Positive results were reported last week in a Phase 2b dose-ranging study, which met the primary endpoint of showing a statistically significant reduction in HbA1c at 16 weeks with delayed-release metformin compared with placebo in subjects with type 2 diabetes. Elcelyx Therapeutics is marketing this drug as Metformin DR, an investigational product designed to target metformin delivery to the lower small intestine, where it is minimally absorbed yet elicits robust glucose lowering effects. The study results support the further development of Metformin DR for type 2 diabetes patients with renal impairment in whom metformin use is contraindicated as well as those patients with gastrointestinal intolerance to current metformin formulations.
“Patients with type 2 diabetes whose advanced kidney disease prevents them from effectively clearing metformin from their circulation are at increased risk for potentially toxic metformin-associated lactic acidosis,” says Endocrine Society member Robert Henry, MD, professor of medicine at the University of California San Diego School of Medicine and chief, endocrinology & metabolism, VA San Diego Healthcare System. “Gut-mediated Metformin DR which has minimal absorption leading to lower systemic exposure with clinically relevant glucose lowering effects is an especially attractive proposition for the treatment of type 2 diabetes patients with renal impairment, as well as for patients unable to take full doses of metformin due to gastrointestinal side effects.”
In the study, Metformin DR exhibited clinically significant dose-related reductions versus placebo in HbA1c and fasting plasma glucose. The glycemic effect of Metformin DR was somewhat less than that seen with a maximally effective dose of metformin immediate release (IR), but with significantly and disproportionally lower systemic exposure. The subgroup of subjects who completed the study and adhered to all protocol requirements showed a pattern of glycemic improvement comparable to that seen with the overall study population. Metformin DR was well tolerated and adverse events were consistent with the well-understood safety profile of metformin, with the most common ones being gastrointestinal effects such as diarrhea and nausea. Metformin DR exhibited a favorable gastrointestinal side effect profile that warrants further development.
The multicenter, randomized, Phase 2b study enrolled 571 subjects with type 2 diabetes and evaluated the glycemic effects of Metformin DR at doses of 600, 900, 1200 and 1500 milligrams, once daily. The study included a single-blind comparator arm of subjects receiving 2000 milligrams of metformin IR per day, administered as equally divided doses (1000 milligrams of metformin IR twice daily).
“The study results confirm that glucose-lowering benefits of Metformin DR result from actions in the gut,” says Alain Baron, MD, president and chief executive officer of Elcelyx. “The study also determined doses to be studied in Phase 3. With its robust size and duration, the Phase 2b study provides good support for the design of pivotal studies in type 2 diabetes patients with more advanced renal disease and those with gastrointestinal intolerance to metformin.”