BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension

Abstract

Inhaled treprostinil is an approved therapy for pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease in the United States. Studies have confirmed the robust benefits and safety of nebulized inhaled treprostinil, but it requires a time investment for nebulizer preparation, maintenance, and treatment. A small, portable treprostinil dry powder inhaler has been developed for the treatment of PAH. The primary objective of this study was to evaluate the safety and tolerability of treprostinil inhalation powder (TreT) in patients currently treated with treprostinil inhalation solution. Fifty-one patients on a stable dose of treprostinil inhalation solution enrolled and transitioned to TreT at a corresponding dose. Six-minute walk distance (6MWD), device preference and satisfaction (Preference Questionnaire for Inhaled Treprostinil Devices [PQ-ITD]), PAH Symptoms and Impact (PAH-SYMPACT®) questionnaire, and systemic exposure and pharmacokinetics for up to 5 h were assessed at baseline for treprostinil inhalation solution and at Week 3 for TreT. Adverse events (AEs) were consistent with studies of inhaled treprostinil in patients with PAH, and there were no study drug-related serious AEs. Statistically significant improvements occurred in 6MWD, PQ-ITD, and PAH-SYMPACT. Forty-nine patients completed the 3-week treatment phase and all elected to participate in an optional extension phase. These results demonstrate that, in patients with PAH, transition from treprostinil inhalation solution to TreT is safe, well-tolerated, and accompanied by statistically significant improvements in key clinical assessments and patient-reported outcomes with comparable systemic exposure between the two formulations at evaluated doses (trial registration: clinicaltrials.gov identifier: NCT03950739).

Keywords: PAH‐SYMPACT; dry powder inhaler; pharmacokinetics; quality of life; treprostinil.

Figure 1

Patient disposition. AE, adverse event; OEP, optional extension phase; TreT, treprostinil inhalation powder.

Figure 2

Mean change from baseline in 6MWD (m) by visit: TreT overall. ^aRepresentative sample data were captured from study start through July 2021. Duration on therapy is dependent on the TreT start date, and the decreasing sample size over time reflects the results for those patients who completed 51 weeks of the treatment phase and OEP; it does not represent dropouts. Not all patients have had the opportunity to reach later time points out to 51 weeks at the time of data cut. The OEP is currently ongoing. 6MWD, 6‐minute walk distance; OEP, optional extension phase; TreT, treprostinil inhalation powder.

Figure 3

Summary of overall satisfaction with the TreT inhaler at Week 3.^{a a}Response to PQ‐ITD question “Overall, I am satisfied with the inhaler.” PQ‐ITD, Preference Questionnaire for Inhaled Treprostinil Devices; TreT, treprostinil inhalation powder.

Figure 4

Mean treprostinil plasma concentration versus time plots by treatment (dose pooled). Mean plasma concentrations may be less than the lower limit of quantification due to imputation of below‐the‐limit‐of‐quantification samples to 0. Each breath of treprostinil inhaled solution is equivalent to 6 μg of treprostinil. Mean plots include patients who received both treprostinil inhaled solution 72 μg (n = 18) or treprostinil inhaled solution 66 μg (n = 1) and treprostinil inhaled powder 64 μg (n = 19).