Orenitram dose of 4 mg three times daily (TID) – or a total daily dose of 12 mg – or higher at week 16.

Secondary objectives of the study were to assess the effect of Orenitram treatment at 16 weeks after induction therapy with Remodulin on the following parameters:

• 6MWD
• Borg dyspnea score
• WHO functional class
• Serum NT-proBNP
• Echocardiogram
• PAH symptom score
• Health-related quality of life as determined by the emPHasis-10 questionnaire
• Treatment Satisfaction Questionnaire for Medication (TSQM) scores
• Percentage of subjects that improve in each of the following individual four clinical parameters at week 16 (6MWD, NT-proBNP, WHO FC, right atrial area) to a lower risk stratum, as defined by the 2015 European Society of Cardiology guidelines, compared to baseline
• Percentage of subjects that meet each of the following four individual clinical parameters at week 16 in the low risk category, as defined by 2015 European Society of Cardiology guidelines: 6MWD > 440 meters, serum NT-proBNP < 300 ng/L, WHO FC I or II, and right atrial area < 18 cm²
• Percentage of subjects that either achieve an Orenitram dose of 4 mg TID (or a total daily dose of 12 mg) or higher at week 16 (or a dose of 0.057 mg/kg TID [or a total daily dose of 0.171 mg/kg] or greater for subjects <70 kg) or the percentage of subjects that achieve an Orenitram dose ≥2 mg TID and <4 mg TID (or a total daily dose ≥6 mg and <12 mg) at week 16, with at least 2 of the following 3 clinical parameters at week 16: 6MWD increase by ≥10% or ≥30 meters from Baseline, serum NT-proBNP reduction >30% from Baseline, or WHO FC I or II
• The percentage of subjects that successfully transitioned to Orenitram at any dose and were maintained on therapy at week 16
• Safety and tolerability as measured by adverse events; an AE Bothersome Survey; clinical laboratory parameters; and vital signs

Additional exploratory objectives of the study evaluated changes in biomarkers and pharmacogenomics from this study.

About Orenitram^® (treprostinil) Extended-Release Tablets

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%).

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.

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.

Please see Full Prescribing Information and Patient Information at www.orenitram.com or call 1-877-UNITHER (1-877-864-8437).

About Remodulin^® (treprostinil) Injection

Indication
Remodulin is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH; WHO Group 1) to diminish symptoms associated with exercise. Studies establishing effectiveness included patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated with connective tissue diseases (19%).

In patients with PAH requiring transition from epoprostenol, Remodulin is indicated to diminish the rate of clinical deterioration. Consider the risks and benefits of each drug prior to transition.

Important Safety Information for Remodulin

Warnings and Precautions

• Chronic intravenous (IV) infusions of Remodulin delivered using an external infusion pump with an indwelling central venous catheter are associated with the risk of blood stream infections (BSIs) and sepsis, which may be fatal. Therefore, continuous subcutaneous (SC) infusion is the preferred mode of administration.
• Avoid abrupt withdrawal or sudden large reductions in dosage of Remodulin, which may result in worsening of PAH symptoms.
• Titrate slowly in patients with hepatic or renal insufficiency, because such patients will likely be exposed to greater systemic concentrations relative to patients with normal hepatic or renal function.
• Remodulin is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, treatment with Remodulin may produce symptomatic hypotension.
• Remodulin inhibits platelet aggregation and increases the risk of bleeding.

Adverse Reactions

• In clinical studies of SC Remodulin infusion, the most common adverse events reported were infusion site pain and infusion site reaction (redness, swelling, and rash). These symptoms were sometimes severe and sometimes required treatment with narcotics or discontinuation of Remodulin. The IV infusion of Remodulin with an external infusion pump has been associated with a risk of blood stream infections, arm swelling, paresthesias, hematoma, and pain. Other common adverse events (≥3% more than placebo) seen with either SC or IV Remodulin were headache (27% vs. 23%), diarrhea (25% vs. 16%), nausea (22% vs. 18%), rash (14% vs. 11%), jaw pain (13% vs. 5%), vasodilatation (11% vs. 5%), edema (9% vs. 3%), and hypotension (4% vs. 2%).

Drug Interactions

• Remodulin dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.

Specific Populations

• In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to 0.625 ng/kg/min of ideal body weight, and monitor closely. Remodulin has not been studied in patients with severe hepatic insufficiency.
• Safety and effectiveness of Remodulin in pediatric patients have not been established.
• It is unknown if geriatric patients respond differently than younger patients. Caution should be used when selecting a dose for geriatric patients.
• There are no adequate and well-controlled studies with Remodulin in pregnant women. It is not known whether treprostinil is excreted in human milk or if it affects the breastfed infant or milk production.

Please see accompanying Full Prescribing Information for Remodulin.

For additional information, visit www.RemodulinPro.com or call Customer Service at 1-877-UNITHER (1-877-864-8437).

United Therapeutics: Enabling Inspiration
At United Therapeutics, our vision and mission are one. We use our enthusiasm, creativity, and persistence to innovate for the unmet medical needs of our patients and to benefit our other stakeholders. We are bold and unconventional. We have fun, we do good. We are the first publicly-traded biotech or pharmaceutical company to take the form of a public benefit corporation (PBC). Our public benefit purpose is to provide a brighter future for patients through (a) the development of novel pharmaceutical therapies; and (b) technologies that expand the availability of transplantable organs.

You can learn more about what it means to be a PBC here: unither.com/PBC.

Forward-looking Statements
Statements included in this press release that are not historical in nature are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements include, among others, statements relating to the results and anticipated impact of the EXPEDITE study, our commitment to optimize available treatment options in order to help PAH patients better manage their disease, our efforts to innovate for the unmet medical needs of our patients, to benefit our other stakeholders, and to pursue our public benefit purpose of developing novel pharmaceutical therapies and technologies that expand the availability of transplantable organs. These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results. Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K. We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements. We are providing this information as of October 31, 2022 and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events, or any other reason.

¹https://pubmed.ncbi.nlm.nih.gov/29582710/

²https://journals.sagepub.com/doi/full/10.1177/2045894020923956

REMODULIN and ORENITRAM are registered trademarks of United Therapeutics Corporation.