CHF6366 / Chiesi - LARVOL DELTA

Lung-targeted M3 antagonist-β2 agonist (MABA) dual pharmacology molecules for the inhaled treatment of respiratory diseases: Discovery strategy and pharmacological validation of the clinical candidate CHF-6366 and its back-up co (ACS-Sp 2024) - "Our approach also emphasized the importance of attaining a crystalline form as a mandatory requirement before advancing in development. Following extensive exploration, CHF-6550 emerged as the most promising candidate exhibiting the desired "soft-drug" behaviour, the required sustained in vivo efficacy and an ideal solid-state profile suitable for dry powder inhaler (DPI) development."

Clinical • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

ADME properties of CHF6366, a novel bi-functional M3-Muscarinic receptor antagonist and ß-2 adrenoceptor agonist (MABA) radiolabeled at both functional moieties. (PubMed, Xenobiotica) - "CHF6366, a dual action β-receptor agonist and M-muscarinic receptor antagonist developed for chronic obstructive pulmonary disease (COPD), was [C]-radiolabeled on the two different functional moieties of the molecule (either aminobutanolic or carbamate) to characterize its ADME profile following intravenous (IV), intratracheal (IT) and oral (PO) administration.A very low oral bioavailability and a good balance between absorption and lung retention after IT administration were observed, together with a rapid distribution throughout the body and a complete metabolic transformation of the parent drug without relevant gender difference.CHF6366 was observed fully hydrolyzed to alcohol (CHF6387) and carboxylic acid (CHF6361) in plasma and urine after IV and IT administration, and mainly unchanged in feces only after oral administration. An important number of metabolites containing aminobutanolic moiety was excreted via urine, whereas carbamate-containing derivatives were..."

Journal • Chronic Obstructive Pulmonary Disease • Immunology • Pulmonary Disease • Respiratory Diseases

Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases. (PubMed, J Med Chem) - "Our SAR studies yielded MABA 29, which demonstrated a balanced in vivo profile up to 24 h, high instability in plasma and the liver, as well as sustained exposure in the lung. In vitro safety and non-GLP toxicity studies supported the nomination of 29 (CHF-6366) as a clinical candidate, attesting to the successful development of a novel super-soft MABA compound."

Journal • Respiratory Diseases

[VIRTUAL] CHF 6366: A Novel Dual Potent Bronchodilator with Antimuscarinic and Beta-2 Agonist Activity - Results from the First-in-Human Healthy Male Volunteers Trial (ATS 2021) - "CHF 6366 was safe and well tolerated at all doses with a profile similar to placebo and negligible systemic exposure of the parent compound."

Clinical • P1 data • Asthma • Chronic Obstructive Pulmonary Disease • Immunology • Respiratory Diseases