New Liver Pathway to Treat Diabetes

Metabasis Therapeutics unveiled another diabetes treatment. This one cuts down on glucose production by the liver. It works by inhibiting an enzyme called Fructose-1,6-bisphosphatase. Metformin, a standard drug for diabetes patients, also cuts down on glucose production in the liver, but how it works is a mystery. MB07803 a Fructose-1,6-bisphosphatase Inhibitor for the Treatment of Type 2 Diabetes is a new product candidate for the treatment of type 2 diabetes, discovered by Metabasis, MB07803 is a prodrug of an orally active, potent and selective inhibitor of fructose-1,6-bisphosphatase (FBPase), a regulatory enzyme in the pathway responsible for the production of glucose in the liver known as the gluconeogenesis pathway. Inhibition of this pathway is believed to reduce blood sugar levels in patients with type 2 diabetes, independent of insulin levels and without increasing body weight.

The majority of patients diagnosed with type 2 diabetes are overweight, and the initial approach to treating the disease is diet modification and increased exercise. This approach often fails to adequately control the disease, and patients must then add an oral anti-diabetic therapy to achieve adequate control of their elevated blood glucose. Most patients are put on the drug metformin. Like MB07803, metformin is believed to reduce liver glucose production, but unlike Metabasis’ product candidate, which directly targets the gluconeogenesis pathway, metformin acts indirectly through an unknown mechanism and is believed to only partially inhibit the pathway at maximal doses. Additionally, metformin is contraindicated in many patients and is associated with gastrointestinal (GI) side effects in 5-10% of patients, ultimately requiring discontinuation of therapy due to GI intolerability. Of those patients able to tolerate metformin, 20-30% report mild to moderate GI side effects even after relatively long-term usage.

MB07803 is a second generation product candidate in the FBPase inhibitor class. The class has been shown to be safe and well tolerated in numerous clinical and preclinical studies for MB07803 and the earlier candidates. Additionally, the class has shown to significantly reduce production of liver glucose in clinical trials. MB07803 was designed to improve upon earlier candidates in the class and appears to have a superior preclinical profile. Some of the improvements include once-a-day dosing, increased oral bioavailability (more potent) and reduced drug variability. These attributes may lead to less patient-to-patient variability and reduced side effects.

The first generation FBPase inhibitor was CS-917, which was being developed by Metabasis licensee, Daiichi Sankyo. In Phase 2a studies CS-917 was shown to be safe and effective for lowering fasting plasma glucose as a mono-therapy; however, CS-917 failed to show significant efficacy across all patients in a subsequent 12-week Phase 2b trial. However, subgroup analysis of this latter trial provided evidence of efficacy in patients with more established disease as compared to the majority of patients in the trial who had newly diagnosed, early stage disease. CS-917 was discontinued in favor of continued development of MB07803, a candidate with a superior profile.

We initiated a Phase 2a proof-of-concept clinical trial for MB07803 in March 2007. This is a 28-day trial involving 100 patients, both newly diagnosed and those with more advanced disease. We expect to see results in the second quarter of 2008. Previously, we successfully completed a Phase 1a single dose clinical trial and a Phase 1b, 14-day multiple dose clinical trial at the end of 2006. To date, MB07803 has shown safety and tolerability well above the estimated efficacious dose range. During 2008, Metabasis plans to study the safety aspects of administering MB07803 in combination with metformin; in an early study with CS-917 combination with metformin led to a drug-drug interaction in certain patients resulting in elevated metformin blood levels, a potentially dangerous condition.

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