SILVER SPRING, Md. and RESEARCH TRIANGLE PARK, N.C., Oct. 21, 2021 /PRNewswire/ -- United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation with a purpose to provide a brighter future for patients, today detailed the new clinical and real-world evidence on pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD) presented at CHEST 2021, the annual meeting of the American College of Chest Physicians. United Therapeutics and its collaborators presented 10 abstracts across a broad range of studies in PAH and PH-ILD, including pharmacokinetic (PK) data from the BREEZE study of Tyvaso DPI™.
"Late last month we officially converted to a public benefit corporation, so now more than ever, our new research underscores our foundational DNA: the mission to improve patients' health and support healthy communities," said Andrew Nelsen, PharmD, United Therapeutics' Vice President, Global Medical Affairs. "Together with our collaborators, we are pleased to share new data derived from the BREEZE study of Tyvaso DPI, the INCREASE study of Tyvaso® in PH-ILD, as well as assessment of the real-world use of Orenitram® and Remodulin® at the annual CHEST 2021 meeting."
Tyvaso DPI BREEZE pharmacokinetic data demonstrate similar exposure as Tyvaso
The CHEST meeting featured a poster detailing data from the BREEZE study of Tyvaso DPI in patients with PAH. New PK data presented at CHEST 2021 demonstrated that systemic exposure between Tyvaso DPI and Tyvaso was similar; in addition, lower variability in PK parameters were observed in Tyvaso DPI when compared with Tyvaso. PK data from a separate healthy volunteer study of Tyvaso DPI will be presented at a future scientific forum.
The BREEZE study enrolled 51 subjects on a stable regimen of Tyvaso who were transitioned to Tyvaso DPI at a corresponding treprostinil dose. The primary objective of the study was to evaluate the safety and tolerability of Tyvaso DPI during a three-week treatment phase in PAH patients previously treated with Tyvaso Inhalation Solution. Secondary objectives of the study included changes in six-minute walk distance (6WMD), device preference and satisfaction as evaluated through the Preference Questionnaire for Inhaled Treprostinil Devices, and patient-reported PAH symptoms and impact. Top line data showing the BREEZE study met its primary objective were released in January 2021, and detailed data on the primary and secondary objectives were presented in September 2021.
United Therapeutics abstracts presented at CHEST 2021 included:
BREEZE: Clinical Outcomes and Pharmacokinetics (PK) of Treprostinil Inhalation Powder (Tyvaso DPI)
Shelley Shapiro, MD; Leslie Spikes, MD; Ricardo Restrepo, MD; Joanna Joly, MD; Trushil Shah, MD; Jason Scoggin; Lisa Edwards, PhD; Peter Smith, PharmD; Melissa Miceli, PharmD
Inhaled treprostinil is currently delivered via a handheld ultrasonic nebulizer (Tyvaso Inhalation System). A dry powder formulation of treprostinil and a small, portable, inhaler (Tyvaso DPI) is in development for PAH. In patients with PAH, transition from Tyvaso to Tyvaso DPI was well-tolerated with significant improvements in 6MWD, device preference and satisfaction, and patient reported outcomes.
Despite a 33% higher peak serum concentration (Cmax) observed for Tyvaso DPI vs. Tyvaso, the adverse event profiles were similar. Between-subject variability for area under the curve (AUC) and Cmax parameters was similar within treatment.
Dose-Response Analysis of Inhaled Treprostinil in Pulmonary Hypertension Associated with Interstitial Lung Disease and Its Effects on Clinical Worsening
Victor Tapson, MD; Steven Nathan, MD, PhD; Micah Fisher, MD; H. James Ford, MD; James Gagermeier, MD; Joseph Parambil, MD; Amresh Raina, MD; Dianne Zwicke, MD; Alicia Gerke, MD; Eric Shen, PharmD; Dasum Lee, MS; Youlan Rao, PhD; Aaron Waxman, MD
In a post-hoc analysis of patients with PH-ILD in the INCREASE trial, patients were divided into two dose groups, less than nine breaths per session and nine breaths per session and above. The higher doses of inhaled treprostinil were associated with a lower risk of clinical worsening. These results underscore the importance of inhaled treprostinil dose titration in the context of adverse event management for patients with PH-ILD.
The Impact of Hemodynamic Parameters on Inhaled Treprostinil Treatment Response – A Subgroup Analysis from the INCREASE Trial
Aaron Waxman, MD, PhD; Victor Tapson, MD; Reda Girgis, MD; James Runo, MD; Remzi Bag, MD; Arunabh Talwar, MD; Peter Smith, PharmD; Dana Johnson, PhD; Christine Park, PharmD; Steven Nathan, MD
This INCREASE post-hoc analysis evaluated the treatment effect of inhaled treprostinil on 6MWD and forced vital capacity (FVC) as a function of baseline hemodynamics in participants with PH-ILD. PH-ILD patients with higher pulmonary vascular resistance (PVR) and/or mean pulmonary artery pressure (mPAP) had a greater response to treatment. This analysis suggests higher PVR and mPAP reflect progressive pulmonary vascular remodeling and demonstrates the importance of considering pulmonary hemodynamics when treating patients with PH-ILD.
Healthcare Resource Utilization and Treatment Patterns Before and After Initiation of Inhaled Treprostinil
Charles Burger, MD, FCCP; Christine Park, PharmD; Peter Classi, MSc, MBA; Andrew Nelsen, PharmD; Benjamin Wu, PharmD
In this retrospective analysis of real-world data, inhaled treprostinil was effective in reducing hospitalization, a known risk factor for poor outcomes. The benefit remained substantial even in patients on prior dual background therapy with an endothelin receptor antagonist and phosphodiesterase-5 inhibitor or soluble guanylate cyclase stimulator.
Burden of Illness in Patients with Pulmonary Hypertension due to Interstitial Lung Disease: A Real-World Analysis Using US Claims Data
Gustavo Heresi, MD; Howard Castillo, NP-C; Henry Lee, PharmD; Peter Classi, MSc, MBA; Dana Stafkey-Mailey, PharmD, PhD; Kellie D. Morland, PharmD; Margaret Sketch, MPH, PharmD; Alexander Kantorovich, PharmD; Benjamin Wu, PharmD; Bonnie Dean, PhD
A retrospective cohort study of patients with PH-ILD was conducted using research databases to characterize healthcare resource utilization and costs associated with PH-ILD. Patients with PH-ILD have significantly increased utilization of healthcare resources, including inpatient admissions, and costs, following an initial diagnosis of pulmonary hypertension.
Comparison of Effects of Inhaled Treprostinil on Lung Function in Patients with Pulmonary Hypertension Associated with Interstitial Lung Disease and Pulmonary Arterial Hypertension
Steven Nathan, MD; Victor Tapson, MD; Gautam Ramani, MD; Boris Medarov, MD; Deborah Levine, MD; Charles Burger, MD; Karim El-Kersh, MD; Eric Shen, PharmD; Youlan Rao, PhD; Peter Smith, PharmD; Aaron Waxman, MD
The aim of this post-hoc analysis was to compare lung function changes due to inhaled treprostinil in both INCREASE, which evaluated inhaled treprostinil over 16 weeks in patients with PH-ILD, and the TRIUMPH study, which evaluated inhaled treprostinil over 12 weeks in patients with PAH. Although baseline characteristics varied between studies, results suggest that pulmonary function test response to inhaled treprostinil in PAH differs mechanistically from PH-ILD. The significant improvements in percent predicted forced vital capacity in patients with PH-ILD not observed in PAH suggest that the benefits of inhaled treprostinil may in part be attributed to improvements in lung disease rather than improved pulmonary hypertension.
Screening for Pulmonary Hypertension in Patients with Interstitial Lung Disease: Recommendations from a Delphi Consensus Panel
Franck Rahaghi, MD; Nicholas Kolaitis, MD; Ayodeji Adegunsoye, MD, MS; Joao de Andrade, MD; Kevin Flaherty, MD; Lisa Lancaster, MD; Joyce Lee, MD; Deborah Levine, MD; Ioana Preston, MD; Zeenat Safdar, MD; Rajan Saggar, MD; Sandeep Sahay, MD; Mary Beth Scholand, MD; Oksana Shlobin, MD; David Zisman, MD, MS; Steven Nathan, MD
A modified Delphi process was utilized to determine recommendations on screening for PH-ILD. Expert panelists reached consensus that patients with most interstitial lung diseases (ILDs) with signs or symptoms disproportionate to the severity of ILD and/or other clinical factors suggestive of PH, such as changes in pulmonary function tests, 6MWD, and BNP/NTproBNP biomarkers, should be considered triggers to screen for PH by echocardiography and PH diagnosis confirmed with right-heart catheterization. These recommendations are the first systematic collection of expert consensus for screening in PH-ILD.
Orenitram and Remodulin abstracts
Real-World Patient Reported Outcomes Using SF-12 and EmPHasis-10 in Patients Receiving Oral Treprostinil: Interim Analysis from the ADAPT Registry
Sandeep Sahay, MD; Akram Khan, MD; Daniel Lachant, DO; Dasom Lee; Christine Park, PharmD; Meredith Broderick, PharmD, JD; Raymond Benza, MD
ADAPT is an active, observational registry following 154 PAH patients up to 78 weeks from initiation of oral treprostinil. In this registry analysis of real-world use of oral treprostinil. Treatment with oral treprostinil improved health-related quality of life at month six, as measured by emPHasis-10 and Short Form-12 scores. Additionally, data indicate Reveal 2.0 Lite risk status is correlated with health-related quality of life.
Health Outcomes and Costs Associated with Oral Treprostinil and Selexipag One-Year into Treatment: a U.S. Claims Database Analysis in Patients with Pulmonary Arterial Hypertension
Peter Classi, MSc, MBA; Kellie Morland, PharmD; Benjamin Wu, PharmD; Alex DeRuiter, PharmD; Henry Lee, PharmD; Dana Stafkey-Mailey, PharmD; PhD; Bonnie Dean, PhD
This retrospective analysis aimed to characterize various outcomes and costs for PAH patients being treated with either oral treprostinil or selexipag one year into treatment. Real-world claims data show similar adherence and persistence, and outcomes for oral treprostinil and selexipag in patients with PAH. However, there were notable differences in costs in the one year following treatment initiation. The mean PAH-related healthcare costs were less for oral treprostinil when compared to selexipag.
Analysis of Real-World Pharmacovigilance Data of Parenteral Treprostinil for Pulmonary Arterial Hypertension (PAH) in the Pediatric Versus Adult Population
Romeo Habaradas, MD; Ashley Higgins, PharmD; Ihab Abdelfattah, MD; Rahul Khajuria, MCA; Youlan Rao, PhD; Eunah Cho; Chunqin Deng, MD, PhD; Ravi Patel, PharmD; Markus Lang, PharmD, PhD
This retrospective study compared United Therapeutics' parenteral treprostinil pharmacovigilance data of pediatrics and adults to determine if there were any significant difference between the two populations. Overall, the safety profile of parenteral treprostinil is comparable between pediatric and adult PAH populations. However, local reactions were observed more frequently in pediatrics.
About Orenitram® (treprostinil) Extended-Release Tablets
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
- 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.
- 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.
- Co-administration of Orenitram and the CYP2C8 enzyme inhibitor gemfibrozil increases exposure to treprostinil; therefore, Orenitram dosage reduction may be necessary in these patients.
- 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.
About Remodulin® (treprostinil) Injection
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.
- 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%).
- Remodulin dosage adjustment may be necessary if inhibitors or inducers of CYP2C8 are added or withdrawn.
- 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).
About TYVASO® (treprostinil) Inhalation Solution
TYVASO (treprostinil) is a prostacyclin mimetic indicated for the treatment of:
- Pulmonary arterial hypertension (PAH; WHO Group 1) to improve exercise ability. Studies establishing effectiveness predominately included patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).
The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.
While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.
- Pulmonary hypertension associated with interstitial lung disease (PH-ILD; WHO Group 3) to improve exercise ability. The study establishing effectiveness predominately included patients with etiologies of idiopathic interstitial pneumonia (IIP) (45%) inclusive of idiopathic pulmonary fibrosis (IPF), combined pulmonary fibrosis and emphysema (CPFE) (25%), and WHO Group 3 connective tissue disease (22%).
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
- TYVASO is a pulmonary and systemic vasodilator. In patients with low systemic arterial pressure, TYVASO may produce symptomatic hypotension.
- TYVASO inhibits platelet aggregation and increases the risk of bleeding.
- Co-administration of a cytochrome P450 (CYP) 2C8 enzyme inhibitor (e.g., gemfibrozil) may increase exposure (both Cmax and AUC) to treprostinil. Co-administration of a CYP2C8 enzyme inducer (e.g., rifampin) may decrease exposure to treprostinil. Increased exposure is likely to increase adverse events associated with treprostinil administration, whereas decreased exposure is likely to reduce clinical effectiveness.
DRUG INTERACTIONS/SPECIFIC POPULATIONS
- The concomitant use of TYVASO with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension.
- Human pharmacokinetic studies with an oral formulation of treprostinil (treprostinil diolamine) indicated that co-administration of the cytochrome P450 (CYP) 2C8 enzyme inhibitor, gemfibrozil, increases exposure (both Cmax and AUC) to treprostinil. Co-administration of the CYP2C8 enzyme inducer, rifampin, decreases exposure to treprostinil. It is unclear if the safety and efficacy of treprostinil by the inhalation route are altered by inhibitors or inducers of CYP2C8.
- Limited case reports of treprostinil use in pregnant women are insufficient to inform a drug associated risk of adverse developmental outcomes. However, pulmonary arterial hypertension is associated with an increased risk of maternal and fetal mortality. There are no data on the presence of treprostinil in human milk, the effects on the breastfed infant, or the effects on milk production.
- Safety and effectiveness in pediatric patients have not been established.
- Across clinical studies used to establish the effectiveness of TYVASO in patients with PAH and PH-ILD, 268 (47.8%) patients aged 65 years and over were enrolled. The treatment effects and safety profile observed in geriatric patients were similar to younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of hepatic, renal, or cardiac dysfunction, and of concomitant diseases or other drug therapy.
- Pulmonary Arterial Hypertension (WHO Group 1)
In a 12-week, placebo-controlled study (TRIUMPH I) of 235 patients with PAH (WHO Group 1 and nearly all NYHA Functional Class III), the most common adverse reactions seen with TYVASO in ≥4% of PAH patients and more than 3% greater than placebo in the placebo-controlled study were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs <1%), and syncope (6% vs <1%). In addition, adverse reactions occurring in ≥4% of patients were dizziness and diarrhea.
- Pulmonary Hypertension Associated with ILD (WHO Group 3)
In a 16-week, placebo-controlled study (INCREASE) of 326 patients with PH-ILD (WHO Group 3), adverse reactions were similar to the experience in studies of PAH.
Please see Full Prescribing Information, the TD-100 and TD-300 TYVASO® Inhalation System Instructions for Use manuals, and other additional information at www.tyvaso.com or call 1-877-UNITHER (1-877-864-8437).
United Therapeutics: Enabling Inspiration
We build on the strength of our research and development expertise and a distinctive, entrepreneurial culture that encourages diversity, innovation, creativity, sustainability, and, simply, fun. Since inception, our mission has been to find a cure for pulmonary arterial hypertension and other life-threatening diseases. Toward this goal we have successfully gained FDA approval for five medicines, we are always conducting new clinical trials, and we are working to create an unlimited supply of manufactured organs for transplantation.
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. At the same time, we seek to provide our shareholders with superior financial performance and our communities with earth-sensitive energy utilization.
You can learn more about what it means to be a PBC here: unither.com/PBC.
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 our mission to improve patients' health and support healthy communities, our development plans for Tyvaso DPI, our mission to find a cure for pulmonary hypertension and other life-threatening diseases, our ongoing and future clinical trials and other research and development efforts, and our goals of furthering our public benefit purpose, providing superior financial performance for shareholders, and providing our communities with earth-sensitive energy utilization. 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 21, 2021 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.
TYVASO, ORENITRAM, and REMODULIN are registered trademarks of United Therapeutics Corporation.
TYVASO DPI is a trademark of United Therapeutics Corporation.
For Further Information Contact:
Dewey Steadman at (202) 919-4097
Email: [email protected]
SOURCE United Therapeutics Corporation