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Santhera Announces Positive Results with Lonodelestat in Early Phase Cystic Fibrosis Trial

Pratteln, Switzerland, MarchA 1, 2021 a?? Santhera Pharmaceuticals (SIX:A SANN) announces positive results from its multiple ascending dose Phase 1b study with lonodelestat, a potent inhibitor of human neutrophil elastase (hNE), in patients with cystic fibrosis (CF). Lonodelestat is a potent and selective peptide inhibitor of human neutrophil elastase (hNE), currently being developed in cystic fibrosis (CF). Neutrophil elastase is an enzyme associated with tissue inflammation, leading to degradation of the lung tissue in cystic fibrosis and several other pulmonary diseases. Data from previous Phase 1a studies demonstrated that single dose inhalation of lonodelestat can lead to high drug concentrations within sputum, resulting in effective hNE inhibition [1, 2]. The double-blind, placebo-controlled dose-escalation Phase 1b study in patients with CF assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of orally inhaled multiple daily doses of lonodelestat for up to four weeks (clinicaltrials.gov id: NCT03748199). In addition, the study investigated proof of mechanism of lonodelestat by measuring activity of hNE, an inflammatory biomarker for monitoring of disease progression in CF. Santhera acknowledges the support of the Cystic Fibrosis Foundation (CFF) by providing funding for the conduct of the Phase 1a and 1b safety trials with lonodelestat.A total of 32 patients were randomized in four cohorts of eight patients each and received lonodelestat starting with 80A mg once daily (QD), 80A mg twice daily (BID), 160A mg QD, each administered for 15 days, followed by a last cohort with 40A mg QD administered for 28 days which was chosen after observing an effect on forced expiratory volume in 1 second (FEV1) in some patients treated with the highest doses (80A mg BID and 160A mg QD). In all four cohorts and over all treatment durations, lonodelestat demonstrated a good tolerability and no serious side effects (SAEs or AEs Grade 3 or higher) were reported by the patients. Results showed a linear dose-exposure relationship over the dose range from 40A mg to 160A mg, with no accumulation in plasma or sputum. In all cohorts, a transient, near complete inhibition of elastase activity was observed after inhalation. In addition, in some patients in the 40A mg QD cohort, a constant level of near complete inhibition gradually developed over the 28 days of drug inhalation. The results from the safety analyses and the confirmed effect on the hNE biomarker by lonodelestat are very encouraging for further development in CF and other inflammatory lung diseases and have established a safe dose regimen. The findings from this study will be taken into account in the design of future studies. a??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,a?? said Marcus Mall, MD, Professor and Head of Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at the CharitA©-UniversitA¤tsmedizin Berlin. a??The landscape of treatment options for patients with cystic fibrosis has changed in the recent years with the approval of new drugs, but there is still a medical need for drugs like lonodelestat that counteract the chronic inflammation and degradation of lung tissue which contributes to pulmonary exacerbations. 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.a??
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