tari cb influenza eccmid 2019final

Cloudbreak Influenza

Cloudbreak InfluenzaLes Tari, SVP ResearchApril 2019

1

Influenza – prophylaxis and treatments are available, but have limitations

SB 13

• Vaccines are strain-specific, providing variable coverage

• 10%-60% effective (2004-2018)1

• Less effective in elderly & immune compromised

• ~2-week lag time to achieve full protection2

• Long, complex manufacturing cycle

• Difficult to scale, low antigen yields can limit production capacity

Vaccines

• Desired Target Product Profile:

• Long-acting prophylactic agent with full seasonal/pandemic coverage

• Coverage of immune compromised subjects

1https://www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm2https://www.cdc.gov/flu/protect/keyfacts.htm

• Short administration window

• 48 hours from symptom onset3

• Drug resistance

• Effectiveness poorly defined, particularly in high-risk patients

• Current treatments provide modest effects in reducing symptoms, infectivity

• Insufficient data to demonstrate that they reduce complications

Antiviral Treatments

• Desired Target Product Profile:

• Broad-spectrum activity, extended treatment window

• Minimize probability of resistance emergence

3https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

2

Cloudbreak platform – multimodal mechanism of action: instrinsic antimicrobial activity & immune engagement

Binds conserved surface targetDirect antimicrobial activity

Engages innate or adaptive immune system

TARGETING MOIETY

Pathogen ImmuneComponentTM EM

EFFECTOR MOIETY

3

Cloudbreak Antiviral Conjugates (AVCs) are not conventional Antibody-Drug Conjugates (ADCs)

TUMOR CELL1

2

3

VIRUS

ONCOLOGY ADC CLOUDBREAK

Fc recruits immune system

Tight binding

SB 9

DirectNeutralization

4

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

VIRUS

• High potency SMs

• Extended half-life

• Broad spectrum (influenza A&B)

• Combining multiple MOAs

SB 9

Conserved, essential target

Intrinsic antiviral activity

5

Cloudbreak AVCs are highly potent in vitro

VIRUS

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1

10

100

1000

10000

100000

1000000

24 48 72

Plaque Assay (H1N1 WSN/33)

PBS

Oseltamivir1µM

CB-0120.01µM

6

Cloudbreak AVCs are highly potent in vitro3,000-fold greater reduction in viral replication at 1/100 the concentration of oseltamivir

VIRUS

SB 9

1

10

100

1000

10000

100000

1000000

24 48 72

Plaque Assay (H1N1 WSN/33)

PBS

Oseltamivir

1µM

CB-0120.01µM

1

100

10000

1000000

24 48 72

H1N1 (A/09/pandemic)

7

CB-012 outperforms oseltamivir in vitroPlaque reduction in infected A549 cells

1

100

10000

1000000

24 48 72

H1N1 (A/WSN/33)

PBS

Oselt (1 µM)

CB-012 (10 nM)

CB-012 (10 nM)

Oselt (1 µM)

PBS

1

100

10000

1000000

24 48 72

H3N2 (A/Wyoming)

PBS

Oselt (1 µM)

CB-012 (10 nM)

1

10

100

1000

10000

24 48

B (Lee/40/Victoria)

Plaq

ues

Time (hrs)

PBS

Oselt (1 µM)

CB-012 (100 nM)1

100

10000

1000000

100000000

24 48 72

H5N1 (A/Vietnam/04 HALo)

PBS

Oselt (1 µM)

CB-012 (100 nM)

Lethal influenza model (H1N1: TX/36/91 in mice)

8

CB-012 has highly potent in vivo activity

100%

0%0 14Days

Surv

ival Neg control

(Fc only)

100%

0%0 14Days

Surv

ival

200

50

10

2

0.4

100%

0%0 14Days

Surv

ival

100%

0%0 14Days

Surv

ival

100%

0%0 14Days

Surv

ival

5 mice per cohort CB-012 dosed 4 hours prior to infection, oseltamivir dosed 8 hrs post infection

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

Total Dose (mg/kg)

CB-012, 10 mg/kg, 1 dose

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

Equivalent protection to oseltamivir at 1/500th the dose

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Body weight data supports robust efficacy & safetySB 12+13

CB-012 Average Body WeightsInfluenza A (H1N1; TX/36/91)

CB-012 (0.4 mpk)

Oseltamivir (20 mpk)CB-012 (50 mpk)

15

16

17

18

19

20

0 2 4 6 8 10 12 14

Negative control

Lethal influenza model (H3N2: HK/1/68 in mice)

10

CB-012 has highly potent in vivo activity

0%0 14Days

Surv

ival

100%

0%14Days

200

2

0.4

0.2

14Days

14Days

5 mice per cohort

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

Total Dose (mg/kg)

CB-012, 0.4 mg/kg, 1 dose


Equivalent protection to oseltamivir at 1/1000th the dose

Neg control (Fc only)

100%

0Su

rviv

al

100%

0%0

Surv

ival

0%0

Surv

ival

100%


Lethal influenza model (H1N1: A/Perth/261/2009 (H275Y))

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CB-012 has potent in vivo activity against the dominant oseltamivirR strain

0%0 14Days

Surv

ival

100%

0%14Days 14Days

14Days

5 mice per cohort

Oseltamivir, 20 mg/kg, 2x/day CB-012, 10 mg/kg, 1 dose CB-012, 2 mg/kg, 1 dose


100%

0Su

rviv

al

100%

0%0

Surv

ival

0%0

Surv

ival

100%


Neg control (Fc only)


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CB-012 improves treatment window versus oseltamivir

5 mice per cohort

Single dose of CB-012 improves treatment window vs 10 doses (BID) of oseltamivir

5 mice per cohort oseltamivir dosed BID for 5 days in each cohort

0 2 4 6 8 10 12 140

20

40

60

80

100

Days Post Infection

Per

cent

sur

viva

l

Vehicle (PBS)

Fc only 10 mpk

CB-012 10 mpk

Controls (dosed 4 hrs prior to infection)

0 2 4 6 8 10 12 140

20

40

60

80

100

Days Post Infection

Per

cent

sur

viva

l

Tamiflu 20 mpk

CB-012 10 mpk

Dosed 8 hrs post infection

0 2 4 6 8 10 12 140

20

40

60

80

100

Days Post Infection

Per

cent

sur

viva

l

Tamiflu 20 mpk

CB-012 10 mpk


0 2 4 6 8 10 12 140

20

40

60

80

100

Days Post Infection

Per

cent

sur

viva

l

CB-012 10 mpk

Tamiflu 20 mpk

0 2 4 6 8 10 12 140

20

40

60

80

100

Days Post Infection

Per

cent

sur

viva

l

CB-012 10 mpk

Tamiflu 20 mpk

Dosed 48 hrs post infection Dosed 72 hrs post infection

0 2 4 6 8 10 12 140

20

40

60

80

100

Days Post InfectionP

erce

nt s

urvi

val

CB-012 10 mpk

Tamiflu 20 mpk


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CB-012 rapidly distributes to lung, supporting treatment applications

SB 12+13

10 mg/kg IV dose, evaluation of levels in whole lungAVC-006_4B Lung Cmax study

H1N1 (A/CA/2009) NA Capture

0 2 4 6 8 10 12 14 16 18 20 22 241

10

100

1000

Time post dose (h)

AVC

-006

_4B

leve

ls

Plasma (µg/ml)

Lung (µg/g)

CB-012 plasma and lung levels

Reaches Cmax in lung by 1 hr

Lung levels track with plasma levels at ~10% relative to plasma

Con

c (µ

g/m

L)

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CB-012 demonstrates extended half-lifeSB 12+13

10

100

1000

0 50 100 150 200

Mea

n P

lasm

a C

onc

(ug/

mL)

Time (hr)

Mouse PK 50 mg/kg IV injection

Half-life in mouse, rat, cynoPK is dose linear across wide dose range

7-12 days:


15

100%

0%0 14Days

Surv

ival Neg control

(PBS)

100%

0%0 14Days

Surv

ival

5 mice per cohort

Oseltamivir 20 mg/kg, 2x/day starting 8 hrs post infection


CB-012 dosed once 28 days prior to viral challenge

Extended half-life translates to long duration of action

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Dose Infect

100%

0%0 14Days

Surv

ival


-28

Dose Infect

100%

0%0 14Days

Surv

ival


-28

Dose Infect

100%

0%0 14Days

Surv

ival


-28

Dose Infect

100%

0%0 14Days

Surv

ival

CB-012, 1.25 mg/kg, 1 dose

-28

Dose Infect


16

0%0 14Days

Neg control (hIgG1)

100%

0%0 14DaysS

urvi

val

5 mice per cohort

CB-012, 1 dose, IV

CB-012 dosed once 4 hours prior to viral challenge

Efficacy is observed using multiple dosing routes

100%

0%0 14Days

Sur

viva

l

CB-012, 1 dose, IM

100%

0%0 14Days

Sur

viva

l

CB-012, 1 dose, SC

100%

Sur

viva

l

0.1 mg/kg

0.4 mg/kg

0.1 mg/kg

0.4 mg/kg

0.1 mg/kg

0.4 mg/kg

Oseltamivir 20 mg/kg, 2x/day starting 8 hrs post infection

260

280

300

320

340

360

380

400

1 2 3 4

Averaged Body Weights (5 rats/group)

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Preclinical safety results consistent with a high therapeutic index

SB 13

CB-012 14-day, dose-range finder toxicity study in rat

• Compounds dosed twice - day 0 & day 7

• 5, 20 and 50 mpk doses tested (IV)

• No significant effects on body weight gain, organ weights or food consumption at any dose

CB-012 (50 mpk)

VehicleCB-012 (20 mpk)

CB-012 (5 mpk)

Body

weig

ht

(g)

Day

1 5 8 12

18

Preclinical safety results consistent with a high therapeutic index

SB 13

Summary: CB-012 14-day, dose-range finder toxicity study in rat• TK: Plasma exposures/AUC increase proportionally with dose, and PK scales from

mouse to rat to cyno approximately by BW

• Exposure margins >15X - based on 28 day mouse prophylaxis model

Parameter Findings at highest dose (50 mpk) vs vehicleClinical observations No findingsHematology No change from vehicleClinical Chemistry No change from vehicleCoagulation No change from vehicleUrinalysis No change from vehicleHistopathology No observations

14-day dose-range finder toxicity study in cyno complete

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Cloudbreak AVCs are being advanced to IND-

enabling studies

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CB-012 has demonstrated robust proof of concept

• Superior in vitro activity vs standard of care antivirals & coverage of Inf A and Inf B strains

• Activity with single, low doses in efficacy models vs multiple strains

• Efficacy via IV, SC and IM dosing

• 28-day protection with a single 2.5 mg/kg dose in mice

• Expanded treatment window in mice vs oseltamivir

• Exposure margins (rat) >15X - based on 28-day mouse prophylaxis model

Molecule EC50 (nM)

Oseltamivir 390

CB-012 4.0

CB-038 0.6

Cytopathic Effect based microneutralization assay (H1N1 CA/09) in MDCK cellsOptimized molecules are being advanced

• 1-2 log improvements in in vitro potency (CB-038)

• Fc engineering underway to extend half-life

• Goal: Extend protection to entire flu season with a single dose

20

AcknowledgementsSB 13

Sanford Burnham

Sumit ChandaPaul De JesusLaura Martin-Sancho

Cidara Research Team

Allen BorchardtTom BradyZhiyong ChenThanh LamWanlong JiangAlain NocovichQuyen Quyen DoJason ColeSimon DöhrmannElizabeth AbelovskiRajvir GrewalJeff Locke

Amanda AlmaguerJoanna DonatelliJames LevinKarin AmundsonGrayson HoughVoon OngSuzanne Akers-RodriguezJoanne FortierMakia NakamuraDan BensenJim Balkovec

Cloudbreak Influenza

April 2019

tari cb influenza eccmid 2019final

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