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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, Diabetologists, Cardiologists and Physicians Clinical Trials: First in Man to Pivotal studies LIPAGLYNTM 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 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 LipaglynTM in Healthy Volunteers Phase I Study (First-in-Man Studies) 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 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. 7 LipaglynTM is rapidly and well absorbed LipaglynTM 4 mg Single Oral Dose PK Parameters Result Cmax(ng/mL) 337.07 ± 90.99 AUC0-inf (hr*ng/mL) 855.96+172.53 t max(hr) 0.71 ± 0.25 t1/2(hr) 2.93 ± 0.87 8 LipaglynTM pharmacokinetic data LipaglynTM 4 mg OD Parameter Day 1 Day 10 Cmax (ng/mL) 332.23 + 87.21 335.68 + 147.31 tmax (hr) 0.67 + 0.13 0.92 + 0.58 AUC0-inf (hr*ng/mL) 955.54 + 250.08 965.37 + 266.52 t1/2 (hr) 3.75 + 1.50 3.76 + 1.98 No Significant Drug Accumulation 9 LipaglynTM in Non-diabetic & Diabetic Dyslipidemia Phase II Studies (Proof-of-Concept Studies) 10 Phase II studies Proof-of-concept of LipaglynTM was established in double blind studies – LipaglynTM doses of 0.5 to 4 mg/day were studied in, – 222 male or female diabetic or non diabetic patients 11 Phase II studies (PRESS-I to PRESS-IV) Prospective Randomized Efficacy & Safety study of Saroglitazar 2001 Ver.01 (PRESS-I) Dyslipidemic and non-diabetics 2002 Ver.01 (PRESS-II) Dyslipidemic and diabetics 2003 Ver.02 (PRESS-III) Dyslipidemic and diabetics 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 0.5, 1, 2, and 4 mg OD mg OD Comparator Fenofibrate 160 mg Rosiglitazone 8/16 mg Pioglitazone 45 mg Pioglitazone 45 mg Number of subjects 63 66 66 27 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) Protocol Subjects 2004* Ver.02 (PRESS-IV) Dyslipidemic with impaired glucose tolerance (IGT). Study design Randomized, double-blind, multicentre, comparative (open arm) Duration 12 week *Trial was not completed due to insufficient patient recruitment. LipaglynTM Vs Fenofibrate in Dyslipidemia in Non Diabetics Protocol 2001 PRESS-I 13 PRESS-I - Dose dependent decrease in TG Observed in non-diabetic subjects with dyslipidemia Percent Changes - Protocol 2001 0 -5 LSM % Change in Efficacy Parameters LSM % Change -10 0.5 mg Lipaglyn 1 mg Lipaglyn 2 mg Lipaglyn 4 mg Lipaglyn N 12 12 12 13 TG -19.92 -16.30 -28.72 -37.83 -15 -16.3 -20 -19.92 -25 -30 -28.72 -35 -40 -37.83 -45 0.5mg Saroglitazar 2mg Saroglitazar 1mg Saroglitazar 4mg Saroglitazar PRESS-II - Decrease in TG was observed in T2DM patients with dyslipidemia Percent Changes from base line : Study 2002 & 2003 L S M % 5 0 -5 LSM % Change in Efficacy Parameters C -10 h a -15 n g -20 e 1 mg Lipaglyn 2 mg Lipaglyn 4 mg Lipaglyn N 25 29 26 25 TG -18.38 -15.17 -31.67 -30.6 -15.17 -18.38 -25 -30 -35 0.5 mg Lipaglyn -31.67 0.5mg Saroglitazar 2mg Saroglitazar -30.6 1mg Saroglitazar 4mg Saroglitazar 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 17 LipaglynTM in Diabetic & Dyslipidemia Subjects Phase III Studies (Pivotal trials) 18 LipaglynTM Vs Pioglitazone In Dyslipidemia With Type 2 Diabetes Mellitus Phase III Studies Protocol ZYH1.08 PRESS-V 19 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 20 Study design Study Duration: 24 weeks Follow-up: 24 weeks after last dose 21 PRESS V - Selection criteria Inclusion Criteria: Exclusion Criteria: 1. 2. 1. 2. 3. 4. 5. 6. 3. 4. 5. 6. 7. 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 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 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 LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Primary efficacy 24 weeks mITT LipaglynTM (Protocol ZYH1.08) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) Baseline Mean ± SE 253.9 ± 11.25 257.0 ± 8.39 265.0 ± 10.73 Absolute change LSM ± SE -78.2 ± 17.60# -115.4 ± 17.13*# -33.3 ± 18.65 Percentage change LSM ± SE -26.4 ± 6.29# -45.0 ± 6.12*# -15.5 ± 6.67 Triglyceride (mg/dL) *Significant Compared to pioglitazone # Significant compared to baseline Up to 51% Reduction in Triglyceride LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy LipaglynTM (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) 134.8 ± 7.00 130.8 ± 6.22 116.6 ± 5.09 Absolute change LSM ± SE 3.6 ± 4.96 -12.0 ± 4.81*# 3.5 ± 5.30 Percentage change LSM ± SE 12.2 ± 5.50 -5.0 ± 5.33 4.8 ± 5.87 50.3 ± 2.33 52.4 ± 1.98 55.1 ± 3.27 Absolute change LSM ± SE -15.2 ± 3.13# -23.9 ± 3.04*# -8.8 ± 3.32# Percentage change LSM ± SE -25.1 ± 5.50 -45.5 ± 5.33* -20.0 ± 5.83 24 weeks mITT LDL-Cholesterol-Direct (mg/dL) Baseline Mean ± SE VLDL Cholesterol (mg/dL) Baseline Mean ± SE *Significant Compared to pioglitazone; # Significant compared to baseline LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy LipaglynTM (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) 202.4 ± 7.83 197.3 ± 6.56 185.8 ± 5.21 Absolute change LSM ± SE 2.5 ± 5.61 -18.5 ± 5.44*# 9.1 ± 5.97# Percentage change LSM ± SE 5.0 ± 3.42 -7.7 ± 3.31* 5.5 ± 3.63 101.3 ± 4.40 98.3 ± 4.00 89.3 ± 3.14 Absolute change LSM ± SE -5.4 ± 3.42 -13.4 ± 3.31# -6.4 ± 3.65 Percentage change LSM ± SE 2.9 ± 4.80 -10.9 ± 4.65 -4.8 ± 5.12 24 weeks mITT Total Cholesterol (mg/dL) Baseline Mean ± SE Apo-lipoproteins B (mg/dL) Baseline Mean ± SE *Significant Compared to pioglitazone; # Significant compared to baseline LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy LipaglynTM (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) Baseline Mean ± SE 36.8 ± 1.99 35.3 ± 1.54 38.3 ± 1.89 Absolute change LSM ± SE 2.8 ± 1.16 0.2 ± 1.14 2.0 ± 1.24 Percentage change LSM ± SE 12.7 ± 3.54 3.8 ± 3.46 7.1 ± 3.76 24 weeks mITT HDL-Cholesterol (mg/dL) *Significant Compared to pioglitazone; # Significant compared to baseline LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy LipaglynTM (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) Baseline Mean ± SE 143.9 ± 6.96 152.7 ± 10.57 138.2 ± 5.56 Absolute change LSM ± SE -11.3 ± 6.51 -22.6 ± 6.37# -21.8 ± 6.92 Percentage change LSM ± SE -1.5 ± 4.98 -8.3 ± 4.87 -12.8 ± 5.29 8.1 ± 0.14 7.9 ± 0.09 8.2 ± 0.13 -0.3 ± 0.11# -0.3 ± 0.11# -0.4 ± 0.12# 24 weeks mITT Fasting Plasma Glucose (mg/dL) HbA1C (%) Baseline Mean ± SE Absolute change LSM ± SE *Significant Compared to pioglitazone; # Significant compared to baseline LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment LipaglynTM (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) 13.6 ± 1.95 13.7 ± 1.71 13.5 ± 1.52 -0.0 ± 0.06 -0.0 ± 0.08 -0.0 ± 0.11 Baseline Mean ± SE 3.1 ± 0.53 4.5 ± 0.85 3.3 ± 0.59 Absolute change LSM ± SE -0.5 ± 0.57 -0.6 ±0.56 -0.7 ±0.61 91.3 ± 62.48 96.3 ± 49.40 97.2 ± 47.82 0.3 ± 0.94 0.3 ± 0.49 0.3 ± 0.46 24 weeks mITT Hemoglobin (gm/dL) Baseline Mean ± SD Absolute change Mean ± SD hs-CRP (mg/L) CPK (U/L) Baseline Mean ± SD Absolute change Mean ± SD LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITT Lipaglyn (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) 31.5 ± 16.48 29.7 ± 15.91 26.3 ± 9.13 -0.1 ± 0.36 -0.2 ± 0.30 -0.2 ± 0.25 25.9 ± 15.75 23.6 ± 9.69 22.1 ± 5.81 0.2 ± 0.63 0.1 ± 0.43 0.0 ± 0.42 81.9 ± 24.93 85.0 ± 31.78 84.1 ± 26.57 -0.2 ± 0.28 -0.2 ± 0.56 -0.1 ± 0.24 ALT (U/L) Baseline Mean ± SD Absolute change Mean ± SD AST (U/L) Baseline Mean ± SD Absolute change Mean ± SD ALP (U/L) Baseline Mean ± SD Absolute change Mean ± SD LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITT LipaglynTM (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) 37.6 ± 22.85 35.3 ± 18.75 36.4 ± 22.86 -0.2 ± 0.40 -0.3 ± 0.43 -0.3 ± 0.25 GGTP (U/L) Baseline Mean ± SD Absolute change Mean ± SD No potential Drug Induced Liver Injury (DILI) -FDA standard LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment 24 weeks mITT Lipaglyn (Protocol ZYH1.08 ) Pioglitazone 2 mg (N=37) 4 mg (N=39) 45 mg (N=33) Baseline Mean ± SD 0.7 ± 0.21 0.7 ± 0.19 0.7 ± 0.20 Absolute change Mean ± SD 0.1 ± 0.26 0.2 ± 0.44 0.0 ± 0.20 Baseline Mean ± SD 10.8 ± 3.66 9.5 ± 2.75 11.1 ± 2.74 Absolute change Mean ± SD 0.1 ± 0.28 0.2 ± 0.47 0.2 ± 0.37 Creatinine (mg/dL) BUN (mg/dL) No Renal Toxicity LipaglynTM 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) 69.8 ± 12.72 73.0 ± 11.49 71.0 ± 12.94 -0.8 ± 5.35 -0.1 ± 2.70 1.6 ± 3.44 Body weight (kg) Baseline Mean ± SD Absolute change Mean ± SD No weight Gain compared to pioglitazone 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) LIPAGLYNTM 4 mg (%) (N=34) Pioglitazone 45 mg (%) (N=22) Not achieved even one criteria 29.4 50.0 Achieved one criteria 26.5 22.7 Achieved two criteria 35.3 27.3 Achieved all three criteria 8.8 0.0 ATP Goal * (week 24 per protocol) * Male : Triglyceride < 150 mg/dL, LDL < 100 mg/dL, HDL > 40 mg/dL Female : Triglyceride < 150 mg/dL, LDL < 100 mg/dL, HDL > 50 mg/dL More patients in Lipaglyn achieves ATP-III goal LipaglynTM Advantages Critical Parameters Benefits Weight Gain • There 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 Tolerance Lipaglyn demonstrated no significant change in : • • • • Safe for heart Safe for Liver LFT : (No DILI) RFT: (Creatinine / eGFR) CPK Hemoglobin Safe for Kidney Safe for muscles LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin Phase III Study Protocol ZYH1.09 PRESS-VI PRESS VI: Randomized Double-blind, Placebocontrolled 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) PRESS VI - Selection Criteria Inclusion Criteria: 1. Age 18- 65 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. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 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. LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Primary Efficacy 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) 273.3 ± 8.47 287.3 ± 9.27 286.6 ± 8.14 -132.7 ± 8.30*# -139.5 ± 8.29*# -78.0 ± 7.93# -45.5 ± 3.03* -46.7 ± 3.02* -24.9 ± 2.89 Triglyceride (mg/dL) Baseline Mean ± SE Absolute change LSM ± SE Percentage change LSM ± SE *Significant Compared to Placebo; # Significant compared to baseline Upto 51% reduction in Triglyceride LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) Baseline Mean ± SE 132.5 ± 3.28 140.2 ± 3.17 140.1 ± 3.46 Absolute change LSM ± SE -40.1 ± 3.01# -45.5 ± 3.00*# -35.6 ± 2.88# Percentage change LSM ± SE -27.5 ± 2.31 -31.3 ± 2.31* -22.9 ± 2.22 52.6 ± 1.77 57.2 ± 1.88 57.1 ± 1.64 Absolute change LSM ± SE -23.3 ± 2.03*# -27.2 ± 2.02*# -15.0 ± 1.94# Percentage change LSM ± SE -39.6 ± 3.71* -46.0 ± 3.70* -24.5 ± 3.54 LDL-Cholesterol-Direct (mg/dL) VLDL Cholesterol (mg/dL) Baseline Mean ± SE *Significant Compared to Placebo; # Significant compared to baseline LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) Baseline Mean ± SE 200.6 ± 4.11 210.4 ± 4.01 209.5 ± 4.05 Absolute change LSM ± SE -48.7 ± 3.54# -56.4 ± 3.53*# -40.3 ± 3.38# Percentage change LSM ± SE -22.6 ± 1.75* -26.1 ± 1.74* -17.7 ± 1.66 Total Cholesterol (mg/dL) *Significant Compared to Placebo # Significant compared to baseline LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) 98.2 ± 2.36 101.7 ± 2.30 104.1 ± 2.40 Absolute change LSM ± SE -29.9 ± 2.11# -34.3 ± 2.09*# -25.6 ± 2.00# Percentage change LSM ± SE -27.4 ± 2.17 -32.0 ± 2.15* -22.9 ± 2.06 Baseline Mean ± SE 36.6 ± 0.91 39.1 ± 1.21 38.5 ± 1.24 Absolute change LSM ± SE 2.5 ± 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 Apo-lipoproteins B (mg/dL) Baseline Mean ± SE HDL-Cholesterol (mg/dL) *Significant Compared to Placebo; # Significant compared to baseline LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) 2 mg (N=86) Placebo 4 mg (N=86) Placebo (N=94) 164.0 ± 3.98 171.3 ± 4.07 171.0 ± 4.22 -51.4 ± 3.59*# -57.7 ± 3.58*# -38.6 ± 3.43# -29.2 ± 2.25* -32.5 ± 2.25* -20.1 ± 2.15 Non-HDL-Cholesterol (mg/dL) Baseline Mean ± SE Absolute change LSM ± SE Percentage change LSM ± SE *Significant Compared to Placebo; # Significant compared to baseline Positive effects on all lipid parameters LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Secondary Efficacy LipaglynTM (Protocol ZYH1.09 ) 12 weeks ITT 2 mg (N=86) Placebo 4 mg (N=86) Placebo (N=94) Fasting Plasma Glucose (mg/dL) Baseline Mean ± SD 179.6 ± 71.23 176.3 ± 71.58 184.1 ± 68.27 Absolute change LSM ± SE -23.6 ± 7.92*# -25.4 ± 7.92*# -2.0 ± 7.58 -9.5 ± 4.85* -4.7 ± 4.85 4.7 ± 4.64 8.9 ± 0.20 8.9 ± 0.19 9.2 ± 0.19 -0.3 ± 0.08# -0.3 ± 0.08# -0.2 ± 0.07# Percentage change LSM ± SE HbA1C (%) Baseline Mean ± SE Absolute change LSM ± SE *Significant Compared to Placebo; # Significant compared to baseline LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) Baseline Mean ± SD 13.9 ± 1.85 13.7 ± 1.72 13.9 ± 1.92 Absolute change Mean ± SD -0.4 ± 1.46 -0.7 ± 0.79 -0.2 ± 0.86 Baseline Mean ± SD 4.0 ± 4.47 3.6 ± 5.25 4.4 ± 6.91 Absolute change LSM ± SE -1.0 ± 0.39 -1.1 ± 0.39 -0.1 ± 0.37 Baseline Mean ± SD 93.3 ± 51.90 85.5 ± 43.67 96.1 ± 63.79 Absolute change Mean ± SD 8.4 ± 53.41 32.3 ± 61.27 5.7 ± 69.26 Hemoglobin (gm/dL) hs-CRP (mg/L) CPK (U/L) LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) Baseline Mean ± SD 26.9 ± 14.46 26.6 ± 15.70 27.9 ± 14.00 Absolute change Mean ± SD -4.0 ± 13.73 -3.9 ± 15.21 -0.7 ± 12.46 Baseline Mean ± SD 23.8 ± 11.11 24.0 ± 12.61 24.4 ± 10.72 Absolute change Mean ± SD 1.1 ± 12.86 0.5 ± 13.09 0.7 ± 16.32 Baseline Mean ± SD 83.6 ± 26.51 87.7 ± 23.93 86.7 ± 22.55 Absolute change Mean ± SD -16.3 ± 22.34 -29.0 ± 22.48 -2.5 ± 20.96 ALT (U/L) AST (U/L) ALP (U/L) 45 LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin: Safety Assessment 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) Baseline Mean ± SD 38.6 ± 36.00 35.9 ± 26.87 36.8 ± 22.82 Absolute change Mean ± SD -12.0 ± 25.49 -16.2 ± 22.83 -1.1 ± 14.63 GGTP (U/L) No potential Drug Induced Liver Injury (DILI) LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin : Safety Assessment 12 weeks ITT LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) Placebo (N=94) Baseline Mean ± SD 0.8 ± 0.22 0.8 ± 0.22 0.8 ± 0.22 Absolute change Mean ± SD 0.0 ± 0.18 0.1 ± 0.20 0.0 ± 0.21 Baseline Mean ± SD 117.9 ± 45.92 110.6 ± 42.18 115.6 ± 38.95 Absolute change Mean ± SD -12.1 ± 35.27 -7.4 ± 26.34 -4.9 ± 32.12 Baseline Mean ± SD 11.1 ± 3.20 11.1 ± 3.90 11.4 ± 3.40 Absolute change Mean ± SD 0.4 ± 4.13 1.0 ± 3.66 -0.3 ± 4.29 Creatinine (mg/dL) Creatinine Clearance (mL/min) BUN (mg/dL) LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin : Safety Assessment 12 weeks (Safety Population) LipaglynTM (Protocol ZYH1.09 ) Placebo 2 mg (N=86) 4 mg (N=86) (N=94) 71.3 ± 13.56 69.1 ± 10.83 69.9 ± 11.53 -0.6 ± 2.63 0.3 ± 2.83 -0.5 ± 2.40 Body weight (kg) Baseline Mean ± SD Absolute change Mean ± SD *Significant Compared to Placebo No weight Gain No Oedema 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) LIPAGLYNTM 4 mg + Atorvastatin 10 mg (%) Placebo + Atorvastatin 10 mg (%) Not achieved even one criteria 10.3# 30.1# Achieved one criteria 30.8 38.6 Achieved two criteria 43.6 24.1 Achieved all three criteria 15.4 6.0 ATP Goal * (12 week) * Male : Triglyceride < 150 mg/dL, LDL < 100 mg/dL, HDL > 40 mg/dL Female : Triglyceride < 150 mg/dL, LDL < 100 mg/dL, HDL > 50 mg/dL More patients in LipaglynTM achieves ATP-III goal 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 Kidney Safe for Muscles Lipaglyn Phase-3 Trial Abstracts have been published in a Supplement of Diabetes Journal (Vol 61, Suppl. 1A, 2012) 51 LipaglynTM: A Unique First-in-class Medicine With Both Lipid and Glucose Lowering Effects in One Single Molecule LipaglynTM: Product Profile Drug Name Lipaglyn TM Generic Name Saroglitazar Indication Lipaglyn is indicated for diabetic dyslipidemia & hypertriglyceridemia with type 2 diabetes mellitus not controlled by statins Dosage Tablet 4 mg Dosing Once daily oral dosing In different clinical trials, LipaglynTM 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 LipaglynTM 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 LipaglynTM 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, LipaglynTM has not been studied for such drug-drug interactions. Proposed place of LipaglynTM in the treatment of Diabetic Dyslipidemia Summary • 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 • 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. • LipaglynTM is a novel dual PPAR-α/γ agonist with 1000 times more selectivity for PPAR-α over PPAR-γ. • LipaglynTM is the 1st PPAR dual agonists to be approved in the world. Summary • LipaglynTM 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 LipaglynTM in diabetic dyslipidemia will help the clinician to improve the glycemic control and lipid profile at the same time. Zydus Research Centre, Ahmedabad The place of birth for Saroglitazar 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-380016, India