Time-Kill Kinetics of the Novel Echinocandin CD101 for Azole- - PowerPoint PPT Presentation

Time-Kill Kinetics of the Novel Echinocandin CD101 for Azole- Susceptible 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 MIC 90 ( µ g/mL)* fungicidal activity against Species CD101 fluconazole Candida species C. albicans (n=304) 0.06 0.25 § However, current echinocandins C. glabrata (n=121) 0.12 16 have limited chemical stability C. parapsilosis (n=83) 2 2 and not suitable for topical C. tropicalis (n=55) 0.06 0.5 formulation/application C. krusei (n=14) 0.06 32 § 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

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 5 0 B io film T h ic k n e s s ( µ m ) 4 0 X T T O D 4 9 2 n m 0 .3 3 0 0 .2 2 0 0 .1 1 0 0 .0 0 C o n tro l 0 .0 6 2 5 0 .2 5 1 C o n tro l 0 .0 6 2 5 0 .2 5 1 CD101 (µg/mL) CD101 (µg/mL) C D 1 0 1 C o n c . (u g /m l) C D 1 0 1 C o n 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 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 § Terconazole (TER) as comparator Susceptibility Species Strain (topical and Rx-only) to FLU ATCC 44858 S § Similar quantities of CD101 and TER C. albicans DPL001 R administered (240 and 120-240 mg, R357 R respectively) CG01* S C. glabrata ATCC 200918 R § Selected 1 azole-S and 2 azole-R MMX 7070 R CP02* S strains for 4 Candida species C. parapsilosis CP01* R MMX 7370 R § C. krusei is intrinsically azole-R so CT02* S 2 strains were used C. tropicalis MMX 7255 R MMX 7525 R § Mimic VVC physiological conditions ATCC 6258 R C. krusei with vagina-simulative medium 1 ATCC 14243 R (VSM) at pH 4.2 * VVC clinical isolate 1 Moosa 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 ( µ g/mL) CD101 TER FLU FLU Species Strain (S/R) VSM RPMI VSM RPMI VSM RPMI ATCC 44858 S 0.06 0.03 2 32 1 1 C. albicans DPL001 R 0.03 0.06 64 32 128 >128 R357 R 0.5 0.25 4 32 0.5 >128 CG01 S 0.06 0.06 8 0.015 16 1 C. glabrata ATCC 200918 R* 0.125 0.06 >128 1 >128 32 MMX 7070 R 0.25 0.03 >128 2 >128 64 CP02 S 2 2 4 0.03 2 0.25 C. parapsilosis CP01 R 2 2 32 0.125 >128 16 MMX 7370 R 2 1 32 0.5 64 64 CT02 S 0.06 0.06 4 4 2 0.5 C. tropicalis MMX 7255 R 0.125 0.03 >128 64 >128 64 MMX 7525 R 0.125 0.06 >128 4 >128 128 ATCC 6258 R 0.125 0.06 16 0.5 64 32 C. krusei ATCC 14243 R 0.06 0.06 32 0.5 64 32 § Trend towards improved FLU activity for C. albicans in VSM, but higher MICs for other species *CLSI MIC value of 32 µ g/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 ( µ g/mL) CD101 TER FLU FLU Species Strain (S/R) VSM RPMI VSM RPMI VSM RPMI ATCC 44858 S 0.06 0.03 2 32 1 1 C. albicans DPL001 R 0.03 0.06 64 32 128 >128 R357 R 0.5 0.25 4 32 0.5 >128 CG01 S 0.06 0.06 8 0.015 16 1 C. glabrata ATCC 200918 R* 0.125 0.06 >128 1 >128 32 MMX 7070 R 0.25 0.03 >128 2 >128 64 CP02 S 2 2 4 0.03 2 0.25 C. parapsilosis CP01 R 2 2 32 0.125 >128 16 MMX 7370 R 2 1 32 0.5 64 64 CT02 S 0.06 0.06 4 4 2 0.5 C. tropicalis MMX 7255 R 0.125 0.03 >128 64 >128 64 MMX 7525 R 0.125 0.06 >128 4 >128 128 ATCC 6258 R 0.125 0.06 16 0.5 64 32 C. krusei ATCC 14243 R 0.06 0.06 32 0.5 64 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 µ g/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 ( µ g/mL) CD101 TER FLU FLU Species Strain (S/R) VSM RPMI VSM RPMI VSM RPMI ATCC 44858 S 0.06 0.03 2 32 1 1 C. albicans DPL001 R 0.03 0.06 64 32 128 >128 R357 R 0.5 0.25 4 32 0.5 >128 CG01 S 0.06 0.06 8 0.015 16 1 C. glabrata ATCC 200918 R* 0.125 0.06 >128 1 >128 32 MMX 7070 R 0.25 0.03 >128 2 >128 64 CP02 S 2 2 4 0.03 2 0.25 C. parapsilosis CP01 R 2 2 32 0.125 >128 16 MMX 7370 R 2 1 32 0.5 64 64 CT02 S 0.06 0.06 4 4 2 0.5 C. tropicalis MMX 7255 R 0.125 0.03 >128 64 >128 64 MMX 7525 R 0.125 0.06 >128 4 >128 128 ATCC 6258 R 0.125 0.06 16 0.5 64 32 C. krusei ATCC 14243 R 0.06 0.06 32 0.5 64 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 µ g/mL derived in this study is characterized as “susceptible-dose dependent” per CLSI interpretive criteria.

Time-kill assay overview Example time-kill plot 1 0 8 drug-free growth control 1 0 7 1 0 6 1 0 5 C F U /m L fungistatic activity 1 0 4 1 0 3 cidality threshold 1 0 2 fungicidal activity limit of detection 1 0 1 0 1 2 2 4 3 6 4 8 6 0 7 2 tim e (h ) § In vitro measure of fungal killing over time § Initial inoculum mid-10 5 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 µ g/mL § Fungicidal: ≥ 3-log CFU reduction, Fungistatic: <3-log CFU reduction

Time-kill assay: CD101 - ATCC 44858 TER - ATCC 44858 C D 1 0 1 - C . a lb ic a n s A T C C 4 4 8 5 8 T E R - C . a lb ic a n s A T C C 4 4 8 5 8 1 0 9 1 0 9 1 0 8 1 0 8 1 0 7 1 0 7 1 0 6 1 0 6 C F U /m L C F U /m L 1 0 5 1 0 5 FLU-S 1 0 4 1 0 4 1 0 3 1 0 3 1 0 2 1 0 2 1 0 1 1 0 1 0 1 2 2 4 3 6 4 8 6 0 7 2 0 1 2 2 4 3 6 4 8 6 0 7 2 tim e (h ) tim e (h ) CD101 – DPL001 CD101 – R357 C D 1 0 1 - C . a lb ic a n s D P L 0 0 1 C D 1 0 1 - C . a lb ic a n s R 3 5 7 1 0 9 1 0 9 1 0 8 1 0 8 1 0 7 1 0 7 1 0 6 1 0 6 FLU-R C F U /m L C F U /m L 1 0 5 1 0 5 1 0 4 1 0 4 1 0 3 1 0 3 1 0 2 1 0 2 1 0 1 1 0 1 0 1 2 2 4 3 6 4 8 6 0 7 2 0 1 2 2 4 3 6 4 8 6 0 7 2 tim e (h ) tim e (h )