HANDS ON An operator at Rhodia's Annan, Scotland, facility works with material in a contained offloading unit.
	RHODIA PHOTO

Rubin is president and chief executive officer of Critical Therapeutics Inc. (CTI), a small biopharmaceutical company in Lexington, Mass. And in his dual quest, he is leveraging two strengths from his past: an intimate knowledge of zileuton and a good working experience with the pharmaceutical services firm Rhodia Pharma Solutions.

From 1987 until 1993, Rubin, a medical doctor, was in charge of a group at Abbott Laboratories responsible for the development of zileuton. When the drug was approved in 1996 as Zyflo, it became the only Food & Drug Administration-approved product that works by blocking the activity of 5-lipoxygenase, the main enzyme responsible for the formation of a family of lipids known as leukotrienes.

Leukotrienes are known to cause many of the biological effects that contribute to inflammation, mucus production, and the closing of the airways in asthmatic patients. CTI believes that zileuton's activity against a range of leukotrienes differentiates it from montelukast, the active ingredient in Singulair, a Merck drug that is the most frequently prescribed leukotriene receptor antagonist. Singulair, according to CTI, blocks only one of the two known receptors and for just a single leukotriene.

Despite zileuton's apparent therapeutic advantages, Rubin says Abbott failed to promote it heavily and, after about a year, ceased all sales calls for the drug.

Rubin, meanwhile, left Abbott in 1993 to spend three years as director of early clinical development and clinical pharmacology at what is now GlaxoSmithKline. He then worked for Sepracor for six years as executive vice president of R&D.

While he was at Sepracor, the company sold SepraChem, its chiral chemistry subsidiary, to the contract research and production firm ChiRex. Sepracor went on to employ ChiRex as the manufacturer for several of its new active pharmaceutical ingredients (APIs). In 2000, ChiRex was acquired by Rhodia, where it is now part of Rhodia Pharma Solutions.

Rubin left Sepracor in August 2002 to join CTI as president and CEO. CTI had been formed a year earlier by three intensive-care experts: Mitchell P. Fink of the University of Pittsburgh's School of Medicine; Kevin J. Tracey of the North Shore-Long Island Jewish Medical System's Institute for Medical Research; and Harvard Medical School's H. Shaw Warren. They had pooled their collective scientific discoveries and won initial financing from HealthCare Ventures and MPM Capital.

When Rubin came aboard, the company was developing the drug candidates on which it had been founded: critical care disease products that work by regulating the body's inflammatory response. However, he saw an opportunity to accelerate CTI's path to profitability by licensing zileuton from Abbott and marketing it to asthma specialists rather than to the primary care physicians on whom Abbott had called.

By this time, Abbott had shut down production of the zileuton API and was selling Zyflo from inventory that eventually ran out early last year. Rubin approached his former company and was able to negotiate a license agreement that included transfer of the API manufacturing technology.

The next step was to find a contract manufacturer to revive production of the API. Rubin had had a favorable experience with ChiRex, and then Rhodia, while he was at Sepracor and decided to open negotiations with the firm again. Working with Trevor Phillips--a former colleague from Glaxo and Sepracor and now CTI's chief operating officer--Rubin struck a long-term zileuton supply agreement with Rhodia.

Nick Green, president of Rhodia Pharma Solutions, acknowledges that past connections made his company a possible manufacturing partner, but he maintains that recent investments in facilities and in the way the firm goes about business also played a role in getting the job. "We try to create a seamless organization--particularly for biotech firms that don't have their own manufacturing--to provide them absolute comfort and security," he says.

Not long after being contacted by CTI, Rhodia made initial quantities of zileuton at its commercial-scale current Good Manufacturing Practices plants in both Annan, Scotland, and Dudley, England. Under the long-term deal signed in February, Rhodia will consolidate production at the Annan plant, where it says zileuton could eventually be one of the site's major activities.

To reintroduce Zyflo to the U.S. market, CTI needs to obtain FDA approval of the Annan facility as well as the third-party plant where the finished formulation will be made. Phillips expects CTI to submit the necessary Supplemental New Drug Application (SNDA) by the end of the first quarter. The company is hoping the agency will review the SNDA and inspect the plants in time to start marketing Zyflo before the end of the year.

CTI's first product will be the original four-times-a-day Zyflo that Abbott launched in 1997. The company has also licensed a twice-daily version of zileuton for which Abbott conducted Phase III clinical trials. CTI plans to file an NDA for this version of the drug by the end of 2005.

According to Phillips, Rhodia has already manufactured all the zileuton required for registration batches and is now gearing up for commercial production. He attributes this success in large part to the technology-transfer group formed by the two companies. "It doesn't matter how good either side is--if you don't create the right team, you won't make progress," he says.

Phillips adds that CTI has a number of other projects in its pipeline that will eventually require third-party manufacturing support. But despite historic ties and good performance with zileuton, a repeat contract isn't a sure thing for Rhodia--a business reality of which Green is well aware. "Rhodia has provided us with good service to date," Phillips says, "and we would consider them for future projects--along with other organizations as well."