Dry-powder Tyvaso Safe, Effective, More Convenient Than Nebulizer
Tyvaso DPI, an investigational dry powder formulation of the vasodilator treprostinil, was equally safe and effective, and more convenient than the approved Tyvaso (inhaled treprostinil) nebulizer for people with pulmonary arterial hypertension (PAH), final results of the BREEZE study show.
These findings may facilitate Tyvaso DPI’s use earlier in the disease course, according to United Therapeutics, the therapy’s developer. And because many trial participants received Tyvaso DPI doses above the current recommended dose of Tyvaso, patients may tolerate higher doses without prolonged treatment sessions.
Last year, the company applied to the U.S. Food and Drug Administration (FDA) seeking Tyvaso DPI’s approval to treat PAH and pulmonary hypertension associated with interstitial lung disease (PH-ILD). Although the agency declined to approve it due to problems at a third-party facility, the company anticipates FDA action by May.
“If approved, I believe Tyvaso DPI could represent a very exciting addition to the treatment paradigm for the PAH population,” first author Leslie Spikes, MD, associate professor of pulmonary and critical care medicine at the University of Kansas Medical Center, said in a press release.
“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,” Spikes said.
The BREEZE findings, “BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension,” were published in Pulmonary Circulation.
In PAH, narrowing of the pulmonary arteries that transport blood through the lungs causes an increase in blood pressure, forcing the heart to work harder to pump blood throughout the body. Treprostinil is a vasodilator therapy that widens these vessels and lowers blood pressure.
The medication is approved as Orenitram in an oral form, Remodulin in an injectable form, as well as Tyvaso — an inhalation formulation delivered via a handheld nebulizer.
Inhaled therapies such as Tyvaso can be time-consuming because of the prolonged preparation and maintenance of the device, and the duration of treatment. United developed a dry powder formation of treprostinil, called Tyvaso DPI, to make treatment more manageable, which may improve compliance.
The Phase 1 BREEZE study (NCT03950739) compared the safety, tolerability, and effectiveness of Tyvaso DPI in 51 PAH patients on a stable regimen of Tyvaso (six to 12 breaths four times a day) who were switched to a corresponding dose of Tyvaso DPI for three weeks.
The dry powder formulation was delivered by MannKind’s small, portable, and easy-to-use Dreamboat inhalation device, approved for use by the FDA.
Early last year, topline data showed the BREEZE study met its primary objective, demonstrating that Tyvaso DPI was safe and well tolerated, with mild to moderate side effects consistent with previous inhaled doses of treprostinil studies with PAH patients. Treatment also improved exercise capacity, reduced patient-reported symptoms, and there was a higher satisfaction with Tyvaso DPI over the nebulizer.
All the participants who completed the initial study entered an optional extension phase (OEP) and are receiving Tyvaso DPI until its completion or the therapy becomes commercially available.
Following an update of trial data at the European Respiratory Society International Congress last year, Spikes and colleagues have published the BREEZE study details. When the manuscript was completed, 17 trial participants had reached 51 weeks (nearly one year) of Tyvaso DPI use, and 39 were still in the OEP.
There were no serious side effects related to Tyvaso DPI during the three-week treatment phase, but 27 (53%) experienced mild side effects, and six (12%) reported moderate side effects. Two patients withdrew from the study due to side effects, the most commonly cited ones being cough (35%), headache (16%), and shortness of breath (8%).
In the OEP, 30 of the 49 remaining patients (61%) experienced mild side effects, 24 (49%) reported moderate side effects. Along with those found during the treatment phase, low occurrences (five or less) of joint stiffness, diarrhea, dizziness, and pneumonia, most commonly occurred during the OEP. Three participants withdrew due to side effects. No relevant findings in vital signs or laboratory or heart tests were observed.
Most patients in the OEP either maintained or increased their Tyvaso DPI dose compared to Tyvaso.
Three weeks of Tyvaso DPI treatment led to a significant 11.5 meter (38 feet) mean increase in the distance walked in six minutes. For OEP participants with data, these improvements were sustained for up to a year, with a mean longer distance of 24.4 meters (80 feet).
About the Tyvaso nebulizer before the study, 31% said they were satisfied with the treatment, and 45% gave a neutral response. With Tyvaso DPI, 96% of participants reported they were satisfied. The SYMPACT questionnaire on PAH-related symptoms and impact demonstrated significant improvements in physical and cognitive/emotional impacts.
Lastly, the body-wide exposure to nebulized Tyvaso and Tyvaso DPI was comparable. Still, there was up to three times less variability in therapeutic exposure and peak level measures for Tyvaso DPI versus Tyvaso.
“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,” Peter Smith, vice president for product development at United, said. “The optional extension phase is still ongoing, and we’ve accrued over 71 patient-years of experience with Tyvaso DPI.”
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