BioWorld International Correspondent

Diabetica Ltd. out-licensed a preclinical program to develop agonists of glucose-dependent insulinotropic polypeptide (GIP) to Amylin Pharmaceuticals Inc. in a deal worth up to $41 million in up-front and milestone payments.

Coleraine, Northern Ireland-based Diabetica also would gain royalties on sales.

The company was formed in 2004 to commercialize the work of the Diabetes Research Group, led by Peter Flatt at the University of Ulster in Coleraine. It has developed an approach to treating diabetes based on introducing targeted modifications to GIP, a 42-amino acid peptide, which, along with glucagon-like peptide-1 (GLP-1), is an incretin hormone released by intestinal cells in response to food intake. Each plays a role in stimulating insulin secretion by pancreatic beta cells.

Amylin, of San Diego, gained FDA approval last year for the first incretin mimetic, Byetta (exenatide), which is an analogue of GLP-1. In 2003, Zealand Pharmaceuticals A/S, of Copenhagen, Denmark, out-licensed a GLP-1 receptor agonist, ZP10, to Sanofi-Aventis Group, of Paris, in a deal worth up to $100 million.

GIP initially was dismissed as having less value, said the University of Ulster’s Neville McClenaghan, one of the co-founders of Diabetica and its current chief operating officer.

"It was a minority sport, if you like," he told BioWorld International. "We now believe it could turn out to be the more important of the two." GIP corresponds to 80 percent of the total peptide produced by the enteroinsular axis. "Nature doesn’t do that by mistake." This deal will, he said, further shift that perception. "Amylin is the peptide company. For it to have invested in GIP validates the science, validates the approach," he said.

Native GIP has a short duration of action. Like GLP-1, it is rapidly cleaved by dipeptidyl peptidase IV, an enzyme that is itself a target for diabetes therapy. The cleavage site is between the second and third amino acid residues at the N-terminus of the peptide, McClenaghan said. Acetylation of either the first or the second N-terminal residues prevents the cleavage reaction, thus allowing the modified peptide to have a longer circulatory half-life than the native peptide and to boost insulin secretion following food intake.

Diabetica has a strong IP position in the area, said Enda Kenny, the newly appointed CEO of the company. "There wasn’t a lot of competing IP," he told BioWorld International. The company had been developing a drug candidate, provisionally named incretide, that was on track to enter the clinic next year. Amylin has gained that molecule as well as exclusive rights to all of the company’s IP for the development of GIP agonists. "It’s not a one-shot deal for them. They have the field," Kenny said.

Diabetica is continuing internal development of a GIP antagonist program, which also has application to diabetes therapy. A proline substitution at the third amino acid residue results in a modified peptide that has an inhibitory effect on GIP action and that appears to enhance insulin sensitivity in muscle, liver and adipose tissues. That mechanism of action appears to mimic a naturally occurring phenomenon. Kenny said there is evidence in the literature that the breakdown product of GIP has an antagonistic effect on GIP action. "It seems to be part of a whole feedback process," he told BioWorld International. "Antagonism at the receptor does occur physiologically." Animal studies indicate that it also appears to promote weight loss.

The two programs are not competitive, McClenaghan said. The agonist program could yield therapies for patients with early stage Type II diabetes, who are currently on sulfonylurea drugs. The antagonist program might yield products with the potential to treat patients with more advanced disease, who are currently taking metformin.

Diabetica gained seed funding last year from Dublin-based Seroba BioVentures and UUTech, the technology transfer arm of the University of Ulster. It now aims to raise €5 million (US$5.9 million) in order to fund ongoing development of its GIP antagonist program and additional earlier-stage programs.

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