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Astellas Pharma Inc.

Focus on Fungal Infections Newsletter
Focus on Fungal Infections Newsletter

Focus on the FDA Challange


Dr. Luis Ostrosky-Zeichner from the University of Texas Houston Medical School gave a presentation entitled “Lipid-Based Preparations of Amphotericin B—Breaking With Tradition.” His presentation challenged physicians to think about the lipid formulations of amphotericin B (LFABs) in a new way.

Three lipid formulations of amphotericin B are commercially available:

  • AmBisome® is amphotericin B located in the lipid membrane of a true liposome at a relatively low concentration (10%). It forms small unilamellar vesicles that are approximately 60–70 nm in diameter.

  • Abelcet® is amphotericin B complexed with 2 phospholipids forming sheets and ribbons (1,600–11,000 nm in diameter).

  • Amphotec® is amphotericin B complexed in a 1:1 ratio with cholesteryl sulfate, forming disc-like particles (115 nm in diameter).

The formulations differ in the way that amphotericin B interacts with lipids, which affects their individual structure and pharmacokinetic profile. Although each agent is a distinct compound, they all bind to ergosterol in the fungal cell membrane, and all are fungicidal.

AmBisome® is a registered trademark of Gilead Sciences, Inc.

Abelcet® is a registered trademark of The Liposome Company, Inc.

Amphotec® is a registered trademark of Sequus Pharmaceuticals Inc.



Dr. Ostrosky began by presenting a historical perspective of antifungal polyene development, and highlighted the fact that even though amphotericin B deoxycholate remains the gold standard for antifungal therapy, it was licensed based upon open-label studies, and probably would not be licensed by the FDA today. Similarly, the LFABs were licensed for treatment of IFI based upon open-label trials. In the past, this has prevented them from being used as comparators in the primary treatment of IFI in clinical trials by the FDA.

Recently, an article published in the journal Clinical Infectious Diseases outlined the FDA challenge.1 While it is not an official FDA position, it says that an LFAB can be used as a comparator if a prospective trial sets out to prove one of two criteria: 1) the new drug is superior to an LFAB, or 2) the new drug has equivalent efficacy but is safer than the drug being tested. For example, liposomal amphotericin B was recently used as a comparator in an empirical antifungal therapy trial with voriconazole.2 This alternative method of performing clinical trials also has the potential of providing clinicians with more data on the LFABs in order to allow them to make better decisions about their use.

In a review of the literature, Dr. Ostrosky demonstrated that the LFABs had consistently higher MICs and MFCs (minimum fungicidal concentrations) in vitro than conventional amphotericin B (CAB). Subsequent animal models showed that higher doses of the LFABs were needed compared to CAB, but that these higher doses were well tolerated. Considering the incidence of amphotericin B-induced nephrotoxicity, clinical trials have shown that the incidence of nephrotoxicity associated with CAB is about 30% and results in expensive outcomes.3,4 In head-to-head comparisons of the LFABs and CAB, there is consistent data demonstrating a lower incidence of nephrotoxicity with the LFABs.5,6

Dr. Ostrosky also reported on 11 open-label trials and 6 head-to-head comparisons demonstrating efficacy of the LFABs. In the figure, an imaginary line is created at 50%, which is the average response rate for CAB between all the fungal organisms. All trials except one had response rates greater than 50%.

Slide2- Open-Label Trials: A View from the Top
ABLC® is a registered trademark of The Liposome Company, Inc.


A meta-analysis conducted by Dr. Ostrosky and his colleagues reported response rates for Aspergillus of 34% in 32 patients treated with Amphotec (ABCD), 46% in 163 patients treated with Abelcet (ABLC), and 61% in 84 patients treated with AmBisome (LAMB). Herbrecht and colleagues reported a response rate of 32% in patients treated with CAB.7 In Candida infections, the response rates were 58% in 33 patients treated with Amphotec, 75% in 123 patients treated with Abelcet, and 80% in 70 patients treated with AmBisome. Rex and colleagues reported a response rate of 79% in patients treated with CAB.8

Slide2- Open-Label Trials: 575 Proven IFI
To assess complete or partial response rates in proven cases of IFI, Dr. Ostrosky extracted 575 cases from the literature. From these cases, the response rate was 49% for Aspergillus, and 74% for Candida.


In general, Dr. Ostrosky feels that the FDA challenge has been met. The LFABs have shown a clear safety advantage over CAB in both pre-clinical and clinical data. In terms of efficacy, there is also a clear advantage for the LFABs against Aspergillus, and equal efficacy against Candida and Cryptococcus. As well, liposomal amphotericin B has shown a clear advantage over CAB against histoplasmosis. In Dr. Ostrosky’s opinion, these facts should make physicians and the FDA reconsider the continued use of CAB as a therapeutic gold standard or as the standard comparator in antifungal clinical trials.


References:

1.   Powers J. Counterpoint: Alternative trial designs for antifungal drugs—Time to talk. Clin Infect Dis 2001;33:107–9.

2.   Walsh TJ, Pappas P, Winston DJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002;346(4):225–34.

3.   Bates DW, et al. Mortality and costs of acute renal failure associated with amphotericin B therapy. Clin Infect Dis 2001;32:686–93.

4.   Wingard JR, et al. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis 1999;29:1402–7.

5.   Wingard JR, et al. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Clin Infect Dis 2003;31:1155–63.

6.    Walsh TJ, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:764–71.

7.   Herbrecht R, Denning DW, Patterson TF, et al. Open, randomised comparison of voriconazole (VRC) and amphotericin B (AmB) followed by other licensed antifungal therapy (OLAT) for primary therapy of invasive aspergillosis (IA). Proceedings of the 41st ICAAC 2001;[abstract J-680].

8.   Rex J, et al. A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 1994;331(20):1325–30.



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