Lipaglyn TM Clinical Studies

1. LipaglynTM Clinical Studies

2. Lead medical investigators included Endocrinologists, Diabetologists, Cardiologists and Physicians The clinical development involved a network of ~47 medical centres across India

3. Clinical Trials: First in Man to Pivotal studies lipaglynTM

4. LipaglynTM clinical trial programs – as per global standard • All these GCP Compliant Trials were approved by regulatory authorities: • DCGI (Drug Controller General of India) on recommendation of expert IND (Investigational New Drugs) committee • Ethics Committees • Data Safety Monitoring Board (DSMB) • Public domain clinical trial registries: • Indian registry - CTRI (www.ctri.nic.in) • WHO registry - (www.apps.who.int/trialsearch) • All the lab investigations were done at *NABL/CAP approved laboratories NABL – National Accreditation Board for testing & Calibration Laboratories CAP – College of American Pathologists CTRI – Clinical Trial Registries of India

5. LipaglynTM: Extensively evaluated by medical experts during various clinical trials • Total of 864 subjects participated in the clinical development of the Lipaglyn program comprising:- • Phase 1 (First-in-man) • Phase 2 (Proof-of-concept & Dose finding studies) • Phase 3 (Confirmatory studies) • Additional 1000 patients being enrolled in Phase IV trial

6. LipaglynTM in Healthy Volunteers Phase I Study (First-in-Man Studies)

7. Phase I study: First-in-man Phase I study was a randomized, double-blind, placebo-controlled, single centre, conducted on healthy human volunteers (n=136). It was performed in 4 parts; • Single Ascending Dose, • Multiple Ascending Dose, • Food Effect Study and • Gender Effect Study.

8. LipaglynTM in single and multiple doses was safe and well tolerated Study Results: • No Serious Adverse Events (SAEs) reported during the study. • Lipaglyn up to 128 mg once orally was well tolerated. • Lipaglyn single and multiple doses, was safe and well tolerated. • Pharmacokinetics (Cmax, AUC) was dose dependent and linear.

9. LipaglynTM is rapidly and well absorbed

10. LipaglynTM pharmacokinetic data No Significant Drug Accumulation

11. LipaglynTM in Non-diabetic & Diabetic Dyslipidemia Phase II Studies (Proof-of-Concept Studies)

12. Phase II studies Proof-of-concept of LipaglynTMwas established in double blind studies • LipaglynTMdoses of 0.5 to 4 mg/day were studied in, • 222 male or female diabetic or non diabetic patients

13. Phase II studies (PRESS-I to PRESS-IV)Prospective Randomized Efficacy & Safety study of Saroglitazar

14. LipaglynTM Vs Fenofibrate in Dyslipidemia in Non Diabetics Protocol 2001 PRESS-I

15. PRESS-I - Dose dependent decrease in TG Observed in non-diabetic subjects with dyslipidemia

16. PRESS-II - Decrease in TG was observed in T2DM patients with dyslipidemia

17. LipaglynTM: Safe, well-tolerated and no toxicity • Liver function test • No potential for drug induced liver injury • Renal function test • No potential for kidney toxicity • Musculoskeletal effect • No report of myositis (CPK>10UNL). • ECG abnormality/cardiotoxicity • No abnormality reported

18. LipaglynTM in Diabetic & Dyslipidemia Subjects Phase III Studies (Pivotal trials)

19. LipaglynTM Vs PioglitazoneIn Dyslipidemia With Type 2 Diabetes Mellitus Phase III Studies Protocol ZYH1.08 PRESS-V

20. PRESS V: Randomized, double-blind, pivotal study with LipaglynTM • Study Title: • A multi-center, randomized, double blind study to evaluate the safety and efficacy of 2 mg and 4 mg of Lipaglyn compared to Pioglitazone 45 mg in dyslipidemia with type 2 diabetes mellitus. [Lipaglyn.08.001.01.1. PROT dated 04.12.2008] • Subjects: • 120 (40 subjects in each arm); Enrolled: 122 • Treatment Duration : • 26 weeks • Cardiac Safety Follow-up: • 24 weeks after the last dose

21. Study design Study Duration: 24 weeks Follow-up: 24 weeks after last dose

22. PRESS V - Selection criteria Inclusion Criteria: • Age 18- 65 years • Subjects of either gender, males and females • Subjects on sulphonylurea and/or metformin for the treatment of T2DM for at least last 3 months and documented history of type 2 diabetes mellitus as per ADA. • Subjects with type 2 diabetes and dyslipidemia which is inadequately controlled by the life-style modifications • Triglycerides > 200 to 400 mg/dl on enrolment visit. • Body mass index (BMI) > 23 kg/m2 • Subject has given informed consent for participation in this trial Exclusion Criteria: • History of > 5% weight loss in past 6 months • Subjects on insulin and/or glitazone / glitazar therapy • Presence of ketonuria • BMI less than 23 kg/m2 • Pregnancy and lactation • Subjects with history of MI, CABG, PTCA, unstable angina or NYHA heart failure of any Class (III-IV) regardless of therapy • BP> 150/100mmHg • Subjects with active liver disease • Hepatic dysfunction demonstrated by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) greater than or equal to 2.5 times of upper limits of normal or Bilirubin more than 2 times UNL. • Thyroid dysfunction demonstrated by abnormal TSH value • Presence of gall stone • Subjects with renal dysfunction (serum creatinine> 1.2 mg %) • Subjects with history of myopathies or evidence of active muscle diseases • Subject on concomitant medications known to affect the lipid level in past 2 weeks. • Subjects with history of any other concurrent serious illness ( e.g. tuberculosis, HIV, malignancy) • Subject with history of alcohol and/or drug abuse • Known allergy, sensitivity or intolerance to the study drugs and their formulation ingredients • Participation in any other clinical trial in past 3 months • Subjects who are unwilling or unable to give informed consent

23. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Primary efficacy Up to 51% Reduction in Triglyceride

24. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy

25. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy

26. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy Favourable Lipid control

27. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy Effective Glycemic control

28. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment

29. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment

30. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment No potential Drug Induced Liver Injury (DILI) -FDA standard

31. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment No Renal Toxicity

32. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment No weight Gain compared to pioglitazone

33. LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Percentage of Patients Achieving ATP III Goal Following Saroglitazar 4 mg Treatment as Compared to Pioglitazone (Protocol ZYH1.08) More patients in Lipaglyn achieves ATP-III goal

34. LipaglynTM Advantages Safe for Liver Safe for muscles Safe for heart Safe for Kidney

35. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin Phase III Study Protocol ZYH1.09 PRESS-VI

36. PRESS VI: Randomized Double-blind, Placebo-controlled Pivotal Study With LipaglynTM • A multi-centre, prospective, randomized, double blind study to evaluate the safety and efficacy of 2 mg and 4 mg of Lipaglyn compared to placebo in hypertriglyceridemia with type 2 diabetes not controlled with Atorvastatin therapy. [Lipaglyn.09.002.01.1. PROT dated 19.02.2009] • Subject Enrolled: • 302 subjects • Study Duration: • 12 Weeks. • Follow-up: • 24 weeks after last dose (2-D ECHO & CV Events)

37. PRESS VI - Selection Criteria Inclusion Criteria: • Age 18- 65 years • Subjects of either gender, males or females • Subjects on treatment of T2DM for at least last 3 months or documented history of type 2 diabetes mellitus as per ADA. • Patient on stable Atorvastatin therapy (10 mg) for at least 4 weeks with LDL greater than or equal to 100mg%. • Triglycerides > 200 up to 500 mg/dl on screening visit. • Body mass index (BMI) > 23 kg/m2 • Subject has given informed consent for participation in this trial Exclusion Criteria: • Pregnancy and lactation • History of > 5% weight loss in past 6 months • Subjects on insulin • Subjects on glitazone / glitazar therapy in the past 1 month • Subjects having unstable angina, Acute MI in past 3 months or heart failure of NYHA class (III-IV). • Uncontrolled hypertension • History of clinically significant edema. • History of thyroid disorder (abnormal TSH value) or subjects on any thyroid modulating drugs • History of active liver disease or gall stones or hepatic dysfunction demonstrated by AST and ALT greater than or equal to 2.5 times of upper normal limit (UNL) or bilirubin greater than or equal to 2 times UNL. • History of myopathies or evidence of active muscle diseases demonstrated by CPK greater than or equal 10 times UNL. • History of any other concurrent serious illness ( e.g. Tuberculosis, HIV, malignancy) • History of alcohol and/or drug abuse • History of known allergy, sensitivity or intolerance to the study drugs and their formulation ingredients. • Renal dysfunction demonstrated by abnormal serum creatinine levels (> 1.2 mg %) or presence of ketonuria. • Subjects on concomitant medications known to affect the lipid level other than Atorvastatin 10 mg in past 4 weeks. • History of contraceptive, hormone replacement therapy (HRT) or steroids since last 3 months. • History of long term use of Non steroidal anti- inflammatory drugs for any treatment such as osteoarthritis, rheumatoid arthritis etc. • Participation in any other clinical trial in the past 3 months • Unable to give informed consent.

38. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Primary Efficacy Upto 51% reduction in Triglyceride

39. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy

40. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy

41. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy

42. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy Positive effects on all lipid parameters

43. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy

44. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment

45. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment

46. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment No potential Drug Induced Liver Injury (DILI)

47. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin : Safety Assessment No potential for Renal injury

48. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin : Safety Assessment No weight Gain No Oedema

49. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin Percentage of Patients Achieving ATP Goal Following Lipaglyn 4 mg Treatment as Compared to Placebo in Combination With Atorvastatin (ZYH1.09) More patients in LipaglynTM achieves ATP-III goal

50. Adverse Events • In two controlled phase III clinical studies of 12 to 24 weeks duration with lipaglyn, the most common AEs ( ≥2%) reported were gastritis, asthenia and pyrexia. • Most of the AEs were mild to moderate in nature and did not result in discontinuation of the study drug. • Because clinical studies are conducted under widely varying conditions, AEs rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Safe for Liver Safe for Muscles Safe for Heart Safe for Kidney