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Burkholderia (B ALX-009 A promising antimicrobial therapy for Cystic Fibrosis Non confidential presentation 08.09.2014 About Alaxia Founded in 2008, 1st Product: ALAXIA is a private biotech company based in Lyon (France) Incorporated into Stragen Group in 2011 ALX-009 OSCN-/Lactoferrin Strong scientific background in respiratory (Cystic Fibrosis, respiratory tract infections…) a promising antimicrobial Main focus: medication Development of medicinal products for the treatment of Cystic targeting respiratory diseases Fibrosis based on our Peroxidase platform Non confidential presentation 2 Presentation Overview Disease overview Scientific rationale and Mode of Action Preclinical overview (antimicrobial) Conclusion Recommended reading Non confidential presentation 3 Cystic Fibrosis The most common orphan disease in Caucasians Genetic autosomal recessive disease Prevalence: 1 / 10000 100 000 patients (EU + US) Chronic, progressive and lethal due to emergence of multiresistant bacteria Life expectancy < 35 y 2 hours of care per day Non confidential presentation 4 Physiopathology Genetic disease of the body’s mucus glands Affects the respiratory and digestive systems Implication of Cftr* gene – CFTR Protein Cftr Dysfunctional Defective Gene Airway CFTR Mutation Environment *CFTR: Cystic Fibrosis Transmembrane conductance Regulator Non confidential presentation 5 Main pathogens in Cystic Fibrosis patient lung Opportunistic bacteria Staphylococcus (S. aureus) Pseudomonas (P. aeruginosa) Burkholderia (B. cepacia complex (BCC)) Lung Mycobacterium (M. abscessus) Stenotrophomonas (S. maltophilia) Inflammation Fungi FEV1 Aspergillus (A. fumigatus) Viruses Influenza Non confidential presentation 6 Main pathogens in Cystic Fibrosis patient lungs Germs Found in the Lungs of People with CF by Age, 2012 CFF. Annual Report 2012. Non confidential presentation 7 Scientific and Medical Rationale In CF patients SCN- hypothesis Airway Surface LPO 1. Defective/absent CFTR Liquid SCN- OSCN- CF CELL - (ASL) Impaired SCN transport H2O2 Adapted from Fisher, 2009 2. Defective Lactoperoxidase system DUOX Decreased OSCN- level in lower airways CFTR 3. Decreased Lactoferrin level/activity A Ciliated cells ALX-009 (OSCN- + bLF) by inhalation ALX-009 compensates defective Thick mucus host protection against microorganisms + defective and provides to CF patients a mucociliary therapeutic option to fight lung infections. clearance Potentially breaking the vicious circle leading to lethal conditions Non confidential presentation 8 Healthy airway epithelium Bacteria 60 µm/s OSCN- Lactoperoxidase SCN- Lactoferrin MUCUS H2O2 O2 CILIA CFTR DUOX - - - - (SCN , Cl , I , HCO3 ) Mucin CILIATED BASAL GOBLET CILIATED BASAL GOBLET CELLS CELLS CELS CELLS CELLS CELS Lactoperoxidase Lactoferrin Overview of airway epithelial cells and glands SUBMUCOSAL GLANDS Non confidential presentation 9 Cystic fibrosis airway epithelium Bacteria - OSCN 0 µm/s Biofilm Lactoperoxidase Lactoferrin MUCUS H2O2 O2 CILIA SCN- DUOX CFTR CILIATED BASAL GOBLET CILIATED BASAL GOBLET CELLS CELLS CELS CELLS CELLS CELS Lactoperoxidase Lactoferrin Overview of airway epithelial cells and glands SUBMUCOSAL GLANDS Non confidential Non confidential presentation 10 ALX-009: an innovative approach OSCN- + Lactoferrin Balance defective innate host immune system Treatment of lung infection Non confidential presentation 11 ALX-009 Association of two key endogenous substances for innate immune response against infections LACTOFERRIN OSCN- Extracted from Enzymatic extemporaneous milk production Non confidential presentation 12 OSCN-: Mode of Action* NX040764341JB Oxidation of free sulfhydryl resulting in disulfide bridges Selective Detoxification Of -SH Reaction Hypothiocyanite By Mammalian HOSCN with amino acids OSCN- (Trp, His, Tyr) Thioredoxin HS- Reductase, The Missing Link In Lung Innate Immunity And Antioxidant Defense Inactivation of metabolic bacterial key enzymes Bacterial glycolysis inhibition (glyceraldehyde 3-P dehydrogenase, hexokinase…) Carlson et al. Infection and immunity. 1984, 44, 581-586 Mickelson, M. N. J. et al. Gen.Microbiol. 1966, 43, 31-43 Bacteriostatic and bactericidal effect Safe for the host Selective Detoxification Of Hypothiocyanite By Mammalian Thioredoxin Reductase, The Missing Link In Lung Innate Immunity And Antioxidant Defense Chandler et al. ATS conference 2013 . Non confidential presentation 13 * Literature data Lactoferrin: Mode of Action* IRON SEQUESTRATION MOLECULAR ANTIOXIDANT INTERACTIONS Binds heavy metals that catalyze oxidation reactions ANTIBACTERIAL (fatty acids) Deconstructs membranes ANTIBACTERIAL Binds iron essential ANTIVIRAL to bacterial growth Prevents entry of virus into host cells by binding to virus or cells receptors GLOBULAR PROTEIN ANTI-INFLAMMATORY Reduces production of EMULSIFIYING TNFα IL-1β IL-6 IL-8 LACTOFERRIN Surfactant * Literature data Non confidential presentation 14 ALX-009 Preclinical data OSCN- LACTOFERRIN Able to disrupt biofilms and to prevent its formation Effective against Gram+ and Gram- bacteria Preliminary evidence indicates that ALX-009 may have the potential to compensate and Biofilm to restart peroxidase system with OSCN- production using endogenous H O Peroxidase 2 2 OSCN- Pseudomonas H2O2 O2 CFTR Respiratory tract SCN- DUOX Airway epithelium Non confidential presentation 15 Target Unmet Medical Need in CF Burkholderia infections EMA/CHMP opinion in Orphan drug designation report interest “The product has a different antimicrobial mechanism of action compared to antibiotics. With regard to significant benefit, a very important point is that Meveol can act on Burkholderia cepacia. Authorised inhaled products target Gram negative only, excluding Burkholderia cepacia indeed. …. Burkholderia cepacia, which was used in in vitro studies in this application, is one of these bacteria” Non confidential 16 Burkholderia cepacia antibiotic sensibility Bcc is resistant to antibiotics available for CF management Susceptibilities of 66 B. cepacia strains to 11 antibiotics determined by the agar dilution method a MIC (µg/ml) % Strains ANTIBIOTIC 50% 90% Range S I R Piperacillin 32 >128 2 - >128 38 24 38 Ceftazidime 8 32 1 - >64 42 46 12 Imipenem 16 64 4 - >64 1 10 89 Meropenem 4 8 1 - 16 67 27 6 Temocillin 8 32 2 - 64 82 - 18 Sulbactam >64 >64 4 - >64 ND ND ND Ciprofloxacin 16 64 1 - >64 6 9 85 Rifampin 64 >64 32 - >64 0 0 100 TMP-SMZ 2/38 8/152 0.25/4 - >8/152 62 - 38 Minocycline 8 64 0.5 - 64 47 17 36 Tobramycin >64 >64 >64 0 0 100 Bonacorsi et al., Antimicro Agents Chemoth. 43(2):213-7. Non confidential presentation 17 Burkholderia cepacia complex in the clinic Rapid decline of lung function Cepacia Syndrome: syndrome at high risk for fatal outcome from respiratory failure Segregation of Burkholderia positive patients from other CF patients Patients are not eligible for antibiotic clinical trials Lung transplantation is compromised/not possible The aim of following study is to test the efficacy of ALX-009 on clinical Bcc strains Non confidential presentation 18 Test efficacy of ALX-009 by Checkboard method Isolates were challenged with bLF and OSCN- alone or in combination. Assays were done according to the CLSI M07-A9 guideline. Lactoferrin Checkboard to measure products interaction. OSCN ALX-009 Non confidential presentation 19 Origin of 155 isolates from CF patients tested 2% EU 13% US 23% Canada 62% South America Non confidential presentation 20 Origin of 155 isolates from CF patients tested GENOMOVAR Proportion tested in Alaxia Prevalence in CF* I 6.35 % 3 % II 30.95 % 37 % III 31.75 % 31 % IV 8.73 % <3 % V 4.76 % 5 % VI 7.14 % 3 % VII 1.59 % VIII 0.79 % <3 % IX 0 % Other Bcc strains 7.94 % *LiPuma et al., 2011 40% 30% 20% 10% 0% I II III IV V VI VII VII IX Other Non confidential presentation 21 OSCN-/bLF (ALX-009) combination is able to inhibit the growth of 100% of the 155 tested clinical isolates* bLF decreases up to 40% the concentration of OSCN- required to inhibit growth when assayed alone (MIC value) 8% of combinations were synergistic and 58% were additive *Representative of clinical Bcc species Presented Burkholderia International Working group congress – 2014 Poster CF Congress – Atlanta - 2014 22 TIME KILL CURVES Figure 4: Trend curves from mean CFU values from 14 Bcc clinical isolates, selected from their low, medium or high susceptibility to OSCN- and/or bLF. Bcc Biofilm – On going Non confidential 24 Bcc only ? Non confidential 25 Efficacy against Pseudomonas aeruginosa CFU counts of Pseudomonas aeruginosa IN VIVO TESTS After treatment or not with OSCN- / bLF infection inoculum 106 CFU Demonstration of efficacy on female mice, previously infected with mucoïd count Pseudomonas aeruginosa strain isolated CFU from CF Patients CER - Unpublished Animal received intra-tracheal ALX-009 injection treatment at 24h and 48h post infection. Bacterial counts were performed at 72h post infection Non confidential presentation 26 Efficacy against Pseudomonas aeruginosa biofilms Dartmouth Medical School 1,E+10 NH 1,E+08 Synergy with tobramycin (Tb) 1,E+06 CFU/ml 1,E+04 1595 non mucoid 1587 non mucoid 1596 non mucoid 1,E+02 5451 Mucoid 1,E+00 1585 Mucoid NACFC – Orlando 2012 5450 Mucoid Non confidential presentation 27 Wide spectrum of efficacy* Achromobacter Xylosoxidans Legionella spp Aeromonas hydrophila Listeria monocytogenes (Gram+) Bacillus brevis, Bacillus cereus (Gram+) Mycobacterium abscessus, M. smegmatis, M. tuberculosis Bacillus megaterium, Bacillus anthracis (Gram+) Neisseria spp BACTERIA Burkholderia cepacia complex Pseudomonas aeruginosa
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