An Approved Novel Drug for Type 2 Diabetes with a Differentiated Mechanism of Action
A new drug application for TWYMEEG® Tablets 500mg (International Nonproprietary Name (INN): Imeglimin hydrochloride), for the treatment of type 2 diabetes, was approved in Japan on June 23, 2021. Japan is the first country in the world to approve Imeglimin.
The TWYMEEG approval is supported by numerous preclinical and clinical studies, including the Phase 3 TIMES (Trials of IMeglimin for Efficacy and Safety) program managed jointly by Poxel and Sumitomo Dainippon Pharma, which included three pivotal trials to evaluate TWYMEEG’s efficacy and safety in over 1,100 patients. In all three trials, TWYMEEG met its primary endpoints and objectives and was observed to exhibit a favorable safety and tolerability profile.
We believe it is the only oral compound with a dual mechanism of action that is directly designed both to increase insulin secretion in response to glucose and to improve insulin resistance. The mitochondrion is the power station of the cell and its dysfunction is implicated in the pathophysiology of type 2 diabetes. By targeting the mitochondria – where dysfunction is a key feature of diabetes pathophysiology, Imeglimin can simultaneously promote insulin secretion from pancreatic b-cells in response to elevated glucose while also alleviating insulin resistance as summarized in the figure below.
Adapted from: Hallakou-Bozec et al, Mechanism of action of imeglimin – a novel therapeutic agent for type 2 diabetes; Diabetes Obes Metab 2021, doi.org/10.1111/dom.14277
As a consequence of these effects, we believe that Imeglimin has the potential to slow disease progression and provide therapeutic options to patients who no longer respond to current treatments. It may also have the potential to complement existing treatments and to impact cardio-renal complications of diabetes.
To date, Imeglimin has been evaluated in 28 clinical trials and administered to an aggregate of 400 non-diabetic subjects and over 1,800 type 2 diabetes patients in the US, Europe and Japan. Imeglimin has been well-tolerated in these trials and we have observed statistically significant reductions of hemoglobin A1c, or HbA1c, and other glycemic parameters versus placebo.
 Dosage and administration: In general, for adults, 1,000 mg of Imeglimin hydrochloride is orally administered twice daily in the morning and evening.
Japan Market Opportunity
According to Decision Resources, Japan is the second largest diabetes market worldwide, behind the United States, with a compounded annual growth rate of more than 18% between 2008 and 2012, and could grow by more than 20% by 2023. It is estimated that there are currently over 10 million diabetic patients in Japan and sales in this market exceeded $4 billion in 2020. The Japanese diabetes market has specific pricing and reimbursement characteristics that could allow a rapid market uptake for new innovative products. We believe that this market trend is likely to continue given that the Japanese government has identified diabetes as a target disease in its ten-year plan for National Health Promotion
Imeglimin Phase 3 TIMES Program in Japan
Across all three pivotal TIMES trials, Imeglimin was observed to reduce HbA1c as a monotherapy, in combination with insulin and in combination with existing therapies available in Japan.
The TIMES program consists of the following three trials, each performed with the dose of 1,000 mg orally administered twice-a-day, or bid.
In this randomized, double-blind, placebo-controlled monotherapy trial, 1,000 mg of Imeglimin was orally administered twice-daily versus placebo for 24 weeks in 213 Japanese patients.
As shown above, the TIMES 1 trial was observed to meet its primary endpoint, with a statistically significant (p<0.0001) HbA1c placebo-corrected mean change from baseline of -0.87%, as well as its main secondary endpoints including Fasting Plasma Glucose. Safety and tolerability were good, similar to placebo.
This 52-week, open label, parallel-group TIMES 2 trial evaluated the long-term safety and efficacy of Imeglimin in 714 Japanese patients with type 2 diabetes. In this trial, 1,000 mg of Imeglimin was orally administered twice daily in combination with existing antihyperglycemic agents. Imeglimin was observed to show an HbA1c decrease from baseline ranging from -0.56 to -0.92% with Imeglimin as an add-on to several existing oral antihyperglycemic agents, as shown in the chart below:
Of particular note, Imeglimin was observed to demonstrate robust efficacy benefits in combination with DPP-4 inhibitors, the market leader in Japan and prescribed to approximately 80% of treated type 2 diabetes patients. (IQVIA data FY2016 and NDB data FY2016).
The first 16-week portion of this double-blind, placebo-controlled, randomized trial evaluated efficacy and safety of Imeglimin versus placebo in 215 patients when added to insulin therapy in Japanese patients with type 2 diabetes associated with insufficient glycemic control.
Here, the overall tolerability and adverse event profile of Imeglimin was observed to be similar to placebo. A similar number of patients experienced hypoglycemia with Imeglimin compared to the placebo group with a fixed insulin daily dose as defined in the protocol. There were no severe hypoglycemia events and the majority of the hypoglycemia events reported were mild.
In the 36-week, open-label extension period of the TIMES 3 trial, 208 patients who completed the first 16 weeks of the study were treated with Imeglimin as well as insulin therapy. As shown in the charts below, the open-label extension period showed a sustained mean HbA1c decrease from baseline of 0.64% in patients receiving Imeglimin for 52 weeks (Imeglimin and insulin for 16 weeks following by Imeglimin and insulin for 36 weeks) and 0.54% in patients receiving Imeglimin and insulin for the last 36 weeks only (placebo and insulin for 16 weeks followed by Imeglimin and insulin for 36 weeks).
China Market Opportunity
According to IQVIA, there were approximately 112 million adults diagnosed with type 2 diabetes in China in 2017 and the prevalence is expected to grow by approximately 1.7% per year. In 2017, sales of type 2 diabetes therapies were approximately $3 billion, with oral drug sales representing approximately 50% of that total. China represents a growing commercial opportunity for Imeglimin, if approved.
We believe that Imeglimin has the potential to target the estimated 29 million patient population in China being treated with Western drugs, as well as the sizeable patient population with co-existing chronic kidney disease (CKD). In line with China’s national plan for non-communicable disease prevention and treatment, we also expect more type 2 diabetes patients to have access to antidiabetic medications. For China and other East and Southeast Asian countries that our partner Sumitomo Dainippon Pharma has rights to, they plan to discuss the development plan with regulatory authorities and the ability to leverage data generated in Japan and other countries.
For the United States, Europe and all other countries not covered by the Sumitomo Dainippon Pharma agreement, Poxel regained Imeglimin rights in Q1 2021 and is considering various options to advance Imeglimin in those countries. Its previous partner, Metavant, a subsidiary of Roivant, had been in discussions with the U.S. Food and Drug Administration, which has provided a pathway forward for Imeglimin in a Phase 3 plan which would evaluate type 2 diabetes patients with chronic kidney disease (CKD) stages 3b/4. Results from a pharmacokinetics, or PK, and pharmacodynamics, or PD, trial of Imeglimin in this population showed that Imeglimin was well-tolerated with a safety profile consistent with that observed in previous trials to date.
Approximately 2.4 million adults in the United States have type 2 diabetes and chronic kidney disease (CKD) stages 3b/4, according to the Centers for Disease Control and Prevention, and these patients have increased cardiovascular, or CV risk and challenging glucose management requirements. We believe that there is a need for a new treatment for patients with type 2 diabetes and advanced CKD, one that can provide efficacy and a safety profile with significantly reduced hypoglycemia risk.
Type 2 diabetes is also the leading cause of CKD; treatment of type 2 diabetes in patients with CKD is more complicated and options are restricted. Most antihyperglycemic medications may be used to treat type 2 diabetes in patients with mild CKD; however, CKD stages 3b/4 present challenges as medications are either not advised, are contraindicated, or require dose adjustments in patients with more advanced renal impairment. These limitations include: 1) safety risks with increasing severity of renal impairment; 2) loss of efficacy (glycemic control) with worsening CKD; and 3) the need for dose adjustment with increasing severity of renal impairment.
As a consequence of these limitations, the segment of type 2 diabetes patients with CKD stages 3b/4 currently face limited therapeutic options for the management of their disease. Imeglimin’s mechanism of action, supported by non-clinical data and clinical findings, offers the potential for effective glycemic control in patients with CKD stages 3b/4.