Antifungal fight

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By Elie Dolgin

Scientist - UK

http://www.the-scientist.com/article/display/55359/

Antifungal fight

Kishor Wasan, a pharmacologist at the University of British

Columbia, needed a negative control. It was 2000, and he was

investigating a new way to deliver anti-fungal drugs in pill form,

generally cheaper and easier to administer than intravenous

injections. " I said, 'Let's take a drug I know doesn't work', " Wasan

recalls. He turned to amphotericin B, an antifungal membrane

disruptor that Wasan had studied a decade earlier for his PhD, and

is not normally absorbed by the body when administered orally. He

embedded amphotericin B and a batch of other drugs into his newly

devised lipid-based delivery vehicle, and fed them to rats. This

turned out to be perhaps one of the worst negative control

experiments ever - but a lucky break for Wasan.

Compared to the other drug treatments, the rats on amphotericin B

had the highest blood levels and lowest kidney levels of the drug,

indicating that the body more readily absorbed amphotericin B than

any other drug. What's more, oral amphotericin B seemed to bypass

the renal toxicity normally associated with intravenous forms of the

drug (Antimicrob Agents Chemother, 47:3339-42, 2003).

Burke: The smart synthesizer

Wasan was bewildered: " I thought, what the heck is going on? "

Further experiments showed the drug was actually working:

Amphotericin B fed to rats wiped out Aspergillus fumigatus

infections (Drug Dev Ind Pharm, 33:703-7, 2007), and 90% of Candida

albicans kidney infections, which is similar to the 95% success rate

seen with intravenous delivery. All with no renal toxicity. " The

fact that we've got an oral formulation that's mimicking IV - that's

a major finding, " Wasan says.

" Amp-B is basically the best antifungal agent we have; the problem

with it is that it has to be given IV and it's toxic, " says

s, a clinical mycologist at the Santa Clara Valley Medical

Center in San , Calif. Eliminate the need for IV and " they've

got half the battle solved, " he adds. " And if it's less toxic, it's

a home run. "

Who will release the first oral fungicide?Amphotericin B in poppable

pill form could treat systemic fungal infections, particularly in

patients with cancer or HIV/AIDS. This may make it highly profitable

in the developed world, but it can also combat parasitic infections,

such as trypanosomiasis and visceral leishmaniasis, that are more

prevalent in developing nations. " We've got a first-world need where

we can make money, " says Wasan, " and a third-world need where you

can sell the drug at a subsidized cost. "

To commercialize his formulation, in 2007 Wasan teamed up with the

UBC chapter of Universities Allied for Essential Medicines, an

international organization that aims to improve access to medicines

and research on neglected diseases at academic research

institutions. In May 2008, Wasan licensed his oral amphotericin B

formulation to iCo Therapeutics, a Vancouver-based biotech company,

which agreed to make the drug available at a subsidized cost to

combat leishmaniasis in developing nations. It's a " win-win "

situation, says Clement, iCo's chief business officer.

Wasan's amphotericin B formulation could prove to be the world's

first available oral fungicidal agent. (Pfizer's oral antifungal

Diflucan (fluconazole) stops fungal growth but does not kill the

infectious agent.) But Raleigh, NC-based BioDelivery Sciences

International (BDSI) has its own oral formulation of amphotericin B

based on its patented Bioral delivery technology, which wraps the

drug in a coiling structure of alternating lipid layers, currently

in phase I trials. (Clearly, amphotericin B is more 'oral-izable'

than originally believed.) Still, Wasan thinks his drug, in

preclinical trials, should have an advantage. His formulation

solubilizes the drug in a glyceride-based liquid, whereas Bioral

relies on a liposomal suspension, which can be difficult to bring up

to a commercial scale, he notes.

Raphael Mannino, BDSI's chief scientific officer, disagrees. " This

is a very simple manufacturing process, " he says. What's more,

BDSI's formulation is effective, nontoxic, and " even in suspension,

we have very long stability of our product, " he says.

The irony of Wasan's drug discovery, he notes, is that he didn't

even want to study amphotericin B again after finishing his PhD; he

only resorted to the drug because he expected it to fail. " Am I

lucky as hell? Yes. Did I think it was going to work? No. Am I fully

believing it? Well, human studies will be needed to play this out. "