Time-Kill Kinetics of the Novel Echinocandin CD101 for Azole

Time-Kill Kinetics of the Novel Echinocandin CD101 for Azole

Time-Kill Kinetics of the Novel
Echinocandin CD101 for AzoleSusceptible and -Resistant Candida
spp. at pH 4 in Vagina-Simulative
Medium
Jeff Locke, PhD
Amanda Almaguer, BSc
Ken Bartizal, PhD
August 13, 2016
IDSOG 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
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
MIC90 (µg/mL)*
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
Control
0.0625 µg/mL
0.25 µg/mL
1 µg/mL
~43 µm
~32 µm
~26 µm
~24 µm
Biofilm thickness
Biofilm metabolic activity
0 .4
40
XTT O D 492 nm
B io film T h ic k n e s s ( µ m )
50
30
20
10
0 .3
0 .2
0 .1
0 .0
0
C o n tro l
0 .0 6 2 5
0 .2 5
CD101 (µg/mL)
C D 1 0 1 C o n c . ( u g /m l)
1
C o n tro l
0 .0 6 2 5
0 .2 5
1
C DCD101
1 0 1 C o n(µg/mL)
c . ( u g /m l)
§ CD101 demonstrates a significant, dose-dependent reduction in
C. albicans biofilm thickness and metabolic activity
(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 vaginasimulative medium at pH 4.2 vs. C. albicans and nonalbicans Candida, including azole-S and azole-R strains
Study drugs and Candida strains
§ 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
1Moosa
Species
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
Strain
Susceptibility
to FLU
ATCC 44858
DPL001
R357
CG01*
ATCC 200918
MMX 7070
CP02*
CP01*
MMX 7370
CT02*
MMX 7255
MMX 7525
ATCC 6258
ATCC 14243
S
R
R
S
R
R
S
R
R
S
R
R
R
R
* VVC clinical isolate
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
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
CD101
TER
FLU
Strain
FLU
(S/R)
VSM
RPMI
VSM
RPMI
VSM
RPMI
ATCC 44858
DPL001
R357
CG01
S
R
R
S
0.06
0.03
0.5
0.06
0.03
0.06
0.25
0.06
2
64
4
8
32
32
32
0.015
1
128
0.5
16
1
>128
>128
1
ATCC 200918
R*
0.125
0.06
>128
1
>128
32
MMX 7070
CP02
CP01
MMX 7370
CT02
MMX 7255
MMX 7525
ATCC 6258
ATCC 14243
R
S
R
R
S
R
R
R
R
0.25
2
2
2
0.06
0.125
0.125
0.125
0.06
0.03
2
2
1
0.06
0.03
0.06
0.06
0.06
>128
4
32
32
4
>128
>128
16
32
2
0.03
0.125
0.5
4
64
4
0.5
0.5
>128
2
>128
64
2
>128
>128
64
64
64
0.25
16
64
0.5
64
128
32
32
§ Trend towards improved FLU activity for C. albicans in VSM, but
higher MICs for other species
*CLSI MIC value of 32 µg/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.
MIC values for VSM (pH 4.2) vs. RPMI (pH 7.0)
MIC (µg/mL)
Species
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
CD101
TER
FLU
Strain
FLU
(S/R)
VSM
RPMI
VSM
RPMI
VSM
RPMI
ATCC 44858
DPL001
R357
CG01
S
R
R
S
0.06
0.03
0.5
0.06
0.03
0.06
0.25
0.06
2
64
4
8
32
32
32
0.015
1
128
0.5
16
1
>128
>128
1
ATCC 200918
R*
0.125
0.06
>128
1
>128
32
MMX 7070
CP02
CP01
MMX 7370
CT02
MMX 7255
MMX 7525
ATCC 6258
ATCC 14243
R
S
R
R
S
R
R
R
R
0.25
2
2
2
0.06
0.125
0.125
0.125
0.06
0.03
2
2
1
0.06
0.03
0.06
0.06
0.06
>128
4
32
32
4
>128
>128
16
32
2
0.03
0.125
0.5
4
64
4
0.5
0.5
>128
2
>128
64
2
>128
>128
64
64
64
0.25
16
64
0.5
64
128
32
32
§ TER has similar trend as FLU towards improved activity for C. albicans
in VSM, but higher MICs for other species
*CLSI MIC value of 32 µg/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.
MIC values for VSM (pH 4.2) vs. RPMI (pH 7.0)
MIC (µg/mL)
Species
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
CD101
TER
FLU
Strain
FLU
(S/R)
VSM
RPMI
VSM
RPMI
VSM
RPMI
ATCC 44858
DPL001
R357
CG01
S
R
R
S
0.06
0.03
0.5
0.06
0.03
0.06
0.25
0.06
2
64
4
8
32
32
32
0.015
1
128
0.5
16
1
>128
>128
1
ATCC 200918
R*
0.125
0.06
>128
1
>128
32
MMX 7070
CP02
CP01
MMX 7370
CT02
MMX 7255
MMX 7525
ATCC 6258
ATCC 14243
R
S
R
R
S
R
R
R
R
0.25
2
2
2
0.06
0.125
0.125
0.125
0.06
0.03
2
2
1
0.06
0.03
0.06
0.06
0.06
>128
4
32
32
4
>128
>128
16
32
2
0.03
0.125
0.5
4
64
4
0.5
0.5
>128
2
>128
64
2
>128
>128
64
64
64
0.25
16
64
0.5
64
128
32
32
§ CD101 has potent MIC values across all species that are mostly
unchanged or shift 2-fold higher in VSM
*CLSI MIC value of 32 µg/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.
Time-kill assay overview
C F U /m L
Example time-kill plot
10
8
10
7
10
6
10
5
10
4
10
3
10
2
10
1
drug-free growth control
fungistatic activity
cidality threshold
fungicidal activity
limit of detection
0
12
24
36
t im e ( h )
48
60
72
§ 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
Time-kill assay:
TER - ATCC 44858
CD101 - ATCC 44858
T E R - C . a lb ic a n s A T C C 4 4 8 5 8
9
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8
10
0
12
24
36
48
60
72
0
12
24
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
9
12
24
36
t im e ( h )
60
72
60
72
C D 1 0 1 - C . a lb ic a n s R 3 5 7
10
0
48
CD101 – R357
CD101 – DPL001
C D 1 0 1 - C . a lb ic a n s D P L 0 0 1
FLU-R
36
t im e ( h )
t im e ( h )
48
60
72
0
12
24
36
t im e ( h )
48
Time-kill assay: C. albicans
TER - ATCC 44858
CD101 - ATCC 44858
T E R - C . a lb ic a n s A T C C 4 4 8 5 8
9
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8
10
0
12
24
36
48
60
72
0
12
24
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
9
12
24
36
t im e ( h )
60
72
60
72
C D 1 0 1 - C . a lb ic a n s R 3 5 7
10
0
48
CD101 – R357
CD101 – DPL001
C D 1 0 1 - C . a lb ic a n s D P L 0 0 1
FLU-R
36
t im e ( h )
t im e ( h )
48
60
72
0
12
24
36
t im e ( h )
48
Time-kill assay: C. albicans
TER - ATCC 44858
CD101 - ATCC 44858
T E R - C . a lb ic a n s A T C C 4 4 8 5 8
9
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8
10
0
12
24
36
48
60
72
0
12
24
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
9
12
24
36
t im e ( h )
60
72
60
72
C D 1 0 1 - C . a lb ic a n s R 3 5 7
10
0
48
CD101 – R357
CD101 – DPL001
C D 1 0 1 - C . a lb ic a n s D P L 0 0 1
FLU-R
36
t im e ( h )
t im e ( h )
48
60
72
0
12
24
36
t im e ( h )
48
Time-kill assay: C. glabrata
TER – CG01
CD101 – CG01
T E R - C . g la b r a t a C G 0 1
10
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . g la b r a t a C G 0 1
9
0
12
24
36
48
60
72
0
12
24
t im e ( h )
10
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
10
9
12
24
36
t im e ( h )
48
60
60
72
C D 1 0 1 - C . g la b r a t a M M X 7 0 7 0
9
0
48
CD101 – MMX 7070
CD101 – ATCC 200918
C D 1 0 1 - C . g la b r a t a A T C C 2 0 0 9 1 8
FLU-R
36
t im e ( h )
72
0
12
24
36
t im e ( h )
48
60
72
Time-kill assay: C. glabrata
TER – CG01
CD101 – CG01
T E R - C . g la b r a t a C G 0 1
10
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . g la b r a t a C G 0 1
9
0
12
24
36
48
60
72
0
12
24
t im e ( h )
10
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
10
9
12
24
36
t im e ( h )
48
60
60
72
C D 1 0 1 - C . g la b r a t a M M X 7 0 7 0
9
0
48
CD101 – MMX 7070
CD101 – ATCC 200918
C D 1 0 1 - C . g la b r a t a A T C C 2 0 0 9 1 8
FLU-R
36
t im e ( h )
72
0
12
24
36
t im e ( h )
48
60
72
Time-kill assay: C. tropicalis
TER – CT02
CD101 – CT02
T E R - C . t r o p ic a l i s C T 0 2
10
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . t r o p ic a l i s C T 0 2
9
0
12
24
36
t im e ( h )
48
60
72
0
10
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
10
9
12
24
36
t im e ( h )
48
60
36
t im e ( h )
48
60
72
C D 1 0 1 - C . t r o p ic a l i s M M X 7 5 2 5
9
0
24
CD101 – MMX 7525
CD101 – MMX 7255
C D 1 0 1 - C . t r o p ic a l i s M M X 7 2 5 5
FLU-R
12
72
0
12
24
36
t im e ( h )
48
60
72
Time-kill assay: C. tropicalis
TER – CT02
CD101 – CT02
T E R - C . t r o p ic a l i s C T 0 2
10
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . t r o p ic a l i s C T 0 2
9
0
12
24
36
t im e ( h )
48
60
72
0
10
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
10
9
12
24
36
t im e ( h )
48
60
36
t im e ( h )
48
60
72
C D 1 0 1 - C . t r o p ic a l i s M M X 7 5 2 5
9
0
24
CD101 – MMX 7525
CD101 – MMX 7255
C D 1 0 1 - C . t r o p ic a l i s M M X 7 2 5 5
FLU-R
12
72
0
12
24
36
t im e ( h )
48
60
72
Time-kill assay: C. parapsilosis
TER – CP02
CD101 – CP02
T E R - C . p a r a p s i lo s i s C P 0 2
10
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . p a r a p s i lo s i s C P 0 2
9
0
12
24
36
48
60
72
0
12
24
t im e ( h )
10
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
10
9
12
24
36
t im e ( h )
60
72
C D 1 0 1 - C . p a r a p s i lo s i s M M X 7 3 7 0
9
0
48
CD101 – MMX 7370
CD101 – CP01
C D 1 0 1 - C . p a r a p s i lo s i s C P 0 1
FLU-R
36
t im e ( h )
48
60
72
0
12
24
36
t im e ( h )
48
60
72
Time-kill assay: C. parapsilosis
TER – CP02
CD101 – CP02
T E R - C . p a r a p s i lo s i s C P 0 2
10
10
9
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-S
C F U /m L
C D 1 0 1 - C . p a r a p s i lo s i s C P 0 2
9
0
12
24
36
48
60
72
0
12
24
t im e ( h )
10
10
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
C F U /m L
10
9
12
24
36
t im e ( h )
60
72
C D 1 0 1 - C . p a r a p s i lo s i s M M X 7 3 7 0
9
0
48
CD101 – MMX 7370
CD101 – CP01
C D 1 0 1 - C . p a r a p s i lo s i s C P 0 1
FLU-R
36
t im e ( h )
48
60
72
0
12
24
36
t im e ( h )
48
60
72
Time-kill assay: C. krusei
***C. krusei is intrinsically FLU-R***
FLU-S
10
10
C D 1 0 1 - C . k ru s e i A T C C 1 4 2 4 3
CD101 – ATCC 6258
10
9
8
10
8
10
7
10
7
10
6
10
6
10
5
10
5
10
4
10
4
10
3
10
3
10
2
10
2
10
1
10
1
C F U /m L
FLU-R
C F U /m L
C D 1 0 1 - C . k ru s e i A T C C 6 2 5 8
9
0
12
24
36
t im e ( h )
48
60
72
CD101 – ATCC 14243
0
12
24
36
t im e ( h )
48
60
72
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
C. albicans
C. glabrata
C. parapsilosis
C. tropicalis
C. krusei
Strain
Susceptibility
to FLU
CD101
TER
ATCC 44858
DPL001
R357
CG01
ATCC 200918
MMX 7070
CP02
CP01
MMX 7370
CT02
MMX 7255
MMX 7525
ATCC 6258
ATCC 14243
S
R
R
S
R
R
S
R
R
S
R
R
R
R
CIDAL
CIDAL
CIDAL
CIDAL
CIDAL
CIDAL
CIDAL
NEAR-CIDAL
NEAR-CIDAL
NEAR-CIDAL
CIDAL
CIDAL
CIDAL
CIDAL
STATIC
ND
ND
STATIC
ND
ND
NEAR-CIDAL
ND
ND
STATIC
ND
ND
ND
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)