Elcelyx Therapeutics, a company develops pharmaceutical and consumer healthcare products based on its proprietary Gut Sensory Modulation (GSM) platform, has reported clinical study results which confirmed that the primary site of action of type 2 diabetes medicine metformin is in the lower bowel rather than in the circulation. The study revealed that contrary to popular belief, greater exposure in the plasma of metformin does not improve efficacy of the most prescribed diabetes medicine in the world.
Elcelyx’s phase IIa study demonstrated this by comparing the glucose-lowering effects of NewMet, the company’s proprietary delayed-release formulation of metformin, to generic metformin in patients with type 2 diabetes.
NewMet is formulated to target the entire dose to the lower bowel and limit absorption into the blood. In the crossover study, five-day treatment with NewMet had similar fasting and post-meal glucose reductions from baseline as five-day treatment with generic metformin despite greater than 45 per cent reductions in metformin plasma concentrations. In addition, NewMet had less gastrointestinal (GI) side effects than generic metformin. Results of the clinical trial will be presented at ADA by Dr Ralph DeFronzo, professor of Medicine and chief of the Diabetes Division at the University of Texas Health Science Center and the Audie L Murphy Memorial Veterans Administration Hospital in San Antonio, Texas.
The significantly lower metformin plasma concentration observed with NewMet suggests that it might be safely used by patients with moderate and severe renal impairment, a population of patients that is unable to use currently available metformin formulations due to the risk of lactic acidosis caused by too much metformin in the blood. Mark Fineman, Ph.D., senior vice president of Research & Development at Elcelyx will present a second poster, accepted as a late-breaker that describes a model designed to predict concentrations of metformin in the blood that would occur if patients with type 2 diabetes and mild, moderate or severe renal impairment were to take NewMet. The results of the model suggest that patients with renal impairment taking effective doses of NewMet would not have an increased risk of lactic acidosis caused by accumulation of metformin in the blood. Elcelyx will be initiating a pharmacokinetic study this summer in type 2 diabetes patients with mild, moderate and severe renal impairment to confirm the predictions of the model.
“Metformin is the preferred initial pharmacological agent for type 2 diabetes, but in the US, 40 per cent of patients with diabetes are not taking it primarily due to issues of GI tolerability or due to the contraindication of their renal impairment. Moreover, of the 60 per cent who are taking metformin, only about 40 per cent are able to titrate to fully effective doses due to tolerability issues,” said John Buse, MD, professor of Medicine and director, Diabetes Care Centre, chief, Division of Endocrinology, executive associate dean for Clinical Research at University of North Carolina School of Medicine, Chapel Hill, North Carolina. “The NewMet results to date hold the promise of addressing all these patient segments. This is very encouraging news for physicians who would like to be in compliance with ADA treatment guidelines and have their patients benefit from metformin therapy.”
Dr Buse was an advisor on the phase IIa NewMet clinical study.
To confirm results observed to date, a multicenter, double-blind dose-finding phase IIb trial evaluating NewMet once-daily doses of 1,000, 800 and 600 milligrams compared to placebo is underway. There are also two comparator arms with generic extended-release metformin dosed once-daily at 1,000 and 2,000 milligrams. The primary endpoint of the study is fasting plasma glucose at four weeks of treatment. Secondary endpoints through 12 weeks include changes in fasting plasma glucose, hemoglobin A1c, body weight and measures of safety and tolerability. The study is fully enrolled with 240 patients with Type 2 diabetes.