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Clostridium Difficile Bringing True Novelty to Anti-Infective Treatment New Class of Antibacterials Based on a Completely New Mechanism of Action BioTrinity London 11th-13th May 2015 MGB Biopharma – Delivering True Novelty • Founded in April 2010 – HQ in Glasgow, Scotland - and funded by an Angel syndicate and the Scottish Co-Investment Fund • Developing a truly novel class of drugs against infectious diseases based on the University of Strathclyde’s DNA Minor Groove Binder (MGB) Platform Technology • This platform provides an opportunity to develop various compounds against bacteria, viruses, fungi and parasites with a completely new mode of action which is distinct from the antimicrobial drugs used in clinical practice today • MGB-BP-3 is the first compound from this platform, with strong activity against Gram-positive pathogens. Currently in clinical phase I study 2 MGB-BP-3 IV formulation for systemic Gram-positive infections 3 MGB-BP-3 intravenous formulation • Under development for the treatment of hospital acquired systemic Gram-positive infections (susceptible and resistant Staphylococcus, Streptococcus and Enterococcus) • MGB-BP-3 lyophilised as a succinic salt • Reconstituted with WFI or 5% dextrose • Manufacturing optimisation and up-scaling successfully completed • Acute tolerability study in mouse confirmed MTD of 100mg/kg (anticipated human dose 7-15mg/kg) • Pharmacokinetic profile supports bolus and continuous intravenous administration • Good in vivo activity confirmed in mouse infection models • ADME ongoing • Nonclinical safety studies started 4 MGB-BP-3 intravenous - Technical Batch • Technical batch manufacture of a lyophilised product is complete • Final formulation is 25mg/mL MGB-BP-3 in 25mg/mL mannitol/0.2 M succinic acid • T=1M stability data available shortly • No issues or concerns with any preliminary data so far • Lyophilised product is ready for use in Project 2 – in vivo POC models 5 Human Plasma Compatibility Study 6 Intravenous Set Compatibility Study • Syringes (Polyethylene, 10mL & 30mL, supplied by HMR London) – There was no significant change to the appearance or pH at ambient, 2-8°C or controlled ambient – After 8 hours storage recovery was ≥100% – No significant increase to the total number of related substances at any of the storage conditions – 25 mg/mL MGB-BP-3 is considered stable when stored in syringes for up to 8 hours at ambient, controlled ambient and 2 - 8°C • Infusion Bags (Ethyl vinyl acetate, supplied by HMR London) – No significant change to the appearance or pH after 24 hours storage at ambient conditions, exposed to light – After 24 hours storage at ambient conditions recovery of 101% was recorded. – No significant increase to the total number of related substances was recorded after 24 hours storage at ambient conditions – 5 mg/mL MGB-BP-3 in 5% dextrose is stable when stored in infusion bags at ambient conditions for up to 24 hours • Infusion Lines (polyethylene clear and amber, supplied by HMR London) – There was no loss of active material for either tubing type with all assay results comparable (98.0 - 102.0%) to that of the bulk solution – There was no change in purity profile for either tubing type 7 Pharmacokinetic Profile of MGB-BP-3 8 PK – tolerability mouse study Mice were dosed at: 30mg/kg, 60mg/kg and 100mg/kg. - 30mg/kg and 60mg/kg were tolerated when administered over a 2 minute period - 100mg/kg was tolerated when administered over a 3 minute period Dose t AUC AUC AUC CL Vz Group C (ng/mL) max 0-t 0-∞ ex t (h) (mg/kg) max (h) (h*ng/mL) (h*ng/mL) (%) 1/2 (mL/min/kg) (mL/kg) 1 30 76300 0.017 22200 22700 2.5 10 22.0 19900 2 60 90400 0.017 29900 31100 3.7 11 32.2 31300 3 100 110000 0.033 46100 48400 4.9 11 34.4 32400 9 PK Mouse Study Time-concentration curve (MGB-BP-3 100 mg/kg) 1000000 Solubility threshold 100000 10000 Therapeutic window 1000 y = 3177.6x-1.018 R² = 0.9906 3 plasma concentration(ng/mL) - 100 BP - MGB 10 1 0.00 5.00 10.00 15.00 20.00 25.00 30.00 Time (h) 10 PK profile in mouse • Time-concentration profiles of five single MGB-BP-3 doses administered intravenously over 1 minute were assessed in mouse. • No mortality was observed. The highest doses provoked some discomfort in the animals, which was prevented on predosing with paracetamol. • This PK profile was used for the PK/PD modelling Therapeutic window 11 Mouse PK profile – compartmental analysis 70 exp 60 model 50 Compartment model fit of conc- 40 time data for 100 mg/kg dose (total 30 20 conc) with i.v. injection time T = 1.0 Concentration in serum(mg/L) 10 minute. 0 0 1 2 3 4 5 6 Time (hour) Compartmental analysis showed that MGB-BP-3 fits a two- exp mean +/- SEM model compartment model with a fast 10 distribution phase and slow elimination phase. 1 Concentration Concentration in serum(mg/L) 0.1 0 6 12 18 24 Time (hour) 12 MGB-BP-3 - Assessment of in vivo activity 13 MGB-BP-3 - Assessment of in vivo activity The following studies were performed in order to profile MGB-BP-3 in vivo activity: 1. Assessment of MIC for the tested pathogens 2. Single dose mouse thigh model with: o Streptococcus pyogenes o Streptococcus pneumoniae o Staphylococcus aureus (MRSA) 3. Fractionated dose mouse thigh model with: o Streptococcus pneumoniae o Staphylococcus aureus (MRSA) 4. Mathematical PK/PD modelling 5. Efficacy assessment in mouse pneumonia model with: o Streptococcus pneumoniae 14 Activity of single MGB-BP-3 doses against S. pyogenes in the thigh mouse model 15 Activity of single MGB-BP-3 doses against S. pneumoniae in the thigh mouse model 16 Activity of single MGB-BP-3 doses against MRSA in the thigh mouse model 17 Project 2 MGB-BP-3 in mouse thigh infection fractionated dosing model with S. pneumoniae MGB-BP-3 against S.pneumoniae was investigated following i.v administration of single and multiple dosing ranging from 20 - 100 mg/kg. The colony counts in the thighs were determined at 24 hrs after start of treatment. Dosing (h) E ffic a c y o f M G B -B P -3 in th e n e u tro p e n ic MGB-BP-3 T=1 T=7 T=13 T=19 th ig h in fe c tio n m o d e l a g a in s t S .p n e u m o n ia e D 3 9 None X 9 Vehicle X X X 8 X X X X 20 mg/kg h g i 7 20 mg/kg X X h t / 6 20 mg/kg X U F 5 C 40 mg/kg X X X X g 4 o 40 mg/kg X L 3 60 mg/kg X X X X 2 60 mg/kg X t 4 2 1 4 1 4 1 2 1 1 m n e x x x x x x x x x x 80 mg/kg X X u e l l ic g g g g g g g g g g u tm h /k /k /k /k /k /k /k /k /k /k c e X o a g g g g g g g g g g 80 mg/kg n e V m I tr m m m m m m m m m f 0 0 0 0 0 0 0 0 0 0 o 2 2 2 4 4 6 6 8 8 0 X t 1 100 mg/kg r ta s 18 Project 2 MGB-BP-3 in mouse thigh infection fractionated dosing model with MRSA MGB-BP-3 against MRSA was investigated following i.v administration of single and multiple dosing ranging from 20 - 100 mg/kg. The colony counts in the thighs were determined at 24 hrs after start of treatment. Dosing (h) E ffic a c y o f M G B -B P -3 in th e th ig h MGB-BP-3 T=1 T=7 T=13 T=19 in fe c tio n m o d e l a g a in s t M R S A 4 3 4 8 4 None X 9 Vehicle X X X 8 20 mg/kg X X X X h g i 7 h X X t 20 mg/kg / U 6 20 mg/kg X F C 40 mg/kg X X X X g 5 o 40 mg/kg X L 4 60 mg/kg X X X X 3 60 mg/kg X t 4 2 1 4 1 4 1 2 1 1 m n e x x x x x x x x x x u e l 80 mg/kg X X l ic g g g g g g g g g g u tm h /k /k /k /k /k /k /k /k /k /k c e o a g g g g g g g g g g n e V m 80 mg/kg X I tr m m m m m m m m m f 0 0 0 0 0 0 0 0 0 0 o 2 2 2 4 4 6 6 8 8 0 t 1 100 mg/kg X r ta s 19 Project 2 MGB-BP-3 in mouse pneumonia infection disease model with S. pneumoniae • Mice were inoculated intranasally and treatment initiated 4h after inoculation. • Mice were treated intravenously with MGB-BP-3, vehicle or vancomycin as a positive control.
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