Cystic Fibrosis Project Has San Diego Unit of Vertex on Verge of a Treatment

By Penni Crabtree, The San Diego Union-Tribune

Oct. 21–Vertex Pharmaceuticals’ small San Diego research unit has toiled quietly behind the scenes for four years, the hard-working stepchild of its bigger, more glamorous Cambridge, Mass.-based parent company.

Now, with any luck, Cinderella will be stepping out to the ball.

This month, Vertex named as one of its key drug development projects for 2006 an experimental treatment for cystic fibrosis that was discovered at its San Diego site.

Though other experimental Vertex drugs have garnered more attention — a Hepatitis C drug about to go into Phase 2 testing is generating most of the buzz — the cystic fibrosis treatment represents a milestone for Vertex’s West Coast research hub, which employs 150.

It is also the legacy of Aurora Biosciences Corp., a former San Diego research “tool” company that Vertex acquired for about $600 million in stock in 2001. Aurora’s novel screening technologies, and expertise in ion channel drug discovery, are the foundation of the current Vertex operations in San Diego.

Founded in 1989, Vertex is one of the oldest biotechnology companies. It is best known for the discovery of two HIV drugs, Agenerase and Lexiva, which are licensed to GlaxoSmithKline.

Though the company remains unprofitable, its stock price has more than doubled in the past year because of its strong pipeline of experimental drugs, which include treatments for hepatitis C, HIV, cancer, rheumatoid arthritis and the potential CF drug.

“The value we got from the Aurora acquisition has exceeded expectations,” said Vertex Chief Executive Officer Joshua Boger, whose company employs 850 in Cambridge, San Diego and England. “We stand here now with the site in San Diego being a fully-integrated drug discovery operation that is as good as any in the world.

“We’re extremely excited by the cystic fibrosis program, and our San Diego site has moved it from basic science to the doorstep of product development,” Boger said. “We can see the light in the near distance.”

The cystic fibrosis program is a unique collaboration between a commercial biotechnology company and a nonprofit patient advocacy and research organization, the Cystic Fibrosis Foundation.

Cystic fibrosis is a life-threatening genetic disease that used to kill most of its victims before their first birthday. A defective gene causes the body to produce an abnormally thick mucus that clogs the lungs and causes life- threatening lung infections.

In the past 20 years, improved infection-fighting treatments have prolonged survival, but most of the 30,000 children and adults in the U.S. with CF can expect to succumb to the disease by their mid-30s.

The CF Foundation has funded efforts to find a cure, including underwriting some of the research that led in 1989 to the discovery of the defective gene that causes CF. In 2000, the foundation began a research effort with Aurora to find new medicines to treat the disease, a project that was inherited by Vertex and expanded.

Bob Beall, chief executive officer of the CF Foundation, said the Vertex drug is the foundation’s “highest priority research project.”

“The collaboration has been outstanding,” said Beall, whose foundation has provided $40 million to fund the Vertex CF project. “We think this approach is custom-made, it aims right at the level of the basic gene defect and mutation that causes cystic fibrosis.

“If it works out, it would be the most significant advance in the history of CF,” Beall said.

Vertex’s goal is to develop a pill that would help repair the ion channel that the defective CF gene encodes. An ion channel is a protein on the surface of a cell that controls the flow into and out of cells of chloride, sodium, potassium and other ions.

In CF, the ion channel that regulates chloride flow is off kilter, which disrupts the normal fluid balance in the lungs. The lungs dry out, can’t get rid of irritants and bacteria and become chronically inflamed. And that leads to the destruction of lung tissue and infections.

Ion channels are targets for perhaps a third of all drugs because they are key to many cellular processes, and Vertex’s San Diego unit is focusing most of its research energies in that field.

“The drug industry has known for a long time that these are good targets, what we’ve not known is how to design drugs that are specific enough against these targets,” said Paul Negulescu, vice president of research at Vertex’s San Diego unit. “Being successful in CF will be evidence of our leadership in the ion channel area — we aim to tame the targets that have eluded others.”

Among the tools that Negulescu’s research group uses in its ion channel drug discovery work is the E-VIPR, a fast, automated drug-screening system that can analyze thousands of samples a day. The E-VIPR is a second-generation system; the forerunner was invented at Aurora.

The machine mimics the normal electrical stimulation patterns that a disease target — an ion channel — experiences in the body, so scientists can measure the activity of a potential drug on the target.

By observing how an ion channel opens and closes many times per second, scientists can better develop drugs that bind to the natural structures and shapes that the ion channel undergoes, Negulescu said.

Aurora Biosciences, which went public in 1997, had hoped to make millions of dollars with its screening technologies. During the genomics boom of 1999 and 2000, the company’s stock soared above $100 per share, fueled by investor hopes that genomics tools would speed the discovery and development of new drugs.

That hope did not pan out, at least not at the pace Wall Street wanted, and investor fascination with companies that supplied genomics information or screening tools cooled. Aurora was trying to transform itself into a drug discovery company when it decided to leapfrog the process and merge with Vertex.

Negulescu, who joined Aurora in 1996 as one of its first five employees, is confident that the biotech industry’s bet on research tools will pay off.

“I think we as an industry were naive. Five years ago it was all about screening and genomics, but we realize now that drug discovery is hard work no matter what technology base you have,” Negulescu said.

Ultimately, the research technologies invented at Aurora, and embraced by Vertex, allow the company to make better decisions about what disease targets to pursue and what drug molecule to select for human clinical studies, he said.

“Of course, we won’t know if that is true for a few more years, when we see those drugs coming through the clinic and into the market,” Negulescu said.

“That’s when we’ll know if the tools made a difference.”

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