CLINICAL TRIALS REVIEW

US Food and Drug Administration Approval of Liposomal Amphotericin

B for the Treatment of Visceral Leishmaniasis: A Model for Orphan

Drug DevelopmentRichard D. Pearson, MD*, Selma M.B. Jeronimo, MD, PhD†,

and Susan M. Lareau, BS*

Address*Division of Geographic and International Medicine, Departments of Internal Medicine and Pathology, Box 485, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.†Department of Biochemistry, Universidade Federal do Rio Grande do Norte, Natal, Brazil.

Current Infectious Disease Reports 1999, 1:415–416Current Science Inc. ISSN 1523–3847Copyright © 1999 by Current Science Inc.

One of the most important and interesting recentadvances in the treatment of parasitic diseases was theapproval by the US Food and Drug Administration (FDA)of liposomal amphotericin B (AmBisome, Nexstar, SanDimas, CA) for the treatment of visceral leishmaniasis. Itis the first drug to be approved for this indication in theUnited States. Liposomal amphotericin B offers impor-tant advantages over pentavalent antimony-containingdrugs, which were the mainstay of therapy for decades,and its approval establishes an important precedent forfuture orphan drugs developed for leishmaniasis or other“exotic” parasitic diseases.

Visceral leishmaniasis refers to the clinical syndromecaused by Leishmania (Leishmania) donovani, Leishmania(Leishmania) infantum, Leishmania (Leishmania) chagasi,and occasionally other Leishmania species. The disease isdue to the dissemination of leishmania amastigotes inmacrophages in the spleen, liver, bone marrow, andthroughout the reticuloendothelial system. Over the pastdecade major epidemics of visceral leishmaniasis haveoccurred in India and among refugees in the Sudan. It hasbecome recognized as an important opportunistic patho-gen in persons with HIV-AIDS in Spain, Southern France,Italy, and elsewhere in the Mediterranean littoral. Largeperiurban epidemics have been reported from cities innortheastern Brazil. On rare occasion, the disease is diag-

nosed in North America among immigrants or returningtravelers, some of whom are immunocompromised by HIVor immunosuppressive therapy.

Since their introduction in the 1920s, pentavalent anti-mony-containing drugs have been the treatment of choicefor visceral leishmaniasis around the world. Two suchcompounds are available: stibogluconate sodium (Pen-tostam, Burroughs Wellcome, Research Triangle Park, NC),and meglumine antimoniate (Glucantime, Rhône-Pou-lenc, Antony Cedex, France). Although there may be slightvariations among lots, they are considered to be of compa-rable efficacy and toxicity when dosed on the basis of theirpentavalent antimony content. Neither drug is FDAapproved. Pentostam can be obtained in the United Statesfrom the Centers for Disease Control Drug Service at theCenters for Disease Control and Prevention in Atlanta,Georgia. Glucantime is widely used in Latin America, but isnot available in the United States.

Pentavalent antimony-containing drugs are relativelytoxic, and therapeutic failures have been increasingly rec-ognized, particularly in India. They must be administeredparenterally over prolonged periods of time. Intramuscularinjections can be given to small children, but the volumeof drug necessitates intravenous administration in olderchildren and adults. They are associated with substantialtoxicity; malaise, myalgias, arthralgias, nausea, and vomit-ing are common. Elevations in liver and pancreaticenzymes are frequent. Clinically apparent pancreatitisoccurs in some persons. Nonspecific ST- T-wave changesare noted on echocardiograms, and sudden death has beenreported in persons who receive more than the recom-mended dose. These untoward effects plus increasingreports of pentavalent antimony failure have fueled thequest for new therapeutic agents.

The development of liposomal amphotericin B for thetreatment of fungal diseases raised exciting new possibili-

416 Clinical Trials Review

ties for the treatment of visceral leishmaniasis. Leishmaniaspecies, like fungi, contain ergosterol, against whichamphotericin acts, rather than cholesterol as in mamma-lian cells. Amphotericin B deoxycholate had been used formany years as an alternative to pentavalent antimony. It iseffective in patients with visceral leishmaniasis, but its tox-icity and the necessity for prolonged parenteral administra-tion have limited its use.

Leishmania species reside solely within mononuclearphagocytes in humans and other mammals, and liposome-encapsulated drugs are theoretically targeted to macroph-ages. In addition, the liposomal preparation is in generalless toxic then amphotericin B deoxycholate, even when itis administered at higher concentrations.

As summarized by Meyerhoff [1], Berman [2], and oth-ers [3,4], data from multiple studies performed in endemicareas in comparison with historical controls indicate thatliposomal amphotericin B is as effective or more effectivethan pentavalent antimony-containing compounds in thetreatment of children and adults with visceral leishmaniasis.The FDA analysis indicated that liposomal amphotericin Bcured 98.9% of immunocompetent patients (95% confi-dence limit 96.6%–100%) and 94.7% of immunocompro-mised patients. Other lipid-associated amphotericin Bpreparations also appear to be effective [5], but they havenot been as extensively studied nor are they FDA approved.

There are limitations with liposomal amphotericin B. Anumber of reports suggest that the majority of HIV-infected patients with visceral leishmaniasis will eventuallyrelapse after treatment with either liposomal amphotericinB or pentavalent antimony. The use of liposomal ampho-tericin B for the treatment of human cutaneous andmucosal leishmaniasis has not yet been systematicallystudied, but failures have been observed in animal modelsof cutaneous leishmaniasis, and failure after a course ofamphotericin B lipid complex was reported in a personwith cutaneous leishmaniasis [6].

The toxicity profile with liposomal amphotericin Bused in the treatment of visceral leishmaniasis appears tobe similar to that observed when it is used for fungal dis-eases. Constitutional symptoms, chills, fever, hypertension,hypotension, azotemia, and hypokalemia can occur, butthey are less frequent and less severe than with amphoteri-cin B deoxycholate. Severe back pain with or without chesttightness or pain occurs occasionally during infusion ofAmBisome. These symptoms do not occur with every doseand usually do not recur if the administration is stoppeduntil symptoms resolve and is then resumed at a slowerrate of infusion.

What is fascinating about the FDA’s approval of liposo-mal amphotericin B for visceral leishmaniasis is the lack offinancial incentive. Only a few cases of visceral leishmania-sis are treated in the United States each year, and in those

cases physicians would have been able to use liposomalamphotericin B off label if they desired, since it is approvedfor the treatment of fungal infections. The number of casesof visceral leishmaniasis worldwide has been estimated tobe in the hundreds of thousands per year, but most occurin impoverished rural areas, making it unlikely thatpatients with the disease will be able to access or pay forthe drug.

In licensing liposomal amphotericin B for the treat-ment of visceral leishmaniasis, the FDA demonstrated itswillingness to evaluate the efficacy and toxicity of orphancompounds for parasitic diseases and to accept data fromstudies done abroad and relevant historical controls.Although FDA approval is obviously not necessary for theuse of liposomal amphotericin B and other drugs outsidethe United States, many developing countries lack the reg-ulatory capacity to evaluate new drugs. FDA approval indi-cates that experts have reviewed data on efficacy andtoxicity, assessed their quality, and in accordance with theadministration’s standards, deemed the drug appropriatefor use.

In some respects liposomal amphotericin B is a specialcase since amphotericin B deoxycholate was previouslylicensed and widely used, and because toxicity data fromthe liposomal preparation were available from studies ofthe treatment of fungal diseases. Gaining FDA approvalprobably would have been more difficult and costly had anapplication for a totally new compound been submitted.Nonetheless, the willingness of the FDA to considerorphan drugs is a very important step. It provides a mecha-nism for the standardized evaluation and approval of newdrugs for parasitic diseases that are exotic in the UnitedStates, but major causes of morbidity and mortality indeveloping areas.

References1. Meyerhoff A: U.S. Food and Drug Administration approval

of AmBisome (liposomal amphotericin B) for treatment of visceral leishmaniasis. Clin Infect Dis 1999, 28:42–48.

2. Berman JD: U.S. Food and Drug Administration approval of AmBisome (liposomal amphotericin B) for treatment of vis-ceral leishmaniasis [editorial]. Clin Infect Dis 1999, 28:49–51.

3. Catania S, Aiassa C, Tzahtzoglou S, et al.: Visceral leishmania-sis treated with liposomal amphotericin B. Pediatr Infect Dis J 1999, 18:73–74.

4. Berman JD, Badaro R, Thakur CP, et al.: Efficacy and safety of liposomal amphotericin B (AmBisome) for visceral leish-maniasis in endemic developing countries. Bull WHO 1998, 76:25–32.

5. Sundar S, Goyal AK, More DK, et al.: Treatment of antimony-unresponsive Indian visceral leishmaniasis with ultra-short courses of amphotericin-B-lipid complex. Ann Trop Med Parasitol 1998, 92:755–764.

6. Wortmann GW, Fraser SL, Aronson NE, et al.: Failure of amphotericin B lipid complex in the treatment of cutaneous leishmaniasis. Clin Infect Dis 1998, 26:1006–1007.