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 LipaglynTMDiscovery, Development & Preclinical Studies
1 LIPAGLYNTMA novel, first-in-class NCE with beneficial effects on both lipid and glycemic parameters07/09/13
2 A milestone in Indian history…… 07/09/13A 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 07/09/13Lipaglyn™ is world’s first approved dual PPAR-α/γ agonistLipaglyn 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 drugCost 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 toxicitySaroglitazar does not have TZD ring and did not cause edema & weight gainAll glitazones have Thiazolidinione ring and caused edema and weight gain
5 LipaglynTM binds more strongly to PPAR- α than Fenofibrate 28675_84LipaglynTM binds more strongly to PPAR- α than FenofibrateLipaglynTMFenofibrateLipaglynTM 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 FenofibrateTest CompoundPPAR activation EC50hPPAR-αFenofibrate10800 nMLipaglynTMnMIn vitro PPAR Agonistic activity in HepG2 CellsLipaglynTM is ‘A million times’ more potent in activating PPAR- than Fenofibrate, which is evident from EC-50 data.
7 4_84LipaglynTM demonstrates thousand fold higher selectivity for PPAR-α over PPAR-γTest CompoundPPAR activation EC50hPPAR-αhPPAR-γLipaglynTMnM3 nMSaroglitazar is a potent and predominantly PPARα agonist with optimal PPARγ agonistic activityLipaglynTM 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 activityIn 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 chartAdapted from -
9 07/09/13PPAR 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 atADA 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 MuraglitazarFarglitazarTesaglitazarRagaglitazarSAROGLITAZARAleglitazarSodelglitazarImiglitazar
11 Saroglitazar is different from TZDs RosiglitazoneTroglitazonePioiglitazoneCiglitazoneBalaglitazoneRivoglitazoneIsoglitazoneSAROGLITAZARWhen 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 FenofibrateGemfibrozilClofibrateBenzafibrateSaroglitazar
13 34819_85LipaglynTM was extensively profiled for efficacy in various preclinical models of dyslipidemiaModels of diabetes & insulin resistancedb/db miceZucker fa/fa ratsNondiabetic animal modelsSwiss albino miceHigh fat-high cholesterol diet-fed Golden Syrian hamstersHigh cholesterol diet-fed Sprague Dawley ratsNonhuman 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 modelsdb/db miceZucker fa/fa ratsDiabetic animal modelsSwiss albino mice miceHigh fat-High Cholesterol Diet Fed HamstersNonhuman Primates (Marmosets)Non-diabetic animal ModelsIn these animal models, Lipaglyn showed a maximum dose dependent reduction in TG levels up to 90%.Diabetic & Insulin Resistant ModelsUp to 55% TG reduction in db/db miceUp to 86 % TG reduction in Zucker fa/fa ratsNon-diabetic Abimal ModelsUp to 76 % TG reduction in Swiss Albino MiceUp to 90 % TG reduction in High fat-High cholesterol-fed HamstersUp to 61% reduction in serum triglycerides in Primates
15 Potential to reduce Post-prandial hyperlipidemia LipaglynTM improved lipid clearance and reduced serum cholesterol levelsImproved Lipid Clearance in Swiss Albino MiceHigh Cholesterol Diet Fed Sprague Dawley ratsPotential to reduce Post-prandial hyperlipidemiaLipaglynTM improved lipid clearance and reduced serum cholesterol levels post lipid load- Potential to reduce Post-prandial hyperlipidemiaUp to 68% improvement in lipid clearance in Swiss Albino miceUp to 77 % reduction in serum cholesterol in high-cholesterol diet-fed Sprague Dawley ratsPotential for Post prandial hyperlipidemia
16 LipaglynTM also has anti-diabetic effects in various animal models 43011_85LipaglynTM also has anti-diabetic effects in various animal modelsEffects in db/db miceEffects in Zucker fa/fa ratsGlucose Clamp study in Zucker fa/fa rats for Insulin sensitizing effectsLipaglynTM 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 glucoseEffect on AUCglucose in OGTTEffect on Serum Insulindb/db micedb/db mice : Animal Model for Type 2 Diabetes Mellitus & Insulin ResistanceUp to 65 % reduction in serum glucose; Up to 59 % reduction in AUCGlu in OGTT; 91 % reduction in serum insulin at 1mg/kgHyperinsulinemic Euglycemic Clamp StudyEffect on Glucose Infusion rateEffect on AUCglucose in OGTTEffect on Serum Insulin & FFALipaglyn showed a dose dependent reduction in serum glucose & insulin levels upto 65% & 91% resp in diabetic & insulin resistant animal modelsZucker fa/fa RatsZucker fatty fa/fa Rats: Animal model for Insulin-resistance85% reduction in serum insulin; Up to 52 % reduction in AUCGlu in OGTTImprovement in Glucose infusion rate in hyperinsulinemic euglycemic clamp study
18 Preclinical Evidence of Safety 3_857_8907/09/13Preclinical Evidence of SafetyAll Preclinical toxicity studies conducted in GLP (OECD) certified lab (Global quality standard)Our research center (ZRC) also has AAALAC, NABL & CAP accreditationData acceptable globallyAll 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 DevelopmentAAALAC – Association for Assessment and Accreditation of Laboratory Animal Care InternationalNABL – National Accreditation Board for Testing and Calibration LaboratoriesCAP – College of American Pathologists
19 Safety pharmacology studies show that LipaglynTM does not affect CNS, CVS, Respiratory and GI functionsSafety 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_85Overall Conclusions of Preclinical Safety & Toxicity StudiesLipaglynTM is safe and well toleratedNo hepatotoxicity, myotoxicity, nephrotoxicity or cardiotoxicity at doses equivalent to or higher than efficacy dosesNon-genotoxic & Non-teratogenicPassed 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 dosesNon-genotoxic & Non-teratogenicPassed 2-year carcinogenicity study (confirmed by a mechanistic study using non-human primates employing molecular biomarkers).
22 LipaglynTM: Pre-clinical ADME Profile 8_85LipaglynTM: Pre-clinical ADME ProfileADMEFindingsAbsorptionRapidly absorbedGood Oral Bioavailability of ~40 %t1/2 of about 3-4 hrsDistributionPlasma Protein Binding of about 96 % in rodentsNo drug levels detectable in any tissues at 24hr after thelast dose in a 12 month repeated dose toxicology study in Beagledogs.MetabolismStable in liver microsomesDid not show any CYP interaction or induction (in vitro studies)No potential for CYP-mediated drug-drug interactionsExcretionEliminated by non-renal routeUnchanged LipaglynTM was not detectable in urineMainly eliminated by hepato-biliary routeNow, lets look at Lipaglyn’s preclinical pharmacokinetic profile.
23 07/09/13Preclinical Data of LipaglynTM was Presented at 72nd ADA Meeting, June 2012, Philadelphia, USAThis is the Preclinical Data of LipaglynTM which was presented at 72nd ADA meeting, June 2012, Philadelphia, USA.
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