lipaglyn tm discovery, development & preclinical studies
DESCRIPTION
Lipaglyn TM Discovery, Development & Preclinical Studies. LIPAGLYN TM 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. - PowerPoint PPT PresentationTRANSCRIPT
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LipaglynTM
Discovery, Development & Preclinical Studies
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LIPAGLYNTM A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters
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A milestone in Indian history……
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Lipaglyn™ is world’s first approved dual PPAR-α/γ agonist
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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
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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
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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
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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
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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
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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
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MuraglitazarFarglitazar
Ragaglitazar
Sodelglitazar Imiglitazar
Aleglitazar
Tesaglitazar
SAROGLITAZAR
Saroglitazar is different from Other Glitazars
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Rosiglitazone Troglitazone
Pioiglitazone Ciglitazone
Balaglitazone
Rivoglitazone
Isoglitazone
SAROGLITAZAR
Saroglitazar is different from TZDs
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Fenofibrate Gemfibrozil
Clofibrate Benzafibrate
Saroglitazar
Saroglitazar is different from fibrates
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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
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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
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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
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•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
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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
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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
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Safety pharmacology studies show that LipaglynTM does not affect CNS, CVS, Respiratory and GI functions
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Extensive toxicity studies including 2 yr carcinogenicity study have shown no safety concerns
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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).
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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
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Preclinical Data of LipaglynTM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USA
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