During a presentation at the 55th Annual Meeting of the European Association for the Study of Diabetes, held September 16 to 20, 2019, in Barcelona, Spain, researchers presented current data and ongoing clinical trial designs for the experimental drug, imeglimin, for the treatment of type 2 diabetes (T2D). According to results from current trials, the researchers believe the drug, which targets mitochondrial dysfunction, holds promise as a safe and potentially effective therapeutic option for achieving glycemic control.
Ralph DeFronzo, MD, from the University of Texas Health Science Center in San Antonio, opened the session by discussing the role of mitochondrial dysfunction in the pathophysiology of T2D. During his talk, Dr DeFronzo noted that mitochondrial dysfunction is a characteristic defect in individuals with T2D, as well as those with obesity. He highlighted several studies regarding mitochondrial dysfunction in patients and offspring with insulin resistance and discussed the implications for imeglimin therapy in these individuals.
Dr DeFronzo explained that imeglimin improves mitochondrial function by reducing the overproduction of reaction oxygen species, protecting mitochondria from excessive oxidative stress. The drug also increases the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and increases the number of mitochondria. Overall, the improvement in mitochondrial function associated with imeglimin may increase muscle insulin sensitivity and insulin secretion while reducing hepatic glucose production.
“Imeglimin decreases hepatic glucose production, improves insulin sensitivity in muscle, and also improves insulin secretion,” Dr DeFronzo added. “This particular drug increases complex II activity, markedly increasing the oxidation of complex substrates, such as lipids.”
Julie Dubourg, MD, discussed the methodology and results of phase 1, phase 2, and phase 3 clinical trials of imeglimin conducted in Europe, the United States, and Japan. A total of 17 phase 1 clinical trials and 8 phase 2 clinical trials have been completed, whereas the phase 3 program is currently ongoing.
“Imeglimin is an oral drug administered twice a day [that] has very low protein binding,” Dr Dubourg said during her presentation. “It also has very low hepatic metabolism, and there is no drug-drug interaction with metformin.”
According to results from a phase 2 clinical trial using imeglimin as an add-on to metformin, imeglimin demonstrated a significantly greater reduction in glycated hemoglobin compared with placebo during a 12-week period (-0.65% vs -0.21%; P <.001). Imeglimin also demonstrated good safety and tolerability up to 6000 mg, with the highest dose (8000 mg) inducing mild gastrointestinal effects. Dr Dubourg also described the TIMES 1, TIMES 2, and TIMES 3 trials, all of which are testing the efficacy of imeglimin for glucose control. These trials are currently ongoing, but results will be available later in 2019.
“Imeglimin is a first-in-class oral agent for T2D with a dual mode of action,” Dr Dubourg added. “The drug has been observed to demonstrate robust efficacy in patients with T2D, as well as in subgroups, including elderly and patients with chronic kidney disease. Imeglimin is a potential new treatment option as monotherapy or add-on therapy in these patients.”
DeFronzo R, Dubourg J. Imeglimin: a first-in-class oral medication with a unique mechanism of action targeting mitochondrial bioenergetics. Presented at: European Association for the Study of Diabetes 55th Annual Meeting; September 16-20, 2019; Barcelona, Spain. Session S22.