Clinical Trials

Date: 2017-09-14

Type of information: Presentation of results at a congress

phase: 2b

Announcement: presentation of results at the European Association for the Study of Diabetes (EASD) 53rd Annual Meeting

Company: Poxel (France)

Product: imeglimin

Action mechanism:

• glimin. Imeglimin is the first in a new chemical class of oral anti-diabetic agents, the glimins. Imeglimin acts on three main target organs involved in glucose homeostasis: the liver, the muscle, and the pancreas and has therefore a distinct mode of action compared to existing treatments for Type 2 diabetes. Imeglimin has shown a significant anti-diabetic efficacy combined with an excellent tolerance in earlier monotherapy clinical trials.
• Imeglimin has completed Phase 2 development in over 850 patients in the United States and Europe.

Disease: type 2 diabetes

Therapeutic area: Metabolic diseases

Country: Japan

Trial details:

• The Phase 2b randomized, double-blind, placebo-controlled study tested three doses of Imeglimin (500 mg, 1000 mg and 1500 mg) administered twice-daily for 24 weeks in 299 Japanese patients for the treatment of type 2 diabetes.

Latest news:

• • On September 14, 2017, results from the imeglimin Phase 2b study in Japan have been presented at the European Association for the Study of Diabetes (EASD) 53rd Annual Meeting (poster 843). In this study, the primary endpoint achieved statistical significance for the change from baseline in glycated hemoglobin (HbA1c) versus placebo in all treatment groups at 24 weeks.  Placebo-adjusted HbA1c reduction was 0.52%, 0.94% and 1.00% for the 500 mg, 1000 mg and 1500 mg dose twice-daily, respectively. In this study, consistent, statistically significant decreases at the top two doses in the key secondary endpoints of fasting plasma glucose, glycated albumin and percentage of patients reaching a target HbA1c of less than 7% were also achieved.
• A statistically significant dose dependent (500 mg p=0.008,1000 mg p=0.0008, and 1500 mg p<0.0001) improvement of the homeostasis model assessment of beta-cell function (HOMA-B), a marker of beta cell function in fasting condition, was also observed. In addition, there was a significant decrease in two of the most relevant liver enzymes, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), which are considered biomarkers in liver disease. The ALT and GGT results are consistent with previously published data in animal models.
• Overall, the study showed that imeglimin was safe and well tolerated and the adverse event profile was consistent to what was observed in the U.S. and EU Phase 1 and 2 programs. No serious adverse events related to imeglimin were reported. There was no difference in the overall incidence of patients presenting with at least one treatment emergent adverse event between treatment and placebo groups. Of particular note, in this study, the safety and efficacy of imeglimin in patients with mild to moderate chronic kidney disease was similar to patients with normal renal function. In addition, no weight gain from Imeglimin was observed.
• Poxel plans to initiate the phase 3 program for imeglimin in Japan during the fourth quarter of this year.
• • On June 6, 2017, Poxel announced additional results from the imeglimin Phase 2b study conducted in Japan. In addition to the highly statistically significant top-line results for the primary and key secondary endpoint, the Company is reporting additional data from this study.
• In this study, a statistically significant decrease in the primary endpoint of HbA1c was observed along with consistent, statistically significant decreases in the key secondary endpoints of fasting plasma glucose, glycated albumin and percentage of patients reaching a target HbA1c of less than 7%. A statistically significant dose dependent (500 mg p=0.008,1000 mg p=0.0008, and 1500 mg p<0.0001) improvement of the homeostasis model assessment of beta-cell function (HOMA-B), a marker of beta cell function in fasting condition, was also observed and is consistent with previously published data. In addition, there was a significant decrease in two of the most relevant liver enzymes, alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), which are considered biomarkers in liver disease. The ALT and GGT results reflect an improvement of liver function and are consistent with previously published data in animal models. These data support Imeglimin’s unique dual mechanism of action of improving both insulin secretion and sensitivity, which are the two key defects that cause type 2 diabetes.
• In this study, imeglimin was safe and well tolerated and the adverse event profile was consistent to what was observed in the U.S. and EU Phase 1 and 2 programs. No serious adverse events related to imeglimin were reported. There was no difference in the overall incidence of patients presenting with at least one treatment emergent adverse event between treatment and placebo groups. Of particular note, in this study, the safety and efficacy of imeglimin in patients with mild to moderate chronic kidney disease was similar to patients with normal renal function. Furthermore, no weight gain from imeglimin was observed.
• As previously reported, the primary endpoint of the trial achieved statistical significance for the change from baseline in HbA1c versus placebo in all treatment groups at 24 weeks. In the study, placebo adjusted HbA1c reduction was 0.52%, 0.94% and 1.00% for the 500 mg, 1000 mg and 1500 mg dose twice-daily, respectively.
• Poxel anticipates meeting with the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan during the third quarter of this year, and pending feedback from the meeting, the Company anticipates advancing Imeglimin into a Phase 3 program in Japan during the fourth quarter of 2017.
• • On May 4, 2017, Poxel announced positive top line Phase 2b data results for imeglimin for the treatment of type 2 diabetes in Japan. The randomized, double-blind, placebo-controlled study of Imeglimin administered twice-daily for 24 weeks, demonstrated dose-dependent efficacy on two key measures of diabetes control in 299 Japanese patients.
• The trial achieved statistical significance (p<0.0001) for its primary endpoint of glycated hemoglobin A1c reduction versus placebo in all treatment groups at 24 weeks.
• In the study, hemoglobin A1c reduction was 0.52%, 0.94% and 1.00% for the 500 mg, 1000 mg and 1500 mg dose twice-daily, respectively. The level of reduction of hemoglobin A1c for Imeglimin was even more pronounced in the Japanese Phase 2b data than what has previously been shown in the U.S. and EU Phase 2b data.
• For the study’s key secondary endpoint of a decrease in Fasting Plasma Glucose (FPG), the top two imeglimin doses of 1000 mg and 1500 mg achieved statistical significance (p<0.0001) versus placebo at 24 weeks. Analyses of data for the additional secondary endpoints are ongoing. In this study, imeglimin was shown to be safe and well tolerated and the adverse event profile was consistent to what was observed in the U.S. and EU Phase 1 and 2 programs.
• • On June 30, 2016, Poxel announced that it has completed patient enrollment for the Phase 2b clinical trial of Imeglimin in type 2 diabetes patients in Japan. The dose-ranging, randomized, double-blind, placebo-controlled Phase 2b study in Japan has been designed to include approximately 300 naïve and pre-treated patients. Following recruitment and a six-to-ten week washout period, patients are randomized into 24 weeks of treatment. The primary endpoint of the trial is efficacy measured by change in glycated haemoglobin HbA1c concentrations. Poxel is now on track to report the Phase 2b results during the first half of next year. The company expects to initiate the Phase 3 development program in Japan during the second half of 2017.
• Poxel’s Imeglimin program in Japan is being supported by a Japanese Scientific Advisory Board (SAB) in diabetes research. The SAB members have worked with Poxel in guiding the Company’s regulatory interactions and clinical development plans. The members include Pr. M. Kasuga, President of the National Center for Global Health and Medicine in Tokyo;  Pr. K. Ueki, Professor of the Department of Molecular Sciences on Diabetes of Tokyo University; and  Pr. H. Watada, Professor of the Department of Medicine, Metabolism and Endocrinology of the Juntendo University in Tokyo.
• • On December 14, 2015, Poxel announced that the first Phase 2b clinical trial site for Imeglimin has been opened in Japan, starting the planned rapid late-stage clinical development program for Imeglimin in the Japanese market. The first trial site has been opened, thereby kicking off the Phase 2b study of Imeglimin in Japan, the second largest single market for type 2 diabetes. Supervised by Professor Ueki, Department of Diabetes and Metabolic Disease, University of Tokyo, this double-blinded, placebo-controlled Phase 2b trial has been designed to include up to 300 naïve and pre-treated patients. Primary endpoint of the trial will be efficacy as measured by change in glycated haemoglobin HbA1c concentrations. Poxel expects data from this trial in the first half of 2017. Additionally, Poxel has also already started regulatory discussions with the PMDA for a subsequent Phase 3 program design and protocol.

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