Theravance Biopharma and Mylan today announced that positive new data from multiple studies of YUPELRI™ (revefenacin) inhalation solution were presented at the 2018 CHEST annual meeting, which was held in San Antonio, Texas on October 6-10, 2018. YUPELRI is an investigational long-acting muscarinic antagonist (LAMA) currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of chronic obstructive pulmonary disease (COPD). The Prescription Drug User Fee Act (PDUFA) date for YUPELRI is November 13, 2018. If approved, YUPELRI would be the first and only once-daily, long-acting nebulized bronchodilator for the treatment of COPD. YUPELRI is designed to be compatible with any standard jet nebulizer.
Details from the three CHEST presentations are as follows:
Efficacy in COPD Patients with Suboptimal PIFR – YUPELRI vs. Tiotropium
Researchers presented new data from a randomized, double-blinded study comparing the efficacy of YUPELRI to tiotropium in patients with moderate to very severe COPD and suboptimal peak inspiratory flow rates (PIFR) (< 60 L/min). 207 subjects were enrolled and randomized to receive either YUPELRI (175 mcg once daily) or tiotropium once daily for 28 days. Efficacy assessments included forced expiratory volume in one second (FEV1) and forced vital capacity (FVC).
In the intent-to-treat population, the YUPELRI group showed improvements in trough FEV1 and trough FVC on day 29 compared with tiotropium group; however, these differences did not reach statistical significance. In the prespecified analysis of subjects with severe to very severe COPD (FEV1 < 50% predicted), which represented approximately 80% of the study population, YUPELRI demonstrated statistically significant improvements in trough FEV1 (p = 0.025) and FVC (p = 0.034) as compared to tiotropium. No new adverse events (AEs) were noted for either YUPELRI or tiotropium, and there were numerically fewer AEs observed in patients receiving YUPELRI (11.7%) compared to patients receiving tiotropium (37.5%).
“These results are noteworthy as this represents the first head-to-head study conducted between tiotropium dry powder via Handihaler and a nebulized treatment, such as YUPELRI. Furthermore, by focusing on COPD patients with suboptimal PIFR, the study provides important context around a patient group believed to be well positioned to benefit from once-daily, long-acting nebulized therapy,” said Donald A. Mahler, M.D., emeritus professor of medicine at the Geisel School of Medicine at Dartmouth College and lead author of the study. “The statistically significant improvements in trough FEV1 and FVC shown for YUPELRI as compared to tiotropium in the severe to very severe subpopulation of patients with FEV1 < 50% predicted suggest that these individuals may be best suited for nebulized therapy. Further confirmation incorporating the learnings from this study is recommended.”
Efficacy in COPD Patients with Markers of More Severe Disease – Phase 3 Program Data Analysis
Researchers presented prespecified analyses of data from the YUPELRI Phase 3 program, highlighted by the demonstration of efficacy advantages for YUPELRI dosed at 175 mcg once daily compared to YUPELRI dosed at 88 mcg once daily in four subgroups of patients categorized as being at risk of COPD exacerbations based on markers of more severe COPD. The subgroups included patients on concomitant long-acting beta agonists (LABA), patients on inhaled corticosteroids (ICS), elderly patients (aged > 65 years in the 12-week efficacy trials, aged ≥ 65 in the 12-month safety trial) and patients classified as Global Initiative for Chronic Obstructive Lung Disease Category D (GOLD D).
Pooled data from the two replicate 12-week pivotal Phase 3 efficacy trials demonstrated that YUPELRI dosed at 175 mcg once daily produced greater improvements in trough FEV1 than YUPELRI dosed at 88 mcg once daily in each of the four analyzed subgroups. These efficacy trends favoring the 175 mcg once daily dose in the subgroups are consistent with those reported for the entire intent-to-treat population in the two Phase 3 efficacy trials.
Additionally, data from the 12-month Phase 3 safety trial demonstrated that YUPELRI dosed at 175 mcg once daily produced greater improvements in trough FEV1 than YUPELRI dosed at 88 mcg once daily in the LABA subgroup. The YUPELRI doses were equally effective at improving trough FEV1 in the ICS and elderly subgroups in the 12-month safety study.
Cardiovascular Safety: Review of Randomized, Controlled Trial Data, Including Phase 3 Program
Researchers conducted a review of cardiovascular (CV) safety data from four clinical studies of YUPELRI including the two replicate 12-week pivotal Phase 3 efficacy trials, the 12-month Phase 3 safety trial and a Phase 1 QT study in healthy subjects. The data analysis demonstrated that once-daily YUPELRI dosed for up to 52 weeks did not prolong QT interval or increase risk of major adverse cardiac events (MACE). Detailed findings include:
