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Lipaglyn TM Clinical Studies. The clinical development involved a network of ~47 medical centres across India Lead medical investigators included  Endocrinologists,

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Presentation on theme: "Lipaglyn TM Clinical Studies. The clinical development involved a network of ~47 medical centres across India Lead medical investigators included  Endocrinologists,"— Presentation transcript:

1 Lipaglyn TM Clinical Studies

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

3 LIPAGLYN TM Clinical Trials: First in Man to Pivotal studies

4 Lipaglyn TM 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)www.ctri.nic.in WHO registry - (www.apps.who.int/trialsearch)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 Lipaglyn TM : 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 Lipaglyn TM 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. 6

8 Lipaglyn TM 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 (C max, AUC) was dose dependent and linear. 7

9 Lipaglyn TM is rapidly and well absorbed 8 Lipaglyn TM 4 mg Single Oral Dose PK ParametersResult C max (ng/mL) ± AUC 0-inf (hr*ng/mL) t max (hr)0.71 ± 0.25 t 1/2 (hr)2.93 ± 0.87

10 Lipaglyn TM pharmacokinetic data 9 Lipaglyn TM 4 mg OD ParameterDay 1Day 10 Cmax (ng/mL) tmax (hr) AUC 0-inf (hr*ng/mL) t 1/2 (hr) No Significant Drug Accumulation

11 Lipaglyn TM in Non-diabetic & Diabetic Dyslipidemia Phase II Studies (Proof-of-Concept Studies ) 10

12 Phase II studies Proof-of-concept of Lipaglyn TM was established in double blind studies –Lipaglyn TM doses of 0.5 to 4 mg/day were studied in, –222 male or female diabetic or non diabetic patients 11

13 Phase II studies (PRESS-I to PRESS-IV) Prospective Randomized Efficacy & Safety study of Saroglitazar Protocol2001 Ver.01 (PRESS-I) 2002 Ver.01 (PRESS-II) 2003 Ver.02 (PRESS-III) 2004* Ver.02 (PRESS-IV) SubjectsDyslipidemic and non-diabetics Dyslipidemic and diabetics Dyslipidemic with impaired glucose tolerance (IGT). Doses of Saroglitazar 0.5, 1, 2, and 4 mg OD 0.5, 1, 2, and 4 mg OD 0.5, 1, 2, and 4 mg OD ComparatorFenofibrate 160 mg Rosiglitazone 8/16 mg Pioglitazone 45 mg Pioglitazone 45 mg Number of subjects Primary objective Change in following parameter: Triglyceride (TG) Secondary objectives Change in following parameters: Low density lipoproteins (LDL) Total cholesterol (TC) Fasting glucose (FSG) Glycosylated hemoglobin (HbA1C) Insulin C - reactive protein (CRP) High density lipoproteins (HDL) Study designRandomized, double-blind, multicentre, comparative (open arm) Duration12 week *Trial was not completed due to insufficient patient recruitment.

14 Lipaglyn TM Vs Fenofibrate in Dyslipidemia in Non Diabetics Protocol 2001 PRESS-I 13

15 PRESS-I - Dose dependent decrease in TG Observed in non-diabetic subjects with dyslipidemia LSM % Change in Efficacy Parameters 0.5 mg Lipaglyn 1 mg Lipaglyn 2 mg Lipaglyn 4 mg Lipaglyn N12 13 TG

16 PRESS-II - Decrease in TG was observed in T2DM patients with dyslipidemia LSM % Change in Efficacy Parameters 0.5 mg Lipaglyn 1 mg Lipaglyn 2 mg Lipaglyn 4 mg Lipaglyn N TG

17 Lipaglyn TM shows efficacy in both diabetics and non-diabetics with dyslipidemia Lipaglyn demonstrated: –Reduction in Triglyceride levels LDL Total cholesterol Fasting plasma glucose Insulin C-reactive protein –Increase in HDL levels

18 Lipaglyn TM : 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 17

19 Lipaglyn TM in Diabetic & Dyslipidemia Subjects Phase III Studies (Pivotal trials ) 18

20 Lipaglyn TM Vs Pioglitazone In Dyslipidemia With Type 2 Diabetes Mellitus Phase III Studies Protocol ZYH1.08 PRESS-V 19

21 PRESS V: Randomized, double-blind, pivotal study with Lipaglyn TM –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 PROT dated ] –Subjects: 120 (40 subjects in each arm); Enrolled: 122 –Treatment Duration : 26 weeks –Cardiac Safety Follow-up: 24 weeks after the last dose 20

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

23 PRESS V - Selection criteria Inclusion Criteria: 1.Age years 2.Subjects of either gender, males and females 3.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. 4.Subjects with type 2 diabetes and dyslipidemia which is inadequately controlled by the life-style modifications 5.Triglycerides > 200 to 400 mg/dl on enrolment visit. 6.Body mass index (BMI) > 23 kg/m 2 7.Subject has given informed consent for participation in this trial Exclusion Criteria: 1.History of > 5% weight loss in past 6 months 2.Subjects on insulin and/or glitazone / glitazar therapy 3.Presence of ketonuria 4.BMI less than 23 kg/m2 5.Pregnancy and lactation 6.Subjects with history of MI, CABG, PTCA, unstable angina or NYHA heart failure of any Class (III-IV) regardless of therapy 7.BP> 150/100mmHg 8.Subjects with active liver disease 9.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. 10.Thyroid dysfunction demonstrated by abnormal TSH value 11.Presence of gall stone 12.Subjects with renal dysfunction (serum creatinine > 1.2 mg %) 13.Subjects with history of myopathies or evidence of active muscle diseases 14.Subject on concomitant medications known to affect the lipid level in past 2 weeks. 15.Subjects with history of any other concurrent serious illness ( e.g. tuberculosis, HIV, malignancy) 16.Subject with history of alcohol and/or drug abuse 17.Known allergy, sensitivity or intolerance to the study drugs and their formulation ingredients 18.Participation in any other clinical trial in past 3 months 19.Subjects who are unwilling or unable to give informed consent

24 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia: Primary efficacy 24 weeks mITTLipaglyn TM (Protocol ZYH1.08)Pioglitazone 2 mg (N=37)4 mg (N=39)45 mg (N=33) Triglyceride (mg/dL) Baseline Mean ± SE253.9 ± ± ± Absolute change LSM ± SE-78.2 ± # ± 17.13* # ± Percentage change LSM ± SE-26.4 ± 6.29 # ± 6.12* # ± 6.67 *Significant Compared to pioglitazone # Significant compared to baseline Up to 51% Reduction in Triglyceride

25 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy 24 weeks mITTLipaglyn TM (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) LDL-Cholesterol-Direct (mg/dL) Baseline Mean ± SE134.8 ± ± ± 5.09 Absolute change LSM ± SE3.6 ± ± 4.81* # 3.5 ± 5.30 Percentage change LSM ± SE12.2 ± ± ± 5.87 VLDL Cholesterol (mg/dL) Baseline Mean ± SE50.3 ± ± ± 3.27 Absolute change LSM ± SE-15.2 ± 3.13 # ± 3.04* # -8.8 ± 3.32 # Percentage change LSM ± SE-25.1 ± ± 5.33*-20.0 ± 5.83 *Significant Compared to pioglitazone; # Significant compared to baseline

26 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy 24 weeks mITTLipaglyn TM (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) Total Cholesterol (mg/dL) Baseline Mean ± SE202.4 ± ± ± 5.21 Absolute change LSM ± SE2.5 ± ± 5.44* # 9.1 ± 5.97 # Percentage change LSM ± SE 5.0 ± ± 3.31*5.5 ± 3.63 Apo-lipoproteins B (mg/dL) Baseline Mean ± SE101.3 ± ± ± 3.14 Absolute change LSM ± SE-5.4 ± ± 3.31 # -6.4 ± 3.65 Percentage change LSM ± SE 2.9 ± ± ± 5.12 *Significant Compared to pioglitazone; # Significant compared to baseline

27 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy 24 weeks mITTLipaglyn TM (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) HDL-Cholesterol (mg/dL) Baseline Mean ± SE36.8 ± ± ± 1.89 Absolute change LSM ± SE2.8 ± ± ± 1.24 Percentage change LSM ± SE 12.7 ± ± ± 3.76 *Significant Compared to pioglitazone; # Significant compared to baseline Favourable Lipid control

28 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy 24 weeks mITTLipaglyn TM (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) Fasting Plasma Glucose (mg/dL) Baseline Mean ± SE143.9 ± ± ± 5.56 Absolute change LSM ± SE-11.3 ± ± 6.37 # ± 6.92 Percentage change LSM ± SE-1.5 ± ± ± 5.29 HbA1C (%) Baseline Mean ± SE8.1 ± ± ± 0.13 Absolute change LSM ± SE-0.3 ± 0.11 # -0.4 ± 0.12 # *Significant Compared to pioglitazone; # Significant compared to baseline Effective Glycemic control

29 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITTLipaglyn TM (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) Hemoglobin (gm/dL) Baseline Mean ± SD 13.6 ± ± ± 1.52 Absolute change Mean ± SD -0.0 ± ± ± 0.11 hs-CRP (mg/L) Baseline Mean ± SE3.1 ± ± ± 0.59 Absolute change LSM ± SE-0.5 ± ± ±0.61 CPK (U/L) Baseline Mean ± SD91.3 ± ± ± Absolute change Mean ± SD0.3 ± ± ± 0.46

30 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITTLipaglyn (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) ALT (U/L) Baseline Mean ± SD31.5 ± ± ± 9.13 Absolute change Mean ± SD-0.1 ± ± ± 0.25 AST (U/L) Baseline Mean ± SD25.9 ± ± ± 5.81 Absolute change Mean ± SD0.2 ± ± ± 0.42 ALP (U/L) Baseline Mean ± SD81.9 ± ± ± Absolute change Mean ± SD-0.2 ± ± ± 0.24

31 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITTLipaglyn TM (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) GGTP (U/L) Baseline Mean ± SD37.6 ± ± ± Absolute change Mean ± SD-0.2 ± ± ± 0.25 No potential Drug Induced Liver Injury (DILI) -FDA standard

32 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITTLipaglyn (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) Creatinine (mg/dL) Baseline Mean ± SD0.7 ± ± ± 0.20 Absolute change Mean ± SD0.1 ± ± ± 0.20 BUN (mg/dL) Baseline Mean ± SD10.8 ± ± ± 2.74 Absolute change Mean ± SD0.1 ± ± ± 0.37 No Renal Toxicity

33 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks (Safety population) Lipaglyn (Protocol ZYH1.08 )Pioglitazone 2 mg (N=37)4 mg (N=39) 45 mg (N=33) Body weight (kg) Baseline Mean ± SD69.8 ± ± ± Absolute change Mean ± SD-0.8 ± ± ± 3.44 No weight Gain compared to pioglitazone

34 Lipaglyn TM Vs Pioglitazone in Diabetic Dyslipidemia ATP Goal * (week 24 per protocol) LIPAGLYN TM 4 mg (%) (N=34) Pioglitazone 45 mg (%) (N=22) Not achieved even one criteria Achieved one criteria Achieved two criteria Achieved all three criteria * Male : Triglyceride 40 mg/dL Female : Triglyceride 50 mg/dL 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

35 Critical ParametersBenefits Weight GainThere was no increase in the weight in Lipaglyn group, However Pioglitazone has shown an average increase of 1.6 kg Cardiovascular safety 2D Echo and ECG Examinations  No change in cardiac function No edema observed Safety and ToleranceLipaglyn demonstrated no significant change in : LFT : (No DILI) RFT: (Creatinine / eGFR) CPK Hemoglobin Lipaglyn TM Advantages Safe for heart Safe for Liver Safe for muscles Safe for Kidney

36 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin Phase III Study Protocol ZYH1.09 PRESS-VI

37 PRESS VI: Randomized Double-blind, Placebo- controlled Pivotal Study With Lipaglyn TM –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 PROT dated ] –Subject Enrolled: 302 subjects –Study Duration: 12 Weeks. –Follow-up: 24 weeks after last dose (2-D ECHO & CV Events)

38 PRESS VI - Selection Criteria Inclusion Criteria: 1.Age years 2.Subjects of either gender, males or females 3.Subjects on treatment of T2DM for at least last 3 months or documented history of type 2 diabetes mellitus as per ADA. 4.Patient on stable Atorvastatin therapy (10 mg) for at least 4 weeks with LDL greater than or equal to 100mg%. 5.Triglycerides > 200 up to 500 mg/dl on screening visit. 6.Body mass index (BMI) > 23 kg/m2 7.Subject has given informed consent for participation in this trial Exclusion Criteria: 1.Pregnancy and lactation 2.History of > 5% weight loss in past 6 months 3.Subjects on insulin 4.Subjects on glitazone / glitazar therapy in the past 1 month 5.Subjects having unstable angina, Acute MI in past 3 months or heart failure of NYHA class (III-IV). 6.Uncontrolled hypertension 7.History of clinically significant edema. 8.History of thyroid disorder (abnormal TSH value) or subjects on any thyroid modulating drugs 9.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. 10.History of myopathies or evidence of active muscle diseases demonstrated by CPK greater than or equal 10 times UNL. 11.History of any other concurrent serious illness ( e.g. Tuberculosis, HIV, malignancy) 12.History of alcohol and/or drug abuse 13.History of known allergy, sensitivity or intolerance to the study drugs and their formulation ingredients. 14.Renal dysfunction demonstrated by abnormal serum creatinine levels (> 1.2 mg %) or presence of ketonuria. 15.Subjects on concomitant medications known to affect the lipid level other than Atorvastatin 10 mg in past 4 weeks. 16.History of contraceptive, hormone replacement therapy (HRT) or steroids since last 3 months. 17.History of long term use of Non steroidal anti- inflammatory drugs for any treatment such as osteoarthritis, rheumatoid arthritis etc. 18.Participation in any other clinical trial in the past 3 months 19.Unable to give informed consent.

39 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Primary Efficacy 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Triglyceride (mg/dL) Baseline Mean ± SE273.3 ± ± ± 8.14 Absolute change LSM ± SE ± 8.30* # ± 8.29* # ± 7.93 # Percentage change LSM ± SE-45.5 ± 3.03*-46.7 ± 3.02*-24.9 ± 2.89 *Significant Compared to Placebo; # Significant compared to baseline Upto 51% reduction in Triglyceride

40 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) LDL-Cholesterol-Direct (mg/dL) Baseline Mean ± SE132.5 ± ± ± 3.46 Absolute change LSM ± SE-40.1 ± 3.01 # ± 3.00* # ± 2.88 # Percentage change LSM ± SE-27.5 ± ± 2.31*-22.9 ± 2.22 VLDL Cholesterol (mg/dL) Baseline Mean ± SE52.6 ± ± ± 1.64 Absolute change LSM ± SE-23.3 ± 2.03* # ± 2.02* # ± 1.94 # Percentage change LSM ± SE-39.6 ± 3.71*-46.0 ± 3.70*-24.5 ± 3.54 *Significant Compared to Placebo; # Significant compared to baseline

41 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Total Cholesterol (mg/dL) Baseline Mean ± SE200.6 ± ± ± 4.05 Absolute change LSM ± SE-48.7 ± 3.54 # ± 3.53* # ± 3.38 # Percentage change LSM ± SE ± 1.75*-26.1 ± 1.74*-17.7 ± 1.66 *Significant Compared to Placebo # Significant compared to baseline

42 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Apo-lipoproteins B (mg/dL) Baseline Mean ± SE98.2 ± ± ± 2.40 Absolute change LSM ± SE-29.9 ± 2.11 # ± 2.09* # ± 2.00 # Percentage change LSM ± SE ± ± 2.15*-22.9 ± 2.06 HDL-Cholesterol (mg/dL) Baseline Mean ± SE36.6 ± ± ± 1.24 Absolute change LSM ± SE2.5 ± 0.89* # 1.3 ± 0.89*-1.6 ± 0.85 Percentage change LSM ± SE 9.5 ± 2.36*7.6 ± 2.36*-0.7 ± 2.26 *Significant Compared to Placebo; # Significant compared to baseline

43 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Non-HDL-Cholesterol (mg/dL) Baseline Mean ± SE164.0 ± ± ± 4.22 Absolute change LSM ± SE ± 3.59* # ± 3.58* # ± 3.43 # Percentage change LSM ± SE ± 2.25*-32.5 ± 2.25*-20.1 ± 2.15 *Significant Compared to Placebo; # Significant compared to baseline Positive effects on all lipid parameters

44 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITT Lipaglyn TM (Protocol ZYH1.09 ) Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Fasting Plasma Glucose (mg/dL) Baseline Mean ± SD179.6 ± ± ± Absolute change LSM ± SE-23.6 ± 7.92* # ± 7.92* # -2.0 ± 7.58 Percentage change LSM ± SE-9.5 ± 4.85*-4.7 ± ± 4.64 HbA1C (%) Baseline Mean ± SE8.9 ± ± ± 0.19 Absolute change LSM ± SE-0.3 ± 0.08 # -0.2 ± 0.07 # *Significant Compared to Placebo; # Significant compared to baseline

45 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Hemoglobin (gm/dL) Baseline Mean ± SD13.9 ± ± ± 1.92 Absolute change Mean ± SD-0.4 ± ± ± 0.86 hs-CRP (mg/L) Baseline Mean ± SD4.0 ± ± ± 6.91 Absolute change LSM ± SE-1.0 ± ± ± 0.37 CPK (U/L) Baseline Mean ± SD93.3 ± ± ± Absolute change Mean ± SD8.4 ± ± ± 69.26

46 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) ALT (U/L) Baseline Mean ± SD26.9 ± ± ± Absolute change Mean ± SD -4.0 ± ± ± AST (U/L) Baseline Mean ± SD23.8 ± ± ± Absolute change Mean ± SD 1.1 ± ± ± ALP (U/L) Baseline Mean ± SD83.6 ± ± ± Absolute change Mean ± SD ± ± ±

47 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) GGTP (U/L) Baseline Mean ± SD38.6 ± ± ± Absolute change Mean ± SD ± ± ± No potential Drug Induced Liver Injury (DILI)

48 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin : Safety Assessment 12 weeks ITTLipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)Placebo (N=94) Creatinine (mg/dL) Baseline Mean ± SD0.8 ± 0.22 Absolute change Mean ± SD0.0 ± ± ± 0.21 Creatinine Clearance (mL/min) Baseline Mean ± SD117.9 ± ± ± Absolute change Mean ± SD-12.1 ± ± ± BUN (mg/dL) Baseline Mean ± SD11.1 ± ± ± 3.40 Absolute change Mean ± SD0.4 ± ± ± 4.29 No potential for Renal injury

49 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin : Safety Assessment 12 weeks (Safety Population)Lipaglyn TM (Protocol ZYH1.09 )Placebo 2 mg (N=86)4 mg (N=86)(N=94) Body weight (kg) Baseline Mean ± SD71.3 ± ± ± Absolute change Mean ± SD-0.6 ± ± ± 2.40 *Significant Compared to Placebo No weight Gain No Oedema

50 Lipaglyn TM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin ATP Goal * (12 week) LIPAGLYN TM 4 mg + Atorvastatin 10 mg (%) Placebo + Atorvastatin 10 mg (%) Not achieved even one criteria10.3 # 30.1 # Achieved one criteria Achieved two criteria Achieved all three criteria * Male : Triglyceride 40 mg/dL Female : Triglyceride 50 mg/dL Percentage of Patients Achieving ATP Goal Following Lipaglyn 4 mg Treatment as Compared to Placebo in Combination With Atorvastatin (ZYH1.09) More patients in Lipaglyn TM achieves ATP-III goal

51 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 Heart Safe for Liver Safe for Muscles Safe for Kidney

52 51 Lipaglyn Phase-3 Trial Abstracts have been published in a Supplement of Diabetes Journal (Vol 61, Suppl. 1A, 2012)

53 Phase-3 Clinical Data of Lipaglyn TM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USA

54 No weight gain No potential for edema First-in-class drug in the world to treat diabetic dyslipidemia – a global unmet healthcare need Novel action with an excellent safety profile World’s 1 st approved Glitazar Has a non-renal route of elimination No CV adverse events No potential for liver, kidney and muscle toxicity Lipaglyn TM : A Unique First-in-class Medicine With Both Lipid and Glucose Lowering Effects in One Single Molecule

55 Lipaglyn TM : Product Profile Drug NameLipaglyn TM Generic NameSaroglitazar IndicationLipaglyn is indicated for diabetic dyslipidemia & hypertriglyceridemia with type 2 diabetes mellitus not controlled by statins DosageTablet 4 mg DosingOnce daily oral dosing In different clinical trials, Lipaglyn TM has been used in patients who were concurrently on atorvastatin or metformin and / or sulfonylureas. No drug-drug interactions were reported. Although there is no report of hypoglycaemia following Lipaglyn TM treatment in healthy subjects or patients during the trials, it is advisable to monitor blood glucose levels in patients who are one or more anti-diabetic drugs specially on insulin. Concurrent administration of Lipaglyn TM with any other PPAR-α and/or PPAR-γ agonist is not recommended, as there is potential for drug-drug interactions mechanistically. Like other PPAR-α/γ agonists, Lipaglyn TM has not been studied for such drug-drug interactions.

56 Proposed place of Lipaglyn TM in the treatment of Diabetic Dyslipidemia

57 Atherogenic Diabetic Dyslipidemia (ADD) is an important CVD risk factor. Indians are at higher risk of ADD due to genetic, dietary and lifestyle factors. Though statins reduce CV complications in diabetic patients by 20-30%, a significant residual CV risk remains a concern. Hypertriglyceridemia is one of the important causes for this residual risk Hypertriglyceridemia also causes significant insulin resistance, Atherogenicity and inflammatory changes in the body, which increase CV risk. Non-HDL is now considered a better indicator of CV risk than LDL or ApoB Optimal glycemic control is important for reducing the CV events in diabetic patients. Though Metformin is very effective for reducing CV complications in diabetic patients, most of them can not achieve optimal glycemic control with metformin alone. Summary

58 PPAR gamma agonists are effective insulin sensitizers and they when administered with metformin, helps to achieve glycemic control. Both PPAR- α and PPAR-γ agonists have shown CV benefits individually in diabetic patients. So, there is a possibility that dual PPAR- α / γ agonists can improve CV outcomes with lesser side effects in diabetic patients. Lipaglyn TM is a novel dual PPAR- α / γ agonist with 1000 times more selectivity for PPAR- α over PPAR- γ. Lipaglyn TM is the 1st PPAR dual agonists to be approved in the world. Summary

59 Lipaglyn TM has shown significant reduction in serum TG (up to 47%) and also moderate improvement in the glycemic control in diabetic dyslipidemia. Phase III studies has shown that it is also safe and does not cause adverse effects of PPAR- α agonists (increasing myopathy risk with statins, reduced GFR) and PPAR-γ agonists (weight gain, edema). Use of Lipaglyn TM in diabetic dyslipidemia will help the clinician to improve the glycemic control and lipid profile at the same time. Summary

60 Zydus Research Centre, Ahmedabad The place of birth for Saroglitazar

61 60 Thank you This presentation is the property of Cadila Healthcare Limited. Under no circumstances the information contained in this presentation should be quoted, distributed, copied, reproduced or retrieved, in part or whole, in any form, written, verbal and/or electronic format without the expressed permission from: Registered Office: Cadila Healthcare Limited, Zydus Tower, Satellite Cross Road, Ahmedabad , India


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