A First In Human Randomised, Double-Blind, Placebo-Controlled Study Of Single Ascending Doses In Healthy Male Volunteers And Repeated Ascending Dose In Asthmatic Patients Followed By A 3-Way Cross-Over, Placebo-Controlled, Single-Dose In Copd Patients To Investigate The Safety, Tolerability, Pharmacokinetics And Pharmacodynamics Of CHF6366

CHF6366 is a novel bifunctional compound displaying both muscarinic receptor antagonist and β2-adrenergic receptor agonist properties (MABA), with the potential to deliver optimal bronchodilation after inhalation dosing via two validated mechanisms in one molecule.
The study will consist of three parts:
Part 1 will consit of two cohorts of healthy male subjects to assess the safety, tolerability and pharmacokinetics of Single Ascending Dose (SAD) of CHF 6366
Part 2 will consist of four cohorts of asthmatic subjects to assess the saftey, tolerability and pharmacokinetics of Multiple Ascending Dose (MAD) of CHF6366
Part 3 will consist of one cohort of COPD patients to asess safety, tolerability of a single dose of CHF6366 in an active and placebo controlled design

Start Date28 Dec 2017

Sponsor / Collaborator

CHIESI Farmaceutici SpA

100 Clinical Results associated with CHF-6366

100 Translational Medicine associated with CHF-6366

100 Patents (Medical) associated with CHF-6366

Literatures (Medical) associated with CHF-6366

01 Apr 2023·Xenobiotica; the fate of foreign compounds in biological systems

ADME properties of CHF6366, a novel bi-functional M3 muscarinic receptor antagonist and ß₂ adrenoceptor agonist (MABA) radiolabelled at both functional moieties.

Article

Author: Piutti, Claudia ; Puccini, Paola ; Cinato, Flavio ; Ghiglieri, Alberto ; Cenacchi, Valentina ; Brogin, Giandomenico ; Messina, Monica

CHF6366, a dual action β₂-receptor agonist and M3-muscarinic receptor antagonist developed for chronic obstructive pulmonary disease (COPD) was [¹⁴C]-radiolabelled on the two different functional moieties of the molecule (either aminobutanolic or carbamate) to characterise 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 hydrolysed to alcohol (CHF6387) and carboxylic acid (CHF6361) in plasma and urine after IV and IT administration, and mainly unchanged in faeces only after oral administration. An important number of metabolites containing aminobutanolic moiety was excreted via urine, whereas carbamate-containing derivatives were excreted mainly by bile.The major metabolic routes of the alcoholic moiety (CHF6387) included isomerisation (Ma7), conjugation with glucuronic acid and dehydrogenation, while the carboxylic acid moiety (CHF6361) was mainly metabolised through oxidation, glucuronide conjugation and, in both pathways, combinations of those metabolic reactions.No major differences arose also from in vitro metabolism profiles investigated using liver microsomes and hepatocytes of different species.

11 Aug 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β₂ Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases

Q1 · MEDICINE

Article

Author: Civelli, Maurizio ; Knight, Christopher K. ; Catinella, Silvia ; Accetta, Alessandro ; Rancati, Fabio ; Bassani, Franco ; Cesari, Nicola ; Linney, Ian D. ; Venturi, Luca ; Riccardi, Benedetta ; Carnini, Chiara ; Carzaniga, Laura ; Rizzi, Andrea ; Mileo, Valentina ; Murgo, Annalisa ; Biagetti, Matteo ; Puccini, Paola ; Patacchini, Riccardo ; Pastore, Fiorella ; Schmidt, Wolfgang ; Miglietta, Daniela ; Tondelli, Marina ; Villetti, Gino ; Moretti, Elisa ; Battipaglia, Loredana ; Blackaby, Wesley P. ; Delcanale, Maurizio

The development of molecules embedding two distinct pharmacophores acting as muscarinic antagonists and β₂ agonists (MABAs) promises to be an excellent opportunity to reduce formulation issues and boost efficacy through cross-talk and allosteric interactions. Herein, we report the results of our drug discovery campaign aimed at improving the therapeutic index of a previous MABA series by exploiting the super soft-drug concept. The incorporation of a metabolic liability, stable at the site of administration but undergoing rapid systemic metabolism, to generate poorly active and quickly eliminated fragments was pursued. 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.

100 Deals associated with CHF-6366

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Persistent asthma	Phase 3	United Kingdom	CHIESI Farmaceutici SpA	28 Dec 2017
Pulmonary Disease, Chronic Obstructive	Phase 3	United Kingdom	CHIESI Farmaceutici SpA	28 Dec 2017
Bronchial Spasm	Preclinical	Italy	CHIESI Farmaceutici SpA	01 Sep 2017

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ERS2017	Not Applicable	-	-	CHF6366	fxkbygccum(qjtujmwyja) = rslxuhxzfp nnfbpfwlfw (lewcnlaiyn )	-	01 Sep 2017
				Tiotropium	fxkbygccum(qjtujmwyja) = mlenkjqyyf nnfbpfwlfw (lewcnlaiyn )

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