By Matthew Willett

Metabolex Inc. realigned its research partnership with Pfizer Inc., shifting away from a program focused on insulin-resistant genomics and toward one aimed at discovering drug targets related to insulin secretion.

The restructuring includes a one-time payment to privately held Metabolex of $6 million from Pfizer, which also committed to three years of funding for the insulin-secretion program, now the sole focus of the companies¿ relationship. Pfizer also will make an undisclosed equity investment in Metabolex.

The partnership restructuring returns to Metabolex rights to a program originally partnered with Warner-Lambert Co., of Morris Plains, N.J., focused on the main defect involved in Type II diabetes: insulin resistance ¿ the decreased ability of insulin to stimulate glucose transport to muscles.

The original deal for the insulin-resistance program was struck in July 2000, and was worth more than $50 million in potential funding and payments. That deal was the second of two between the companies worth $50 million. The first, focused on discovering insulin-secretion defect therapeutics and founded in 1999, will now be the sole focus of the companies¿ collaboration. (See BioWorld Today, May 19, 2000, and Jan. 7, 1999.)

Pfizer acquired Warner-Lambert in a $90 billion deal in February 2000. Metabolex said it will seek another partner for the insulin-resistance program and is actively discussing repartnering with several undisclosed companies.

Metabolex CFO Mark Bagnall said the restructured deal captures value from both programs for Metabolex.

¿After the merger between Pfizer and Warner-Lambert, Pfizer came to us and said that the programs have a potential that¿s so enormous they¿d like to focus on one of them,¿ Bagnall told BioWorld Today. ¿They¿re now at the point that they¿ve either spent or committed $30 million to the insulin-secretion program, and it could be well beyond that, so they¿ve decided to focus on one because this really is an area that could be quite comprehensive.¿

The work on the ongoing partnership focused on insulin secretion has so far produced a complete genetic sequence on insulin-producing beta cells in humans, rats and mice, Bagnall said, and customized Affymetrix Inc. GeneChips that already are in use for experiments to identify novel targets ¿ G protein-coupled receptors and ion protein channels, for example ¿ that have a role in insulin secretion.

The other program, now fully Metabolex¿s, focuses on identifying insulin-sensitizing targets. About $10 million of the estimated $15 million dedicated to that project so far was funded by Pfizer, Bagnall said.

The sensitizer program has thus far completed a sequencing of muscle and fat tissues and is currently using Affymetrix chips to mine that sequence, determined using a diverse tissue sample library, for potentially targetable genes.

¿Some of the patients were lean, and some were obese,¿ Bagnall explained. ¿Some were treated with insulin-sensitizer drugs, some were effectively given an overstimulus of insulin, some had very high-fat diets and some had extra glucose pumped into their systems. We were able to take these volunteers who had gone through experiments and get biopsies, and now we¿re able to do expression analysis and show the gene expression changes relative to each of the different states.¿

And those experiments already have given Metabolex an indication that the sensitizer program will produce a healthy pool of potentially targetable genes. With eight series of experiments planned, scientists are finding about 250 genes expressed differentially. About a quarter of those genes are novel, unannotated in any public database, and Bagnall agreed that a broad estimate of the number of potentially targetable genes could total upward of 400.

And those results are turning heads, he added. ¿So far there are about six pharma companies in the U.S. talking to us, and probably between Japan and Europe, another six. They¿re the obvious players, the obvious people interested in Type II diabetes,¿ he said.

Though Bagnall couldn¿t disclose the total of Pfizer¿s equity investment related to the rearrangement of the relationship, he did divulge that New York-based Pfizer will be the third largest investor in Metabolex after the equity transfer.

And beyond the Pfizer collaboration and expected partnering news for the sensitizer program, Metabolex could be making more news with its lead compound, MBX-102, another insulin sensitizer in preclinical testing. ¿Watch this space,¿ Bagnall advised, adding that MBX-102 is ¿very close¿ to moving into the clinic.

The compound, he hinted, is an old compound with an interesting clinical history.

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