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ABSTRACT
Initi
a l 2h r c o u n ts
V e h icle
, IP, 4 8
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F luc o n a zo le
, 2 0m
g /kg , P O
A mp h o te
r icin
B , 1m
g /kg , IV
A mp h o te
r icin
B , 3m
g /kg , IV
C D 1 0 1 , 3m
g /kg , IP
C D 1 0 1 , 1 0m
g /kg , IP
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94 8 h r a fte r in fe c tio n
CD101
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CD101 Gel Formulation is Highly Efficacious Against Azole-Resistant Candida albicans in a Rat Model of Vulvovaginal Candidiasis
V. Ong1, K. Bartizal1, D. Hughes1, L. Miesel21Cidara Therapeutics, San Diego, CA, 2Eurofins Panlabs, Taipei, Taiwan
Voon Ong, Ph.D.Cidara Therapeutics, Inc.6310 Nancy Ridge Dr., Suite 101San Diego, CA 92121 [email protected]
INTRODUCTION RESULTS RESULTS (cont’d) RESULTS (cont’d)METHODS
REFERENCES1. Miesel, et al., ASM Microbe 2016, Efficacy of a Novel Echinocandin, CD101, in a Mouse Model of
Azole-Resistant Disseminated Candidiasis2. Ong, et al., ASM Microbe 2016, Optimization of CD101 Formulation against Candida albicans in a
Rat Model of Vulvovaginal Candidiasis (VVC)
CD101, a novel, stable and long-acting echinocandin, demonstrated efficacy in mouse disseminated infection as well as rat VVC models of azole-resistant candidiasis. The CFU reduction in these tested models shows that CD101 is fungicidal in vivo against C. albicans.
CD101 is a novel echinocandin being developed for the treatment of fungal infections. Echinocandins have been successfully and safely used as intravenous antifungal therapy for 15 years. Like previously approved echinocandins, CD101 is fungicidal against Candida spp. Unlike previously approved echinocandins, CD101 has a uniquely stabilized structure enabling it to be formulated for topical administration and developed for treatment of VVC.
C. albicans strain R357 is an azole-resistant human blood isolate
CONCLUSIONS
We thank A. Chen, W. Lin, J. Webb of Latitude Pharmaceuticals for developing topical formulations of CD101.
ACKNOWLEDGEMENTS
C. albicans (n=351)MIC90 = 0.06 μg/mL
C. glabrata (n=200)MIC90 = 0.06 μg/mL
Antifungalagent
Endpoint(% inhibition)
MIC (μg/mL)
Susceptibility (CLSI)
Fluconazole 50% >64 RVoriconazole 50% >64 RPosaconazole 50% >64 -Miconazole 50% 2 -Nystatin 50% 2 -Amphotericin B 100% 0.5 SCaspofungin 50% 0.25 SCD101 50% 0.125 -
With a long systemic half-life, CD101 was previously shown to be highly effective against azole-resistant C. albicans (R357) in a mouse disseminated infection model1.
Init i
a l 2h r c o u n ts
V e h icle
, IP, 7 2
h r
F luc o n a zo le
, 2 0m
g /kg , P O
A mp h o te
r icin
B , 1m
g /kg , IV
A mp h o te
r icin
B , 3m
g /kg , IV
C D 1 0 1 , 3m
g /kg , IP
C D 1 0 1 , 1 0m
g /kg , IP
C D 1 0 1 , 3 0m
g /kg , IP
0
1
2
3
4
5
6
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97 2 h r a fte r in fe c tio n
In earlier rat VVC studies, topical CD101 gel given BID eradicated azole-susceptible C. albicans (ATCC 44858) up to at least 1 week after treatment cessation2. Fluconazole given orally showed modest improvement whereas topical miconazole (2% cream) showed fungal rebound less than 1 week after treatment cessation.
No treatment
2%MiconazoleBID
Fluconazole20 mg/kg PO
QD
3%CD101 GelBID
Day post-challenge(Day 5 = 1 day after treatment cessation; Day 12 = 8 days after treatment cessation)
Highly stable echinocandin
CD101 was designed to be a highly stable molecule and has shown robust efficacy in mouse infection models of disseminated Candida/Aspergillus. CD101 has an excellent nonclinical safety and toxicology profile enabling high concentration, front-loaded doses, and is currently in Phase 2 clinical trials for candidemia and vulvovaginal candidiasis (VVC).
Topical formulations of CD101 were optimized and found to be efficacious using a rat VVC model. Initial rat VVC studies were performed using an azole-susceptible C. albicans strain (ATCC 44858). We have subsequently developed mouse disseminated and rat VVC infection models using an azole-resistant C. albicans strain (R357). The results of these studies are presented and discussed in this poster.
Prolongs PK
Eliminates toxic degradation products
Enables multiple formulations
(systemic / topical)
With optimization, a slower release gel formulation of CD101 was developed that enabled once daily (QD) topical administration. This slower release CD101 gel formulation was found to be highly effective in the rat VVC model of azole-resistant C. albicans (R357). The vaginal lavage CFU showed that topical CD101 cleared the vaginal infection and reduced fungal burden for at least 1 week after treatment cessation. Nystatin (2.3% or 100,000 USP/g), a polyene antifungal, did not appear to reduce vaginal CFU as effectively on day 5 compared to CD101.
Mouse disseminated infection model• Neutropenic ICR Mice (n = 5/group)
• Cyclophosphamide on Days -4 (150 mg/kg) and -1 (100 mg/kg)
• Infection – Day 0, C. albicans R357, 105 CFU/mouse
• Treatment with a single dose, 2 hr after infection• Vehicle or CD101 – Intraperitoneal (IP)
• Amphotericin B – Intravenous (IV)
• Fluconazole – Oral (PO)
• Kidney CFU – 48, 72 hr after infection
Single IP dose2 hr post-infection
2
Cyclophosphamide
-2 0-3 3Day -4 -1
IV Infection
1
Kidney CFU
Rat VVC model• Oophorohysterectomized Wistar Rats (n = 5/group)
• 17β-estradiol (10 mg/kg) 3 days before infection and 4 mg/kg/week
• Dexamethasone (2 mg/L) added to drinking water
• Vaginal infection – Day 0, C. albicans (ATCC 44858 or R357)
107 CFU/rat vagina
• Treatment starts 2 days after infection for 3 days, Days 2 to 4
• Vaginal lavage/tissue CFU from separate groups – Days 5 to 12
after infection (1 to 8 days after treatment cessation)
Treatment QD or BIDx 3 days dosing
6 8 10
Vaginal Infection
42
Vaginal lavage CFU on days 5 to 125 9
113120
1 7
Reduction in vaginal lavage CFU suggested CD101 was fungicidal (> 3-log reduction) against C. albicans.
CD101 also showed comparable cidality in vaginal tissue CFU reduction.
Day5 1 2 5 1 2 5 1 2 5 1 2 5 1 2
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Day post-challenge(Day 5 = 1 day after treatment cessation; Day 12 = 8 days after treatment cessation)
No treatment
2%MiconazoleQD
Fluconazole20 mg/kg PO
QD
3%CD101 GelQD
2.3%NystatinQD
5 1 2 5 1 2 5 1 2 5 1 2-5
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FU
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-4
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FU
/ra
tv
ag
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lti
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Day post-challenge(Day 5 = 1 day after treatment cessation; Day 12 = 8 days after treatment cessation)
Day post-challenge(Day 5 = 1 day after treatment cessation; Day 12 = 8 days after treatment cessation)
2%MiconazoleQD
Fluconazole20 mg/kg PO
QD3%CD101 Gel
QD2.3%Nystatin
QD
2%MiconazoleQD
Fluconazole20 mg/kg PO
QD3%CD101 Gel
QD2.3%Nystatin
QD
