Imeglimin - Japan/Asia

A Novel Drug Candidate for Type 2 Diabetes with a Differentiated Mechanism of Action

Imeglimin

Our most advanced drug candidate, Imeglimin, is a novel, diabetes treatment that has successfully completed Phase 3 development in Japan. 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 reduce insulin resistance. 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 decrease cardiovascular risk factors. 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, Imeglimin can simultaneously target the pancreas, muscles, and the liver, which are the key organs and tissues involved in type 2 diabetes pathophysiology. 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.

In Japan, together with our partner Sumitomo Dainippon Pharma, we completed the Phase 3 Trials of Imeglimin for Efficacy and Safety, or TIMES, clinical program in December 2019. This program includes three pivotal studies to evaluate the efficacy and safety of Imeglimin in approximately 1,100 patients. The Japanese New Drug Application has been submitted in July 2020.

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 Japanese New Drug Application has been submitted by Sumitomo Dainippon Pharma in July 2020, with first product launch in Japan targeted for 2021, if approved.

In October 2017, together with our partner Sumitomo Dainippon Pharma, we launched the TIMES program in Japan, including three Phase 3 trials, for the development and commercialization of Imeglimin 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.

TIMES 1

In April 2019, we announced topline results from the TIMES 1 trial; this trial met its primary and secondary endpoints. 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.

TIMES 2

In December 2019, we announced topline results from the 52-week, open label, parallel-group TIMES 2 trial, a trial that 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. The TIMES 2 trial, which was open label and not placebo-controlled, was observed to show an HbA1c decrease from baseline ranging from 0.92% to 0.12% with Imeglimin as an add on to several existing hypoglycemic 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)

TIMES 3

In June 2019, we announced topline results from the first 16-week portion of the TIMES 3 trial. This double-blind, placebo-controlled, randomized part of the trial evaluated efficacy and safety of Imeglimin versus placebo in 215 patients. In this trial, Imeglimin at a dosage of 1,000 mg was orally administered twice daily in combination with insulin in Japanese patients with type 2 diabetes associated with insufficient glycemic control on insulin therapy an compared to patients administered placebo and insulin.

In this trial, the overall tolerability 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 addition, the adverse event profile was similar to placebo and consistent with what was observed in the TIMES 1 monotherapy trial and other Imeglimin clinical trials.

In November 2019, we announced topline results from the 36-week, open-label extension period of the TIMES 3 trial, a trial that evaluated efficacy and safety of Imeglimin in combination with insulin. In this part of the 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 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).

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 are expected to grow to over $4 billion by 2020. The Japanese diabetes market has pricing and reimbursement characteristics similar to the United States and has shown 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.

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 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 diabetic medications. For China and other East and Southeast Asian countries that our partner Sumitomo Dainippon Pharma has rights to, they plan to meet with regulatory authorities to discuss development and the ability to leverage data generated in Japan and other countries.