lipaglyn tm discovery, development & preclinical studies
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LipaglynTM
Discovery, Development & Preclinical Studies
LIPAGLYNTM A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters
A milestone in Indian history……
Lipaglyn™ is world’s first approved dual PPAR-α/γ agonist
LipaglynTM is completely different in structure and attributes from TZDs/Glitazones
N NO NH
SO
ORosiglitazone
N O NH
SO
O
Et
Pioiglitazone
N
N
O
O
S
NHO
O
Balaglitazone
OO
SNH
O
O
HOTroglitazone
OS
NH
O
O
Ciglitazone
OS
NH
O
O
F
Isoglitazone
OS
NH
O
O
N
N
O Rivoglitazone
O OHO
O
N
SSAROGLITAZAR
All glitazones have Thiazolidinione ring and caused edema and weight gainSaroglitazar does not have TZD ring and did not cause edema & weight gainStudies have indicated that thiazolidinedione ring may generate reactive metabolites after metabolism, which may cause toxicity
LipaglynTM : Stronger binding with PPAR-α as a result of 4 H-bonding sites as against only 2 H-bonding sites in the case of Fenofibrate
LipaglynTM Fenofibrate
LipaglynTM binds more strongly to PPAR- α than Fenofibrate
Test CompoundPPAR activation EC50
hPPAR-α
Fenofibrate 10800 nM
LipaglynTM 0.00065 nM
In vitro PPAR Agonistic activity in HepG2 Cells
LipaglynTM: ‘A million times’ more potent in activating PPAR- than Fenofibrate
Test Compound
PPAR activation EC50
hPPAR-α hPPAR-γ
LipaglynTM 0.00065 nM 3 nM
Saroglitazar is a potent and predominantly PPARα agonist with optimal PPARγ agonistic activity
LipaglynTM demonstrates thousand fold higher selectivity for PPAR-α over PPAR-γ
In vitro PPAR Agonistic activity in HepG2 Cells
Spectrum of PPAR activity of various agents : Each PPAR agonist is unique
Adapted from - http://www.theheart.org/documents/sitestructure/en/content/programs/1228135/1228135.html
*Illustrative chart
PPAR agonists are not a class of drugs, each drug has unique properties*
“The binding of different ligands to Nuclear Receptors induces different conformational changes. Each drug has a characteristic co-factor binding pattern.”
Dr. Steven Nissen at ADA Meeting, 2012
MuraglitazarFarglitazar
Ragaglitazar
Sodelglitazar Imiglitazar
Aleglitazar
Tesaglitazar
SAROGLITAZAR
Saroglitazar is different from Other Glitazars
Rosiglitazone Troglitazone
Pioiglitazone Ciglitazone
Balaglitazone
Rivoglitazone
Isoglitazone
SAROGLITAZAR
Saroglitazar is different from TZDs
Fenofibrate Gemfibrozil
Clofibrate Benzafibrate
Saroglitazar
Saroglitazar is different from fibrates
Models of diabetes & insulin resistance - db/db mice- Zucker fa/fa rats
Nondiabetic animal models- Swiss albino mice- High fat-high cholesterol diet-fed Golden Syrian hamsters- High cholesterol diet-fed Sprague Dawley rats - Nonhuman Primate (Marmosets)
LipaglynTM was extensively profiled for efficacy in various preclinical models of dyslipidemia
Diabetic & Insulin Resistant Models• Up to 55% TG reduction in db/db mice• Up to 86 % TG reduction in Zucker
fa/fa rats
• Non-diabetic Abimal Models• Up to 76 % TG reduction in Swiss Albino Mice• Up to 90 % TG reduction in High fat-High cholesterol-fed
Hamsters• Up to 61% reduction in serum triglycerides in Primates
db/db mice Zucker fa/fa rats
Swiss albino mice mice High fat-High Cholesterol Diet Fed Hamsters Nonhuman Primates (Marmosets)
Dia
be
tic
an
ima
l m
od
els
No
n-d
iab
eti
c a
nim
al
Mo
de
lsLipaglynTM reduces serum triglycerides in a dose-dependent manner in various animal models
LipaglynTM improved lipid clearance and reduced serum cholesterol levels
• Up to 68% improvement in lipid clearance in Swiss Albino mice
• Up to 77 % reduction in serum cholesterol in high-cholesterol diet-fed Sprague Dawley rats
• Potential for Post prandial hyperlipidemia
High Cholesterol Diet Fed Sprague Dawley ratsImproved Lipid Clearance in Swiss Albino Mice
Potential to reduce
Post-prandial
hyperlipidemia
•Effects in db/db mice
•Effects in Zucker fa/fa rats
•Glucose Clamp study in Zucker fa/fa rats for Insulin sensitizing effects
LipaglynTM also has anti-diabetic effects in various animal models
LipaglynTM showed anti-hyperglycemic and insulin sensitizing effects in diabetic & insulin resistant animals (db/db mice and Zucker fa/fa rats)
db/db mice : Animal Model for Type 2 Diabetes Mellitus & Insulin Resistance
• Up to 65 % reduction in serum glucose; Up to 59 % reduction in AUCGlu in OGTT; 91 % reduction in serum insulin at 1mg/kg
db
/db
mic
eZ
uck
er f
a/fa
Rat
s
Effect on serum glucose Effect on AUCglucose in OGTT Effect on Serum Insulin
Effect on AUCglucose in OGTT Effect on Serum Insulin & FFAHyperinsulinemic Euglycemic Clamp Study Effect on Glucose Infusion rate
Zucker fatty fa/fa Rats: Animal model for Insulin-resistance
• 85% reduction in serum insulin; Up to 52 % reduction in AUCGlu in OGTT• Improvement in Glucose infusion rate in hyperinsulinemic euglycemic clamp study
Preclinical Evidence of Safety
• All Preclinical toxicity studies conducted in GLP (OECD) certified lab (Global quality standard)
• Our research center (ZRC) also has AAALAC, NABL & CAP accreditation
• Data acceptable globally
OECD - The Organization for Economic Co-operation and Development AAALAC – Association for Assessment and Accreditation of Laboratory Animal Care InternationalNABL – National Accreditation Board for Testing and Calibration Laboratories CAP – College of American Pathologists
Safety pharmacology studies show that LipaglynTM does not affect CNS, CVS, Respiratory and GI functions
Extensive toxicity studies including 2 yr carcinogenicity study have shown no safety concerns
Overall Conclusions of Preclinical Safety & Toxicity Studies
•LipaglynTM is safe and well tolerated
•No hepatotoxicity, myotoxicity, nephrotoxicity or cardiotoxicity at doses equivalent to or higher than efficacy doses
•Non-genotoxic & Non-teratogenic
•Passed 2-year carcinogenicity study (confirmed by a mechanistic study using non-human primates employing molecular biomarkers).
ADME Findings
Absorption
• Rapidly absorbed
• Good Oral Bioavailability of ~40 %
• t1/2 of about 3-4 hrs
Distribution
• Plasma Protein Binding of about 96 % in rodents
• No drug levels detectable in any tissues at 24hr after the
last dose in a 12 month repeated dose toxicology study in Beagle
dogs.
Metabolism
• Stable in liver microsomes
• Did not show any CYP interaction or induction (in vitro studies)
• No potential for CYP-mediated drug-drug interactions
Excretion
• Eliminated by non-renal route
• Unchanged LipaglynTM was not detectable in urine
• Mainly eliminated by hepato-biliary route
LipaglynTM: Pre-clinical ADME Profile
Preclinical Data of LipaglynTM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USA
25
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Under no circumstances the information contained in this presentation should be quoted, distributed, copied, reproduced or retrieved, in part or
whole, in any form, written, verbal and/or electronic format without the expressed permission from:
Registered Office: Cadila Healthcare Limited, Zydus Tower, Satellite Cross Road, Ahmedabad-380016, India
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