Transcript Lipaglyn TM
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 All Saroglitazar glitazones does have not Thiazolidinione have TZD ring and and didcaused not cause edema edema and & weight weight gain gain reactive Studies have indicated thatring thiazolidinedione ring may generate metabolites after metabolism, which may cause toxicity LipaglynTM binds more strongly to PPAR- α than Fenofibrate LipaglynTM 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 LipaglynTM: ‘A million times’ more potent in activating PPAR- than Fenofibrate Test Compound PPAR activation EC50 hPPAR-α Fenofibrate 10800 nM LipaglynTM 0.00065 nM In vitro PPAR Agonistic activity in HepG2 Cells LipaglynTM demonstrates thousand fold higher selectivity for PPAR-α over PPAR-γ PPAR activation EC50 Test Compound LipaglynTM hPPAR-α hPPAR-γ 0.00065 nM 3 nM Saroglitazar is a potent and predominantly PPARα agonist with optimal PPARγ agonistic activity In vitro PPAR Agonistic activity in HepG2 Cells Spectrum of PPAR activity of various agents : Each PPAR agonist is unique *Illustrative chart Adapted from - http://www.theheart.org/documents/sitestructure/en/content/programs/1228135/1228135.html PPAR agonists are not a class of drugs, each drug has unique properties* 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.” Saroglitazar is different from Other Glitazars Muraglitazar Farglitazar Tesaglitazar Ragaglitazar Sodelglitazar SAROGLITAZAR Aleglitazar Imiglitazar Saroglitazar is different from TZDs Rosiglitazone Troglitazone Pioiglitazone Ciglitazone SAROGLITAZAR Balaglitazone Isoglitazone Rivoglitazone Saroglitazar is different from fibrates Fenofibrate Gemfibrozil Saroglitazar Clofibrate Benzafibrate 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 reduces serum triglycerides in a dosedependent manner in various animal models Zucker fa/fa rats Diabetic animal models db/db mice High fat-High Cholesterol Diet Fed Hamsters Nonhuman Primates (Marmosets) Non-diabetic animal Models Swiss albino mice mice 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 LipaglynTM improved lipid clearance and reduced serum cholesterol levels Improved Lipid Clearance in Swiss Albino Mice High Cholesterol Diet Fed Sprague Dawley rats • 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 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 showed anti-hyperglycemic and insulin sensitizing effects in diabetic & insulin resistant animals (db/db mice and Zucker fa/fa rats) Effect on AUCglucose in OGTT Effect on Serum Insulin db/db mice Effect on serum glucose 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 Zucker fa/fa Rats Effect on AUCglucose in OGTT Effect 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 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 International NABL – 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). LipaglynTM: Pre-clinical ADME Profile ADME Findings • Rapidly absorbed Absorption • Good Oral Bioavailability of ~40 % • t1/2 of about 3-4 hrs • Plasma Protein Binding of about 96 % in rodents • No drug levels detectable in any tissues at 24hr after the Distribution last dose in a 12 month repeated dose toxicology study in Beagle dogs. • Stable in liver microsomes Metabolism • Did not show any CYP interaction or induction (in vitro studies) • No potential for CYP-mediated drug-drug interactions • Eliminated by non-renal route Excretion • Unchanged LipaglynTM was not detectable in urine • Mainly eliminated by hepato-biliary route Preclinical Data of LipaglynTM 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-380016, India