Imeglmin Slides agents in Types 2 Diabetes Mellitus

1. "Imeglimin: Novel Agent in T2DM
armamentarium with Dual Benefits"

2. IDF Diabetes Atlas 10th edition. Nov -2021
1 in 11 adults has diabetes (537
million) and it will increase up
to 783 million by 2045
South East Asia will have 152
million diabetic population by 2045
which will be growing by 68%
India – 74.2 millions (2021)
124.9 millions (2045)

3. Top 10 countries or territories for number of adults (20–79 years) with
diabetes in 2021 and 2045
INDIA IN THE LEAGUE OF MOST DIABETES CASES
IDF Diabetes Atlas 2021 – 10th edition; www.diabetesatlas.org

4. DIABETES IN SOUTH-EAST ASIA
IDF Diabetes Atlas 2021 – 10th edition; www.diabetesatlas.org

5. CHALLENGES IN T2DM MANAGEMENT
Beta cell
dysfunction
Insulin
Resistance

6. Beta cell dysfunction
• Beta cell dysfunction results from inadequate glucose sensing to stimulate
insulin secretion therefore elevated glucose concentrations prevail
• Beta cell insults include:
• Cytokine-induced inflammation
• Obesity
• Insulin resistance
• Overconsumption of saturated fat and free fatty acids (FFA).
• A progressive decline of beta cell function leading to beta cell exhaustion
precedes beta cell demise.
Beta cell dysfunction and insulin resistance, Frontiers in endocrinology ,March 2013 | Volume 4 | Article 37 | 1

7.  Mitochondrial dysfunction in pancreatic
β-cells leading to impaired insulin
secretion and T2D may be accounted for
by several processes, alone or in
combination.
 A number of mutations in mitochondrial
DNA (mtDNA) cause dysfunction of
mitochondria in pancreatic β-cells.
Pathophysiology
M Fex et al; Journal of Endocrinology (2018) 236, R145–R159

8. Pathophysiology
Diabetologia (2020) 63:2007–2021

9. • Insulin resistance is characterized by a diminished response to insulin stimulation, resulting
in the failure of target tissues to adequately dispose of blood glucose, inhibit lipolysis,
stimulate glycogen synthesis, and inhibit hepatic glucose output.
• Traditionally viewed as a compensatory response, insulin secretion is enhanced leading to
hyperinsulinemia.
• Defects may be reversible by weight loss, exercise, and proper nutritional diets; however, if
left unopposed insulin resistance is a precursor event that likely contributes to β-cell
dysfunction.
INSULIN RESISTANCE
Physiological Reports. 2020;8:e14607

10. MECHANISMS LEADING
TO INSULIN RESISTANCE
Physiological Reports. 2020;8:e14607

11. Mitochondria
Looking Back into BASICS

12. Overview
• Mitochondria are important for adenosine
triphosphate (ATP) production, which is vital
for all living organisms.
• Mitochondria are also the key regulator of
glucose-stimulated insulin secretion in the
pancreatic b-cells
• During the past decades, evidence has shown
that mitochondrial function is closely related
to various facets of diabetes – pancreatic b-
cell dysfunction, insulin resistance, obesity
and vascular complications of diabetes
Journal of Diabetes Investigation Volume 1 Issue 5 October 2010

13. Mitochondrial Dysfunction and Type 2 Diabetes
Journal of Diabetes Investigation Volume 1 Issue 5 October 2010

14. Nutrients 2017, 9, 968;

15. Need of the Hour???
“A drug with dual mechanism of action that is designed to
increase insulin secretion in response to glucose and to improve
insulin resistance”

16. IMEGLIMIN
The first of the group of oral tetrahydrotriazine compounds

17. Introduction
• An Approved Novel Drug for Type 2 Diabetes with a Differentiated
Mechanism of Action
• Approved in Japan in June 2021.
• Japan is the first country in the world to approve Imeglimin
• Also approved by DCGI
• Supported by numerous preclinical and clinical studies
• Phase 3 TIMES (Trials of IMeglimin for Efficacy and Safety) program
managed jointly by Poxel and Sumitomo Dainippon Pharma
• 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
https://www.poxelpharma.com/en_us/pipeline/diabetes accessed on 23 May at 10:00am

18. A New Class with a Differentiated MoA
Imeglimin is the first orally-available anti-
diabetes candidate that simultaneously
targets all three key organs of diabetes:
the pancreas, the liver and the muscles.
Imeglimin targets the two main defects
seen in patients with type 2 diabetes:
• The pancreas by increasing insulin
secretion, in a glucose-dependent
manner
• The muscles and liver by decreasing the
excess production of glucose by the liver
while increasing the effectiveness of
insulin or 'insulin sensitivity' in the
muscles.
Oral Tetrahydrotriazine Compounds
https://speciality.medicaldialogues.in/type-2-diabetes-oral-drug-imeglimin-poxel-pharma-times-trial-new-diabetes-drug-easd?infinitescroll=1

19. Mechanism Of Action
Diabetes Obes Metab. 2021;23:664–673.
*reactive oxygen species; #
PTP - permeability transition pore;
NAMPT- Nicotinamide Phosphoribosyl-transferase;
NAD - Nicotinamide Adenine Dinucleotide (NAD+ )

20. Possible molecular mechanisms by which imeglimin improves
glucose homeostasis.
Hindawi Journal of Diabetes Research Volume 2020, Article ID 8768954

21. Possible molecular mechanisms by which imeglimin improves
glucose homeostasis Contd….
Hindawi Journal of Diabetes Research Volume 2020, Article ID 8768954

22. Imeglimin and Insulin Sensitivity
Imeglimin can induce insulin sensitivity through several molecular
pathways:
• It can promote insulin signal transduction by increasing Akt (protein kinase
B) phosphorylation
• Although the underlying mechanisms of these insulin-sensitizing effects of
imeglimin are not clearly understood, this might potentially include glucose
transporter-4 (Glut-4) expression and modulating insulin receptor substrate
(IRS) phosphorylation.
Hindawi Journal of Diabetes Research Volume 2020, Article ID 8768954
AKT - Ak strain transforming

24. Imeglimin Increases Glucose-Dependent Insulin Secretion and
Improves Beta-cell Function in Patients with Type 2 Diabetes
Aim: The aim of this trial was to assess the glucose-stimulated insulin secretion
(GSIS) effect of imeglimin.
• Materials and Methods: A double-blind, randomized, placebo-controlled
study in 33 patients with type 2 diabetes (hemoglobin A1c: 6.8+/-0.1% (51
mmol/mol)), who were drug naïve or withdrawn from their previous
metformin monotherapy.
• Results - Imeglimin treatment for 7 days raised the insulin secretory response
to glucose by
• +112% (iAUC0-45, p=0.035),
• First phase ISR by +110% (p=0.034) and
• Second phase ISR by +29% (p=0.031).
• Imeglimin improved beta-cell glucose sensitivity by +36% (p=0.034) and
tended to decrease hepatic insulin extraction (-13%, p=0.056). Imeglimin did
not affect glucagon secretion.
Conclusion –
In patients with type 2 diabetes, imeglimin improves beta-cell function, which
may contribute to its glucose-lowering effect
Giovanni Pacini, DSc 1, Andrea Mari, PhD

25. Aim - To evaluate the short-term effects and safety of imeglimin in terms of glycemic
control, as assessed by intermittently scanned continuous glucose monitoring
(isCGM).
Study Design and Participants - This retrospective and observational study of 32
patients who were administered imeglimin in addition to existing treatment regimens was
designed to evaluate glycemic profiles. The patients were monitored for more than 4 weeks
Diabetes Ther (2022) 13:1635–1643

26. Results
Glycemic value differences (before versus after imeglimin administration) evaluated by isCGM
Data shown are median values (25th–75th percentile)
CV coefficient of variation, MODD mean of daily difference, TIR time in range, TAR time above
range, TBR time below range
Data were compared using the Wilcoxon signed-rank test
Diabetes Ther (2022) 13:1635–1643

27. Mean glucose levels evaluated by isCGM before and after imeglimin
before
after
Diabetes Ther (2022) 13:1635–1643
CONCLUSION
Imeglimin clearly shifted daily glucose profiles into an appropriate
range in Japanese T2D patients, indicating a short-term improvement
in glycemic control.

28. PK/PD
; 1000 mg BD

29. Contd…
• Half life - Plasma elimination half-life - 13.0 h
• Excretion - Imeglimin is not metabolized; it is eliminated unchanged
in the urine.
TOMITA et al,Asploro Journal of Biomedical and Clinical Case Reports, 5, 1, (33-37), (2022)..

30. Special Population
Renal patients* –
• Imeglimin is not metabolized; it is eliminated unchanged in the urine.
• Thus, a dosage reduction might be required for patients with renal impairment.
• 500 mg twice daily (b.i.d.) for patients with eGFR 15-45 ml/min/1.73 m2
• 500 mg with a longer dosing interval is suggested for those with eGFR less than 15
Innovator PI .
Hepatic patients-
• Safe and well tolerated in patients with moderate hepatic impairment. (Chevalier et al. )
• Clinical trials have not been conducted in patients with severe (Child-Pugh classification C) liver dysfunction.
Pregnancy
Should not be given
Lactation
 Consider continuing or discontinuing breastfeeding, taking into
account the therapeutic benefits and benefits of breastfeeding.
 Transfer to milk has been observed in animal experiments.
*Clin Transl Sci. 2022 Apr;15(4):1014-1026
As per innovator PI - No clinical trials have been conducted in patients with moderate or severe renal
dysfunction (eGFR < 45 mL / min / 1.73 m ) using efficacy and safety as indicators, and administration is
not recommended

31. Clinical Trial Experience

32. Imeglimin – Dose range Phase 2b study
Dubourg J. Et al. Diabetes Obes Metab. 2021 Mar;23(3):800-810.
Baseline HbA1c of 7.0%-10.0%

33. TIMES 1(Trials of IMeglimin for Efficacy and Safety)
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 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.
Dubourg and Associates, Diabetes Care 2021;44:952–959

34. TIMES 2(Trials of IMeglimin for Efficacy and Safety)
• 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
DUBOURG ET AL, Diabetes Obes Metab. 2021;1–11..

35. Imeglimin was observed to demonstrate robust efficacy benefits in
combination with DPP-4 inhibitors
DUBOURG ET AL, Diabetes Obes Metab. 2021;1–11..

36. TIMES 3 (Trials of IMeglimin for Efficacy and Safety)
• 16-week 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
• 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.
REILHAC ET AL,. Diabetes Obes Metab. 2022;1–11.

37. Study Design
REILHAC ET AL,. Diabetes Obes Metab. 2022;1–11.

38. Time course of
glycated
hemoglobin (HbA1c)
over the 52-week
study period
according to
treatment groups.
The open-label extension period showed a sustained mean HbA1c decrease
from baseline of 0.64% in patients receiving Imeglimin for 52 weeks
0.54% in patients receiving Imeglimin and insulin for the last 36 weeks only
REILHAC ET AL,. Diabetes Obes Metab. 2022;1–11.

39. Indian Study - Data on file.

40. OBJECTIVES
Primary Objective:
• Evaluation of the efficacy of Imeglimin Tablets in patients with type 2 diabetes mellitus
inadequately controlled with diet and exercise alone.
Secondary Objective:
• Evaluation of the safety and tolerability of Imeglimin Tablets in patients with type 2
diabetes mellitus inadequately controlled with diet and exercise alone.
Indian Study - Data on file.

41. STUDY ASSESSMENTS:
Primary Efficacy End Point:
➢ Mean change in glycosylated haemoglobin (HbA1c) from baseline to end of the study visit
(week 16).
Secondary Efficacy End Points:
➢ Mean change in fasting plasma glucose (FPG) from baseline to end of the study visit
(week16).
➢ Mean change in 2-hr post prandial plasma glucose (2-hr PPG) from baseline to end of the
study visit (week 16).
➢ Proportion of patients achieving a therapeutic glycemic response, defined as HbA1c < 7%
at the end of the study visit (week 16).
➢ Proportion of patients requiring rescue medication.
Indian Study - Data on file.

42. Study
Flow Chart
Study Period - 112 days
Indian Study - Data on file.

43. Results
Mean change HbA1c from baseline to end of the
study visit
Indian Study - Data on file.

44. Mean change in FPG from baseline to
end of the study visit
Indian Study - Data on file.

45. Mean change in 2-hr PPG from baseline to
end of the study visit
Indian Study - Data on file.

46. AE grouping by System Organ Class
Indian Study - Data on file.

47. CONCLUSIONS
Imeglimin Hydrochloride Tablets 1000 mg was superior to Placebo
Tablets.
There were no deaths or hospitalizations in both the treatment
groups.
Imeglimin Hydrochloride Tablets 1000mg was found to be safe
and well tolerated in patients with type 2 diabetes mellitus.
Indian Study - Data on file.

48. Adverse drug events
• The following side effects may occur, so careful observation and appropriate
measures such as discontinuing administration should be done if any
abnormalities are observed.
• Hypoglycemia with Monotherapy (symptomatic hypoglycemia and/or
blood glucose level <70 mg/dL, same below) was:
1.3% (1/75 cases) in the 500 mg group,
1.4% (1/74 cases) in the 1000 mg group, and
1.4% (1/74 cases) in the 1500 mg group.
Innovator PI
Serious side effects- Hypoglycemia (6.7%) may occur when used in
combination with an insulin preparation, a sulfonylurea agent, or a fast-acting
insulin secretagogue.

49. Other side effects
Innovator PI

50. Common adverse events of OADs
NAME SIDE EFFECT (%)
METFORMIN Diarrhea (53.2)
Nausea/Vomiting(25.5)
SULPHONYUREAS Hypoglycemia (45.5)
SGLT2-i UTI (6.7)
Genital infections (14.4)
DPP4-i Nasopharyngitis (5.9)
Diarrhoea(4.17)
GLITAZONES Weight gain (35.1)
Osteoporosis(10.5)
Ref- In the comment box below

51. Mode of action of various Anti Diabetic drugs
DRUG INSULIN SENSITIVITY B- CELL STIMULATION
METFORMIN +++ _____
SULPHONYLUREAS +++
DPP4-I/GLP1-RA +++
SGLT2-I ____ ____
IMEGLIMIN +++
THIAZOLIDINEDIONES +++ _______

52. Take home messages
• Type 2 diabetes (T2DM) is a widespread disease, affecting more than 380
million people worldwide
• Currently there are two challenges in T2DM management : Insulin
resistance & Beta cell dysfunction
• Beta cell dysfunction results from inadequate glucose sensing to stimulate
insulin secretion therefore elevated glucose concentrations prevail
• Insulin resistance is characterized by a diminished response to insulin
stimulation, resulting in the failure of target tissues to adequately dispose
of blood glucose
• Mitochondrial Dysfunction also leads to Type 2 Diabetes

53. Contd…
• Currently available OADs address only one facet of T2DM
• Imeglimin is the only oral compound with a dual mechanism of action
• Imeglimin simultaneously targets all three key organs of diabetes: the
pancreas, the liver and the muscles.
• Imeglimin has been shown to have a positive impact on skeletal
muscle glucose uptake, hepatic glucose production, and beta-cell
apoptosis
• Imeglimin demonstrates good efficacy with monotherapy and also
with combination therapy – maximum benefit seen when used
concomitantly with DPP-4 inhibitors

54. THANK YOU