Revefenacin improved trough FEV1 versus placebo in two phase 3 trials for COPD.
Treatment with the nebulized bronchodilator revefenacin (TD-4208) improved trough forced expiratory volume in 1 second (FEV1) on day 85 compared with placebo for patients with moderate to very severe chronic obstructive pulmonary disease (COPD), according to a pooled analysis of two phase 3 trials presentations at the 2017 ATS International Conference.1
In the pooled analysis, the long-acting muscarinic antagonist (LAMA) revefenacin improved trough FEV1 versus placebo by 118 mL (95% CI, 86-150) with the 88-µg dose and by 145 mL (95% CI, 113-178) for the larger 175 µg dose. Moreover, the cumulative incidence of adverse events (AEs) was similar between the treatment arms and placebo across the two studies, with a low incidence of antimuscarinic AEs reported.2
"Revefenacin, administered once daily via a standard jet nebulizer at doses of 88 and 175 µg to patients with moderate to very severe COPD, demonstrated clinically and statistically significant improvements in trough FEV1 relative to placebo at day 85," the authors of the study wrote in their poster. "Both dose levels of REV improved trough FEV1 over the entire treatment period."
The first phase 3 study, known as 0126, enrolled 619 patients and the second study, 0127, recruited 636 patients. Across both studies (N = 1255), patients were randomized to placebo (n = 428) or once-daily revefenacin at 88 µg (n = 425) or 175 µg (n = 402). The mean age of patients was 63.7 years and the baseline FEV1 was 1320 mL. Overall, 38% of patients continued concomitant LABA or ICS/LABA therapy.
In the 0126 study, the improvement in FEV1 versus placebo was 79 mL (95% CI, 37-121) with the 88-µg dose of revefenacin and 146 mL (95% CI, 104-189) with the 175-µg dose. The overall treatment effect (OTE) on trough FEV1 was 104 mL (95% CI, 95-113) and 156 mL (95% CI, 147-165) for the 88-µg and 175-µg doses, respectively.
Patients in the 0127 study had improvements in FEV1 versus placebo of 155 mL (95% CI, 94-190) with the 88-µg dose and 142 mL (95% CI, 94-150) with the 175-µg dose. For the 88-µg and 175-µg doses the OTE FEV1 was 117 mL (95% CI, 108-126) and 122 mL (95% CI, 112-131), respectively.
AEs were experienced by 48.3% of patients in the placebo arm and by 53.4% and 50.7% of those in the 88 µg and 175 µg groups, respectively. Serious AEs were experienced by 4.9% of those in the placebo arm and for 4.9% in the 88-µg group and 3.7% in the 175 µg groups. There was not a different in noncardiovascular deaths, myocardial infarction/unstable angina, and arrhythmias between the groups.
In addition to the two already reported phase 3 studies, a 52-week 1050-patient trial is currently ongoing to explore the two dose levels of revefenacin in comparison with tiotropium. This trial is focused on safety. Once the third phase 3 study is complete, the companies developing revefenacin, Theravance Biopharma and Mylan, plan to submit data from all three trials to the FDA, as part of a new drug application (NDA).
"We believe that these results position revefenacin favorably as a potentially key therapeutic option for COPD patients if approved, particularly as revefenacin would represent the first once-daily nebulized bronchodilator for COPD," Brett Haumann, MD, chief medical officer at Theravance Biopharma, said in a statement. "We anticipate completing the ongoing phase 3 safety trial of revefenacin in mid-2017 with the goal of filing an NDA by the end of 2017."
In addition to moderate to severe COPD, another phase 3b study is currently enrolling patients with COPD and low peak inspiratory flow rate (PIFR). This trial is comparing nebulized revefenacin with tiotropium bromide powder delivered using the HandiHaler. The primary endpoints of the trial focus on changes in lung function (NCT03095456).