novel antibiotics discovery at bugworks in the … · 2019. 3. 7. · gyrox different from...
TRANSCRIPT
11/22/2018
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NOVEL ANTIBIOTICS DISCOVERY AT BUGWORKS IN THE BACKDROP
OF AMR SITUATION IN INDIA
SANTANU DATTACO‐FOUNDER, DIRECTOR & CSO BUGWORKS RESEARCH INC.
Public Funding Support: CARB‐X, BIRAC
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THE NEED IS REAL, THE NEED IS NOW• 30% of all ICU deaths owing to Hospital acquired Infections
• In the US alone $50B extra healthcare costs owing to hospital acquired infection– 6‐12 extra days in hospital. $12‐30K in hospital costs. (Source : Tufts).
• 2050: #1 Killer Deaths due to DRI 10M, Cancer 8.2M.
• Drug approval all time low.
• Global antibiotics market: – Currently ~$40 Billion; $57B by 2024
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AMR IN INDIA
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Fluoro
qunilones
Cephal
osporin
s
Carbap
enem
s
Amin
oglyco
sides
Amox/
Clav;
Pip
/Taz
o
Tetra
cycl
ine
Colistin
0
20
40
60
80
100
% R
esis
tance
Resistance among Gram Negative Infections(Data from ICMR)
E. coli
K. pneumoniae
E. cloacae
A. baumannii
P. aeruginosa
http://bic.icmr.org.in/iamrsn/index.php/amrsn/data
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AMR IN INDIA
4http://bic.icmr.org.in/iamrsn/index.php/amrsn/data
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BUGWORKS PLATFORM AND ASSETS
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YAWNING DISCOVERY GAP…
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GRAM‐NEGATIVE BACTERIAL INFECTIONS
• Massive Urgent Problem
• No new Gram‐negative antibiotic since 1962
• Causes many life‐threatening illnesses– Pneumonia, Sepsis, complicated
urinary tract infections, post‐surgical intra‐abdominal infections, burn injury infections etc.
• Extremely Well Protected– Three‐layered outer shell
– Multiple Efflux Pumps
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ELUDETM: EFFLUX AVOIDANCE PLATFORM
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Platform Solution
Not bind to Efflux Pumps; drug retained inside to KILL Bacteria EFFECTIVE DRUG
Lead Asset Family: GYROX
Problem
Efflux Pumps
Drugs bind to Efflux Pumps; thrown out of Bacteria
INEFFECTIVE DRUG
E. coli WT MIC = 0.25 µg/ml
ΔacrB MIC = 0.008 µg/mlΔtolC MIC = 0.008 µg/ml
32x Efflux liability
E. coli WT MIC = 0.03 µg/ml
ΔacrBMIC = 0.008 µg/mlΔtolCMIC = 0.008 µg/ml
4x Efflux liability
Initial Lead
Late Lead
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GYROX: A NOVEL BROAD SPECTRUMSMALL MOLECULE ANTIBACTERIAL AGENT
www.bugworksresearch.com
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BWC0977PRE‐CLINICAL CANDIDATE: DATA DEEP DIVE
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DUALTARGETINHIBITOR
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E. coli topo IV inhibition
E. coli gyrase inhibition
0 120 60 30 15 7.5 3.75 1.88 0.938 0.469 0.234 no E
Ciprofloxacin IC50 = 11.18 µM
no E 25 8 3 1 0.3 0.10 0.03 0.011 0.0038 0.0013 0
Ciprofloxacin IC50 = 0.253 µM BWC0977 IC50 = 0.0046 µM
no E 5 2 0.6 0.2 0.06 0.021 0.007 0.0023 0.0008 0.0003 0
R
SC
BWC0977 IC50 = 0.0096 µM
no E 30 10 3.3 1.1 0.37 0.123 0.041 0.014 0.005 0
kDNA
MC
R = relaxed DNA, SC = supercoiled DNA, kDNA = kinetoplast DNA, MC = mini‐circles
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GYROX DIFFERENT FROM FLUOROQUINOLONES
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CompoundEco gyrasesupercoiling, IC50 (µM)
Eco topo IV decatenation, IC50
(µM)
Human topo IIα decatenation, IC50 (µM)
BWC0977 0.004 0.010 >120
Gepotidacin 0.26 0.21 56.1
Ciprofloxacin 0.25 9.6 100
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BWC0977: LEAD COMPOUND MIC90
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Testing done at St.Johns, Narayana Health, Eurofins, JMI and NIAID
0.015625 0.0625 0.25 1 4 160
50
100
150
200
250
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
ency
Dis
trib
uti
on
E. coli (675 isolates)MIC90 = 0.25
%C
um
ulative F
requ
ency
MIC90
0.0156250.031250.0625 0.125 0.25 0.5 1 2 4 80
20
40
60
80
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
ency
Dis
trib
uti
on
A. baumannii (314 isolates)MIC90 = 0.5
%C
um
ulative F
requ
ency
MIC90
0.03125 0.125 0.5 2 8 320
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
ency
Dis
trib
uti
on
K. pneumoniae (393 isolates)MIC90 = 2
%C
um
ulative F
requ
ency
MIC90
0.00097656250.003906250.0156250.0625 0.25 1 4 16 640
20
40
60
80
100
120
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
en
ce D
istr
ibu
tio
n
Enterobacter spp. (332 isolates)MIC90 = 1
%C
um
ulative F
requ
ency
MIC90
0.015625 0.0625 0.25 1 4 160
50
100
150
200
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
en
cy
Dis
trib
uti
on
P. aeruginosa (348 isolates) MIC90 = 1
%C
um
ulativ
e Fre
qu
ency
MIC90
0.00097656250.003906250.0156250.0625 0.25 1 4 16 640
20
40
60
80
100
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
ency
Dis
trib
uti
on
S. marcesens (208 isolates)MIC90 = 1
%C
um
ulative F
requ
ency
MIC90
0.00097656250.003906250.0156250.0625 0.25 1 4 16 640
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
en
cy
Dis
trib
uti
on
Citrobacter spp. (234 isolates)MIC90 = 1
%C
um
ulative
Freq
uen
cy
MIC90
0.015625 0.0625 0.25 1 4 160
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
enc
y D
istr
ibu
tio
n
K. oxytoca (120 isolates)MIC90 = 0.5
%C
um
ulativ
e Fre
qu
enc
y
MIC90
0.015625 0.0625 0.25 1 4 160
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
en
cy
Dis
trib
uti
on
M. morganii (122 isolates)MIC90 = 0.5
%C
um
ulative
Freq
uen
cy
MIC90
0.015625 0.0625 0.25 1 40
10
20
30
40
50
60
0
10
20
30
40
50
60
70
80
90
100
Conc g/ml
Fre
qu
enc
y D
istr
ibu
tio
n
P. mirabilis (126 isolates)MIC90 = 0.5
%C
um
ulativ
e Fre
qu
enc
y
MIC90
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COMPARISON OF INDIA & US/EUROPE
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0.015625 0.0625 0.25 1 4 160
5
10
15
20
25
30
35
40
45
50
Conc g/ml
% F
requen
cy
E. coli
Bangalore (513)
JMI (Global; 140)
0.0156250.0625 0.25 1 4 16 640
5
10
15
20
25
30
35
40
45
50
Conc g/ml
% F
requen
cy
K. pneumoniae
Bangalore (176)
JMI (Global; 189)
0.0156250.0625 0.25 1 4 16 640
5
10
15
20
25
30
35
40
45
50
Conc g/ml
% F
requen
cy
P. aeruginosa
Bangalore (166)
JMI (Global; 135)
0.0156250.0625 0.25 1 4 16 640
5
10
15
20
25
30
35
40
45
50
Conc g/ml
% F
requen
cy
Enterobacter spp.
Bangalore (88)
JMI (Global; 235)
0.0156250.0625 0.25 1 4 16 640
5
10
15
20
25
30
35
40
45
50
Conc g/ml
% F
requen
cy
S. marcesens
Bangalore (83)
JMI (Global; 118)
0.0156250.0625 0.25 1 4 16 640
5
10
15
20
25
30
35
40
45
50
Conc g/ml
% F
requen
cy
A. baumanii
Bangalore (130)
JMI (Global; 141)
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BWC0977: EXTENDED SPECTRUM
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Species Strain ID MIC (μg/ml) Species Strain ID MIC (μg/ml)
Haemophilus influenzae ATCC 35056 0.016 Enterococcus faecalis ATCC 29212 0.06
Haemophilus influenzae ATCC 49247 0.016 Enterococcus faecalis 1768 (VanB) 0.03
Moraxella catarrhalis ATCC 25238 0.016 Enterococcus faecium 1593 (VanA) 0.25
Neisseria gonorrhoeae ATCC 49226 0.016 Staphylococcus aureus ATCC 29213 0.03
Neisseria gonorrhoeae CCUG 57596 0.016 Staphylococcus aureus 6215 (USA100) 0.03
Neisseria gonorrhoeae CCUG 57601 0.016 Staphylococcus aureus 6229 (USA300) 0.03
Proteus hauseri ATCC 13315 0.016 Streptococcus Group A 2008‐818 0.03
Helicobacter pylori ATCC 43504 0.5 Streptococcus Group A 2008‐1732 0.03
Salmonella typhimurium ATCC 13311 0.125 Streptococcus Group A 2009‐37 0.03
Salmonella senftenberg, NDM CDC AR‐BANK#0127 2 Streptococcus Group B 2008‐87 0.06
Candida albicans ATCC 90028 >32 Streptococcus Group B 2009‐61 0.03
Saccharomyces cereviseae ATCC9763 >32 Streptococcus Group B 2009‐62 0.06
Streptococcus pneumoniae ATCC 49619 0.03
Streptococcus pneumoniae MD77773 (R:Pen) 0.03
Streptococcus pneumoniae CO314937 (R:Levo) 0.03
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RESISTANCE FREQUENCY
• S. aureus
– Single step mutation frequency: < 10‐9 cfu/ml
– Resistance mapped to D83N & I86V in Sau GyrA (non‐overlapping with FQ)
• E. coli & P. aeruginosa
– Single‐step antibiotic exposure did not yield resistant mutants
– Serial passage MIC up to a month did not yield target‐site resistant mutants
– Single‐step antibiotic exposure of hyper‐mutable E. coli (ΔalkB/ΔmutS and ΔmutS /ΔmiaA) did not produce stable resistant mutants, while Ciprofloxacin yielded 50‐fold higher frequency of mutants in comparison to wild‐type
– GYROX resistance frequency inferred to be < 10‐10 cfu/ml
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MICE ORAL EFFICACY…1
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Formulation: 0.25% CMC, 0.1% Tween 80 suspensionDone at TheraIndx (CRO), Bangalore
-4 -2 0 2 4 6 8 10
4
Time (hrs)
cyclophosphamide infection sac
q2h
q4h
days
Start End Ciprofloxacin BWC0977-A BWC0977-B0
1
2
3
4
5
6
7
8
9
10 P. aeruginosa
Lo
g 10
CF
U/g
Th
igh
(M
ean
± S
D)
A: 100 mg/kg, 2 doses, q4h
B: 100 mg/kg, 3 doses, q2h
Start End CiprofloxacinBWC0977-A BWC0977-B BWC0977-C0
1
2
3
4
5
6
7
8
9
10 K. pneumoniae
Lo
g 1
0 C
FU
/g T
hig
h (
Mea
n ±
SD
)
A: 10 mg/kg, 3doses, q2h
B: 30 mg/kg, 3 doses, q2h
C: 100 mg/kg, 3 doses, q2h
Start End CiprofloxacinBWC0977-A BWC0977-B BWC0977-C0
1
2
3
4
5
6
7
8
9
10 E. coli
Lo
g 1
0 C
FU
/g T
hig
h (
Mea
n ±
SD
)
A: 10 mg/kg, 3doses, q2h
B: 30 mg/kg, 3 doses, q2h
C: 50 mg/kg, 2 doses, q4h
Start End CiprofloxacinBWC0977-A BWC0977-B BWC0977-C0
1
2
3
4
5
6
7
8
9
10 A. baumannii
Lo
g 10
CF
U/g
Th
igh
(M
ean
± S
D)
A: 10 mg/kg, 3doses, q2h
B: 30 mg/kg, 3 doses, q2h
C: 100 mg/kg, 3 doses, q2h
Bactericidal efficacy seen against all ATCC strains; Required thrice dosing (q2h) within the 10h model
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K. PNEUMONIAE IN RAT(THIGH, LUNG, UTI)
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-4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hrs)
Infection SacCyclophosphamide
Infusion
Intravenous 1‐hour infusion in 10% ascorbic acid (pH4)
days
1 10 100 1000-6
-4
-2
0
2
AUC/MIC
Red
uct
ion
in L
og
10C
FU
/un
it t
issu
e
K. pneumoniae (ATCC, MIC 0.06 g/ml)
AUC/MIC1 Log kill: 150Stasis: 10
Kidneys, UTI model
Bladder, UTI modelThigh model
Lung model
1 10 100 1000-6
-4
-2
0
2
AUC/MIC
Red
uct
ion
in L
og
10C
FU
/un
it t
issu
e
K. pneumoniae (SKB067, MIC 2 g/ml)
AUC/MIC1 Log kill: 70Stasis: 20
SKB067, MIC 2 µg/ml, Lung
SKB067, MIC 2 µg/ml, thigh
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DOSE TO MAN PREDICTIONS
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Predicted Doses and Cmax based on PKPD driver: AUC/MIC following iv infusion and sampling at 24 hrs post infection in Rat infection models
300‐600 mg thrice daily will meet the AUC, Cmax requirements for efficacy with adequate safety margins
Target AUC for cidal and stasis is based on lung and UTI models
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POTENTIAL DRUG CANDIDATE
Novel chemical and novel mechanism
Extensive Gram negative broad spectrum
Intravenous and Oral dosage
Efficacy demonstrated against key Gram negative pathogens in multiple infection models (rats and mice)
Safety: ~10x margin in guinea pig cardiotoxicity studies; ~15x margin in rat 7‐day repeat dose comprehensive toxicity studies
Estimated dose in human: 350 mg thrice daily or 500 mg twice daily for 5‐7 days, administered via infusion
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Ready for IND Enabling Studies in 2019; Phase 1 and Phase 2 studies in 2020
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TARGET PRODUCT PROFILE
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Brand VisionA safe, effective broad spectrum antibacterial agent with a novel mechanism of action for treating drug‐sensitive and
drug‐resistant infections in hospital and critical care settings.
TPP‐1: Treatment of cUTI patients TPP‐2: Treatment of HAP patients TPP‐3: Treatment of VAP patients
Key pathogensE. coli, Klebsiella, Proteus, Enterobacter, S. marcescens, Acinetobacter, P. aeruginosa,
Enterococci, and Staphylococci
Failing TreatmentsESBL, Amp‐C, CRE (KPC, NDM), fluroquinolones, MDR (efflux up‐regulation, loss of porin etc.), methicillin, vancomycin
Key pathogensAcinetobacter, P. aeruginosa, Klebsiella,
Enterobacter, and Staphylococci
Key pathogensP. aeruginosa, Klebsiella, S. marcescens, Enterobacter, Citrobacter, S. maltophilia, Acinetobacter, B. cepacia & Staphylococci
BWC0977: Reasons to SupportNovel mechanism of action with very low resistance frequency; Potent against ESBLs, AmpC, KPCs and FQ resistant strains (MIC90 < 2 μg/ml); Efficacious in lung, UTI and thigh infection models; No significant drug‐drug interaction risk identified
Adequate presence in key sites (lung, urine, bile and plasma); Superior safety profile vs Tigeycycline and colistin
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THE PATH AHEAD
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2018 2019
IND Enabling StudiesLead Selection
IV for WHO Critical, High and Medium Priority Bacterial Infections
LEAD
2020
PH 1 PH 2
• PHASE 1: intravenous SAD, MAD studies in healthy volunteers
• PHASE 2: 1st POC trial in patients (cUTI or HAP?)
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BUGWORKS TEAM
• Globally reputed work force with complimentary skills
• Cumulative experience in AMR area of > 200 years
• Full Time employees 18
• Globally distributed execution mode
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OUR DISCOVERY PARTNERS
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Drug Design & Medicinal Chemistry Systems Biology, Biochemistry Non‐clinical Microbiology
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COLLABORATIONS
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Structural biology of efflux pumps in Gram negative bacteria;Enhancement of the Elude Platform
Structural biology of Targets implied in Bugworks Drug Discovery
Institute for Stem Cell Biology and Regenerative Medicine
Rams Laboratory
Murakami LaboratoryDepartment of Life Science and Technology
School of Life Science and TechnologyTokyo Institute of Technology
Hope Laboratory
Department of Molecular & Clinical
Pharmacology
Antimicrobial pharmacokinetics and pharmacodynamics of Bugworks Lead compounds
Anti‐microbial Susceptibility of Bugworks Lead compounds against recent clinical isolates
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Ideas have zero value Unless it is executed