Immunobiotics: CloudbreakAntibody Drug Conjugates (ADC)

Les Tari, PhDVP Discovery

SB 1

2

Cidara’s pipeline addresses multiple unmet needsSB 2+3

IV Treatment (Candida)

IV Fungal Prophylaxis

Subq. FungalInfections

Cloudbreak

Program Indication Discovery IND- enable Ph 1 Ph 2 Ph 3

REZAFUNGIN

Antibacterial MDR G–

3

Cloudbreak is a bispecific immunobiotic

Binds conserved cell surface target

Engages innate or adaptive immune system

TARGETING MOIETY

Microbe ImmuneComponentTM EM

EFFECTOR MOIETY

4

Cloudbreak’s antibacterial action is multifaceted

G- PATHOGEN

Direct kill

Immune recruitment

1

2

Potentiation3 Protection from septic shock4

Superior PK/ADME

1. Long half-life(similar to antibodies)

2. Good lung exposures

3. Avoids kidney toxicity

5

Cloudbreak binds and enters bacterial cells

PermeabilizationBinding

A. baumannii

SB 2

Cloudbreak binds to the cell

In presence of Cloudbreak, SYTOX Green enters cell

6

Cloudbreak antibacterials are broad spectrum agents

E. coli64X-1 col-Rmcr-1 col-R

Log10 MIC (µM)

25922

P. aeruginosaMMX7746

PAO1LES 431

0.01 0.1 1 10 100

A. baumanniiMX8990 col-R

196065075

K. pneumoniaeMX6951 col-R

4381610031

ColistinADC-08

7

Immune engagement enhances antibacterial activity

0 0.4 0.8 1.2 1.6 2

P. aeruginosa (PAO1)

A. baumannii (5075)

E. coli (25922)

MICs (µM)

MICs (µM)

ADC-08 MIC (RPMI)ADC-08 MIC (Blood)

• Complement active human blood (Hirudin)

• 90 min incubation, 40% blood

8

Cloudbreak demonstrates efficacy in vivoSB 2

0

2

4

6

8

10mg/kg1x/Day

CFU

/g ti

ssue

10mg/kg1x/2 Days

2.5mg/kg2x/Day

Placebo Cloudbreak Cloudbreak Colistin

A. baumannii pneumonia model, dosing over 4 days

KAPE spectrum, low RI

Immune potentiation

Efficacy in MDR G- infection models

Long acting (weekly/biweekly dosing)

9

Cidara’s pipeline addresses multiple unmet needsSB 2+3

IV Treatment (Candida)

IV Fungal Prophylaxis

Subq. FungalInfections

Cloudbreak

Program Indication Discovery IND- enable Ph 1 Ph 2 Ph 3

REZAFUNGIN

Antibacterial MDR G–

Antiviral Viral Infections

10

Influenza remains a huge medical problem

226,000 HOSPITALIZATIONS (US)

SB 4+5

• 25 to 50 million influenza cases/yr• 2-3 fold increase in pneumonia

• $25B in health care costs (US)

Thompson WW, et al. Influenza Other Respir Viruses. 2009; 3(1): 37-49Thompson WW, et al. JAMA. 2004; 292(11):1333-4CDC. MMWR Morb Mortal Wkly Rep. 2010; 59(33):1057-62

11

Influenza remains a huge medical problem

OCTOBER 1, 2018

SB 4+5

Over 80,000 Americans Died of Flu Last Winter, Highest Toll in YearsAmong the dead were 180 babies, children and teenagers, more than in any year since the CDC began tracking pediatric deaths.NY Times

12

Vaccines are trying to hit a moving targetSB 6

’FLU SEASON6 MONTHS BEFORE ’FLU SEASON

VACCINE EFFICACY

30-50%*

*https://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm

13

A narrow treatment window limits clinical utility

48 HOURS

Therapeutics target more highly conserved regions

2xDaily

14

CLOUDBREAK™

A novel mechanism of action

Potential advantages

New applications

SB 7+8

structure and gives a

15

CLOUDBREAK™

A novel mechanism of action

Potential advantages

New applications

SB 7+8

16

Cloudbreak is not a conventional ADC

TUMOR CELL1

2

3

VIRUS

ONCOLOGY ADC CLOUDBREAK

Fc recruits immune system

Tight binding

SB 9

Direct kill

17

Cloudbreak combines the power of small molecules (SMs) and monoclonal antibodies

VIRUS

• High potency SMs

• Extended half-life

• Broad spectrum (’flu A&B)

• Combining multiple MOAs

SB 9

Tight binding

Direct kill

18

Cloudbreak has highly potent in vitro activity

VIRUS

SB 9

1

10

100

1000

10000

100000

1000000

24 48 72

Plaque Assay (H1N1 WSN/33)

PBS

Tamiflu1µM

CB-0120.01µM

19

Cloudbreak has highly potent in vitro activity3,000-fold greater reduction in viral plaques at 1/100 the dose of Tamiflu

VIRUS

SB 9

1

10

100

1000

10000

100000

1000000

24 48 72

Plaque Assay (H1N1 WSN/33)

PBS

Tamiflu

1µM

CB-0120.01µM

20

Cloudbreak has highly potent in vitro activity

1.E+00

1.E+01

1.E+02

1.E+03

1.E+00 1.E+03 1.E+06

Dos

e (h

M)

Viral reduction

Influenza Strain

MORE POTENT

GREATER VIRAL REDUCTION

21

Cloudbreak has highly potent in vitro activity

1.E+00

1.E+01

1.E+02

1.E+03

1.E+00 1.E+03 1.E+06

Dos

e (h

M)

Viral reduction

Influenza Strain

MORE POTENT

GREATER VIRAL REDUCTION

1.E+00

1.E+01

1.E+02

1.E+03

1.E+00 1.E+03 1.E+061.E+00

1.E+01

1.E+02

1.E+03

Dos

e (h

M)

Viral reduction

H1N1 (WSN/33)

22

Cloudbreak has highly potent in vitro activity

1.E+00

1.E+01

1.E+02

1.E+03

1.E+00 1.E+03 1.E+061.E+00

1.E+01

1.E+02

1.E+03

1.E+00 1.E+03 1.E+061.E+00

1.E+01

1.E+02

1.E+03

1.E+00 1.E+03 1.E+06

Dos

e (h

M)

Viral reduction Viral reduction Viral reduction

H1N1 (WSN/33) H3N2 (Wyoming) H1N1 (Pandemic)

CB-012 CB-012 CB-012

Tamiflu Tamiflu Tamiflu

3,200x 10x 200x

Lethal influenza model (H1N1 in mice)

23

Cloudbreak has highly potent in vivo activity

100%

0%0 14Days

Surv

ival Neg control

(Fc only)

100%

0%0 14Days

Surv

ival

200 mg

50 mg

10 mg

2 mg

0.4 mg

100%

0%0 14Days

Surv

ival

100%

0%0 14Days

Surv

ival

100%

0%0 14Days

Surv

ival

5 mice per cohort

Tamiflu, 20 mg/kg, 2x/day CB-012, 50 mg/kg, 1 dose

Total Dose

CB-012, 10 mg/kg, 1 dose

CB-012, 2 mg/kg, 1 dose CB-012, 0.4 mg/kg, 1 dose

100% protection at 1/500th the dose of Tamiflu

24

Body weight data supports robust efficacy & safetySB 12+13

CB-012 Average Body Weights: Influenza A(H1N1; TX/36/91)

0 2 4 6 8 10 12 1415

16

17

18

19

20

Day

Body

Weig

ht

(g)

Fc control

0 2 4 6 8 10 12 1415

16

17

18

19

20

Day

Body

Weig

ht

(g) Tamiflu (20 mpk)

0 2 4 6 8 10 12 1415

16

17

18

19

20

Day

Body

Weig

ht

(g)

CB-012 (50 mpk)

0 2 4 6 8 10 12 1415

16

17

18

19

20

Day

Body

Weig

ht

(g)

CB-012 (0.4 mpk)

25

Cloudbreak demonstrates extended half-lifeSB 12+13

10

100

1000

0 50 100 150 200

Mea

n Pl

asm

a C

onc

(ug/

mL)

Time (hr)

Mouse PK 50 mg/kg IV injection

Mouse half-lifeProjected human half-life

10 days:30-50 days:

26

Preliminary results look promisingSB 13

• Efficacious at 0.4 mg/kg

• Dosed safely up to 50 mg/kg

• No acute toxicity at ≥100x efficacious dose

• Chronic toxicity testing underway

structure and gives a

27

CLOUDBREAK™

A novel mechanism of action

Potential advantages

New applications

SB 14

28

Cloudbreak approach an alternative to vaccinesSB 15

VIRUS

• No need to reinvent a new vaccine every year

• Confident coverage

• Robust intrinsic activity –useful in immune compromised patients

29

Cloudbreak approach an alternative to current treatmentsSB 16

VIRUS

• Compliance (long acting)

• Safety profile (combines safe components)

• Resistance (targets small, essential viral component)

structure and gives a

30

CLOUDBREAK™

A novel mechanism of action

Potential advantages

New applications

SB 17

31

This platform can be applied to other viral diseasesSB 18

VIRUS

An antiviral with promising potency and half-lifeSB 20

32

100%

0%0 14Days

Surv

ival

CB-012, 0.4 mg/kg, 1 dose

10

100

1000

0 50 100 150 200Mea

n Pl

asm

a C

onc

(ug/

mL)

Time (hr)

High potency

Prolonged half-life

An antiviral with promising potency and half-life

SB 20

33

NEXT STEPS

Expand data set

Lead optimization

Preclinical toxicology

100%

0%0 14Days

Surv

ival

CB-012, 0.4 mg/kg, 1 dose

10

100

1000

0 50 100 150 200Me

an

Pla

sm

a C

on

c

(ug/m

L)

Time (hr)

Immunobiotics: CloudbreakAntibody Drug Conjugates (ADC)

Les Tari, PhDVP Discovery