In its phase 2 trial, acebilustat (CTX-4430) was found to show clinically meaningful improvement in pulmonary exacerbations in patients with cystic fibrosis.
Data from Celtaxsys, Inc.’s phase 2 EMPIRE-CF trial evaluating acebilustat (CTX-4430) for the treatment of cystic fibrosis, irrespective of the causative genotype, have been released.
The first novel, oral, once-daily anti-inflammatory molecule showed evidence of clinically meaningful improvements in pulmonary exacerbations (PEx) by both reducing the frequency of the exacerbations and increasing time to next exacerbation over 48 weeks of therapy. The findings have inspired plans for a phase 3 trial.
"The emerging standard for efficacy in the evaluation of anti-inflammatory therapy in cystic fibrosis is a reduction in pulmonary exacerbations, which are associated with disease progression,” US principal investigator for the EMPIRE-CF trial, Steven Rowe, MD, MSPH, professor of medicine and the director of the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham, told Rare Disease Report®. “While caution is needed since this was a secondary outcome measure that did not reach statistical significance, the consistent benefit observed among cystic fibrosis patients treated with acebilustat, across several pre-defined subgroups, is a compelling finding.”
For the double-blind, placebo-controlled phase 2 trial, investigators set out to evaluate the safety and tolerability of CTX-4430 administered once-daily to patients with cystic fibrosis by looking at the incidence of treatment-emergent adverse events as compared with placebo in a timeframe of 52 weeks. They also sought to assess the effectiveness of the drug as determined by the absolute change from baseline in FEV1 (forced expiratory volume 1 second) percent predicted (FEV1pp) within the same time frame.
Secondary outcome measures for the trial included evaluation of the efficacy of acebilustat administered orally once-daily as determined by the relative change from baseline in FEV1 percent predicted, the forced vital capacity (FVC) percent predicted and FEF25-75% (forced expiratory flow during the middle half of the forced vital capacity) percent predicted, the time to first pulmonary exacerbation while in the study, the number of pulmonary exacerbations, and specified biomarkers as measured in the timeframe of 52 weeks.
Depending on the treatment arm, 200 patients with cystic fibrosis were administered either 50 mg or 100 mg of acebilustat once-daily for the duration of 48 weeks.
On a per protocol assessment, patients who were administered acebilustat displayed a 19% reduction in PEx and a 22% reduced risk in progressing to first PEx versus placebo. Furthermore, over 40% of patients treated with acebilustat completed the study without experiencing a PEx, an increase of 32% as compared with patients who were treated with placebo. As early as 4 months after start of treatment, the benefits of acebilustat on pulmonary exacerbations were obvious and continued throughout the 48 weeks of the trial.
However, as measured by the primary endpoint of FEV1pp, no difference in lung function was observed in acebilustat-treated patients compared with placebo-treated patients over 48 weeks of treatment. In addition, FEV1pp response was not found to correlate with PEx rates.
The largest benefit from acebilustat treatment was achieved by patients with less severe impairment of lung function (FEV1pp >75); these patients achieved a 34% reduction in PEx rate, a 43% reduction in risk of experiencing their first exacerbation, and a 96% increased likelihood of being exacerbation-free after 48 weeks of treatment.
Additionally, a clinically meaningful 20% reduction in PEx, a 29% increased time to first exacerbation, and a 47% higher likelihood of no exacerbations were exhibited by patients concomitantly treated with CFTR modulator therapy compared with patients who were treated with CFTR modulators and placebo.
“Acebilustat, when added to the background of CFR modulatory therapy, demonstrated a reduction in exacerbations of 20% versus patents on CFR modulators alone,” president and CEO of Celtaxsys, Inc., Greg Duncan said to Rare Disease Report®. “We think that’s important because the modulators are a very important part of background therapy today, they are projected to become background therapy for the vast majority of patients in the future. The fact that we have a potential signal to demonstrate that acebilustat could reduce exacerbations by about 20% in patients already on a modulator for that incremental health benefit is a very exciting potential finding.”
Next steps for acebilustat, according to Duncan, include exploring the phase 2 EMPIRE-CF data with the Cystic Fibrosis Foundation to design a first draft for a phase 3 program. Engagement with the US Food and Drug Administration (FDA), European Medical Agency (EMA), and regulators from Canada and Australia is also anticipated in order to discuss plans with a target start date in the second half of 2019.
“While cystic fibrosis care has improved over the past decade, if acebilustat continues to exhibit clinically meaningful reductions in pulmonary exacerbations, increases time to first exacerbation, and overall achieves higher levels of exacerbation freedom, acebilustat has the potential to further contribute to the ongoing upraising of patients’ care,” Duncan added.
Full results from the phase 2 EMPIRE-CF trial will be presented this fall at the North American Cystic Fibrosis Foundation annual meeting.