Long‐term safety and efficacy of imeglimin as monotherapy or in combination with existing antidiabetic agents in Japanese patients with type 2 diabetes (TIMES 2): A 52‐week, open‐label, multicentre phase 3 trial

1 INTRODUCTION

Type 2 diabetes is a widespread disease, affecting more than 500 million people worldwide.1 It is characterized by chronic hyperglycaemia associated with various macrovascular and microvascular complications. Diabetes is a growing public health issue worldwide; Japan is one of the nations most greatly impacted, with 18.7% of men and 9.3% of women ‘in whom diabetes is strongly suspected’.2 In Japan, diabetes has also been identified as a healthcare priority by the Ministry of Health, Labour and Welfare.2

Imeglimin is a first-in-class novel oral antidiabetic agent to treat type 2 diabetes that was recently approved in June 2021 as a new oral antidiabetic drug by the Pharmaceuticals and Medical Devices Agency in Japan. Its mode of action is distinct from all other antihyperglycaemic classes; imeglimin's underlying mechanism involves the targeting of mitochondrial bioenergetics3, 4 and improving mitochondrial function. Imeglimin modulates mitochondrial respiratory chain complex activities while decreasing reactive oxygen species production.5 Imeglimin has been shown to amplify glucose-stimulated insulin secretion by improving β-cell glucose responsiveness in patients with type 2 diabetes6 and to improve insulin sensitivity in a rodent model of diabetes, allowing for normalization of glucose tolerance.5 Recently, imeglimin has been shown to prevent the death of human endothelial cells by inhibiting opening of the mitochondrial permeability transition pore—a known cause of cell death—without inhibiting mitochondrial respiration7; this finding suggests the potential for end organ protection (e.g. kidney or heart).

In a phase 2, dose-ranging trial conducted in Japanese subjects, the dose of imeglimin 1000 mg twice-daily (BID) as monotherapy showed optimal efficacy (−0.94% HbA1c reduction vs. placebo) and favourable safety and tolerability.8 This dose was selected for the phase 3 programme in Japan named the Trial for Imeglimin Efficacy and Safety (TIMES). The completed phase 3 programme included three pivotal studies: TIMES 1 (assessing the efficacy of imeglimin monotherapy),9 TIMES 2 (reported in this article), and TIMES 3 (assessing the long-term safety and efficacy of imeglimin as an add-on to insulin for 1 year). The efficacy of imeglimin was confirmed in TIMES 1, in which 1000 mg BID as monotherapy for 6 months achieved a significant HbA1c reduction of −0.87% versus placebo.9 In addition, imeglimin has been previously studied in two 12-week, add-on, phase 2 studies, to metformin and sitagliptin, conducted in Caucasian subjects with imeglimin at the dose of 1500 mg BID.10, 11 After 12 weeks of treatment, imeglimin decreased HbA1c versus placebo by 0.72% when combined with sitagliptin and by 0.44% when combined with metformin.10, 11

The TIMES 3—add on to insulin—trial has been completed but is not yet published. TIMES 2 long-term (52 weeks) efficacy and safety of imeglimin as monotherapy or as an add-on to other antidiabetic drugs is described herein and has not been previously published.

This article reports the findings from the largest of the three phase 3 trials in Japan (TIMES 2), which assessed 1000 mg imeglimin BID long-term monotherapy and long-term combination therapies in Japanese patients with type 2 diabetes insufficiently controlled with diet and exercise.

2 RESEARCH DESIGN AND METHODS 2.1 Study design

This was a phase 3, long-term (52-week), open-label, multicentre trial (TIMES 2) at 68 sites in Japan. The study protocol was approved by institutional review boards at each site according to local practice. This study was conducted in accordance with the International Conference on Harmonized Tripartite Guideline for Good Clinical Practice, the Japanese Good Clinical Practice regulations (Ministry of Health and Welfare Ordinance No. 28; 27 March 1997), and with the Helsinki Declaration of 1964, as revised in 2013. Written informed consent was obtained from all participants before the beginning of any study-related activities.

Japanese adults aged 20 years or older with type 2 diabetes treated with diet/exercise alone or together with a single antidiabetic monotherapy were enrolled in this 52-week, long-term study.

The inclusion criteria for the patients who received imeglimin long-term monotherapy included the following: treated with diet and exercise without an antihyperglycaemic agent during at least 12 weeks prior to screening, HbA1c of 7.0%-10.0%, and an estimated glomerular filtration rate (eGFR; estimated with the Japanese modification of diet in renal disease [MDRD] equation) greater than or equal to 50 ml/min/1.73m2.

Patients treated with diet and exercise plus treatment with an α-glucosidase inhibitor (AGI), biguanide (BIG), dipeptidyl peptidase-4 inhibitor (DPP4-I), glinide (GLIN), injectable glucagon-like peptide-1 receptor agonist (GLP1-RA), sodium-glucose co-transporter-2 inhibitor (SGLT2-I), sulphonylurea (SU), or thiazolidinedione (TZD), were included in the long-term combination groups. Type, dose, and regimen of background antidiabetic therapy were to be unchanged for at least 12 weeks prior to screening. Other inclusion criteria for combination therapy included an HbA1c of 7.5%-10.5% and an eGFR superior or equal to 60 ml/min/1.73m2.

Key exclusion criteria for all groups included insulin therapy in the 30 days before screening, heart failure (New York Heart Association class III or IV), or any acute coronary or cerebrovascular events in the 24 weeks before screening.

2.2 Procedures

After a screening period, all participants received oral placebo BID during a 2-week, single blind, run-in period. From the start of the open-label period, participants received 1000 mg imeglimin BID for 52 weeks, followed by a 1-week, follow-up period. For the long-term combination therapy groups, patients who had been using a background antidiabetic therapy according to the package insert of the drug continued to receive the same dose/regimen of this drug in addition to 1000 mg imeglimin BID until the end of the treatment period. Patients were assessed (physical examination, vital signs, and safety and efficacy assessments) at week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, at the end of treatment at week 52, and at follow-up 1 week after the last dose.

The trial implemented complete follow-up for all participants, including those who discontinued treatment prematurely, meaning that all participants remained in the study, except in any case of withdrawal of consent.

Participants with unacceptable hyperglycaemia (i.e. any fasting plasma glucose [FPG] value >250 mg/dl (>13.9 mmol/L) from baseline to week 4; FPG > 240 mg/dl (>13.3 mmol/L) from week 4 to week 8; and/or any HbA1c value of at least 10.0% for the long-term monotherapy group and ≥10.5% for the long-term combination groups from week 8 to week 52) should discontinue the study drug and a rescue therapy should be initiated. The initiation, choice, and dose of rescue medication used were at the discretion of the investigator, according to local prescribing information, but insulin was not allowed. Any increase in the dosing of the background antidiabetic therapy was considered as a rescue medication. In any case of rescue medication, participants discontinued treatment prematurely but continued the study.

2.3 Outcomes

The primary objective of this study was to assess the safety of imeglimin as monotherapy and combination therapy. Safety endpoints included vital signs, physical examination, 12-lead ECG, clinical laboratory variables, and adverse events (preferred terms coded according to the Medical Dictionary for Drug Regulatory Activities [MedDRA] version 20.1). Patients were asked to check their glucose levels, using self-monitoring blood glucose (SMBG) devices, at least twice a week. Events of hypoglycaemia were categorized into asymptomatic hypoglycaemia (an event not accompanied by typical symptoms of hypoglycaemia but with a measured capillary or plasma glucose <3.9 mmol/L), probable symptomatic hypoglycaemia (an event during which symptoms typical of hypoglycaemia are not accompanied by a capillary or plasma glucose determination), documented symptomatic hypoglycaemia (an event during which typical symptoms of hypoglycaemia are accompanied by a measured capillary or plasma glucose concentration <3.9 mmol/L), and severe hypoglycaemia (an event requiring the assistance of another person to actively administer carbohydrates, glucagon, or to take other corrective actions).12

Secondary efficacy endpoints included the change from baseline in HbA1c at week 52 (assessed at a central laboratory), the percentage of responders as defined by the percentage of patients reaching a target HbA1c of less than 7.0% at week 52, and the percentage of responders as defined by the percentage of patients with a relative decrease of at least 7% of baseline HbA1c at week 52. Efficacy was also analysed in subgroups of patients according to baseline age (<65 and ≥65 years) and baseline chronic kidney disease (CKD) stage (CKD stage 1, 2, and 3a). Other secondary efficacy endpoints included the percentage of patients requiring rescue medication and change from baseline to week 52 in FPG.

2.4 Statistical analysis

For the long-term imeglimin monotherapy group, the sample size was determined to be 125 patients to collect data from 100 patients, as required by the Japanese Guidelines for Clinical Evaluation of Hypoglycemic Agents (revised draft),13 assuming a drop-out rate of 20% during the open-label treatment period.

For the long-term combination therapy arms, in accordance with the guidance,13 and based on the knowledge of each available drug and their use as monotherapy in the Japanese population, the number of patients in each combination therapy was determined to be 63 to collect data from 50 patients (assuming a drop-out rate of 20%) in each combination group, except for SUs, where 125 patients was determined to be necessary to collect data from approximately 100 patients.

Safety analysis was performed on all as-treated patients who received at least one dose of the study drug and was descriptive in nature. Adverse events reported included those which occurred between first drug intake (open-label visit) and 7 days after cessation of drug administration, or which started before drug intake and worsened during the open-label treatment period.

Efficacy analyses were primarily performed on the safety population (i.e. patients who received at least one administration of imeglimin). Measurements after imeglimin discontinuation were censored 7 days after imeglimin discontinuation (i.e. replaced by missing data in the primary efficacy analysis). The primary efficacy analysis was performed using a mixed model for repeated measures (MMRM) fitted within each treatment arm. The MMRM included visit (categorical variable from week 4 to week 52), baseline HbA1c as a continuous covariate, and a term for baseline HbA1c by visit interaction. Least square means of change from baseline along with their 95% confidence intervals (CIs) were estimated by visit in the MMRM model fitted separately within each treatment arm. Analyses were performed using SAS version 9.4. This trial was registered on JAPIC (JapicCTI-173782).

3 RESULTS 3.1 Patient disposition and baseline characteristics

The TIMES 2 trial was carried out from 12 January 2018 to 23 October 2019. Of the 981 patients who provided signed informed consent, 714 entered the open-label treatment period and received at least one dose of imeglimin, including 134 patients with imeglimin long-term monotherapy, and 580 patients with imeglimin long-term combination therapy: 64 patients with an AGI, 64 patients with a BIG, 63 patients with a DPP4-I, 64 patients with a GLIN, 70 patients with a GLP1-RA, 63 patients with an SGLT2-I, 127 patients with an SU, and 65 patients with a TZD. Eighty-two (11.5%) patients prematurely discontinued treatment, including 10 (7.5%) with imeglimin long-term monotherapy, and 72 patients with imeglimin long-term combination therapy: four (6.2%) with an AGI, 11 (17.2%) with a BIG, eight (12.7%) with a DPP4-I, six (9.4%) with a GLIN, 19 (27.1%) with a GLP1-RA, three (4.7%) with an SGLT2-I, 17 (13.4%) with an SU, and four (6.2%) with a TZD. The main reason for premature treatment discontinuation was withdrawal of consent for imeglimin long-term monotherapy and for long-term combination with an AGI/GLIN/SU/SGLT2-I, or, occurrence of a treatment emergent adverse event (TEAE) or serious TEAE for long-term combination with a BIG/DPP4-I/GLP1-RA/TZD.

Demographic and baseline characteristics in each treatment group are shown in Table 1. Mean age ranged from 56.6 to 63.6 years. Baseline HbA1c ranged from 7.92% to 8.70%.

TABLE 1. Demographic and baseline characteristics Imeglimin monotherapy Combination with AGI Combination with BIG Combination with DDP4-I Combination with GLIN Combination with SGLT2-I Combination with SU Combination with TZD Combination with GLP1-RA Number of patients 134 64 64 63 64 63 127 65 70 Sex Female 28 (20.9%) 16 (25.0%) 18 (28.1%) 24 (38.1%) 21 (32.8%) 18 (28.6%) 26 (20.5%) 11 (16.9%) 26 (37.1%) Male 106 (79.1%) 48 (75.0%) 46 (71.9%) 39 (61.9%) 43 (67.2%) 45 (71.4%) 101 (79.5%) 54 (83.1%) 44 (62.9%) Age (y) 59.4 (10.8) 56.6 (12.0) 57.6 (10.8) 63.6 (8.95) 58.1 (10.8) 57.1 (10.0) 60.3 (10.4) 57.1 (10.0) 57.4 (11.0) Age group (y) <65 86 (64.2%) 41 (64.1%) 47 (73.4%) 28 (44.4%) 42 (65.6%) 45 (71.4%) 76 (59.8%) 44 (67.7%) 46 (65.7%) ≥65 48 (35.8%) 23 (35.9%) 17 (26.6%) 35 (55.6%) 22 (34.4%) 18 (28.6%) 51 (40.2%) 21 (32.3%) 24 (34.3%) HbA1c (%) 7.92 (0.705) 8.44 (0.758) 8.22 (0.618) 8.28 (0.653) 8.46 (0.747) 8.52 (0.725) 8.69 (0.824) 8.70 (0.889) 8.64 (0.728) Diabetes duration (y) 5.9 (6.0) 7.5 (6.8) 9.0 (6.3) 8.0 (5.6) 7.9 (4.9) 9.6 (5.7) 10.6 (6.6) 9.3 (6.6) 10.7 (5.9) Body weight (kg) 71.3 (13.7) 73.1 (16.9) 72.6 (11.4) 65.0 (12.8) 68.3 (13.8) 73.1 (16.6) 70.7 (13.7) 75.5 (16.0) 71.0 (15.1) BMI (kg/m2) 25.7 (3.9) 26.4 (4.6) 26.3 (3.7) 24.6 (3.4) 25.3 (4.6) 26.5 (4.4) 25.6 (4.2) 27.2 (4.9) 26.3 (4.3) eGFR (MDRD; ml/min/1.73m2) 75.5 (15.0) 78.9 (15.5) 81.4 (14.7) 77.2 (11.6) 80.2 (13.0) 81.5 (13.1) 77.3 (11.5) 78.3 (12.6) 80.0 (14.6) CKD stage CKD stage 1 24 (17.9%) 13 (20.3%) 15 (23.4%) 11 (17.5%) 14 (21.9%) 21 (33.3%) 18 (14.2%) 15 (23.1%) 17 (24.3%) CKD stage 2 89 (66.4%) 51 (79.7%) 49 (76.6%) 52 (82.5%) 50 (78.1%) 42 (66.7%) 109 (85.8%) 50 (76.9%) 53 (75.7%) CKD stage 3a 21 (15.7%) 0 0 0 0 0 0 0 0 Note: Data are mean (SD) or n (%). Abbreviations: AGI, α-glucosidase inhibitor; BIG, biguanide; BMI, body mass index; CKD, chronic kidney disease; DDP4-I, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLIN, glinide; GLP1-RA, glucagon-like peptide-1 receptor agonist; MDRD, modified diet in renal disease; SGLT2-I, sodium glucose cotransporter 2 inhibitor; SU, sulphonylurea; TZD, thiazolidinedione. 3.2 Safety

Overall, during the 52-week, open-label treatment period, the percentage of patients experiencing at least one TEAE was 75.5% (Table 2). Of note, this overall TEAE rate was similar to the rate observed in either the imeglimin (62%-73%) or placebo (68%) arms of the 24-week Japanese phase 2b trial.8

TABLE 2. Patients with adverse events Imeglimin monotherapy, n (%) [95% CI] Combination with AGI, n (%) [95% CI] Combination with BIG, n (%) [95% CI] Combination with DDP4-I, n (%) [95% CI] Combination with GLIN, n (%) [95% CI] Combination with SGLT2-I, n (%) [95% CI] Combination with SU, n (%) [95% CI] Combination with TZD, n (%) [95% CI] Combination with GLP1-RA, n (%) [95% CI] Number of patients 134 64 64 63 64 63 127 65 70 Any TEAEs 98 (73.1%) [65.6-80.6] 33 (51.6%) [39.4-63.8] 48 (75.0%) [64.4-85.6] 50 (79.4%) [69.4-89.4] 54 (84.4%) [75.5-93.3] 48 (76.2%) [65.7-86.7] 102 (80.3%) [73.4-87.2] 50 (76.9%) [66.7-87.1] 56 (80.0%) [70.6-89.4] Mild 95 (70.9%) [63.2-78.6] 32 (50.0%) [37.8-62.3] 45 (70.3%) [59.1-81.5] 50 (79.4%) [69.4-89.4] 53 (82.8%) [73.6-92.0] 47 (74.6%) [63.9-85.3] 100 (78.7%) [71.6-85.8] 48 (73.8%) [63.1-84.5] 55 (78.6%) [69.0-88.2] Moderate 9 (6.7%) [2.5-10.9] 4 (6.3%) [0.3-12.3] 4 (6.3%) [0.3-12.3] 8 (12.7%) [4.5-20.9] 5 (7.8%) [1.2-14.4] 4 (6.3%) [0.3-12.3] 15 (11.8%) [6.2-17.4] 12 (18.5%) [9.1-27.9] 4 (5.7%) [0.3-11.1] Severe 2 (1.5%) [0.0-3.6] 1 (1.6%) [0.0-4.7] 4 (6.3%) [0.3-12.3] 1 (1.6%) [0.0-4.7] 0 1 (1.6%) [0.0-4.7] 5 (3.9%) [0.5-7.3] 1 (1.5%) [0.0-4.5] 2 (2.9%) [0.0-6.8] Drug-related TEAEs 13 (9.7%) [4.7-14.7] 6 (9.4%) [2.3-16.5] 24 (37.5%) [25.6-49.4] 14 (22.2%) [11.9-32.5] 10 (15.6%) [6.7-24.5] 7 (11.1%) [3.3-18.9] 27 (21.3%) [14.2-28.4] 6 (9.2%) [2.2-16.2] 8 (11.4%) [4.0-18.8] Serious TEAEs 4 (3.0%) [0.1-5.9] 4 (6.3%) [0.3-12.3] 4 (6.3%) [0.3-12.3] 3 (4.8%) [0.0-10.1] 1 (1.6%) [0.0-4.7] 4 (6.3%) [0.3-12.3] 11 (8.7%) [3.8-13.6] 4 (6.2%) [0.3-12.1] 5 (7.1%) [1.1-13.1] Serious drug-related TEAEs 0 0 0 0 0 0 0 0 0 Death 1 (0.7%) [0.0-2.1] 0 0 0 0 0 0 0 0 TEAE leading to study drug discontinuation 3 (2.2%) [0.0-4.7] 2 (3.1%) [0.0-7.3] 7 (10.9%) [3.3-18.5] 5 (7.9%) [1.2-14.6] 1 (1.6%) [0.0-4.7] 1 (1.6%) [0.0-4.7] 9 (7.1%) [2.6-11.6] 4 (6.2%) [0.3-12.1] 15 (21.4%) [11.8-31.0] TEAEs occurring in more than 5% of patients in any treatment group Nasopharyngitis 40 (29.9%) [22.1-37.7] 5 (7.8%) [1.2-14.4] 16 (25.0%) [14.4-35.6] 19 (30.2%) [18.9-41.5] 27 (42.2%) [30.1-54.3] 20 (31.7%) [20.2-43.2] 39 (30.7%) [22.7-38.7] 18 (27.7%) [16.8-38.6] 20 (28.6%) [18.0-39.2] Pharyngitis 8 (6.0%) [2.0-10.0] 2 (3.1%) [0.0-7.3] 0 3 (4.8%) [0.0-10.1] 4 (6.3%) [0.3-12.3] 5 (7.9%) [1.2-14.6] 5 (3.9%) [0.5-7.3] 3 (4.6%) [0.0-9.7] 1 (1.4%) [0.0-4.2] Influenza 4 (3.0%) [0.1-5.9] 1 (1.6%) [0.0-4.7] 5 (7.8%) [1.2-14.4] 1 (1.6%) [0.0-4.7] 2 (3.1%) [0.0-7.3] 2 (3.2%) [0.0-7.5] 9 (7.1%) [2.6-11.6] 3 (4.6%) [0.0-9.7] 1 (1.4%) [0.0-4.2] Bronchitis 1 (0.7%) [0.0-2.1] 0 2 (3.1%) [0.0-7.3] 0 4 (6.3%) [0.3-12.3] 2 (3.2%) [0.0-7.5] 1 (0.8%) [0.0-2.3] 4 (6.2%) [0.3-12.1] 0 Nausea 9 (6.7%) [2.5-10.9] 1 (1.6%) [0.0-4.7] 8 (12.5%) [4.4-20.6] 5 (7.9%) [1.2-14.6] 0 4 (6.3%) [0.3-12.3] 1 (0.8%) [0.0-2.3] 1 (1.5%) [0.0-4.5] 3 (4.3%) [0.0-9.1] Diarrhoea 4 (3.0%) [0.1-5.9] 0 11 (17.2%) [8.0-26.4] 2 (3.2%) [0.0-7.5] 4 (6.3%) [0.3-12.3] 2 (3.2%) [0.0-7.5] 3 (2.4%) [0.0-5.1] 2 (3.1%) [0.0-7.3] 3 (4.3%) [0.0-9.1] Constipation 5 (3.7%) [0.5-6.9] 2 (3.1%) [0.0-7.3] 1 (1.6%) [0.0-4.7] 5 (7.9%) [1.2-14.6] 2 (3.1%) [0.0-7.3] 2 (3.2%) [0.0-7.5] 8 (6.3%) [2.1-10.5] 1 (1.5%) [0.0-4.5] 1 (1.4%) [0.0-4.2] Gastroesophageal reflux disease 3 (2.2%) [0.0-4.7] 0 2 (3.1%) [0.0-7.3] 0 1 (1.6%) [0.0-4.7] 0 9 (7.1%) [2.6-11.6] 0 1 (1.4%) [0.0-4.2] Vomiting 1 (0.7%) [0.0-2.1] 0 4 (6.3%) [0.3-12.3] 2 (3.2%) [0.0-7.5] 0 1 (1.6%) [0.0-4.7] 0 2 (3.1%) [0.0-7.3] 2 (2.9%) [0.0-6.8] Back pain 5 (3.7%) [0.5-6.9] 2 (3.1%) [0.0-7.3] 1 (1.6%) [0.0-4.7] 1 (1.6%) [0.0-4.7] 3 (4.7%) [0.0-9.9] 0 10 (7.9%) [3.2-12.6] 4 (6.2%) [0.3-12.1] 0 Spinal osteoarthritis 1 (0.7%) [0.0-2.1] 1 (1.6%) [0.0-4.7] 0 4 (6.3%) [0.3-12.3] 0 1 (1.6%) [0.0-4.7] 0 0 1 (1.4%) [0.0-4.2] Intervertebral disc protusion 0 1 (1.6%) [0.0-4.7] 0 4 (6.3%) [0.3-12.3] 1 (1.6%) [0.0-4.7] 0 0 0 1 (1.4%) [0.0-4.2] Hypoglycaemia 5 (3.7%) [0.5-6.9] 2 (3.1%) [0.0-7.3] 6 (9.4%) [2.3-16.5] 5 (7.9%) [1.2-14.6] 9 (14.1%) [5.6-22.6] 4 (6.3%) [0.3-12.3] 21 (16.5%) [10.0-23.0] 2 (3.1%) [0.0-7.3] 2 (2.9%) [0.0-6.8] Hyperglycaemia 5 (3.7%) [0.5-6.9] 1 (1.6%) [0.0-4.7] 0 2 (3.2%) [0.0-7.5] 0 1 (1.6%) [0.0-4.7] 7 (5.5%) [1.5-9.5] 1 (1.5%) [0.0-4.5] 8 (11.4%) [4.0-18.8] Eczema 2 (1.5%) [0.0-3.6] 0 0 5 (7.9%) [1.2-14.6] 3 (4.7%) [0.0-9.9] 2 (3.2%) [0.0-7.5] 4 (3.1%) [0.1-6.1] 1 (1.5%) [0.0-4.5] 4 (5.7%) [0.3-11.1] Hypertension 0

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