Triangle proceeded in partnership with the custom manufacturing arm of the drug firm Abbott Laboratories, forming an alliance in 1999 that encompassed emtricitabine and three other compounds in its pipeline. Abbott applied its expertise in enzymatic chiral chemistry to develop an immobilized version of PLE that is easy to transport and recycle in a large-scale manufacturing process.

Under the alliance, Abbott was to manufacture emtricitabine and comarket the drug, which Triangle branded Coviracil. That changed, however, when the alliance was terminated just before Triangle was acquired by Gilead Sciences, a deal announced in late 2002 and finalized in January 2003.

Gilead, which competes with Abbott in HIV therapy, transferred all bulk emtricitabine manufacturing to Yuhan Chemical, an arm of South Korean Yuhan Corp. Abbott and Triangle had previously agreed that Yuhan would also manufacture emtricitabine on the basis of its production of oxalacetate, a starting material. Abbott's role ended up being technology transfer to Yuhan and a contract to manufacture the encapsulated formulation of emtricitabine for Gilead.

The changes started when the Triangle-Abbott alliance was terminated in July 2002, with Triangle acquiring full product rights to the four drug candidates it was developing with Abbott. Both firms cited an interest in focusing research on key projects--the four HIV drugs in the case of Triangle and other HIV and hepatitis C therapies in the case of Abbott.

A new manufacturing and supply agreement was announced under which Abbott was to manufacture enough emtricitabine for the first year's sales and supply additional amounts through July 2005 at Triangle's request. Abbott also agreed to transfer the emtricitabine manufacturing process to a third-party manufacturer.

	Prisbe
	GILEAD PHOTO

Prisbe says Gilead's contractor change was a business decision. "Abbott has its own line of HIV drugs, which we compete against in the market," he says. "It may not be always the best idea to have your drug made by a competitor."

In addition, Prisbe says Gilead did not want to have to be concerned about competing with a contractor's parent company for time and attention at the production site. "When you do contract manufacturing with some of the big pharma companies like Abbott, it is difficult not to worry about some of the priorities that company might have--that some of their internal programs will get a higher priority than some outside program."

While Yuhan Chemical is also the contract manufacturing wing of a drug company, Prisbe says there is less concern because Yuhan does not make a competing HIV drug, and the plant near Seoul at which the work is being done is not used to manufacture Yuhan products, other than some antibiotics that are made in a separate building.

Gilead was not interested in pursuing a comarketing agreement on emtricitabine. While joint marketing alliances such as the one with Abbott were a key means for Triangle to bring drugs to market, Gilead has 13 sales offices around the world and only comarkets HIV drugs in Asia, Prisbe says.

According to Robert B. Miller, Abbott's program manager for pharmaceutical R&D, the alliance with Triangle was essentially a comarketing agreement, but manufacturing was "key to taking the project forward. They were making tens of kilos. We moved it into a process that we hoped would get up to 25 tons."

Miller acknowledges that Gilead's concerns about contracting with the services division of a large drug company are typical, but not necessarily deal breakers. "We have been asked about the priority issue on a number of occasions," he says. "Invariably, the answer we give is that the project that gets the priority is the project that needs the most work." In 2003, Miller says, Abbott's biggest job was done for a third party.

HE ADDS that Abbott has also become more flexible, strategically, in its contract process R&D work since forming the alliance with Triangle. "In the model going forward," he says, "we develop a process and transfer it to the eventual manufacturer. We are evolving to a multiservice offering as opposed to a one-stop shop."

Gilead made one more change. Having resolved patent issues with Glaxo in 2003, the company switched to a more economic menthol-based diastereomeric chemistry to promote stereoselectivity, eliminating the use of PLE in emtricitabine production altogether.

Prisbe emphasizes that the change of manufacturer does not reflect on Abbott's performance. Rather, Gilead, which does its own R&D and process development, prefers to work with small, "boutique" contractors that he says have extremely focused expertise and are more flexible and transparent than large contract manufacturers.

"There is nothing wrong with Abbott, or with DSM and Lonza," Prisbe says. "But the firms we contract with tend to be smaller." He says Gilead has contracted with Aerojet Fine Chemicals for energetic chemistry, Raylo and Torcan for nucleotide work, EaglePicher for cytotoxics, PPG-Sipsy for chiral reductions, and Pfanstiehl Laboratories for carbohydrates.