Liposomal amphotericin B as a treatment for human leishmaniasis

Figures & data

Table 1. Summary of currently available monotherapies for VL*.

Drugs	SSG/MA	Amphotericin B deoxycholate	LAMB	MF	PM
Drug class	Pentavalent antimonial	Polyene antibiotic	Polyene antibiotic	Alkyllysophospholipid	Aminoglycoside
Regimen	20 mg/kg daily for 20 – 30 days (depending on geographic area)	1 mg/kg every other day for 30 days (15 mg/kg total dose)	10 – 30 mg/kg total dose in 1 – 6 doses over 1 – 10 days	1.5 – 2.5 mg/kg/day over 28 days (South Asia only)	11 mg/kg (= 15 mg/kg sulfate) for 21 days (in monotherapy)
Marketing authorization holder	Albert David (generic SSG) GSK (Pentostam^™) Sanofi-Aventis (Glucantime^™)	Bristol-Myers Squibb (Fungizone^™)	Gilead (AmBisome^™)	Paladin (Impavido^™)	Gland Pharma
Administration	i.v. or i.m.	Slow i.v.	Slow i.v.	Oral	i.m.
Clinical efficacy (cure at 6 months post-treatment)	35 – 95% (depending on geographic area)	> 90% all regions	95% in South Asia (dose of ≥ 10 mg/kg) ∼ 90% in other regions (doses of 20 – 30 mg/kg)	> 90% in South Asia not clearly established in other regions	> 90% in monotherapy in South Asia and in combination with SSG for 17 days in Africa
Resistance	Failure rate as high as 60% (Bihar state, India)	Not documented	Not documented	Laboratory isolates	Laboratory isolates
Toxicity	+++ Cardiac toxicity Pancreatitis Nephrotoxicity Hepatotoxicity	+++ Nephrotoxicity Hypokalemia Rigors and chills during infusion	+/- Rigors and chills during infusion Hypokalemia and renal failure are rare	+ Gastrointestinal effects (in 20 – 55% of patients, usually mild) Nephrotoxicity Hepatotoxicity Possible teratogenicity	+ Nephrotoxicity Ototoxicity Hepatotoxicity Pain at injection site
Approximate cost of drugs per course USD [70]	SSG ∼ US$55 Glucantime ∼ US$60	Generic versions price ∼ US$20	WHO negotiated price: US $126 – 378	WHO negotiated price: ∼ US$65 – 150	∼ US$15
Issues	Quality control Availability Length of treatment Painful injection (i.m.) Toxicity Resistance in India	Slow i.v. infusion Dose-limiting Nephrotoxicity Heat stability	High price Slow i.v. infusion Heat stability (storage < 25°C) Efficacy variable between regions	Relatively high price Possible teratogenicity Potential for resistance Patient compliance	Efficacy variable between and within regions

*Based on data from the WHO expert committee report 2010.

i.m.: Intramuscular; i.v.: Intravenous; LAMB: Liposomal amphotericin B; MA: Meglumine antimoniate; MF: Miltefosine; PM: Paromomycin; SSG: Sodium stibogluconate.

Table 2. TPP for new clinical entities against VL (as monotherapy)*.

	Optimal target profile	Minimal target profile
Target label	VL and PKDL	VL
Species	All species	Leishmania donovani
Distribution	All areas	Either India or Africa
Target population	Immunocompetent and immunosuppressed	Immunocompetent
Clinical efficacy	> 95%	> 90%
Resistance	Active against resistant strains
Safety and tolerability	No AEs requiring clinical monitoring	One clinical monitoring visit in mid/end point
Contraindications	None	Pregnancy/lactation
Interactions	None – compatible for combination therapy	None for malaria, TB and HIV concomitant therapies
Formulation	Oral/i.m. depot	Oral/i.m. depot
Treatment regimen	1/day for 10 days p.o./3 shots over 10 days‡	b.i.d. for < 10 days p.o.; or > 3 shots over 10 days
Stability	3 years in zone 4	Stable under conditions that can be reasonably achieved in the target region (> 2 years)
Cost	< US$10/course	< US$125/course

*Developed by and reproduced with permission by DNDi.

‡For primary VL only. PKDL, HIV co-infection and relapse case treatments may require longer treatment durations.

DNDi: Drugs for Neglected Diseases initiative; PKDL: Post-kala azar dermal leishmaniasis; TPP: Target product profile; VL: Visceral leishmaniasis.

Table 3. Potential regimens of LAMB that have been developed for use against VL*.

Regimen	Cost (USD) [70]	Efficacy (phase of trial done)	Comments
LAMB i.v. 10 mg/kg single dose	126	95% (P3)	South Asia only, poor efficacy in East Africa
LAMB 20 mg/kg over 4 doses	252	98% (P4)	South Asia only and possibly Europe and Latin America, poor efficacy in East Africa
LAMB 5 mg/kg + MF 100 mg/kg/day for 8 days	88 – 109	97.5% (P3)	South Asia only; teratogenicity of MF may hinder uptake
LAMB 5 mg/kg + PM 15 mg/kg/day for 11 days	79	97.5% (P3)	South Asia only; use of daily PM injections may hinder uptake
LAMB 30 mg/kg over 6 – 10 doses	378	90% (observational field data only)	East Africa only; no clinical trial data available at this dose

*Based on data from the WHO expert committee report 2010.

LAMB: Liposomal amphotericin B (all trials here have used AmBisome^™); MF: Miltefosine; PM: Paromomycin.

Box 1. Review of LAMB treatment for cutaneous, mucosal and post-kala azar leishmaniasis as leishmaniasis also refer back to cutaneous and mucosal.

CL

Geographical distribution of CL, its clinical features, potential to spread (e.g., to mucosae), as well as recommended treatment (e.g., local vs systemic) and response to anti-leishmanial drugs vary with the Leishmania species [71]. Published data on LAMB use for CL are limited to individual case reports or small case series. Out of 19 patients with CL caused by various Leishmania species, treatment with LAMB (median total dose: 21 mg/kg) was curative in 16 (84%), while 3 patients required a second course of LAMB [72]. In Israel, 11/13 (83%) patients with L. tropica and 29/34 (85%) travelers with L. braziliensis CL (88% returning from Bolivia) were cured with LAMB (total dose: 18 mg/kg) [73,74]. In the L. braziliensis CL study, LAMB was more effective and better tolerated than SSG administered for 3 weeks. However, in Brazil, only 50% of 16 patients with CL caused by various Leishmania species who received a lower dose of LAMB (total dose: 7.5 mg/kg) were cured [75]

ML

In contrast to CL, patients with ML do not self-heal and require systemic treatment. Pentavalent antimonials and conventional amphotericin B have been the mainstay of ML treatment during the last decades with 51 – 88% reported cure rates [76]. There are very scarce published data on LAMB use for ML. In Brazil, 5/6 (83%) patients unresponsive to antimonials were cured after receiving 2 – 3 mg/kg/day for a minimum of 20 days [77]. The largest case series includes eight patients who were cured after a mean total dose of 35 mg/kg of LAMB [78], which is lower than the total dose recommended in the most recent WHO technical report (40 – 60 mg/kg)

PKDL

Anti-leishmanial therapy is indicated in severe or prolonged PKDL in East Africa and in all forms of PKDL in South Asia. Treatment still relies on prolonged – sometimes up to several months – regimens of pentavalent antimonials, which are cumbersome, painful (daily intramuscular injections) and sometimes toxic. LAMB (2.5 mg/kg/day for 20 days) was successful in 10/12 (83%) patients with SSG-unresponsive PKDL in Sudanese patients [79]. Apart from rare isolated case reports, there are no other published case series of LAMB use in PKDL. In Bangladesh, a large cohort (n = 1303) of PKDL patients were recently treated with LAMB (5 mg/kg twice a week for 3 weeks; 30 mg/kg total dose) with encouraging results (K. Ritmeijer, personal communication)

CL: Cutaneous leishmaniasis; LAMB: Liposomal amphotericin B; ML: Mucosal leishmaniasis; PKDL: Post-kala azar dermal leishmaniasis; SSG: Sodium stibogluconate.

Table 4. Summary of studies and clinical trials on LAMB use for VL.

Country/Author/Ref.	Study design	Regimen used	Indication	Sample size	Efficacy/effectiveness	Comments
Ethiopia/Ritmeijer et al.; 2011 [24]	Retrospective cohort analysis	LAMB 30 mg/kg split over 6 doses*	A: Severely ill B: HIV/VL +/- relapse	A: N = 94 B: N = 195 (79 relapses)	A: IC = 93% B: IC = 60%	IC among HIV+ relapse patients = 38%
India/Sinha et al.; 2011 [28]	Retrospective cohort analysis	LAMB 20 – 25 mg/kg split over 4 – 15 days*	HIV/VL +/- relapse	N = 55 (27 relapses)	Survival at 2 years = 85.5%	Relapse at 1 and 2 years = 8% and 26.5%
India/Sundar et al.; 2011 [5]	Phase III non-inferiority RCT	A: ampho B B: LAMB and MF* C: LAMB and PM* D: MF and PM	Primary uncomplicated VL (e.g., no HIV or severely ill)	A: N = 157 B: N = 160 C: N = 158 D: N = 159	A: ITT DC = 93% B: ITT DC = 97.5% C: ITT DC = 97.5% D: ITT DC = 98.7%	LAMB regimens were single LAMB doses + MF/PM (7 – 10 days)
India/Sundar et al.; 2011 [34]	Non-comparative clinical trial	LAMB and MF* (single dose + 14-day MF)	Primary uncomplicated VL	N = 135	ITT DC = 91.9%	Some GI side effects noted with MF use
India/Sinha et al.; 2010 [27]	Prospective cohort study	LAMB 20 mg/kg split over 4 doses*	Primary and relapse cases in routine care	N = 251	DC = 98.8% (lost to follow-up = 17.5%)	1% of cases experienced lip swelling
India/Mondal et al.; 2010 [20]	Open-label dose finding (Phase II) clinical trial	A: LAMB 5 mg/kg B: LAMB 7.5 mg/kg C: LAMB 10 mg/kg (total doses)	Uncomplicated VL	A: N = 10 B: N = 10 C: N = 10	A: ITT DC = 60% (5 people excluded) B: ITT DC = 50% C: ITT DC = 90%	Fungisome^™ (Lifecare) formulation used
India/Sundar et al.; 2010 [6]	Phase III non-inferiority RCT	A: ampho B B: LAMB 10 mg/kg single dose*	Uncomplicated VL	A: N = 108 B: N = 306	A: ITT DC = 96.3% B: ITT DC = 95.7%	Only 1% SAEs (nephro/hepatotoxicity) per group
India/Sundar et al.; 2008 [33]	Phase II RCT	A: LAMB 5 mg/kg* B: LAMB 5 mg/kg and MF 10 days* C: LAMB 5 mg/kg and MF 14 days* D: LAMB 3.75 mg/kg and MF 14 days* E: LAMB 5 mg/kg and MF 7 days*	Uncomplicated VL	A: N = 45 B: N = 46 C: N = 45 D: N = 45 E: N = 45	A: ITT = 91% B: ITT = 98% C: ITT = 96% D: ITT = 96% E: ITT = 98% cure rates are at 9 months follow-up for all groups	All treatments were tolerated to completion, but hepatotoxicity noted especially in group C
Spain/Molina et al.; 2007 [19]	Retrospective cohort analysis	LAMB 40 mg/kg total initial Rx + 5 mg/kg secondary prophylaxis*	HIV co-infected relapses cases	N = 17	Free of relapse: 6 months = 89.7% 12 months = 79.1% 36 months = 55.9%	Significant increase seen in CD4 count in the non-relapses
Sudan/Mueller et al.; 2007 [22]	Retrospective cohort analysis	LAMB 15 – 49 mg/kg given over 6 doses*	52 relapses and 12 complicated cases	N = 64	IC = 55% only	TB, HIV, initial parasite density linked with failure
Sudan/Mueller et al.; 2006 [21]	Retrospective cohort analysis	A: SSG alone B: SSG and LAMB* C: LAMB alone*	VL in pregnant women	A: N = 23 B: N = 4 C: N = 12	IC = 100% all groups; 13 abortions noted in group A, none in B and C	LAMB appears safer than SSG in pregnant women with VL
India/Sanath et al.; 2005 [25]	Post-marketing cohort study	LAMB 1 – 3 mg/kg/day for 7 – 76 days	Mixed population in routine care	91 out of 144 assessed for cure	IC = 73.6%, 8.7% had no response	Fungisome^™ (Lifecare) used, no drug-related SAEs noted
Greece/Kafetzis et al.; 2005 [18]	Retrospective cohort analysis	A: MA (20 mg/kg for 21 days) B: LAMB varying doses*	Children under the age of 15	A: N = 10 B: N = 19	All patients initially cured, no relapses noted after	Shorter median hospitalization with LAMB (19 vs 7 days)
Italy/Cascio et al.; 2004 [14]	Retrospective cohort analysis	LAMB 3 mg/kg in 6 doses over 10 days*	HIV negative children under the age of 15	N = 164	IC = 100% 4.3% relapsed 3 – 15 months after	All relapses cured with LAMB (total dose 30 mg/kg)
India/Sundar et al.; 2004 [32]	Open-label RCT	A: ampho B B: LAMB 2 mg/kg/5 days*	Uncomplicated VL	A: N = 51 B: N = 51	A: ITT DC = 96% B: ITT DC = 96%	2 patients in group A died, 2 failures in group B
India/Sundar et al.; 2003 [30]	Non-comparative clinical trial	LAMB 7.5 mg/kg single dose*	Uncomplicated VL	N = 203	ITT IC = 96% ITT DC = 90%	Few AEs noted, mainly infusion reactions
Italy/Pagliano et al.; 2003 [23]	Retrospective cohort analysis	A: MA (20 mg/kg for 21 days) B: LAMB 3 mg/kg in 6 doses over 10 days*	HIV negative adults	A: N = 24 B: N = 40	After 2 years post-treatment: A: 12% failures B: 5% failures	Faster recovery time noted with LAMB
Greece/Syriopoulou et al.; 2003 [35]	Prospective study	LAMB 10 mg/kg over 2 days*	HIV negative children	N = 41	DC = 98%	Fast recovery time, mild infusion related reactions in < 10% of patients
India/Sundar et al.; 2002 [31]	Double-blind Phase II RCT	A: LAMB 3.75 mg/kg over 5 days* B: LAMB 7.5 mg/kg over 5 days* A: LAMB 15 mg/kg over 5 days*	Refractory cases to antimonials	A: N = 28 B: N = 28 C: N = 28	A: ITT DC = 89% B: ITT DC = 93% C: ITT DC = 97%	Mild/moderate infusion-related reactions were common
India/Sundar et al.; 2001 [29]	Open-label Phase II RCT	A: LAMB 5 mg/kg single dose* B: LAMB 5 mg/kg over 5 days*	Uncomplicated VL	A: N = 46 B: N = 45	A: ITT DC = 91% B: ITT DC = 93%	Mild infusion-related reactions were common
India/Thakur; 2001 [36]	Open-label RCT	A: LAMB 15 mg/kg single dose* B: ampho B (1 mg/kg × 20 days)	Uncomplicated VL	A: N = 17 B: N = 17	A: ITT DC = 100% B: ITT DC = 100%	Fewer adverse events noted in the LAMB group
India/Bodhe et al.; 1999 [13]	Dosing study (Phase II) clinical trial	Various doses of LAMB ranging from 1 mg/kg for 21 days to 3 mg/kg for 7 days	Primary and relapse cases	N = 63	Cure rates varied from 90 to 100% depending on dose	Used L-AMP-LRC 1 (liposome pharmacology center)
India, Kenya, Brazil/ Berman et al.; 1998 [12]	Phase II dose ranging clinical trial	A: LAMB 14 mg/kg total dose* B: LAMB 10 mg/kg total dose* C: LAMB 6 mg/kg total dose* D: LAMB 20 mg/kg total dose (Brazil only)*	Groups were done sequentially in descending doses; parallel studies done in India, Kenya and Brazil	A: N = 10 (India, Kenya) N = 13 (Brazil) B: N = 10 (India, Kenya) C: N = 10 (India, Kenya) D: N = 15 (Brazil only)	India: 100% DC rates in A, B, C Kenya: 100%, 80% and 20% DC in A, B, C Brazil: 62% and 83% DC in groups A and D, respectively	Differential efficacy seen across 3 continents with India > Kenya ≥ Brazil
Italy/di Martino et al.; 1997 [17]	Prospective study	LAMB various doses*	Pediatric population	N = 106	Up to 100%	18 mg/kg total identified as the optimum dose
Italy, Brazil, UK/ Davidson et al.; 1996 [15]	Dose decreasing (Phase II) clinical trial	A: LAMB 24 mg/kg total dose* B: LAMB 18 mg/kg total dose* C: LAMB 15 mg/kg total dose* D: LAMB 12 mg/kg total dose* (split into 6 doses)	Adult and pediatric population Uncomplicated VL	A: N = 13 B: N = 42 C: N = 32 D: N = 1	Cure at 1 year = A: 10/13 (3 LTFU were IC) B: 41/42 (1 relapse) C: 29/32 (1 failure, 2 relapse) D: 1/1	Treatment well tolerated with no cessation of treatment; and well tolerated in children
Sudan/Seaman et al.; 1995 [26]	Open label, dosing (Phase II) clinical trial	A: LAMB 3 – 5 mg/kg × 3 doses* B: LAMB 3 – 5 mg/kg × 6 doses* C: LAMB 4 – 5 mg/kg × 4 doses*	Relapse and complicated (severely ill) cases included	A: N = 16 B: N = 16	A: 50% cured B: 88% cured C: 64% cured	Long-term follow-up not done
Europe/Davidson et al.; 1994 [16]	Open label, dosing (Phase II) clinical trial	A: LAMB 1 – 1.38 mg/kg × 21 doses* B: LAMB 3 mg/kg × 10 doses* C: LAMB 1.38 – 1.85 mg/kg × 21 doses*	Gp A and B were immune-competent Gp C was immune-compromised	A: N = 10 B: N = 10 C: N = 11	Cure rates at over 12 months: A: 100% B: 100% C: 27% (100% were IC)	Groups A and B were largely made up of children; Group C included adults only

Country denotes where patients were recruited.

*Denotes when AmBisome^™ (currently Gilead, previously Vestar) was used.

AE: Adverse event; ampho B: Conventional amphotericin B 15 mg/kg total dose; DC: Definitive cure at 6 months; indication is for type of VL (primary, relapse, HIV co-infected); IC: Initial cure; ITT: Intention to treat; LAMB: Liposomal amphotericin B; MA: Meglumine antimoniate; MF: Miltefosine; PM: Paromomycin; RCT: Randomised controlled trial; SAE: Serious adverse event; VL: Visceral leishmaniasis.

Table 5. Injectable liposomal products approved by the US FDA.

Trade name	Drug formulation	Year of US FDA approval
Doxil^™	Pegylated liposomal doxorubicin injection	1995
Daunoxome^™	Liposomal daunorubicin injection	1996
Ambisome^™	LAMB injection	1997
Depocyt^™	Liposomal cytarabine injection	1999
Visudyne^™	Liposomal verteporfin injection	2000
Definity^™	Liposomal perflutren injection	2001
Depodur^™	Liposomal morphine sulfate injection	2004
Exparel^™	Liposomal bupivacaine injection	2011

LAMB: Liposomal amphotericin B; US FDA: United States Food and Drug Administration.

Table 6. Overview of LAMB formulations introduced in the market or under development*.

Company	Country	Brand name	Year of marketing approval in the country of origin	Storage conditions	Presentation (special warnings before use)
Gilead	USA	AmBisome^™	1997	Below 25°C	Lyophilized (reconstitution, filtration and dilution before use)
Lifecare	India	Fungisome^™	2003	2 – 8°C	Liquid (sonication 45 min before use)
Cipla	India	Phosome^™	2008	2 – 8°C	Lyophilized (reconstitution, filtration and dilution before use)
Sun Pharma	India	Lambin^™	2009	2 – 8°C	Lyophilized (reconstitution, filtration and dilution before use)
Lyka Labs	India	Lipholyn^™	2010	2 – 8°C	Lyophilized (reconstitution, filtration and dilution before use)
Celon Labs	India	Under development		2 – 8°C	Lyophilized (reconstitution, filtration and dilution before use)
Laboratorios Richmond	Argentina	Withdrawn, under further development (Anfogen)			Lyophilized (reconstitution, filtration and dilution before use)
Genex Pharma	India	Under development
Claris Lifescience	India	Under development
TTY Pharma	Taiwan	Under development

*This table is not exhaustive as some producers from India and Taiwan have chosen not to disclose information about their products under development.

LAMB: Liposomal amphotericin B.

Figure 1. Young female patient with visceral leishmaniasis receiving liposomal amphotericin B infusion at Vaishali District Hospital, Bihar State, India.

Figure 2. Nursing chart showing rapid clearance of fever after initiation of liposomal amphotericin B treatment in a patient with visceral leishmaniasis at Vaishali District Hospital, Bihar State, India.

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