FDA Panel Endorses Miltefosine for Leishmaniasis

Miriam E. Tucker

October 21, 2013

SILVER SPRING, MD — A US Food and Drug Administration (FDA) advisory panel has endorsed miltefosine capsules for the treatment of visceral, cutaneous, and mucosal leishmaniasis.

The FDA's Anti-Infective Drugs Advisory Committee took 3 separate votes on the efficacy and safety profile of Paladin Labs Inc's alkyllysophospholipid analogue miltefosine (Impavido),voting 15 to 1 in favor of treatment of visceral leishmaniasis (VL) caused by Leishmania donovani, 14 to 2 for treatment of cutaneous leishmaniasis (CL) caused by members of the Leishmania viannia subgenus (Lv braziliensis, Lv guyanensis, and Lv panamensis), and 13 to 3 for treatment of mucosal leishmaniasis (ML) caused by the 3 aforementioned Leishmania viannia subtypes.

Paladin's proposed indication for the oral miltefosine capsules is for children and adults aged 12 years and older who weigh 30 kg or more. The drug has been marketed for the last decade in 14 countries for VL and CL, but not ML. Most of those countries, including several in Latin America and Asia, are where the parasitic infection is most endemic.

Leishmaniasis is rare in developed countries, typically only imported by travelers and members of the military, but Paladin is seeking US market clearance to make the medication more available worldwide, in line with the FDA's thinking on drug development for "neglected tropical diseases," Jonathan Berman, MD, PhD, vice president , clinical affairs, Fast-Track Drugs and Biologics, LLC, North Potomac, Maryland, said on behalf of the Canada-based company.

In voting to support licensure, panel members cited the drug's demonstrated efficacy and the unmet need for an oral leishmaniasis medication. However, many also said the package label should include cautions regarding some of the drug's potential toxicities, including vomiting, diarrhea, and adverse male and female reproductive effects.

Several committee members also requested that the FDA recommend direct observation of therapy for miltefosine treatment for leishmaniasis, as is currently done with tuberculosis treatment. Some panel members also requested more data on use of the drug in children younger than 12 years and on dosing for patients with weights above the cutoffs in the studies performed in endemic countries.


VL, an infection of the liver, spleen, and bone marrow, affects about 0.5 million people, primarily in the Indian subcontinent and East Africa. It is fatal if untreated. Current treatments include intravenous or intramuscular antimonials or intravenous amphotericin B for antimonial-resistant cases. Both of these treatments have high rates of adverse effects, Dr. Berman noted.

In the pivotal study, conducted in India, 299 patients with VL were randomly assigned to receive miltefosine and 99 to amphotericin B infusion for 1 month. The proportions meeting the primary endpoint of "final cure" at 6 months were 94.3% for miltefosine and 97.0% for amphotericin B, with the 2.7% difference meeting both the prespecified noninferiority margin of 15% and the FDA's preferred margin of 10%, FDA reviewer Hala Shamsuddin, MD, said.

Other data on miltefosine for VL, presented by Dr. Berman, came from another randomized comparator trial in Ethiopia; phase 4 studies in India, Nepal, and Bangladesh; and published literature for studies in India and Nepal.

CL and ML

There are about 1.5 million cases worldwide of CL, an infection of the macrophages of the skin. Although routine cases self-heal in 3 to 15 months, CL can metastasize to ML, a progressive destruction of the mucosa and the cartilage and bones of the nose, pharynx, and larynx that does not usually self-heal.

There are no drugs approved for either CL or ML in the United States, Dr. Berman said.

In a randomized superiority trial conducted in Columbia and Guatemala, "definite cure" (improvement at 2 weeks plus resolution of all lesions by 6 months) occurred in 66.3% of 89 patients randomly assigned to receive miltefosine compared with 29.6% of 44 patients who received placebo, a significant difference at P < .001.

Other data supporting the use of miltefosine for CL were presented from studies conducted in Brazil and Bolivia.

Data from just 1 study were available for ML, involving 79 patients in Bolivia. It was designed as a randomized equivalency comparison but turned into an open-label trial of miltefosine after patients refused to be randomly assigned to either pentavalent antimony or amphotericin B comparator groups. After 28 days of treatment, cure rates at 1 year were 49 (64.5%) of 76 patients for the per protocol analysis and 49 (62%) of 79 patients for intent-to-treat.

In all of the studies, the most common adverse effects occurring with miltefosine were vomiting, occurring in 40% to 50% of all patients, and diarrhea, seen in 15% to 26% of the patients. Because both male and female reproductive toxicity had been seen in animal studies and reduced sperm count had been reported in human males, the study protocols either excluded women entirely or required all participants to use contraception and excluded pregnant/lactating women.

Three pregnancies occurred nonetheless, all resulting in healthy babies, Dr. Berman reported.

Support, With Caveats

On the VL vote, panel member Barbara Herwaldt, MD, a leishmaniasis expert from the Centers for Disease Control and Prevention, Atlanta, Georgia, voted yes. "I think miltefosine would be advantageous to have available, but I do have issues in terms of what I think should be in the package insert." She recommended that the label stress the importance of contraception and explain that there are differences between leishmaniasis species, and even among the same species in different areas, so the drug may not work everywhere uniformly.

For CL, Alan J. Magill, MD, malaria director for the Bill and Melinda Gates Foundation, Seattle, Washington, said "I voted an enthusiastic yes.... I think it really fulfills an unmet need in the United States. The numbers of patients are not huge, but it's important to have options available," he said, adding that there are data to suggest that miltefosine could work for CL because of species other than those listed in the indication.

Before the third vote, a panel member asked whether there is evidence that treating CL will prevent mucosal disease. Dr. Magill responded that there has not been a randomized controlled trial showing that, but "of course, that would be a very difficult study to perform.... Most people feel that adequate treatment of the primary lesion, if it doesn't eliminate, certainly decreases the incidence of mucosal leishmaniasis."

The 3 panel members who voted no for the ML indication cited the lack of adequate study data as their reason. Antonio Carlos Arrieta, MD, chief of infectious diseases at Children's Hospital of Orange County, Orange, California, said "I really, really wanted to vote yes. This is not a self-limited disease, it's really bad…. I just didn't think that a single-arm study could be used as proof of efficacy."

In contrast, acting panel chief Thomas A. Moore, MS, clinical professor at the University of Kansas School of Medicine, Wichita, voted yes. "This is a difficult, destructive and disfiguring disease...and it's tough to do clinical studies on this entity. Although the data aren't as voluminous as we're used to in looking at other drugs on this committee, this one gets a pass due to the specific nature of the disease."

FDA panel members are vetted for conflicts of interest and are granted waivers for participation if necessary. No waivers were granted for this hearing.


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