Cloudbreak Influenza
Cloudbreak InfluenzaLes Tari, SVP ResearchApril 2019
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Influenza – prophylaxis and treatments are available, but have limitations
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• 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
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DirectNeutralization
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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
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Conserved, essential target
Intrinsic antiviral activity
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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
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Cloudbreak AVCs are highly potent in vitro3,000-fold greater reduction in viral replication at 1/100 the concentration of oseltamivir
VIRUS
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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)
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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)
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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
CB-012, 0.2 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%
5 mice per cohort CB-012 dosed 4 hours prior to infection, oseltamivir dosed 8 hrs post infection
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
CB-012, 0.4 mg/kg, 1 dose
100%
0Su
rviv
al
100%
0%0
Surv
ival
0%0
Surv
ival
100%
5 mice per cohort CB-012 dosed 4 hours prior to infection, oseltamivir dosed 8 hrs post infection
Neg control (Fc only)
Lethal influenza model (H1N1: TX/36/91 in mice)
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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
Dosed 24 hrs post infection
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
Dosed 96 hrs post infection
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CB-012 rapidly distributes to lung, supporting treatment applications
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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:
Lethal influenza model (H1N1: TX/36/91 in mice)
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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, 50 mg/kg, 1 dose
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
CB-012, 10 mg/kg, 1 dose
-28
Dose Infect
100%
0%0 14Days
Surv
ival
CB-012, 5 mg/kg, 1 dose
-28
Dose Infect
100%
0%0 14Days
Surv
ival
CB-012, 2.5 mg/kg, 1 dose
-28
Dose Infect
100%
0%0 14Days
Surv
ival
CB-012, 1.25 mg/kg, 1 dose
-28
Dose Infect
Lethal influenza model (H1N1: TX/36/91 in mice)
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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
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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
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Preclinical safety results consistent with a high therapeutic index
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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
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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