The U.S. Army Medical Research and Materiel Command (USMRMC) marked a major advance against the disease cutaneous leishmaniasis when the U.S. Food and Drug Administration (FDA) approved the marketing of a new diagnostic test developed by a partnership of the Walter Reed Army Institute of Research (WRAIR), the U.S. Army Medical Materiel Development Activity (USAMMDA), and the molecular diagnostics company Cepheid USA Inc.[image align=”right” caption=”Leishmaniasis as seen under a microscope at Walter Reed Army Institute of Research in Silver Spring, MD. (U.S. Army photo by SFC Roddy Rieger.)” linkto=”/web/wp-content/uploads/army.mil-88442-2010-10-13-081010-compressed.jpg” linktype=”image_vt”]”/wp-content/uploads/army.mil-88442-2010-10-13-081010-compressed.jpg” height=”246″width=”167″[/image]
On the treatment front, USAMMDA continues to work with the Tunisian Ministry of Public Health and the Institute Pasteur of Tunis to develop the Paromomycin/Gentamicin Topical Cream for the treatment of cutaneous leishmaniasis. Because there is no topical treatment approved by the FDA, U.S. service members have to be evacuated from the theater of operations to be treated with expensive and often toxic intravenous therapies. An approved topical treatment would allow physicians to prescribe the topical cream for service members, allowing them to treat their own cutaneous leishmaniasis in theater and return to duty quickly.
Leishmaniasis is endemic throughout Africa, Asia, Europe, and North and South America. It is caused by single-cell organisms transmitted by the bite of the tiny sand fly. Cutaneous leishmaniasis, the most common form of the disease, affects more than 1 million people a year worldwide. About 3,000 U.S. service members have been infected since 2003, primarily troops serving in Iraq and Afghanistan.
Although not considered life-threatening, cutaneous leishmaniasis can cause disfiguring skin ulcers that take months to heal. If left untreated, it results in potentially disfiguring scars and occasionally can progress to the less common and much more serious mucocutaneous and visceral forms of leishmaniasis.
USAMRMC worked for several years to develop the SMART Leish PCR assay for people with signs and symptoms of leishmaniasis. Up to this point, there were no FDA-cleared devices to diagnose cutaneous leishmaniasis. Traditional testing methods require a small tissue sample of the skin ulcer lesion. These samples are examined by microscopy and culture to determine the presence of the intracellular form of the leishmania parasites, called amastigotes. These traditional testing methods can take anywhere from 30 minutes (for staining and microscopy) to four weeks (for cultures) to produce results.
In contrast, the SMART Leish PCR is a qualitative test that uses a real-time polymerase chain reaction to amplify genetic sequences unique to the organism that causes cutaneous leishmaniasis. Samples are acquired from skin lesions in the same way as for traditional methods.
“The Smart Leish Real-Time PCR assay can provide consistent results within hours of sample receipt, even when the numbers of parasites in the skin are so low that microscopy and culture results will be negative at Day 30. This allows for timely treatment of the disease,” said Lisa Hochberg, Department Chief of Molecular Diagnostics, Division of Entomology at WRAIR.
The new assay will be part of the battery of tests run at the Leishmania Diagnostic Laboratory in WRAIR’s Division of Experimental Therapeutics. “In the near future, this assay may be utilized at additional strategically located DOD medical facilities,” said COL Max Grogl, Director of the division.
According to Hochberg, this assay represents the first FDA-cleared, real-time PCR diagnostic device for infectious diseases that was developed and cleared by the Department of the Army. WRAIR developed the intellectual property for this assay and licensed it to Cepheid USA, which manufactures the Smart Cycler, primers, and probes for the SMART Leish test.
USAMMDA played two roles in helping to forward the development of the assay, serving as the sponsor’s representative for the Office of the Surgeon General of the Army and as the advanced development program management office, said Product Manager Louis Jasper. Its Division of Regulated Activities and Compliance provided regulatory oversight and guidance throughout the product’s development.
In coordination with the USAMRMC Integrated Product Team and commercial partner, the Pharmaceutical Systems Project Management Office provided funding and leadership to mature the SMART Leish PCR assay from the technology base through advanced development.
Meanwhile, USAMMDA’s ongoing work with the Tunisian Ministry of Public Health and the Institute Pasteur of Tunis to develop the Paromomycin/Gentamicin Topical Cream for the treatment of cutaneous leishmaniasis has shifted in focus from the need to demonstrate that topical paromomycin is safe and effective, to the manufacturing and commercialization of the product, said COL Russell Coleman, Commander of USAMMDA.
“From the beginning, the Tunisians understood we were fighting a common enemy—cutaneous leishmaniasis,” Grogl said. “Access to endemic areas is fundamental to the conduct of pivotal trials that comply with current Good Clinical Practices.”
The population of Tunisia is significantly affected by cutaneous leishmaniasis, with approximately 2,000 to 3,000 cases per year, straining the resources of the Tunisian health system. The current standard of care for cutaneous leishmaniasis in Tunisia is intralesional injections of the toxic antimonial compound Glucantime. This treatment is especially painful in children, who are predominantly affected by the disease.
The nearly 10-year collaboration among USAMRMC, the Institute Pasteur of Tunis, and the Tunisian Ministry of Health has resulted in the successful conduct of three clinical trials of the Paromomycin/Gentamicin cream in Tunisia: two Phase 2 trials and an ongoing Phase 3 pivotal efficacy trial. The Phase 3 trial will provide a critical part of the clinical data package that will be submitted to the FDA for approval of this product.
The Phase 3 trial has taken on particular significance amid the political unrest in Tunisia. The Tunisian revolution began in the town of Sidi Bouzid, which is also the location of the central clinic for the Phase 3 trial. The Tunisian study team has gone to great lengths to ensure that the study continued uninterrupted without jeopardizing the safety and welfare of the study subjects or the quality of the results.
“Total trust and respect are a great gift and a sign of a mature and healthy collaboration. This was a fantastic opportunity to work in probably the most neglected of the neglected diseases,” Grogl said.
Additional information about leishmaniasis is available at the Centers for Disease Control and Prevention website at http://www.cdc.gov/parasites/leishmaniasis.
- CAREY PHILLIPS is the USAMMDA Public Affairs Officer at Fort Detrick, MD. She holds a B.A. in communication arts from Framingham State College and is pursuing an M.S. in management/marketing from the University of Maryland University College.