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