DSM – TACE in comparison with c- and DEB-TACE EmboCept® S, DSM 35 – 50* *) DSM = degradable starch microspheres (Amilomer)

DSM (Embocept® s) in comparison vs. DC Beads Pharmacokinetics Clinics Therapeutic/technical recommendation vs. lipiodol

Chemoembolization – DsM-tace EmboCept® S - parameters cross-linked, partially hydrolyzed starch polymere matrix median diameter: 50 /um (lodge in precapillary vessel area) half-time: app. 35-40 min. degadation by -amylase fragments: 100 - 106 Dalton (water-soluble)

advantages of a degradable material Chemoembolization – advantages of a degradable material Angiographic documentation of vessels permanent embolization N collateral tumor vessels 6 h 4 4 h 5 3 2 h Persson BG et al. World J Surg 1987;11(5):672–7

Dsm (EmboCept® s) vs. Dc beads pharmacokinetics clinics therapeutic/technical recommendation

5-fu-concenttration in tumor and liver (locoregional with and without amilomer) 15 30 45 60 90 Min 10 20 40 50 70 µg/g 5-FU Tumor Liver 25,09 µg/g 58,65 µg/g 10 mg 5-FU i.a. AUC: 10 mg 5-FU i.a. versus 10 mg 5-FU + 6 mg Amilomer i.a. 655 62655 1704 27822 5-FU i.a. 5-FU+Amilomer i.a. 95 x 60000 50000 40000 AUC (15-120 min) µg/g*min 15 30 45 60 90 2 h 4 h 8 h 12 h 24 h 100 200 300 400 500 600 700 µg/g 5-FU Tumor Liver 433.39 µg/g 664.39 µg/g 20000 10000 10 mg 5-FU i.a. + 6 mg Amilomer Chirurgische Klinik I Universitätsklinikum Benjamin Franklin FU Berlin

Pharmacokinetic with de beads: Tumor doxorubicin concentration Doxorubicin in tumor (nmoles/g) 450 400 350 300 250 200 150 100 50 Time from doxorubicin administration (hours) 0 100 200 300 400 HAI DE Beads Hong K, et al. Clin Cancer Res 2006;12:2563–7, Courtesy: R. Lencioni, Pisa 7

AUC ? EmboCept S vs. Beads Pk data 0 100 200 300 400 + 3 x Doxorubicin in tumor (nmoles/g) 450 400 350 300 250 200 150 100 50 0 100 200 300 400 TACE DE Beads + 3 x AUC ? Time from doxorubicin administration (hours) 5-FU-concentration in tumor and liver (locoregional with and without Amilomer) 8

Tumor growth and necrosis Dt. Krebskongress Berlin2014

Dsm (EmboCept® s) vs. Dc beads pharmacokinetics clinics therapeutic/technical recommendation

Dsm – clinical data clinics (TACE) Taguchi, T. (1992): random. phase III - study indications: 1) HCC (n=60) 2) liver metastases (n=60) Taguchi et al. Reg Cancer Treatment 3-4:117 1992

Dsm – clinical data clinics (TACE) Taguchi, T. results (HCC) DSM CR PR MR NC PD Median survival* (days) With 2 6 36,4 4 10 661 without 9,5 1 11 7 259 Taguchi et al. Reg Cancer Treatment 3-4:117 1992

Dc beads – clinical data

Dc beads vs. DSM-TACE – tolerability PRECISION V Bonn data Event DC beads (N=93) Lipiodol TACE (N=108) (N=263) DSM-TACE (N=98) PES (pain) 25 26 23 2 Nausea 16 14 15 3 Vomiting 11 13 10 4 Pyrexia 17 24 Vogl et al. AJR 197 2011, Schlee et al. 1999

c-TACE vs. dsm-tace – tolerability Schlee et al. 1999

long term results of a retrospective analysis Sequence of repeated non-selective non-occlusive TACE of far advanced HCC with degradable starch microspheres (DSM) – long term results of a retrospective analysis Thomas Albrecht, Julian Wirsching, Gerd Berger Institut für Radiologie und Interventionelle Therapie Vivantes-Klinikum Neukölln, Berlin Charité, Campus BF, Berlin thomas.albrecht@vivantes.de

Dsm (EmboCept® s) vs. Dc beads pharmacokinetics clinics therapeutic/technical recommendation

Handling of dc beads

Handling of dsm application modus 1

Handling of dsm application modus 2

Handling of dsm application modus 3

non-selective (incl. IA ports) Dsm (emboCept® S) vs. Dc beads application modus   DC beads® EmboCept® S Vials 2x2 1 Preparation time app. 24 h app. 5 min. Catheter positioning (super-) selective non-selective (incl. IA ports) Micro-catheter X - Additional embol. material (e.g. Bead block)

indications and schedules Dsm-tace – indications and schedules Indication (liver mets) Active substances in combination Cycles Pancreatic Ca Gemcitabin, Mitomycin C every 3-4 weeks CRC Irinotecan, Oxaliplatin, Mitomycin C Neuroendocrine Tm Doxorubicin, Mitomycin C Breast Ca Gemcitabin, Mitomycin C, Taxanes Melanoma Fotemustine, cisDDP

DSM (Embocept® s) in comparison vs. DC Beads Pharmacokinetics Clinics Therapeutic/technical recommendation vs. lipiodol

Chemoembolization – Lipiodol ® + / - dsm

Chemoembolization – Lipiodol® + / - DSM Randomization 60-80 mg cisplatin + Lipiodol(4.8+/-2 mL) DSM 120-3000 mg Lipiodol 4.1+/-2 mL + (+CM) DSM 427+/-405 mg + CM (until stasis) Yamasaki T et al. J Gastroenterol (2011) 46: 359-66

Chemoembolization – Lipiodol® + / - Dsm Results 2 (progression-free survival): 1y 2y 3y Lipiodol-group: 13 % 13 % DSM-group: 27 % Lipiodol+DSM-group: 53 % 13 % 7 % p=0.02/0.035 Yamasaki T et al. J Gastroenterol (2011) 46: 359-66

of hepatocellular carcinoma (HCC): Transarterial chemoembolization (tace) of hepatocellular carcinoma (HCC): Comparison of tumor response rates between c(lipiodol)-TACE and DSM-TACE plus lipiodol   Gruber-Rouh T, Nagy N, Eichler K, Lehnert T, Harth M, Zangos S, Beeres M, Nour-Eldin NE, Vogl TJ Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Purpose Evaluation and comparison of local tumor response under transarterial chemoembolization (TACE) of HCC with lipiodol or lipiodol plus DSM-microspheres (EmboCept® S) Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Material and methods (3-15) Patients: n = 50 Recruitment time: 2010-2012 Median Age: 60,3 years (39-80) TACE: n = 367 medium: 7,3 treatments/patient (3-15) therapeutic interval:: 4 weeks Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Material and methods TACE-protocol: chemotherapy Mitomycin (n=50) Embolization Lipiodol (n=25) lipiodol + DSM (n=25) Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Material and methods Evaluation: Radilogical tumor response: MRT, CT (RECIST-criterias) Statistical significance: (Wilcoxon-Mann-Whitney-Test) Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Results Amount of liver metastasis: multiple (≥ 5): 50% (n=25) Location of the metastasis: both sides: 70% (n=35) Right lobe: 30% (n=15) left lobe: 0% (n=0) Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Results Local tumor control (RECIST- criterias): ►partial response (PR): 26 % (n=13) ►stable disease (SD): 60 % (n=30) ►progressive disease (PD): 14 % (n=7) Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Results Tumor response (PR + SD) Lipiodol-group DSM-lipiodol-group Institut of Diagnostic and Interventional Radiology Johann Wolfgang Goethe-University, Frankfurt am Main

Summary 1/4 DSM – TACE: highest accumulation of co-applicated drugs within the tumor tissue EmboCept® S (DSM 35/50) – short-time embolization: no initiation signals for collateral tumor vessel comparable high tumor necrosis

Summary 2/4 DSM-TACE comparable to DEB-TACE in tumor response, but better in tolerability DSM-TACE better than c-TACE

Summary 3/4 DSM-TACE: options for new scientific concepts combination with: LITT/RF, Radiation / SIRT immune-/ genembolization

Summary 4/4 EmboCept® S: unique chemoembolization material combination indication application