Methods of treating mycobacterial infections using tetracycline compounds
Inventors
Cynamon, Michael Henry • DRAPER, MICHAEL P. • Steenbergen, Judith N. • Tanaka, S. Ken
Assignees
Paratek Pharmaceuticals Inc • US Department of Veterans Affairs
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Publication Number
US-12161655-B2
Publication Date
2024-12-10
Expiration Date
2039-09-03
Abstract
The present invention provides methods of treating mycobacterial infections or mycobacterial diseases by administering a tetracycline compound, e.g., omadacycline, or a pharmaceutically acceptable salt thereof.
Core Innovation
The invention provides methods of treating or preventing mycobacterial infections or mycobacterial diseases by administering a tetracycline compound, specifically omadacycline or its pharmaceutically acceptable salts, esters or prodrugs. Omadacycline, a 9-aminomethyl tetracycline derivative, has been found to be particularly effective against mycobacterial species, including non-tuberculous mycobacteria such as Mycobacterium abscessus, Mycobacterium chelonae, and Mycobacterium fortuitum, and against Bacille Calmette Guerin (BCG), an attenuated Mycobacterium bovis species closely related to Mycobacterium tuberculosis.
Mycobacterial infections are challenging to treat due to the unique, thick, hydrophobic, and waxy cell wall of mycobacteria, which contributes to persistence and resistance. Current treatments involve long durations and combinations of antibiotics, and existing tetracycline compounds like tigecycline, while active, have limited clinical use due to adverse gastrointestinal effects and intravenous-only administration. The invention solves the problem of limited therapeutic options for mycobacterial infections by introducing omadacycline which achieves higher concentrations in the lungs, including epithelial lining fluid and alveolar cells, the common sites of mycobacterial infection, and is associated with fewer side effects and oral bioavailability.
Furthermore, omadacycline may be administered once or twice daily, including orally, and penetrates infected tissues and cells effectively, including macrophages that harbor mycobacteria. This property favors targeted delivery to infection sites such as granulomas. The invention also encompasses methods of administration in combination with other anti-mycobacterial agents and various dosing regimens enabling prolonged treatment periods necessary for mycobacterial diseases.
Claims Coverage
The claims focus on methods of treating or preventing mycobacterial infections and diseases by administering omadacycline or its pharmaceutically acceptable salts or esters, covering various mycobacterial species and treatment modalities.
Use of omadacycline for mycobacterial infections and diseases
Methods comprising administering an effective amount of omadacycline, or its pharmaceutically acceptable salt or ester, to treat or prevent mycobacterial infections or diseases in a subject.
Treatment targeting slow-growing mycobacteria
Treatment of infections caused by slow-growing mycobacteria belonging to Terrae clade, Triviale clade, Tuberculosis-Simiae clade, or Mycobacterium tuberculosis complex (MTBC).
Treatment targeting rapid-growing mycobacteria
Treatment of infections caused by rapid-growing mycobacteria, specifically nontuberculous mycobacteria within Abscessus-Chelonae or Fortuitum-Vaccae clades, including species such as M. abscessus, M. chelonae, and M. fortuitum.
Treatment of infections at diverse sites
Methods for treating mycobacterial infections located in lung, lymph nodes, osteoarticular sites, skin, soft tissues, or involving foreign objects such as medical devices, implants, or tattoo inks.
Administration as monotherapy or combination therapy
Omadacycline may be administered alone or in combination with additional anti-mycobacterial agents including diarylquinolones, rifapentine, nitroimidazoles, macrolides, aminoglycosides, fluoroquinolones, linezolid, and others.
The claims comprehensively cover methods using omadacycline for treating or preventing a wide range of mycobacterial infections and diseases, targeting various mycobacterial species, infection sites, and dosing regimens including monotherapy and combination therapy.
Stated Advantages
Omadacycline has promising activity against multiple mycobacterial species including non-tuberculous mycobacteria and Mycobacterium tuberculosis complex.
Omadacycline achieves higher concentrations in the lungs, especially in epithelial lining fluid and alveolar macrophages, important sites for mycobacterial infections.
Omadacycline can be administered orally and is associated with fewer gastrointestinal side effects such as nausea and vomiting, improving tolerability over tigecycline.
The drug's pharmacokinetic properties support prolonged administration necessary for treating mycobacterial infections requiring extended therapy.
Documented Applications
Treatment or prevention of mycobacterial infections caused by species of Mycobacterium, including tuberculosis and nontuberculous mycobacterial diseases.
Treatment or prevention of specifically named mycobacterial diseases such as tuberculosis, leprosy, bronchiectasis, cavitary lung disease, lymphadenitis, soft tissue infections, aquarium granuloma, Buruli ulcer, and eye and bone diseases.
Treatment of infections localized in the lungs, lymph nodes, joints, bones, skin, or soft tissues, including infections involving foreign objects like medical devices, implants, and tattoo inks.
Treatment of subjects with lung diseases including cystic fibrosis, chronic obstructive pulmonary disease, occupational lung diseases, primary ciliary dyskinesia, allergic bronchopulmonary aspergillosis, alpha 1 antitrypsin deficiency, pneumoconiosis, interstitial lung disease, chronic aspiration syndrome, and pulmonary alveolar proteinosis.
Treatment of immunocompromised or immunosuppressed subjects, including those with HIV/AIDS, post organ transplant, on immunosuppressive or anti-cancer therapy, or having genetic immunodeficiencies.
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