Transcript Slide 1

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
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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
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