Lining up to Make a Cancer Drug

Producing paclitaxel, the naturally derived cancer drug, requires a rare combination of farming and chemistry skills. The drug's raw material, the yew tree, is grown on plantations or gathered in the wild. More than three tons of yew needles must be collected and ground up--and the target compound extracted, separated, sometimes reacted, and purified--just to make a kilogram of finished product.

Nevertheless, the bulk paclitaxel business is a cutthroat one, supplied by numerous companies in the U.S., Europe, and Asia. And within the past month, two new firms--Bioxel Pharma in Canada and Paxis Pharmaceuticals in the U.S.--made their first shipments of bulk product. As Roland R. Franke, co-chief executive officer of Natural Pharmaceuticals Inc. (NPI), puts it, "At the end of the day, this business will be a race for scale and quality at the lowest cost."

To be assessed in such stark economic terms is an ignominious fate for a product with a background as storied as paclitaxel's. The compound was discovered in the 1960s by researchers at the National Cancer Institute in an extract from the bark of the rare Pacific yew tree. By 1983, the first human trials of the drug's antitumor activity had begun.

In 1991, NCI awarded drugmaker Bristol-Myers Squibb (BMS) the rights to develop and produce paclitaxel. Shepherded by the big company under an agreement that has since become controversial (C&EN, Sept. 15, 2003, page 17), the drug was quickly approved as Taxol, a second-line therapy for ovarian and, later, breast cancer.

Obtaining bulk paclitaxel was a problem from the start. BMS contracted with Hauser Inc. to extract the drug from the bark of the Pacific yew. However, in addition to drawing fire from environmental activists, the process wasn't likely to meet projected demand for the drug.

BMS soon ended its agreement with Hauser and switched to a pact with Indena, the Italian natural products firm. Under the deal, Indena extracted the taxane 10-deacetylbaccatin III (10-DAB) from the needles of the English yew, a common ornamental plant known botanically as Taxus baccata. BMS then converted the compound to paclitaxel using a process licensed from Florida State University.

ALTHOUGH INDENA is still a major paclitaxel producer, the initial push to find new sources spawned an industry of companies using extractive and semisynthetic approaches to making the drug, which was protected by use patents until 2000. Several new firms started up in the 1990s, while others are just now hitting the market, making for a potential glut of a product that once sold for more than $600,000 per kg and is now less than $400,000 per kg. The English yew's main taxane component is 10-DAB, but researchers soon determined that North America's ground hemlock, T. canadensis, contains 10-DAB and paclitaxel in equal amounts. It also contains large amounts of 13-acetyl-9-dihydrobaccatin III, known as DHB, as well as numerous other analogs and related taxane compounds.

One of the first North American companies to follow Hauser into the business was British Columbia's Phytogen, which was started in 1990 to crack the paclitaxel market. According to Diane Wierzbicki, vice president of regulatory affairs and business development, the firm was making paclitaxel commercially by 1996. Today, it supplies Mylan Laboratories, which entered the generic paclitaxel market in 2001, as well as the Taiwanese firm Sinphar and other companies.

NaPro Biotherapeutics of Boulder, Colo., had similar roots. The company was formed in 1991 and by 1995 had shipped paclitaxel to its first customer. In 2003, NaPro was acquired by Mayne, an Australian drug company active in the generic paclitaxel business. Mayne now calls itself the world's largest marketer of finished paclitaxel after BMS, thanks to the purchase of Abbott Laboratories' generic paclitaxel business, also in 2003, and a recent agreement to market for Ivax Corp. in Europe.

According to Brian McCudden, vice president of Mayne's Boulder operations, Mayne is also the only vertically integrated paclitaxel supplier. The company, he says, starts with several plantations spread across North America that grow a cultivated form of yew called T. x media 'Hicksii.' It maintains contracts with yew drying and grinding companies and operates one of the world's longest running paclitaxel plants in Boulder.

Although NPI, Franke's six-year-old company, is by comparison a newcomer to the paclitaxel trade, one of its first moves after being formed was to acquire an old-timer--the former Hauser oncology division. The 1999 deal included contracts for millions of plantation-grown yew trees, most of Hauser's related intellectual property, and an inventory of semifinished paclitaxel.

NPI obtains its paclitaxel via a geographically diverse process. Yew trees are grown, harvested, and dried in Michigan. The resulting biomass is shipped to a retrofitted marigold extract plant in Mexico for extraction of crude taxanes, which are then transferred to a leased facility in Fall River, Mass., near NPI's headquarters, for what Franke calls "primary taxane refinement and release."

The special step that NPI is banking on comes next: A mixture that can contain up to 10 different primary taxanes is shipped from Fall River to the Food & Drug Administration-inspected contract manufacturer Cedarburg Pharmaceuticals in Grafton, Wis., where it undergoes a proprietary chemical conversion.

As Franke explains, most firms working with T. canadensis obtain paclitaxel via a tricky chromatographic separation from a family of closely related taxanes. NPI's chemistry-based technology, in contrast, clips the end of the side chain off all the analogs in the mix, leaving a single primary amine compound. In the final step, NPI adds a benzoyl group back to the amine to obtain the desired analog, paclitaxel, in high yield. Depending on the type of yew tree used, Franke claims that this process gives NPI up to twice the yield of paclitaxel per unit of biomass than other firms get.

Other companies claim their own competitive advantages. Sainte-Foy, Quebec-based Bioxel, which announced its first kilogram-lot sales of paclitaxel last month, has sewed together what it considers an unbeatable supply chain. According to Gaetan Caron, vice president of R&D and regulatory affairs, the firm has rights to harvest T. canadensis from 250,000 sq km of public and private land in Quebec.

INITIAL BIOMASS extraction is carried out by Atlantis BioActives, a firm on Canada's Prince Edward Island that supplies Bioxel with a 70% pure paclitaxel. Purification to current Good Manufacturing Practices (cGMP) standards occurs at a high-tech simulated moving bed chromatography facility operated in Sacramento, Calif., by Aerojet Fine Chemicals. Paxis, a subsidiary of Integrated BioPharma, brings a Hauser pedigree to its bid for the paclitaxel market. The company, which announced its initial shipment of cGMP paclitaxel earlier this month, is headed by Dean Stull, a founder of Hauser and the firm's CEO back when it was BMS's supplier.

Paxis acquired Hauser's paclitaxel plant in Boulder in 2002 and says it has since upgraded the site to the latest cGMP standards. Last year, the firm signed a raw material agreement with Chatham Biotec, a Riverview, New Brunswick, T. canadensis harvesting firm.

If all this competition weren't enough, BMS has stayed aggressive in bulk paclitaxel manufacturing. After signing its agreement with Indena, BMS began to explore other sources of the important active ingredient. In 2002, it agreed to bankroll Phyton, an Ithaca, N.Y., biotechnology firm that was developing a plant cell process for producing paclitaxel in large fermentation tanks.

BMS is still marketing stockpiled 10-DAB-based paclitaxel while it obtains regulatory approvals for the new product. However, its production has shifted entirely to the cell culture process. Indena's relationship with BMS is now primarily that of a purifier of the cell culture product. BMS manufactures mainly for its own use, although Clifford C. Young, director of third-party sales, notes that the company does supply some firms for business development purposes.

Mayne Pharma is pursuing its own new technology. According to McCudden, the firm licensed a method of making paclitaxel semisynthetically from 10-DAB that is distinct from the patented Florida State approach. Mayne expects to start marketing the product next year, he says, after gaining regulatory approval for the new method.

And NPI is planning a second paclitaxel facility, this one in an industrial park in Shanghai, China. Franke says the company will begin construction in the next few weeks there on a plant producing primary taxanes and natural paclitaxel. He expects it to open in January, serving both local and international markets.

THIS BURGEONING supply picture is emerging at the same time as the U.S. market for paclitaxel is, at least for now, stagnating. Worldwide sales of finished-dosage taxane drugs were more than $4 billion last year. But in the U.S., Aventis' Taxotere is the faster growing taxane-based cancer treatment. It is a still-patented drug that is based on the active ingredient docetaxel, a 10-DAB derivative that Aventis manufactures in-house. Prospects for bulk paclitaxel makers are brighter in Europe, where the BMS drug is just now going generic after the expiration of a 10-year protection period. The Ivax/Mayne partnership launched its generic paclitaxel in May, becoming the first pan-European marketer of an alternative to Taxol. Mayne anticipates a six- to nine-month head start over its generic competitors.

NPI's Franke acknowledges that his firm may have entered the business too late to capitalize on the U.S. generic market, but he sees an opportunity to supply the generic firms that enter Europe after Mayne and Ivax. He and other bulk paclitaxel makers are also bullish on drug companies that are developing new ways of delivering the potent compound to chemotherapy patients.

An insoluble compound, paclitaxel is now delivered with the help of Cremophor, a solubilizer made by BASF via reaction of castor oil with ethylene oxide. However, Cremophor's toxicity limits the size of the paclitaxel dose that can be administered; as it is, patients receiving the drug require premedication with steroids to limit the side effects associated with the solubilizing agent.

In May, FDA accepted American Pharmaceutical Partners' New Drug Application for Abraxane, a drug in which paclitaxel is encapsulated in the human protein albumin for better penetration of cancerous tissue. The filing follows APP's December report of a Phase III clinical trial showing that a dose of Abraxane achieved almost double the tumor response rate of Taxol at its maximum dose.

Not far behind APP is Cell Therapeutics, which is conducting Phase III trials on Xyotax, a drug that links paclitaxel to a biodegradable polyglutamate polymer. The firm claims that blood vessels in tumor tissue, unlike those in normal tissue, are porous to the paclitaxel-polymer combination and preferentially trap it. Cell Therapeutics has agreements to obtain paclitaxel from both NPI and Bioxel.

Sonus Pharmaceuticals is also on the novel delivery trail with its Tocosol, which uses vitamin E and surfactants to deliver paclitaxel. Sonus, now conducting Phase II trials of Tocosol, is supplied by Indena.

FRANKE IS confident that the new, better-tolerated delivery forms will create additional cancer-fighting applications for paclitaxel. Even without such indications, the new forms may allow current chemotherapy patients to tolerate higher doses. "I believe that reducing side effects and targeting the drug will allow higher doses, longer treatment cycles, and better overall results," he says. Executives with the more established paclitaxel companies aren't so optimistic. Wierzbicki from Phytogen points out that oncology is a conservative field that does not readily adopt new therapies. If a patient is responding to an established drug like paclitaxel, she says, an oncologist is unlikely to experiment with something new. "It goes back to 'do no harm.' Oncology drugs have long life spans for this reason."

Meanwhile, on paper at least, overcapacity is rampant. It's estimated that the worldwide market for bulk paclitaxel is 400 kg per year. Bioxel alone is claiming annual paclitaxel capacity of 120 kg, and Paxis says it will be able to make 200 kg annually by the beginning of next year. The more established players don't disclose their capacity figures, although they profess to be skeptical of the newcomers' claims.

McCudden predicts that the bulk paclitaxel survivors will be those firms, like Mayne, with ties to the handful of firms worldwide that are significant marketers of the finished-dosage forms of the drug. "There may be a shakeout of the rest of the suppliers," he says.

For her part, Wierzbicki wants the new delivery techniques to succeed--after all, they could help cancer victims while spurring demand for Phytogen's main product. But she has the slightly jaded attitude of an executive who has lived through the excitement of creation and has seen her company's big idea mature into a mere product. "We don't have a hope and a prayer to sell," she says. "All we have is some white powder."