Issue Date: August 15, 2011
In a rural Bolivian village, a kissing bug alights on a young girl’s cheek. But instead of stealing a kiss, the blood-sucking bug takes a bite. As the girl scratches the sore spot, parasites enter her bloodstream from a dollop of feces the insect left behind. Thirty years later, she develops a dangerous heart rhythm and eventually needs a pacemaker. Her condition was caused by a class of protozoans called trypanosomes, which wormed their way into her heart muscle and slowly destroyed the nerves there. If she’s lucky, they will stay away from her colon. The same parasites have been known to attack the nerves there as well, causing life-threatening digestive problems.
She is one of more than 10 million people worldwide with Chagas disease, which is caused by the parasite Trypanosoma cruzi. A smaller group of people, perhaps 30,000 in Africa, suffer from a deadly illness called sleeping sickness or human African trypanosomiasis. It is caused by similar trypanosomes—including several subspecies of T. brucei—all of which are transmitted by bites from tsetse flies. If left untreated, those parasites eventually cross the blood-brain barrier where they cause brain swelling and death.
“Treatment options for both sleeping sickness and Chagas disease are old, relatively toxic drugs with limited efficacy,” says Robert Jacobs, director of chemistry at the Durham, N.C.-based drug discovery and contract research firm Scynexis. Treatment regimens are also arduous, he notes. And it remains difficult to diagnose these diseases in the poor, rural areas where they hit hardest. Big drug companies have left research on these diseases largely behind. But a handful of scientists continue to push ahead, looking for better drugs and more effective, easier-to-use diagnostics to aid in the fight against these devastating parasites.
For decades, the prevailing treatment for late-stage sleeping sickness was melarsoprol, an arsenic-containing compound that kills nearly 5% of the people who take it. Some countries have replaced it with eflornithine, a drug that was originally intended to treat cancer and excessive hair growth. That regimen requires two weeks of hospitalization with dozens of intravenous infusions. Most recently, clinical trials have shown that a combination of eflornithine with another drug, nifurtimox, can cut down treatment time, but it still requires a 10-day hospital stay and a series of lengthy injections.
Current treatments for Chagas are no cup of tea either. They can take more than a month and have numerous side effects. Benznidazole often causes stomach pain and a rash, whereas nifurtimox can cause intense gastric pain, nausea, and loss of appetite. Those adverse reactions can be so intense that many patients don’t take their benznidazole pills consistently, and some will outright quit their treatment. Chagas tends to strike the poorest of the poor, and some of those people don’t have access to hospitals and elect not to receive treatment at all, explains Patricia Doyle-Engel, a researcher at the University of California, San Francisco, who is developing new drugs for the disease.
Because the treatment options for sleeping sickness and Chagas disease are so poor, and the drug industry has little incentive to discover new treatments, organizations such as the Geneva-based nonprofit Drugs for Neglected Diseases initiative (DNDi) are collaborating with drugs firms in repurposing old medications, salvaging old clinical candidates, and testing new drug combinations.
A golden example of this drug rediscovery strategy is the resurrection of a decades-old agent called fexinidazole. Hoechst (now part of Sanofi) developed the broad-spectrum antiparasitic compound in the early 1980s but later abandoned it. In the 1990s, researchers reported that the compound can kill trypanosomes, but nobody pursued it at that time, explains Els Torreele, a researcher who ran a sleeping-sickness drug combination trial for DNDi before moving to the Open Society Foundations’ Access to Essential Medicines Initiative. Nearly a decade later, a team at DNDi rediscovered the drug during a systematic search for sleeping-sickness treatments and shepherded it into the clinic. So far, the organization has completed several Phase I trials in which fexinidazole was given orally to healthy male volunteers.
There’s also a push under way to repurpose two antifungal medications to fight Chagas disease. One of them, posaconazole, is already on the market for fungal infections, but at a cost of about $84 per day, it’s unaffordable for most Chagas patients. The other one, an azole called E-1224, is an experimental substance that Eisai Pharmaceuticals originally developed as an antifungal. In preclinical tests, E-1224 proved highly active against T. cruzi, and it recently entered the clinic for that indication. Scientists have known for quite some time that azoles and triazoles can inhibit ergosterol biosynthesis in trypanosomes in vitro, explains Isabela Ribeiro, who heads up Chagas disease research at DNDi. But it wasn’t until recently that such compounds have entered clinical trials for trypanosome infections, she says.
Much of the work to discover truly new drugs for sleeping sickness has taken place at Scynexis. The company’s screening efforts have turned up several promising compounds, Jacobs says. Earlier this year, Scynexis scientists showed that several 2,4-diaminopyrimidines are active against the sleeping-sickness parasite T. brucei (Bioorg. Med. Chem. Lett., DOI: 10.1016/j.bmcl.2011.03.097). The firm has also been working with Anacor Pharmaceuticals, a Palo Alto, Calif.-based company that builds antimicrobial drugs with boron-studded pharmacophores, to create new sleeping-sickness leads. One of the compounds from that partnership, the oxaborole SCYX-7158, can be taken orally and will likely enter clinical trials within a year, Jacobs says.
Not long after oxaboroles showed promise as a treatment for sleeping sickness, researchers in Australia began testing them as treatments for Chagas disease. Those studies remain in the lead optimization stage. In the meantime, Manuel Sánchez-Moreno at the University of Granada, in Spain, has developed several benzo[g]phthalazine derivatives that show impressive in vitro activity against the parasites that cause Chagas disease (J. Med. Chem., DOI: 10.1021/jm101198k). His lab has also shown that flavonoid extracts from a flower, Delphinium staphisagria, have potent anti-Chagas activity in mice (J. Nat. Prod., DOI: 10.1021/np1008043).
Unfortunately, none of these medications can be properly evaluated in the clinic until someone develops a definitive test that can determine whether a patient with Chagas disease has been cured.
Most tests for Chagas disease function by probing for antiparasite antibodies in patients’ blood samples. But because antibodies don’t go away until decades after a patient has been treated, such tests can’t be used to figure out whether patients have been successfully treated. A handful of groups have developed polymerase chain reaction tests that can monitor the parasites’ disappearance by amplifying a telltale trypanosome DNA sequence, but they have not yet been widely adopted nor thoroughly validated.
But rapid field tests emerging from medical diagnostic organizations may offer some hope. The Seattle-based nonprofit organization PATH developed a quick test for Chagas disease. It functions a lot like a home pregnancy test, but it screens patients’ blood for antitrypanosome antibodies. Its main recognition element is a recombinant protein that contains five different trypanosome antigens. The test is intended for rapid screening of finger-prick blood samples in the field, says Cori Barfield, a senior researcher at PATH.
Meanwhile, another nonprofit organization, the Geneva-based Foundation for Innovative New Diagnostics, recently developed a rapid field test for sleeping sickness that functions much like PATH’s Chagas assay. Mix a drop of blood with dilution solution, put it onto a lateral-flow assay, and wait for colored lines to appear. What that test can’t do, however, is determine the stage of a sleeping-sickness infection.
If someone tests positive with the new sleeping-sickness assay, it’s time to give them a spinal tap. At that point, workers will manually comb through the patient’s cerebrospinal fluid with a microscope, a technique that is dangerous, time-consuming, and not terribly sensitive.
“The main challenge here is that we need to get rid of the lumbar puncture,” which often has to be conducted in rural villages, Torreele says. She hopes that a day will come when there is a sleeping-sickness drug so safe and effective that anyone can take it, without getting a spinal tap. But for now, checking the spinal fluid for parasites remains essential because doctors don’t want to give a potentially deadly course of sleeping-sickness treatments to someone who hasn’t reached the most serious stage of the disease.
It’s too soon to tell whether the experimental sleeping-sickness drugs currently under investigation will solve the spinal-tap problem. Likewise, it remains unclear whether any of the molecules now in the pipeline for Chagas will allow patients to recover from the disease without immense discomfort.
In fact, in the past three years, a pair of antitrypanosome compounds that seemed promising at first both washed out. One of them, DB289, was starting Phase III trials in Africa when it became clear that some of the study subjects were experiencing liver failure and kidney problems. Another compound, DDD85646, proved effective in animal tests. But scientists later concluded that it can’t adequately cross the blood-brain barrier, making it useless as a treatment for late-stage sleeping sickness.
These failures have made one thing clear: To make sure that these diseases go away, the world needs to have a lot more in its antitrypanosome pipeline.
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