West Coast Editor

To investigate a Chinese herbal drug that might hold the key to malaria, computer magnate Bill Gates and his wife Melinda are granting $42.6 million to a nonprofit group and fledgling Amyris Biotechnologies Inc., which will work with the University of California at Berkeley to develop artemisinin.

"We anticipate we'll have material for the clinic in two to three years, and we could have roll-out [of an approved product] in five years," said Jack Newman, one of three founding scientists of Albany, Calif.-based Amyris, which gets $12 million in non-dilutive cash in the deal. "Not a bad seed round for a start-up," he noted.

"We need to get this project well under way before we go out and seek additional financing," Newman added.

Between $8 million and $10 million of the grant goes to UC Berkeley and the rest to the San Francisco-based Institute for OneWorld Health, the first nonprofit pharmaceutical firm in the U.S.

Amyris is focused on synthetic biology to make chemicals for drugs and other uses, although the targeted form of artemisinin is "not really a synthetic; it's a natural product," Newman said. "What we've done is taken the natural process out of the plant and reconstituted it in a biological system."

Some have tried synthetic chemistry with artemisinin, which is derived from the wormwood plant, "but it's way too complex, a 30- or 40-step process," he said.

Under the terms of the grant, UC Berkeley will conduct research toward a microbial factory for artemisinin, currently the best treatment for malaria, and Amyris - which started in 2003 as a result of work at the university - will develop the process for industrial fermentation.

OneWorld takes the ball from there, doing drug development and regulatory work to prove bioequivalence of the developed drug to the existing form.

"One of the reasons we, as a business, chose this project is that we're making a pharmaceutical that's been used for quite a while and there's a lot of data in terms of its efficacy, as well as anecdotal toxicity evidence," Newman said, adding that OneWorld will do "all the rigorous work" of proving artemisinin's safety and efficacy for regulators.

The mosquito-borne malaria germ easily swats away front-line medication, but combination therapies using artemisinin beat the bug almost every time after a three-day regimen. However, millions of poor people can't afford the $2.40 price tag on the adult course of artemisinin combo treatment provided through the World Health Organization.

"We're trying to get it down to under a buck, or at least cut the price in half," Newman said. To keep expenses low, UC Berkeley issued a royalty-free license to OneWorld and Amyris, which has agreed to produce the drug at cost.

Between 300 million and 500 million people become infected every year, and at least 1.5 million die, most of them children in Africa and Asia, though artemisinin "basically starts to cure you within 24 hours," Newman said. Some early experiments suggest the drug also might work in cancer.

Amyris' methodology, which also can be used to make isoprenoids that form the basis for perfumes and flavorings, could help with artemisinin. Not only is the naturally occurring form of the malaria drug laborious to extract, but also in some developing countries involves diesel fuel purification, risking impurities that could contaminate the final drug product.

"You have crop failure and variations in a crop, and all of that is compounded with extraction anomalies and land usage," Newman said. The fermentation process, on the other hand, "is very consistent, the product is always the same, and you don't have to purify the plant matter," he said. "The main upside is a consistent and reliable supply."

For Amyris, the upside is considerable, too.

"Another part of the win-win situation is that the money we use to develop this process develops a platform technology, so it's applicable to other pharmaceuticals we'll be working on in parallel," Newman told BioWorld Today, pointing to cancer drugs, antivirals and nutraceuticals, including antioxidants such as the carotenoids and lycopene.

"The time to revenue is much shorter for the nutraceuticals but it's a smaller revenue stream," he noted, so they might be used as a bootstrap to making drugs. "We're already forging the corporate partnerships" for drug development while recruiting management, Newman added.

Meanwhile, the malaria effort is center stage. Amyris' fix to the supply problem finds "a perfect analogy" in Taxol (paclitaxel), he said, the chemotherapeutic agent introduced in 1993 by Bristol-Myers Squibb Co., of New York, development of which was "delayed 20 years because extraction from trees was prohibitive." Taxol is derived from the Pacific yew tree, but might be made in genetically engineered bacteria.

UC Berkeley researchers published their work in Nature Biotechnology "a couple of years ago and it attracted quite a bit of attention," Newman said. "People have done similar things, but they only get a trickle of the product coming out of the cells. We got a firehose of small molecule being made in the microbes. It created quite a splash in the industrial realm."

Alerted by UC Berkeley, Gates took notice, inspecting the university's 120-page proposal before deciding to commit the money. "The foundation loves this project," Newman said.

Amyris' name comes from a plant, Amyris balsamifera, which grows in Haiti and also is known as West Indian sandalwood, though it's not botanically related.

"We used it as a replacement for sandalwood," Newman said, citing the plant's similarly pleasant aroma, ideal for scents and in stabilizing oils but much lower in cost.

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