United Therapeutics Presents Tyvaso DPI? BREEZE Clinical Data At The European Respiratory Society International Congress 2021
In subjects with PAH, transition from Tyvaso? to Tyvaso DPI? demonstrated safety and tolerance with significant improvements in six-minute walk distance, device preference and satisfaction, and patient reported outcomes
FDA action on New Drug Application for Tyvaso DPI expected in October 2021
SILVER SPRING, Md. and RESEARCH TRIANGLE PARK, N.C., Sept.?7, 2021 /PRNewswire/ --?United Therapeutics Corporation (Nasdaq: UTHR) today presented new clinical data from the?BREEZE?study evaluating Tyvaso DPI? (treprostinil) in patients with pulmonary arterial hypertension (PAH) at the European Respiratory Society (ERS) International Congress 2021.
Tyvaso DPI is a next-generation dry powder formulation of Tyvaso??(treprostinil) Inhalation Solution (Tyvaso), which is currently under 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.
"The transition from nebulized Tyvaso to Tyvaso DPI demonstrated safety and tolerance with significant improvements in six-minute walk distance and other key factors," said Leslie Spikes, M.D., Associate Professor of Pulmonary and Critical Care Medicine at the University of Kansas Medical Center. "The results of the study, even when taken into the context of the unblinded study design, indicate that Tyvaso DPI is a convenient, tolerable treprostinil formulation that could increase prostacyclin accessibility, with the potential to improve patient outcomes."
"At United Therapeutics, we continue to strive to make treprostinil therapy more accessible for our pulmonary hypertension patients," said Peter Smith, PharmD, Vice President, Product Development at United Therapeutics. "As such, we are thrilled to share the?BREEZE?study data demonstrating the safety and tolerability of treprostinil administered as Tyvaso DPI, which, if approved by the FDA, could represent a more convenient formulation of inhaled treprostinil."
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. Top line data showing the BREEZE study met its primary objective were?released?in January 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.
- 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.
- 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%).
- 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.
- 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.
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SOURCE United Therapeutics Corporation