An orally administered therapeutic polymer, GLY-200, designed to bind to and enhance the barrier function of mucus in the gastrointestinal tract to establish duodenal exclusion noninvasively, appears to mimic the effects of gastric bypass surgery and is providing fresh hope for people living with type 2 diabetes and obesity.
"The short (five day) study indicates that the pill works in healthy volunteers. It reduced the rise in blood glucose after a meal substantially and also resulted in a small amount of weight loss. Importantly, it was well tolerated by the volunteers," said Professor Michael Horowitz from the University of Adelaide's Center of Research Excellence in Translating Nutritional Science to Good Health. "This is an exciting development. For most people with type 2 diabetes, weight loss and improvements in blood glucose control are extremely important, but often difficult to achieve. We have a potential treatment that's non-invasive and appears to mimic the positive effects of metabolic surgery without the risks, high cost or adverse effects.”
University of Adelaide researchers were selected by US biotechnology company Glyscend Therapeutics to carry out the first phase of testing the medication in healthy volunteers. The researchers carried out a phase 1, randomised, double-blind, placebo-controlled, single- (SAD) and multiple-ascending-dose (MAD) healthy volunteer study. In the SAD arm, four cohorts received a single dose of 0.5g up to 6.0g GLY-200 or placebo, while in the MAD arm, four cohorts received five days of twice-daily or three-times-daily dosing (total daily dose 2.0g up to 6.0g GLY-200 or placebo). Assessments included safety and tolerability (primary) and exploratory pharmacodynamics, including serum glucose, insulin, bile acids and gut hormones.
The researchers reported no safety signals; tolerability signals were limited to mild to moderate dose-dependent gastrointestinal events. In the MAD arm (day five), reductions in glucose and insulin and increases in bile acids, glucagon-like peptide-1, peptide YY and glicentin, were observed following a non-standardised meal in subjects receiving twice-daily dosing of 2.0g GLY-200 (n=9) versus those receiving placebo (n=8).
“GLY-200 is safe and generally well tolerated at doses of ≤2.0g twice daily. Pharmacodynamic results mimic the biomarker signature observed after Roux-en-Y gastric bypass and duodenal exclusion devices, indicating a pharmacological effect in the proximal small intestine,” the researchers concluded. “This study represents the first clinical demonstration that duodenal exclusion can be achieved with an oral drug and supports further development of GLY-200 for the treatment of obesity and/or T2D.”
The University of Adelaide's industry partner Glyscend carried out an additional 14-day study in the US in people with type 2 diabetes which produced similar results.
"We are highly encouraged to see the acute clinical benefits of our orally administered first-in-class drug. The totality of the data on GLY-200 suggest it has the potential to replicate the mechanism of surgery and provide a non-invasive alternative to today's invasive approaches," said Dr Mark Fineman, Glyscend's Chief Development Officer and first author on the Phase 1 publication.
"The early results suggest that this drug could be a game changer. Now what's required is an improved understanding of the mechanisms responsible for the beneficial effects and proof that these effects are sustained," added Horowitz.
With other University of Adelaide researchers (Professor Chris Rayner and Professor Karen Jones), Professor Horowitz plans to initiate another clinical trial related to these mechanisms in Adelaide within the next six months.
The findings were reported in the paper, ‘First‐in‐human study of a pharmacological duodenal exclusion therapy shows reduced postprandial glucose and insulin and increased bile acid and gut hormone concentrations’, published in Diabetes, Obesity and Metabolism. To access this paper, please click here