NOVEL ANTIBIOTICS DISCOVERY AT BUGWORKS IN THE … · 2019. 3. 7. · GYROX DIFFERENT FROM...

11/22/2018

1

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

Not for circulation without Bugworks Research Inc. Permission

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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11/22/2018

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AMR IN INDIA

3

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


AMR IN INDIA

4http://bic.icmr.org.in/iamrsn/index.php/amrsn/data

11/22/2018

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BUGWORKS PLATFORM AND ASSETS


YAWNING DISCOVERY GAP…

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11/22/2018

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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

7


ELUDETM: EFFLUX AVOIDANCE PLATFORM

8

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

11/22/2018

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GYROX: A NOVEL BROAD SPECTRUMSMALL MOLECULE ANTIBACTERIAL AGENT

www.bugworksresearch.com


BWC0977PRE‐CLINICAL CANDIDATE: DATA DEEP DIVE

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11/22/2018

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DUALTARGETINHIBITOR

11

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


GYROX DIFFERENT FROM FLUOROQUINOLONES

12

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

11/22/2018

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BWC0977: LEAD COMPOUND MIC90

13

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


COMPARISON OF INDIA & US/EUROPE

14

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)

11/22/2018

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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


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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11/22/2018

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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


C: 100 mg/kg, 3 doses, q2h


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

)





1

2

3

4

5

6

7

8

9

10 A. baumannii

Lo

g 10

CF

U/g

Th

igh

(M

ean

± S

D)




Bactericidal efficacy seen against all ATCC strains; Required thrice dosing (q2h) within the 10h model


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

11/22/2018

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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


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

20

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


THE PATH AHEAD

22

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?)

11/22/2018

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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

11/22/2018

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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

Not for circulation without Bugworks Research Inc. Permission26

Ideas have zero value Unless it is executed

NOVEL ANTIBIOTICS DISCOVERY AT BUGWORKS IN THE … · 2019. 3. 7. · GYROX DIFFERENT FROM...

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