Sandison S378 RZF.CD101 ASM 2019 static · 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

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”




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



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



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




• Novel PK/PD

à Prolonged t1/2 (~130 h)

à High drug exposure

à Maximized pharmacometric drivers of efficacy

• Improved safety


Rezafungin



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


Rezafungin




• Improved safety


• Novel PK/PD




Distinctive pharmacokinetics of rezafunginLong half-life… and more


• Novel PK/PD




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)




• Novel PK/PD

• Improved safety

• Increased solubility and stability Rezafungin



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




• Novel PK/PD

• Improved safety


à Multiple formulations (IV, SC)Rezafungin



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

Documents

Sandison S378 RZF.CD101 ASM 2019 static · 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