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LIPAGLYNTM A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters 07/09/13.

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Presentation on theme: "LIPAGLYNTM A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters 07/09/13."— Presentation transcript:

0 LipaglynTM Discovery, Development & Preclinical Studies

1 LIPAGLYNTM A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters 07/09/13

2 A milestone in Indian history……
07/09/13 A milestone in Indian history…… It’s indeed a great pleasure to share this breakthrough of Zydus - India’s 1st NCE LipaglynTM (Saroglitazar) discovered and developed through indigenous efforts, which has been approved for Diabetic Dyslipidema.

3 Lipaglyn™ is world’s first approved dual PPAR-α/γ agonist
07/09/13 Lipaglyn™ is world’s first approved dual PPAR-α/γ agonist Lipaglyn is world’s first approved dual PPAR-α/γ agonist for diabetic Dyslipidemia. The journey of lipaglyn from concept to market started in 2001, and went through various phase 1, 2, 3 studies and finally received market authorization this year. compounds synthesized, 250 goes for animal testing, 5 for human trial, 1 becomes drug Cost of development of 1 NCE - ~1.3 Bn USD

4 LipaglynTM is completely different in structure and attributes from TZDs/Glitazones
LipaglynTM has been rationally designed to have dual PPAR- alpha gamma agonism barring the adverse effects of TZDs. Lipaglyn is completely different in structure and attributes from TZDs/Glitazones as studies have indicated that thiazolidinedione ring may generate reactive metabolites after metabolism, which may cause toxicity. Saroglitazar does not have TZD ring and did not cause edema & weight gain. Studies have indicated that thiazolidinedione ring may generate reactive metabolites after metabolism, which may cause toxicity Saroglitazar does not have TZD ring and did not cause edema & weight gain All glitazones have Thiazolidinione ring and caused edema and weight gain

5 LipaglynTM binds more strongly to PPAR- α than Fenofibrate
28675_84 LipaglynTM binds more strongly to PPAR- α than Fenofibrate LipaglynTM Fenofibrate LipaglynTM binds more strongly to PPAR- α than Fenofibrate; as a result of 4 H-bonding sites in Lipaglyn as against only 2 H-bonding sites in Fenofibrate. 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

6 Fenofibrate 10800 nM LipaglynTM 0.00065 nM
LipaglynTM: ‘A million times’ more potent in activating PPAR- than Fenofibrate Test Compound PPAR activation EC50 hPPAR-α Fenofibrate 10800 nM LipaglynTM nM In vitro PPAR Agonistic activity in HepG2 Cells LipaglynTM is ‘A million times’ more potent in activating PPAR- than Fenofibrate, which is evident from EC-50 data.

7 4_84 LipaglynTM demonstrates thousand fold higher selectivity for PPAR-α over PPAR-γ Test Compound PPAR activation EC50 hPPAR-α hPPAR-γ LipaglynTM 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 thus it is a potent and predominantly PPARα agonist. Nevertheless it also has optimal  PPARγ agonistic activity In vitro PPAR Agonistic activity in HepG2 Cells

8 Spectrum of PPAR activity of various agents : Each PPAR agonist is unique
Let us look at the spectrum of PPAR activity of various agents. At one end rosiglitazoine which is a pure PPAR gamma agonist whereas on the other extreme fenofibrate, a pure PPAR alpha agonist. Lipaglyn is a predominantly PPARα agonist with optimal  PPARγ agonistic activity *Illustrative chart Adapted from -

9 07/09/13 PPAR agonists are not a class of drugs, each drug has unique properties* Dr Steven Nissen who is an expert in this field has endorsed at the ADA meeting in 2012 that PPAR agonists have unique properties & their binding at the Nuclear Receptors induces unique actions. Dr. Steven Nissen at ADA Meeting, 2012 “The binding of different ligands to Nuclear Receptors induces different conformational changes. Each drug has a characteristic co-factor binding pattern.”

10 Saroglitazar is different from Other Glitazars
Muraglitazar Farglitazar Tesaglitazar Ragaglitazar SAROGLITAZAR Aleglitazar Sodelglitazar Imiglitazar

11 Saroglitazar is different from TZDs
Rosiglitazone Troglitazone Pioiglitazone Ciglitazone Balaglitazone Rivoglitazone Isoglitazone SAROGLITAZAR When we compare Saroglitazar structure with TZDs, we see that Saroglitazar does not have TZD ring (which is a pharmacophore & also a toxicophore), hence it is different & safe. But, in case of Glitazars, few glitazar have similar pharmacophore (acid part) as Saroglitazar, but they are still toxic. But we know that Saroglitazar is unique & different from all glitazars, TZDs & fibrates. Hence, in order to illustrate this point, we’ve generated 3D Structure of all Glitazars. Here, we can clearly see that 3D structure of each molecule is different. The 3D structures to explain why Saroglitazar is unique & different from all other molecules, which could be the reason, why it is safer as well.

12 Saroglitazar is different from fibrates
Fenofibrate Gemfibrozil Clofibrate Benzafibrate Saroglitazar

13 34819_85 LipaglynTM was extensively profiled for efficacy in various preclinical models of dyslipidemia 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 diabetic & non-diabetic animal models of dyslipidemia.

14 Diabetic animal models Non-diabetic animal Models
LipaglynTM reduces serum triglycerides in a dose-dependent manner in various animal models db/db mice Zucker fa/fa rats Diabetic animal models Swiss albino mice mice High fat-High Cholesterol Diet Fed Hamsters Nonhuman Primates (Marmosets) Non-diabetic animal Models In these animal models, Lipaglyn showed a maximum dose dependent reduction in TG levels up to 90%. 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

15 Potential to reduce Post-prandial hyperlipidemia
LipaglynTM improved lipid clearance and reduced serum cholesterol levels Improved Lipid Clearance in Swiss Albino Mice High Cholesterol Diet Fed Sprague Dawley rats Potential to reduce Post-prandial hyperlipidemia LipaglynTM improved lipid clearance and reduced serum cholesterol levels post lipid load- Potential to reduce Post-prandial hyperlipidemia 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

16 LipaglynTM also has anti-diabetic effects in various animal models
43011_85 LipaglynTM also has anti-diabetic effects in various animal models 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

17 LipaglynTM showed anti-hyperglycemic and insulin sensitizing effects in diabetic & insulin resistant animals (db/db mice and Zucker fa/fa rats) Effect on serum glucose Effect on AUCglucose in OGTT Effect on Serum Insulin db/db mice 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 Hyperinsulinemic Euglycemic Clamp Study Effect on Glucose Infusion rate Effect on AUCglucose in OGTT Effect on Serum Insulin & FFA Lipaglyn showed a dose dependent reduction in serum glucose & insulin levels upto 65% & 91% resp in diabetic & insulin resistant animal models Zucker fa/fa Rats 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

18 Preclinical Evidence of Safety
3_85 7_89 07/09/13 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 All preclinical studies were conducted at ZRC (Zydus Research Center), which is among few such centers across the country which have got accreditation from national & international agencies like OECD, NABL, AAALAC & CAP. As of now 6-7 pharma companies only have GLP approved facility for generating such data. OECD - The Organization for Economic Co-operation and Development AAALAC – Association for Assessment and Accreditation of Laboratory Animal Care International NABL – National Accreditation Board for Testing and Calibration Laboratories CAP – College of American Pathologists

19 Safety pharmacology studies show that LipaglynTM does not affect CNS, CVS, Respiratory and GI functions Safety pharmacology studies show that LipaglynTM does not affect CNS, Respiratory and GI functions & especially in CVS studies, lipaglyn did not show any cardio toxicity as assessed by telemetry in Beagle dogs & HERG study.

20 Extensive toxicity studies including 2 yr carcinogenicity study have shown no safety concerns

21 Overall Conclusions of Preclinical Safety & Toxicity Studies
61443_85 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). The overall conclusions of preclinical safety & toxicity studies was – LipaglynTM is safe and well tolerated, Not hepatotoxic, myotoxic, nephrotoxic or cardiotoxic 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).

22 LipaglynTM: Pre-clinical ADME Profile
8_85 LipaglynTM: Pre-clinical ADME Profile 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 Now, lets look at Lipaglyn’s preclinical pharmacokinetic profile.

23 07/09/13 Preclinical Data of LipaglynTM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USA This is the Preclinical Data of LipaglynTM which was presented at 72nd ADA meeting, June 2012, Philadelphia, USA.

24 Thank you This 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 , India


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