By Karen Pihl-Carey

Capitalizing on last summer's discovery of the ABC1 gene, Xenon Genetics Inc. entered into a major collaboration with Warner-Lambert Co. that could result in therapeutics to treat low levels of HDL, a condition associated with cardiovascular disease.

The three-year deal means US$57.7 million (C$87 million) to Vancouver, British Columbia-based Xenon for a single product. If additional products come out of the collaboration, the money will increase. The deal includes an up-front payment, an equity purchase, research funding and preclinical and clinical milestone payments, as well as royalties on product sales.

It is the single largest preclinical collaboration agreement in Canadian biotechnology, said Xenon's president and CEO, Frank Holler.

"This will be one of the strongest, if not the strongest, drug discovery programs in HDL-cholesterol," Holler told BioWorld Today. "From our company's perspective, it's a tremendous validation of our technology platform. We think using our clinical genomics approach, we have a faster and more direct route to new drugs."

The collaboration follows the discovery by Xenon researchers and collaborators of mutations in the ABC1 gene that impair a person's ability to regulate levels of HDL (high-density lipoprotein). Their discovery was published last August in Nature Genetics. (See BioWorld Today, Aug. 3, 1999, p. 1.)

The researchers worked with families in the Netherlands and Quebec who had a history of heart disease in order to reveal that the mutated gene leads to low HDL levels, making those people more susceptible to heart attacks.

"More people are actually affected by having too little good cholesterol, HDL-cholesterol, than having too much of the LDL, the bad cholesterol," Holler said. "It's a more common lipid abnormality."

Holler said that coronary artery disease is the leading cause of death in North America, and is expected to be the leading cause of death worldwide by 2020. Low levels of HDL-cholesterol are the most common lipid abnormality, affecting about half of those people with coronary artery disease.

Xenon was able to secure the collaboration with Warner-Lambert, of Morris Plains, N.J., because the company already has identified two targets, the ABC1 gene and another undisclosed target. "The reason Warner-Lambert is prepared to pay that kind of money is because what we're bringing them is not just one compound that might be hit or miss," Holler said. "We're bringing them two drug targets now, but we'll be working with them to increase that number. We think over the next three years, we should be able to generate 10 to 12 new drug targets in the program.

"Warner-Lambert brings, of course, tremendous capabilities in cardiovascular research and development," he added. "This is the company that commercialized and developed Lipitor, the world's leading heart medication."

While the initial collaboration will last for three years, Holler said it could be expanded. It brings significant revenues to Xenon in the early years, which is important for any privately held drug discovery company, he said.

Coronary artery disease occurs not only with low levels of HDL, but also with high levels of LDL (low-density lipoprotein). When LDL gets oxidized, it becomes injurious to the blood vessel wall, leading to obstruction of the vessel in areas where the lumen is not large, such as in the coronary arteries. As LDL pushes the vessel wall in, HDL brings it out, illustrating a battle between the bad and good cholesterol.

While sales of drugs to lower LDL-cholesterol total $8 billion to $10 billion a year, there is no effective treatment to raise low levels of HDL-cholesterol.

"So we certainly think this is a large market opportunity," Holler said. "There's no drug today. So there's a strong unmet clinical need."

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