Presentation is loading. Please wait.

Presentation is loading. Please wait.

Lipaglyn TM Discovery, Development & Preclinical Studies.

Similar presentations

Presentation on theme: "Lipaglyn TM Discovery, Development & Preclinical Studies."— Presentation transcript:

1 Lipaglyn TM Discovery, Development & Preclinical Studies

2 LIPAGLYN TM A novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters

3 A milestone in Indian history……

4 Lipaglyn is worlds first approved dual PPAR-α/γ agonist

5 Lipaglyn TM is completely different in structure and attributes from TZDs/Glitazones All glitazones have Thiazolidinione ring and caused edema and weight gain 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

6 Lipaglyn TM : 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 Lipaglyn TM Fenofibrate Lipaglyn TM binds more strongly to PPAR- α than Fenofibrate

7 Test Compound PPAR activation EC 50 hPPAR-α Fenofibrate10800 nM Lipaglyn TM 0.00065 nM In vitro PPAR Agonistic activity in HepG2 Cells Lipaglyn TM : A million times more potent in activating PPAR- than Fenofibrate

8 Test Compound PPAR activation EC 50 hPPAR-αhPPAR-γ Lipaglyn TM 0.00065 nM3 nM Saroglitazar is a potent and predominantly PPARα agonist with optimal PPARγ agonistic activity Lipaglyn TM demonstrates thousand fold higher selectivity for PPAR-α over PPAR-γ In vitro PPAR Agonistic activity in HepG2 Cells

9 Spectrum of PPAR activity of various agents : Each PPAR agonist is unique Adapted from - 28135/1228135.html *Illustrative chart

10 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

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

12 Rosiglitazone Troglitazone Pioiglitazone Ciglitazone Balaglitazone Rivoglitazone Isoglitazone SAROGLITAZAR Saroglitazar is different from TZDs

13 FenofibrateGemfibrozil Clofibrate Benzafibrate Saroglitazar Saroglitazar is different from fibrates

14 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) Lipaglyn TM was extensively profiled for efficacy in various preclinical models of dyslipidemia

15 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 miceZucker fa/fa rats Swiss albino mice miceHigh fat-High Cholesterol Diet Fed HamstersNonhuman Primates (Marmosets) Diabetic animal models Non-diabetic animal Models Lipaglyn TM reduces serum triglycerides in a dose- dependent manner in various animal models

16 Lipaglyn TM 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

17 Effects in db/db mice Effects in Zucker fa/fa rats Glucose Clamp study in Zucker fa/fa rats for Insulin sensitizing effects Lipaglyn TM also has anti-diabetic effects in various animal models

18 Lipaglyn TM 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 AUC Glu in OGTT; 91 % reduction in serum insulin at 1mg/kg db/db mice Zucker fa/fa Rats Effect on serum glucoseEffect on AUCglucose in OGTTEffect on Serum Insulin Effect on AUCglucose in OGTTEffect on Serum Insulin & FFA Hyperinsulinemic 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 AUC Glu in OGTT Improvement in Glucose infusion rate in hyperinsulinemic euglycemic clamp study

19 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 International NABL – National Accreditation Board for Testing and Calibration Laboratories CAP – College of American Pathologists

20 Safety pharmacology studies show that Lipaglyn TM does not affect CNS, CVS, Respiratory and GI functions

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

22 Overall Conclusions of Preclinical Safety & Toxicity Studies Lipaglyn TM 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).

23 ADMEFindings Absorption Rapidly absorbed Good Oral Bioavailability of ~40 % t 1/2 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 Lipaglyn TM was not detectable in urine Mainly eliminated by hepato-biliary route Lipaglyn TM : Pre-clinical ADME Profile

24 Preclinical Data of Lipaglyn TM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USA

25 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-380016, India

Download ppt "Lipaglyn TM Discovery, Development & Preclinical Studies."

Similar presentations

Ads by Google