United to seek FDA approval of Tyvaso after successful Phase 3 trials
Therapy outperformed placebo at slowing lung function decline in IPF patients
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Two Phase 3 clinical trials testing Tyvaso (treprostinil) in people with idiopathic pulmonary fibrosis (IPF) both met their main goals, showing that the inhalation therapy significantly outperformed a placebo at slowing the decline in lung function among IPF patients.
With these data in hand, Tyvaso’s developer, United Therapeutics, is planning to ask the U.S. Food and Drug Administration (FDA) this summer to approve Tyvaso as a treatment for IPF.
“The profound impact of the TETON clinical program in IPF, with combined results showing significantly improved preservation of lung function and quality of life, as well as reductions in disease worsening and acute IPF exacerbations, represents a truly important advancement for people living with this progressive, life-threatening disease,” Martine Rothblatt, PhD, United’s chairperson and CEO, said in a company press release.
Positive results from TETON 2 (NCT05255991) were announced last year. Now results from another trial, TETON 1 (NCT04708782), have been published in The New England Journal of Medicine, in a paper titled “Phase 3 Trials of Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis.” The study, funded by United, also includes pooled analyses of both Phase 3 studies.
Tyvaso FDA-approved to treat certain forms of pulmonary hypertension
IPF is characterized by fibrosis (scarring) of the lungs, leading to progressive worsening of lung function over time. Tyvaso works by mimicking the activity of prostacyclin, a naturally occurring signaling molecule that helps regulate blood pressure. The inhaled therapy is currently FDA-approved to treat certain forms of pulmonary hypertension, where blood pressure in the lungs’ vessels is abnormally high.
“Nebulized Tyvaso combines direct lung delivery with multimodal activity across fibrotic, vascular, and inflammatory pathways that are not currently addressed by existing IPF therapies. The unprecedented results of our TETON clinical program — in which nebulized Tyvaso achieved statistical significance in endpoints [outcome measures] never before attained in other IPF clinical trials — support the importance of this differentiated, multi-pathway activity,” said Peter Smith, senior vice president of product development at United and lead for the global TETON program.
The TETON 1 study enrolled nearly 600 adults with IPF, many of whom were already taking the approved therapies Ofev (nintedanib) and/or pirfenidone (sold as Esbriet and generics). Participants were randomly assigned to take Tyvaso or the placebo (target dose of 12 breaths four times daily) for 52 weeks, or about one year.
The study’s main goal was to determine whether Tyvaso would slow the decline in forced vital capacity (FVC), a standard measure of lung function that assesses how much air someone can forcefully exhale. In patients given the placebo, median FVC declined (worsened) by 196.2 mL over the course of a year. By comparison, in patients given Tyvaso, the median FVC decline was only 43.3 mL, representing a statistically significant difference.
Rates of clinical worsening events — a composite measure that included death, hospitalization due to lung problems, or a decline of at least 10% in percent predicted FVC — were also significantly lower with Tyvaso than with the placebo (31.8% vs. 44.5%).
The results were broadly consistent across subgroups, irrespective of factors including background treatment, use of supplemental oxygen, and smoking status.
Pooled analysis showed Tyvaso reduced clinical worsening risk by 31%
The TETON 2 study also showed that Tyvaso outperformed the placebo in slowing the decline in FVC and reducing the risk of clinical worsening events. In a pooled analysis of nearly 1,200 patients across both trials, the median FVC decline was 45.4 mL in patients given Tyvaso, compared with 161.7 mL in those given the placebo. The pooled analysis also showed Tyvaso reduced the risk of clinical worsening by 31%, and reduced the risk of IPF exacerbation (disease flares in which lung function suddenly worsens) by 48%.
Further, the pooled analysis showed that Tyvaso led to improvements in other outcomes, including the King’s Brief Interstitial Lung Disease questionnaire, a health-related quality-of-life measure tailored for people with lung disease. In fact, statistically significant differences favoring Tyvaso over the placebo were observed for all trial endpoints except the risk of death, which was generally lower with Tyvaso but did not reach statistical significance.
“The combined analysis provides an incredibly powerful dataset with both studies complementing each other well,” said Steven D. Nathan, MD, chair of the TETON Steering Committee and medical director of the advanced lung disease and lung transplant program at Inova Fairfax Hospital in Virginia. “The meaningful effect on FVC decline observed across all subgroups, as well as achieving positive results for five out of six secondary endpoints in the combined analysis, is truly impressive for a 52-week treatment duration. These findings have the potential to fundamentally impact how we target IPF and manage patients living with this devastating disease.”
Across both TETON trials, most safety-related issues were nonserious, with cough and headache being the most common. Of note, more than a third of patients receiving Tyvaso discontinued treatment during the study, mainly due to cough or other side effects.
