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Time-Kill Kinetics of the Novel Echinocandin CD101 for Azole-Susceptible and -Resistant Candida spp. at pH 4 in Vagina-Simulative Medium
Jeff Locke, PhDAmanda Almaguer, BScKen Bartizal, PhD
186, 89, 21
43, 124, 154
28, 83, 102
102, 102, 102
170, 170, 170
August 13, 2016IDSOG Annual Meeting
Forward-Looking Statements
These slides and the accompanying oral presentation (the “Presentation”) contain forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the effectiveness, safety, dosing, potential to treat infections and other attributes of CD101 topical, as well as related information regarding the effectiveness and treatment protocols for competitive therapies. Risks that contribute to the uncertain nature of the forward-looking statements include: the success and timing of Cidara’s preclinical studies, clinical trials and other research and development activities; regulatory developments in the United States and foreign countries; changes in Cidara’s plans to develop and commercialize its product candidates; Cidara’s ability to obtain additional financing; Cidara’s ability to obtain and maintain intellectual property protection for its product candidates; and the loss of key scientific or management personnel. These and other risks and uncertainties are described more fully in Cidara’s Form 10-K and Form 10-Q, each as most recently filed with the United States Securities and Exchange Commission (SEC), under the heading “Risk Factors.” All forward-looking statements contained in the Presentation speak only as of the date on which they were made. Cidara undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
Disclosures
§ Jeff Locke, Amanda Almaguer and Ken Bartizal are employees and shareholders of Cidara Therapeutics, Inc.
Background
§ 75% of women will experience at least one VVC episode in their lifetime; 5-8% of women have recurrent VVC (RVVC)
§ VVC is caused by Candida albicans (~85%) and non-albicans (~15%)
§ Azole resistance is increasing as are non-albicans Candida
§ Azoles remain the predominant therapeutic class
§ Oral fluconazole used despite relapse, drug-drug interactions and pregnancy risk
§ No FDA-approved therapy for RVVC and no novel agent for VVC in >20 years
MIC90 (µg/mL)*
CD101 – A novel echinocandin antifungal
§ Echinocandins have potent fungicidal activity against Candida species
§ However, current echinocandins have limited chemical stability and not suitable for topical formulation/application
§ Structural modification gives CD101 remarkable chemical and biological stability
§ CD101 could offer a new fungicidal therapy for VVC
*JMI 2015 SENTRY international surveillance study data
Species CD101 fluconazole
C. albicans (n=304) 0.06 0.25
C. glabrata (n=121) 0.12 16
C. parapsilosis (n=83) 2 2
C. tropicalis (n=55) 0.06 0.5
C. krusei (n=14) 0.06 32
CD101 fungicidal activity vs. C. albicans biofilm
§ CD101 demonstrates a significant, dose-dependent reduction in C. albicans biofilm thickness and metabolic activity
Control
~43 µm
0.25 µg/mL
~26 µm
1 µg/mL
~24 µm
0.0625 µg/mL
~32 µm
C o n tr o l 0 .0 6 2 5 0 .2 5 1 0
1 0
2 0
3 0
4 0
5 0
C D 1 0 1 C o n c . (u g /m l)
Bio
film
Th
ick
ne
ss
(µ
m)
C o n tr o l 0 .0 6 2 5 0 .2 5 1 0 .0
0 .1
0 .2
0 .3
0 .4
C D 1 0 1 C o n c . (u g /m l)
XT
T O
D 4
92
nm
Biofilm metabolic activity
CD101 (µg/mL)CD101 (µg/mL)
Biofilm thickness
(M. Ghannoum, unpublished data, 2016)
Study rationale
§ How is the potency and fungicidal activity of CD101 impacted by physiological conditions of the vaginal environment?
§ How does CD101 activity compare with azoles vs. non-albicans Candida and/or azole-R Candida?
Conduct MIC and in vitro time-kill assays in vagina-simulative medium at pH 4.2 vs. C. albicans and non-albicans Candida, including azole-S and azole-R strains
Study drugs and Candida strains
Species StrainSusceptibility
to FLU
C. albicansATCC 44858 S
DPL001 RR357 R
C. glabrataCG01* S
ATCC 200918 RMMX 7070 R
C. parapsilosisCP02* SCP01* R
MMX 7370 R
C. tropicalisCT02* S
MMX 7255 RMMX 7525 R
C. kruseiATCC 6258 RATCC 14243 R
§ Terconazole (TER) as comparator (topical and Rx-only)
§ Similar quantities of CD101 and TER administered (240 and 120-240 mg, respectively)
§ Selected 1 azole-S and 2 azole-R strains for 4 Candida species
§ C. krusei is intrinsically azole-R so 2 strains were used
§ Mimic VVC physiological conditions with vagina-simulative medium1
(VSM) at pH 4.2 * VVC clinical isolate
1Moosa MY, Sobel JD, Elhalis H, Du W, Akins RA. “Fungicidal activity of fluconazole against Candida albicans in a synthetic vagina-simulative medium” 2004. Antimicrob Agents Chemother. 48:161-167.
MIC values for VSM (pH 4.2) vs. RPMI (pH 7.0)MIC (µg/mL)
Species StrainFLU (S/R)
CD101 TER FLU
VSM RPMI VSM RPMI VSM RPMI
C. albicansATCC 44858 S 0.06 0.03 2 32 1 1
DPL001 R 0.03 0.06 64 32 128 >128R357 R 0.5 0.25 4 32 0.5 >128
C. glabrata
CG01 S 0.06 0.06 8 0.015 16 1
ATCC 200918 R* 0.125 0.06 >128 1 >128 32
MMX 7070 R 0.25 0.03 >128 2 >128 64
C. parapsilosisCP02 S 2 2 4 0.03 2 0.25CP01 R 2 2 32 0.125 >128 16
MMX 7370 R 2 1 32 0.5 64 64
C. tropicalisCT02 S 0.06 0.06 4 4 2 0.5
MMX 7255 R 0.125 0.03 >128 64 >128 64MMX 7525 R 0.125 0.06 >128 4 >128 128
C. kruseiATCC 6258 R 0.125 0.06 16 0.5 64 32ATCC 14243 R 0.06 0.06 32 0.5 64 32
*CLSI MIC value of 32 µg/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.
§ Trend towards improved FLU activity for C. albicans in VSM, but higher MICs for other species
MIC values for VSM (pH 4.2) vs. RPMI (pH 7.0)MIC (µg/mL)
Species StrainFLU (S/R)
CD101 TER FLU
VSM RPMI VSM RPMI VSM RPMI
C. albicansATCC 44858 S 0.06 0.03 2 32 1 1
DPL001 R 0.03 0.06 64 32 128 >128R357 R 0.5 0.25 4 32 0.5 >128
C. glabrata
CG01 S 0.06 0.06 8 0.015 16 1
ATCC 200918 R* 0.125 0.06 >128 1 >128 32
MMX 7070 R 0.25 0.03 >128 2 >128 64
C. parapsilosisCP02 S 2 2 4 0.03 2 0.25CP01 R 2 2 32 0.125 >128 16
MMX 7370 R 2 1 32 0.5 64 64
C. tropicalisCT02 S 0.06 0.06 4 4 2 0.5
MMX 7255 R 0.125 0.03 >128 64 >128 64MMX 7525 R 0.125 0.06 >128 4 >128 128
C. kruseiATCC 6258 R 0.125 0.06 16 0.5 64 32ATCC 14243 R 0.06 0.06 32 0.5 64 32
*CLSI MIC value of 32 µg/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.
§ TER has similar trend as FLU towards improved activity for C. albicansin VSM, but higher MICs for other species
MIC values for VSM (pH 4.2) vs. RPMI (pH 7.0)MIC (µg/mL)
Species StrainFLU (S/R)
CD101 TER FLU
VSM RPMI VSM RPMI VSM RPMI
C. albicansATCC 44858 S 0.06 0.03 2 32 1 1
DPL001 R 0.03 0.06 64 32 128 >128R357 R 0.5 0.25 4 32 0.5 >128
C. glabrata
CG01 S 0.06 0.06 8 0.015 16 1
ATCC 200918 R* 0.125 0.06 >128 1 >128 32
MMX 7070 R 0.25 0.03 >128 2 >128 64
C. parapsilosisCP02 S 2 2 4 0.03 2 0.25CP01 R 2 2 32 0.125 >128 16
MMX 7370 R 2 1 32 0.5 64 64
C. tropicalisCT02 S 0.06 0.06 4 4 2 0.5
MMX 7255 R 0.125 0.03 >128 64 >128 64MMX 7525 R 0.125 0.06 >128 4 >128 128
C. kruseiATCC 6258 R 0.125 0.06 16 0.5 64 32ATCC 14243 R 0.06 0.06 32 0.5 64 32
*CLSI MIC value of 32 µg/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.
§ CD101 has potent MIC values across all species that are mostly unchanged or shift 2-fold higher in VSM
Time-kill assay overview
§ In vitro measure of fungal killing over time
§ Initial inoculum mid-105 colony-forming units (CFU)/mL
§ Measured CFU at 0, 1, 3, 6, 9, 24, 48, and 72 h
§ CD101 and TER tested at 0, 2, 8, 32, 128 µg/mL
§ Fungicidal: ≥3-log CFU reduction, Fungistatic: <3-log CFU reduction
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
t im e (h )
CF
U/m
LExample time-kill plot
fungistatic activity
fungicidal activitycidality threshold
limit of detection
drug-free growth control
Time-kill assay:
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . a lb ic a n s A T C C 4 4 8 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s D P L 0 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s R 3 5 7
tim e (h )
CF
U/m
L
FLU-S
FLU-R
CD101 - ATCC 44858 TER - ATCC 44858
CD101 – DPL001 CD101 – R357
Time-kill assay: C. albicans
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . a lb ic a n s A T C C 4 4 8 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s D P L 0 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s R 3 5 7
tim e (h )
CF
U/m
L
FLU-S
FLU-R
CD101 - ATCC 44858 TER - ATCC 44858
CD101 – DPL001 CD101 – R357
Time-kill assay: C. albicans
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . a lb ic a n s A T C C 4 4 8 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s D P L 0 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . a lb ic a n s R 3 5 7
tim e (h )
CF
U/m
L
FLU-S
FLU-R
CD101 - ATCC 44858 TER - ATCC 44858
CD101 – DPL001 CD101 – R357
Time-kill assay: C. glabrata
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . g la b r a ta C G 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . g la b r a ta C G 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . g la b r a ta A T C C 2 0 0 9 1 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . g la b r a ta M M X 7 0 7 0
tim e (h )
CF
U/m
L
CD101 – CG01 TER – CG01
CD101 – ATCC 200918 CD101 – MMX 7070
FLU-S
FLU-R
Time-kill assay: C. glabrata
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . g la b r a ta C G 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . g la b r a ta C G 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . g la b r a ta A T C C 2 0 0 9 1 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . g la b r a ta M M X 7 0 7 0
tim e (h )
CF
U/m
L
CD101 – CG01 TER – CG01
CD101 – ATCC 200918 CD101 – MMX 7070
FLU-S
FLU-R
Time-kill assay: C. tropicalis
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . t r o p ic a lis C T 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . t r o p ic a lis C T 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . t r o p ic a lis M M X 7 2 5 5
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . t r o p ic a lis M M X 7 5 2 5
tim e (h )
CF
U/m
L
CD101 – CT02 TER – CT02
CD101 – MMX 7255 CD101 – MMX 7525
FLU-S
FLU-R
Time-kill assay: C. tropicalis
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . t r o p ic a lis C T 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . t r o p ic a lis C T 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . t r o p ic a lis M M X 7 2 5 5
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . t r o p ic a lis M M X 7 5 2 5
tim e (h )
CF
U/m
L
CD101 – CT02 TER – CT02
CD101 – MMX 7255 CD101 – MMX 7525
FLU-S
FLU-R
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . p a r a p s ilo s is C P 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . p a r a p s ilo s is C P 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . p a r a p s ilo s is C P 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . p a r a p s ilo s is M M X 7 3 7 0
tim e (h )
CF
U/m
L
Time-kill assay: C. parapsilosis
CD101 – CP02 TER – CP02
CD101 – CP01 CD101 – MMX 7370
FLU-S
FLU-R
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . p a r a p s ilo s is C P 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
T E R - C . p a r a p s ilo s is C P 0 2
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . p a r a p s ilo s is C P 0 1
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . p a r a p s ilo s is M M X 7 3 7 0
tim e (h )
CF
U/m
L
Time-kill assay: C. parapsilosis
CD101 – CP02 TER – CP02
CD101 – CP01 CD101 – MMX 7370
FLU-S
FLU-R
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . k ru s e i A T C C 6 2 5 8
tim e (h )
CF
U/m
L
0 1 2 2 4 3 6 4 8 6 0 7 21 0 1
1 0 2
1 0 3
1 0 4
1 0 5
1 0 6
1 0 7
1 0 8
1 0 9
C D 1 0 1 - C . k ru s e i A T C C 1 4 2 4 3
tim e (h )
CF
U/m
L
Time-kill assay: C. krusei
CD101 – ATCC 6258 CD101 – ATCC 14243
FLU-S
FLU-R
***C. krusei is intrinsically FLU-R***
Time-kill results summary
§ CD101 had fungicidal or near-fungicidal activity against all strains
§ TER had fungistatic activity against FLU-S C. albicans, C. glabrata, C. tropicalis strains (near-fungicidal activity vs. C. parapsilosis)
Species StrainSusceptibility
to FLUCD101 TER
C. albicansATCC 44858 S CIDAL STATIC
DPL001 R CIDAL NDR357 R CIDAL ND
C. glabrataCG01 S CIDAL STATIC
ATCC 200918 R CIDAL NDMMX 7070 R CIDAL ND
C. parapsilosisCP02 S CIDAL NEAR-CIDALCP01 R NEAR-CIDAL ND
MMX 7370 R NEAR-CIDAL ND
C. tropicalisCT02 S NEAR-CIDAL STATIC
MMX 7255 R CIDAL NDMMX 7525 R CIDAL ND
C. kruseiATCC 6258 R CIDAL NDATCC 14243 R CIDAL ND
Conclusions
§ CD101 retained potent MIC values and demonstrated fungicidal activity under in vitro conditions simulating the vaginal environment against all major VVC species, including azole-R strains
§ Terconazole had higher MIC values and fungistatic activity against all strains evaluated
§ The potential for CD101 to offer a new therapeutic option for the treatment and prevention of VVC is currently being investigated in a Phase 2 clinical trial
Acknowledgements
§ Dr. Jack Sobel (Wayne State)
§ Dr. David Perlin (Rutgers)
§ Dr. Chris Pillar (Micromyx)
§ Dr. Lynn Miesel (Eurofins)
§ Dr. Mahmoud Ghannoum (Case Western)