WR279,396, a Third Generation Aminoglycoside Ointment for the Treatment of Leishmania major Cutaneous Leishmaniasis: A Phase 2, Randomized, Double Blind, Placebo Controlled Study

Abstract

BackgroundCutaneous leishmaniasis (CL) is a disfiguring disease that confronts clinicians with a quandary: leave patients untreated or engage in a complex or toxic treatment. Topical treatment of CL offers a practical and safe option. Accordingly, the treatment of CL with WR279,396, a formulation of paromomycin and gentamicin in a hydrophilic base, was investigated in a phase 2 clinical study in Tunisia and France.MethodsA phase 2, randomized, double blind, vehicle-controlled study was conducted to assess the safety and efficacy of topical WR279,396 when applied twice a day for 20 days as treatment for parasitologically confirmed CL. The study protocol established the primary efficacy end point as complete clinical response (CCR) defined as 50% or greater reduction in the ulceration size of an index lesion by day 50 (D50) followed by complete re-epithelialization by D100, and no relapse through D180.ResultsNinety-two subjects were randomized. Leishmania major was identified in 66 of 68 isolates typed (97%). In the intent-to-treat population, 47 of 50 WR279,396 treated participants (94%) met the definition of CCR, compared with 30 of 42 vehicle-placebo participants (71%) [p = 0.0045]. Erythema occurred in 30% and 24% of participants receiving WR279,396 and placebo, respectively [p = 0.64]. There was no clinical or laboratory evidence of systemic toxicity.ConclusionApplication of WR279,396 for 20 days was found to be safe and effective in treating L. major CL, and offers great potential as a new, simple, easily applicable, and inexpensive topical therapy for this neglected disease.Trial RegistrationClinicalTrials.gov NCT00703924

Clinical and Epidemiologic Profile of Cutaneous Leishmaniasis in Colombian Children: Considerations for Local Treatment

“…Topical antileishmanial treatments containing paramomycin daily for 20 days have proven effective for the treatment of CL caused by L. major. 32,33 Topical treatments that can be managed at the primary care level or even as home-based care could overcome many of the technical impediments for local treatment of CL in children. However, in addition to being an experimental formulation and hence, unavailable, the efficacy and effectiveness of paramomycin for New World CL have not been established.…”

Identification of the molecular attributes required for aminoglycoside activity against Leishmania

“…However, due to the emergence of pronounced parasite drug resistance in some regions, relatively high costs, and/or the severe toxic effects, there has been an extensive search over the last few years for new therapeutic agents. Paromomycin, a clinically approved AG for the treatment of various bacterial and parasitic infections, is the major component of a topical ointment (Leishcutan) used to treat cutaneous leishmaniasis caused by several species of parasites, and attempts have been made to further improve existing formulations (13)(14)(15). Paromomycin is also effective against visceral leishmaniasis, the fatal form of this disease (16), and it is registered in India and Nepal.…”

Drug Discovery Algorithm for Cutaneous Leishmaniasis

“…Currently, the drugs used for CL are the classic agents pentavalent antimony, pentamidine, and amphotericin B; and the newer agents imidazoles, miltefosine, paromomycin (injectable and topical 5 ), and liposomal amphotericin B. Because these agents were grandfathered in or developed for other diseases, there are no examples of a pre-clinical testing strategy that has lead to formal clinical development of anti-CL agents.…”