Galectin Therapeutics Inc. · NASDAQ:GALT
Galectin Therapeutics — Anti-Fibrotic Drug Development Summit 2018
45 slides from Galectin Therapeutics's conference presentation, Nov 29, 2018
Slide 1: Anti-Fibrotic Drug Development Summit
Anti-Fibrotic Drug Development Summit November 29, 2018 Cambridge, MA Harold H. Shlevin, PhD President & CEO
Slide 2: Agenda
Agenda • Galectins – a structural perspective • Galcetin-3 – molecular targets for therapeutic intervention • Galectin-3 – Function in disease • Pharmacological Targeting of Galectin-3 • Preclinical Results • Clinical Results in NASH-cirrhosis • Summary ©2018 Galectin Therapeutics 2
Slide 3: What are Galectins?
What are Galectins? • Family of highly conserved, molecular effectors that mediate various biological processes • Currently 15 mammalian galectins have been reported • Many more are found in different organisms • Function by interacting with cell surface glycoconjugates • Usually target β-galactosid
Slide 4: Galectins - Structural
Galectins - Structural • Three groupings • Prototype – single core domain referred to as CRD • Gal-1, -2, -5, -7, -10, -11, -13, -14 • Chimera – C-terminal CRD linked to a lengthy, collagen-like, dynamic and structurally aperiod N-terminal tail • Gal-3 • Tandem Repeats – two homologous, distinct, CR
Slide 5: Galectin Oligomer States
Galectin Oligomer States • β - sandwich structure consists of 11 strands • 6 of strands define the sugar binding face (S- face) of the CRD • 5 of remaining strands define the opposing F- Face • High resolution structures of the CRDs of human galectins have been reported • CRD structures are highly c
Slide 6: Galectin-3 Carbohydrate Binding
Galectin-3 Carbohydrate Binding • Lactose binding affinity • Gal-3: 26x10-6 to 0.6x10-3 M • Gal-3 • α- galactomannan binds to the F- face of the CRD in both Gal-3 and Gal-1 (e.g., GM-CT-01) • Rhamnogalacturonan polysaccharide binds relatively strongly to the N-terminal sequence of Gal-3 NT (e.g., GR
Slide 7: Overview
Overview • Galectins – a structural perspective • Galectin-3 – molecular targets for therapeutic intervention • Galectin-3 Function in disease • Pharmacological Targeting • Preclinical • Clinical Results in NASH-cirrhosis ©2018 Galectin Therapeutics 7
Slide 8: Galectin Functions in Cancer
Galectin Functions in Cancer Tumorigenicity • Pro: ↑ • Anti: ↓ • Galectin expression varies from cell type • All cells express at least one galectin • Galectins are synthesized on cytosolic ribosomes • Galectins control cell-cell and cell-matrix interactions, adhesion, proliferation, apoptosis, pre-
Slide 9: Galectin Function in Fibrosis
Galectin Function in Fibrosis • Fibrosis represents the end result of chronic inflammatory reactions induced by a variety of stimuli • Mechanisms driving fibrogenesis are distinct from those regulating acute inflammatory reactions • Studies indicate that Gal-3 is increased in fibrosis affecting many
Slide 10: Overview
Overview • Galectins – a structural perspective • Galcetin-3 – molecular targets for therapeutic intervention • Galectin-3 Function in disease • Pharmacological Targeting • Preclinical • Clinical Results in NASH-cirrhosis ©2018 Galectin Therapeutics 10
Slide 11: Gal-3 Plays a Critical Role in Fibrosis
Gal-3 Plays a Critical Role in Fibrosis • Galectin-3 expression is up-regulated in human liver fibrosis. (a) Galectin-3 expression in normal human liver. (b) Galectin-3 in cirrhosis secondary to hepatitis C infection. • Galectin-3 expression is temporally and spatially related to fibrosis in a rever
Slide 12: Galectin-3 Critical Role in Fibrosis
Galectin-3 Critical Role in Fibrosis Galectin-3 mediated activation of HSCs in vivo is a central mechanism underlying hepatic fibrosis. • Hepatic stellate cell (HSC) is the key fibrogenic cell liver • HSCs activation to proliferative, fibrogenic, and contractile myofibroblasts with increased express
Slide 13: Galectin-3 effects on macrophages and stellate cells in liver fibrosis
Galectin-3 has important effects on two key cell types in liver fibrosis - macrophages and stellate cells Stellate Cell Monocytes TGF-βR Recruitment TGF-βR Macrophage Integrin R ↑Proliferation Gal-3 Integrin R ↑Apoptotic body phagocytosis + ↑TGFβ signaling Phagocytosis + + Gal-3? Myofibroblast Resto
Slide 14: What is the Role of TGF-β?
What is the Role of TGF-β ? • TGF- β is a major profibrogenic cytokine and is thought to be a key mediator of fibrosis in many different organs; but, is it ? • TGF-β mRNA expression was markedly elevated after hepatic injury • However, expression of TGF-β was similar in whole liver homogenates from
Slide 15: Mechanisms of Galectin-3-mediated regulation of alternative macrophage activation
Mechanisms of Galectin-3-mediated regulation of alternative macrophage (M2) activation. A Galectin-3 feedback loop drives alternative macrophage activation. Henderson et al, 2009 © 2018 Galectin Therapeutics 16
Slide 16: Overview
Overview • Galectins – a structural perspective • Galcetin-3 – molecular targets for therapeutic intervention • Galectin-3 Function in disease • Pharmacological Targeting • Preclinical • Clinical Results in NASH-cirrhosis ©2018 Galectin Therapeutics 17
Slide 17: Approaches to targeting Galectin-3 with pharmacological agents
Approaches to targeting Galectin-3 with pharmacological agents • Disaccharides such as lactose and n-acetyl lactosamine bind to the canonical carbohydrate recognition domain • Derivative disaccharides are in phase 1development for lung fibrosis (inhaled formulation) (TD-139; Galecto Biotech, license
Slide 18: Galectin Protein Targeting with a Complex Carbohydrate, GR-MD-02
Galectin Protein Targeting with a Complex Carbohydrate, GR-MD-02 The theoretical basis for complex carbohydrate drugs is that terminal galactose residues bind to galectin proteins in the context of a macromolecular structure, similar to the situation with glycoproteins GR-MD-02 Characteristics of bi
Slide 19: Critical attributes of GR-MD-02
Critical attributes of GR-MD-02 The GR-MD-02 is a non-biological complex drug substance which is a polymer comprised of a repeating unit, which is represented by the structure diagram below: The active moiety is defined analytically by the combination of the following key characteristics of the comp
Slide 20: Interaction of GR-MD-02 with Galectin-3
Interaction of GR-MD-02 with Galectin-3 NMR-HSQC (nuclear magnetic resonance-heteronuclear single quantum coherence). lactose • Many resonances within the CRD (carbohydrate recognition domain) are shifted, at both the canonical carbohydrate binding site on the β-sandwich S- face and the opposing F-f
Slide 21: Overview
Overview • Galectins – a structural perspective • Galcetin-3 – molecular targets for therapeutic intervention • Galectin-3 Function in disease • Pharmacological Targeting • Preclinical • Clinical Results in NASH-cirrhosis ©2018 Galectin Therapeutics 22
Slide 22: GR-MD-02 Has Therapeutic Effect On NASH With Fibrosis In Mouse Model
GR-MD-02 Has Therapeutic Effect On NASH With Fibrosis In Mouse Model* Normal NASH: Control NASH: GR-MD-02 GR-MD-02 Effects H & E Stain NAFLD Activity Score • Fat • Cell death • Inflammation Collagen Stain Collagen (Fibrosis) *Traber PG and Zomer E. Therapy of Experimental NASH and Fibrosis with Gale
Slide 23: GR-MD-02 Markedly Improved NASH in the Mouse Model
GR-MD-02 Markedly Improved NASH in the Mouse Model, with similar improvements to those seen in Galectin-3 null mice © 2018 Galectin Therapeutics NASDAQ:GALT CONFIDENTIAL 24
Slide 24: GR-MD-02 Prevented and Completely Reversed Fibrosis in NASH Mouse Model
GR-MD-02 Prevented and Completely Reversed Fibrosis in NASH Mouse Model and Efficacy Not Dependent on When Treatment was Started Early Treatment Late Treatment normal mouse 0.33 Given IV twice weekly. These results have been confirmed in repeat studies with different dosing regimens © 2018 Galectin
Slide 25: Galectin-3 Expression Is Increased in Macrophages in NASH Mice
Galectin-3 Expression Is Increased in a Subset of Macrophages in NASH Mice NASH No major change in total number of macrophages, as shown with macrophage staining, but increase in gal-3 expression © 2018 Galectin Therapeutics | NASDAQ:GALT CONFIDENTIAL 26
Slide 26: Galectin-3 Expressed In Liver Macrophages, Increased In Human NASH
Galectin-3 is Expressed In Liver Macrophages And Is Markedly Increased In Human NASH Kupffer cells= liver resident macrophages Portal macs=macrophages located in portal regions © 2018 Galectin Therapeutics | NASDAQ:GALT CONFIDENTIAL 27
Slide 27: GR-MD-02 Reduces Gal-3 Expressing Macrophages in NASH Mice
Treatment with GR-MD-02 Markedly Reduces Gal-3 Expressing Macrophages in NASH Mice Vehicle GR-MD-02 © 2018 Galectin Therapeutics | NASDAQ:GALT CONFIDENTIAL 28
Slide 28: Activated Stellate Cells Decreased By Therapy with GR-MD-02
Activated Stellate Cells Expressing α-Smooth Muscle Actin Are Decreased By Therapy with GR-MD-02 Vehicle Activated stellate cells have a myofibroblast phenotype and are primary cellular source of fibrotic tissue GR-MD-02 © 2018 Galectin Therapeutics | NASDAQ:GALT CONFIDENTIAL 29
Slide 29: Dose response of once weekly GR-MD-02 in mouse NASH
Dose response of once weekly doses of GR-MD-02 in mouse NASH shows efficacy in reducing fibrosis down to 10 mg/kg per week The difference in the results of Sirius red staining and hydroxyproline content in the 10 mg/kg group may be related to differences in the sensitivity and reproducibility of the
Slide 30: Dose Response Effect On Hydroxyproline and iNOS Defines Therapeutic Window
Dose Response Effect On Liver Hydroxyproline and iNOS Expression Defines Therapeutic Window © 2018 Galectin Therapeutics | NASDAQ:GALT CONFIDENTIAL 31
Slide 31: Blood and Tissue Levels Of Galectin-3 Are Not Correlated
Blood and Tissue Levels Of Galectin-3 Are Not Correlated In Mouse NASH Model Nor Human NASH Marked changes in expression of galectin-3 in liver macrophages are not reflected in changes in blood galectin-3 Liver Gal-3 Staining Liver Tissue Level Blood Level Normal NASH • No evidence for correlation b
Slide 32: GR-MD-02 Reversed Cirrhosis And Improved Portal Hypertension In Rat Model
GR-MD-02 Reversed Cirrhosis And Improved Portal Hypertension In Rat Model* Vehicle-Treated Collagen Portal Pressure GR-MD-02-Treated N=10 N=10 N=10 N=10 N=10 *Traber PG, Chou H, Zomer E, Hong F, Klyosov A Fiel M-I, Friedman, SL. Therapy of Regression of fibrosis and reversal of cirrhosis in rats by
Slide 33: GR-MD-02 reversed cirrhosis and reduced portal inflammation and hepatocyte ballooning
GR-MD-02 reversed cirrhosis and reduced portal inflammation and hepatocyte ballooning Liver histology from each animal was evaluated in a blinded fashion by an experienced pathologist. Statistical analysis was done using Mann-Whitney test for non-parametric measurements and graph shows median with i
Slide 34: Preclinical Data Shows That GR-MD-02 Can Reverse NASH, Fibrosis, and Cirrhosis
Preclinical Data Shows That GR-MD-02 Can Reverse NASH, Fibrosis, and Cirrhosis Effect NASH mouse1 Cirrhotic rat2 Reduces inflammation X X Reduces fat X N/A Reduces cell death X X Prevents fibrosis X X Reverses fibrosis X X Reduces portal pressure N/A X Targets macrophages in liver X X Reduces galect
Slide 35: Overview
Overview • Galectins – a structural perspective • Galcetin-3 – molecular targets for therapeutic intervention • Galectin-3 Function in disease • Pharmacological Targeting • Preclinical • Clinical Results in NASH-cirrhosis - highlights ©2018 Galectin Therapeutics CONFIDENTIAL 36
Slide 36: NASH-CX Phase 2b Clinical Trial
NASH-CX Phase 2b Clinical Trial • Enrolled 162 Patients • NASH cirrhosis with portal hypertension • Well compensated disease with no complications of cirrhosis • Primary Endpoint • Portal pressure (HVPG—hepatic venous pressure gradient) • Change in baseline adjusted HVPG from beginning to end of stu
Slide 37: Clinically Relevant Reduction in HVPG in Patients Without Varices
43% of patients without varices in the GR-MD-02 2mg/kg group showed a ≥2 mmHg and ≥20% decrease from baseline compared to 13% in the placebo group Percentage of Patients Who Had a Clinically Relevant Reduction in HVPG With: Highlights • ≥ 2 mmHg Decrease From Baseline AND • ≥ 20% Decrease From Basel
Slide 38: Change in Hepatocyte Ballooning Score at Week 54
Patients in the 2 mg/kg treatment group showed statistically significant improvement of liver cell death on liver biopsy1 Highlights p = 0.03 p = 0.09 0.4 Ballooning Score at Week 54 Change in Hepatocyte In the total 0.2 population there was improvement in cell death, a critical feature of n=54 n=54
Slide 39: Highlights of Results NASH-CX – reported Dec. 2017
Highlights of Results NASH-CX – reported Dec. 2017 NASH-CX is the first clinical trial to show positive results in compensated NASH cirrhosis without esophageal varices • Clinically meaningful effect in reducing portal pressure in a subgroup of patients • Improvement in liver cell death, a key com
Slide 40: NASH Cirrhosis Therapy Program with GR-MD-02: Summary
NASH Cirrhosis Therapy Program with GR-MD-02: Summary • Unmet medical need with a very large potential market • Competitively well positioned in NASH cirrhosis • Reversal of fibrosis/cirrhosis in preclinical models • Strong patent portfolio supporting composition of matter, production, and use of GR
Slide 41: © 2018 Galectin Therapeutics
© 2018 Galectin Therapeutics 42
Slide 42: Galectin-3 is at the apex of multiple pathophysiological processes in NASH and fibrogenesis
Galectin-3 is at the apex of multiple pathophysiological processes in NASH and fibrogenesis Metabolic Syndrome Cause of Liver Injury Potential sites of Glucose Fat Impaired Lipid Intolerance Accumulation Metabolism anti-galectin activity Mediators Hyperglycemia Adipo-Cytokines Free Fatty Acids Macro
Slide 43: Summary
Summary • Galectin-3 is critical to the fibrotic process • Galectin-3 also plays an important role in various cancers • Preclinical models demonstrate that a galectin antagonist (GR-MD-02) can reverse fibrosis in various animal models • Liver, Lung, Kidney and Heart • Mechanistic models were present
Slide 44: Critical Role of Galectin-3
Critical Role of Galectin-3 Galectin 3 Galectin 3 Modified from Shuppan et al 2017 © 2018 Galectin Therapeutics 45
Slide 45: Thanks for your attention
Thanks for your attention For further information see www.galectintherapeutics.com © 2018 Galectin Therapeutics 46
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