lipaglyn tm clinical studies
DESCRIPTION
Lipaglyn TM Clinical Studies. Lead medical investigators included E ndocrinologists, D iabetologists , C ardiologists and P hysicians. The clinical development involved a network of ~47 medical centres across India. Clinical Trials: First in Man to Pivotal studies. lipaglyn TM. - PowerPoint PPT PresentationTRANSCRIPT
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
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.
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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
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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
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LipaglynTM in Diabetic & Dyslipidemia Subjects
Phase III Studies
(Pivotal trials)
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LipaglynTM Vs PioglitazoneIn Dyslipidemia With Type 2 Diabetes
MellitusPhase III StudiesProtocol ZYH1.08
PRESS-V
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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
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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
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)
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
*Significant Compared to pioglitazone; # Significant compared to baseline
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
Favourable
Lipid control
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 (%)
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
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 ± 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
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)
Baseline Mean ± SD 25.9 ± 15.75 23.6 ± 9.69 22.1 ± 5.81
Absolute change Mean ± SD 0.2 ± 0.63 0.1 ± 0.43 0.0 ± 0.42
ALP (U/L)
Baseline Mean ± SD 81.9 ± 24.93 85.0 ± 31.78 84.1 ± 26.57
Absolute change Mean ± SD -0.2 ± 0.28 -0.2 ± 0.56 -0.1 ± 0.24
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
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)
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
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)
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
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)
Baseline Mean ± SE 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
*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)
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
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)
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
*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)
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
Positive effects on all lipid
parameters
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
Absolute change LSM ± SE -0.3 ± 0.08# -0.3 ± 0.08# -0.2 ± 0.07#
*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)
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)
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
Absolute change Mean ± SD 8.4 ± 53.41 32.3 ± 61.27 5.7 ± 69.26
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)
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
ALP (U/L)
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
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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)
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 0.8 ± 0.22 0.8 ± 0.22
Absolute change Mean ± SD 0.0 ± 0.18 0.1 ± 0.20 0.0 ± 0.21
Creatinine Clearance (mL/min)
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
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
61
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