Brandon Banaschewski1, Deepshikha Verma2, Lian J Pennings3, Matthew Zimmerman4, Qihua Ye2, Jake Gadawa2, Veronique Dartois4, Diane Ordway2, Jakko van Ingen3, Stefan Ufer5, Kevin Stapleton5, Thomas Hofmann5. 1. Qrumpharma, Inc, Doylestown, PA, United States of America. Electronic address: bbanaschewski@qrumpharma.com. 2. Mycobacteria Research Laboratories, Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, United States of America. 3. Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands. 4. Public Health Research Institute, New Jersey Medical School, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, NJ 07103, United States of America. 5. Qrumpharma, Inc, Doylestown, PA, United States of America.
Abstract
BACKGROUND: Nontuberculous mycobacteria are recognized as a concern for cystic fibrosis (CF) patients due to increasing disease prevalence and the potential for detrimental effects on pulmonary function and mortality. Current standard of care involves prolonged systemic antibiotics, which often leads to severe side effects and poor treatment outcomes. In this study, we investigated the tolerability and efficacy of a novel inhaled therapeutic in various mouse models of NTM disease. METHODS: We developed clofazimine inhalation suspension (CIS), a novel formulation of clofazimine developed for inhaled administration. To determine the efficacy, minimum inhibitory concentrations were evaluated in vitro, and tolerability of CIS was determined in naïve mouse models over various durations. After establishing tolerability, CIS efficacy was tested in in vivo infection models of both Mycobacterium avium and M. abscessus. Lung and plasma clofazimine levels after chronic treatments were evaluated. RESULTS: Clofazimine inhalation suspension demonstrated antimycobacterial activity in vitro, with MIC values between 0.125 and 2 μg/ml for M. avium complex and M. abscessus. Administration into naïve mice showed that CIS was well tolerated at doses up to 28 mg/kg over 28 consecutive treatments. In vivo, CIS was shown to significantly improve bacterial elimination from the lungs of both acute and chronic NTM-infected mouse models compared to negative controls and oral clofazimine administration. Clofazimine concentrations in lung tissue were approximately four times higher than the concentrations achieved by oral dosing. CONCLUSION: Clofazimine inhalation suspension is a well tolerated and effective novel therapeutic candidate for the treatment of NTM infections in mouse models.
BACKGROUND:Nontuberculous mycobacteria are recognized as a concern for cystic fibrosis (CF) patients due to increasing disease prevalence and the potential for detrimental effects on pulmonary function and mortality. Current standard of care involves prolonged systemic antibiotics, which often leads to severe side effects and poor treatment outcomes. In this study, we investigated the tolerability and efficacy of a novel inhaled therapeutic in various mouse models of NTM disease. METHODS: We developed clofazimine inhalation suspension (CIS), a novel formulation of clofazimine developed for inhaled administration. To determine the efficacy, minimum inhibitory concentrations were evaluated in vitro, and tolerability of CIS was determined in naïve mouse models over various durations. After establishing tolerability, CIS efficacy was tested in in vivo infection models of both Mycobacterium avium and M. abscessus. Lung and plasma clofazimine levels after chronic treatments were evaluated. RESULTS:Clofazimine inhalation suspension demonstrated antimycobacterial activity in vitro, with MIC values between 0.125 and 2 μg/ml for M. avium complex and M. abscessus. Administration into naïve mice showed that CIS was well tolerated at doses up to 28 mg/kg over 28 consecutive treatments. In vivo, CIS was shown to significantly improve bacterial elimination from the lungs of both acute and chronic NTM-infected mouse models compared to negative controls and oral clofazimine administration. Clofazimine concentrations in lung tissue were approximately four times higher than the concentrations achieved by oral dosing. CONCLUSION:Clofazimine inhalation suspension is a well tolerated and effective novel therapeutic candidate for the treatment of NTM infections in mouse models.
Authors: Oliver W Meldrum; Kylie B R Belchamber; Kiarina D Chichirelo-Konstantynovych; Katie L Horton; Tetyana V Konstantynovych; Merete B Long; Melissa J McDonnell; Lidia Perea; Alberto L Garcia-Basteiro; Michael R Loebinger; Raquel Duarte; Holly R Keir Journal: ERJ Open Res Date: 2022-05-23
Authors: Juan Manuel Belardinelli; Deepshikha Verma; Wei Li; Charlotte Avanzi; Crystal J Wiersma; John T Williams; Benjamin K Johnson; Matthew Zimmerman; Nicholas Whittel; Bhanupriya Angala; Han Wang; Victoria Jones; Véronique Dartois; Vinicius C N de Moura; Mercedes Gonzalez-Juarrero; Camron Pearce; Alan R Schenkel; Kenneth C Malcolm; Jerry A Nick; Susan A Charman; Timothy N C Wells; Brendan K Podell; Jonathan L Vennerstrom; Diane J Ordway; Robert B Abramovitch; Mary Jackson Journal: Sci Transl Med Date: 2022-02-23 Impact factor: 19.319
Authors: Jan-Willem Alffenaar; Anne-Grete Märtson; Scott K Heysell; Jin-Gun Cho; Asad Patanwala; Gina Burch; Hannah Y Kim; Marieke G G Sturkenboom; Anthony Byrne; Debbie Marriott; Indy Sandaradura; Simon Tiberi; Vitali Sintchencko; Shashikant Srivastava; Charles A Peloquin Journal: Clin Pharmacokinet Date: 2021-03-10 Impact factor: 6.447