Compound might defeat African sleeping sickness

One of the most devastating diseases in sub-Saharan Africa almost disappeared in the late 1950s. That disease, African sleeping sickness, or trypanosomiasis, largely succumbed to heroic public health efforts — including relocating entire villages. But in the past several decades, because of post-colonial turmoil, the catastrophic illness has come back to ravage parts of Angola, the Democratic Republic of the Congo, the Sudan and other countries. In some regions, the tsetse fly-borne infection rivals or exceeds the toll AIDS takes.

Trypanosomiasis is passed from human to human by tsetse fly bites. It produces fever, lymph nodes inflammation, eventual impairment of the brain and nervous system in its late stage and, if not treated, death. The World Health Organization has estimated that more then 300,000 people are infected, and more than 60 million living in the region are at risk.

Now, real hope for a better treatment is on the horizon, based on research conducted in part at the University of North Carolina at Chapel Hill. In Phase II clinical trials, a new oral drug, DB289, demonstrated safety and high effectiveness in subjects with the early stage of sleeping sickness. Scientists are launching a Phase III trial this summer involving for the first time hundreds of patients who will be treated with the drug.

The Bill & Melinda Gates Foundation is supporting the work, which is being led by Dr. Richard R. Tidwell, professor of pathology and laboratory medicine at the UNC School of Medicine.

“This is very exciting time for us and the international consortium we pulled together to develop the first drug made to specifically combat this terrible re-emerging disease,” Tidwell said. “The compound DB289 will be the first new drug for early stage (blood stage) African sleeping sickness in 50 years, and the only oral drug that’s ever been specifically developed for it.”

Oral administration is important for treating the disease which occurs in villages where it can devastate afflicted populations, he said. Small villages do not have access to clinics or trained staff that can give injections or administer drugs intravenously.

“Immtech International, Inc. of Vernon Hills, Ill., a pharmaceutical company and a contributor to this drug development effort, has an exclusive, worldwide license to DB289 and related compounds developed by the UNC-based scientific consortium for African sleeping sickness and other devastating diseases such as TB, which together affect millions of people annually,” Tidwell said. “Besides DB289, several potential drug candidates in early development appear to be promising for treating late stage African sleeping sickness, which occurs when the parasite over time enters the brain.”

The new drug candidates are active because they can cross the blood-brain barrier, a biological wall that protects the nervous system naturally but can block beneficial drugs, he said. Work is also progressing rapidly on a new drug for drug-resistant malaria, another major threat in developing countries.

The UNC-led Consortium to Develop New Drugs for Protozoan Diseases established an advisory board chaired by Dr. Frederick Sparling at UNC, with Drs. Terry Shapiro at Johns Hopkins University, Ann Moore at the Centers for Disease Control and Prevention and Thomas Brewer at the Bill & Melinda Gates Foundation as board members. Laboratories involved in the discovery of the new drug candidates are run by internationally known scientists including Drs. David Boykin and David Wilson at Georgia State University, Michael Barrett at the University of Glasgow, Raymond Mdachi at Kenya Trypanosomiasis Research Institute and Steven Meshnick and J. Ed Hall of UNC. Scientists also closely involved are Drs. Simon Croft at the London School of Hygiene and Tropical Medicine and Reto Brun and Christian Burri at the Swiss Tropical Institute.

“New drugs for illnesses in developing countries often fly beneath the profit radar of large pharmaceutical companies,” Tidwell said. “That’s because large companies require a high return on their investments, which means they don’t have sufficient incentives to develop low-cost drugs. Despite being one of Africa’s most prevalent and economically devastating illnesses, sleeping sickness is definitely one of those that has been neglected. For that reason, we decided to put this consortium together, and that’s why the Bill & Melinda Gates Foundation was very interested in supporting our work.”

The group has since become one of the models for public-private partnerships to discover and develop drugs for poorer countries or neglected diseases, Tidwell said.

“We have been able to reduce the cost of drug discovery to a fraction of the cost it would take a large drug company to do it, but we’re not cutting corners, and we’re using some of the best technology and scientists in the world to accomplish these goals,” he said.

Dr. Carol Olson, vice president and chief medical officer of Immtech, said she and colleagues started the Phase III clinical trial this month. The new pivotal trial will involve approximately 250 patients in the Democratic Republic of the Congo and the Sudan. Angola will be included if a recent outbreak there of the Ebola-like Marburg virus remains under control.

“The Swiss Tropical Institute will be responsible for selecting patients and carefully monitoring the trials,” said Olson, who helped design and will oversee the study. She is an infectious disease expert who retired after a long career with Abbott Laboratories.

“We’re trying to improve the lives of these patients by treating the disease early on in the local villages before it progresses to the terminal brain stage,” the physician said. “When a drug works and helps a lot of people, that’s when all our hard work really pays off, and we can be proud of our efforts.”

Three years ago, the National Foundation for Infectious Diseases presented its Jimmy and Roselyn Carter Humanitarian Award to Bill and Melinda Gates. That day, a talk by former President Jimmy Carter about the work Roselyn and he did in Africa inspired Olson to work on deadly but neglected illnesses, she said.

“What goes ’round, comes ’round,” Olson said. “We have a real opportunity with DB289 and other drug candidates in the pipeline to help solve some very difficult health problems affecting millions of people in developing countries.”

From University of North Carolina