Transcript Document

Operations
 Started research operations (10 FTEs) in September 2011
 Redx Anti-Infectives launched in Alderley Park in April 2013
 Currently 55 scientists
Focus
 Antibiotics for serious, drug-resistant Gram-negative and Grampositive infections
 Antiviral therapies for indications of high unmet need (e.g.
Influenza & hepatitis B)
 Novel therapeutics targeting bacterial resistance mechanisms
GSK (1995-2001)
- 70 HTS (260,000-530,000 compounds)
- Mainly enzyme based
- 16 HTS screens gave hits
- 5 translated into leads
- 7% success rate (4-5 fold lower vs non-AB targets)
- Each screen estimated $1 million
Pfizer
- 6.5% success rate
• HTS screening sets not geared to binding AB targets
• Challenges of crossing bacterial membranes
• Lack of druggability
 Leverage Structural Based Drug Discovery
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Scaffold hopping
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Explore uncharted potential binding opportunities
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Execution of 21st century synthetic methodology
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Knowledge based SAR
Known Chemotype
- lack classic FQ COOH function
- 4 points of SAR tractable diversity
- balanced dual inhibitors
- low frequency of resistance < 10-10
- not cytotoxic (HepG2)
- low activity vs human Topo (II)
Novel Core
- target MRSA
Strain key:
S. aureus ATCC 29213: wild-type
S. aureus NRS1: GyrA S84L; GrlA S80F
S. aureus NRS482: GyrA S84L; GrlA S80Y
S. aureus CIP1-SP25*: GrlA E84G
*Ciprofloxacin-resistant mutant generated in-house
by serial passage
RedxA
 Whole-cell susceptibility data indicate that RedxA retains
potent activity against quinolone-resistant strains
 Mouse PK
- low clearance (18% LBF)
- high oral bioavailability (70%)
- oral efficacy S. aureus induced septicaemia model (50 mg/kg)
*** RedxA
*** Cipro
O
Vehicle
***P<0.0001
 No change in bodyweight or temperature
 Lead Optimisation ongoing
- key focus on ADMET
Inhibitor
RedxA
RedxB
RedxC
S. aureus
ATCC 29213 ug/mL
0.015
0.5
0.5
Free AUC/MIC
@ po 5 mg/kg
3.9
1.8
9.9
 Neutropenic murine MRSA induced thigh infection model
on going with RedxC
 Funded by Royal Liverpool & Broadgreen University Hospital Trusts
- ground breaking collaboration between industry & NHS
- complete human PoC studies
- 3 points of SAR tractable diversity
- low frequency of resistance < 10-9
- not cytotoxic (HepG2)
- low activity vs human Topo (II)
- no significant cross resistance with
FQ resistant strains
Known Chemotype
Adapted
Novel Core
Gram+ve
Organism
MIC (µg/mL)
RedxD
RedxE
RedxF
Acinetobacter baumannii NCTC 13420
32
2
0.5
Enterobacter cloacae NCTC 13406
64
8
2
Escherichia coli ATCC 25922
4
0.5
0.06
Haemophilus influenzae ATCC 49247
16
4
1
Klebsiella pneumoniae ATCC 700603
128
16
8
Pseudomonas aeruginosa ATCC 27853
>128
8
4
Staphylococcus aureus ATCC 29213
1
1
0.25
Streptococcus pneumoniae ATCC 49619
1
2
2
 Single digit activity against several of the ESKAPE pathogens
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MIC (µg/mL)
Strain
RedxD
RedxE
RedxF
Cipro
E. coli MG1655 (Wild-type)
8
0.5
0.25
0.008
E. coli MG1655 S83L
8
0.5
0.12
0.12
E. coli MG1655 D87G
16
1
0.5
0.06
15x
 No significant cross resistance with FQ resistant strains
 Extended to clinical isolates
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 Hit to lead phase
 Funded in part through European Gram Negative Antibacterial
Engine (ENABLE)
 Project infrastructure moving from an internal base to one of
working partnerships with consortium partners
- Med Chem (Redx & Upsalla); Microbiology (Upsalla) etc
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