CD101: A Novel Echinocandin Taylor Sandison, MD MPH Chief Medical Officer TIMM Belgrade, Serbia October 8, 2017 1
Disclosures Dr. Sandison is an employee of and stockholder in Cidara Therapeutics 2
Cidara s Platforms CD101 IV Echinocandin Antifungal Cloudbreak Immunotherapy Candidemia / invasive candidiasis Prophylaxis MDR Gram-negative bacteria 3
CD101: A Novel Echinocandin Structural modification yields improved chemical & biological properties Permanent Charge and Highly Stable Ring Structure: Prolongs PK: 1x Weekly Dosing Allows High Exposures: Treats Less Susceptible Pathogens Eliminates Toxic Degradation Products: Improved Safety & Dose Range Enables Multiple Formulations: Intravenous & Subcutaneous ICAAC 2015 4
CD101 Penetrates and Accumulates at High Levels at the Site of Infection Drug distribution in liver after single dose CD101 at 20 mg/kg determined by MALDI MS Imaging 6h 72h M u ltid o s e s M ic a fu n g in v s. s in g le d o s e C D 1 0 1 7 0 s in g le d o s e C D 1 0 1 6 0 tis s u e d ru g le v e l (µ g /m l) 5 0 4 0 3 0 2 0 2 d o s e s M C F 3 d o s e s M C F Fungi location stained by GMS 1 0 0 L e s io n (4 8 h ) s u r r o u n d (4 8 h ) L e s io n (7 2 h ) s u r r o u n d (7 2 h ) L e s io n (4 8 h ) s u r r o u n d (4 8 h ) L e s io n (7 2 h ) s u r r o u n d (7 2 h ) Zhao and Perlin, Microbe 2016; and unpublished
Dose Fractionation Study of CD101 in Mouse Candidiasis Model Free-Drug Concentration (mg/l) 0.05 0.04 0.03 0.02 0.01 0.00 Dose: 2mg/kg 0 40 80 120 160 Time (hours) N = 5 Mice/Group 1 Week Same Weekly Exposure / Group Lakota ASM 2016 6
Front Loading Echinocandins Improves Efficacy N = 5 Mice/Group 1 Week Same Weekly Exposure / Group Less disease More disease Vehicle Daily Twice weekly Single dose Lakota ASM 2016-3 -2-1 0 1 2 Change in Log 10 CFU at 168h 7
CD101: Improved Target Attainment Percent probabilities of PK-PD target attainment in Candida spp. 90% probability of target attainment CD101 (400mg, weekly for 3 weeks) Caspofungin (70mg 1xq24; 50mg 13xq24h) MIC mg/l C. albicans C. glabrata C. auris C. albicans C. glabrata Rows represent different strains of Candida 0.008 0.015 0.030 MIC 90 0.060 MIC 90 97.8 0.120 50.1 97.2 0.250 98.0 0.40 40.1 0.500 19.3 0.0 0.2 1.000 0.0 0.0 0.0 2.000 0.0 98.7 4.000 0.0 91.1 22.8 8.000 0.0 4.4 0.0 TIMM 2017/ IDSA 2017/ data on file 8
CD101 PK/PD: Exposure Drives Better Target Attainment especially when facing less susceptible pathogens Caspofungin (14 daily doses) 70mg 50mg CD101 (3 weekly doses) Free-drug Plasma AUC 0-24 : MIC Ratio 150 100 50 Weekly fauc:mic Ratio 1600 1200 800 400 400mg 400mg 400mg 0mg Target AUC/MIC 1 7 Days of Therapy 14 0 1 2 3 4 Weeks of Therapy Target fauc/mic=10 MIC=0.25 for caspofungin. MIC=0.12 for CD101 Bader. Emerging Candida glabrata Resistance and Echinocandin Dosing: A Call to Arms! IDWeek 2016 9
STRIVE trial: Phase 2 Candidemia & Invasive Candidiasis Study Design Mycological response Mycological & clinical response: 1 ENDPOINT Mycological & clinical response (IC only) Mycological & clinical response CD101 IV 400/400/(400)mg n=30 CD101 IV 400/200/(200)mg n=30 Caspofungin 70/50/(50)mg n=30 Dose Optional dose Week 1 2 3 4 5 6 7 8 9 1 5 8 15 22 28 Day 35 42 45 49 56 59 Week 1 2 3 4 5 6 7 8 9 1 5 8 15 22 28 35 42 45 49 56 59 Day 70mg Dose 50mg Dose Week 1 2 3 4 5 6 7 8 9 1 5 8 15 22 28 35 42 45 49 56 59 Day 10
Current Prophylaxis Requires Multiple Drugs For Coverage Day -10 0 10 20 30 40 50 60 70 80 SOC for Candida and Aspergillus SOC for Pneumocyctis (PCP) or Fluconazole Posaconazole or Voriconazole Posaconazole or Voriconazole Anti-PCP: Bactrim, dapsone or atovaquone High Risk of IFI Low Candida Aspergillus Pneumocystis Aspergillus Transplant Pre-engraftment Engraftment Post-engraftment Day -10 0 10 20 30 40 50 60 70 80 11
Aspergillus prophylaxis with CD101-100% success at humanized doses STUDY DESIGN 6 mice per arm Controls: Amphotericin B control 3 mg/kg; CD101 at 3 mg/kg; one hour after infection 9 CD101 groups at 5, 10 and 20 mg/kg as prophylaxis was once at Day -5, -3 or -1 before infection All animals immunosuppressed Day 0, infected with A. fumigatus SURVIVAL (%) 100 75 50 25 0 A. fumigatus Prophylaxis Immunocompromised Mice All 10 & 20mg/kg and Controls CD101, 5mg/kg, SC day -1 CD101, 5mg/kg, SC day -3 CD101, 5mg/kg, SC day -5 Vehicle 5 10 15 DAYS 10-20 mg/kg expected humanized dose Mice clear CD101 2-3 fold faster than humans. Accepted abstract ECCMID 2017 12
CD101 Shows Equivalent Efficacy to TMP/SMX in PCP Prophylaxis Mouse Model STUDY DESIGN Prophylaxis with CD101, which blocked cyst/asci formation, offers a new means to prevent PJP 10 mice per arm Infected with P. murina by intranasal inoculation Immunosuppression with dexamethasone throughout study CD101 was administered at the same time the mice were infected Quantification of PCP from lung Source: Cushion et al. ASM. 2016 13
CD101: Simplified Single Drug Paradigm Day -10 0 10 20 30 40 50 60 70 80 SOC for Candida and Aspergillus CD101 SOC for Pneumocyctis (PCP) High Risk of IFI Low Candida Aspergillus Pneumocystis Aspergillus Transplant Pre-engraftment Engraftment Post-engraftment Day -10 0 10 20 30 40 50 60 70 80 14
Phase 3 Antifungal Prophylaxis Trial in HSCT Patients Planned 2018 CD101 Arm (n=220) Week 1 2 3 4 5 12 13 CD101 IV Azole placebo Bactrim placebo Day 1 1 Day 90 Fungal Free Survival Non-Inferiority 2 Day 90 Safety/Tolerability - Superiority 17 90 120 Follow up Comparator Arm (n=220) Week 1 2 3 4 5 12 13 17 CD101 IV Placebo Azole* *Fluconazole or Posaconazole Bactrim Day 1 84 90 120 Adaptive design: interim analysis @ 35% enrollment for futility/sample size. Apx. 15 sites globally, with planned initiation in 2018. Timing and size pending regulatory input 15
Thank You 16