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Efficacy of CD377, a Novel Antiviral Fc-Conjugate, Against Seasonal Influenza in Lethal Mouse Infection ModelsJames Levin, PhD Cidara TherapeuticsSan Diego, CA

IDWeek 2020Abstract 159

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All authors are employees and stockholders of Cidara Therapeutics, Inc.

Disclosures

Long acting antiviral activity and potential immune engagement

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Cidara’s Cloudbreak AVCs: a new class of long-acting antiviralSB 10

AVC = Anti Viral Conjugate

Designed for rapid onset, potent activity coupled with 3-6 months of protectionNot vaccines, monoclonal antibodies, or traditional small-molecule therapeutics

• Direct anti-viral activity• Inhibits essential surface target

• To engage immune system• To extend PK: 3 – 6 months

TARGETING MOIETY (TM)

Potent antivirals Fc antibody fragment

Fc MOIETY

A stable conjugate of a potent neuraminidase inhibitor with a human antibody Fc

34,200Deaths

16.5 millionSeek HCP care

490,600Hospitalizations

35.5 million Sick

Source: CDC, WHO

Need for preventatives with broad, universal

activity Influenza A (95%)

Influenza B (5%)

H1N1H3N2

Victoria YamagataSignificant healthcare burden and mortality

Dominant influenza type varies by season and even within a season

From the 2018-2019 flu season (USA)The challenges of seasonal influenza

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1 8 -4 9 5 0 -6 4 6 5 +0

1 0

2 0

3 0

V a c c in e E f fe c t iv e n e s s (2 0 1 8 -1 9 )

A g e G ro u p

% V

E

The challenges of seasonal influenza – incomplete vaccine coverage

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Now in IND-enabling studies

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FLU AVC profile summary

Target Attribute AVCs in Preclinical Development

Indication Universal prevention and treatment Data are supportive

Spectrum A & B + drug resistant strains, low resistance potential

Potent in-vivo activity against all seasonal and pandemic strains

Safety/Tolerability High safety margin for long term prevention

> 50x exposure margin in 14-day primate toxicity studies

Dosing Frequency 1 to 2x per flu season Estimated 3 to 6-month coverage with single SC or IM dose

Route of Administration SubQ, IM and IV dosing Equivalent exposures and efficacy

Target Populations Higher risk populations where vaccines are not effective

Equally effective in immune compromised & immune competent models at similar doses

Data available at: https://ir.cidara.com/presentations

BALB/c, SCID, Tg32 mice(ketamine or isoflurane anesthesia)

Dose route (IV, SC, IM)Single dose (0.03 to 3 mg/kg)

CRLT-28d T-7d T+72hT+2h

14 – 28 days post viral challenge

SurvivalBody weight (BW)Lung burdenHistopathologyCytokines

Virus (3x LD95)T+0h

CD377 mouse efficacy screening models

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0 2 4 6 8 1 0 1 2 1 40

2 0

4 0

6 0

8 0

1 0 0

C D 3 7 7 a c t iv ity a g a in s t p a n d e m ic H 1 N 1(A /C A /1 2 /2 0 1 2 )

D a y P o s t C h a lle n g e

% S

urv

iva

l

V e h ic le

h Ig G 1 F c (3 m g /k g )

C D 3 7 7 (0 .3 m g /k g )

! CD377 has been tested against 10 H1N1 isolates with fully protective doses between 0.03 and 0.3 mg/kg

Lethal infection in BALB/c mice. Single IM dosing at T+2hPotency of CD377 against an H1N1 pandemic isolate

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0 2 4 6 8 1 0 1 2 1 40

2 0

4 0

6 0

8 0

1 0 0

C D 3 7 7 a c tv ity a g a in s t H 3 N 2(A /H K /6 8 )

D a y p o s t in fe c tio n

% S

urv

iva

l

V e h ic le

h Ig G 1 F c (3 m g /k g )

C D 3 7 7 (0 .1 m g /k g )

Slightly greater potency against H3N2

CD377 dose response evident in daily body weight measurements 0 2 4 6 8 1 0 1 2 1 4

7 0

8 0

9 0

1 0 0

1 1 0

C D 3 7 7 a c tv ity a g a in s t H 3 N 2(A /H K /6 8 )

D a y p o s t in fe c tio n%

Bo

dy

We

igh

t

V e h ic le (P B S )h Ig G 1 F c (3 m g /k g )

U n in fe c te d

C D 3 7 7 (0 .1 m g /k g )

C D 3 7 7 (0 .3 m g /k g )

C D 3 7 7 (1 m g /k g )

C D 3 7 7 (3 m g /k g )

Lethal infection in BALB/c mice. Single IM dosing at T+2hPotency of CD377 against an H3N2 isolate

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0 2 4 6 8 1 0 1 2 1 40

2 0

4 0

6 0

8 0

1 0 0

C D 3 7 7 a c t iv ity a g a in s t In f lu e n z a B (Y a m a g a ta )(B /F lo r id a /4 /0 6 )

D a y p o s t in fe c tio n

% S

urv

iva

l

V e h ic le (P B S )

h Ig G 1 F c (1 0 m g /k g )

C D 3 7 7 (0 .0 3 m g /k g )

0 2 4 6 8 1 0 1 2 1 40

2 0

4 0

6 0

8 0

1 0 0

C D 3 7 7 a g a in s t in f lu e n z a B (V ic to r ia )(B /C o lo ra d o /6 /2 0 1 7 )

D a y P o s t In fe c t io n

% S

urv

iva

l

V e h ic leh Ig G 1 F c (1 m g /k g )

C D 3 7 7 (0 .3 m g /k g )

Lethal infection in BALB/c mice. Single IM dosing at T+2hPotency of CD377 against influenza B isolates

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! A single 0.3 mg/kg dose of CD377 is fully protective against seasonal influenza! Against highly pathogenic influenza (H5N1), 1.0 mg/kg was protective

! CD377 demonstrated exceptional potency against 16 seasonal isolates

CD377 efficacy screening against influenza A/B (to date)Influenza Subtype n Fully protective dose (mg/kg)

A

H1N1 10H3N2 1H5N1 1

H1N1 (H275Y) 2

BVictoria 2

Yamagata 1

0.30.11.00.30.30.1

Summary of CD377 activity against influenza A/B

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-2 8 -2 4 -2 0 -1 6 -1 2 -8 -4 0 4 8 1 2 1 6 2 0

2 0

4 0

6 0

8 0

1 0 0

A /C a lifo rn ia /0 7 /2 0 0 9 p d m (H 1 N 1 )

D a y p o s t in fe c tio n

% S

urv

iva

l

V e h ic le (P B S )

C D 3 7 7 (1 m g /k g )

C D 3 7 7 (0 .3 m g /k g )

! Single 1 mg/kg (or less) doses protective against H1N1, H3N2, B (Yamagata/Victoria)

! Data strongly supportive of CD377 use as a long-term preventativeDose Virus

Lethal infection in BALB/c mice. Single, IM dosing at T-28 daysActivity of CD377 in long-term prevention models

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0 2 4 6 8 1 0 1 2 1 4 1 6 1 8 2 07 0

8 0

9 0

1 0 0

1 1 0

2 8 D a y P re v e n tio n S tu d y - B o d y W e ig h ts(A /C A /0 7 /0 9 )

D a y p o s t in fe c tio n

% B

od

y W

eig

ht

V e h ic le (P B S )

h Ig G 1 F c (3 m g /k g )

C D 3 7 7 (3 m g /k g )

C D 3 7 7 (1 m g /k g )

C D 3 7 7 (0 .3 m g /k g )

Question: Is the initial BW loss a technical artifact of a severescreening model?

Virus: 3x LD95Ketamine anesthesia

Increasing the translatability of data to the clinicInvestigating body weight trends in our LRT screening model

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When virus was introduced in the URT, the model was still lethal, with CD377 fully protective at 0.1 mg/kg

When virus was seeded into the URT the previously observed BW loss was absent for all dose groups (0.1, 0.3, 1 mg/kg)

0 2 4 6 8 1 0 1 2 1 47 0

8 0

9 0

1 0 0

1 1 0

U p p e r re s p ira to ry t ra c t s e e d in g m o d e l(A /C A /0 7 /0 9 )

D a y P o s t In fe c t io n

% B

od

y W

eig

ht

V e h ic le

C D 3 7 7 (1 m g /k g )

C D 3 7 7 (0 .3 m g /k g )

C D 3 7 7 (0 .1 m g /k g )

0 2 4 6 8 1 00

2 0

4 0

6 0

8 0

1 0 0

U p p e r re s p ira to ry t ra c t s e e d in g m o d e l(A /C A /0 7 /0 9 )

D a y P o s t In fe c t io n

% S

urv

iva

l

V e h ic le

C D 3 7 7 (0 .1 m g /k g )

Isoflurane anesthesia

Lethal infection in BALB/c mice. Single IM dosing at T-3dImproved translational model (upper respiratory tract seeding)

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0 2 4 6 8 1 0 1 2 1 40

2 0

4 0

6 0

8 0

1 0 0

D o s in g 7 2 h o u rs p o s t in fe c tio n

D a y p o s t in fe c tio n

% S

urv

iva

l

V e h ic le (P B S )

O s e lta m iv ir (2 0 m g /k g )

C D 3 7 7 (1 m g /k g )

! Oseltamivir was not protective when dosed 72h post-challenge at 20 mg/kg (bid x 5)

! A single dose of CD377 at 1 mg/kg was protective

! CD377 has significant potential as both a preventative and a therapeutic treatment against seasonal influenza

Dose

Lethal influenza model (H1N1: TX/36/91 in mice)Extended treatment window with CD377

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! Highly active against seasonal influenza with single doses of 0.3 mg/kg or less

! Active against seasonal influenza in 28-Day prevention models @ 1 mg/kg or less

! Active against H275Y harboring H1N1 isolates

! Effective in immune compromised (SCID) models (see poster 1276)

! Superior activity to oseltamivir in therapeutic models

! Equivalent potency by IV, SC, or IM dosing routes

! Significant reduction in lung burden in mouse and ferret models (see talk 162)

Summary of key CD377 AVC data

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"a supportive management team

"an innovative and dedicated R&D team

# Chemistry department

# Protein Chemistry department

# Microbiology department

# Immunology department

# In vivo team

Special thanks to Dr. Amy Krafft (NIH/NIAID) and their Preclinical Services Program for the H5N1 study run at Utah State.

Acknowledgments

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