Rezafungin (CD101)Taylor Sandison, MD MPH
Chief Medial Officer
Rezafungin: a novel echinocandindesigned for next-generation properties
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
• Broad spectrum of activity and in vivo efficacy
• Novel PK/PD
• Improved safety
• Increased solubility and stability Rezafungin
“… confers much greater stability, leading to an exceptionally longer half-life and
an improved safety profile”
Rezafungin: a novel echinocandindesigned for next-generation properties
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
• Broad spectrum of activity and in vivo efficacy
à Candida, Aspergillus, Pneumocystis including a subset of azole- and echinocandin-R isolates
à Potential prevention of resistance
• Novel PK/PD
• Improved safety
• Increased solubility and stability
Rezafungin
“… confers much greater stability, leading to an exceptionally longer half-life and
an improved safety profile”
MIC90 (µg/mL)a
C. albicans(n=1098)b
C. glabrata(n=477)b
C. tropicalis(n=224)b
C. krusei(n=130)b
C. parapsilosis(n=387)b
C. kefyr(n=51)c
C. lusitaniae (n=43)c
C. guilliermondii
(n=20)c
C. dubliniensis
(n=21)c
C. auris(n=19)c
C. auris(n=100)d
Rezafungin 0.06 0.125 0.06 0.06 2 0.12 0.25 1 0.06 0.25 0.5
Anidulafungin 0.03 0.125 0.06 0.125 2 0.06 0.06 2 0.03 0.25 NA
Caspofungin 0.03 0.06 0.06 0.25 0.5 0.5 1 1 0.25 1 NANC=not available.aCLSI broth microdilution methodology was employed for MIC determination (M27-A3).bClinical isolates collected internationally in the JMI Laboratories SENTRY Antimicrobial Surveillance Program (2014-2017).cClinical isolates collected in Hungary (2005-2018), except for C. auris obtained from the National Mycology Reference Laboratory (Bristol, UK), tested as part of a retrospective study.dClinical isolates collected by the CDC, representing each of the 4 known clades of C. auris, including 8 isolates with elevated MICs to one or more echinocandins.
Berkow and Lockhart. Diagn Microbio Infect Dis. 2018;90:196-197; Hall et al. Diag Microbio Infect Dis. 2017;89:205-211; Pfaller et al. Int J Antimicrob Agents. 2017a;50:352-358. Pfaller et al. Antimicrob Agents Chemother. 2017b;61:e02045-16; Toth et al. ECCMID 2018; poster P2161.
Rezafungin broad-spectrum in vitro activityagainst common and rare Candida spp.
Rezafungin in vitro activity against Candida aurisMIC90 of 0.5 µg/mL includes echinocandin-R isolates
aCLSI BMD methodology, M27-A3Berkow and Lockhart. Diagn Microbio Infect Dis. 2018;90:196-197.
IsolateFKS1 mutation
Rezafungin Anidulafungin Caspofungin Micafungin
B11211 S639P 4 8 1 4
B11222 None 0.25 2 16 2
B11780 None 0.06 4 0.5 0.5
B11784 None 0.5 >16 >16 >8
B11858 None 0.25 4 >16 1
B12131 S639P 8 8 >16 8
B12137 S639P 8 8 >16 8
B12149 S639P 8 8 >16 8
Rezafungin MIC Distribution (µg/mL)a
0.03 0.0625 0.125 0.25 0.5 1 2 4 8
2 21 28 32 13 - - 1 3
MICs (µg/mL)a against 8 echinocandin-R isolates
Rezafungin demonstrated activity against C. auris
CDC collection of clinical C. auris (N=100) had all 4 known clades and 8 isolates with elevated echinocandin MICs
MEC90 (µg/mL)a
A. fumigatus(n=261)b
A. terreus(n=19)b
A. niger(n=16)b
A. flavus(n=43)b
azole-R A. fumigatus (n=31)c
A. lentulus(n=11)c
A. calidoustus (n=11)c
Rezafungin 0.015 0.015 ≤0.008 0.015 Rezafungin 0.12 ≤0.015 0.06
Anidulafungin 0.015 0.015 ≤0.008 0.015 Posaconazole 0.4 0.5 4
Caspofungin 0.03 0.125 0.06 0.03 Voriconazole >16 8 4aCLSI broth microdilution methodology was employed for MEC determination (M38-A2).bClinical isolates collected internationally in the JMI Laboratories SENTRY Antimicrobial Surveillance Program (2014-2017).cClinical isolates collected in the US and resistance genotypes confirmed by DNA sequence analysis (CYP51A only, n=13; TR34/L98H, n=2; TR46/Y121F/T289A, n=2; resistant/no CYP51A mutation, n=6; resistant/CYP51A status unknown, n=8). (Wiederhold et al, 2018a; 2018b).
Pfaller et al. J Antimicrob Chemother. 2016;71:2868-2873; Pfaller et al. Int J Antimicrob Agents. 2017;50:352-358. Wiederhold et al. AAA, 2018a; oral presentation; Wiederhold et al. J Antimicrob Chemother. 2018b;73:3063-3067.
Rezafungin broad-spectrum in vitro activityagainst Aspergillus spp., including azole-R and cryptic spp.
Rezafungin treatment efficacy against Candida aurissignificantly lower fungal burden in immunosuppressed mice
a p=0.023 on day 1 postinfectionHager et al. J Antimicrob Chemother. 2018;73:2085-2088.
Kidney Tissue Fungal Burden on Days 1, 4, 7, and 10
Rezafungin-treated mice showed significantly lower C. auris fungal burden
• vs amphotericin B, all days (p<0.0001)a
• vs micafungin, day 10 (p=0.0128)
Rezafungin prophylaxis efficacy against Aspergillus survival in immunosuppressed mouse model
Ong et al. ECCMID 2017; poster EP0703; Ong et al. EHA 2017; poster P645.
Single SC dose of Rezafungin on either
D -5, -3, or -1
CPM
-2 0-3-4 -1
IV Infection with A. fumigatus (ATCC 13073)
1-5 4 14
CPM CPM
Survival Up To Day 14
2 3
Rezafungin: one subcutaneous dose of 5, 10 or 20 mg/kga on days -5, -3, or -1 as prophylaxis
Control/Amphotericin B: 3 mg/kgone hour after infection
CPM=cyclophosphamide
10 mg/kg ≈ human dose of 200mg20 mg/kg ≈ human dose of 400mg2-3 fold faster clearance in mice than in humans.
n=6/arm
Rezafungin prophylaxis efficacy against Aspergillus survival in immunosuppressed mouse model
CPM=cyclophosphamide.Ong et al. ECCMID 2017; poster EP0703; Ong et al. EHA 2017; poster P645.
Rezafungin at human equivalent doses demonstrated 100% efficacy as
prophylaxis against Aspergillus, even when administered 5 days pre-infection
(≈2 weeks in humans)
Days
100
75
50
25
0
5 10 15
Vehicle
Reza, 5 mg/kg, SC day -5
Reza, 5 mg/kg, SC day -3
Reza, 5 mg/kg, SC day -1
All 10 & 20 mg/kg and Controls
Surv
ival
(%)
Pneumocystis pneumoniareview and reappraisal of a pathogen and its prophylaxis
Cushion et al. ASH, 2016; oral presentation.
Current Approach to Prophylaxis • TMP-SMX: TMP 15–20 mg/kg/d and
SMX 75–100 mg/kg/d), PO in 3 divided doses or TMP-SMX DS, 2 tablets TID
• Dapsone plus pyrimethamine + leucovorin
• Aerosolized pentamidine
• Atovaquoneplus pyrimethamine + leucovorin
• NOT recommended: oral clindamycin plus primaquine
Pneumocystis jiroveci (carinii) • Obligate fungi• Opportunistic pathogen of lethal pneumonia
HIV-infected, chemotherapy, corticosteroids, other diseases states
• Biphasic life cycleasexual - trophic forms asexual - asci/cysts
Life Cycle of Pneumocystis
Rezafungin prophylaxis efficacy against Pneumocystis equivalent to TMP/SMX in immunosuppressed mouse model
Cushion et al. ASH 2016, oral presentation; Cushion and Ashbaugh. TCT 2019; poster.
Rezafungin administered at time of Pneumocystis inoculation (P. murina)
• Rezafungin significantly reduced counts of both nuclei and asci
• No significant differences in survival rates
• Rezafungin efficacy equivalent to the gold standard TMP/SMX
• Efficacy seen with much lower doses than required for Candida or Aspergillus models
Study1
Nuclei Counts
Study2
Asci Counts
*
20 mg/
kg/3
x/wk
20 mg/
kg/1x/
wk
2 mg/
kg/3x/
wk
2 mg/
kg/1x/
wk
0.2 mg/
kg/3x/
wk
0.2 mg/
kg/1x/
wk
TMP/S
MX 3x/wk
C/S
TMP/S
MX 3x/wk
20 mg/
kg/3x/
wk
20 mg/
kg/1x/
wk
2 mg/
kg/3x/
wk
2 mg/
kg/1x/
wk
0.2 mg/
kg/3x/
wk
0.2 mg/
kg/1x/
wk
**
0.5 mg/
kg/1
x/wk
0.5 mg/
kg/2x/
wk
0.5 mg/
kg daily
5 mg/
kg 1x/
wk
5 mg/
kg daily
CSF 5 m
g/kg d
aily
TMP/S
MX 3x/wk
C/S
0.5 mg/
kg/1
x/wk
0.5 mg/
kg/2x/
wk
0.5 mg/
kg daily
5 mg/
kg 1x/
wk
5 mg/
kg daily
CSF 5 m
g/kg d
aily
TMP/S
MX 3x/wk
C/S
*p<0.05 vs C/S (control/steroid only)
C/S
Rezafungin: a novel echinocandindesigned for next-generation properties
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
• Broad spectrum of activity and in vivo efficacy
• Novel PK/PD
à Prolonged t1/2 (~130 h)
à High drug exposure
à Maximized pharmacometric drivers of efficacy
• Improved safety
• Increased solubility and stability
Rezafungin
“… confers much greater stability, leading to an exceptionally longer half-life and
an improved safety profile”
Rezafungin: exposure shape mattersPK/PD determinant of antifungal efficacy
Lakota et al. Antimicrob Agents Chemother. 2017;61:e00758-17.
*High drug exposure early in therapy
High drug exposure following once-weekly dosing resulted in greater fungal killing than divided doses (same weekly exposure)
Allows Front-Loaded
Dosing*
Antimicrobials with:Concentration-dependent killing
Long half-lifeSafety
Dose fractionation of rezafungin 2 mg/kgin neutropenic mice
(n=5/grp)
Rezafungin C. albicans and C. glabrata target attainment
Lakota et al. ID Week, 2018; poster 1390.
RZF: 400 mg once then 200 mg once weeklyRZF: 400 once weekly
Rezafungin dosing: front-loaded and once-weekly Distributions of weekly AUC:MIC ratios
Bader et al. Antimicrob Agents Chemother. 2018; 62:e02614-17.
1 2 3 4
1600
1200
800
400
0
400mg 0mg 0mg 0mg
Target®
Target above which
efficacy is observed in the mouse
model
Wee
kly
fAUC
:MIC
Rat
io
1x 400mg
1 2 3 4
400mg 200mg 200mg 0mg
1x 400mg, 2x 200mg
Week
‘Silent epidemic’ of antifungal underdosingPK/PD target attainment against Candida glabrata
Bader JC et al. IDWeek 2016; poster 1973; Pea and Lewis. J Antimicrob Chemother. 2018;73:i33-i43.
Micafungin 100 mg q24h (MIC=0.03 µg/mL)
Anidulafungin 200 mg followed by 100 mg q24h
(MIC=0.12 µg/mL)
Caspofungin 70 mg followed by50 mg q24h
(MIC=0.12 µg/mL)
Rezafungin optimized PK/PD mattersTarget attainment in treatment of less susceptible Candida
Bader JC et al. IDWeek 2016; poster 1973; Lakota EA et al. IDWeek 2016; poster 1994.
Caspofungin 70 mg followed by50 mg q24h (MIC=0.25 µg/mL)
Rezafungin 400 mg x 1 (MIC=0.12 µg/mL)
Echinocandin target attainment percent probabilitiesfor current echinocandins
Bader et al. IDWeek 2017; poster 833.
MIC (mg/L)
C. albicans C. glabrata
Anidulafungin Caspofungin Micafungin Anidulafungin Caspofungin Micafungin
0.008 100a,b 100 99.4 100 100 100
0.015 99.1 100 71.2 100 100 100
0.03 52.7 100 10.1 99.2 100 97.5
0.06 0.90 97.9 0.10 54.3 100 49.9
0.12 0 76.7 0 0.95 100 3.4
0.25 0 35.7 0 0 100 40.1
0.5 0 12.1 0 0 97.0 0.15
1 0 4.4 0 0 73.2 0
2 0 1.35 0 0 33.9 0
4 0 0.25 0 0 11.3 0
8 0 0.05 0 0 4.35 0
Shading reflects relative probability of PK/PD target attainment
Bader et al. IDWeek 2017; poster 833.
MIC (µg/mL)
C. albicans MIC (µg/mL)
C. glabrata
Anidulafungin Caspofungin Micafungin Rezafungin Anidulafungin Caspofungin Micafungin Rezafungin
0.008 100a,b 100 99.4 100 0.008 100 100 100 100
0.015 99.1 100 71.2 100 0.015 100 100 100 100
0.03 52.7 100 10.1 100 0.03 99.2 100 97.5 100
0.06 0.90 97.9 0.10 100 0.06 54.3 100 49.9 100
0.12 0 76.7 0 100 0.12 0.95 100 3.4 100
0.25 0 35.7 0 100 0.25 0 100 40.1 100
0.5 0 12.1 0 90.55 0.5 0 97.0 0.15 100
1 0 4.4 0 15 1 0 73.2 0 100
2 0 1.35 0 0 2 0 33.9 0 100
4 0 0.25 0 0 4 0 11.3 0 100
8 0 0.05 0 0 8 0 4.35 0 100
Echinocandin target attainment percent probabilitiesfor current echinocandins and rezafungin
Distinctive pharmacokinetics of rezafunginLong half-life… and more
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
Rezafungin
“… confers much greater stability, leading to an exceptionally longer half-life and
an improved safety profile”
• Broad spectrum of activity and in vivo efficacy
• Improved safety
• Increased solubility and stability
• Novel PK/PD
à Prolonged t1/2 (~130 h)
à High drug exposure
à Maximized pharmacometric drivers of efficacy
Distinctive pharmacokinetics of rezafunginLong half-life… and more
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
• Novel PK/PD
à Prolonged t1/2 (~130 h)
à High drug exposure
à Maximized pharmacometric drivers of efficacy
à Extensive distribution
• uniform tissue penetration across major organs (rat model) up to 4-fold higher compared to plasma
• limited CNS penetration
à Elimination similar across all tissues
Rezafungin penetrates & accumulates vs micafunginincluding difficult-to-treat infection (IAC mouse model)
IAC = intraabdominal candidiasis; GMS = Gömöri methenamine silver stain; MALDI MS = matrix-assisted laser desorption/ionization mass spectrometry; MCF = micafungin; RZF = rezafungin.Zhao et al. Antimicrob Agents Chemother. 2017; 61:e01009-17.
6h 72h
Drug distribution in liver after single dose CD101 at 20 mg/kg determined by MALDI MS Imaging
Fungi location stained by GMS
RZF distribution in liver after20 mg/kg single dose
MALDI MS imaging
6 h 72 h
A single dose ofrezafungin 20 mg/kg or 2-3 doses of micafungin 5 mg/kg on day 3 post-infection with C. albicans
MALDI-MS imaging assessed drug penetration at site of infection in an IAC mouse model
Rezafungin penetrates & accumulates vs micafunginincluding difficult-to-treat infection (IAC mouse model)
IAC = intraabdominal candidiasis; GMS = Gömöri methenamine silver stain; MALDI MS = matrix-assisted laser desorption/ionization mass spectrometry; MCF = micafungin; RZF = rezafungin.Zhao et al. Antimicrob Agents Chemother. 2017; 61:e01009-17.
6h 72h
Drug distribution in liver after single dose CD101 at 20 mg/kg determined by MALDI MS Imaging
Fungi location stained by GMS
RZF distribution in liver after20 mg/kg single dose M u ltid o s e s M ic a fu n g in v s . s in g le d o s e C D 1 0 1
L e s ion (4
8 h )
s u r ro u n d (4
8 h )
L e s ion (7
2 h )
s u r ro u n d (7
2 h )
L e s ion (4
8 h )
s u r ro u n d (4
8 h )
L e s ion (7
2 h )
s u r ro u n d (7
2 h )0
1 0
2 0
3 0
4 0
5 0
6 0
7 0
tiss
ue
dru
g le
vel (
µg
/ml)
2 d o s e s M C F
3 d o s e s M C F
s in g le d o s e C D 1 0 1
2 doses MCF
3 doses MCF
Single dose RZF
Multidose MCF vs. Single dose RZF
MALDI MS imaging
6 h 72 h• 6- to 8-fold higher
RZF exposure at site of infection
• Multidose MCF did not reach tissue drug levels achieved with single dose RZF
ELF
Rezafungin distributes to key sites for infectionhigher levels and longer duration in ELF vs micafungin
ELF = epithelial lining fluid.Ong et al. HTIDE, 2018; poster.
Micafungin
Rezafungin
RZF Concentrations
• >20-fold higher than MEC90 for A. fumigatus and A. flavus(0.015 µg/mL) after 3 days in mice
– plasma: 3 µg/mL
– ELF: 4 µg/mL
• Comparable human levels after 1 weekexpected, based on RZF plasma t1/2 (133 h, human vs. 21 h, mouse)
Rezafungin: a novel echinocandindesigned for next-generation properties
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
• Broad spectrum of activity and in vivo efficacy
• Novel PK/PD
• Improved safety
• Increased solubility and stability Rezafungin
“… confers much greater stability, leading to an exceptionally longer half-life and
an improved safety profile”
Rezafungin preclinical safety vs anidulafunginnormal findings vs elevated enzymes and necrosis
Ong et al. Antimicrob Agents Chemother 2016;60:6872–6879.
Normal Plasma Liver Enzymes
Normal Liver Histology
Plasma Liver Enzymes Elevated
Hepatocellular Necrosis
AnidulafunginRezafungin
20-min IV Infusion via Tail Vein at Comparable Plasma Exposures
2-week Rat Hepatotoxicity Screening Study
Rezafungin Phase 1 drug-drug interaction studyNo changes in dose required when rezafungin coadministered
Ong et al. TCT 2019; poster 535.
• Single-center, RCT (N=26)
• Substrate drugs dosed alone for 3 weeks, then again with rezafungin for 3 weeks
• Designed to assess the effect of rezafungin on the PK of multiple drugs
Drug Possible Mechanism(s) Observations Suggested Action
Tacrolimus CYP3A4, P-gp↔Cmax
↓AUC ~15%
No change in dose
Repaglinide CYP2C8, OATP↔Cmax
↑AUC ~15%
Metformin OCT, MATEs↔Cmax
↔AUC
Rosuvastatin BCRP, OATP↑Cmax ~12%↑AUC ~15%
Pitavastatin OATP↔Cmax
↔AUC
Caffeine CYP1A2↔Cmax
↔AUC
Efavirenz CYP2B6↔Cmax
↔AUC
Midazolam CYP3A↔Cmax
↔AUC
Digoxin CYP2B6↔Cmax
↔AUC
Rezafungin: a novel echinocandindesigned for next-generation properties
James et al. Antimicrob Agents Chemother 2017;61:e01541-16; Krishnan et al. J Antibiot 2017;70:130-135; Ong et al. Antimicrob Agents Chemother 2017;61:e01626-16. Sandison et al. Antimicrob Agents Chemother 2017;61:e01627-16
• Broad spectrum of activity and in vivo efficacy
• Novel PK/PD
• Improved safety
• Increased solubility and stability
à Multiple formulations (IV, SC)Rezafungin
“… confers much greater stability, leading to an exceptionally longer half-life and
an improved safety profile”
Program Indication DiscoveryResearch/
in vitro in vivoIND-
enabling Ph 1 Ph 2 Ph 3
Rezafungin
Rezafungin IV Treatment (Candida)
Rezafungin IV Fungal prophylaxis
RezafunginSubcutaneous
FungalInfections With NIH
Cloudbreak Immunotherapy Platform
Antiviral Conjugates (AVC)
Influenza
RSV, HIV, Dengue, Zika
Cidara Therapeutics PipelineRezafungin subcutaneous for outpatient/clinic
REZAFUNGIN CLINICAL TRIAL PROGRAM
Rezafungin treatment studiesPhase 2 STRIVE
• Part A met objectives of establishing clinical safety and efficacy and determining dosing for Phase 3 (400 mg/200 mg)
• Part B enrollment completed; anticipated topline data mid-2019
Phase 2
Phase 3
• Enrollment underway, similar to STRIVE in design except a more severe patient population is expected (~ 25% invasive candidiasis vs ~10% in STRIVE Part A)
400/400/(400) mg n=35400/200/(200) mg n=36
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
Caspofungin Week 1 2 3 4 5 6 7 8 9
Day1 5 8 15 22 28 4535 42 49 56 59
70mg Dose 50mg Dose®
All cause mortalityRezafungin
Analysis Populations:§ Intent-to-treat (ITT): all randomized subjects § Safety: all subjects who received any amount of study drug§ Microbiological Intent-to-treat (mITT): all subjects in safety population who had documented Candida infection
70/50/(50) mg n=36
Rezafungin treatment of candidemia and ICPhase 2 trial design
Part A
Rezafungin efficacy in treatment of candidemia and ICPhase 2 results support dose selection for Phase 3
*Excluding Indeterminate Response (inability to assess outcome due to missing data point[s]).
400/200/(200)mg QWkDose selected for P3
100%
75%
50%
25%
0%Overall Response D14
Rezafungin 400mg/400mg QWk
Rezafungin 400mg/200mg QWk
Caspofungin 70mg/50mg QD
73%79%
69%
22/28
Invasive Candidiasis Patients
50%
100%
33%
1/2 5/5 1/3
Response – High APACHE II Score
Patients
60%
80%
58%
6/10 8/10 7/12
Investigator Assessment D14
78%
86%
71%
25/32 24/28 20/2819/26 18/26
51
3
All Cause Mortality D30
15%
3%
11%
51
3
Part A
Rezafungin treatment studiesPhase 3 RESTORE
• Enrollment underway, similar to STRIVE in design except a more severe patient population is expected (~ 25% invasive candidiasis vs ~10% in STRIVE Part A)
• Part A met objectives of establishing clinical safety and efficacy and determining dosing for Phase 3 (400 mg/200 mg)
• Part B enrollment completed; anticipated topline data mid-2019
Phase 2
Phase 3
Today’s antifungal prophylaxis paradigmmultiple agents with multiple considerations
HSCT: hematopoietic stem cell transplantation; TMP/SMX: Trimethoprim/sulfamethoxazole (co-trimoxazole, Bactrim).
Day -10. 0 10 20 30 40 50 60 70 80
Post-engraftment
Transplant Engraftment
Pre-engraftment
SOC for Pneumocystis
pneumonia (PCP)
SOC for Candidaand Aspergillus
or…
Risk of IFICandida
Aspergillus
PneumocystisCandida
Aspergillus
PneumocystisLow
High
Anti-PCP: TMP/SMX, dapsone, atovaquone
Fluconazole Posaconazole or voriconazole
Posaconazole or voriconazole
Comprehensive antifungal prophylaxis requires one or more azole plus an anti-PCP agent
Fluconazole
Rezafungin for antifungal prophylaxispotential to improve and simplify today’s paradigm
Day -10. 0 10 20 30 40 50 60 70 80
Post-engraftment
Transplant Engraftment
Pre-engraftment
SOC for CandidaAspergillus
Pneumocystis pneumonia (PCP)
Risk of IFICandida
Aspergillus
PneumocystisCandida
Aspergillus
PneumocystisLow
High
Rezafungin
Safety vs polyenes, azoles, and TMP-SMX
No DDIs or myelosuppression
Once-weekly dosing (IV or SC) with no drug monitoring required
Unique PK profile may be advantageous against resistant pathogens
Rezafungin prophylaxis in patients receiving allogeneic BMTPhase 3 trial design
Adaptive design: interim analysis @ 50% enrollment for futility/sample size.Approximately 25-30 sites globally; size and timing pending additional regulatory input.
Week 1 2 3 4 12
Azole placebo
Bactrim placebo
Rezafungin5 13
Day 1
17
90 120
1° Endpoint: Day 90 Fungal-Free Survival Follow up
17Week 1 2 3 4 12
Azole*
Bactrim
Rezafungin Placebo5 13
Day 1 84 90 120
*Fluconazole to start in all patients. Posaconazole optional in patients who develop GVHD per label.
Standard of Care (n=150)
Rezafungin (n=300)
Rezafungin for treatment and prophylaxisnovel and unique properties of a next-generation echinocandin
• Potent and Broad-Spectrum against Candida, Aspergillus, and Pneumocystis: including Candida auris and subset of azole- and echinocandin-resistant isolates
• Enhanced PK: once-weekly, high-exposure, front-loaded dosing and greater tissue penetration maximizes pharmacometrics of efficacy and may prevent resistance
• Safety and DDI profile of the echinocandin class: spares myelosuppression, TDM, hepatic & renal toxicity, non-compliance, and complications of managing/avoiding DDIs
• Dosing & Administration: inpatient and outpatient use dosed once-weekly, earlier hospital discharge, multiple formulations
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