CD101: A Novel Echinocandin

Transcription

1 CD101: A Novel Echinocandin Taylor Sandison, MD MPH Chief Medical Officer TIMM Belgrade, Serbia October 8,

2 Disclosures Dr. Sandison is an employee of and stockholder in Cidara Therapeutics 2

3 Cidara s Platforms CD101 IV Echinocandin Antifungal Cloudbreak Immunotherapy Candidemia / invasive candidiasis Prophylaxis MDR Gram-negative bacteria 3

4 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

5 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 s in g le d o s e C D tis s u e d ru g le v e l (µ g /m l) d o s e s M C F 3 d o s e s M C F Fungi location stained by GMS 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io n (4 8 h ) s u r r o u n d (4 8 h ) L e s io n (7 2 h ) s u r r o u n d (7 2 h ) Zhao and Perlin, Microbe 2016; and unpublished

6 Dose Fractionation Study of CD101 in Mouse Candidiasis Model Free-Drug Concentration (mg/l) Dose: 2mg/kg Time (hours) N = 5 Mice/Group 1 Week Same Weekly Exposure / Group Lakota ASM

7 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 Change in Log 10 CFU at 168h 7

8 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 MIC MIC TIMM 2017/ IDSA 2017/ data on file 8

9 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 Weekly fauc:mic Ratio mg 400mg 400mg 0mg Target AUC/MIC 1 7 Days of Therapy 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

10 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 Day Week Day 70mg Dose 50mg Dose Week Day 10

11 Current Prophylaxis Requires Multiple Drugs For Coverage Day 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

12 Aspergillus prophylaxis with CD % 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 (%) 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 DAYS mg/kg expected humanized dose Mice clear CD fold faster than humans. Accepted abstract ECCMID

13 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

14 CD101: Simplified Single Drug Paradigm Day 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

15 Phase 3 Antifungal Prophylaxis Trial in HSCT Patients Planned 2018 CD101 Arm (n=220) Week CD101 IV Azole placebo Bactrim placebo Day 1 1 Day 90 Fungal Free Survival Non-Inferiority 2 Day 90 Safety/Tolerability - Superiority Follow up Comparator Arm (n=220) Week CD101 IV Placebo Azole* *Fluconazole or Posaconazole Bactrim Day Adaptive design: interim 35% enrollment for futility/sample size. Apx. 15 sites globally, with planned initiation in Timing and size pending regulatory input 15

16 Thank You 16