United Therapeutics Announces the Publication of Tyvaso DPI™ BREEZE Clinical and Long-term Data in the Journal Pulmonary Circulation

In subjects with PAH, transition from Tyvaso^® to Tyvaso DPI™ demonstrated safety and tolerability with significant improvements in six-minute walk distance, device preference and satisfaction, and patient reported outcomes

Tyvaso DPI safety confirmed through 51 weeks of optional extension phase data with no study drug-related serious adverse events

FDA action on the New Drug Application for Tyvaso DPI is expected by May 2022

United Therapeutics Corporation (Nasdaq: UTHR), a public benefit corporation, today announced the publication of additional clinical and long-term safety data from the BREEZE study evaluating Tyvaso DPI™ (treprostinil) in patients with pulmonary arterial hypertension (PAH) in the journal Pulmonary Circulation.

The publication evaluated the BREEZE study and its ongoing optional extension phase (OEP), and concluded:

• Tyvaso DPI’s delivery device, along with the clinical results from BREEZE, may facilitate the introduction of inhaled treprostinil earlier in the clinical course of PAH for appropriate patients;

• Doses of Tyvaso DPI above the current recommended dose of nebulized Tyvaso (9-12 breaths four times daily) were well tolerated, potentially allowing for titration to higher dose levels without resulting in prolonged treatment sessions;

• A simplified dosing regimen could potentially increase patient compliance; and

• Tyvaso DPI has a pharmacokinetic (PK) profile comparable to nebulized Tyvaso, such that patients will not have to use more drug than nebulized Tyvaso to get the same treprostinil blood concentration or treatment effect.

Tyvaso DPI is a next-generation dry powder formulation of Tyvaso, which is currently undergoing review by the U.S. Food and Drug Administration (FDA). If approved, Tyvaso DPI is expected to provide a more convenient method of administration as compared with traditional nebulized Tyvaso therapy.

“If approved, I believe Tyvaso DPI could represent a very exciting addition to the treatment paradigm for the PAH population,” said Leslie Spikes, M.D., Associate Professor of Pulmonary and Critical Care Medicine at the University of Kansas Medical Center. “The ease of use, portability, and ability to titrate the dose with Tyvaso DPI should have a beneficial impact on patient compliance and persistence and could result in improved exercise ability.”

“We’re thrilled that this manuscript builds on earlier data presented at the European Respiratory Society’s 2021 International Congress, with additional long-term follow-up data that continues to show a strong safety profile for patients transitioning from nebulized Tyvaso to Tyvaso DPI,” said Peter Smith, PharmD, Vice President, Product Development, at United Therapeutics. “The optional extension phase is still ongoing, and we’ve accrued over 71 patient-years of experience with Tyvaso DPI.”

The BREEZE study

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; the majority of patients in the study were on dual background PAH therapies.

Top line data showing the BREEZE study met its primary objective were released in January 2021 and clinical data was presented at the European Respiratory Society International Congress in September 2021.

Secondary objectives of the study included changes in six-minute walk distance (6MWD), device preference and satisfaction as evaluated through the Preference Questionnaire for Inhaled Treprostinil Devices (PQ-ITD), and patient reported PAH symptoms and impact (PAH-SYMPACT^®).

Primary safety and tolerability objective. Transition from Tyvaso to Tyvaso DPI demonstrated safety and tolerance. Forty-nine out of 51 patients (96%) completed the three-week treatment phase, while two subjects discontinued due to treatment-related adverse events during the treatment phase. There were no study drug-related serious adverse events. Most adverse events experienced during the study were mild to moderate in severity and occurred at severities and frequencies consistent with those seen in other inhaled treprostinil studies in patients with PAH. Please see Important Safety Information about Tyvaso at the end of this press release.

Secondary objectives. Three weeks after switching from Tyvaso to Tyvaso DPI, patients in the BREEZE study demonstrated:

• Significant improvements in 6MWD compared to baseline. Improvements of 11.5 meters (p=0.0217) in 6MWD compared to baseline were observed through the three-week treatment phase;

• Significant improvements in overall satisfaction with the Tyvaso DPI inhaler. Using the PQ-ITD, significant improvements (p<0.0001) were observed in overall satisfaction with the Tyvaso DPI inhaler; and

• Significant improvements in PAH impact. The SYMPACT questionnaire includes domains on physical impacts, cognitive/emotional impacts, cardiopulmonary symptoms, and cardiovascular symptoms. Significant improvements in PAH impacts were observed in physical impacts (p=0.0438) and cognitive/emotional impacts (p=0.0048) at week three as well as physical impacts (p=0.0429) at week 11.

Pharmacokinetic results. Systemic exposure between the nebulized Tyvaso and Tyvaso DPI was comparable between the two formulations. Between-subject variability for area under the curve (AUC) and peak serum concentration (C­_max) parameters was similar across dose levels for each formulation (Tyvaso or Tyvaso DPI). However, variability of AUC and C­_max was 2- to 3-fold lower for Tyvaso DPI when compared to Tyvaso.

Optional extension phase. Subjects in BREEZE were given the opportunity to continue in an OEP. All subjects who completed the treatment phase (49/51) elected to continue in the OEP. At the July 2021 data cutoff for this manuscript, 17 patients had reached 51 weeks of Tyvaso DPI use and 39 patients were still participating in the OEP, but not all patients had reached the 51-week visit at the cut-off. Additional data from the OEP also demonstrated:

• Long-term safety. Most patients in the OEP either maintained or increased their study dose from baseline and there were no treatment-related serious adverse events; and

• Long-term efficacy. Improvements in 6MWD were sustained for patients in the OEP up to week 51 at the data cut-off date.

The manuscript, entitled “BREEZE: Open-label Clinical Study to Evaluate the Safety and Tolerability of Treprostinil Inhalation Powder as Tyvaso DPI in Patients With Pulmonary Arterial Hypertension,” is available on the Pulmonary Circulation Journal website and at https://doi.org/10.1002/pul2.12063.

About PAH

Also known as World Health Organization Group 1 Pulmonary Hypertension, PAH is life-threatening high blood pressure in the arteries of the lungs, affecting the ability of the heart and lungs to work properly in afflicted patients. PAH is a serious, progressive disease for which there is no known cure.

About Tyvaso DPI

Tyvaso DPI is an investigational drug-device combination therapy comprised of a dry powder formulation of treprostinil and a small, portable, dry powder inhaler. If approved, Tyvaso DPI is expected to provide a more convenient method of administration compared with traditional nebulized Tyvaso therapy. United Therapeutics has developed Tyvaso DPI under a collaboration and license agreement with MannKind Corporation (Nasdaq: MNKD).

United Therapeutics and MannKind are also developing BluHale^®, a Bluetooth-connected accessory for the Tyvaso DPI inhaler with a companion mobile application intended to help the patient track information about inhaler use.

United Therapeutics has submitted a New Drug Application (NDA) to the FDA seeking approval of Tyvaso DPI to treat adult patients with PAH and pulmonary hypertension associated with interstitial lung disease. FDA action on the NDA is anticipated by May 2022.

About TYVASO (treprostinil) Inhalation Solution

INDICATION

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 C_max 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 C_max 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.

ADVERSE REACTIONS

• 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.

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 our pending NDA for Tyvaso DPI, the timing of its potential approval, the potential clinical benefits of Tyvaso DPI if and when it is approved by the FDA, our ability to create value and sustain our success in the long-term, as well as our efforts to develop technologies that either delay the need for transplantable organs or expand the supply 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 April 6, 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.

TYVASO is a registered trademark of United Therapeutics Corporation.

TYVASO DPI is a trademark of United Therapeutics Corporation.

BLUHALE is a registered trademark of MannKind Corporation.

PAH-SYMPACT is a registered trademark of Actelion Pharmaceuticals Ltd société anonyme.

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