Precise Identification and Treatment of Macrophage- Mediated Diseases. April nd Annual NASH Summit

Transcription

1 Precise Identification and Treatment of Macrophage- Mediated Diseases April nd Annual NASH Summit

2 Disclaimer The private securities litigation reform act of 1995 (the act) provides a safe harbor for forward-looking statements made by or on behalf of the company. Statements in this presentation, which relate to other than strictly historical facts, such as statements about the Company s plans and strategies, expectations for future financial performance, new and existing products and technologies, anticipated clinical and regulatory pathways, and markets for the Company s products are forward-looking statements within the meaning of the Act. The words believe, expect, anticipate, estimate, project, and similar expressions identify forward-looking statements that speak only as of the date hereof. You are cautioned that such statements involve risks and uncertainties that could cause actual results to differ materially from historical or anticipated results due to many factors including, but not limited to, the Company s continuing operating losses, uncertainty of market acceptance of its products reliance on third party manufacturers, accumulated deficit, future capital needs, uncertainty of capital funding, dependence on limited product line and distribution channels, competition, limited marketing and manufacturing experience, risks of development of new products, regulatory risks and other risks detailed in the Company s most recent Annual Report on Form 10-K and other Securities and Exchange Commission filings. You are further cautioned that the foregoing list of important factors is not exclusive. The Company undertakes no obligation to publicly update or revise any forward-looking statements. 2

3 Addressing Disease Pathology in NASH Inflammation & Fibrosis A significant number of agents under investigation for the treatment of NASH are focused on metabolic pathways/targets (PPAR, FXR, bile acids) The operating assumption for above approach is based on the role of FFA (free fatty acids) in oxidative stress and resultant lipotoxicity Yet, steatosis alone is often benign and progression to NASH requires additional events Lipotoxicity, caused by the accumulation of lipid metabolites within non-adipose tissues, induces chronic inflammation by promoting macrophage activation and infiltration Emerging evidence suggests that macrophage activation represents a common pathogenic mechanism underlying lipotoxicity in inflammatory diseases such as NASH Release of inflammatory cytokines and chemokines by M1 macrophages leads to the development of NASH; while excess M2 macrophage activity (tissue healing/remodeling) drive the fibrotic processes 3

4 Macrophages induce liver cancer in subjects with steatosis Hepatosteatosis promotes activation of Wnt / beta-catenin Wnt signaling is significantly induced in tumor samples vs. healthy liver 90% of tumors in a cohort of 558 patients had Wnt induction (Oncogene (2017) 36, ) Depletion of macrophages abrogates tumor development Arrow, tumor nodules developed in livers without macrophage depletion Expression of Wnt ligands is significantly reduced by macrophage depletion (p<0.05) Infiltrating macrophages are a key source of steatosis-induced Wnt activation and tumor formation Selective depletion of macrophages lowers Wnt activation and suppresses tumor development 4

5 Fatty Liver Disease Steatosis Macrophage activation Wnt expression Hepatic inflammation Fibrosis NASH Liver cancer 5 5

6 Macrophages and CD206 Receptors Inactive macrophage Macrophages are activated in multiple ways Active macrophage Environmental Exposure Viruses Other infectious agents Drugs/chemicals Other (e.g. ultraviolet light) Hormonal Effects Intrinsic and extrinsic Variable depending on disease M 1 The mannose receptor, CD206, is only expressed on activated macrophages and dendritic cells (CD209) Innate: Phagocytosis of foreign materials + pathogens Adaptive: Stimulating activation of other immune cells B T H Activated macrophages function in both innate + adaptive immunity T C 6

7 Selective Binding Enables Precise Targeting Tilmanocept selectively binds only to activated macrophages without targeting lymphocytes (non-activated macrophages), or non-activated tissue resident macrophages (kuppfer cells, microglial cells, etc.) 7

8 Navidea Imaging Strategy Image M1 or M2 Mediated Disease Dose it Same for all indications Image it Focus the camera on area of interest 3 hour image RA (M1) Cardiovascular Disease Images (M1 & M2) 8

9 RA imagining Demonstrates binding affinity to M1 Macrophages 3 hour image RA Precisely Identifying Active Disease 9

10 Quantifiable Inflammation Score Computer Read of CV images Creates Quantitative Inflammation Score Compiled 2D/3D Imaging Computer Generated Score of CV Images Mean CD206+ macrophages/mm Percent aortic volume with high -level tilmanocept uptake

11 Small Molecule with short in-vivo half-life Demonstrated penetration through Blood Brain Barrier and kidney clearance SPECT/CT SCAN: DIRECTED BY ASYMETRIC LOCALIZATION ON WHOLE BODY SCAN SPECT WHOLE BODY SCAN: Injection site lower left leg; KS lesions match tracings of leg lesions; TC99m- tilmanocept localizes in KS chain linked by lymphatic ducts; localizes in (KS+?) inguinal nodes; left of nodes in image is bladder LOCALIZATION IN NASOPHARYNX AND BRAIN 11

12 Tc99m-Tilmanocept is Targeted to CD206 on Activated MØs x Higher affinity than Mab to Receptors (2.7x10E-11 to -12 M) CD206 Tc99m-Tilmanocept 12

13 Representative views Coronal 13

14 Representative views Transverse 14

15 Representative views Sagittal 15

16 Patient 1 NASH Ultrasound Elastometry Score µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 169 Max Uptake Value = 274 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 16

17 Patient 1 NASH Ultrasound Elastometry Score µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT Link to video file found at: A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 169 Max Uptake Value = 274 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 17

18 Patient 2 NASH Ultrasound Elastometry Score µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 157 Max Uptake Value = 188 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 18

19 Patient 2 NASH Ultrasound Elastometry Score µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT Link to video file found at: A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 157 Max Uptake Value = 188 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 19

20 Patient 3 NASH Ultrasound Elastometry Score µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 190 Max Uptake Value = 215 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 20

21 Patient 3 NASH Ultrasound Elastometry Score µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT Link to video file found at: A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 190 Max Uptake Value = 215 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 21

22 Patient 4 NASH Ultrasound Elastometry Score 0/1 200 µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT A B A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 68 Max Uptake Value = 193 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 22

23 Patient 4 NASH Ultrasound Elastometry Score 0/1 200 µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT A B Link to video file found at: A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 68 Max Uptake Value = 193 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 23

24 Patient A Normal (RA Patient) 200 µg w/ 8 mci Tc99m-Tilmanocept, Imaged 180 min post-injection Gamma Camera with SPECT/CT A B Link to video file found at: A SPECT B Fused SPECT/CT TILMANOCEPT ASSESSMENT SCORE* à Mean Uptake Value = 45 Max Uptake Value = 102 HOTTER (Greater Tc99m-Tilmanocept Uptake)* *Based on Image-J Analysis and Tc99m-Tilmanocept Uptake Assessment 24

25 NASH VS NORMAL 3D MID LIVER LOCALIZATION Link to video files found at: NASH Pt-1 NASH Pt-2 Normal Patient HOTTER (Greater Tc99m-Tilmanocept Uptake)* NASH Pt-3 NASH Pt-4 *Based on Image-J Analysis and Tc99m- Tilmanocept Uptake Assessment 25

26 NASH Imaging Scores Virtual biopsy provides multiple degrees of freedom as to reporting and monitoring NASH Patients RA Patients Patient Identifier Pt 1 Pt 2 Pt 3 Pt 4 Pt A Pt B Pt C US Elastometry Score /1 60 Min 75 / / / Min 146 / / / Min 169 / / / / / / / 214 *Mean Whole Liver Intensity of Voxels / Maximum Voxel Intensity 26

27 Therapeutic Concept Selectively targeting Activated Macrophages Platform for immuno-constructs that preferentially target CD206+ (and CD209+ dendritic cells) activated macrophages 1 GPS 2 Delivery 3 Payload Mannose Moiety With One Hardwired Address - CD206 Activated Macrophages Manocept TM Backbone Chemotherapeutics Immune-modulators Tc 99 Other Isotopes 27

28 Thank you Contact Details Michael Goldberg, M.D.