By Karen Pihl-Carey

Metabolex Inc. entered into its second five-year diabetes collaboration with Parke-Davis, again providing the company with more than $50 million in potential funding and payments.

This time the collaboration will focus on the discovery and development of new therapeutics to treat Type II diabetes by counteracting insulin resistance, the first major defect in Type II diabetics.

"One of our goals here is to understand as much as possible, hopefully everything there is to know about the genetic basis of Type II diabetes with these two agreements," said Thomas Glaze, president and CEO of Metabolex.

The companies' initial collaboration, signed in January 1999, focused on the second major defect - insulin secretion. That collaboration also was worth more than $50 million to Metabolex. (See BioWorld Today, Jan. 7, 1999, p. 1.)

Metabolex, of Hayward, Calif., will receive substantial research funding through the second agreement. The deal also includes an up-front license fee and an equity investment in Metabolex, as well as research milestone payments and royalties on eventual product sales. Parke-Davis, which is the pharmaceutical research division of Warner-Lambert, of Morris Plains, N.J., will receive exclusive worldwide commercialization rights to products generated. The collaboration could mean more than $50 million to privately held Metabolex prior to any commercialization. Other financial terms were not disclosed.

"This is a five-year program of research, but I can't really project the outcome of the research at this point in terms of when products might come from it," Glaze told BioWorld Today. "But clearly the first part of the whole program is being productive in identifying genes that are involved in the mechanisms of diabetes, and from those genes, [identifying] drug targets."

The two major defects that lead to Type II diabetes are in two different tissues of the body, Glaze said. Insulin resistance is a condition in which the key target tissues for insulin - muscle and fat - do not respond normally to that hormone. Genetic traits and environmental factors play a role in the development of insulin resistance. Insulin secretion occurs with the abnormality of beta cells - or pancreatic cells - that regulate glucose levels in the bloodstream by producing insulin. The beta cells eventually lose their ability to produce enough insulin to control the blood sugar levels. Metabolex believes the best solution for Type II diabetes is to treat the insulin resistance and beta cell insufficiency with different drugs that are complementary.

"These programs are quite similar in their scientific approach using genomics, using large custom-gene arrays," Glaze said.

Diabetes is the leading cause of adult blindness, lower limb amputations and kidney disease in the U.S. It also is one of the leading causes of death. More than 100 million people have the disease worldwide, and about 90 percent to 95 percent of them have Type II diabetes.

Aside from its two collaborations with Parke-Davis, Metabolex partnered with Abbott Laboratories, of Abbott Park, Ill., on the diabetes aspects of its Glucose Transport Signal Transduction pathways program. The deal, along with a financing that was announced at the same time, meant $33.5 million for Metabolex. (See BioWorld Today, June 26, 1997, p. 1.)

Metabolex also has a separate collaborative agreement with Abbott's Ross Products Division, which covers development and marketing of a nutritional supplement for diabetics. And the company has acquired an exclusive license to more than 100 compounds from Shaman Pharmaceuticals Inc., of South San Francisco. Metabolex plans to characterize the mechanisms of the glucose-lowering activity of the compounds to determine if there are any suitable drug leads.

The company's most advanced product is MBX-102, a small-molecule glucose-lowering diabetes drug that is expected to enter Phase I trials this year. Metabolex recently raised $10.75 million in a private equity financing round designed to fund development of the unpartnered MBX-102. (See BioWorld Today, March 8, 2000, p. 2.)

Founded in 1991, Metabolex has raised more than $50 million to date.