Lipaglyn TM Clinical Studies

LipaglynTM Clinical Studies

The clinical development involved a network of ~47 medical centres across India

Lead medical investigators included

Endocrinologists,

Diabetologists,

Cardiologists and

Physicians

LIPAGLYNTM

Clinical Trials: First in Man to Pivotal studies

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 LaboratoriesCAP – College of American PathologistsCTRI – Clinical Trial Registries of India

http://www.ctri.nic.in/

http://www.apps.who.int/trialsearch

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.

7

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.

8

LipaglynTM is rapidly and well absorbed

9

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

LipaglynTM pharmacokinetic data

10

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

LipaglynTM in Non-diabetic & Diabetic Dyslipidemia

Phase II Studies

(Proof-of-Concept Studies)

11

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

12

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

Protocol 2001 Ver.01 (PRESS-I)

2002 Ver.01(PRESS-II)

2003 Ver.02(PRESS-III)

2004* Ver.02(PRESS-IV)

Subjects Dyslipidemic and non-diabetics

Dyslipidemic and 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

0.5, 1, 2, and 4 mg OD

Comparator Fenofibrate 160 mg

Rosiglitazone8/16 mg

Pioglitazone45 mg

Pioglitazone45 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)

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

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

LSM % Change in Efficacy Parameters

0.5 mg

Lipaglyn1 mg

Lipaglyn2 mg

Lipaglyn4 mg

Lipaglyn

N 12 12 12 13

TG -19.92 -16.30 -28.72 -37.83

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

-19.92

-16.3

-28.72

-37.83

Percent Changes - Protocol 2001

FSG

LSM

% C

hang

e

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 25 29 26 25

TG -18.38 -15.17 -31.67 -30.6

-35

-30

-25

-20

-15

-10

-5

0

5

-18.38

-15.17

-31.67 -30.6

Percent Changes from base line : Study 2002 & 2003

TG

LSM % Change

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

MellitusPhase III StudiesProtocol 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

22

Study Duration: 24 weeksFollow-up: 24 weeks after last dose

PRESS V - Selection criteria

Inclusion Criteria:1. Age 18- 65 years2. Subjects of either gender,

males and females3. 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/m2

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

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)

Triglyceride (mg/dL)

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

*Significant Compared to pioglitazone # Significant compared to baseline

Up to 51% Reduction inTriglyceride

LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia: Secondary efficacy

24 weeks mITT LipaglynTM (Protocol ZYH1.08 ) Pioglitazone

2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

LDL-Cholesterol-Direct (mg/dL)

Baseline Mean ± SE 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

VLDL Cholesterol (mg/dL)

Baseline Mean ± SE 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

*Significant Compared to pioglitazone; # Significant compared to baseline



2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

Total Cholesterol (mg/dL)

Baseline Mean ± SE 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

Apo-lipoproteins B (mg/dL)

Baseline Mean ± SE 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




2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

HDL-Cholesterol (mg/dL)

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


Favourable

Lipid control



2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

Fasting Plasma Glucose (mg/dL)

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

HbA1C (%)

Baseline Mean ± SE 8.1 ± 0.14 7.9 ± 0.09 8.2 ± 0.13

Absolute change LSM ± SE -0.3 ± 0.11# -0.3 ± 0.11# -0.4 ± 0.12#

*Significant Compared to pioglitazone; # Significant compared to baselineEffective

Glycemic control

LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia Safety Assessment


2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

Hemoglobin (gm/dL)

Baseline Mean ± SD13.6 ± 1.95 13.7 ± 1.71 13.5 ± 1.52

Absolute change Mean ± SD-0.0 ± 0.06 -0.0 ± 0.08 -0.0 ± 0.11

hs-CRP (mg/L)

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

CPK (U/L)

Baseline Mean ± SD 91.3 ± 62.48 96.3 ± 49.40 97.2 ± 47.82

Absolute change Mean ± SD 0.3 ± 0.94 0.3 ± 0.49 0.3 ± 0.46


24 weeks mITT Lipaglyn (Protocol ZYH1.08 ) Pioglitazone

2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

ALT (U/L)

Baseline Mean ± SD 31.5 ± 16.48 29.7 ± 15.91 26.3 ± 9.13

Absolute change Mean ± SD -0.1 ± 0.36 -0.2 ± 0.30 -0.2 ± 0.25

AST (U/L)

Baseline Mean ± SD 25.9 ± 15.75 23.6 ± 9.69 22.1 ± 5.81


ALP (U/L)

Baseline Mean ± SD 81.9 ± 24.93 85.0 ± 31.78 84.1 ± 26.57




2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

GGTP (U/L)

Baseline Mean ± SD 37.6 ± 22.85 35.3 ± 18.75 36.4 ± 22.86


No potential Drug Induced Liver Injury (DILI)

-FDA standard


24 weeks mITT Lipaglyn (Protocol ZYH1.08 ) Pioglitazone

2 mg (N=37) 4 mg (N=39) 45 mg (N=33)

Creatinine (mg/dL)

Baseline Mean ± SD 0.7 ± 0.21 0.7 ± 0.19 0.7 ± 0.20


BUN (mg/dL)

Baseline Mean ± SD 10.8 ± 3.66 9.5 ± 2.75 11.1 ± 2.74


No Renal Toxicity


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 ± SD 69.8 ± 12.72 73.0 ± 11.49 71.0 ± 12.94

Absolute change Mean ± SD -0.8 ± 5.35 -0.1 ± 2.70 1.6 ± 3.44

No weight Gain compared to pioglitazone

LipaglynTM Vs Pioglitazone in Diabetic Dyslipidemia

ATP Goal * (week 24 per protocol)

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

* 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

Percentage of Patients Achieving ATP III Goal Following Saroglitazar4 mg Treatment as Compared to Pioglitazone (Protocol ZYH1.08)

More patients in Lipaglyn achieves ATP-III goal

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 :

• LFT : (No DILI)• RFT: (Creatinine / eGFR)• CPK • Hemoglobin

LipaglynTM Advantages

Safe for heart

Safe for Liver

Safe for muscles

Safe for Kidney

LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by

Atorvastatin

Phase III StudyProtocol ZYH1.09

PRESS-VI

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)

PRESS VI - Selection Criteria

Inclusion Criteria:1. Age 18- 65 years2. Subjects of either gender,

males or females3. 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 lactation2. 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.

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)

Triglyceride (mg/dL)

Baseline Mean ± SE 273.3 ± 8.47 287.3 ± 9.27 286.6 ± 8.14

Absolute change LSM ± SE -132.7 ± 8.30*# -139.5 ± 8.29*# -78.0 ± 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 inTriglyceride

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


2 mg (N=86) 4 mg (N=86) Placebo (N=94)

LDL-Cholesterol-Direct (mg/dL)

Baseline Mean ± SE 132.5 ± 3.28 140.2 ± 3.17 140.1 ± 3.46



VLDL Cholesterol (mg/dL)

Baseline Mean ± SE 52.6 ± 1.77 57.2 ± 1.88 57.1 ± 1.64






2 mg (N=86) 4 mg (N=86) Placebo (N=94)

Total Cholesterol (mg/dL)

Baseline Mean ± SE 200.6 ± 4.11 210.4 ± 4.01 209.5 ± 4.05



*Significant Compared to Placebo # Significant compared to baseline



2 mg (N=86) 4 mg (N=86) Placebo (N=94)

Apo-lipoproteins B (mg/dL)

Baseline Mean ± SE 98.2 ± 2.36 101.7 ± 2.30 104.1 ± 2.40



HDL-Cholesterol (mg/dL)

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




2 mg (N=86) 4 mg (N=86) Placebo (N=94)

Non-HDL-Cholesterol (mg/dL)

Baseline Mean ± SE 164.0 ± 3.98 171.3 ± 4.07 171.0 ± 4.22




Positive effects on all lipid

parameters



2 mg (N=86) 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

Percentage change LSM ± SE -9.5 ± 4.85* -4.7 ± 4.85 4.7 ± 4.64

HbA1C (%)

Baseline Mean ± SE 8.9 ± 0.20 8.9 ± 0.19 9.2 ± 0.19

Absolute change LSM ± SE -0.3 ± 0.08# -0.3 ± 0.08# -0.2 ± 0.07#


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


2 mg (N=86) 4 mg (N=86) Placebo (N=94)

Hemoglobin (gm/dL)

Baseline Mean ± SD 13.9 ± 1.85 13.7 ± 1.72 13.9 ± 1.92


hs-CRP (mg/L)

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

CPK (U/L)

Baseline Mean ± SD 93.3 ± 51.90 85.5 ± 43.67 96.1 ± 63.79




2 mg (N=86) 4 mg (N=86) Placebo (N=94)

ALT (U/L)

Baseline Mean ± SD 26.9 ± 14.46 26.6 ± 15.70 27.9 ± 14.00


AST (U/L)

Baseline Mean ± SD 23.8 ± 11.11 24.0 ± 12.61 24.4 ± 10.72


ALP (U/L)

Baseline Mean ± SD 83.6 ± 26.51 87.7 ± 23.93 86.7 ± 22.55


46



2 mg (N=86) 4 mg (N=86) Placebo (N=94)

GGTP (U/L)

Baseline Mean ± SD 38.6 ± 36.00 35.9 ± 26.87 36.8 ± 22.82


No potential Drug Induced Liver

Injury (DILI)

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


2 mg (N=86) 4 mg (N=86) Placebo (N=94)

Creatinine (mg/dL)

Baseline Mean ± SD 0.8 ± 0.22 0.8 ± 0.22 0.8 ± 0.22


Creatinine Clearance (mL/min)

Baseline Mean ± SD 117.9 ± 45.92 110.6 ± 42.18 115.6 ± 38.95


BUN (mg/dL)

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

No potential for Renal injury

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)

Body weight (kg)

Baseline Mean ± SD 71.3 ± 13.56 69.1 ± 10.83 69.9 ± 11.53

Absolute change Mean ± SD -0.6 ± 2.63 0.3 ± 2.83 -0.5 ± 2.40

*Significant Compared to Placebo

No weight GainNo Oedema

LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin

ATP Goal * (12 week)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

* 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

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

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

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

• 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 1st

approved

Glitazar

• Has a non-renal

route of

elimination

• No CV adverse

events

• No potential for

liver, kidney and

muscle toxicity

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 dosingIn 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

• 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.

Summary

Zydus Research Centre, Ahmedabad

The place of birth for Saroglitazar

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