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New therapy for "Black fever" is 95% effective

India licenses the first oral drug for visceral leishmaniasis, a lethal disease of poverty

Scientists have developed a new treatment for the 500,000 people who develop visceral leishmaniasis each year, a disease also known as "black fever" and "kala azar." The new drug, miltefosine (Impavido®), could save most of the 60,000 who die from the disease every year. Miltefosine is likely to cost less and is much easier to deliver than all current therapies. In clinical trials, it cured 95% of treated patients.

Miltefosine is the first oral drug against leishmaniasis. It moved from the laboratory bench through to registration in six years (most medicines can take as long as twice that time) thanks to a collaboration between the Government of India, the drug’s manufacturer, German biopharmaceutical company Zentaris, and TDR (Tropical Diseases Research), a program cosponsored by the World Bank, the U.N. Development Programme and the World Health Organization. Miltefosine has now been approved for use in India, which has 50% of the global burden of visceral leishmaniasis. With this drug, the Government of India hopes to reach its goal of eliminating visceral leishmaniasis by 2010.

Leishmaniasis is one of the Neglected Diseases that have become a special focus at WHO. These are diseases which afflict the world’s poorest people. About 80% of the victims of leishmaniasis, for example, earn less than $2 a day. Yet neglected diseases receive relatively little funding or public attention.

"This is fantastic progress," says WHO Director-General Gro Harlem Brundtland. "We now have a powerful new tool to fight this terrible disease. The combined efforts of these partners have opened a new era in the fight against visceral leishmaniasis. In doing so, we can free the poor from one of their many burdens."

Leishmaniasis is a parasitic disease which is transmitted through the bite of the tiny and silent sandfly. The disease is found in parts of 88 countries. While the 350 million people living in those areas are the most vulnerable, others at risk include people travelling through these areas such as adventure vacationers, missionaries, development workers, and soldiers.

The regions where leishmaniasis is endemic have expanded significantly since 1993. Mass population movements are fuelling the growing epidemic. Major outbreaks in Brazil, for example, were triggered by large migrations of rural families into the suburbs of the country’s largest cities. An outbreak in Sudan killed 100,000 in an area with a population of less than one million. More recently, co-infections of HIV and leishmaniasis are becoming more common. The interaction of the two diseases makes each more destructive -- accelerating the onset of AIDS and shortening the life expectancy of HIV-infected people.

The infection can take one of four major forms but the most deadly is visceral leishmaniasis and that is the type of leishmaniasis the new treatment targets. Visceral leishmaniasis attacks the liver and spleen, causing irregular bouts of fever and substantial weight loss. In developing countries where patients generally have poor nutrition and compromised immune function, it is 100% fatal without treatment. Ninety percent of all cases occur in five countries: India, which has the greatest burden of the disease, Bangladesh, Brazil, Nepal and Sudan.

Until now, all treatments for the disease have had substantial drawbacks. Some are toxic and can cause permanent, irreversible damage such as diabetes. Up to 60% of cases in India are now resistant to the first line drug. Other drugs trigger dangerous reactions that can be lethal in about 9% of treated patients. Some treatments require injections while others need to be provided intravenously over a period of 15 to 30 days in a hospital. And all are so expensive that most of the people infected are unable to afford them.

Now comes miltefosine. The drug is the fruit of a collaboration between the German biopharmaceutical company Zentaris and the Tropical Disease Research programme, a programme co-sponsored by the World Bank, UNDP and WHO. The company, then part of ASTA Medica, originally developed the compound to fight breast cancer, but a TDR-sponsored scientist assigned to screen new compounds discovered that it also had an effect on the leishmania parasite while German scientists demonstrated the oral activity. With financial and administrative support from TDR and official cooperation from the Government of India, clinical trials conforming to international regulatory best practice were launched with Zentaris as a sponsor. The drug proved to be highly effective and safe and was approved by Indian authorities in March this year. A price has not been set, but is likely to be considerably cheaper than current treatments.

No drug is without some side effects and miltefosine also has its own, though they are less severe than current treatments for visceral leishmaniasis. The drug can induce vomiting but this does not occur immediately after taking the drug and the vomiting is not strong and usually limited to a few days. Due to a potential danger to developing foetuses, care must be taken when administering the drug to women of child-bearing age. Data in some laboratory animals also hint that miltefosine may have an impact on the reproductive health of men. So far clinical studies have demonstrated that this is not an issue, but this, along with other properties of the drug, will be further monitored in Phase 4 studies that will get under way in India in July. The phase 4 studies will be designed primarily to assess how well the drug performs in a real life situations and hence its potential long term impact on the control of leishmaniasis. They are also evaluated in parallel to the Phase 4 trail of miltefosine in India.

Researchers hope the future will bring better methods of diagnosing visceral leishmaniasis without expensive lab equipment. In many tropical settings, the high fever brought on by the disease is easily confused with malaria. An easy to use test, which could be applied near the home, would greatly facilitate visceral leishmaniasis control. Trials, supported by TDR, of such diagnostic kits are now under way in Ethiopia, Kenya and Sudan.

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Mr Dick Thompson
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