0. LipaglynTM
Clinical Studies

1. The clinical development involved a network of ~47 medical centres across India
Lead medical investigators included
Endocrinologists,
Diabetologists,
Cardiologists and
Physicians
The clinical trials were carried out at ~47 medical centres across India. The Lead medical investigators including eminent Endocrinologists, Diabetologists, Cardiologists and Physicians.

2. lipaglynTM Clinical Trials: First in Man to Pivotal studies
Now, coming to Lipaglyn clinical trials…..

3. 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 (
WHO registry - (
All the lab investigations were done at *NABL/CAP approved laboratories
All Lipaglyn trials were GCP compliant, approved by various regulatory authorities like DCGI, ethics committees, regularly monitored by DSMB and are registered in public domain with CTRI & WHO
ICMR - Indian Council of Medical Research
DSMB – which was voluntarily constituted by zydus and having members from ICMR, ex national chair pharmacology, member of Indian Pharmaceutical Association, member from API, Retd professor of Cardiology, Retd DMER member and Endocrinologists
NABL – National Accreditation Board for testing & Calibration Laboratories
CAP – College of American Pathologists
CTRI – Clinical Trial Registries of India

4. 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
Lipaglyn was extensively evaluated by medical experts during phase 1,2,3 clinical trials in 864 subjects. Additional 1000 patients being enrolled in Phase IV trial.

5. LipaglynTM in Healthy Volunteers
Phase I Study
(First-in-Man Studies)
Now, lets look at Lipaglyn phase 1 study…

6. 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.
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(0.125 – 128mg), 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.
LipaglynTM in single and multiple doses was safe with no SAEs and upto 128 mg single dose was tolerated. Pharmacokinetics (Cmax, AUC) was dose dependent and linear.

8. LipaglynTM is rapidly and well absorbed
LipaglynTM 4 mg Single Oral Dose
PK Parameters
Result
Cmax(ng/mL)
± 90.99
AUC0-inf (hr*ng/mL)
t max(hr)
0.71 ± 0.25
t1/2(hr)
2.93 ± 0.87
LipaglynTM is rapidly and well absorbed with tmax less than a hour and shows a half life of 3-4 h

9. LipaglynTM pharmacokinetic data
LipaglynTM 4 mg OD
Parameter
Day 1
Day 10
Cmax (ng/mL)
tmax (hr)
AUC0-inf (hr*ng/mL)
t1/2 (hr)
No Significant Drug Accumulation
Pk data of multiple dosing shows no sig changes in pk parameters between day 1 and day 10. thus we deduce no significant accumulation.

10. LipaglynTM in Non-diabetic & Diabetic Dyslipidemia
Phase II Studies
(Proof-of-Concept Studies)
Now look at Lipaglyn Phase 2 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
Looking into Phase II studies (proof-of-concept) of lipaglyn, there were 222 diabetic diabetic/non-diabetic subjects of either sex in randomized double-blind studies.

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 with impaired glucose tolerance (IGT).
Doses of Saroglitazar
0.5, 1, 2, and 4 mg OD
0.5, 1, 2, and
4 mg OD
Comparator
Fenofibrate
160 mg
Rosiglitazone
8/16 mg
Pioglitazone
45 mg
Number of subjects 63 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.
in the 4 phase II studies (PRESS I – PRESS IV) each of 12 weeks, Lipaglyn 0.5 – 4 mg was compared to fenofibrate, rosiglitazone and pioglitazone. The primary end point was reduction in TG levels and the secondary end points included effects on other lipids, glycemic parameters and inflammatory markers.

13. LipaglynTM Vs Fenofibrate in Dyslipidemia in Non Diabetics
Protocol 2001
PRESS-I
Lets look at the results of the LipaglynTM Vs Fenofibrate study

14. LSM % Change in Efficacy Parameters
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 N 12 13 TG
-19.92
-16.30
-28.72
-37.83
Lipaglyn produced a dose dependent reduction in TG levels upto nearly 38% in non diabetic dyslipidemic patients

15. LSM % Change in Efficacy Parameters
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 TG
-18.38
-15.17
-31.67
-30.6
Lipaglyn also produced a reduction in TG levels upto nearly 30% in diabetic dyslipidemic patients

16. LipaglynTM 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
LipaglynTM shows efficacy in both diabetics and non-diabetics with dyslipidemia in terms of TG reduction, LDL, TC & FPG reduction and increase in HDL levels.

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
In PRESS I – PRESS IV studies lipaglyn showed no potential for toxicity to the vital organs

18. LipaglynTM in Diabetic & Dyslipidemia Subjects
Phase III Studies
(Pivotal trials)
Coming to the lipaglyn trials in phase III diabetic and dyslipidemic subjects. These are the pivotal trials.

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

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 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
PRESS V was 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 in 120 patients for 26 weeks.
CARDIAC SAFETY FOLLOW UP WAS DONE FOR 24 WEEKS AFTER LAST DOSE.

21. Study design Study Duration: 24 weeks
post screening there was a run in period of 2 weeks where in the patients were standardised. And active treatment period lasted for 24 weeks
Study Duration: 24 weeks
Follow-up: weeks after last dose

22. PRESS V - Selection criteria
Inclusion Criteria:
Age 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
The following were the inclusion/ exclusion criteria.
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.

23. 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#
± 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
Coming to the results of primary endpoint.
Lipaglyn 4mg produced mg/dL or 45% decrease in TG levels as compared to 33mg/dL or 15% decrease seen in pioglitazone arm.
Up to 51% Reduction in
Triglyceride

24. LipaglynTM (Protocol ZYH1.08 )
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)
50.3 ± 2.33
52.4 ± 1.98
55.1 ± 3.27
-15.2 ± 3.13#
-23.9 ± 3.04*#
-8.8 ± 3.32#
-25.1 ± 5.50
-45.5 ± 5.33*
-20.0 ± 5.83
*Significant Compared to pioglitazone; # Significant compared to baseline
LDL C reduction was 12 mg/dL in Lipaglyn 4mg and 3.5 mg/dL in pioglitazone arm. Reduction in Lipaglyn arm was significant compared to pioglitazone arm as well as to baseline.
VLDL C reduction in Lipaglyn arm was 45.5% and this reduction was also significant compared to reduction in pioglitazone arm.

25. LipaglynTM (Protocol ZYH1.08 )
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)
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)
101.3 ± 4.40
98.3 ± 4.00
89.3 ± 3.14
-5.4 ± 3.42
-13.4 ± 3.31#
-6.4 ± 3.65
2.9 ± 4.80
-10.9 ± 4.65
-4.8 ± 5.12
*Significant Compared to pioglitazone; # Significant compared to baseline
Total cholesterol was reduced by 18.5 mg/dL by Lipaglyn 4mg and this was significant compared to pioglitazone arm as well as baseline.
Lipaglyn also showed significant reduction compared to baseline in ApoB level of 13 mg/dL

26. LipaglynTM (Protocol ZYH1.08 )
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)
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
*Significant Compared to pioglitazone; # Significant compared to baseline
HDL C parameter was increased by 3.8% by Lipagyn 4 mg.
Favourable Lipid control

27. LipaglynTM (Protocol ZYH1.08 )
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)
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 (%)
8.1 ± 0.14
7.9 ± 0.09
8.2 ± 0.13
-0.3 ± 0.11#
-0.4 ± 0.12#
*Significant Compared to pioglitazone; # Significant compared to baseline
Lipagyln has also shown beneficial effects on glycemic parameters. Lipaglyn 4mg has shown to reduce FPG by 22.6 mg/dL and Hba1c by 0.3%. Both of these parameters are significant compared to baseline.
Effective Glycemic control

28. 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)
Hemoglobin (gm/dL)
Baseline Mean ± SD
13.6 ± 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)
91.3 ± 62.48
96.3 ± 49.40
97.2 ± 47.82
0.3 ± 0.94
0.3 ± 0.49
0.3 ± 0.46
This slide shows that no hemodilution , increase in inflammatory markers or muscle toxicity was seen with Lipaglyn.

29. 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)
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)
25.9 ± 15.75
23.6 ± 9.69
22.1 ± 5.81
0.2 ± 0.63
0.1 ± 0.43
0.0 ± 0.42
ALP (U/L)
81.9 ± 24.93
85.0 ± 31.78
84.1 ± 26.57
-0.2 ± 0.28
-0.2 ± 0.56
-0.1 ± 0.24
As we can see there is no increase in the liver enzymes.

30. 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)
GGTP (U/L)
Baseline Mean ± SD
37.6 ± 22.85
35.3 ± 18.75
36.4 ± 22.86
Absolute change Mean ± SD
-0.2 ± 0.40
-0.3 ± 0.43
-0.3 ± 0.25
No potential Drug Induced Liver Injury (DILI)
-FDA standard
Thus we can safely conclude that lipaglyn has no potential for drug induced liver injury.

31. 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)
Creatinine (mg/dL)
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
BUN (mg/dL)
10.8 ± 3.66
9.5 ± 2.75
11.1 ± 2.74
0.1 ± 0.28
0.2 ± 0.47
0.2 ± 0.37
Looking into the renal parameters we see that Lipaglyn has not shown any renal toxicity
No Renal Toxicity

32. 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)
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
And the safety assessment has also shown that Lipaglyn has shown weight loss compared to weight gain in pioglitazone arm.
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)
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
Compilation of the Percentage of patients achieving ATP III goals-
( TG <150 mg/Dl, LDL C- < 100mg/dL and HDL C > 40/50mg/dL in males /females respectively)
following saroglitazar 4mg as compared to pioglitazone shows that more % of subjects on Lipaglyn 4mg achieve these goals as compared to those on pioglitazone
More patients in Lipaglyn achieves ATP-III goal

34. 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 :
LFT : (No DILI)
RFT: (Creatinine / eGFR)
CPK
Hemoglobin
Hence Lipaglyn has not got deleterious effect on weight, has proven cardiovascular safety, and has no potential for DILI, Renal injury, muscle toxicity or hemodilution.
Safe for heart
Safe for Liver
Safe for Kidney
Safe for muscles

35. Phase III Study Protocol ZYH1.09 PRESS-VI
LipaglynTM Vs Placebo in Hypertriglyceridemia Not Controlled by Atorvastatin
Phase III Study
Protocol ZYH1.09
PRESS-VI
This is the other phase III study also known as the 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 PROT dated ]
Subject Enrolled:
302 subjects
Study Duration:
12 Weeks.
Follow-up:
24 weeks after last dose (2-D ECHO & CV Events)
PRESS VI was 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 in 302 subjects for 12 weeks
In this study also cardiac safety follow up was done for 24 weeks after last dose

37. PRESS VI - Selection Criteria
Inclusion Criteria:
Age 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.
The following were the inclusion/ exclusion criteria of PRESS VI.
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.

38. LipaglynTM (Protocol ZYH1.09 )
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
± 8.30*#
± 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
In PRESS VI add on Lipaglyn 4mg showed a reduction of mg/dL (more than 46%) in primary endpoint-TG which was significant compared to baseline as well as atorvastatin plus placebo arm
Upto 51% reduction in
Triglyceride

39. LipaglynTM (Protocol ZYH1.09 )
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)
LDL-Cholesterol-Direct (mg/dL)
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
VLDL Cholesterol (mg/dL)
52.6 ± 1.77
57.2 ± 1.88
57.1 ± 1.64
-23.3 ± 2.03*#
-27.2 ± 2.02*#
-15.0 ± 1.94#
-39.6 ± 3.71*
-46.0 ± 3.70*
-24.5 ± 3.54
*Significant Compared to Placebo; # Significant compared to baseline
In the secondary end points
Lipaglyn 4mg arm showed 31.3% decrease in LDL C levels which is significant when compared to atorva 10 mg plus placebo arm
And there was 46 % decrease in VLDLC levels which is significant when compared to atorva 10 mg plus placebo arm

40. LipaglynTM (Protocol ZYH1.09 )
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)
Total Cholesterol (mg/dL)
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
*Significant Compared to Placebo # Significant compared to baseline
Total cholestrol reduction was 26 % in the lipaglyn 4mg arm compared to 17.7 % in the atorva 10 mg plus placebo arm.

41. LipaglynTM (Protocol ZYH1.09 )
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)
Apo-lipoproteins B (mg/dL)
Baseline Mean ± SE
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
HDL-Cholesterol (mg/dL)
36.6 ± 0.91
39.1 ± 1.21
38.5 ± 1.24
2.5 ± 0.89*#
1.3 ± 0.89*
-1.6 ± 0.85
9.5 ± 2.36*
7.6 ± 2.36*
-0.7 ± 2.26
*Significant Compared to Placebo; # Significant compared to baseline
Lipaglyn also showed reduction of 32% & increase of 7.6% in ApoB levels & HDLC levels which was significant compared to the other placebo arm.

42. LipaglynTM (Protocol ZYH1.09 )
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)
Non-HDL-Cholesterol (mg/dL)
Baseline Mean ± SE
164.0 ± 3.98
171.3 ± 4.07
171.0 ± 4.22
Absolute change LSM ± SE
-51.4 ± 3.59*#
-57.7 ± 3.58*#
-38.6 ± 3.43#
Percentage change LSM ± SE
-29.2 ± 2.25*
-32.5 ± 2.25*
-20.1 ± 2.15
*Significant Compared to Placebo; # Significant compared to baseline
Today non HDL C is one of the most important indicators for CV risk reduction. Lipaglyn 4 mg with atorva 10 mg decreases non HDL C by 32.5% which is significant as compared to 20.1 % by atorva 10 mg plus placebo.
Positive effects on all lipid parameters

43. LipaglynTM (Protocol ZYH1.09 )
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)
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
-0.3 ± 0.08#
-0.2 ± 0.07#
*Significant Compared to Placebo; # Significant compared to baseline
In PRESS VI too Lipaglyn has shown beneficial effects on glycemic parameters with 25.4 mg/dL decrease in FPG which is significant as compared to Placebo arm and to baseline and 0.3 % decrease in HbA1c which is significant as compared to baseline.

44. LipaglynTM (Protocol ZYH1.09 )
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)
Hemoglobin (gm/dL)
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
hs-CRP (mg/L)
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)
93.3 ± 51.90
85.5 ± 43.67
96.1 ± 63.79
8.4 ± 53.41
32.3 ± 61.27
5.7 ± 69.26
Safety assessment of Lipaglyn in PRESS VI shows
No hemodilution
No increase in inflammatory markers
No potential for muscle toxicity.

45. LipaglynTM (Protocol ZYH1.09 )
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)
ALT (U/L)
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
AST (U/L)
23.8 ± 11.11
24.0 ± 12.61
24.4 ± 10.72
1.1 ± 12.86
0.5 ± 13.09
0.7 ± 16.32
ALP (U/L)
83.6 ± 26.51
87.7 ± 23.93
86.7 ± 22.55
-16.3 ± 22.34
-29.0 ± 22.48
-2.5 ± 20.96
Lipaglyn does not show increase in liver enzymes

46. LipaglynTM (Protocol ZYH1.09 )
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)
GGTP (U/L)
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
No potential Drug Induced Liver Injury (DILI)
Thus we can safely say Lipaglyn has no potential in drug induced liver injury.

47. LipaglynTM (Protocol ZYH1.09 )
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)
Creatinine (mg/dL)
Baseline Mean ± SD
0.8 ± 0.22
Absolute change Mean ± SD
0.0 ± 0.18
0.1 ± 0.20
0.0 ± 0.21
Creatinine Clearance (mL/min)
117.9 ± 45.92
110.6 ± 42.18
115.6 ± 38.95
-12.1 ± 35.27
-7.4 ± 26.34
-4.9 ± 32.12
BUN (mg/dL)
11.1 ± 3.20
11.1 ± 3.90
11.4 ± 3.40
0.4 ± 4.13
1.0 ± 3.66
-0.3 ± 4.29
Renal parameters in PRESS VI assessment revealed no significant alteration in renal parameters
No potential for Renal injury

48. 12 weeks (Safety Population) LipaglynTM (Protocol ZYH1.09 )
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
Even in PRESS VI there was no increase in weight or edema in Lipaglyn arm.
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)
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
In PRESS VI the % of subjects who achieved all three ATP III goals was 2.5 times higher in Lipaglyn arm than in placebo arm.
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.
Adverse events seen in PHASE III trials i.e. PRESS V & VI lasting for 12 & 24 WeEKS were gastritis asthenia and pyrexia in ≥2%
Most Aes were mild to moderate and did not lead to discontinuation of study drug
Safe for Heart
Safe for Liver
Safe for Kidney
Safe for Muscles

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

52. 07/09/13
Phase-3 Clinical Data of LipaglynTM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USA
This is the Preclinical Data of LipaglynTM which was presented at 72nd ADA meeting, June 2012, Philadelphia, USA.

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

54. LipaglynTM: Product Profile
4/11/2017
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.
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.
Prescribed as a 4 mg tablet once daily for Lipaglyn is indicated for diabetic dyslipidemia & hypertriglyceridemia with type 2 diabetes mellitus not controlled by statins
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.

55. Proposed place of LipaglynTM in the treatment of Diabetic Dyslipidemia
07/09/13
Proposed place of LipaglynTM in the treatment of Diabetic Dyslipidemia

56. 5656
07/09/13
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.

57. 5757
07/09/13
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.

58. 5858
07/09/13
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.

59. Zydus Research Centre, Ahmedabad
07/09/13
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 , India