IMEGLIMIN - Times Talk Presentation.pptx

Imeglim

1. “Ime glimin – a novel agent in T2DM Armamentarium”

2. IME GLIMIN : Need of the hour ???

3. 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 ” IME GLIMIN

4. 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

5. Mechanism Of Action PLoS ONE 16(2): e0241651. https://doi.org/10.1371/ journal.pone.0241651

6. 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+ )

7. PK/PD Dose – 1000mg BD Very low protein binding(1-8%) Urinary excretion of unchanged drug – clearance driven by creatinine clearance No drug –drug interaction with metformin, sitagliptin and cimetidine No QT/QTc prolongation No difference between Caucasian and Japanese subjects

8. Special Population 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. Pregnancy Should not be given 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 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. Innovator PI .

9. Clinical Trial Experience

10. Aim: To assess the glucose-stimulated insulin secretion (GSIS) effect of IME GLIMIN . Study Design- Double-blind, randomized, placebo-controlled study in 33 patients Results - IME GLIMIN 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). IME GLIMIN improved beta-cell glucose sensitivity by +36% (p=0.034) and tended to decrease hepatic insulin extraction (-13%, p=0.056). IME GLIMIN did not affect glucagon secretion. Imeglimin Increases Glucose-Dependent Insulin Secretion and Improves Beta-cell Function in Patients with Type 2 Diabetes Giovanni Pacini, DSc 1, Andrea Mari, PhD

11. Aim: To assess the efficacy and safety of imeglimin monotherapy compared with placebo for 24 weeks in Japanese patients with type 2 diabetes (T2D). 24-week , randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2b clinical trial, Patients were randomly assigned (1:1:1:1) to receive orally imeglimin 500, 1000 or 1500 mg, or placebo twice-daily over a 24-week period. The primary endpoint was the placebo-adjusted change at week 24 in HbA1c.

12. Baseline HbA1c of 7.0%-10.0% Conclusions: Given the marginal increase in efficacy with the 1500 versus 1000 mg dose (along with the potential for gastrointestinal tolerability issues), a dose of 1000 mg twice-daily was selected for subsequent phase 3 studies.

13. TIMES 1 ( T rials of  IME GLIMIN for  E fficacy and  S afety) 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.

14. TIMES 2 ( T rials of  IME GLIMIN for  E fficacy and  S afety) 52-week , open label, parallel-group trial evaluated the long-term safety and efficacy of IME GLIMIN in 714 Japanese patients with type 2 diabetes. In this trial, 1,000 mg of IME GLIMIN was orally administered twice daily in combination with existing anti-hyperglycemic agents. IME GLIMIN was observed to show an HbA1c decrease from baseline ranging from -0.56 to -0.92%

15. IME GLIMIN was observed to demonstrate robust efficacy benefits in combination with DPP-4 inhibitors

16. TIMES 3 ( T rials of  IME GLIMIN for  E fficacy and  S afety) 16-week double-blind, placebo-controlled, randomized trial evaluated efficacy and safety of Imeglimin versus placebo in 215 patients when added to insulin therapy 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 IME GLIMIN as well as insulin therapy. REILHAC ET AL,. Diabetes Obes Metab . 2022;1–11 .

17. The open-label extension period showed a sustained mean HbA1c decrease from baseline of 0.64% in patients receiving IME GLIMIN for 52 weeks 0.54% in patients receiving IME GLIMIN and insulin for the last 36 weeks only

18. HbA1c reduction in CKD patients (Times 1,2 & 3) on Ime glimin DUBOURG ET AL, Diabetes Obes Metab . 2021;1–11 Dubourg and Associates, Diabetes Care 2021;44:952–959 REILHAC ET AL,. Diabetes Obes Metab . 2022;1–11 .

19. Aim - To evaluate the short-term effects and safety of IME GLIMIN in terms of glycemic control, as assessed by intermittently scanned continuous glucose monitoring ( isCGM ).

20. Results Glycemic value differences (before versus after IME GLIMIN 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

21. Mean glucose levels evaluated by isCGM before and after Ime glimin Ime glimin clearly shifted daily glucose profiles into an appropriate range in Japanese T2D patients, indicating a short-term improvement in glycemic control.

22. Results Mean change HbA1c from baseline to end of the study visit

23. Mean change in FPG from baseline to end of the study visit

24. Mean change in 2-hr PPG from baseline to end of the study visit

25. AE grouping by System Organ Class

26. CONCLUSIONS

27. The Differences: Mechanism of Action Ime glimin In vivo (clinical) Glucose-stimulated insulin secretion Evidence of insulin sensitivity. Cell and organ Glucose-stimulated insulin secretion Islet β-cell protection; preserved β-cell mass Muscle glucose uptake Metformin In vivo (clinical) No reported effect on insulin secretion No clear increase in insulin sensitivity Cell and organ No effect on glucose-stimulated insulin secretion No known in vivo effects on β-cell mass ± Muscle glucose uptake

28. The Differences: Mechanism of Action Ime glimin Metformin Intracellular Competitive/partial mitochondrial Complex I inhibition No decrease in mitochondrial respiration Increased NAD+ synthesis; potentially via NAMPT; increased glucose-responsive intracellular Ca ++ Intracellular Uncompetitive mitochondrial Complex I inhibition Decreased respiration No increase in Ca++; no effect on NAD+ reported

29. Ime glimin : Effect on CV system

30. Recent data suggest that IME GLIMIN prevents the death of human endothelial cells by inhibiting mitochondrial permeability without inhibiting mitochondrial respiration, which may improve cardiovascular risk profile in patients with T2DM. Introduction

31. Aim: A thorough QT study was conducted to establish electrophysiological effects of therapeutic and supra therapeutic doses of IME GLIMIN on cardiac repolarization. Methods: Randmized , double-blind, four-period, placebo and active controlled crossover study, healthy subjects (55) were administered a single dose of imeglimin 2250 mg, IME GLIMIN 6000 mg, moxifloxacin 400 mg, and placebo. 12-Lead Holter ECGs were recorded from 1 h before dosing until at least 24 h after each dose.

32. Estimates of ΔΔ QTcF Conclusion: This thorough QT study demonstrated that therapeutic and supra therapeutic exposures of IME GLIMIN did not induce a QT/ QTc prolongation with a strong confidence as evidenced by the assay sensitivity

33. Mode of action of various Anti Diabetic drugs

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

35. “Ime glimin – a novel agent in T2DM Armamentarium ” THANK YOU