Pipeline Liquid Embolics: Glimpse into the Future. Daniel Sze, MD PhD Stanford University

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1 Pipeline Liquid Embolics: Glimpse into the Future Daniel Sze, MD PhD Stanford University

2 Daniel Sze, M.D., Ph.D. Stock: SureFire Medical, Inc., NDC, Inc Consultant/Advisory Board: EmboIX, Inc., Koli Medical, Inc., Boston Scientific, Inc., BTG, Inc., Codman, Inc., Covidien/Medtronic, Inc., W.L. Gore, Inc., Viralytics, Inc. Research Grants: Amgen, inc., Merit Medical, Inc., W.L. Gore, Inc.

3 Daniel Sze, M.D., Ph.D. Reference Unlabeled/Unapproved uses of drugs or products: Histoacryl, B.Braun Trufill n-bcs, Codman Lipiodol, Guerbet, Onyx, Covidien/Medtronic, TheraSphere, BTG, SIR- Spheres, Sirtex

4 Liquid embolics Block flood flow by forming cast Adaptations of industrial products acrylic thermoplastics polymeric foams cyanoacrylates resin copolymers

5 Liquid embolics pipeline What is available now? In situ polymers (cyanoacrylates) Precipitating copolymers What are the unmet needs? How is research addressing the unmet needs?

6 In situ polymerization Cyanoacrylates Discovered during WW2, material for gunsights Isobutyl caused sarcomas; n-butyl since 1980s TruFill FDA-approved Histoacryl, Glubran, Enbucrilate, Neuracryl, Derma+Flex, Rekseal, Cutseal, Leukosan, Endocryl, PeriAcryl, TruSeal, etc.

7 Cyanoacrylates Advantages: Permanent (very slowly biodegradable) Complete obstruction from cast Can reach nidus Not dependent on thrombosis Inexpensive in some countries Disadvantages: Unpredictable flow/polymerization Too proximal, too distal, reflux Adherent to catheter

8 New cyanoacrylates Properties can be engineered e.g. Sapheon Venaseal for GSV ablation Chemical sidebranch affects rate of polymerization, exothermicity Carrier affects viscosity, compliance, rate of polymerization

9 Precipitating copolymers: EVOH Ethylene vinyl alcohol precipitating copolymer Dimethyl sulfoxide (DMSO) solvent Micronized tantalum radiopaque additive Different concentrations/viscosities 2 available products: Onyx Squid Peri

10 EVOH Advantages: Permanent Complete obstruction from cast Can reach nidus Not dependent on thrombosis More deliberate, controllable flow Coherent, not adherent Disadvantages: Unpredictable final location Too proximal, reflux Slow DMSO toxicity Need DMSO compatible catheter Expensive Still adheres to catheter Pigmented

11 New copolymers Can be engineered to tailor properties Precipitating hydrophobic injectable liquid (PHIL) Polylactide-coglycolide/polyhydroxyethylmethacrylate in DMSO CE Marked Faster plug formation More inflammation, less necrosis More distal penetration 2.9 um vessels Triiodophenol bound to copolymer no tantalum precipitation, no shaking, less artifact

12 New products in pipeline In situ polymerization (like existing cyanoacrylates) PPODA-QT Precipitates (like existing copolymers) Calcium alginate Eudragit-E Temperature sensitive hydrogels poly(n-isopropylacrylamide-co-butyl methylacrylate) nanogel Chitosan/β-glycerophosphate Coacervates (hydrostatically driven liquid-liquid phase separation) Polyphosphate coacervate Polyelectrolyte (protamine/ip 6 ) coacervate Liquid crystals Phytantriol

13 In situ polymerization: PPODA-QT Polymerization, not precipitation - OH catalyst formulated into gelling system Tailor gelling rate by adjusting ph 1-2 min injection, 10 min gel time No incremental filling Swine aneurysm model only

14 In situ polymerization (thanks to Upma Sharma) Polymer designed for very fast curing from the outside in; enables control while flowing into small vessels. Immediate and durable occlusion. No details - proprietary Coil alone Material 1 alone Coil + Material 1

15 Precipitants: Calcium alginate Sugar-based copolymer derived from seaweed Forms tissue-like gel matrix when contact with co-injected concentrated Ca ++ Physiologic Ca ++ insufficient to gel injected liquid alone nontoxic 30 sec gel time Not cohesive, no incremental May be resorbable? Swine model, pilot human studies

16 Precipitants: Eudragit-E Copolymer dissolved in ethanol and iopamidol (Isovue) Cationic copolymer, precipitates upon exposure to blood anions Originally FDA-approved as a coating material for oral tablets Need for pharmacy compounding Flush microcatheter with EtOH first Iopamidol eventually diffuses out, leaving it radiolucent May be loadable with other diffusable drugs

17 Temperature sensitive hydrogels: PIB Nanogel Hydrophobic interactions above phase transition temperature form 3D hierarchical gel network Nonadhesive, no solvents Radioopaque with iohexol Non degradeable?reversible?drug eluting PIB Lipiodol

18 Temperature sensitive hydrogels: Chitosan/β-Glycerophosphate Chitosan linear polysaccharide made from shrimp shells, N- deacetylated chitin Liquid at 25 C, hydrogel at 37 C Nonadhesive, nontoxic Resorbable? Swine model only

19 Coacervates: Polyphosphate coacervate Naturally occurring, linear inorganic polymer found in platelets, activates contact pathway of thrombosis Solidifies after chelating divalent cations Resorbable Made radiopaque with strontium and barium Rabbit ear model

20 Coacervates: GPX (Fluidx) (thanks Shawn Fojtik) Based on chemistry of marine worm tube formation Proprietary gel-coated particle, in high salinity Increases viscosity at physiologic salinity All ingredients found in other FDA cleared products (Protamine, NaP 6, embolization fiber, Pt) 2 different viscosity formulations Toothpaste like delivery & control Non-cytotoxic, non-hemolytic, non-inflammatory, non-adhesive

21 Liquid crystal: Phytantriol Cubic phase liquid crystals formed by polar amphiphilic materials in aqueous environment, consisting of curved bicontinuous lipid bilayer in 3 dimensions separating 2 congruent networks of water channels Liquid crystal gel can enclose hydrophilic, amphiphilic, and hydrophobic substances to achieve sustained and controlled release. Nonviscous precursor isotropic solution may be injected, gels in situ to cubic phase by water absorption Injected liquid that solidifies when it absorbs water It can elute an irinotecan derivative, kill tumor cells in culture

22 Conclusions Only 2 classes of products currently commercially available Cyanoacrylate polymers Precipitating copolymers New concepts/products (Off-label) Less adhesiveness Different viscosity, heat sensitivity Less toxicity, solvents Different permanence, biodegradability Potential to elute drugs