Chiesi Farmaceutici has completed a Phase I trial of its inhaled PDE-IV inhibitor, denoted CHF 6001, a new chemical entity developed for the treatment of inflammatory respiratory disorders, such as chronic obstructive pulmonary disease (COPD) and asthma.
The study was conducted to evaluate safety, tolerability and pharmacokinetics after administration of single doses (up to 2,000mcg) and repeated doses (up to 2,000mcg for seven days) to healthy volunteers. CHF 6001 was well-tolerated up to the highest doses administered, both in single- and multiple-dose parts of the study, particularly with respect to gastro-intestinal side-effects: an area which has reportedly posed significant development hurdles for other PDE-IV inhibitors in the past. No relevant safety findings, including cardiac side-effects, were observed. The long-lasting exposure in the systemic circulation supports once-a-day dosing. Based on these positive results, two Phase IIa proof-of-concept studies are ongoing in patients with asthma and COPD.
CHF 6001 is a novel selective PDE-IV inhibitor, optimised for inhaled delivery to improve efficacy and tolerability. The anti-inflammatory activity of CHF 6001 has been proven in vitro and in several animal models of airway inflammation, showing higher potency than the marketed oral PDE-IV inhibitor (roflumilast) and more targeted anti-inflammatory effects than corticosteroids in COPD models. The compound is characterised by a low oral bioavailability, inactive metabolites, high plasma protein binding, low plasma/lung concentration ratio and low brain exposure. Moreover, CHF 6001 was well-tolerated in extended preclinical safety studies and the safety margin between the anti-inflammatory action and side-effects (such as nausea and emesis) is much larger in comparison with oral and inhaled PDE-IV inhibitors developed to date.
The doses achievable in humans with most PDE-IV inhibitors are limited by side-effects, and therefore the optimal therapeutic effects of this class of drug have never been achieved. The profile of CHF 6001 indicates that it will not be under-dosed in humans to achieve an acceptable side effect profile, supporting its high potential for the treatment of COPD and asthma.