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Clinical Trials

Date: 2017-08-28

Type of information: Presentation of results at a congress

phase: preclinical

Announcement: presentation of results at the European Society of Cardiology (ESC) Congress 2017

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, muscle, and the pancreas and has therefore a distinct mode of action compared to existing treatments for Type 2 diabetes. In that, it looks like the best partner to complement other treatments. Imeglimin phase 2a monotherapy results were published in Diabetes, Obesity and Metabolism in April 2012.
  • Imeglimin is the first clinical candidate in a new chemical class of oral agents called the Glimins. Imeglimin has a unique mechanism of action (MOA) that targets mitochondrial bioenergetics. Imeglimin acts on the three main target organs involved in glucose homeostasis: the liver, muscle, and the pancreas. This MOA has the potential for glucose lowering benefits, as well as the potential to prevent endothelial dysfunction, which can provide protective effects on micro- and macro-vascular defects induced by diabetes. The additional protective effect on beta-cell survival and function may lead to a delay in disease progression. This unique mode of action compared to existing treatments for type 2 diabetes makes Imeglimin a prime candidate in all stages of the current anti-diabetic treatment paradigm, including monotherapy or as an add-on to other glucose lowering therapies for the treatment of patients with type 2 diabetes.

Disease: type 2 diabetes

Therapeutic area: Metabolic diseases

Country:

Trial details:

Latest news:

  • • On August 28, 2017, Poxel announced that preclinical imeglimin data showed a benefit in peripheral and coronary vascular function that was associated with an improvement of cardiac function (diastolic dysfunction), in a rat model of metabolic syndrome. These data were presented in poster P577 in the chronic heart failure session at the European Society of Cardiology (ESC) Congress. These results positively reinforce the data recently presented at the American Diabetes Association (ADA) Scientific Session and further strengthen imeglimin’s profile as a novel treatment for type 2 diabetes (See below). The preclinical study in a rat model of metabolic syndrome was designed to investigate imeglimin’s protective effects on diabetic cardiomyopathy. Obese Zucker fa/fa rats, which are known to develop cardiac dysfunction very similar to cardiomyopathy observed in type 2 diabetes patients, were treated with150 mg/kg imeglimin twice-daily for 9 and 90 days. The effects of imeglimin were evaluated through key parameters of both left ventricular (LV) function (echocardiography, MRI) and hemodynamics (LV catheterization). Endothelium-dependent relaxation of coronary and peripheral arteries was also evaluated. The study demonstrated that very early in the course of treatment, imeglimin significantly improved vascular function, which was strongly impaired in this rat model. Concomitantly, all the parameters of LV diastolic dysfunction as well as myocardial perfusion were improved compared to the untreated controls, suggesting a clear beneficial effect on the progression of diabetic cardiomyopathy. In addition, imeglimin was also shown to improve glucose tolerance in this model.
  • • On June 12, 2017, Poxel announced that new preclinical imeglimin data showing protective effects for diabetic cardiomyopathy in a rat model of metabolic syndrome was presented in a poster session at the 77th American Diabetes Association (ADA) Scientific Session at the San Diego Convention Center in San Diego, California. The preclinical study in a rat model of metabolic syndrome was designed to investigate imeglimin’s protective effects on diabetic cardiomyopathy. Obese Zucker fa/fa rats, which are known to develop cardiac dysfunction very similar to cardiomyopathy observed in type 2 diabetes patients, were treated with 150 mg/kg imeglmin twice-daily for 9 and 90 days. The effects of imeglimin were evaluated through key parameters of both left ventricular (LV) function (echocardiography, MRI) and hemodynamic (LV catheterization). The study demonstrated that very early in the course of treatment, imeglimin strongly improved all the parameters of LV diastolic dysfunction in the rats compared to untreated controls, suggesting a clear beneficial effect on the progression of diabetic cardiomyopathy.
  • In addition, imeglimin was also shown to improve glucose tolerance in this model. These results are consistent with its mechanism of action and with previous data showing protective effects on endothelial dysfunction, an early sign of cardiovascular complication, in diabetic animal models (EASD 2016). These newly demonstrated effects on diastolic dysfunction, in a model of metabolic syndrome, further strengthen Imeglimin’s therapeutic profile in type 2 diabetes where heart failure remains a key complication with limited therapeutic options.
  • • On May 22, 2017, Poxel announced the presentation of additional preclinical mechanistic data on imeglimin’s mechanism of action in insulin secretion in response to glucose. The data were presented in an oral presentation at the 9th Scientific Meeting of the Asian Association for the Study of Diabetes (AASD) in Nagoya, Japan.  The oral presentation titled “Imeglimin Increases Insulin Secretion in Response to Glucose as a Unique Mechanism of Action Depending on NAD Synthesis,” provides data that further strengthens the understanding of imeglimin’s mechanism of action resulting in an improvement of insulin secretion in response to glucose. This response has been shown in different preclinical models of diabetes as well as in type 2 diabetic patients. This increase in insulin secretion in response to glucose was demonstrated to be dependent on imeglimin’s effect on nicotinamide adenine dinucleotide (NAD) biosynthesis, a crucial component of mitochondrial function.
  • In addition to improving beta cell function, imeglimin has also been shown to preserve the beta-cell mass, which could potentially delay disease progression. Furthermore, a synergistic effect between imeglimin and GLP-1 on insulin secretion in response to glucose was observed, highlighting a distinct mode of action compared to GLP-1. In addition to being a prime candidate for monotherapy, these data also support use of Imeglimin in combination therapy with GLP-1 agonists and DPPIV inhibitors.
  • • On June 13, 2016, Poxel announced the presentation of novel data on imeglimin. The results were discussed during two poster presentations at the American Diabetes Association’s 76th Scientific Sessions in New Orleans, Louisiana. Both preclinical studies highlighted Imeglimin’s novel and unique mechanism of action and indicated the specific pathways through which imeglimin improves insulin secretion and action. The first preclinical study confirmed imeglimin’s beneficial effect on insulin sensitivity in a streptozotocin-induced diabetic rat model. After both acute and chronic treatment, imeglimin was observed to improve glucose tolerance and to improve overall insulin sensitivity during a euglycemic hyperinsulinemic clamp, with a significant effect on hepatic insulin sensitivity, confirming previous results observed in various preclinical models, as well as in type 2 diabetes patients.
  • In the second preclinical study, imeglimin was observed for the first time to increase glucose stimulated insulin secretion through a unique MoA that targets NAD synthesis. The treatment of isolated islet cells from a diabetic rat model with Imeglimin was observed to lead to a significant increase in NAD content, a crucial component of mitochondrial function. Poxel has previously demonstrated that Imeglimin increases glucose stimulated insulin secretion in vivo and in type 2 diabetes patients. The new results highlighted at the ADA 76th Scientific Sessions provide additional insight into the underlying mechanisms. Posters presented at the ADA 76th Scientific Sessions: Imeglimin Improves Insulin Sensitivity in an Adult STZ Rat Model and  Imeglimin Increases Insulin Secretion in Response to Glucose as a Unique Mechanism of Action Depending on NAD Synthesis
  • • On January 18, 2016, Poxel announced that Nature's Cell Death Discovery has published an article showing that imeglimin prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration. Imeglimin protective effects have been studied on hyperglycemia-induced death of human endothelial cells (HMEC-1). These cells were incubated in several oxidative stress environments which led to mitochondrial permeability transition pore (PTP) opening, cytochrome c release and cell death. Imeglimin treatment was able to prevent these events.
  • • On November 2, 2015, Poxel announced that the Company’s presentation, ‘Imeglimin, a New Mitochondria Targeted Agent for Type 2 Diabetes Treatment’, was selected as the Best Short Oral Communication at the 6th World Congress on Targeting Mitochondria in Berlin, Germany, 30 October, 2015. The presentation was awarded for providing insights into the unique mitochondrial mechanism of action for Imeglimin, Poxel’s first-in-class oral anti-diabetic agent leading to its ability to increase both glucose-dependent insulin secretion and sensitivity, the two key defects of type 2 diabetes.
  • • On October 30, 2015, Poxel announced the presentation of preclinical data on imeglimin at the 6th World Congress on Targeting Mitochondria. Imeglimin has been proven to have a beneficial effect on both insulin sensitizing and insulin secretion defects in type 2 diabetes. The new data demonstrate the drug candidate’s positive impact on the mitochondrial respiratory chain, providing critical insights to Imeglimin’s molecular mechanism of action. In detail, the data demonstrate Imeglimin’s ability to improve mitochondria respiratory chain function, triggering an improvement of insulin and glucose sensing in the target tissues, muscle, liver and pancreas, which translates into an improvement of both insulin sensitizing and insulin secretion defects in patients suffering from type 2 diabetes.
  • This results in metabolic benefits to patients, namely improved insulin action in peripheral tissues and insulin secretion, in a glucose-dependent manner. These benefits translate into a significant reduction of Hemoglobin A1c and other glycemic parameters such as fasting and post-prandial glucose, as Poxel has demonstrated in seven Phase 2 trials to date. The data presented at the World Congress on Targeting Mitochondria also demonstrate Imeglimin’s ability to delay opening of the mitochondrial permeability transition pore (mPTP), preventing apoptotic cell death induced by various forms of oxidative stress including excess glucose, as shown in endothelial cells and human pancreatic islet cells exposed to high glucose concentrations.
  • • On October 7, 2013, Poxel announced that during a human hyperglycemic clamp trial, imeglimin, a novel compound in development to treat Type 2 diabetes, increases insulin secretion in response to glucose, confirming previous preclinical and clinical results. Imeglimin acts directly on the three main organs affected by type 2 diabetes: the pancreas, the liver and the muscle. Poxel’s objective was to confirm, in diabetic patients, Imeglimin’s impact on glucose-stimulated insulin secretion, using the reference method of hyperglycemic clamp technique, including arginine stimulation to assess maximal secretory capacity. This clinical pharmacology trial was a randomized, double-blind, placebocontrolled, parallel-group study investigating insulin secretion after Imeglimin chronic treatment. The trial included 30 patients; 15 per group. Results showed that Imeglimin met the primary and secondary endpoints, with a statistically significant increase in the incremental area under the curve of insulin response to glucose (iAUC0-45min insulin) and a statistically significant increase in the incremental area under the curve of C-peptide and proinsulin response (iAUC0-45min C-peptide, iAUC0-45min proinsulin), in comparison to placebo. The full study results will be submitted soon to a diabetes peer-reviewed journal.

Is general: Yes