Role of Anidulafungin in Hematology Patients M j2016.pdf · FOR MORE PATIENTS THAN YOU THINK Role of Anidulafungin in Hematology Patients Matjaz Sever MD, PhD Hematology Department

FOR MORE PATIENTS THAN YOU THINK

Role of Anidulafungin in Hematology Patients

Matjaz Sever MD, PhD

Hematology Department

University Medical Center Ljubljana


Invasive candidiasis (IC) is the most common fungal disease among hospitalized patients in the developed world.

IC comprises candidemia (more common) and deep-seated candidiasis.

Mortality is as high as 40% even among patients receiving antifungal therapy.

Incidence of IC is between 2-14/100.000.

Invasive candidiasis

Kullberg BJ, NEJM 2015


Diagnosis:

1. Culture is the only approach for subsequent susceptibility testing.

2. Candida mannan antigens, antimannan antibodies and beta-D-glucan are the primary surrogate markers for IC.

3. There are several PCR tests for detection of IC being evaluated.

.

Pathogenesis of invasive candidiasis

Kullberg BJ, NEJM 2015


ECALTA® Recommended worldwide by US and EU guidelines

References: 1. Pappas PG, et al. Clin Infect Dis. 2009;48(5):503-35. 2. Cornely OA, et al. Clin Microbiol Infect. 2012;18 Suppl 7:19-37. 3. Ullmann AJ, et al. Clin Microbiol Infect. 2012;18 Suppl 7:53-67.

Ecalta® is AI recommended in non-neutropenic adult patients for the initial treatment of candidaemia by the IDSA guidelines and for the initial treatment of candidaemia/invasive candidiasis by the ESCMID guidelines1,2

TREATMENT GUIDELINES

ESCMID 2012 Guidelines

● AI for Ecalta® in non-neutropenic adult patients with candidaemia/invasive candidiasis2

● BII for Ecalta® in patients with haematological malignancies, usually with neutropenia, with invasive candidiasis/ candidaemia3

IDSA 2009 Guidelines

● AI for Ecalta® in non-neutropenic adult patients with candidaemia1

● AIII for Ecalta® in most neutropenic patients with candidaemia1


Pharmacokinetic properties of the echinocandins – summary

Echinocandins have poor oral bioavailability and are therefore administered intravenously1

Summary of pharmacokinetic (PK) properties of echinocandins after IV administration

1. Cappelletty D, et al. Pharmacother. 2007; 27: 369-388.

2. Anidulafungin summary of product characteristics. Pfizer. 2014.

3. Caspofungin summary of product characteristics. MSD. 2014.

4. Micafungin summary of product characteristics. Astellas. 2014.

5. Stone JA, et al. Antimicrob Agents Chemother. 2004; 48: 815-823.

Anidulafungin2 Caspofungin3 Micafungin4

Absorption Linear PK over daily

doses of 15–130mg

Moderate non-linear PK

with increased

accumulation as dose is

increased

Linear over daily dose

range of 12.5–200mg. No

evidence of accumulation

Plasma protein

binding

>99% 92.4–96.5% 99%

Volume of

distribution

30–50 litres Not obtained* 18–19 litres

Elimination

half-life

~24h 9–11h 10–17h

Clearance 1 L/h 10–12 ml/min 0.15–0.3 ml/min/kg

*Steady state volume of distribution of caspofungin has been estimated to be 9.5 litres5


Anidulafungin has more favourable pharmacokinetics than caspofungin or micafungin

Steady state

data

Steady state is achieved more rapidly with anidulafungin1

Dose-linear

exposure

Plasma levels of anidulafungin and micafungin linearly correlate with dosage, whereas

caspofungin shows moderately non-linear PK2-4

Longer half

life

Anidulafungin has a longer half life than micafungin and caspofungin2-4

Larger

volume of

distribution

Anidulafungin has a larger volume of distribution than micafungin and caspofungin5

In surgical intensive care patients, caspofungin has shown significantly lower plasma

trough levels in patients with a body weight > 75kg and low plasma albumin levels6

Weight did not have any clinically relevant impact on anidulafungin PK5

Favourable

elimination

profile

Anidulafungin undergoes non-hepatic spontaneous chemical degradation only, whereas

caspofungin and micafungin undergo hepatic metabolism7

Anidulafungin undergoes negligible renal clearance2

Anidulafungin has no restrictions or requirement for dose adjustment in patients

with hepatic or renal impairment2

Anidulafungin has no clinically relevant effect on CYP450 enzymes2

Anidulafungin has a low potential for drug-drug interactions2

5. Raasch RH. Expert Rev Anti Infect Ther. 2004; 2: 499-508.

6. Nguyen TH, et al. J Antimicrob Chemother. 2007; 60: 100-106.


1. Glockner A, et al. Mycoses. 2008


3. Caspofungin summary of product characteristics. MSD. 2014

4. Micafungin summary of product characteristics. Astellas. 2014


Properties of echinocandins in patients with hepatic or renal impairment

Critically ill patients in the ICU commonly have organ dysfunction such as renal or hepatic impairment4

Anidulafungin is suitable for hepatically and renally impaired patients without dose adjustment


2. Caspofungin summary of product characteristics. MSD. 2009.

3. Micafungin summary of product characteristics. Astellas. 2008.

4. Nguyen TH, et al. J Antimicrob Chemother. 2007; 60: 100-106.

*Liver function should be carefully monitored during micafungin treatment. To minimise the risk of adaptive regeneration and potentially subsequent liver

tumour formation, early discontinuation of micafungin is recommended in the presence of significant and persistent elevations of alanine

aminotransferase or aspartate aminotransferase. Micafungin treatment should be conducted on a careful risk/benefit basis, particularly in patients

having severe liver function impairment or chronic liver diseases known to represent preneoplastic conditions, such as advanced liver fibrosis, cirrhosis,

viral hepatitis, neonatal liver disease or congenital enzyme defects, or receiving a concomitant therapy including hepatotoxic and/or genotoxic

properties.3


Hepatic

impairment

No dose adjustment needed in

patients with mild, moderate, or

severe hepatic insufficiency

No dose adjustment in patients with

only mild hepatic insufficiency

In patients with moderate hepatic

insufficiency reduce daily dose

No clinical experience in patients with

severe hepatic insufficiency

No dose adjustment in patients

with mild to moderate hepatic

insufficiency

No clinical data in patients with

severe hepatic insufficiency;

therefore, not recommended*

Renal

impairment

No dose adjustment required for

patients with any degree of renal

insufficiency, including those on

dialysis

No dose adjustment in patients with

renal impairment

No dose adjustment in patients

with renal impairment


Drug interactions of echinocandins

1. Anidulafungin summary of product characteristics. Pfizer. 2014

2. Caspofungin summary of product characteristics. MSD. 2014

3. Micafungin summary of product characteristics. Astellas. 2014


No known clinically relevant

interactions

Not an inhibitor, inducer or

substrate of CYP450

Interactions with:

Cyclosporine

Tacrolimus

Rifampicin

Efavirenz

Nevirapine

Dexamethasone

Phenytoin

Carbamazepine

Low potential for interactions

with medications metabolised

via CYP3A-mediated pathways

However, it is recommended

that patients receiving sirolimus,

nifedipine or itraconazole in

combination with micafungin

should be monitored for

sirolimus, nifedipine or

itraconazole toxicity and the

sirolimus, nifedipine or

itraconazole dose should be

reduced if necessary


All of the echinocandins are effective against a range of Candida species

Anidulafungin has a broad spectrum of activity1,2

MIC90 (µg/ml)

Anidulafungin Caspofungin Micafungin

C. albicans 0.03 0.06–1 0.03

C. glabrata 0.13 0.06–2 0.015–0.06

C. tropicalis 0.13 0.25–1 0.06

C. dubliniensis 0.06 0.5 0.033

C. krusei 0.13 0.25–2 0.06–0.25

C. lusitaniae 0.25 1–2 2

C. parapsilosis 2 1–4 2

C. guilliermondii 1 2–>8 0.5

MIC90, minimum inhibitory concentration for 90% of tested strains

Table adapted from Cappelletty D, et al. 2007.


2. Ghannoum M, et al. Infect Dis Clin Pract. 2005; 13: 165-178.


ECALTA® VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS Study design and methodology

Pivotal, Phase 3, randomised, double-blind, multicentre, multinational non-inferiority study, with a pre-specified two-step statistical analysis for superiority1

Primary endpoint: global success (clinical and microbiologic) at the end of IV therapy1

Secondary endpoints included: global response at the end of all study therapy (IV and oral) and at follow-up visits at 2 weeks and 6 weeks; the per-patient and per-pathogen microbiologic response at all time points; death from all causes1

*Patients were stratified by APACHE II score (≤20 and >20) and absolute neutrophil count (≤500/mm3 or >500/mm3).1 †Study drugs were administered for 14 to 42 days and for ≥14 days after a negative blood culture and improvement in signs and symptoms.1

Reference: 1. Reboli A, et al. N Engl J Med. 2007;356(24):2472-82.

42

Patients

≥16 years of age with confirmed

candidaemia or other forms of

invasive candidiasis within 96

hours before enrollment and ≥1

of the following criteria: fever,

hypothermia, hypotension, local

signs and symptoms, or

radiologic findings of invasive

candidiasis

Ecalta®

200 mg on Day 1,

then 100 mg/day

Fluconazole IV

800 mg on Day 1,

then 400 mg/day

Treatment duration: 14 to 42 days†

After Day 10:

Treatment could be switched

to oral fluconazole 400

mg/day at the investigator’s

discretion and according to

pre-specified criteria RA

ND

OM

ISA

TIO

N*

14 0

STUDY DETAILS


ECALTA® VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS Baseline characteristics (1)

*Patients were included if bacterial sepsis occurred within 1 month before randomisation.1


Adapted from Reboli et al. 2007.1

Key characteristics of the modified ITT population1

Ecalta® group (n=127)

Fluconazole group (n=118)

p-value

Mean age (± SD) 57.0 years

(±17.0) 59.2 years

(±16.5) 0.29

Coexisting disease

Diabetes mellitus 35% 25% 0.13

Renal failure or insufficiency

37% 36% 0.89

Bacterial sepsis* 46% 42% 0.52

Neoplastic disease 22% 23% 0.88

Disorder requiring transplantation

6% 4% 0.77

Risk factors for invasive candidiasis

Central venous catheter 78% 78% 1.00

Broad-spectrum antibiotics

69% 70% 1.00

Recent surgery 42% 43% 0.9

Recent hyperalimentation 24% 26% 0.77

Immunosuppressive therapy

14% 23% 0.10

STUDY DETAILS


ECALTA® VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS Baseline characteristics (2)


Key characteristics of the modified ITT population1

Ecalta® group (n=127)

Fluconazole group (n=118)

p-value

APACHE II score

≤20 80% 83% 0.52

>20 21% 17% 0.51

Absolute neutrophil count

>500/mm3 98% 97% 0.71

≤500/mm3 2% 3%

Baseline Candida pathogen

C. albicans 64% 59% 0.51

C. glabrata 16% 25% 0.08

C. parapsilosis 10% 14% 0.44

C. tropicalis 12% 9% 0.54

Other Candida spp. 5% 3% 0.50


STUDY DETAILS


ECALTA® VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS Summary of adverse events

*ITT population. NS: not significant.


Ecalta® (n=131)* Fluconazole (n=125)* p-value

Treatment-related adverse events

24.4%

(n=32; 59 events)

26.4%

(n=33; 64 events) NS

Treatment-related elevated hepatic enzymes

1.5%

(n=2)

7.2%

(n=9) 0.03

Treatment-related serious adverse events

Atrial fibrillation (n=1)

Seizures (n=1)

Deep vein thrombosis

(n=1)

Elevated hepatic

enzymes (n=1)

NS

Adverse events leading to discontinuation of the study drug

11.5%

(n=15)

21.6%

(n=27) 0.02

Lower frequency of elevated hepatic enzyme levels vs fluconazole in

non-neutropenic patients*1


STUDY DETAILS


ECALTA® VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS Safety profile in non-neutropenic patients*

*The modified ITT population comprised 97% non-neutropenic and 3% neutropenic patients.1 †ITT population.



Ecalta® (n=131)† Fluconazole (n=125)†

Hypokalaemia 3.1% 2.4%

Diarrhoea 3.1% 1.6%

Elevated ALT 2.3% 3.2%

Elevated hepatic enzymes 1.5% 7.2%†

Elevated alkaline phosphatase 1.5% 4.0%

Flushing 1.5% 1.6%

Elevated bilirubin 1.5% 0.8%

Hypomagnesaemia 1.5% 0.8%

Electrocardiogram QT prolonged 1.5% 0

Pruritus 1.5% 0

Elevated AST 0.8% 2.4%

Deep vein thrombosis 0.8% 2.4%

Anaemia 0 1.6%

Dizziness 0 1.6%

Rigors 0 1.6%

Treatment-related adverse events experienced by ≥2 patients

in either study arm1

STUDY DETAILS


Global success at pre-specified time points in the MITT population*1

ECALTA® VS FLUCONAZOLE FOR INVASIVE CANDIDIASIS Global responses at prespecified time points

Pe

rce

nta

ge

6-week follow-up

EOIVT

p<0.02

EOT

p<0.02

2-week follow-up

44.1

55.9 60.2

75.6

56.8

74.0

49.2

64.6

p<0.02

Fluconazole (n=118) Ecalta® (n=118)

40

60

80

100

0

20

EOVIT, end of IV therapy. EOT, end of all therapy. MITT, modified intention-to-treat. *The modified ITT population comprised 97% non-neutropenic and 3% neutropenic patients.1



STUDY DETAILS


Global success rate significantly higher with Ecalta® vs fluconazole (75.6% vs 60.2%; p<0.02)†1

More effective than fluconazole in severely ill patients

‒ A secondary analysis showed that Ecalta® was also more effective than fluconazole in patients with critical illness (70.8% vs 54.1%; p=0.03)2

ECALTA® – EFFICACY IN ADULT NON-NEUTROPENIC PATIENTS WITH INVASIVE CANDIDIASIS

Superior efficacy to fluconazole in a pivotal Phase 3 study1*

*This trial was designed primarily as a non-inferiority study, with a prespecified two-step statistical analysis for superiority. †Data at end of intravenous therapy (EOIVT) for the modified intention-to-treat (MITT) population, comprising 97% non-neutropenic and 3% neutropenic patients.1

References: 1. Reboli A, et al. N Engl J Med. 2007;356(24):2472-82. 2. Kett DH, et al. Critical Care. 2011;15:R253.


Patients Characteristics

Study Design Other Efficacy

Results Safety

Global success at the end of IV therapy (EOIVT)

in the MITT population (primary endpoint)†1

Methods Other Efficacy

Results 20

40

60

80

100

Fluconazole

75.6

60.2

0

Glo

ba

l s

uc

ce

ss

rate

(%

)

96/127

71/118

p<0.02

Ecalta®

EFFICACY IN NON-NEUTROPENIC PATIENTS


Rate of death from all causes was 22.8% for Ecalta® and 31.4% for fluconazole (p=0.13, NS)*1

Persistent infection at EOIVT was 6.3% for Ecalta® and 14.4% for fluconazole (p=0.06, NS)*1

ECALTA® – EFFICACY IN ADULT NON-NEUTROPENIC PATIENTS WITH INVASIVE CANDIDIASIS

Survival and persistent rates of infection vs fluconazole1

*Data are at end of intravenous therapy (EOIVT) for the modified intention-to-treat (MITT) population, comprising 97% non-neutropenic and 3% neutropenic patients.1





Results Safety

Kaplan–Meier estimates of survival through 60 days*1

25

75

100

Su

rviv

al

(%)

0

50

0

10 20 30 40 50 60

Fluconazole Ecalta®

No. at risk

127 122 112 105 96 89 78

118 104 92 90 80 74 62

p=0.10

Days



ECALTA® FOR INVASIVE CANDIDIASIS IN NEUTROPENIC PATIENTS Study design and methodology

Pooled analysis of data from one randomised, double-blind, comparative study and four open-label, non-comparative studies, to determine the efficacy of Ecalta® in neutropenic patients with invasive candidiasis1

Data from neutropenic patients (baseline absolute neutrophil count ≤500 cells/mm3 or classified as neutropenic by the investigator) with microbiologically-confirmed invasive candidiasis1

‒ Each patient was initially treated with Ecalta® (200 mg loading dose on Day 1, then 100 mg/day thereafter)*1

‒ In the four open-label studies, a switch to oral therapy (fluconazole or voriconazole) was permitted after 5-10 days of Ecalta® treatment1

Primary endpoint: global response (clinical and microbiologic) at the end of IV therapy (EOIVT) in the modified ITT population (patients who received treatment and had microbiologically-confirmed Candida infection)1

Secondary endpoint: global response at the end of all treatment (EOT)1

*Patients were required to receive total antifungal treatment for ≥14 days after the last positive culture for Candida spp. and resolution of symptoms.1

Reference: 1. Herbrecht R, et al. Presented at the 24th ECCMID 2014. Abstract R692.

STUDY DETAILS


ECALTA® FOR INVASIVE CANDIDIASIS IN NEUTROPENIC PATIENTS Baseline characteristics

*In the 28 patients who had baseline and post-baseline absolute neutrophil counts


n=46

Mean age 56 years

Most common Candida species:

C. tropicalis 34.8%

C. krusei 19.6%

C. parapsilosis 17.4%

C. albicans 15.2%

C. glabrata 15.2%

C. kefyr 8.7%

Sites of infection:

Blood only 84.8%

Blood and other sterile site 4.3%

Other sterile site only 10.9%

Duration of neutropenia* 16.0 days (range 1-43)

Adapted from Herbrecht et al. 2014.1

STUDY DETAILS


ECALTA® FOR INVASIVE CANDIDIASIS IN NEUTROPENIC PATIENTS Global responses at prespecified time points

Global success in neutropenic patients with invasive candidiasis1

20

40

100

Glo

ba

l s

uc

ce

ss

(%

)

80

60

EOIVT Primary endpoint

EOT

56.5

52.2

0



STUDY DETAILS


ECALTA® FOR INVASIVE CANDIDIASIS IN NEUTROPENIC PATIENTS Rate of all-cause mortality


n/N %

14-day all-cause mortality 9/46 19.6

28-day all-cause mortality 11/46 23.9


STUDY DETAILS


Overall global success rate at EOIVT in neutropenic patients was 56.5%1

Global success was especially high (80% at EOIVT) in patients with resolved neutropenia1

ECALTA® – FOR MORE PATIENTS THAN YOU THINK Effective in neutropenic patients*1

ANC, absolute neutrophil count. EOIVT, end of intravenous therapy.

Resolved neutropenia, ANC >500 cells/mm3 before EOIVT. Persistent neutropenia, ANC ≤500 cells/mm3 at EOIVT. *Pooled analysis of data from one randomised, double-blind, comparative study and four open-label, non-comparative studies. The neutropenic subset comprised 46 patients at baseline; post-baseline ANC data were available for 28/46 patients.1


Global success at EOIVT in neutropenic patients*1


Study Design


NEW

Pa

tie

nts

(%

)

20

40

60

80

100

All patients

56.5

Resolved neutropenia Persistent neutropenia

Patients with ANC data available

80.0

12/15

53.8

7/13

0

Other Results

EFFICACY IN NEUTROPENIC PATIENTS


Anidulafungin in GvHD setting

Retrospective analysis in 25 pt:

aGvHD n=15,

Progressive cGvHD n=7,

Overlap GvHD n=3,

Standard dose of anidulafungin,

85% pt had prophylaxis, 15% pt were treated with anidulafungin,

Median time on therapy was 8 days,

Two (8%) pt developed IFI after therapy withdrawal.

Anidulafungin in reduced dosing outpatient setting

Prospective study on 20 pt:

200 mg/48h dosing schedule,

300 mg/72h dosing schedule,

Comparable dose-normalized exposure between the two dosing schedule and licensed regimen,

Opportunity for personalized care in the outpatient setting.

Ecalta in HSCT

Yanez L, Transplant Infectious Disease 2015 Bruggemann RJM, J Antimicrob ChemotTher 2015


ECALTA® – FOR MORE PATIENTS THAN YOU THINK Effective in complex ICU patients with high-risk of candidaemia/invasive candidiasis*1

*Patients had confirmed candidiasis/invasive candidiasis plus one or more of the following characteristics: post-abdominal surgery; solid tumour; renal insufficiency; hepatic insufficiency; solid organ transplant; neutropenia; age ≥65 years. Around 8% of patients in the modified intention-to-treat (MITT) population (14/170) were neutropenic.1 †If missing and unknown responses among MITT patients (n=170) were treated as failures, the global success rate decreased to 65.3%. ‡The differences between success rates in patients with C. albicans and non-albicans infections were not statistically significant (p=0.17 for global response, p=0.19 for microbiological response). §Excluding patients with multiple pathogens at baseline.

Reference: 1. Ruhnke M, et al. Clin Microbiol Infect. 2012;18:680-7.

Adapted from Ruhnke et al. 2012.1



Results Safety

Global success rates for selected

ICU populations1

Global success rates for C. albicans

and non-albicans infections1

Pa

tie

nts

(%

)

Post abdominal

surgery

20

40

60

80

100

68.4

Elderly (≥65

years)

68.1

Renal insufficiency

75.9

Solid tumour

75.6

Hepatic insufficiency

72.0

Neutro- penic

50.0

Solid organ

transplant recipient

37.5

0

Pa

tie

nts

(%

)

C. albicans

20

40

60

80

100

0

C. glabrata C. parapsilosis C. tropicalis Any non-albicans‡

74.4

68.2 66.7

36.4

63.8

Baseline organism§

Overall global success at the end of treatment (EOT) was 69.5% (95% CI, 61.6–76.6) (primary endpoint)†1



Global success rates at EOIVT in patients with deep tissue candidiasis were:

‒ Consistent with response rates observed in published studies, with relatively low mortality1

‒ Similar to response rates reported for the overall population in the Ecalta® pivotal trial1,3

ECALTA® – FOR MORE PATIENTS THAN YOU THINK Effective in patients with deep tissue candidiasis*1

Global success rates at EOIVT

for the most common sites of infection†1

EOIVT, end of intravenous therapy.

*Ecalta® has been studied primarily in patients with candidaemia and only in a limited number of patients with deep tissue Candida infections or with abscess-forming disease.2

†Pooled analysis of data from one randomised, double-blind, comparative study and four open-label, non-comparative studies.1

References: 1. Aram J, et al. Presented at the 24th ECCMID 2014. Abstract R691. 2. Ecalta® Summary of Product Characteristics. EMA, 2013. 3. Reboli A, et al. N Engl J Med. 2007;356(24):2472-82.


Study Design Other Results

Adapted from Aram et al. 2014.1

NEW

Pa

tie

nts

(%

)

Peritoneal cavity infection

20

40

60

80

100

Hepatobiliary infection

Pleural cavity infection

Kidney infection

72.9

51/70

77.8

85.7

75 6/7

7/9

3/4

0



*Decision analytic model was constructed to estimate potential treatment costs of Ecalta® vs comparator agents in a UK hospital setting. Each model pathway was defined by the probabilities of an event occurring and the costs of clinical outcomes.1

Reference: 1. Auzinger G, et al. Presented at the 33rd ISICEM 2013. Poster P087.

"The clinical effectiveness and cost effectiveness of Ecalta® mean that it is a sensible option for the treatment of

candidaemia in a cost-constrained economic environment"1

ECALTA® – A COST-EFFECTIVE CHOICE Cost-effectiveness analytic model from a UK perspective*1

Methods Inputs & Assumptions Other Results

Treatment outcomes for each antifungal treatment1

Proportion of patients alive at the end of treatment

20

30

40

60

80

Clin

ica

l s

uc

ce

ss

rate

(%

)

Micafungin Ecalta® Fluconazole Caspofungin

70

50

10

Proportion of patients experiencing clinical success

0

ECALTA® COST-EFFECTIVENESS


*Decision analytic model was constructed to estimate potential treatment costs of Ecalta® vs comparator agents in a UK hospital setting. Each model pathway was defined by the probabilities of an event occurring and the costs of clinical outcomes.1

Reference: 1. Auzinger G, et al. Presented at the 33rd ISICEM 2013. Poster P087.

"The clinical effectiveness and cost effectiveness of Ecalta® mean that it is a sensible option for the treatment of candidaemia in a cost-constrained

economic environment"1

ECALTA® – A COST-EFFECTIVE CHOICE Cost-effectiveness analytic model from a UK perspective*1

Methods Inputs & Assumptions Other Results

Treatment outcomes for each antifungal treatment1

5,000

10,000

20,000

30,000

Co

st

(£)

25,000

15,000

Ecalta® Fluconazole Caspofungin Micafungin 0

Adverse-event costs

Other hospital room and board costs

ICU room and board costs

Antifungal drug costs



Overall healthcare costs in critically ill patients may be lower with Ecalta® than with fluconazole, due to shorter ICU and hospital stays1

ECALTA® – A COST-EFFECTIVE CHOICE Pharmacoeconomic analysis from a North-American perspective*1


Methods Patients

Characteristics Other Outcomes

Total invasive candidiasis-

related costs (ICU

population)*1

Global success at the end

of all therapy (ICU

population)*1

Pa

tie

nts

(%

)

20

40

60

80

100

Fluconazole

68.6†

24/35

42.9

12/28

0

Ecalta®

*Pharmacoeconomic analysis of resource use data from a subset of patients (n=159) originally enrolled in a Phase 3 clinical study who also participated in a chart review study. Global response was defined as combined clinical success and microbiological success. Total cost is the sum of the costs of IV medication, oral medication, other systemic fungal medication, and hospital stay, and is given in $US (year 2008 values).1

†p<0.05 vs fluconazole after adjustment for baseline covariates.

Reference: 1. Reboli AS, et al. Pharmacoeconomics. 2011;29(8):705-17.


To

tal c

os

t ($

US

th

ou

sa

nd

s)

20

40

60

80

100

Fluconazole

80,594

95,631

0

Ecalta®


Ecalta® vs fluconazole in the treatment of candidaemia or invasive candidiasis provided higher efficacy at a lower total cost*1

Treatment with Ecalta® resulted in higher anti-fungal drug costs; however, overall costs were lower for treatment with Ecalta® than for treatment with fluconazole due to an offset in other medical costs1

ECALTA® – A COST-SAVING CHOICE Cost-saving analytic model from a Spanish perspective*1

Adapted from Grau et al. 2013.1

Ecalta® Fluconazole

Cost and outcomes

Total costs € 40,047 € 41,350

% with clinical success† 74% 57%

Incremental cost-effectiveness ratios (ICER) for the incremental cost per successfully treated patient gained

ICER € -7,559

CE plane quadrant 4

ICER detail Ecalta® is cost-saving versus fluconazole

Decision Tree Model

Model Probabilities Cost Analysis

*Cost effectiveness was assessed using a decision analysis model, constructed on the basis of current clinical practice (Spanish hospital setting) and currently available clinical data.1 †Patient numbers: n=74 for Ecalta®; n=61 for fluconazole.

Reference: 1. Grau S, et al. J Mycol Med. 2013;23(3):155-63.

Model outcomes and incremental

cost-effectivenss ratio1



IDSA 2009 CLINICAL PRACTICE GUIDELINES FOR THE MANAGEMENT OF CANDIDIASIS

Grading System for ranking recommendations in clinical guidelines1

Adapted from Pappas et al. 2009.1

Category, grade Definition

Strength of recommendation

A Good evidence to support a recommendation for or against use

B Moderate evidence to support a recommendation for or against use

C Poor evidence to support a recommendation

Quality of evidence

I Evidence from ≥1 properly randomised, controlled trial

II

Evidence from ≥1 well-designed clinical trial, without randomisation; from cohort or case-

controlled analytic studies (preferably from >1 centre); from multiple time-series; or from

dramatic results from uncontrolled experiments

III Evidence from opinions of respected authorities, based on clinical experience, descriptive

studies, or reports of expert committees

Reference: 1. Pappas PG, et al. Clin Infect Dis. 2009;48(5):503-35.

STUDY DETAILS


ECALTA® Recommended in US guidelines


Initial therapy

Fluconazole AI • In patients with moderately severe to severe illness,

or patients who have had recent azole exposure, an echinocandin is favoured (AIII)

• In patients who are less critically ill and who have had no recent azole exposure, fluconazole is recommended (AIII)

• For infection due to Candida glabrata, an echinocandin is preferred (BIII)

• For infection due to Candida parapsilosis, fluconazole is recommended (BIII)

Ecalta® AI

Caspofungin AI

Micafungin AI

Alternatives

Amphotericin B deoxycholate

AI • If there is intolerance to or limited availability

of other antifungals Lipid formulation of amphotericin B

AI

IDSA 2009 recommendations on the initial treatment of candidaemia

in non-neutropenic adult patients1


STUDY DETAILS


ECALTA® Recommended in US guidelines


IDSA 2009 recommendations on the initial treatment of candidaemia

in neutropenic adult patients1

Initial therapy

Ecalta® AIII • For infections due to C. glabrata, an echinocandin

is preferred (BIII); a lipid formulation of amphotericin B is an effective but less attractive alternative (BIII)

• For infections due to C. parapsilosis, fluconazole or a lipid formulation of amphotericin B is preferred as initial therapy (BIII)

• For infections due to C. krusei, an echinocandin, a lipid formulation of amphotericin B, or voriconazole is recommended (BIII)

Caspofungin AII

Micafungin AII

Lipid formulation of amphotericin B

AII

Alternatives

Fluconazole BII • For patients who are less critically ill and who have

no recent azole exposure

Voriconazole BIII • Can be used in situations in which additional mould

coverage is desired (BIII)


STUDY DETAILS


ECALTA® Recommended in European guidelines

Adapted from Cornely et al. 2012.1

ESCMID 2012 recommendations on initial targeted treatment of candidaemia and invasive

candidiasis in non-neutropenic adult patients1

Ecalta® AI Consider local epidemiology (Candida parapsilosis, C. krusei), less drug-drug interactions than caspofungin

Caspofungin AI Consider local epidemiology (C. parapsilosis)

Micafungin AI Consider local epidemiology (C. parapsilosis), less drug-drug interactions than caspofungin, consider EMA warning label

Amphotericin B liposomal BI Similar efficacy as micafungin, higher renal toxicity than micafungin

Voriconazole* BI Limited spectrum compared to echinocandins, drug-drug interactions, limitation of IV formulation in renal impairment, consider therapeutic drug monitoring

Fluconazole* CI Limited spectrum, inferiority to anidulafungin (especially in the subgroup with high APACHE scores), may be better than echinocandins against C. parapsilosis

Amphotericin B lipid complex CII

Amphotericin B deoxycholate DI Substantial renal and infusion-related toxicity

Amphotericin B deoxycholate plus fluconazole DI Efficacious, but increased risk of toxicity in ICU patients. No survival benefit

Amphotericin B deoxycholate plus 5-fluorocytosine DII

Efungumab plus lipid-associated amphotericin B DII

Amphotericin B colloidal dispersion DII

Itraconazole DII

Posaconazole DIII

*Not all experts agreed, strength of recommendation results from a majority vote.

Reference: 1. Cornely OA, et al. Clin Microbiol Infect. 2012;18 Suppl 7:19-37.

STUDY DETAILS


ECALTA® Recommended in European guidelines

Adapted from Ullmann et al. 2012.1

ESCMID 2012 recommendations on targeted treatment of candidaemia and invasive candidiasis in

adults with haematological malignancies, usually with neutropenia1

Fluconazole CII Caution regarding resistance Fluconazole should rather be considered as a step-down treatment option

Itraconazole DIII Only abstract in non-neutropenics

Posaconazole DIII One case report in a non-neutropenic

Voriconazole CII Alternative agent due to better susceptibility data in comparison with fluconazole but limited clinical data

Amphotericin B colloidal dispersion CIII Considerable nephrotoxicity

Amphotericin B deoxycholate DII Unacceptable toxicity

Amphotericin B lipid complex CII Considerable nephrotoxicity

Ecalta® BII <3% of study participants were neutropenic

Caspofungin AII ~10% of study participants were neutropenic

Liposomal amphotericin B BII

Micafungin AII ~10% of study participants were neutropenic Consider EMA warning

Reference: 1. Ullmann AJ, et al. Clin Microbiol Infect. 2012;18 Suppl 7:53-67.

STUDY DETAILS


ECIL recommendations


Superior efficacy to fluconazole in adult non-neutropenic patients1

Proven efficacy in complex patients, including neutropenic patients2,3,4

Efficacy against most clinically relevant Candida spp.2

No known drug interactions5

No dose adjustments required for age or renal or hepatic impairment5

May represent a cost-effective choice6,7

A1 recommended in non-neutropenic adult patients8,9

References: 1. Reboli A, et al. N Engl J Med. 2007;356(24):2472-82. 2. Ruhnke M, et al. Clin Microbiol Infect. 2012;18:680-7. 3. Aram J, et al. Presented at the 24th ECCMID 2014. Abstract R691. 4. Herbrecht R, et al. Presented at the 24th ECCMID 2014. Abstract R692. 5. Ecalta® Summary of Product Characteristics. EMA, 2013. 6. Reboli AS, et al. Pharmacoeconomics. 2011;29(8):705-17. 7. Grau S, et al. J Mycol Med. 2013;23(3):155-63. 8. Pappas PG, et al. Clin Infect Dis. 2009;48(5):503-35. 9. Cornely OA, et al. Clin Microbiol Infect. 2012;18 Suppl 7:19-37.

SUMMARY

ECALTA SUMMARY

Documents

Role of Anidulafungin in Hematology Patients M j2016.pdf · FOR MORE PATIENTS THAN YOU THINK Role of Anidulafungin in Hematology Patients Matjaz Sever MD, PhD Hematology Department