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Rezafungin: A Novel Echinocandin
Taylor Sandison, MD MPH
Chief Medical Officer
ISHAM- Amsterdam
July 2, 2018
Disclosures
Dr. Sandison is an employee of and stockholder in Cidara Therapeutics.
Cidara Pipeline
Program Indication DiscoveryResearch/in vitro in vivo
IND-enabling Phase 1 Phase 2 Phase 3
Rezafungin
Rezafungin IV Treatment (Candida)
Rezafungin IV Fungal prophylaxis
RezafunginSubcutaneous
FungalInfections
With NIH, 3Q18
CloudbreakTM Immunotherapy Platform
CloudbreakAntibody Drug Conjugates (ADC)
Gram (-) Infections
Infectious Disease Focus
Hematology/Transplant Focus
Significant Mortality Due to IFIs in Immunocompromised
1 The PATH (Prospective Antifungal Therapy) Alliance registry and invasive fungal infections: update 2012 (2012).
90 day mortality % by patient category1
63%
52%
40%
38%
26%
24%
23%
HSCT
Hematologic malignancy
Solid tumor
General medicine
Surgical (nontransplant)
HIV/AIDS
Solid organ transplant
Bone marrow transplant
Increasing Complexity of Immunocompromised Hosts
Host and Macroenvironment
Antifungal Therapies
ISSUES ISSUESOlder patients
More comorbidities
Chronic immunosuppression
Novel biologics
Shifting epidemiology
Azole-resistant Aspergillus
Flu-resistant Candida
Drug-Drug Interactions
GI Intolerance
Hepatotoxicity
Nephrotoxicity
QT prolongation
Bone marrow suppression
Allergy
Underdosing/TDM
Rezafungin: A Better Echinocandin. A Better Antifungal.
ICAAC 2015
• Designed for prolonged PK
• Designed for high exposures
• Eliminates toxic degradation products
• Enables multiple formulations
once weekly dosing in clinical studies
potential for improved efficacy vs Candida and Aspergillus infections
potential for improved safety
intravenous; subcutaneous under development
Structural modification yields improved chemical & biological properties
Zhao, Perlin et al, AAC July 2017
10
20
30
40
50
60Tissue Drug Level(µg/ml)
Data Favors Rezafungin in Severe Infections
1 dose of rezafungin vs.2 doses of micafungin
1 dose of rezafungin vs.3 doses of micafungin
10
20
30
40
50
60
48 HOURS 72 HOURS
RezaMica RezaMica
Intra-abdominal Invasive Candidiasis Abscess Model
Accumulates to Higher Levels than Micafungin at Infection Site
400/400/(400)mg n=30
400/200/(200)mg n=30
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28
Dose Optional dose
Mycological response
Mycological & clinical response: 1° ENDPOINT
Mycological & clinical response (IC only)
4535 42 49 56 59
Mycological & clinical response
Caspofungin70/50/(50)mg n=30
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28 4535 42 49 56 59
70mg Dose
50mgDose®
All cause mortalityRezafungin
Analysis Populations:§ The Intent-to-treat (ITT) population: all randomized subjects § The Safety population: all subjects who received any amount of study drug§ The Microbiological Intent-to-treat population (mITT): all subjects in safety population who had documented
Candida infection
STRIVE Part A: Candidemia & Invasive CandidiasisNot Powered for Inferential Statistics
Summary of Adverse EventsSafety Population
Parameter
Rezafungin400 mg/400 mg (QWk)
N= 35
Rezafungin400 mg/200 mg (QWk)
N= 36
Caspofungin70 mg/50 mg (QD)
N= 33
n (%)
≥1 TEAESevere
31 (88.6)13 (37.1)
34 (94.4)10 (27.8)
27 (81.8)13 (39.4)
Study-drug related TEAE 4 (11.4) 6 (16.7) 4 (12.1)
Serious AEStudy-drug related SAE
13 (37.1)0
18 (50.0)1 (2.8)
13 (39.4)1 (3.0)
AE=adverse event.TEAE=treatment-emergent adverse event: AE that occurs after the first dose of study drug is administered.
Response
Rezafungin400 mg/400 mg (QWk)
N= 33
Rezafungin400 mg/200 mg (QWk)
N= 31
Caspofungin70 mg/50 mg (QD)
N= 28
n (%)
Overall Response- Success 19 (57.6) 22 (71.0) 18 (64.3)
- Failure 7 (21.2) 6 (19.4) 8 (28.6)
- Indeterminatea 7 (21.2) 3 (9.7) 2 (7.1)
Overall Response and PI Assessment of Clinical ResponseDay 14 – mITT Population
aIndeterminate response indicates inability to assess outcome due to missing data point(s)
Response
Rezafungin400 mg/400 mg (QWk)
N= 33
Rezafungin400 mg/200 mg (QWk)
N= 31
Caspofungin70 mg/50 mg (QD)
N= 28
n (%)
Overall Response- Success 19 (57.6) 22 (71.0) 18 (64.3)
- Failure 7 (21.2) 6 (19.4) 8 (28.6)
- Indeterminatea 7 (21.2) 3 (9.7) 2 (7.1)
Overall Response and PI Assessment of Clinical ResponseDay 14 – mITT Population
Excluding Indeterminate Response
Success 19/26 (73.1) 22/28 (78.6) 18/26 (69.2)
Failure 7/26 (26.9) 6/28 (21.4) 8/26 (30.8)
aIndeterminate response indicates inability to assess outcome due to missing data point(s)
Response
Rezafungin400 mg/400 mg (QWk)
N= 33
Rezafungin400 mg/200 mg (QWk)
N= 31
Caspofungin70 mg/50 mg (QD)
N= 28
n (%)
Overall Response- Success 19 (57.6) 22 (71.0) 18 (64.3)
- Failure 7 (21.2) 6 (19.4) 8 (28.6)
- Indeterminatea 7 (21.2) 3 (9.7) 2 (7.1)
Overall Response and PI Assessment of Clinical ResponseDay 14 – mITT Population
Clinical Cureb 25 (75.8) 24 (77.4) 20 (71.4)
- Failure 7 (21.2) 4 (12.9) 8 (28.6)
- Indeterminatea 1 (3.0) 3 (9.7) 0
Excluding Indeterminate Response
Success 19/26 (73.1) 22/28 (78.6) 18/26 (69.2)
Failure 7/26 (26.9) 6/28 (21.4) 8/26 (30.8)
aIndeterminate response indicates inability to assess outcome due to missing data point(s)bOutcome most closely approximating primary outcome from prior IC clinical trials
Response
Rezafungin400 mg/400 mg (QWk)
N= 33
Rezafungin400 mg/200 mg (QWk)
N= 31
Caspofungin70 mg/50 mg (QD)
N= 28
n (%)
Overall Response- Success 19 (57.6) 22 (71.0) 18 (64.3)
- Failure 7 (21.2) 6 (19.4) 8 (28.6)
- Indeterminatea 7 (21.2) 3 (9.7) 2 (7.1)
13
Overall Response and PI Assessment of Clinical ResponseDay 14 – mITT Population
Clinical Cureb 25 (75.8) 24 (77.4) 20 (71.4)
- Failure 7 (21.2) 4 (12.9) 8 (28.6)
- Indeterminatea 1 (3.0) 3 (9.7) 0
Excluding Indeterminate Response
Success 19/26 (73.1) 22/28 (78.6) 18/26 (69.2)
Failure 7/26 (26.9) 6/28 (21.4) 8/26 (30.8)
Excluding Indeterminate Response
Success 25/32 (78.1) 24/28 (85.7) 20/28 (71.4)
Failure 7/32 (21.9) 4/28 (14.3) 8/28 (28.6)aIndeterminate response indicates inability to assess outcome due to missing data point(s)bOutcome most closely approximating primary outcome from prior IC clinical trials
14
Mycological Response in Candidemia / Overall Response in ICDay 14 – mITT Population
Response
Rezafungin400 mg/400 mg (QWk)
N= 30
Rezafungin400 mg/200 mg (QWk)
N= 26
Caspofungin70 mg/50 mg (QD)
N= 25
n (%)
Mycological Success in Candidemia
20 (70.0) 17 (65.4) 18 (72.0)
- Failure 6 (20.0) 6 (23.1) 6 (24.0)
- Indeterminatea 3 (10.0) 3 (11.5) 1 (4.0)
aIndeterminate response indicates inability to assess outcome due to missing data point(s)
15
Mycological Response in Candidemia / Overall Response in ICDay 14 – mITT Population
Response
Rezafungin400 mg/400 mg (QWk)
N= 30
Rezafungin400 mg/200 mg (QWk)
N= 26
Caspofungin70 mg/50 mg (QD)
N= 25
n (%)
Mycological Success in Candidemia
20 (70.0) 17 (65.4) 18 (72.0)
- Failure 6 (20.0) 6 (23.1) 6 (24.0)
- Indeterminatea 3 (10.0) 3 (11.5) 1 (4.0)
Excluding Indeterminate Response
Success 21/27 (77.8) 17/23 (73.9) 18/24 (75.0)
Failure 6 (22.2) 6 (26.1) 6 (25.0)
aIndeterminate response indicates inability to assess outcome due to missing data point(s)
16
Mycological Response in Candidemia / Overall Response in ICDay 14 – mITT Population
Response
Rezafungin400 mg/400 mg (QWk)
N= 30
Rezafungin400 mg/200 mg (QWk)
N= 26
Caspofungin70 mg/50 mg (QD)
N= 25
n (%)
Mycological Success in Candidemia
20 (70.0) 17 (65.4) 18 (72.0)
- Failure 6 (20.0) 6 (23.1) 6 (24.0)
- Indeterminatea 3 (10.0) 3 (11.5) 1 (4.0)
Excluding Indeterminate Response
Success 21/27 (77.8) 17/23 (73.9) 18/24 (75.0)
Failure 6 (22.2) 6 (26.1) 6 (25.0)
Overall Success in IC 1/3 (33.3) 5/5 (100.0) 1/3 (33.3)
- Failure 1 (33.3) 0 2 (66.7)
- Indeterminatea 1 (33.3) 0 0
aIndeterminate response indicates inability to assess outcome due to missing data point(s)
Rezafungin PK/PD: Dose Selection and Target Attainment
TargetfAUC/MIC
Free
-dru
g Pl
asm
a AU
C 0-2
4: M
IC R
atio
100
150
Caspofungin (14 daily doses)
70mg 50mg
Days of Therapy
14
50
1 7
MIC=0.25 for caspofungin. MIC=0.12 for CD101.
Bader et al. Emerging Candida glabrata Resistance and Echinocandin Dosing: A Call to Arms! IDWeek 2016. Bader et al. Overcoming the Resistance Hurdle: PK-PD Target Attainment Analyses of Rezafungin (CD101) for Candida albicans and Candida glabrata. Submitted AAC 2018; revised with Phase 2 results.
Weeks of Therapy
Rezafungin (4 weekly doses)
Wee
kly
fAU
C:M
ICRa
tio
400
300
200
100
01 2 3
400mg
200mg 200mg
TargetfAUC/MIC
400mg
400mg
4
200mg
400mg
ReSTORE: Candidemia & Invasive Candidiasis
400 mg then 200mg qWk n=92
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28
Dose Optional dose
Global Response
Global Response: 1° EMA ENDPOINT
EOT (latest): Global Response
4535 42 52 56 59
Global Response
Caspofungin70 mg then 50mg qDay n=92
Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28 4535 42 52 56 59
70mg Dose
50mg Dose®
All Cause Mortality:1° FDA ENDPOINT
Phase 3 Pivotal Clinical Treatment Trial
Rezafungin
Global Response: Clinical and Mycological Response (DRC determined)
Antifungal Prophylaxis
Current Prophylaxis (Allo-HSCT) Requires Multiple Drugs for Coverage
Day
Risk of IFIHigh
Low
Post-engraftmentPre-engraftment
CandidaAspergillusPneumocystis
PneumocystisAspergillusCandida
0 10 20 30 6040 70 8050-10
SOC for Candidaand Aspergillus
Posaconazole or Voriconazole
Day 0 10 20 30 6040 70 8050-10
Anti-PCP: Bactrim, dapsone or atovaquone
Posaconazole or Voriconazole
or…
Fluconazole
Transplant Engraftment
SOC for Pneumocyctis
(PCP)
29
Rezafungin: Potential for Simplified Single Drug Paradigm
Day 0 10 20 30 6040 70 8050-10
SOC for Candidaand Aspergillus
Rezafungin
Risk of IFIHigh
Low
Post-engraftmentPre-engraftment
Day 0 10 20 30 6040 70 8050-10
Transplant Engraftment
SOC for Pneumocyctis
(PCP)
CandidaAspergillusPneumocystis
PneumocystisAspergillusCandida
Week 1 2 3 4 12
Azole placebo
Bactrim placebo
Rezafungin5 13
Day 1
17
90 120
1° Day 90 Fungal Free Survival – Non-Inferiority2° Day 90 Safety/Tolerability - Superiority
Follow upRezafungin Arm (n=~300)
Adaptive design: interim analysis @ 50% enrollment for futility/sample size Apx. 20 sites globally. Size and timing pending additional regulatory input
17Week 1 2 3 4 12
Azole*
Bactrim
Rezafungin Placebo5 13
Day 1 84 90 120
Comparator Arm (n=~150)
*Fluconazole or Posaconazole
Phase 3 Pivotal Clinical Prophylaxis Trial
ReSPECT: Antifungal Prophylaxis in Allogeneic HSCT
Rezafungin Overall Phase 3 Development Plan*
Phase 3 Treatment Trial
Indication
Phase 3Size
Duration of Therapy,
Endpoints and Comparators
Treatment ofcandidemia & invasive
candidiasis in patients with limited treatment options
~ 184 patients
2- to 4-week treatmentDay 30 all-cause mortality (US)
Caspofungin
Phase 3 Prophylaxis Trial
Prophylaxis against Aspergillus, Candida & PCP in patients undergoing allogeneic bone
marrow transplant
~450 patients w/ adaptive design
90-day prophylaxis90-day fungal-free survivalFluconazole, posaconazole,
Bactrim
*Plans and timelines for Phase 3 treatment trial subject to regulatory interactions and cash resources. Phase 3 prophylaxis trial subject to regulatory interactions, cash resources and preclinical studies to establish long term dosing
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