U F-761 Prolonged Efficacy Following One Dose of a Novel ...

F-761

Prolonged Efficacy Following One Dose of a Novel Echinocandin, CD101, in a

Neutropenic Mouse Model of Disseminated Candidiasis

Voon Ong, Ph.D.

Cidara Therapeutics, Inc.

6310 Nancy Ridge Dr., Suite 101

San Diego 92121 USA

vong@

V. Ong,1 L. Miesel,2 K. Bartizal,1 H.H. Huang,2 and J.C. Chien2

1Cidara Therapeutics, Inc., San Diego, CA, USA; 2Eurofins Panlabs, Taiwan

ABSTRACT

METHODS

RESULTS (cont¡¯d)

RESULTS (cont¡¯d)

RESULTS (cont¡¯d)

Background: CD101 is a novel echinocandin antifungal with long-acting pharmacokinetics

and chemical stability that is being developed for once-weekly administration. The systemic

candidiasis model with neutropenic mouse was employed to assess the duration of CD101

efficacy over a one week time course.

Minimum inhibitory concentration (MIC). The MIC in a broth

susceptibility test was read at 50% inhibition of growth as defined by

CLSI M27-A2. CD101 and anidulafungin (ANID) were each tested by

2-fold serial dilution from 16 to 0.0156 ?g/mL. A 2 ?L aliquot of each

dilution was added to 198 ?L of RPMI + MOPS with 1-5 x 103 CFU/mL

of C. albicans (R303). The plates were incubated at 35-37?C for

48 hrs and then visually scored.

Table 1. Comparative MIC values of CD101 and ANID against

C. albicans (R303) would not suggest that CD101 performs better

than ANID in vivo.

Figure 3. 7-day time-kill in neutropenic mouse C. albicans model

suggests prolonged effect from as low as one dose of 1 mg/kg.

Figure 5. Bar graph format of Figure 4. A >2-log reduction (*) in the

kidney counts of the treatment groups compared to vehicle. The % of

animals with counts below the LOD is in parentheses.

Conclusion: Efficacy of CD101 in the murine model indicates promise for the treatment of

human systemic candidiasis with a once per week dosing regimen.

INTRODUCTION

Figure 1. CD101 was efficacious at single doses of 0.5, 1.5, and

4.5 mg/kg given IP at 24 h after infection, demonstrating dosedependent reductions of kidney burden that were greater than those of

anidulafungin (ANID) at the 0.5 and 1.5 mg/kg doses and similar to

that of ANID at the high dose.1

6

2

1

Anidulafungin

CD101

1

D

C

Compound

Dose-Normalized

Cmax

([?g/mL]/[mg/kg])

Dose-Normalized

AUC0-24

([?g.h/mL]/[mg/kg])

CD101

1 - 16

3.5

33

ANID3,4

5 - 40

1.2

17

45

CD101

40

1 mg/kg IP

35

3 mg/kg IP

30

10 mg/kg IP

25

20

15

Steady State

24

48

72

96

120

144

h

6 r

1 h

4 r

4

1 h

9 r

2

h

r

9

8

4

h

6 r

1 h

4 r

4

1 h

9 r

2

h

r

8

8

C D101,

C D101,

C D101,

C D101,

1 m g /k g

3 m g /k g

1 0 m g /k g

3 0 m g /k g

CD101 displays a concentration-dependent pattern of activity in vivo,

consistent with that observed for other echinocandins.6 Its superior PK

properties suggest that a front-loaded CD101 dosing regimen is an

optimal approach to maximize drug effect early in the course of

therapy when the density of the pathogen is the greatest, providing the

opportunity to increase the rate and extent of pathogen killing and

resistance prevention.

REFERENCES

V e h ic le

C D 1 0 1 , 1 m g /k g , IP

C D 1 0 1 , 3 m g /k g , IP

C D 1 0 1 , 1 0 m g /k g , IP

5

* *

(1 0 0 )(1 0 0 )

CONCLUSIONS

Drug treatment at 24 h post infection

6

*

(1 0 0 )

168

T im e (h )

7

4

4

V e h ic le

C D 1 0 1 , 3 0 m g /k g , IP

1. ICAAC 2015, Poster F-750.

2. ICAAC 2015, Poster A-015.

4

3. Seyedmousavi S, et al. Antimicrob Agents Chemother. 2013;57:303¨C308.

3

4. Gumbo T, et al. Antimicrob Agents Chemother. 2006;50:3695-3700.

5. ICAAC 2015, Slide Session 044: Pharmacokinetics-Pharmacodynamics

(PK-PD) of a Novel Echinocandin, CD101, in a Neutropenic Murine

Disseminated Candidiasis Model.

2

1

0

10

h

8 r

h

7 r

2

h

r

0

0

*

LO D

2

Figure 4. Even with a delayed treatment start at 24 hrs post-infection

in the same neutropenic mouse C. albicans model, the efficacy was

observed from as low as one dose of 1 mg/kg.

Figure 2. Mouse concentration-time profiles at different IP doses

with terminal half-life >30 hrs; PK-PD analysis from dose

fractionation studies of efficacy in a neutropenic mouse model is

explored in a separate presentation.5

*

( 1 0 0 )( 1 0 0 )

3

0

Doses

(mg/kg)

(4 0 )

2

1

1

* ( 2*0 )

(6 0 )

9

4

* *

4

C D 1 0 1 , 3 0 m g /k g , IP

*

* *

(6 0 )

h

6 r

1 h

4 r

4

1 h

9 r

2

h

r

C D 1 0 1 , 1 0 m g /k g , IP

*

9

5

3

*

8

C D 1 0 1 , 3 m g /k g , IP

* *

4

6

4

h

6 r

1 h

4 r

4

1 h

9 r

2

h

r

C D 1 0 1 , 1 m g /k g , IP

9

V e h ic le

0

24

48

72

96

120

144

168

192

6. Perlin DS. Future Microbiol. 2011;6:441-457.

T im e (h )

5

/k

g

m

.5

4

,

0

1

ID

A

N

1

0

1

D

C

g

g

/k

m

.5

4

,

1

,

,

ID

N

A

g

/k

g

m

.5

.5

1

.5

0

,

1

0

1

D

C

g

g

/k

m

g

m

m

.5

0

,

ID

N

A

g

/k

/k

g

4

2

,

le

ic

h

e

V

g

r

h

r

h

2

,

le

ic

h

e

V

We aim to show that the superior pharmacokinetic properties of

CD101 translates to prolonged efficacy in vivo in a neutropenic mouse

model of disseminated candidiasis.

g

0

0.0078

Table 2. Comparative PK from IP administration of CD101 and ANID

in ICR mouse showing superior pharmacokinetics of CD101 that likely

accounts for better efficacy compared with ANID (given comparable

protein binding of both compounds2).

Plasma Concentration (?g/mL)

L o g ( C F U /g ) in k id n e y

3

7

4

ANID

5

4

0.031

2

CD101

L o g ( C F U /g ) in k id n e y

Neutropenic animal infection model. ICR mice (N=5/group) were

rendered neutropenic by IP injections of cyclophosphamide at

150 mg/kg 4 days before infection (Day ¨C4) and at 100 mg/kg 1 day

before infection (Day ¨C1). On Day 0, animals were inoculated with

C. albicans (R303) intravenously (IV, 0.2 mL/mouse) with the

inoculum size at 103 or 105 CFU depending on study. CD101 doses

(at 1, 3, 10 or 30 mg/kg) were administered IP once at 2 or 24 h after

infection. Animals were euthanized at time points up to 7 days posttreatment followed by CFU enumeration in kidney homogenates.

MIC (?g/mL)

5

Mouse pharmacokinetics. PK of CD101 was evaluated in ICR mice

(N=3/dose) after 1, 4, or 16 mg/kg intraperitoneal (IP) administration.

Plasma was harvested at pre-selected times post-dose and analyzed

by LC-MS/MS.

RESULTS

Echinocandins are potent inhibitors of numerous pathogenic fungal

species, including Candida spp. The primary pharmacodynamics (PD)

of CD101, a novel echinocandin with improved pharmacokinetic (PK)

properties relative to the other agents in the class, has been evaluated

in both in vitro and in vivo studies with a focus on properties that

support the proposed clinical use of once-weekly treatment of

invasive/systemic candidiasis.

Compound

6

L o g ( C F U /g ) in k id n e y

Results: CD101 was significantly efficacious when administered by the IP route across a wide

range of doses and exposures that are projected to be achievable in the clinic (Panel A;

P ¡Ü 0.005 for the 24 and 72 h time points). Efficacy was observed when dosing was delayed

to 24 h after infection (Panel B; P < 0.005 for the 48 h time point).

Drug treatment at 2 h post infection

L o g ( C F U /g ) in k id n e y

Methods: Neutropenic mice were infected by injection of C. albicans strain R303

suspensions into the tail vein, with an inoculum size of 103 CFU per mouse. Test agent and

vehicle were administered to groups of 5 animals with a single intraperitoneal (IP) injection at

2 h or 24 h after infection. Animals were humanely euthanized at time points up to 7 days

post-treatment then Candida counts were measured in kidney homogenates (CFU/g-tissue).

Unpaired Student¡¯s t test was performed to determine the significance of treatment effects

relative to the vehicle control groups.

0

0

4

8

12

Time (h)

16

20

24

ACKNOWLEDGEMENTS

We thank K. James and R. Krishnan for providing the mouse IP

pharmacokinetics data for CD101.

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