Elixir Pharmaceuticals Inc. kicked off what it hopes will be its first and last Phase III trial of lead drug candidate mitiglinide in the treatment of Type II diabetes.

The drug already is marketed in Japan by Kissei Pharmaceutical Co. Ltd., of Tokyo, which licensed Latin and North American rights to Elixir last year. Despite the fact that Kissei had collected clinical data on more than 4,000 mitiglinide patients, including data from multiple Phase III trials, the FDA told Elixir during a pre-new drug application meeting that it wanted to see a trial in U.S. patients, specifically minorities.

To satisfy this request, Elixir initiated a randomized, double-blind, placebo-controlled Phase III trial of mitiglinide, previously referred to as Glufast. The trial will enroll more than 300 U.S. diabetic patients, including minorities, for whom metformin alone has not adequately controlled blood glucose levels. Patients will be randomized to one of three groups: metformin plus twice-daily mitiglinide, metformin plus three-times-daily mitiglinide or metformin plus placebo. The primary endpoint of the trial is improvement in hemoglobin A1c (HbA1c) levels, and the secondary endpoints include improvement in fasting plasma glucose and two-hour post-meal glucose levels.

Previous trials have demonstrated the benefit of adding mitiglinide to metformin. Data published earlier this year in the abstract book for the American Diabetes Association 67th Annual Scientific Sessions showed that in a trial of more than 300 diabetic patients with inadequate glycemic control, treatment with metformin and mitiglinide lowered HbAlc levels to 7.13 after seven months, compared to 7.7 with metformin alone.

Cambridge, Mass.-based Elixir expects to complete the newly initiated Phase III trial in mid-2008 and file a new drug application in 2009. The regulatory package will combine the Phase III data with Kissei's existing clinical database. Elixir's Chief Financial Officer Gregory Perry said the company plans to seek approval for both twice-daily and three-times-daily doses of mitiglinide in combination with metformin for patients who have failed metformin alone.

If approved, mitiglinide will join two other marketed diabetes drugs in the meglitinide class of compounds: Starlix (nateglinide, Novartis AG) and Prandin (repaglinide, Novo Nordisk A/S). Meglitinides are insulin secretagogues, like sulfonylurea, and are predominantly used to manage meal-time hyperglycemia.

Elixir estimates that Starlix and Prandin generated about $300 million in U.S. sales in 2006, but Perry said mitiglinide may offer an opportunity in "reaching beyond" the current market. While the two marketed drugs must be taken three-times daily, Perry said twice-daily dosing would be more convenient for patients and better coincides with how metformin is often dosed.

Additionally, positive data in the twice-daily dosing regimen would support Elixir's ongoing development of a metformin-mitiglinide combination product. Perry said the combination could potentially be approved based on studies showing its bioequivalence to the two products taken separately.

Although diabetes is a crowded market, Perry said mitiglinide has the potential to "quickly" generate revenues that would be used to support Elixir's earlier-stage programs.

Chief among those is the company's ghrelin antagonist program for obesity and diabetes. Lead candidate EX-1350 is slated to enter the clinic next year, and preclinical studies have shown it decreases body weight, improves blood glucose and insulin levels, lowers liver fat and improves liver function.

Elixir also is conducting IND-enabling studies with EX-1314, a ghrelin agonist to stimulate appetite and growth hormone release. Other preclinical programs center on the Sirtuin class of proteins and AMP-activated kinase, both of which are involved in metabolism.

For now, those programs are being supported with the $46 million Series C financing Elixir completed last fall. That money is expected to last into 2008, but with mitiglinide not even slated for an new drug application filing until 2009, Perry said the company will complete another financing round prior to launching the diabetes drug. (See BioWorld Today, Nov. 29, 2006.)

"I think we'll do a private round before testing the public markets, but we're certainly moving down that path," Perry said.