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

Thank youThis 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-380016, India