Immunobiotics: Cloudbreak Antibody Drug Conjugates (ADC) Les Tari, PhD VP Discovery

Transcription

1 Immunobiotics: Cloudbreak Antibody Drug Conjugates (ADC) Les Tari, PhD VP Discovery

2 Cidara s pipeline addresses multiple unmet needs Program Indication Discovery IND- enable Ph 1 Ph 2 Ph 3 REZAFUNGIN IV IV Subq. Treatment (Candida) Fungal Prophylaxis Fungal Infections Cloudbreak Antibacterial MDR G 2

3 Cloudbreak is a bispecific immunobiotic Microbe TM EM Immune Component TARGETING MOIETY EFFECTOR MOIETY Binds conserved cell surface target Engages innate or adaptive immune system 3

4 Cloudbreak s antibacterial action is multifaceted G- PATHOGEN 1 Direct kill Superior PK/ADME 1. Long half-life (similar to antibodies) 2. Good lung exposures 3 Potentiation Protection from 3. Avoids 4 septic kidney shock toxicity 2 Immune recruitment 4

5 Cloudbreak binds and enters bacterial cells Binding Permeabilization A. baumannii Cloudbreak binds to the cell In presence of Cloudbreak, SYTOX Green enters cell 5

6 Cloudbreak antibacterials are broad spectrum agents E. coli mcr-1 col-r 64X-1 col-r ADC-08 Colistin P. aeruginosa LES 431 PAO1 MMX7746 A. baumannii MX8990 col-r K. pneumoniae MX6951 col-r Log 10 MIC (µm) 6

7 Immune engagement enhances antibacterial activity E. coli (25922) A. baumannii (5075) MICs (µm) ADC-08 MIC (RPMI) ADC-08 MIC (Blood) Complement active human blood (Hirudin) 90 min incubation, 40% blood P. aeruginosa (PAO1) MICs (µm) 7

8 Cloudbreak demonstrates efficacy in vivo A. baumannii pneumonia model, dosing over 4 days CFU/g tissue Placebo Cloudbreak Cloudbreak Colistin KAPE spectrum, low RI Immune potentiation Efficacy in MDR G- infection models Long acting (weekly/biweekly dosing) mg/kg 1x/Day 10mg/kg 1x/2 Days 2.5mg/kg 2x/Day 8

9 Cidara s pipeline addresses multiple unmet needs Program Indication Discovery IND- enable Ph 1 Ph 2 Ph 3 REZAFUNGIN IV IV Subq. Treatment (Candida) Fungal Prophylaxis Fungal Infections Cloudbreak Antibacterial MDR G Antiviral Viral Infections 9

10 Influenza remains a huge medical problem 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): Thompson WW, et al. JAMA. 2004; 292(11): CDC. MMWR Morb Mortal Wkly Rep. 2010; 59(33): ,000 HOSPITALIZATIONS (US) 10

11 Influenza remains a huge medical problem Over 80,000 Americans Died of Flu Last Winter, Highest Toll in Years Among the dead were 180 babies, children and teenagers, more than in any year since the CDC began tracking pediatric deaths. NY Times OCTOBER 1,

12 Vaccines are trying to hit a moving target 6 MONTHS BEFORE FLU SEASON FLU SEASON VACCINE EFFICACY 30-50% * * 12

13 A narrow treatment window limits clinical utility Therapeutics target more highly conserved regions 2x Daily 48 HOURS 13

14 CLOUDBREAK A novel mechanism of action Potential advantages New applications 14

15 CLOUDBREAK A novel mechanism of action Potential advantages New applications 15

16 Cloudbreak is not a conventional ADC TUMOR CELL 3 1 Fc recruits immune system Direct kill 2 VIRUS Tight binding ONCOLOGY ADC CLOUDBREAK 16

17 Cloudbreak combines the power of small molecules (SMs) and monoclonal antibodies High potency SMs Extended half-life Direct kill Broad spectrum ( flu A&B) Combining multiple MOAs VIRUS Tight binding 17

18 Cloudbreak has highly potent in vitro activity Plaque Assay (H1N1 WSN/33) PBS Tamiflu 1µM CB µM VIRUS 18

19 Cloudbreak has highly potent in vitro activity 3,000-fold greater reduction in viral plaques at 1/100 the dose of Tamiflu Plaque Assay (H1N1 WSN/33) PBS Tamiflu 1µM CB µM VIRUS 19

20 Cloudbreak has highly potent in vitro activity Dose (hm) 1.E+03 1.E+02 Influenza Strain MORE POTENT 1.E+01 GREATER VIRAL REDUCTION 1.E+00 1.E+00 1.E+03 1.E+06 Viral reduction 20

21 Cloudbreak has highly potent in vitro activity Dose (hm) 1.E+03 1.E+02 Influenza Strain MORE POTENT Dose (hm) 1.E+03 1.E+02 1.E+01 H1N1 (WSN/33) 1.E 1.E 1.E 1.E+01 GREATER VIRAL REDUCTION 1.E+00 1.E+00 1.E+03 1.E+06 Viral reduction 1.E+00 1.E+00 1.E+03 1.E+06 Viral reduction 1.E 21

22 Cloudbreak has highly potent in vitro activity H1N1 (WSN/33) H3N2 (Wyoming) H1N1 (Pandemic) Dose (hm) 1.E+03 1.E+02 1.E+01 1.E+03 1.E+03 Tamiflu Tamiflu Tamiflu 3,200x 1.E+02 10x 1.E x CB E+01 CB E+01 CB E+00 1.E+00 1.E+00 1.E+00 1.E+03 1.E+06 1.E+00 1.E+03 1.E+06 1.E+00 1.E+03 1.E+06 Viral reduction Viral reduction Viral reduction 22

23 Cloudbreak has highly potent in vivo activity Lethal influenza model (H1N1 in mice) 100% protection at 1/500th the dose of Tamiflu Tamiflu, 20 mg/kg, 2x/day 100% CB-012, 50 mg/kg, 1 dose 100% CB-012, 10 mg/kg, 1 dose 100% Survival Neg control (Fc only) Survival Survival 0% 0 Days 14 0% 0 Days 14 0% 0 Days 14 CB-012, 2 mg/kg, 1 dose 100% Survival 0% 0 Days 14 CB-012, 0.4 mg/kg, 1 dose 100% Survival 0% 0 Days 14 Total Dose 200 mg 50 mg 10 mg 2 mg 0.4 mg 5 mice per cohort 23

24 Body weight data supports robust efficacy & safety CB-012 Average Body Weights: Influenza A (H1N1; TX/36/91) 20 Body Weight (g) Fc control Tamiflu (20 mpk) CB-012 (50 mpk) CB-012 (0.4 mpk) Day 24

25 Cloudbreak demonstrates extended half-life Mouse PK 50 mg/kg IV injection Mean Plasma Conc (ug/ml) days: days: Mouse half-life Projected human half-life Time (hr) 25

26 Preliminary results look promising Efficacious at 0.4 mg/kg Dosed safely up to 50 mg/kg No acute toxicity at 100x efficacious dose Chronic toxicity testing underway 26

27 CLOUDBREAK A novel mechanism of action Potential advantages New applications 27

28 Cloudbreak approach an alternative to vaccines VIRUS No need to reinvent a new vaccine every year Confident coverage Robust intrinsic activity useful in immune compromised patients 28

29 Cloudbreak approach an alternative to current treatments VIRUS Compliance (long acting) Safety profile (combines safe components) Resistance (targets small, essential viral component) 29

30 CLOUDBREAK A novel mechanism of action Potential advantages New applications 30

31 This platform can be applied to other viral diseases VIRUS 31

32 An antiviral with promising potency and half-life High potency CB-012, 0.4 mg/kg, 1 dose 100% Survival 0% 0 Days 14 Prolonged half-life Mean Plasma Conc (ug/ml) Time (hr) 32

33 An antiviral with promising potency and half-life CB-012, 0.4 mg/kg, 1 dose 100% NEXT STEPS Mean Plasma Conc (ug/ml) Survival 0% 0 Days Time (hr) Expand data set Lead optimization Preclinical toxicology 33

34 Immunobiotics: Cloudbreak Antibody Drug Conjugates (ADC) Les Tari, PhD VP Discovery