BARCELONA — A novel investigational first-in-class drug called imeglimin (Poxel Pharma) has shown promise in treating type 2 diabetes in a phase 3 study conducted in Japan.
Findings from the Trials of Imeglimin for Efficacy and Safety (TIMES) clinical development program were presented September 18 during a symposium here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting by Julie Dubourg, MD, Poxel's medical director of clinical development.
"In all phase 2 and phase 3 trials, imeglimin has demonstrated very robust efficacy in the type 2 diabetic population, as well as in subpopulations such as elderly patients and those with chronic kidney disease. The safety and tolerability profile is also very good. So this [may be] a new option for the treatment of patients with type 2 diabetes as mono- or add-on therapy," Dubourg told Medscape Medical News.
Imeglimin works by improving mitochondrial function, which in turn increases insulin secretion and insulin sensitivity in the muscle while also decreasing hepatic glucose production, Ralph A. DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Sciences Center, San Antonio, said during the symposium.
Imeglimin is the first of what will be a new "glimin" class of glucose-lowering agents.
"These drugs actually correct three of the big problems that are present in our diabetic patients...It provides us with a new mechanism of action," DeFronzo said.
In addition, because preclinical data suggest that imeglimin also mobilizes fat in the liver, "this drug also has the potential to be used in [nonalcoholic steatohepatitis]," he noted.
Asked to comment, Harold E. Lebovitz, MD, professor of medicine at the State University of New York-Brooklyn, said: "The Japanese data are very impressive, but we don't know yet how other populations will respond to it."
"It is clearly a new class with unique mechanisms, but we have to define what that role is," he added.
Lebovitz, who conducted early studies on imeglimin but isn't involved in its development now, also pointed out that the drug could work in some patients for whom other classes of glucose-lowering agents might not be effective, or appropriate, such as those with kidney disease.
"Glucose-lowering drugs are not all for the same group of people...People with kidney disease are very sensitive and have a lot of hypoglycemia...Every drug is probably useful for a subset of patients because type 2 diabetes is not a single disease."
Drug Achieved All Endpoints Without Safety Issues in Japanese Patients
The ongoing phase 3 TIMES program with imeglimin includes three individual randomized, double-blind, placebo-controlled trials involving more than 1100 patients at 29 sites in Japan. TIMES 1, a 6-month monotherapy efficacy trial, TIMES 2, a 1-year safety trial with imeglimin as mono- and add-on therapy, and TIMES 3, a 16-week efficacy trial of imeglimin added to insulin, followed by a 36-week safety extension period.
Dubourg reported the results of TIMES 1 here at the EASD annual meeting. Patients had had type 2 diabetes for more than 3 months, were aged 20 years or older, were managed with diet and exercise, with or without one oral agent, and had a baseline HbA1c of 7-10%. Rescue therapy could be given after week 4 if necessary. A total of 213 participants were randomized and 205 completed the trial (103 were randomized to imeglimin and 102 to placebo).
The primary endpoint, change from baseline in HbA1c at week 24, was significantly greater with imeglimin compared to placebo (–0.87%; P < .0001), consistent with results seen in a phase 2 trial that was pivotal in selecting the 1000-mg dose of imeglimin for the phase 3 trials, Dubourg said.
Fasting plasma glucose also dropped significantly at 24 weeks by an average of 19 mg/dL (P < .0001), also similar to the phase 2 results.
Proportions of patients achieving an HbA1c < 7% were 35.8% (from baseline of 7.99%) in the imeglimin group versus just 7.5% (from a baseline of 7.93%) with placebo. No patient in the imeglimin group required rescue therapy, whereas 5.7% of the placebo group did.
Results were consistent across age groups, above and below 65 years of age (both P < .0001), and across chronic kidney disease stages 1, 2, and 3 (P < .0900, P < .0001, and P = .0007, respectively).
Overall adverse event rates were similar (44.3% vs 44.9% for imeglimin and placebo, respectively). Gastrointestinal disorders occurred in 11.3% of patients with imeglimin versus 8.4% with placebo. There were no severe hypoglycemic events in either group.
Adverse events leading to study discontinuation were less common with imeglimin than placebo (2.8% vs 5.6%). Serious adverse events were more common with imeglimin (3.8% vs 0.9%). No deaths occurred.
TIMES 2 and TIMES 3 results are expected around the end of 2019.
Poxel expects to submit a New Drug Application for imeglimin in Japan by the end of 2020. Phase 3 trials will also be conducted in the United States and Europe.
EASD 2019 Annual Meeting. Presented September 18, 2019.
Dubourg is a Poxel employee. DeFronzo has reported being an advisor for, receiving research support from, and/or being a speaker for AstraZeneca, Novo Nordisk, Janssen, Boehringer-Ingelheim, Intarcia, Elcelyx, Janssen, and Merck. Lebovitz formerly consulted for Poxel but hasn't done so for more than a year and currently receives no funding from them. He now works with Indian biosimilar manufacturer Biocon.
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Cite this: Novel Agent Imeglimin Improves Glucose Control in Type 2 Diabetes - Medscape - Sep 19, 2019.