cd101: a novel echinocandin · 2017-10-09 · 4 cd101: a novel echinocandin structural modification...
TRANSCRIPT
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CD101: A Novel Echinocandin
Taylor Sandison, MD MPHChief Medical Officer
TIMM – Belgrade, Serbia
October 8, 2017
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Disclosures
Dr. Sandison is an employee of and stockholder in Cidara Therapeutics
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Cidara’s Platforms
CD101 IV Echinocandin Antifungal
Candidemia / invasive candidiasis
Prophylaxis
Cloudbreak™ Immunotherapy
MDR Gram-negative bacteria
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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 & SubcutaneousICAAC 2015
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
L e s ion (4
8 h )
s u r ro u n d (4
8 h )
L e s ion (7
2 h )
s u r ro u n d (7
2 h )
L e s ion (4
8 h )
s u r ro u n d (4
8 h )
L e s ion (7
2 h )
s u r ro u n d (7
2 h )0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
tiss
ue
dru
g le
vel (
µg
/ml)
2 d o s e s M C F
3 d o s e s M C F
s in g le d o s e C D 1 0 1
6h 72h
Drug distribution in liver after single dose CD101 at 20 mg/kg determined by MALDI MS Imaging
Fungi location stained by GMS
Zhao and Perlin, Microbe 2016; and unpublished
CD101 Penetrates and Accumulates at High Levels at the Site of Infection
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Dose Fractionation Study of CD101 in Mouse Candidiasis Model
12080400 160
0.05
0.04
0.03
0.02
0.01
0.00
Free
-Dru
g Co
ncen
trat
ion
(mg/
L)
Time (hours)
Dose: 2mg/kg
Lakota ASM 2016
N = 5 Mice/Group1 WeekSame Weekly Exposure / Group
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Front Loading Echinocandins Improves Efficacy
Single doseSingle dose
Vehicle
Twice weekly
Daily
10-1-2-3 2
Change in Log10 CFU at 168h
More disease ®¬ Less disease
Lakota ASM 2016
N = 5 Mice/Group1 WeekSame Weekly Exposure / Group
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CD101: Improved Target Attainment
Percent probabilities of PK-PD target attainment in Candida spp.
MIC mg/L
0.008
0.015
0.030
0.060
0.120
0.250
0.500
1.000
2.000
4.000
8.000
100.0
100.0
100.0
100.0
100.0
98.0
19.3
0.0
0.0
0.0
0.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
91.1
4.4
100.0
100.0
100.0
100.0
100.0
100.0
100.0
100.0
98.7
22.8
0.0
C. albicans C. glabrata C. auris
100.0
100.0
100.0
97.8
50.1
0.40
0.0
0.0
100.0
100.0
100.0
100.0
97.2
40.1
0.2
0.0
C. albicans C. glabrata
Caspofungin≥90% probability of target attainment
MIC90
MIC90
Rows represent different strains of Candida
(70mg 1xq24; 50mg 13xq24h)CD101 (400mg, weekly for 3 weeks)
TIMM 2017/ IDSA 2017/ data on file
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CD101 PK/PD: Exposure Drives Better Target Attainmentespecially when facing less susceptible pathogens
TargetAUC/MIC
Free
-dru
g Pl
asm
a AU
C 0-2
4: M
IC R
atio
100
150
Caspofungin (14 daily doses)
70mg 50mg
Days of Therapy
14
50
1 7
MIC=0.25 for caspofungin. MIC=0.12 for CD101 Bader. Emerging Candida glabrata Resistance and Echinocandin Dosing: A Call to Arms! IDWeek 2016
Weeks of Therapy
CD101 (3 weekly doses)
Wee
kly
fAU
C:M
ICRa
tio 1600
1200
800
400
01 2 3 4
400mg 400mg 400mg 0mg
TargetfAUC/MIC=10
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STRIVE trial: Phase 2 Candidemia & Invasive CandidiasisStudy Design
CD101 IV400/400/(400)mgn=30
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28
Dose Optional dose
Mycological response
Mycological & clinical response: 1° ENDPOINT
Mycological & clinical response (IC only)
4535 42 49 56 59
Mycological & clinical response
CD101 IV400/200/(200)mgn=30
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28 4535 42 49 56 59
Caspofungin70/50/(50)mgn=30
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28 4535 42 49 56 59
70mg Dose 50mg Dose®
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Current Prophylaxis Requires Multiple Drugs For Coverage
Day 0 10 20 30 6040 70 8050-10
SOC for Candida and Aspergillus
Posaconazole or Voriconazole
Anti-PCP: Bactrim, dapsone or atovaquone
Posaconazole or Voriconazole
or…
Fluconazole
Risk of IFIHigh
Low
Post-engraftmentPre-engraftment
CandidaAspergillus
PneumocystisAspergillus
Day 0 10 20 30 6040 70 8050-10
Transplant Engraftment
SOC for Pneumocyctis
(PCP)
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Aspergillus prophylaxis with CD101-100% success at humanized doses
10-20 mg/kg ≈ expected humanized doseMice clear CD101 2-3 fold faster than humans.
Accepted abstract ECCMID 2017
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
DAYS
100
75
50
25
05 10 15
Vehicle
CD101, 5mg/kg, SC day -5
CD101, 5mg/kg, SC day -3
CD101, 5mg/kg, SC day -1
All 10 & 20mg/kg and Controls
A. fumigatus ProphylaxisImmunocompromised Mice
SUR
VIVA
L (%
)
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CD101 Shows Equivalent Efficacy to TMP/SMX in PCP Prophylaxis Mouse Model
*Denotes statistical significance reduction from C/S group - p value <0.05
RESULTS‘Prophylaxis with CD101, which blocked cyst/asci formation, offers a new means to prevent PJP’
Source: Cushion et al. ASM. 2016
STUDY DESIGN
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
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CD101: Simplified Single Drug Paradigm
Day 0 10 20 30 6040 70 8050-10
SOC for Candida and Aspergillus
CD101
Risk of IFIHigh
Low
Post-engraftmentPre-engraftment
CandidaAspergillus
PneumocystisAspergillus
Day 0 10 20 30 6040 70 8050-10
Transplant Engraftment
SOC for Pneumocyctis
(PCP)
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Week 1 2 3 4 12
Azole placebo
Bactrim placebo
CD101 IV5 13
Day 1
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Phase 3 Antifungal Prophylaxis Trial in HSCT PatientsPlanned 2018
90 120
1° Day 90 Fungal Free Survival – Non-Inferiority2° Day 90 Safety/Tolerability - Superiority
Follow up
CD101 Arm (n=220)
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
17Week 1 2 3 4 12
Azole*
Bactrim
CD101 IV Placebo5 13
Day 1 84 90 120
Comparator Arm (n=220)
*Fluconazole or Posaconazole
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Thank You