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Anti-infective drug discovery at Evotec
Evotec, Anti-infective drug discovery
PAGE
Evotec, an ideal partner in
anti-infective drug discovery
1
The different ways to work with us
On your specific
target or programme
Starting from a phenotypic
assay concept
On an existing
Evotec programme
Access to Evotec drug
discovery expertise and
capabilities to support
your programme
Access to Evotec phenotypic
screening expertise followed
by target deconvolution
leading into a drug discovery
programme
Sponsor an
established theme in
the anti-infective field
Flexible commercial solutions:
multiple business models available to suit our partners
Access to expert discovery platform as stand-alone activities or as part of
integrated drug discovery programmes
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Evotec’s foundations in anti-infective drug discovery are built upon many years of experience
State-of-the art capabilities & extensive expertise
2
Contribution to
the discovery and
development of
multiple ‘anti-
infective’ agents
including pre-
clinical and clinical
candidates through
to marketed drugs
1
2
3
4
Experienced anti-infective drug discovery team with >80 FTEs covering HTS,
medicinal chemistry and disease specific biology
Experience encompasses multiple compound classes: Small molecules, natural
products, biologics, peptides, antibodies, combinations, biocides, vaccines,
anti-bacterials, -virals, -fungals, -parastics
Multiple drug discovery approaches from phenotypic screening to target-based
discovery: Folate, non-mevalonate, aromatic biosynthesis, protein synthesis,
ribosome, virulence attributes and resistance pathways
Extensive portfolio of drug discovery capabilities
Medicinal chemistry and structure-based drug design
Hit finding and library screening
In vitro microbiology/virology
Molecular profiling/Mechanism of Action/Mechanism of resistance determination
Evostrain™: a unique strain collection
In vivo models of infection, strongly coupled with PK/PD profiling expertise
translating discovery data to clinical trial design
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Two screening platforms for BSL 2 biological agents
HTS & MTS on micro-organisms
3
>15 years of expertise in screening, from assay development to hit finding and
hit profiling with >30 HTS campaigns in the anti-infective space
Primary screening for actives identification
Screening against BSL 2 biological agents: human cells and micro-organisms
Assay development and miniaturization
HTS in 384 and 1536 well format
Screening collection adapted to the targets or approaches (25K to 900K)
Characterization of actives/hits: diverse range of secondary assays
Support for back screening and hit expansion
State-of-the-art robotic platforms
HTS: ET-1 and ET-2 robotic platforms (up to 100 plates/run, 30-100K/run)
MTS: 1 Beckman robotic system and 1 Agilent workstation
(42 plates/run, 15K/run)
BSL 2/2+ cabinet and containment
Access to Evotec, Aptuit and Sanofi compound collections
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Strong screening expertise with multiple microorganisms and targets
Phenotypic and target-based assays
4
Phenotypic assays: growth inhibition of microorganisms and cells
Up to 6 strains screened in a single run
Gram positive bacteria (Staphylococcus aureus incl. MRSA,
Streptococcus, Enterococcus spp …)
Gram negative bacteria (Escherichia coli, Pseudomonas
aeruginosa, Klebsiella spp …)
Mycobacterium species (Mycobacterium bovis …)
Yeasts and fungi (Candida and Aspergillus spp …)
Viruses (HPIV, HBV)
Target-based assays
Biochemical assays
Cell-based assays with incubation of cells and pathogen
(infection of human cells by bacteria and intracellular killing)
Cellular assays with reporter gene (luciferase, beta-lactamase …)
Readouts: fluorescence, luminescence, optical density, HCS …
Track record
Assay type (%) Evotec TLS
Micro-organism type (%) Evotec TLS
21
70
2 2
5Gram positive bacteria
Gram negative bacteria
Mycobacterium
Yeast & Fungi
Virus
20
80
Target-based
Phenotypic
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Best in Class microbiological profilingand characterisation
Breadth and depth of microbiology expertise
5
Antimicrobial Susceptibility Testing (AST) and hit follow-up
Primary screening
Panels include fully susceptible organisms and multidrug resistant strains that
exhibit a broad range of resistant mechanisms and phenotypes; e.g. KPC,
NDM-1, ESBL; VRSA; Azole and echinocandin resistant fungi
Large and rapidly evolving collection of highly characterised clinical isolates
and strains (EvostrAInTM)
Potencies of compounds (MICs and MBC/MFC/MPC)
Standardised methods where available (CLSI, EUCAST)
Detailed screening against broad panels of pathogens
Bespoke methods developed for non-conventional drugs, human targets
Combination studies
Chequerboard assays
Assessment for synergy, additive activity, and antagonism
Mathematical modelling of data
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EvostrAIn™ – Best in Class microbiological profiling and characterisation
Evotec’s collection of characterised strains and clinical isolates
6
Evotec strain collection is a constantly evolving
resource of thousands of primary clinical isolates
and reference strains
Broad collection of bacteria, fungi, viruses and parasites
Obtained from clinics and culture collections
Global, recent sources
High degree of characterisation (susceptibility profiles,
mechanisms of resistance and in vivo drug response)
Highly valuable collection used to establish spectrum of
activity and potential clinical use of new antibiotics and
antifungals
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EvostrAInTM
Bacteria, Fungi, Viruses and Parasites
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Bacteria: Gram positive pathogens
Staphylococcus aureus including MRSA,
VISA and VRSA strains
β-Haemolytic streptococci groups A, B, C
and G
Streptococcus pneumoniae (including
penicillin, macrolide, fluoroquinolone,
cephalosporin and MDRSP resistant strains)
Vancomycin Resistant Enterococci (VRE)
Bacillus species
Listeria species
Corynebacterium and Propionibacterium
species
Clostridium difficile (multiple ribotypes
including 012, 027 and 078)
Other Clostridia (including C. perfringens)
Bacteria: Gram negative pathogens
E. coli including Extended Beta lactamase
producing strains
Klebsiella pneumoniae Carbapenemase
producing strains (KPCs and MDR XDR)
Acinetobacter baumannii incl. MDR XDR
Pseudomonas spp. including MDR XDR
Haemophilus influenzae
Bacteroides spp.
Neisseria gonorrhoeae and N. meningitidis
Intestinal pathogens: Vibrio spp,
Campylobacter spp including pylori,
Salmonella spp, Shigella spp, Yersinia spp.
Legionella spp.
Mycobacterium (Mtb and non-MTb BSL2)
Chlamydia
Fungi
Aspergillus spp. (resistant to azoles,
polyenes and echinocandins)
Candida spp. (iresistant to azoles, polyenes
and echinocandins
Mucorales
Cryptococcus
Dermatophytes Fusarium
Viruses
Influenza virus
Respiratory syncytial virus
Human rhinovirus
Protozoa, parasites
Plasmodium falciparum
(multiple resistance phenotypes)
Acanthamoeba spp.
Toxoplasma gondii (lux and GFP)
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Highly validated and bespoke studies for target identification and molecular profiling
Mechanism of action determination
8
Resistant mutant generation to assist Mechanism-of-Action studies
Serial passage in presence of drug or isolation from gradient agar plates
Whole-cell random mutagenesis of bacteria
Determination of mutation frequencies/stability or mutation
Sequencing of mutants
Verification that mutation correlates with resistance. Mutations can be
recreated in wild-type backgrounds where tools are available.
Generation of targeted gene knockout mutants in a number of bacterial species
Screening of mutant libraries for increased susceptibility or resistance
Other molecular microbiology techniques available at Evotec include
Gene cloning & vector construction, expression studies (e.g. novel drug targets)
Site-directed mutagenesis or random mutagenesis of target genes
RT-PCR analysis of gene expression, use of reporter constructs
State-of-the-art proteomics and biomarker platform for cellular target profiling
and mode-of-action studies
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Capabilities and expertise to reduce cycle time and efficiently progress anti-infective programmes
An integrated synthetic and medicinal chemistry platform
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Experience encompasses multiple compound classes
Heterocyclic molecules, natural products, linear or cyclized peptides, carbohydrate
antigens) and targets (including Ribosome, DNA gyrase, Topoisomerase IV, Kinases)
Optimising anti-microbial activities for metabolism and pharmacokinetics
Medicinal
chemistry
know-how
SBDD and computational design of antimicrobials
Compound library enhancement strategies
Rapid synthetic execution; ability to address difficult chemistry
Strong expertise in peptide synthesis (from 200mg to 10-15g scale)
Synthetic
excellence
Guaranteed high chemical and chiral purity of molecules; multiple purification technologies
including SFC
Separation of chiral compounds (intermediates or final compounds)
Higher resolution techniques for difficult purifications (peptides, macrolides …)
Purification
platform
Analytical support for >20 antimicrobial programmes (LI and LO)
Expertise in analysis of multiple compound classes: small molecules, natural products,
peptides, unusual peptides, oligosaccharides, steroids, macrolides …
Deconvolution of mixtures and structural elucidation of unknown natural products
Analytical
Chemistry
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A fully comprehensive in vivo pharmacology offering
In vivo pharmacology/DMPK
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State-of-the-art animal facilities (BSL 2) equipped to house rodents,
immunocompromised animals, genetic models and other models
In vivo services include: target validation, tolerability studies, DMPK studies,
PK/PD studies and MoA studies, efficacy screening, in vivo pharmacology
profiling, pre-clinical imaging
Multiple hosts and fully validated models of infection: Rat, mouse, guinea pig,
hamster, cotton rat, rabbit
Multiple sites / routes of infection include: lung, thigh, blood (sepsis), skin,
urinary tract, GI tract, vagina, bone
Full range of endpoints: pathogen burden (culture, qPCR) and host response
Real time imaging of microbes during infection: IVIS, MRI, CAT
Custom design protocols and model development
Fully validated invertebrate screening model for bacteria and fungi
(wax moth larva rapid screening models)
Ongoing programmes of new model development
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Pharmacokinetic profiling inanti-infective drug discovery
From in vivo characterisation to bioanalysis and biomarker assessment
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Standard and specialised PK studies in multiple rodent species
Administration routes; intravenous (prolonged infusion), per oral,
intraperitoneal, subcutaneous, intra cerebrospinal, intramuscular, pulmonary
(nebulized, aerosolized), iPrecio and Alzet pumps
Sampling types: jugular vein cannulation, cardiac puncture, tail vein
microsampling
Matrices: blood, plasma, CSF, BALF, whole tissues, bile, urine and faeces
PK in infected animals assessing impact of disease state on drug exposure
Data directly translated into efficacy studies to optimise outcomes
PK experiments designed to accompany PK/PD profiling programmes
State-of-the-art bioanalytics
Highly sensitive biophysical methods including LC-MSMS
Bioassay techniques: tracking biological activity
Biomarker quantification: pathogen/infection specific and host response
1
10
100
1000
0 4 8 12 16 20 24
Pla
sma
Co
nce
ntr
atio
n (
nM
)
Time (h)
Compound XXX plasma concentrations following intravenous and oral administration to male Han Wistar rats at nominal doses of 2 and 4 mg/kg
intravenous
oral
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Delivering Rapid proof of concept anddetailed in vivo characterisation
Validated and bespoke preclinical efficacy models
12 1) Fully aligned with the principles of NC3Rs (National Committee for the 3Rs (Refinement, Reduction, Replacement)) and ethical alternatives for animal models.
Preclinical efficacy models and PK/PD Profiling
Study of multiple pathogens across large portfolio of infectious disease
Infecting pathogens: fully susceptible through to multidrug resistant (MDR)
Multiple hosts and fully validated models of infection: Rat, mouse, guinea pig, hamster, cotton rat, rabbit
Immunosuppressed and immunocompetent backgrounds
Multiple sites / routes of infection include: lung, thigh, blood (sepsis), skin, urinary tract, GI tract, vagina, bone
Routine and specialised routes and methods of infection and drug administration
Constantly expanding portfolio of ‘specialised models’: e.g. Chronic models, C. difficile infection (mouse and hamster)
Endpoints: pathogen burden (culture / qPCR) and host response
IVIS imaging of microbes during infection
From early in vivo Proof of Concept to detailed characterisation
‘High throughput’ screening models for early stage discovery and in vivo proof of concept (typically 1-4 days)
Detailed efficacy/pharmacodynamic assessment for later stage discovery and early development (typically 1-28 days)
Flexible dosing regimens adapted to optimise study outcomes and for PKPD studies (up to 6 IV doses daily)
Bespoke model development (e.g. shorter duration to accommodate frequent dosing, new strains)
Fully validated invertebrate screening model for bacteria and fungi (wax moth larva rapid screening models)1)
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Providing clinical translation for our partners
Tailored pharmacology and biomarker solutions
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In life Ex vivo
A clinical translation platform in anti-infectives for our partners and collaborators
In vivo pharmacology
Highly skilled
scientists
Drug discovery
PK/PD relationships
Efficacy
In vivo kinetics
(micro-dialysis)
Multiple models of
infection in rodents
Imaging technologies
Animal welfare
State-of-the-art
animal facilities
Trained veterinary
staff
Early toxicity
assessments
Rodent species
Biomarker discovery
and target identification
MS-based proteomics
and metabolomics
Target discovery and
selectivity profiling
Biomarker validation
Target validation
in vitro and in vivo
Clinical translation
Processing of animal
tissues for ex vivo
and biomarker
analyses (IHC, MS,
ELISA, FACS etc.)
Established relation-
ships enabling access
to clinical isolates
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Case study: In vivo models ofGram negative bacterial infection
PK/PD profiling of new antimicrobial drugs
14 NOTE: Presented at ICAAC and ECCMID
Partner Program Target Outcome
Early PK/PD profiling Gram negative infectionsPK/PD Profiling to
support clinical studies
Dose fractionation experiments indicated: increased frequency of dosing of BAL30072, aztreonam, meropenem and
ceftazidime, results in greater efficacy as measured by a reduction in bacterial burden in a murine thigh infection model
Designed and selected the appropriate models, dosing regimens, and showed how they can be used to
investigate the in vivo pharmacodynamic properties of developmental drugs against a selection of multi-resistant
Gram-negative organisms
Profiled BAL30072 in vitro and in vivo against MDR bacteria including those expressing ESBL,
NDM-1, CTX-M, VIM10/VEB, AmpC and OXA
Demonstrated that the in vivo efficacy of BAL30072 against most Enterobacteriaceae and
P. aeruginosa isolates was time dependent and rapid in vivo bactericidal activity was induced
when fT>MIC is greater than 50% for these species
Produced data to show that BAL30072 could be an effective treatment option for MDR and
carbapenemase-producing Gram-negative bacteria & that further clinical studies were warranted
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Case study: SMT19969: A novel agent for the treatment of C. difficile infection
In vitro and in vivo pharmacodynamic profiling
15 NOTE: Presented at ICAAC and ECCMID
Partner Program Target Outcome
SMT19969 (Ridinilazole):
A new drug for the treatment
of C. difficile infection
Clostridium difficile
Detailed in vitro and in vivo
characterisation of SMT19969
(Ridinilazole) to support
progression into clinical trials
Full characterisation demonstrating that SMT19969 (Ridinilazole) Is bactericidal in vitro at ≥2xMIC Demonstrates prolonged PAE at 5xMIC that results in bactericidal activity after
3 hours exposure
Maximum clinical efficacy of SMT19969 is likely to occur following exposure of >5xMIC for 3 hours
Bridged data from in vivo pharmacokinetic studies demonstrates such exposure is readily achieved in the GI tract following oral dosing
Studies support the potential use of SMT19969 in the treatment of C. difficile infection
Comprehensive Tier 1 microbiology work up
In vivo characterisation of SMT19969 (Ridinilazole) in Golden Syrian hamster model of C. difficile infection (CDI) against multiple strains of Clostridium difficile
0 4 8 12 16 20 24
102
103
104
105
106
107
108
109
Control
20xMIC
LOD
5xMIC
1xMIC
Time (hours)
CF
U/m
L
SMT19969
BI1 Ribotype 027
0 5 10 15 20 25 300
20
40
60
80
100VehicleVAN 10mg/KgFDX 25 mg/KgFDX 12.5 mg/KgFDX 2.5mg/KgFDX 1mg/KgSMT 25mg/KgSMT 12.5mg/Kg
Days Post Infection
Surv
ival
(%
)
0 5 10 15 20 25 300
20
40
60
80
100Vehicle
VAN 10mg/Kg
FDX 2.5mg/Kg
FDX 1mg/Kg
SMT 25mg/Kg
SMT 12.5mg/Kg
Days Post Infection
Su
rviv
al (%
)
C. difficile Ribotype 027 C. difficile Ribotype 012
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Case study: optimization and efficacy studies of new Gram positive antibacterials
Gram positive infections
16 NOTE: Presented at GRC “New Antibacterial Discovery & Development” Gordon Conference, March 16-21, 2014, Ventura, CA, USA,
Partner Program Target Outcome
Lipopeptide antibiotics Gram positive infections
In vivo proof of concept
established in a novel class
of antibacterial agent
Medicinal chemistry optimisation led to the discovery of new
hemisynthetic lipopeptide derivatives exhibiting favourable profile against
Gram positive bacteria
Excellent in vitro activity spectrum: activity against major Gram positive
pathogens (MRSA, VRE & PRSP), low serum shift, rapid bactericidal activity
(comparable to Daptomycin), low frequency of resistance (<10-10), no cross-
resistance to marketed antibiotics (suggesting a new mode of action)
Good in vitro activity against MRSA and MRSE in biofilm conditions
Promising in vivo activity in septicemia mouse model (CFU reduction at
5 hours pi and survival at 96hours pi). Good exposure in plasma and tissues.
Favorable in vitro Early ADMET, early TOX and physchem profiles
x
y
x
x (3mg/kg, iv) x (30mg/kg, iv)x (60mg/kg, iv)
Time Kill Curve MRSA/x
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Case study: Characterisation of a Polymyxin B derivative developed to enhance efficacy of existing antibiotics
Gram negative infections
17 Data presented at ASM Microbe 2016 and 2017
Corbett et al. (2017) Antimicrob Agents Chemother. 61(8) e00200-17
Partner Program Target Outcome
Potentiator Program Gram negative infectionsIn vitro and in vivo proof of
concept; Phase I clinical trial
Demonstrated ability of SPR741 to potentiate the
activity of several classes of antibiotics using in vitro
susceptibility testing and checkerboard analysis
In vivo models of thigh, lung and urinary tract
infection demonstrated efficacy of SPR741 in
combination with existing antibiotics (e.g. rifampicin,
clarithromycin) and novel antibiotics (e.g. SPR719)
against susceptible and multi-drug resistant strains
of E. coli, K. pneumoniae, and A. baumannii
Spero reported positive outcomes from Phase I
clinical trial of SPR741 in October 2017
CF
U/g
Th
igh
Tis
su
e
Pre
-tre
atm
ent
Veh
icle
SPR74
1, 3
x 6
0 m
pk
SPR71
9, 3
x 1
00 m
pk
SPR71
9, 3
x 1
00 m
pk & S
PR74
1, 3
x 6
0 m
pk
SPR71
9, 2
x 1
50 m
pk
SPR71
9, 2
x 1
50 m
pk & S
PR74
1, 3
x 6
0 m
pk
SPR71
9, 1
x 3
00 m
pk
SPR71
9, 1
x 3
00 m
pk & S
PR74
1, 3
x 6
0 m
pk
SPR71
9, 1
x 1
50 m
pk & S
PR74
1, 3
x 6
0 m
pk
SPR71
9, 2
x 7
5 m
pk & S
PR74
1, 3
x 6
0 m
pk
SPR71
9, 3
x 5
0 m
pk & S
PR74
1, 3
x 6
0 m
pk
TIG, 2
x 6
0 m
pk100
101
102
103
104
105
106
107
108
109
1010
CF
U/g
Th
igh
Tis
su
e
Pre
-tre
atm
ent
Veh
icle
SFI
MEM
, 3 x
10
mpk
RIF
, 2 x
4 m
pk
SPR74
1, 3
x 1
0 m
pk
SPR74
1, 3
x 2
0 m
pk
SPR74
1, 3
x 4
0 m
pk
RIF
, 2 x
4 m
pk & S
PR74
1, 3
x 1
0 m
pk
RIF
, 2 x
4 m
pk & S
PR74
1, 3
x 2
0 m
pk
RIF
, 2 x
4 m
pk & S
PR74
1, 3
x 4
0 m
pk
CLA
Veh
icle
CLA
, 1 x
100
mpk
CLA
, 1 x
100
mpk
& S
PR74
1, 3
x 1
0 m
pk
CLA
, 1 x
100
mpk
& S
PR74
1, 3
x 2
0 m
pk
CLA
, 1 x
100
mpk
& S
PR74
1, 3
x 4
0 m
pk100
101
102
103
104
105
106
107
108
109
1010
1011
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Why us?
18
Evotec – The right partner in anti-infective drug discovery
A track record of
success means that
we consistently
deliver on our
clients’ needs
State-of-the-art
capabilities and
scientific excellence
will maximise your
chances of success
Fully integrated drug
discovery platform
and project man-
agement expertise
will accelerate your
drug discovery
programme
Evotec is a low-risk
outsourcing partner
who is continually
investing in its
platform to the
benefit of the
customer
Flexible commercial solutions:
multiple business models available to suit our partners
