Celtaxsys, Inc., a clinical stage pharmaceutical development company focused on advancing treatments for patients with rare inflammatory diseases, announced top line results of its Phase 2 EMPIRE-CF trial evaluating oral, once daily anti-inflammatory molecule, acebilustat, for the treatment of cystic fibrosis (CF), irrespective of the causative genotype.
In the 200 patient, double-blind, placebo controlled study, acebilustat demonstrated clinically meaningful improvements in pulmonary exacerbations, both reducing the frequency of pulmonary exacerbations (PEx) and increasing time to next exacerbation over 48 weeks of therapy. Full results from the trial will be presented this fall at the North American Cystic Fibrosis Foundation annual meeting.
“The trial data provide credible evidence to advance the development of this novel anti-inflammatory molecule,” said Steven M. Rowe, M.D. MSPH, professor of medicine and director of the Gregory Fleming James Cystic Fibrosis Research Center at the University of Alabama at Birmingham. “Patients in key prospectively-identified sub-groups, including those with mild obstruction at baseline or taking CFTR modulator therapy, derived the most benefit in pulmonary exacerbations. 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. This supports the unmet need to address lung inflammation adequately for the optimal treatment of patients with cystic fibrosis.”
On a per protocol assessment, acebilustat-treated patients exhibited an 19% reduction in PEx and a 22% reduced risk in progressing to first PEx versus placebo. Additionally, over 40% of patients treated with acebilustat completed the study without experiencing a PEx, an increase of 32% as compared with patients treated with placebo. The benefits of acebilustat on pulmonary exacerbations were apparent as early as four months after start of treatment and persisted throughout the 48 weeks of the study. No difference in lung function, as measured by the primary endpoint of FEV1 percent predicted (FEV1pp), was observed in acebilustat-treated patients compared to placebo-treated patients over 48 weeks of treatment. Additionally, FEV1pp response did not correlate with PEx rates.
Patients with less severe impairment of lung function (FEV1pp >75) achieved the largest benefit from acebilustat treatment, achieving 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. Furthermore, patients concomitantly treated with CFTR modulator therapy exhibited a clinically meaningful 20% reduction in PEx, a 29% increased time to first exacerbation and a 47% higher likelihood of no exacerbations compared to patients treated with CFTR modulators and placebo.
Acebilustat was well tolerated with no increased risk of infection, a key attribute for any anti-inflammatory development candidate to treat CF patients who have an increased risk of infection. The majority of adverse events were mild or moderate in severity with the most common adverse events regardless of treatment group, were infective pulmonary exacerbation, cough, nasopharyngitis, nasal congestion, headache, sputum increased, hemoptysis and fatigue. There was a low discontinuation rate from adverse events among patients treated with acebilustat, in line with patients treated with placebo.
Stuart Elborn, M.D., professor of respiratory medicine at Imperial College, director of the Adult CF Centre, Royal Brompton Hospital London and professor of respiratory medicine at Queen’s University Belfast, said, “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. It was also interesting to see that a higher proportion of acebilustat-treated patients remained exacerbation free during the study compared to placebo.
These data suggest that anti-inflammatory therapy effectiveness may be better assessed using clinical events such as pulmonary exacerbations. Pulmonary exacerbations, which are a clinical marker of unbridled lung inflammation, are significant events leading to acute decompensation and chronic decline of lung function and are strongly related to reduced survival. Given this, acebilustat has the potential to help protect patients from the progressive and irreversible damage that is associated with CF.”
Sanjeev Ahuja, M.D., chief medical officer of Celtaxsys, said, “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. We would like to thank all the patients who participated in this trial and their families who supported them. We are grateful to the study investigators and coordinators and our advisors who helped us design and execute the program. We also appreciate the scientific insights and financial support of the CF Foundation that were essential in enabling us to conduct this important study.”
Acebilustat is a once-daily oral drug candidate progressing to Phase 3 development. It is a novel small molecule inhibitor of Leukotriene A4 Hydrolase (LTA4H), the key enzyme in the production of the potent inflammatory mediator Leukotriene B4 (LTB4). LTB4 can create an over activation of neutrophil mediated immune response and inflammation and has been strongly implicated in the pathogenesis of many diseases involving excessive inflammation, including cystic fibrosis (CF). More specifically, an overactive immune response driven by neutrophils results in excessive inflammation in the CF lung. This leads to irreversible damage resulting in excessive morbidity and mortality in CF patients. Acebilustat is designed to modulate the neutrophil driven immune response bringing the inflammation to homeostasis, preventing overactive inflammation from occurring, and thus could be potentially helpful in CF patients. By contrast, pro-resolving agents theoretically tone down inflammation once it is overactive and already contributing to lung damage in patients. Furthermore, unlike immunosuppressive treatments, such as corticosteroids, acebilustat has not demonstrated any evidence of immunosuppression in preclinical studies or in clinical trials in humans, including healthy volunteers and CF patients. Acebilustat is the most advanced therapy in development in the CF anti-inflammatory pipeline.
About Cystic Fibrosis:
Cystic fibrosis (CF) is a life-threatening disease that affects the lung and digestive system of 70,000 patients worldwide. CF is caused by mutations in the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene leading to abnormal CFTR protein functioning, which causes excessively high levels of thick mucus to accumulate in the lungs, pancreas, and GI tract. Thickened mucus clogs the lungs and serves as a perfect environment to catalyze persistent bacterial infection and inflammation of the lungs. Chronic infection of the lungs in turn elicits an excessive neutrophil driven inflammatory immune response, with the overabundance of neutrophils clogging the lungs, thereby further compromising a patient’s breathing capacity. Excessive production of a neutrophil byproduct, neutrophil elastase, has been shown to be the best predictor of lung damage and dysfunction over the life of a CF patient. Excessive production of neutrophil elastase can also lead to reduced bacterial clearance. Over time, the amplification of this synergistic cycle of infection and inflammation leads to lung function decline and an increase in life-threatening pulmonary exacerbations. Lung inflammation is still the leading cause of morbidity and mortality associated with CF, leading the CF Foundation to identify development of safe and effective anti-inflammatory therapies as a key research priority.