Efficacy of CD377, a Novel Antiviral Fc-Conjugate, Against ...
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Efficacy of CD377, a Novel Antiviral Fc-Conjugate, Against Seasonal Influenza in Lethal Mouse Infection Models James Levin, PhD Cidara Therapeutics San Diego, CA IDWeek 2020 Abstract 159
Transcript of Efficacy of CD377, a Novel Antiviral Fc-Conjugate, Against ...
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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
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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
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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
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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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