In Vivo Behavior of Drug-Eluting Embolics. J. Namur, PhD Archimmed SARL

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1 In Vivo Behavior of Drug-Eluting Embolics J. Namur, PhD Archimmed SARL

2 Julien Namur, Ph.D. Employee: Archimmed SARL Research Grants: BTG, Terumo, Microvention, Merit Medical, Nanobiotix, Covidien, Cardiatis, Universite René Descartes Paris 5 The use of the following product/drug is considered unlabeled/unapproved in the USA: DC Bead / LC Bead loaded with doxorubicin DC Bead / LC Bead loaded with irinotecan HepaSphere / QuadraSphere loaded with doxorubicin HepaSphere / QuadraSphere loaded with irinotecan Lifepearl loaded with doxorubicin

3 Behavior of Drug-Eluting Embolics 1. In syringe 2. In plasma 3. In the occluded vessel 4. In the tissue

4 1. In syringe Release may start while mixing Release in suspension medium between 4% and 30% of target loading Depend on drug and bead. Product DC Bead 100/300 DC Bead HepaSphere 30/60 HepaSphere 30/60 Drug / Loading 50 mg IRI 50 mg 50 mg IRI 50mg Loading efficiency (n vials) 99.9% (n=3) 96.0% (n=2) 98.6% (n=4) 92.4% (n=2) % release in syringe * (n injections) 4.2% (n=6) 7.4% (n=5) 3.8% (n=5) 29.1% (n=5) * after reconstitution with drug and mixing with non-ionic contrast agent, measured just before injection Adapted from Namur et al. JVIR 2014;25(3) and Namur et al. JVIR 2015;26(7)

5 1. In syringe Look in the syringe DEE are slowly injected one by one DEE form aggregates in µkt hub 1mL -DEE µm diluted 1:20 and injected with a 1mL syringe in a 1.7 Fr microcatheter Echelon 10 in ~5min

6 IRI plasma (ng/ml) 2. In plasma In vitro predicts in vivo plasma levels Faster release in vitro Higher plasma drug levels in vivo HS-IRI HS-IRI DC-IRI DC-IRI Jordan et al. JVIR 2010;21(7) Time (h) Namur et al. JVIR 2015;26(7)

7 2. In plasma Lowered plasma level of drug Requirement is DEB < ctace or DEB < systemic therapy Demonstrated for DC- and HS- in patients Same profiles and same levels for DC- and HS- ctace ctace DC- Varela et al. J Hepatol 2007;46(3) Malagari et al. CVIR 2014;37(1)

8 2. In plasma Lowered plasma level of drug Requirement is DEB < ctace or DEB < systemic therapy Demonstrated for DC-IRI and HS-IRI in preclinical models Rao et al. CVIR 2012;35(6) Tanaka et al. JVIR 2014;25(1) IA IRI IV IRI IA IRI + HS DC-IRI HS-IRI

9 3. In the occluded vessel Location of DEE? 800µm 400µm 100µm 40µm Peri-tumoural

10 3. In the occluded vessel Location of MS? Head & neck tumors embolised with calibrated MS Surgery Histology : location of MS and vessel diameter Median 240µm Vessel diameter: IntraT < ExtraT but overlap, no threshold Median 400µm Laurent et al. JVIR 2005;16(4)

11 Diameter of occluded vessel (µm) 3. In the occluded vessel Location of DEE? 1 tumour 3.9 cm explanted 8h after DEB- with µm. Occlusion of intra-t (42%) and peri-t (58%). No size threshold between intra-t and peri-t vessels Extra-tumoural Intra-tumoural Extra- Tumoral 58% Intra- Tumoral 42% Namur et al. J Hepatol 2011;55(6) p=0.050 Rho= Distance to tumour boundary (mm)

12 3. In the occluded vessel Location of DEE? Nicolini et al. World J Gastroenterol 2013;19(34) 38 nodules embolised with / DEB- Mean tumour diameter 1.8 cm IntraT 29% / IntraT + PeriT 37% / PeriT 26% / ExtraT 8% Odisio et al. CVIR 2014;37(4) 27 nodules embolised with DEB- Mean tumour size 2.34 cm Presence of beads within and in parenchyma surrounding all the lesions

13 3. In the occluded vessel Location of DEE? 800µm 400µm 100µm 40µm Peri-tumoural Intra-tumoral + Peri-tumoural Intratumoral

14 3. In the occluded vessel Microsatellites 100 pts with HCC < 5.0 cm (median: 3.4 cm). Surgery and histology Median distance microsatellite main HCC nodule: 5.0 mm Correlation with size of tumour HCC microsatellite Main HCC nodule Median distance µsat - HCC Sasaki et al. Cancer 2005;103(2)

15 4. In the tissue Quantification of in DEE after embolisation DRUG PRODUCT Loading DC Bead LifePearl 100 HepaSphere 30/60 DC Bead LifePearl 100 HepaSphere 30/60 Time point % elution released per ml DEE Ref 37mg/mL 7 days 73% 28mg (1) 37mg/mL 7 days 71% 27mg (1) 25mg/mL 7 days 72% 18mg (2) 37mg/mL 30 days 86% 32mg (1) 37mg/mL 30 days 87% 33mg (1) 25mg/mL 30 days 100% 25mg (2) (1) Namur et al. ECIO 2015 (2) D inca et al. CIRSE 2012

16 4. In the tissue Release is fast Quantification of in DEE after embolisation release: 70-80% in 7 days, % in 1 month No major difference between products DRUG PRODUCT Loading DC Bead LifePearl 100 HepaSphere 30/60 DC Bead LifePearl 100 HepaSphere 30/60 Time point % elution released per ml DEE Ref 37mg/mL 7 days 73% 28mg (1) 37mg/mL 7 days 71% 27mg (1) 25mg/mL 7 days 72% 18mg (2) 37mg/mL 30 days 86% 32mg (1) 37mg/mL 30 days 87% 33mg (1) 25mg/mL 30 days 100% 25mg (2) (1) Namur et al. ECIO 2015 (2) D inca et al. CIRSE 2012

17 4. In the tissue Release is fast DC Bead mg /ml Embolization of hepatic artery in swine Highest tissue levels recorded in the first 8h following embolization Dreher et al. JVIR 2012;23(2)

18 4. In the tissue Release is fast, except for clusters DC Bead mg /ml Embolization of hepatic artery in swine Higher around clusters Concentration ( m) Single Multiple 1 hour post embolization ( µm): Nuclei, Doxorubicin Distance ( m) Dreher et al. JVIR 2012;23(2)

19 4. In the tissue Release is fast, except for clusters DC Bead mg/mL 4 HCC patients embolized then transplanted 57 to 105 days after No in single beads vs 20% in clusters of beads at 57 days No around single beads, High around clusters at 80 days Histology slide from patient 57 days after DEB-TACE 2 beads in a vessel Cluster in a vessel Patient at 80 days No. DEB in vessel Dinca et al. PhD thesis 2015

20 4. In the tissue diffuses ~1mm from DEE DC Bead mg/mL 6 HCC patients embolized then transplanted Histopathology tissue concentration decreases over time diffuses radially around DEE up to a distance of ~1mm Dreher et al. JVIR 2012;23(2) Namur et al. J Hepatol 2011;55(6)

21 4. In the tissue diffuses ~1mm from DEE DC Bead mg/mL 6 HCC patients embolized then transplanted Histopathology tissue concentration decreases over time diffuses radially around DEE up to a distance of ~1mm At 8h, same distribution profile inside and outside tumour Namur et al. J Hepatol 2011;55(6)

22 Conclusions 1. In syringe look at suspension and injectability 2. In plasma drug levels should be < ctace or < systemic therapy 3. In occluded vessel DEE > 100µm occlude intra-t and peri-t vessels DEE < 100µm occlude intra-t vessels What is the best? => X-ray / MRI imageable beads will help 4. In tissue High levels are delivered for hours-day Drug () diffuses ~1 mm from the DEE

23 Thank you R&D, ArchimMed, Jouy en Josas, France J Namur F Pascale SH Ghegediban V Verret Matrice Extracellulaire et Dynamique Cellulaire, CNRS, Reims, France H D Inca M Manfait Radiology, Osaka University Graduate School of Medicine, Osaka, Japan N Maeda Neuroradiology, Lariboisière Hospital JP Saint Maurice A Laurent Pathology, Lariboisière Hospital Paris, France M Wassef Radiology, Centre Hospitalo-Universitaire de Caen, France JP Pelage