Lonodelestat Safely Blocks Inflammatory Marker in CF Patients in Early Trial

Lonodelestat (also known as POL6014), Santhera Pharmaceuticals’ investigational therapy to treat chronic lung inflammation, was safe and effective at blocking the activity of a pro-inflammatory biomarker in patients with cystic fibrosis (CF), according to data from a Phase 1b trial.

“We are very much encouraged by the trial results which support the hypothesis that lonodelestat may possess properties to counteract underlying inflammatory processes and which indicate treatment was well tolerated in patients with CF,” Dario Eklund, Santhera’s CEO, said in a press release.

Lonodelestat is a potent, selective inhibitor of human neutrophil elastase (hNE), a pro-inflammatory enzyme normally released by immune cells known as neutrophils. It is being developed by Santhera to treat lung inflammation associated with CF.

Under normal conditions, neutrophils release hNE to digest damaged cells and to prevent infections from spreading. In CF patients, however, neutrophils release excessive amounts of this enzyme, causing additional inflammation and tissue damage that progressively diminishes lung function.

In earlier Phase 1 studies, a single dose of the therapy was found to be safe and effective at inhibiting hNE in healthy volunteers and in CF patients.

The Phase 1b trial (NCT03748199), which concluded in December, evaluated the safety, tolerability, and pharmacological properties of orally inhaled lonodelestat in adults with CF.

It enrolled 40 patients, who were randomly divided into four groups, and given either a placebo or multiple ascending doses of lonodelestat for up to a month. In total, 32 patients were assigned to treatment.

Lonodelestat use started at a dose of 80 mg once daily in a first patient group, a second group of eight patients were treated at 80 mg twice daily, and a third group with 160 mg once daily; all were treated for about two weeks (15 days). Then, after evaluating lung health in the second and third patient groups, a final group of eight inhaled 40 mg of lonodelestat once daily for 28 days.

Lonodelestat was well-tolerated across all groups, regardless of dosing or treatment duration, the company reported. No serious side effects were observed.

“This study provides promising data on the safety of lonodelestat and its potential to inhibit elastase in cystic fibrosis and maybe other chronic inflammatory conditions of the lung where neutrophils play a prominent role in the disease process,” said Marcus Mall, MD, a professor and head of the department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at the Charité-Universitätsmedizin Berlin.

After inhalation, hNE activity was temporarily and nearly completely blocked in all treatment groups. Some patients in the 40 mg lonodelestat group gradually developed a constant level of near total hNE inhibition over their 28 days of treatment.

“This demonstrates for the first time that complete inhibition of neutrophil elastase can be achieved over a prolonged treatment duration by local delivery through inhalation,” Eklund said, adding that Santhera plans to advance lonodelestat in clinical testing in CF patients.

Lonodelestat has been designated an orphan drug in Europe for the treatment of CF, and was similarly recognized as a potential treatment of other pulmonary diseases in both the U.S. and Europe. Orphan drug status supports the development of promising treatments for rare diseases.

“Lonodelestat may add a new treatment modality for CF patients and I am very excited about the future development of lonodelestat and the next study,” Mall said.