BIO 2008: Waking up to sleeping sickness

Experts in the fields of organic, synthetic and medicinal chemistry, Australian company Epichem is best known for exporting its products and services to international clients, ranging from small drug discovery companies to multinational pharmaceutical corporations.

But the four-year-old company, which was founded by synthetic chemist Dr Wayne Best and a handful of colleagues after leaving the government-run WA Chemistry Centre in 2004, has another, more charitable side that often goes unnoticed.

For more than 10 years, the staff at Epichem and their collaborators in the Parasitology Group at nearby Murdoch University have persisted in their work to develop new drugs to treat African trypanosomiasis - also known as "sleeping sickness" - as well as other, similarly dangerous parasitic diseases that affect both people and animals.

According to Best and his chief collaborator Andrew Thompson, professor of parasitology at Murdoch University and president of the Australian Society for Parasitology, their pioneering research into combating parasites known as Trypanosomes struggled for years to find adequate funding.

"As you can imagine, when you're talking about making drugs for neglected diseases, it's difficult to get large amounts of money from pharmaceutical companies to fund that sort of work, and getting research grants is not always as easy as you'd like," Best says.

Indeed, over the years Best and Thompson applied for ARC grants, obtained funding from multinational pharmaceutical corporation GlaxoSmithKline (GSK) and even approached the World Health Organisation for assistance, to varying degrees of success.

In 2005, however, the project's fortunes changed when it caught the attention of the Drugs for Neglected Diseases Initiative (DNDi ), a non-profit drug development organisation dedicated to improving the health of people who suffer from diseases that are often overlooked by the major drug companies.

Based in Geneva, Switzerland, DNDi was founded in 2003 by Medecins Sans Frontieres and five public-sector research organisations - the Kenya Medical Research Institute, the Indian Council of Medical Research, the Malaysian Ministry of Health, the Oswaldo Cruz Foundation in Brazil, and France's Institut Pasteur.

The organisation targets diseases that afflict poor people in developing nations and other regions where the size of the market - and the profit margins - are not big enough to encourage big pharma to undertake research and development. Most of DNDi 's current projects focus on parasitic diseases, such as human African trypanosomiasis, leishmaniasis, Chagas disease and malaria.

In December of last year, DNDi received a $US25.7 million injection of funds from the Bill & Melinda Gates Foundation, in the form of a grant to research and develop new medicines to treat human African trypanosomiasis and visceral leishmaniasis.

"Someone like Bill Gates is much happier to give his money to an organisation like DNDi because he knows that they're going to be able to use it more quickly and more effectively than is the case with bureaucracies," Best says.

"We've been on and off with this project over the last 10 years, but we've been a lot more successful since DNDi became involved in late 2005 because it is an organisation that's specifically designed to fund these sort of projects," says Thompson.

One of the advantages of DNDi coming onboard was that the organisation provided Epichem with enough funding to enable a pharmacokinetics group to join the project. Since 2006, Epichem and the Parasite Group at Murdoch have been collaborating closely with Melbourne's Centre for Drug Candidate Optimisation (CDCO), which operates out of the Victorian College of Pharmacy.

"Since CDCO came onboard a couple years ago, they've been providing a lot of very useful feedback in terms of the 'drugability' of our compounds," Best says. "So at the moment it's really a three-way collaboration between Epichem, Murdoch University and the CDCO."

---PB--- Asleep all day, awake all night

Trypanosomiasis is a particularly cruel disease. Fever, headaches, and joint pains are the initial symptoms, but they gradually get more severe as the parasites move into the blood and lymphatic systems. First the lymph nodes swell to a large size. Then, if left untreated, the disease gradually overcomes the sufferer's defences and the symptoms get more severe, often leading to anaemia as well a range of endocrine, cardiac and kidney disorders.

The parasites eventually pass through the blood-brain barrier and the disease enters the second "neurological" phase, which gives African sleeping sickness its name. Beset by confusion and loss of coordination, the patient's sleep cycle gradually becomes unbalanced.

Fatigue alternates with manic episodes until the sleep pattern is practically reversed; the patient sleeps during the day and suffers from insomnia at night. Without treatment, the disease is fatal.

"There are very few drugs that are currently available to treat these diseases," says Best, who also points out that nearly all of drugs that are available were developed decades ago. These drugs have side-effects, many of them quite severe, and several are highly toxic in their own right.

One example is the organo-arsenical melarsoprol (or Arsobal), which is the current treatment for African sleeping disease. Melarsoprol kills about 10-20 per cent of the people who take it, so it's almost as bad as the disease itself.

Such treatments are also elaborate in nature, which severely hampers the ability of health organisations to go out into the field and treat the disease effectively, especially in impoverished regions. Melarsoprol, for instance must be given intravenously over several days.

"Trying to give such a treatment intravenously to people who are hospitalised in a developing country is really not cost effective, and it's very difficult to do," Best says.

"What we're trying to develop is a simple pill that a patient can take maybe once or twice that completely eradicates the disease. That will allow aid agencies to go out there and treat large numbers of people cost-effectively, which at the moment they can't do."

---PB--- Targeting tubulins

The initial spark for the project to develop drugs for use against parasites goes back 18 years, when Murdoch University's Thompson's first discovered that a particular drug used against intestinal worms was also very effective against Giardia intestinalis, the single cell parasite that causes Giardiasis, a common diarrheal illness prevalent throughout the world.

What Thompson found was, in fact, a new indication for the drug, albendazole, currently marketed around the world as Zentel.

"From a research point of view that got us thinking: why is albendazole so good against Giardia? What is it targeting in the parasite? Is it the same target as in the worms?" Thompson says.

Thompson soon discovered that the target was indeed the same. The solution lies in microtubules, one of the components of the cytoskeleton of these kinds of parasitic organisms. According to Thompson, Epichem's compounds target tubulins, the globular proteins that help to make up microtubules.

The next step was to find out whether albendazole and similar drugs were as effective against other protozoa as they were against Giardia. "That was when we formed the relationship with Wayne and we started to make drugs that were focused on this target that albendazole focused on," Thompson says. "Today, we're looking at a whole stable of compounds that affect these different parasites."

Currently, Epichem's synthetic compounds are still in the preclinical phase and have yet to be tested on humans. The lead compound has shown itself to work in a validated mouse model, which Best and Thompson claim is a reliable indicator of treating the disease in humans.

The compounds have also undergone a number of sophisticated toxin studies - in vivo, oral toxicity, Ames test - and they appear unlikely to be carcinogenic or mutagenic. Best also claims that compound is very cheap to make, which is rather important with this type of disease.

"If we had to start this work as part of Epichem, we'd be hard pressed to justify why Epichem is doing it," Best says. "But we've managed to keep this project alive and finally after all these years it is getting properly funded and is going somewhere.

"The fact that it could potentially cure a really horrible disease, that's a great buzz," he says. "Being able to say we've been involved in getting a drug to marketplace that can save millions of lives would be a great feeling for a small company like us."

---PB--- Act locally, compete globally

Epichem, which will be exhibiting as part of the Australian Pavilion at BIO 2008, exports its products and services to drug discovery and pharmaceutical companies around the world. With clients scattered everywhere from North America to South Africa, India, France and beyond, Epichem has had to adapt quickly to learn how to service its far-flung customer base from the company's head office in Perth.

"Being so far away from your market can be a negative," Wayne Best says. And apart from the usual difficulties of having to communicate with clients in a variety of time zones, Best and the team at Epichem also deal with more sensitive issues, like the hassles that attend shipping chemicals to and from Australia.

"Shipping chemicals across the globe is problematic at times," Best says. "It's very much a chemophobic world that we live in, so shipping these things can sometimes be frustrating, but generally speaking the stuff that we send to our clients gets cleared within five days, so turnaround time isn't too bad."

Epichem has a laboratory in Melbourne, adjacent to Monash University, but the company's main lab and head office are both located in Perth. This facility is on the campus of Murdoch University, in close proximity to Andrew Thompson and university's renowned Parasite Group.

Best says that it is precisely this close working relationship between the biologists, parasitologists and the chemists that gives Epichem an edge over its competitors.