Liposomal amphotericin B: 20 years of clinical experience

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Liposomal amphotericin B 20 years of clinical
experience

• Luis Ostrosky-Zeichner, MD, FACP
• Assistant Professor of Medicine and Epidemiology
• University of Texas Health Science Center at
  Houston

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The Antifungal Timeline
1970
1980
1990
2000
1950
1960
LBAPs
Nystatin
Triazoles (1)
5-FC
Candins
Amphotericin B
Imidazoles
Triazoles (2)
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Amphotericin B deoxycholate

• The gold standardbut why?

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Amphotericin B (1958)

• Package insert says it is indicated for
• Potentially life-threatening infections
  aspergillosis, cryptococcosis, North American
  blastomycosis, systemic candidiasis,
  coccidioidomycosis, histoplasmosis,
  sporotrichosis, and zygomycosis including
  mucormycosis due to susceptible species of the
  genera Absidia, Mucor, Rhizopus, Conidiobolus,
  and Basidiobolus
• But, .

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The problem with LBAP

• As with AmB-D, they were licensed based on
  open-label data
• The data on their use for IFI are almost entirely
  open-label salvage data
• Comparative studies of IFI are difficult!
• As a consequence
• There is debate about when to use them
• From a regulatory standpoint, they cant be the
  comparator for clinical trials

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There are two paradigm shifts

• Use of LBAP in clinical practice
• Evidence-based medicine
• This type of analysis
• Cochrane collaboration
• Guidelines
• Regulatory issues
• Clinical trial design in medical mycology Can an
  LBAP be a comparator?

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One but.

• AMBD remains safe and useful in some situations
• Aggressive toxicity prevention protocols
• Neonates
• Relatively healthy adults who require short
  courses of therapy
• Pyelonephritis and other urinary tract disease?

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The Lipid Polyenes Safety and Efficacy from
Preclinical Data
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A Classic Example
Toxicity, but with survival
Cr Rise
LAMB 5
0 mg/dl
LAMB 10
3 mg/dl
LAMB 1
0 mg/dl
AmB-D 1
2 mg/dl
Control
0 mg/dl
Francis, J Inf Dis 1994 169356-68.
Aspergillosis in neutropenic rabbits
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The Lipid Polyenes Safety from the Clinical
Literature
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Nephrotoxicity of AmB-D is Notable
Average of 30
? LOS (10d) ? Mortality 30,000/episode
Bates, CID 200132686
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LBAP are less nephrotoxic than AMB-D
Cr gt2.5
Cr gt2.5
Cr gt3.0
AMB-D
AMB-D
ABLC
L
L
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LBAPs are NOT problem free

• Acute infusion-related reactions
• Chills, rigor, fever, phlebitis, hypotension, and
  arrhythmia
• May be compound specific
• AmB-D gt ABCD gt ABLC gt LAMB
• Cumulative dose-related toxicity
• K Mg wasting, arrhythmia, anemia, renal failure
• AmB-D gt ABCD gt ABLC gt LAMB
• Overall, however
• They are definitely safer than AmB-D

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The Lipid Polyenes Efficacy from the Clinical
Literature
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Data are somewhat scattered

• Classic trials
• Open-label 8
• LBAP vs. AmB 10
• Data fall into two large groups
• Febrile neutropenia a fair bit of data
• Good randomized data, great safety data
• Salvage of proven IFI
• Although mostly open-label, there are rather a
  lot of cases in the literature

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Open-Label Trials A View from the Top
AmB-D Average
ABLC ABCD LAMB
Ostrosky-Zeichner, CID 2003.
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Open-Label Trials 575 Proven IFI
N279
226
30
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16
23
26
31
Failure
42
51
Success (CR/PR)
49
74
69
58
77
Mehta 1997 Mills 1994 Ng 19958 Oppenheim
1995 Ringden 1991 Tollemar 1992 Walsh 1998 Walsh
1999
Ostrosky-Zeichner, CID 2003.
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Controlled Studies vs. AmB-D

• Febrile neutropenia x 4 studies
• Equal efficacy, clear safety advantage
• Walsh Breakthru IFI, AmB-D 8, LAMB 3
• Defined disease
• Histo/AIDS/LAMB, n73 (Johnson, 2000)
• AmB-D 59 success, LAMB 89 success
• Crypto/AIDS/LAMB, n 28 (Leenders, 1997)
• AmB-D 89 success, LAMB 80 success
• CSF neg at 2 wks AmB-D 11, LAMB 67

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New data for LAMB
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Empirical Therapy- Febrile Neutropenia Studies
Walsh, et al. NEJM 1999340764-71, Walsh, et
al. NEJM 2002346225-34, Walsh, et al. NEJM
20043511391-402.
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Micafungin vs. LAMB for Candidemia
6.4 with SCr increase
Ruhnke et al. ICAAC 2005.
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Micafungin vs. LAMB for Candidemia
Biofilms!
Ruhnke et al. ICAAC 2005.
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LAMB in Histoplasmosis (HIV)
Johnson PC, et al. Ann Intern Med 2002.
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AMBILoad Trial Design

• 201 patients/71 sites/10 countries
• Proven/probable aspergillosis and other
  filamentous fungi (EORTC/MSG).
• LAMB 10mg/kg vs. 3mg/kg
• 93 hematological malignancies
• 70 neutropenic

Cornely OA, et al, Blood. 2005 106 3222 (ASH
47th Annual Meeting Abstracts).
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AmBiLoad Trial Endpoints

• Endpoints
• Overall response at investigator-determined EOT
• Favorable Complete Partial responses
• Unfavorable Stable Failure Unevaluable
• Survival at d14, EOT, 4 wks post-EOT and 12 weeks
• Safety of 10 mg/kg/day dose compared to standard
  dose
• MITT population
• Data Review Board confirmed all IFI cases and
  overall response assessments

Cornely OA, et al, Blood. 2005 106 3222 (ASH
47th Annual Meeting Abstracts).
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Fungal pathogens
Cornely OA, et al, Blood. 2005 106 3222 (ASH
47th Annual Meeting Abstracts).
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AMBILoad trial
NS
NS
Cornely OA, et al, Blood. 2005 106 3222 (ASH
47th Annual Meeting Abstracts).
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12 Week SurvivalTreatment Effect by Predictive
Factors

• AmBi-3 (72) vs. AmBi-10 (59) P-value
• Unadjusted .053
• Adjusted for
• Allo-SCT .078
• Uncontrolled malignancy .078
• Allo-SCT Uncontrolled malignancy .12
• P-value for treatment effect (3 vs. 10mg) on
  survival at 12 weeks
• Survival driven by underlying risk factors, not
  treatment dose received

Cornely OA, et al, Blood. 2005 106 3222 (ASH
47th Annual Meeting Abstracts).
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Putting AmBiLoad in Context

• Voriconazole vs. AmB-d

• AmBiLoad

Survival at week 12
Survival at week 12
Cornely OA, et al, Blood. 2005 106 3222 (ASH
47th Annual Meeting Abstracts).
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So
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Time for a New Standard?

• Are you convinced?
• Many of us are!
• Many would choose a LBAP if price was NOT a
  concern in fact many do!
• Early pharmacoeconomic data is favorable
• Is AmB-D a good comparator for the next
  generation of antifungals?
• Use as comparator in current clinical studies
  mainly proves that AmB-D is toxic!

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Key Messages

• Safety
• Clear advantage of LBAP over AMB-D
• Safety is directly related to efficacy!
• Efficacy
• Aspergillus
• Candida
• Cryptococcus
• Histoplasma
• Febrile neutropenia

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Thank You