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A5921 - Development and Efficacy of a Novel Nebulized Antibiotic Formulation for the Treatment of Mycobacterium Abscessus Pulmonary Infections
Author Block: T. Hofmann1, B. Banaschewski1, M. Hittinger2, C. Lehr2, M. Stapleton3, D. Verma3, D. Ordway3, S. Ufer1, K. Stapleton1; 1QrumPharma, Inc, Doylestown, PA, United States, 2PharmBioTec GmbH, Saarbruecken, Germany, 3Microbiology, Immunology, Pathology, Fort Collins, CO, United States.
Background: The rate of nontuberculous mycobacterial (NTM) infections in cystic fibrosis (CF) patients is rapidly increasing, from 5% of patients presenting with positive sputum cultures for NTM bacteria in 2000 to approximately 12% of CF patients as of 2015. NTM infections in CF patients may lead to decreased pulmonary function, severe necrotizing inflammation, and bronchiectasis. Despite the increasing prevalence of infections, antibiotic therapies are protracted and poorly effective. Current standard of care involves extended courses of multiple antibiotics via oral or intravenous administration, however these treatment regimens are hampered by high rates of drug toxicity and poor efficacy. The development of new therapeutics is desperately needed. Hypothesis: The administration of a novel inhaled, nebulized therapeutic, in conjunction with current treatment regimens, will improve patient outcomes and reduce the duration of therapy. Methods: QrumPharma has developed QRM-003, a novel formulation of an oral antibiotic for inhalation therapy of NTM infections. Efficacy of QRM-003 was investigated in a mouse model of NTM infection. SCID mice were infected with Mycobacterium abscessus via intratracheal administration. Two days following infection, animals were treated every other day for 8 days with a) saline (control), b) QRM-003 (via aerosolized administration), or c) active pharmaceutical ingredient (API) via systemic administration (oral gavage). Two days following the final treatment, animals were then euthanized, and tissues were harvested to determine bacterial recovery. Results: For the mouse M. abscessus infection model, the CFU recovered from lung, spleen and liver were as follows: QRM-003 (pulmonary aerosol) (2.25±0.15, 3.09±1.4, and 4.18±1.5), and API (oral gavage) (3.58±0.10, 3.63±0.60, and 4.79±0.10). QRM-003 treatment resulted in CFU lung, spleen and liver counts that were approximately 1.33±0.02, 0.54±0.01, and 0.61±0.10 log10 CFU/ml, respectively, lower than those in mice receiving the API by gavage alone. Conclusion: QrumPharma has developed QRM-003, a novel formulation for inhalation therapy of NTM infections in CF patients. QRM-003 demonstrated potent antimycobacterial activity in vivo, as administration significantly reduced bacterial recovery in an acute M. abscessus infection model. Future Directions: Future directions include the expansion of these in vivo infection models to investigate both chronic infections, as well as infections with Mycobacterium avium. Pharmacokinetic evaluations will be performed to quantify the tissue distribution of QRM-003 compared to conventional systemic administration of the API. Selection of a commercially available nebulizer device will allow for optimal therapeutic delivery in future clinical investigations.