Topline data from a Phase 2b trial showed that the investigative therapy acebilustat taken once daily can reduce the number and frequency of pulmonary exacerbations in patients with cystic fibrosis (CF). It did not, however, seem to affect patients’ overall lung function.
Pulmonary exacerbations — temporary worsening of lung function — are caused by uncontrolled lung inflammation, and these acute episodes can lead to the chronic decline of lung function and a shortened lifespan.
Acebilustat is an inhibitor of an enzyme involved in the production of leukotriene B4 (LTB4), a potent signaling molecule that promotes inflammation. The investigational therapy was developed by Celtaxsys to reduce inflammation that contributes to the development and worsening of diseases such as CF.
In the EMPIRE-CF trial (NCT02443688), 200 CF patients from clinical centers across the United States and Europe were given either a placebo or one of two oral doses of acebilustat — 50 mg or 100 mg — once a day for 48 weeks.
Global assessment showed acebilustat reduced the rate of pulmonary exacerbations by 19%, regardless of their genetic mutation causing CF. Treatment with the investigational therapy reduced by 22% the risk of a first acute episode compared to placebo.
More than 40% of acebilustat-treated patients completed the study without having a pulmonary exacerbation; only 8% of those taking a placebo did.
The impact of this new therapy for pulmonary exacerbations was noted as soon as four months after treatment began, and sustained throughout the study’s duration.
Acebilustat did not have an impact on a patient’s lung function, as determined by forced expiratory volume in 1 second percent predicted (FEV1pp) — the volume of air that can be forced out in one second after taking a deep breath — as compared to placebo. In addition, FEV1pp was not found to be correlated with pulmonary exacerbation rates.
“I am encouraged by the data from this trial showing that acebilustat-treated patients had reduced frequency of pulmonary exacerbations, particularly as we recruited patients who had exacerbations in the year prior to study entry and therefore at high risk of new exacerbations,” Stuart Elborn, MD, professor of respiratory medicine at Imperial College and at Queen’s University Belfast, said in a press release.
“Acebilustat has the potential to help protect patients from the progressive and irreversible damage that is associated with CF,” said Elborn, who is also director of the Adult CF Centre, Royal Brompton Hospital London.
Patients with less severe impairment of lung function (those with FEV1pp above 75) benefited the most from treatment with acebilustat. They experienced a 34% reduction in pulmonary exacerbation rate, a 43% reduction in the risk of experiencing their first exacerbation, and a 96% increased likelihood of being exacerbation-free during the trial.
In addition, patients who at the same time received a CFTR modulator therapy (CFTR is the gene that’s defective in CF patients) also had a clinically meaningful 20% reduction in pulmonary exacerbations, a 29% prolonged time to first exacerbation, and were 47% more likely to be exacerbation-free compared to patients treated with CFTR modulators alone.
“That benefit, when used in combination with a CFTR modulator, is an important consideration given the likelihood of an increase in the number of CF patients who are eligible to be treated with new CFTR modulators over the coming years,” said Steven M. Rowe, MD, MSPH, professor of medicine and director of the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham.
“This supports the unmet need to address lung inflammation adequately for the optimal treatment of patients with cystic fibrosis,” Rowe said.
The experimental therapy was well-tolerated and was not associated with an increased risk of infection, a common effect among anti-inflammatory therapies in CF patients.
Most of the adverse events reported in all patient groups were mild or moderate, the most common being infective pulmonary exacerbation, cough, irritation of the upper airways (nasopharyngitis), nasal congestion, headache, sputum increase, release of pulmonary mucus with blood, and fatigue.
Celtaxsys will present the full results of the trial at the North American Cystic Fibrosis Foundation annual meeting set for Oct. 18-20 in Denver.
“Acebilustat is notably the first novel anti-inflammatory molecule to prospectively demonstrate benefits in both reducing the frequency of pulmonary exacerbations and prolonging time to first exacerbation, when added to a CF patient’s existing treatment regimen in a clinical trial,” said Sanjeev Ahuja, MD, chief medical officer of Celtaxsys.
The U.S. Food and Drug Administration and the European Medicines Agency have granted acebilustat orphan drug status, a designation expected to support and expedite its clinical development and regulatory approval.