Confidence_Alogliptin_13_Mar_2023 (1).pptx

Alogliptin

1. Confidence with Alogliptin

2. What brings confidence ?

3. Promising Efficacy Data CVOT (EXAMINE) study in 5380 high-CV risk Diabetic Patients with mean follow up of 4.75 years CVOT Trial Extensively studied in phase II/III studies in patients with type 2 diabetes mellitus (T2DM) alone or as add-on/combination therapy with other antidiabetic agents FDCs of Alogliptin + Metformin and Alogliptin + Pioglitazone are also approved in Japan, the USA, and the EU Once a day dosing Confidence Trial Indian Patients Phase 4 study in 344 Indian patients re-ensuring safety and efficacy BE Studies with Innovator ( Nesina ) : Showing Bioequivalence Meta-analysis demonstrating safety and efficacy of Alogliptin Real World evidence with Alogliptin Long term safety and efficacy data

4. Approved in India by Indian regulatory authority, DCGI 2014 , available with brand name : ALOJA Alogliptin Takeda Pharmaceuticals (Osaka, Japan) FDA & EU approval: 2013 Selectively inhibits DPP -4 with an IC50 of 7 nmol /L Single-dose administration to healthy subjects led to peak inhibition of DPP-4 within 2-3 h post dose Exhibited >14000-fold DPP -4 selectivity over related serine proteases DPP -8 and DPP -9 USFDA approved the drug in 3 formulations: a stand-alone; in combination with metformin ( Kazano ); and in combination with pioglitazone ( Oseni )

5. Approval status of Alogliptin & FDCs of Alogliptin across Globe

6. Approval status of Alogliptin & FDCs of Alogliptin across Globe Alogliptin Alogliptin was first approved to treat T2DM in 2010 in Japan NASINA (USA) Vipidia (EU) ALOJA (India) 2014 Available : Tablets, 6.25 mg, 12.5 mg and 25 mg alogliptin Alogliptin + Metformin KAZANO (USA) 25 Jan 2013 VIPDOMET (Australia) 22 Oct-2013 KAZANO (Canada) 30 Apr 2014 VIPDOMET (Europe) 19 Sep 2013 Inisync ® Combination Tablets November 29, 2016 ALOJA M & ALOJA M Forte (Indi) ( Feb 2020) Alogliptin + Pioglitazone OSENI (USA) January 25, 2013 INCRESYNC (EU) 19 September 2013 LIOVEL HD & LIOVEL LD (Japan) July 2011 Alogliptin : Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

7. Promising PK properties

8. Pharmacokinetic edge of Alogliptin vs other DPP4i 100% Bioavailability allows Alogliptin to be taken before/during/after food thus offers better patient compliance Journal of Diabetes mellitus 2016, 6,113-131

9. DPP-4 Selectivity With Alogliptin Alogliptin’s selectivity for DPP-4 is over 14,000-fold greater than that for other DPP isoenzymes , DPP- 8 & 9 * *Adopted from respective product monographs

10. Alogliptin ensures consistent glycemic control Hosp Pharm. 2013 Jul-Aug; 48(7): 580–592.

11. HbA1c CHANGE WITH ALOGLIPTIN Diabetes Ther. 2017 Apr;8(2):251-273. ALOG LIPTI N 25MG V I L DA G L I P T I N 1 M G SAXA G LI P T I N 5 M G L I NA G I I P T I N 5 M G S ITA G LI P T I N 1 OO M G S I TA G LIP T I N 1 OO M G Alogliptin has shown a reduction of HbA1c 0f 0.62 % in larger population Heller 604 606 -0.62 Lukashevich 152 160 -0.76 Moses 127 127 -0.66 Owens 778 262 -0.62 Hermansen 115 107 -0.89 NCT01590771 111 112 -0.41 Drug Placebo Mean difference HbA1c (%) change from baseline with gliptins DPP -4 inhibitor HbA1c change

12. Acceptable safety profile

13. Safety profile of Alogliptin vs other DPP4i Nasopharyngitis URTI Headache Alogliptin has lesser chances of adverse effects with as compared to other DPP-4i due to ↑↑ DPP-4 selectivity BMC Pharmacology and Toxicology 2017;18(1). J Diabetes Investig . 2013; 4(6): 576–584.

14. Well established Clinical efficacy

15. Summary of Clinical Trials In Patients with No Prior Antihyperglycemic Therapy

16. Summary of Clinical Trials In Patients Receiving Metformin

17. Summary of Clinical Trials

18. Alogliptin compared with Glipizide in T2DM: a 2-year study Endure Trial Sample Size from India= 400

19. Endure Trial Title Durability of the efficacy and safety of Alogliptin compared with Glipizide in T2DM: a 2-year study Study Population : 2639 T2DM with inadequately controlled on stable-dose metformin Treatment groups: Group 1: Metformin + Alogliptin 12.5 mg Group 2: Metformin + Alogliptin 25 mg Group 3: Metformin + Glipizide 5 mg Evaluation Parameters: Change from baseline in HbA1c level at 104 weeks HbA1c change from baseline Prato SD et al. Diabetes, Obesity and Metabolism 16: 1239–1246, 2014.

20. Conclusion: Alogliptin 12.5 and 25 mg once daily was found to have sustained antihyperglycaemic efficacy over 2 years in patients with inadequate glycaemic control of T2DM on Metformin. The safety and tolerability profiles were similar among the three treatments with the exception of hypoglycaemia , which occurred at a substantially higher incidence rate with Glipizide. Prato SD et al. Diabetes, Obesity and Metabolism 16: 1239–1246, 2014 FPG change from baseline Patients without hypoglycemia

21. Alogliptin Use in Elderly People

22. Alogliptin Use in Elderly People: A Pooled Analysis from Phase 2 and 3 Studies Objectives: To compare the efficacy and safety of Alogliptin, in elderly (> or =65) and younger (<65) patients with T2D Patients aged 18 to 80 with type 2 diabetes mellitus and inadequate glycemic control. Results: Mean HbA1c decreased from baseline by 0.7% and 0.8% in elderly patients receiving Alogliptin 12.5 and 25 mg, respectively, and 0.5% and 0.6%, respectively, in younger patients (P<.001 for both Alogliptin doses vs placebo for both age groups). Conclusion: Alogliptin was effective and well tolerated in the elderly patients enrolled in these studies Improvements in HbA1c were similar to those seen in younger patients No increase in the risk of hypoglycemia, weight gain, or other adverse events was apparent in elderly patients

23. Alogliptin in CKD patients

24. Effects of Alogliptin in Chronic Kidney Disease Patients with Type 2 Diabetes 36 CKD patients with type 2 diabetes were recruited The patients were followed up for six months after adding alogliptin Results The mean HbA1c value was not decreased the 1,5-AG values tended to improve (p= 0.1023) The mean eGFR was unchanged. There were no significant changes in the patients with an eGFR of 60 mL/min/1.73 m2 or more (25 patients) or in the patients with an eGFR less than 60 mL/min/1.73 m2 (11 patients)  Neither the blood glucose levels nor renal function were exacerbated before or after the start of treatment. The results of this study suggest that alogliptin can be administered safely in CKD patients. Intern Med 53: 195-203, 2014

25. Long-Term Effects of Alogliptin Benzoate in Hemodialysis Patients with Diabetes: A 2-year Study 16 diabetic HD patients with inadequate glycemic control ( hemoglobin A 1c (HbA1c) level >6.5% and glycated albumin (GA) level >20%) on diet and exercise participated in the study Alogliptin 6.25 mg was administered to patients once daily Results: Both HbA1c and GA levels decreased after starting alogliptin administration. HbA1c and GA levels decreased from 7.1 ± 0.2 to 5.8 ± 1.6% and from 22.5 ± 0.7 to 19.6 ± 0.6%, respectively, 24 months after beginning treatment. Glucagon-like peptide-1 levels (8.9 ± 5.7 pmol /l before treatment) doubled after treatment.   Long term (2-year) effects of alogliptin benzoate monotherapy suggest its efficacy as a new treatment strategy in diabetic HD patients. Nephron Clin Pract 2013;123:46–51

26. Alogliptin in NASH

27. Efficacy of Alogliptin in preventing non-alcoholic fatty liver disease progression in patients with type 2 diabetes Single arm, multi- center , non-randomized study of NAFLD patients with type 2 diabetes 39 patients were recruited from 8 centers in Japan between June 2012 and December 2013. Out of 39 patients, 16 patients (40.3%) had NAFIC scores >2 points, indicating the presence of NASH Patients received 25 mg/day of alogliptin for 12 months Median patient age – 61 years , HbA1c level - 6.8% (53.0 mmol/mol) , Body mass index 28.6 kg/m2 Results NAFIC scores were significantly decreased at 52 weeks after the initiation of alogliptin therapy NAFIC scores decreased in 13 patients and remained >2 points in 10 patients, indicating NASH had possibly persisted in these patients. NAFIC scores had increased in only 1 patient at the end of the study compared to baseline scores. BIOMEDICAL REPORTS 4: 183-187, 2016

28. Long term studies with Alogliptin

29. Long-term safety and efficacy of alogliptin , a DPP-4 inhibitor, in patients with type 2 diabetes: a 3-year prospective, controlled, observational study (J-BRAND Registry) Alogliptin, as a representative of DPP-4 inhibitors, was safe and efficacious for a 3-year period The results strongly suggest the safe and durably efficacious profile of DPP-4 inhibitors in comparison with other oral hypoglycemic agents including biguanides

30. Meta-analysis of Alogliptin

31. Efficacy of alogliptin in type 2 diabetes treatment: a meta-analysis of randomized double-blind controlled studies Alogliptin alone or in combination with other antidiabetic drug has shown a significant reduction in HbA1c and FPG level in patients with type 2 diabetes Meta-analysis of Alogliptin

32. Results : A total of 15 RCTs with 4456 patients with type 2 diabetes were included in this study. Alogliptin lowered glycated hemoglobin (HbA1c) to a much greater extent in Asian dominant studies [ - 0.75% (95% CI - 0.84 to - 0.65)] than in non-Asian-dominant studies [ - 0.61% (95% CI - 0.68 to - 0.54)] ( P = 0.02). The postprandial blood glucose-lowering efficacy was higher in Asian-dominant studies [ - 2.42 mmol /l (95% CI - 2.99 to - 1.85)] than in non-Asian-dominant studies [ - 0.60 mmol /l (95% CI - 1.60 to 0.40)] ( P = 0.002), Conclusions : Alogliptin is more effective in improving glycemic levels in Asians than in other ethnic populations . Future studies are required to explore the potential mechanisms. Diabetes Ther (2018) 9:177–191

33. Real world evidence with Alogliptin

34. Real world evidence with Alogliptin In r eal-world settings Alogliptin has been generally well-tolerated and has demonstrated a reduction in hemoglobin A1c (HbA1c) when administered alone or as add-on/combination therapy with other antidiabetic agents

35. Objective of Examine Trial: To determine whether A logliptin is non-inferior to placebo with respect to major CV events in patients with T2D at very high CV risk — those with recent acute coronary syndromes (ACS). NEJM 369;14 nejm.org october 3, 2013

36. ENROLMENT OF SUBJECTS (N=5380), Alogliptin (n=2701), Placebo (n=2679) 15.9% 25.9% 28.0% 11.4% United States, Canada (N=853) Mexico, Central/South America (N=1393) Eastern Europe and Africa (N=1508) Western Europe, Australia, New Zealand, Middle East (N=616) Asia/Pacific (N=1010) 18.8% (400 Patients from India across 33 centers )

37. Study Patients INCLUSION CRITERIA T2DM A cute coronary syndrome (ACS) within 15 to 90 days before randomization. HbA1c: ≥ 6.5-11.0% T1DM Unstable cardiac disorders (e.g., Class IV HF, refractory angina, uncontrolled arrhythmias, critical valvular heart disease, or severe uncontrolled HT), Dialysis within 14 days before screening. Inclusion Criteria Exclusion Criteria

38. Examine trial - end points Primary outcomes 3 point MACE: CV death Nonfatal myocardial infarction (MI) Nonfatal stroke Secondary outcomes 4 point MACE: CV death Nonfatal MI Nonfatal stroke Hospitalization for unstable angina

39. Results Conclusion: In patients with T2D with recent ACS, the rates of MACE were not increased with Alogliptin as compared with placebo.

40. Safety of Alogliptin in HF & HHF outcomes

41. Due to concerns regarding increased rates of HHF for other DPP-4i ( Saxagliptin ), evaluation of pre-specified and post hoc analyses of heart failure (HF) outcomes in EXAMINE trial was performed. Alogliptin in Patients With T2D After ACS: HF outcomes & CV Safety In HF patients Within this composite endpoint, HHF occurred in 3.1% patients on Alogliptin vs 2.9% on placebo . In addition, Alogliptin showed no effect on the post hoc composite of CV death and HHF , and no effect on its individual components: (CV death 3.5% vs. 4.2%) and (HHF 3.9% vs. 3.3%) for Alogliptin vs. placebo respectively . In patients with T2DM and recent ACS, CV outcomes inclusive of HHF were not increased with Alogliptin compared with placebo, including pts with a history of HF. Objective Results Conclusion Journal of the American College of Cardiology 63(12), Supplement, April 2014 The lancet, VOLUME 385, ISSUE 9982, P2067-2076, MAY 23, 2015

42. What recent guidelines says !!

43. DPP-4i moderate the risk of genitourinary tract infections associated with SGLT2i

44. Bioequivalence Studies

45. Bioequivalence Studies Fixed dosed combination of Alogliptin Benzoate and Metformin Hydrochloride tablets 12.5 mg and 1000 mg of Indoco Remedies Limited, India comparing with KAZANO ( alogliptin and metformin HCl) tablets 12.5 mg and 1000 mg of Takeda Pharmaceuticals in healthy, adult, human subjects, under fasting & fed conditions. Test product Alogliptin and Metformin tablets is BIOEQUIVALENT to the US- Reference product, KAZANO tablets of Takeda Pharmaceuticals. 2 BE studies conducted for 25 mg and 2 stidies conducted for 12.5 mg Alogliptin (FED AND FASTED condition) ALOJA is bioequivalent to reference product Nesina (US) in fed as well as fasting state.

46. Confidence Trial Alogliptin Presented at 7th International Diabetes Summit happened at Pune on 10-12 March 2023

47. Confidence Study Title of Study: “A Phase-IV, Multi-Centric, Open Label, comparative Clinical Trial to Evaluate Safety, Tolerability and Efficacy of Oral Tablets of Fixed-dose Combination of Alogliptin & Metformin Hydrochloride vs Alogliptin in the treatment of type-2 Diabetic mellitus.” Efficacy Endpoints: Primary Endpoint: % change of mean HbA1C & % of patients achieving target HbA1c (≤ 7%) after 180 days. Secondary Endpoint: Change of mean FPG and 2 -hour PPG levels from baseline after 180 days Total no of patients: Alogliptin + Metformin (166) & Alogliptin (178) Chronicle of Diabetes Research and Practice ¦ Volume 2 ¦ Abstracts-International Diabetes Summit ¦ Supplement 1 ¦ March 2023,S11

48. Change in % mean of HbA1C from baseline to Day 180 Significant ↓in HbA1C by 2.07% in Alogliptin + Metformin group vs 1.29% in Alogliptin group after 180 days (p<0.001) P<0.001 (-1.29) (-2.07)

49. Secondary Endpoints: Mean change in FPG & PPG levels from baseline to Day 90 and Day 180 visit Significant ↓in FPG by 103mg/dl in Alogliptin+Metformin group vs 60mg/dl in Alogliptin group after 180 days (p<0.001) Significant ↓in PPG by 143mg/dl in Alogliptin+Metformin group vs 89mg/dl in Alogliptin group after 180 days (p<0.001) P<0.001 P<0.001 (-60.32) (-103.65) (-89.36) (-143.11)

50. Summary of Adverse Events Common adverse events seen with both groups were dizziness, GI disturbance, headache, hepatic enzyme elevation, hunger, nasopharyngitis, sweating, URTI, vomiting. No SAE was reported in both treatment groups. All the reported adverse events were mild in severity. Conclusion of the study: Alogliptin and FDC of Alogliptin plus Metformin was found to be a promising option in management of T2DM in relation to safety and efficacy.

51. Take home message : Alogliptin A highly selective Dipeptidyl peptidase-4 inhibitor (DPP- 4i) Extensively studied in phase II/III studies in patients with type 2 diabetes mellitus (T2DM) alone or as add-on/combination therapy with other antidiabetic agents Approved in Japan (2010), USA & EU (2013) and approved in India by Indian regulatory authority, DCGI 2014 , available with brand name : ALOJA The recommended dose of alogliptin as monotherapy is 25 mg once a day Fixed-dose combinations (FDCs) of alogliptin + metformin and alogliptin + pioglitazone are also approved in Japan, the USA, and the EU Alogliptin is generally safe , with a low risk of hypoglycemia , weight gain, acute pancreatitis , and gastrointestinal adverse events ; however, dosage adjustment is required when treating patients with renal and/or hepatic impairment EXAMINE trial clearly demostrate that there was no indication that alogliptin led to any increase in new hospital admissions for heart failure or worsened outcomes for patients with a previous history of heart failure Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet . 2015;385:2067-2076. Benefit‑Risk Assessment of Alogliptin for the Treatment of Type 2 Diabetes Mellitus Drug Safety https://doi.org/10.1007/s40264-019-00857-8

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