ALX-109 potentiates the effect of inhaled antibiotics at killing Pseudomonas aeruginosa biofilms on human airway cells

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1 ALX-109 potentiates the effect of inhaled antibiotics at killing Pseudomonas aeruginosa biofilms on human airway cells Sophie Moreau-Marquis, Ph.D. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA D a r t m o u t h L u n g B i o l o g y C e n t e r

2 PRESENTER DISCLOSURE Sophie Moreau-Marquis, Ph.D. No Relationships to Disclose

3 Permanent eradication of P. aeruginosa in CF airways is currently impossible About 80% of adults with CF have chronic P. aeruginosa infection. Able to persist for several decades in the respiratory tract of CF patients in spite of intensive antibiotic therapy. Linked to the ability of P. aeruginosa to form biofilms. WS 17.2 Moreau-Marquis S. et al. (ECFS 2013)

4 Permanent eradication of P. aeruginosa in CF airways is currently impossible Intermittent inhalation of Cayston or TOBI reduces CFUs by logs but: Sputum P. aeruginosa density increases back up at the end of treatment MIC increases in some patients (resistance) WS 17.2 Moreau-Marquis S. et al. (ECFS 2013)

5 Goal Because neither TOBI nor Cayston eradicate chronic airway infections in CF, our goal is to identify new drugs that potentiates the killing effect of inhaled antibiotics and abolishes bacterial biofilms grown on CF airway epithelial cells.

6 Methods: Co-Culture Biofilm Model on Human Airway Epithelial Cells T=2h T=6h T=22h Previously, we showed that P. aeruginosa biofilms grown at the apical surface of human CF bronchial epithelial cells develop an increased resistance to killing by antibiotics (Moreau-Marquis et al., Am J Physiol Lung Cell Mol Physiol Jul;295(1):L25-37).

7 TOBRAMYCIN AZTREONAM ALX-109 PAO1 Clinical Isolates

8 ALX-109 (Alaxia, France) Composed of Lactoferrin [8 g/l] and hypothiocyanite (OSCN - ) [100 µm]. Airway levels of Lactoferrin and OSCN - are reduced in CF. A combination of both compounds was granted Orphan Drug designation by the FDA and the EMA. The final formulation is scheduled to be administered by inhalation. O S C N Lactoferrin Iron-binding glycoprotein Bacteriostatic OSCN - Bactericidal product of the Duox/LPO host defense system

9 P. aeruginosa BIOFILM PREVENTION ASSAY WS 17.2 Moreau-Marquis S. et al. (ECFS 2013)

10 P. aeruginosa BIOFILM DISRUPTION ASSAY WS 17.2 Moreau-Marquis S. et al. (ECFS 2013)

11 Additivity in Disrupting Biofilms Formed by P. aeruginosa Clinical Isolates 1,E+10 1,E+08 1,E+06 1,E+04 1,E non mucoid 1,E mucoid WS 17.2 Moreau-Marquis S. et al. (ECFS 2013)

12 Sputum concentration (µg Tb/g sputum) Tobramycin Concentration Rapidly Declines in Airway Surface Liquid Pharmacokinetics data from 2004 Prescribing Information TOBI Novartis Extrapolated

13 Dose Dependent Effect of Tb + ALX-109 on Disrupting P. aeruginosa Biofilms SMC1587 Tb Tb+ALX-109 SMC1596 SMC1595 SMC5450 mucoid

14 Conclusion ALX-109 potentiates the effect of Tobramycin and Aztreonam at disrupting P. aeruginosa biofilms by several log units. Combined treatment is efficacious against mucoid and non-mucoid clinical isolates of P. aeruginosa. Additivity between Tb and ALX-109 was observed even at very low concentrations of Tobramycin.

15 Inhalation therapy combining OSCN - /Lactoferrin with TOBI or Cayston may be beneficial to CF patients by decreasing the airway bacterial burden in patients infected with P. aeruginosa. Phase I clinical trials with an improved formulation of OSCN - /Lactoferrin are planned.

16 Acknowledgments Department of Microbiology and Immunology Philippe Bordeau Victor Juarez Perez Sandrine Perrotto Bruce Stanton Jocelyn Drexinger Roxanna Barnaby Bonnie Coutermarsh George O Toole D a r t m o u t h L u n g B i o l o g y C e n t e r