Delcath Systems, Inc. · NASDAQ:DCTH
Delcath Systems — Technical Presentation
100 slides from Delcath Systems's technical presentation
Slide 1: Melblez Kit for Ocular Melanoma: FDA Oncologic Drugs Advisory Committee Meeting
M lbl Kit Melblez for Ocular Melanoma FDA Oncologic Drugs Ad i Advisory Committee C itt Meeting M ti Delcath Systems, Inc. 1
Slide 2: Context for Use of Melblez Kit in Liver Metastases of Ocular Melanoma
Context for Use of Melblez Kit in Liver Metastases of Ocular Melanoma • Very rare and rapidly fatal disease • No approved therapies • Clinically meaningful hPFS benefit balanced against considerable toxicities • Restricted R i d to very specialized i li d centers and d physicians with expertise in l
Slide 3: Proposed Indication for Melblez Kit
Proposed Indication for Melblez Kit • For the treatment of patients with unresectable metastatic ocular melanoma in the liver 3
Slide 4: The Melblez Kit
The Melblez Kit • Combination drug/device product – Melphalan hydrochloride – Delcath Hepatic Delivery System • Purpose – Administers high dose melphalan to tumor • Maximize efficacy in liver – Filters blood and returns it to systemic circulation • Controls systemic exposure to melphalan 4
Slide 5: How the Combination Product Works
How the Combination Product Works 4. Filtered Blood 3. Filters returned to systemic Filters circulation i l ti via i jugular vein Veno-veno Veno- 1. Melphalan Bypass Pump Administration 2. Blood and directly into melphalan collected in Hepatic Artery IVC as they exit liver blood flow via hepatic vei
Slide 6: Filters Utilized During Clinical Development
Filters Utilized During Clinical Development Asahi Filter Gen 1 Filter (Clark) Phase I Phase II Phase III N=29 Pt N=10 Pt N=44 Pt N=65 Pt N=83 Tx N=25 Tx N=102 Tx N=177 Tx 6
Slide 7: Experience Outside Clinical Trials
Experience Outside Clinical Trials EU Commercial Experience (7 countries countries, 9 sites) Patients treated 35 Total cycles y 40 OM patients treated 17 Total cycles in OM 23 Compassionate Use/Expanded Access in OM Patients P ti t treated t t d 12 Total cycles 19 7
Slide 8: Current Clinical Safety Data Collection
Current Clinical Safety Data Collection • EU Retrospective Registry – ongoing • US EAP/Compassionate Use – ongoing • EU Prospective Registry – Implemented 3Q13 • US Post Post--approval Registry – under discussion 8
Slide 9: Regulatory History
Regulatory History June 2001 Melphalan IND opened End of Phase 2 meeting and Fast Track April 2005 designation g for malignant g melanoma Special Protocol Assessment (SPA) for February 2006 the phase 3 study DSI MEL 2005- 2005-001 Orphan Drug designations for ocular and November 2008 cutaneous melan
Slide 10: Presentation Overview
Presentation Overview Introduction John Purpura EVP Regulatory Affairs, Delcath Systems, Inc. Medical Need Steven O’Day, MD Director, Clinical Research The Beverly Hills Cancer Center Procedure, Richard Alexander, MD, FACS Phase 1 Study Professor of Surgery, Associate Chairman for Clinical Research,
Slide 11: Responders and Experts
Responders and Experts Delcath Systems, Inc. Bill Appling SVP, Medical Device R&D Daniel Johnston,, PhD VP,, Pharmaceutical R&D Johnny John, MD Director, Clinical Operations Jennifer Simpson, PhD EVP, Global Head of Business Operations Consultants Richard Alexander, MD Associate Chairman, Clinical R
Slide 12: Medical Need
Medical M di l Need N d Steven O’Day, MD Director, The Los Angeles Skin Cancer Institute Th Beverly The B l Hills Hill CCancer C Center t Clinical Associate Professor of Medicine, USC Member, The John Wayne Cancer Institute 12
Slide 13: Epidemiology of Ocular Melanoma
Epidemiology of Ocular Melanoma • Rare, orphan disease • Approximately 2,000 US cases/year • Uveal pigmented cells • 50% metastasize • No FDA FDA--approved therapies 13
Slide 14: Ocular Melanoma
Ocular Melanoma • 90% liver dominant metastases • Cause of death – liver • Rare CNS metastases • Absence of BRAF, c- c-kit • Median OS 4- 4-6 months • 1 year OS 10 10--15% • 5 year survival <1% 14
Slide 15: Collaborative Oncology in Melanoma Study Report
Collaborative Oncology in Melanoma Study Report 1.0 0.9 n=739 0.8 0.7 Proporttion who diied 0.6 0.5 04 0.4 0.3 02 0.2 0.1 0 0 1 2 3 4 5 Years since diagnosis of metastasis Adapted from: Diener-West, M et al. Arch Ophthalmol 2001;119:961-5 15
Slide 16: Sites of Metastasis of Ocular Melanoma
Sites of Metastasis of Ocular Melanoma Liver Lung Bone Skin y p node Lymph ode Brain Spleen Kidney Kid Heart Stomach Colon 0 20 40 60 80 100% Adapted from Sato, HemOnc Today Melanoma, 2012 16
Slide 17: Clinical Presentation: Liver Metastases
Clinical Presentation: Liver Metastases • 10% surgically resectable • Majority multi multi--focal, multi multi--lobular • Imaging I i underestimates d i extent off disease di 17
Slide 18: Liver Dominant Ocular Melanoma Management
Liver Dominant Ocular Melanoma Management • Systemic treatments ineffective • Hepatic artery directed therapies – Hepatic p perfusion p – Chemoembolization – Immunoembolization – Radiospheres – Drug eluting beads • Clinical Cli i l trials ti l 18
Slide 19: Ocular Melanoma: Optimal Therapy
Ocular Melanoma: Optimal Therapy • Overcome innate resistance • Deliver multiple cycles • Treat macro and microscopic liver disease • Direct therapy to the entire liver 19
Slide 20: Ocular Melanoma: Unmet Medical Need
Ocular Melanoma: Unmet Medical Need • Unique biology and metastatic pattern • Liver most frequent cause of death • Rare R and dddevastating i • No available standard of care • <1000 patients are candidates per year 20
Slide 21: Procedure (PHP)
Procedure (PHP) H. Richard Alexander, MD Professor of Surgery, Associate Chairman for Clinical Research U i University it off M Maryland l dM Medical di l CCenter t 21
Slide 22: IHP: Surgical Procedure
IHP: Surgical Procedure • One time only treatment • Delivers high dose melphalan to liver • Controls systemic exposure by complete surgical i l isolation i l ti • Extensive abdominal surgery • 8 hours to complete • 2-3 days in ICU • 10 10--15 days in hospital 22
Slide 23: PHP Procedure
PHP Procedure Chemofiltration Circuit 4 Isolation and melphalan p delivery y Internal jugular return catheter Isolation Filtration balloon catheter 3 2 Melphalan Veno-veno Veno- 1 b bypass pump delivery catheter 23
Slide 24: Treatment Team
Treatment Team Team Member Roles and Responsibilities Medical or Surgical Oncologist Patient’s complete management Training, coordination and Interventional Radiologist communication Sedation, analgesia, Sedation, analgesia hemodynamic Anesthesiologist support Establishing, monitoring and Establishi
Slide 25: Pre-Procedural Patient Selection
Pre--Procedural Patient Selection Pre • Ensure adequate cardiac, hepatic, hematologic and renal function • Complete CT/ MRI, pelvis, abdomen, chest, brain • Exclude hepatic failure and portal hypertension – Laparoscopy and biopsy if liver tumor >50% on imaging – Delay y treatment if residual effects
Slide 26: Patient Experience and Support during PHP
Patient Experience and Support during PHP • Pre Pre--procedure preparation – Pre Pre--hydration, embolization and medications (antibiotics, ( , PPI,, allopurinol) p ) • Procedure (3 hours on table) – General anesthetic, heparinization, heparinization, hemodynamic support – Venous and arterial access
Slide 27: Blood Pressure Management during PHP
Blood Pressure Management during PHP MAP 90 mmHg Balloons 85 inflated Infusion 80 started Filters 75 opened 70 65 Vasopressor support 60 weaned d during d i 30 minute i t infusion 55 50 45 Vasopressor support needed. Chemo infusion not started until MAP above 65 mmHg 40 0 9 10 20 21 22 25 30 40 50 M
Slide 28: NCI Phase I Study Design
NCI Phase I Study Design ((01 01--C-0215 0215)) Trial Design Open-label, single Open- single--center, multiple- p -ascending multiple ascending- g-dose Patients Unresectable primary or metastatic hepatic malignancies g from a non- non-liver primary site Objectives To determine DLT/MTD, toxicities, P
Slide 29: Adjudicated DLT and MTD Determination
Adjudicated DLT and MTD Determination 2.0 mg/kg 2.5 mg/kg 3.0 mg/kg 3.5 mg/kg N=14 N=3 N=10 N=6 No. of patients with a DLT 0 0 1 2 Neutropenia p 0 0 – 2 Leukopenia 0 0 1 1 Thrombocytopenia 0 0 1 2 Febrile neutropenia 0 0 1 1 NCI investigators adjudicated toxicities to support dose escalation and DLT
Slide 30: Activity in Phase I Study
Activity in Phase I Study Ocular Cutaneous Other Hepatic Objective Melanoma Melanoma Tumor Type Response N=12 N=3 N=19 Response 4 (33.3) 0 0 Complete Response 3 (25.0) 0 0 Partial Response 1 (8.3) 0 0 Stable Disease 3 (25.0) 1 (33.3) 7 (36.8) hPFS (median, months) 8.9 2.1 2.9 30
Slide 31: Phase I Overall Conclusions
Phase I Overall Conclusions • Defined MTD as 3.0 mg/kg • DLTs were due to bone marrow suppression – No deaths on study • Clinically meaningful hepatic responses in ocular melanoma – 3 complete responses 31
Slide 32: Phase III Efficacy Study DSI MEL 2005-001
Phase III Efficacy y Study DSI MEL 2005- 2005-001 February 2006- 2006-April 2010 Krishna Kandarpa, MD, PhD Chief Scientific Officer Delcath Systems, Inc. 32
Slide 33: Clinical Program
Clinical Program 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 Phase I Unresectable hepatic tumors N=34 PHP Phase II Unresectable hepatic tumors N=56 PHP Phase III Melanoma Survival Follow-up N=93 44 PHP, 49 BAC 33
Slide 34: Pivotal Trial Design
Pivotal Trial Design • Open Open--label, randomized, multi multi--center (US), PHP vs. Best Alternative Care (BAC) • Primary endpoint: hPFS by IRC – Assessed week 6,, 12 then every y 8 weeks both arms • Seco Secondary da y e endpoint: dpo t – hPFS – hOR – Overall O ll survival i l – xPFS xPFS,, over
Slide 35: Statistical Analysis Plan
Statistical Analysis Plan • Planned sample size 92 patients – 46 per treatment group • Powered for hPFS – Analysis y after 73 events • Primary hPFS analysis of ITT population – 80% power to detect difference of 4 months at median – Log rank test with two- two-sided alpha = 0.05 • Stratification fact
Slide 36: Phase III Study Schema
Phase III Study Schema Melanoma PHP Follow up Follow-up Metastatic Arm to Liver (N=44) Cross Over Hepatic (N=93) to PHP Follow-up Progression Randomized BAC n=28 1:1 Arm (Ocular N=83) (N=49) Follow-up 36
Slide 37: Melphalan Dosing
Melphalan Dosing • Starting dose 3.0 mg/kg ideal body weight – Maximum melphalan dose 220 mg – Dose reduction permitted for severe toxicity • Cycle interval 4 weeks – Up to 4- 4-week delay for resolution of toxicity • Permanent P t discontinuation di ti ti if persistent i t t toxicity > grade 2 eigh
Slide 38: Key Inclusion Criteria
Key Inclusion Criteria • Surgically unresectable melanoma mets in the liver • Histologically g y or cytologically cytologically- y g y-proven melanoma – Ocular or cutaneous • Disease measurable by CT and/or MRI • Limited unresectable extrahepatic disease – If life- life-limiting component in liver •
Slide 39: Baseline Patient Characteristics
Baseline Patient Characteristics PHP BAC N=44 N=49 Median ag ge,, y years (range) ( g ) 55 ((33- (33-74)) 56 ((31- (31-77)) Female, n (%) 21 (47.7) 27 (55.1) Male, n (%) 23 (52.3) 22 (44.9) White, n (%) 44 (100) 48 (98.0) Black/African--American, n (%) Black/African 0 1 (2.0) ECOG PS 0 28 (63.6) 42
Slide 40: Baseline Disease Characteristics
Baseline Disease Characteristics PHP BAC N=44 N=49 Ocular melanoma 39 ((88.6)) 44 ((89.8)) Cutaneous melanoma 5 (11.4) 5 (10.2) Median time since diagnosis, 49.2 38.1 months (range) (3- (3-292) (1- (1-162) Median time since liver metastasis, 1.9 2.1 months ((range) g ) (0.0--44.1)) ((0.0 (0.1--28.9)
Slide 41: Baseline Tumor Characteristics
Baseline Tumor Characteristics PHP BAC N=44 N=49 Hepatic p lesions only y 27 ((61.4)) 28 ((57.1)) Hepatic and extrahepatic lesions 17 (38.6) 21 (42.9) 1 extrahepatic lesion 10 (22.7) 14 (28.5) ≥ 2 extrahepatic lesions 7 (15.9) 7 (14.3) Lung metastasis 8 (18.2) 13 (26.5) <50% liver involvement 35 (79
Slide 42: Best Alternate Care (BAC) Treatment Arm
Best Alternate Care (BAC) Treatment Arm Selected Treatment % Patients Active treatment 81.6 Systemic chemotherapy 49.0 Temozolomide 41.0 Dacarbazine 2.0 Carboplatin plus paclitaxel 6.1 Chemoembolization 22 4 22.4 Radioembolization 6.1 Systemic chemo plus chemoembolization 2.0 20 Surgery 2.0 pp Suppo
Slide 43: Primary hPFS by IRC Analysis
Primary hPFS by IRC Analysis • Clinically meaningful improvement in hPFS • Median hepatic progression- progression-free survival – 7.03 months PHP vs.1.64 months BAC – 5.5 5 5 month extension – p=0.0001 (log- (log-rank) • HR=0.39 HR 0 39 (95% CI 0 0.24 0.24- 24-0.64) 0 64) – 61% hazard reduction 43
Slide 44: Kaplan Meier Curve of hPFS by IRC
Kaplan Meier Curve of hPFS by IRC ITT population 1.00 BAC 0.90 0 90 PHP gression 0.80 Censored observation 0.70 oportion wiithout Prog 0.60 1.64 7.03 HR 0.39 (95% CI 0.24-0.64) 0.50 months months p--value = 0.0001 p 0.40 0.30 0.20 0 20 Pro 0.10 0.00 0 5 10 15 20 25 30 Time to Progression (Months) 44
Slide 45: Kaplan Meier Curve of hPFS by IRC: Ocular
Kaplan Meier Curve of hPFS by IRC Ocular ITT population 1.00 BAC 0.90 0 90 PHP gression 0.80 Censored observation 0.70 oportion wiithout Prog 0.60 1.64 7.03 HR 0.42 (95% CI 0.25-0.72) 0.50 months months p--value = 0.0011 p 0.40 0.30 0.20 0 20 Pro 0.10 0.00 0 5 10 15 20 25 30 Time to Progression (Mon
Slide 46: hPFS in Subgroups
hPFS in Subgroups NCI (N=44) Non--NCI (N=49) Non Ocular (N=83) Cutaneous (N=10) Age < 65 (N=80) Age ≥ 65 (N=13) Female (N=48) Male (N=45) Tumor Burden: < 50% (N=74) Tumor Burden: ≥ 50% (N=19) ECOG=0 (N=70) ECOG>0 (N=19) 0.00 0.25 0.50 0.75 1.00 1.25 PHP bette better BAC C bette better Hazard Ratio 4
Slide 47: Sensitivity Analyses of hPFS
Sensitivity Analyses of hPFS Correcting for Early Scans Converting All Censored Observations to Events A l i per Table Analysis T bl C off FDA G Guidance id Using Only Treated Patients (Safety Population) Adjusting for Premature Crossover to PHP Using the Earliest Time to Progression 0.00 0 00 0.25
Slide 48: Efficacy Results: Key Secondary Endpoints
Efficacy Results: Key Secondary Endpoints PHP BAC N=44 N=49 p-value hPFS (Investigator), months 8.05 1.64 0.0001 hPFS (Investigator), HR 0.28 <0.0001 hOR (IRC), % 36.4 2 <0.0001 hOR (Investigator), (Investigator) % 38 6 38.6 2 <0.0001 <0 0001 PFS (Investigator), months 4.76 1.64 <0.0001 OS, months 9
Slide 49: Waterfall Plots of Hepatic Response (IRC)
Waterfall Plots of Hepatic Response (IRC) Responder 60 Non-responder 40 PHP 20 0 eline -20 % change from base -40 -60 -80 60 40 BAC 20 0 -20 -40 -60 49
Slide 50: Kaplan-Meier Curve of Overall Survival
Kaplan--Meier Curve of Overall Survival Kaplan ITT population 1.00 BAC 0.90 PHP Censored observation 0.80 0.70 ortion Alive e 0.60 9.89 months 9.79 months HR 0.92 (95% CI 0.55, 1.54) 0.50 p-value = 0.75 Propo 0.40 0.30 0.20 0.10 0.00 0 12 24 36 48 Survival Time (Months) 50
Slide 51: Exploratory Analysis of Overall Survival
Exploratory Analysis of Overall Survival ITT population June 2012 1.00 PHP - randomized BAC cross to PHP 0.90 BAC no switch Censored observations Alive 0.80 oportion off Patients A 0.70 0.60 PHP-randomized median = 9.79 months PHP- BAC cross to PHP median = 14.24 months 0.50 BAC no switch it h media
Slide 52: Efficacy Results: Cross-Over Group
Efficacy Results: Cross- Cross-Over Group Overall Cross C Cross- oss-O Over e PHP N=28 N=44 hPFS (IRC), (IRC), months 8.44 7.03 95% CI 3.06- 3 06- 3.06 06-11.17 11 17 5.22- 5 22- 5.22 22-9.66 9 66 hPFS (investigator), (investigator), months 6.70 8.05 95% CI 3.88--9.72 3.88 5.78--8.90 5.78 hOR (IRC),
Slide 53: Phase III Efficacy Conclusions
Phase III Efficacy Conclusions • PHP had a clinically meaningful effect on hPFS – 5.5 month improvement in the overall study population – Statistically y significant g • OS confounded by significant cross- cross-over • Consistent PHP treatment effect in – Investigator and IRC assessments – Patient P
Slide 54: Safety
SAFETY 54
Slide 55: Pooled Safety Population
Pooled Safety Population Study N Phase 3 PHP Randomized 42 Phase 3 Cross- Cross-over to PHP 28 Phase 2 52 Pooled Safety Population† 121 † Combines enrollments of 1 patient who was included in phase 3 then phase 2 55
Slide 56: Definition of Peri- and Post-Procedure Safety
Definition of Peri- Peri- and Post Post--Procedure Safety • Peri Peri--procedure – Starting within 72 hrs (3 days) of initiation of PHP – Likely due to device, procedure or direct effect of melphalan p infusion • Post Post--procedure – Starting > 72 hrs (3 days) after initiation of PHP – Until next
Slide 57: Treatment Exposure
Treatment Exposure Pooled Variable N=121 Number of Completed Cycles n 116 Median 3.0 Range 1-7 Cumulative Dose n 116 Median 449.5 Range 81 81--1430 57
Slide 58: Overview of Adverse Events
Overview of Adverse Events Phase 3 Pooled PHP BAC N=121 N=42 N=49 n (%) All Grade 4 All Grade 4 All Grade 4 115 110 40 40 31 6 AE (95.0) (90.9) (95.2) (95.2) (63.3) (12.2) 101 88 33 28 8 1 Serious AE (83.5) (83 5) (72.7) (72 7) (78.6) 78 6) (66.7) 66 7) (16.3) (16 3) (2.0) (2 0) AE Resulting in 5* 3
Slide 59: Most Common Adverse Events (>15%) Peri- and Post-procedure
Most Common Adverse Events (>15%) Peri-- and Post- Peri Post-procedure Pooled N=121 Event, n (%) All Grade 4 Thrombocytopenia 111 (91.7) 95 (78.5) Neutropenia p 106 ((87.6)) 87 ((71.9)) Febrile neutropenia 22 (18.2) 9 (7.4) Anemia 98 (81.0) 16 (13.2) Hypoalbuminemia 46 (38.0) 0 AST increased 40 (33.
Slide 60: AEs Leading to Death in PHP Development Program
AEs Leading to Death in PHP Development Program (Phase II, II and III) Tx Cause Study Cycle Group Age Sex of Death Day Cycle Day Comment Prior Whipple’s Whipple s procedure GI hemorrhage/ • Liver abscess, liver Ph2 67 M ruptured 74 1 74 dysfunction 001--038 001 R hepatic artery • Renal insufficiency
Slide 61: Review Additional Treatment-related Deaths from FDA Analysis
Review Additional Treatment- Treatment-related Deaths from FDA Analysis Tx Cause Study Cycle Group Age Sex of Death Day Cycle Day Comment Cerebral PD FDA PD D30 brain and liver Ph3 31 M hemorrhagic 499 2 38 • G4 thrombocytopenia 001--024 001 brain lesions + thrombocyto-- thrombocyto g in brain met •
Slide 62: Timeline of Treatment Related Deaths
Timeline of Treatment Related Deaths P ti t ID: Patient ID Hepatic failure A/001--023 A/001 X Hepatic failure B/001--006 B/001 X Hepatic failure C/001--005 C/001 X RHA hemorrhage D/001--038 D/001 X GI perforation E/001--010 E/001 X Streptococcal sepsis F/009--650 F/009 X Hemorrhage/bone marrow failu
Slide 63: Most Common SAEs (≥5%)
Most Common SAEs (≥5%) Pooled Peri Post n (%) N=121 N=121 N=121 Neutropenia 71 ((58.7) 58.7) 0 71 (58.7) (58.7) Thrombocytopenia 62 ((51.2) 51.2) 9 (7.4) (7.4) 60 ((49.6) 49.6) Febrile neutropenia 20 (16.5) (16.5) 0 20 (16.5) (16.5) Anemia 13 (10 ((10.7) 10 10.7) 7) 2 (1 ((1.7) 1.7) 1 7) 12 (9 ((9.9
Slide 64: Hospitalization
Hospitalization Pooled N=121 Median Duration Reason % Patients (Days) For procedure 100 4 Total duration of 29 8 29.8 5.5 55 prolongation due to AE Re--hospitalization for AE Re 51.2 5 64
Slide 65: Most Common AEs Leading to Treatment Discontinuation
Most Common AEs Leading to Treatment Discontinuation Pooled n (%) N=121 Any AE resulting in drug discontinuation 46 (38.0) Thrombocytopenia 19 (15.7) Neutropenia 9 (7.4) (7 4) Hyperbilirubinemia 5 (4.1) 65
Slide 66: Cycle Delays and Dose Reductions
Cycle Delays and Dose Reductions Pooled Patients with >1 cycle PHP N=92 Any cycle delayed, % patients 57.6 Median, days y 6 • Dose reductions in 23.1% 23 1% (28/121) • Reasons: thrombocytopenia, neutropenia 66
Slide 67: Most Common Adverse Events (>15%) Peri- and Post-procedure
Most Common Adverse Events (>15%) Peri-- and Post- Peri Post-procedure Peri Pooled Post Pooled N=121 N=121 n (%) All Grade 4 All Grade 4 Thrombocytopenia 89 (73.6) 53 (43.8) 97 (80.2) 81 (66.9) Neutropenia 5 (4.1) 0 105 (86.8) 87 (71.9) Febrile neutropenia 0 0 22 (18.2) 9 (7.4) Anemia 75 (62.0) 8 (6
Slide 68: Adverse Events of Special Interest
Adverse Events of Special Interest • Cardiovascular toxicity • CNS • Nephrotoxicity • Hepatotoxicity • GI toxicity • Bleeding 68
Slide 69: Cardiovascular Safety
Cardiovascular Safety • 6 arrhythmias in pooled database – 3 were transient sinus tachycardias – There were 2 AF, 1 VT, all transient and resolved • 2 at filter opening • all cardioverted – VT led to patient withdrawal – No N llong term t consequences • 7 ischemic- ischemic-type events included trop
Slide 70: CNS Ischemic Events
CNS Ischemic Events • There were 4 cerebral infarct events – 3 infarcts leading to withdrawal – 1 associated with brain metastases, occurring late, after PD • There were 3 TIA- TIA-type events, all resolved, with no withdrawals • Timing can be on D1 or post post--procedure 70
Slide 71: Nephrotoxicity
Nephrotoxicity • No evidence that hypotension led to severe renal toxicity in any patient • 3 patients with renal failure AEs – Temporally p y dissociated from procedure p – Patients Ph3 001- 001-006 and 001 001--024, Ph2 001 001--038 – Late events during multi- multi-organ failure, death due to oth
Slide 72: Hepatotoxicity
Hepatotoxicity • All intra- intra-arterial liver liver--directed therapies have liver toxicity • High dose melphalan for myeloablation and IHP is associated with liver toxicity y • All liver- liver-related deaths had >50% tumor burden at baseline and hPD prior to death • Careful patient selection, l
Slide 73: Overview of Hepatic Adverse Events
Overview of Hepatic Adverse Events Pooled n (%) N=121 N 121 Hepatic AE 53 (43.8) Grade 4 18 (14.9) SAE 11 ((9.1) 9.1) Leading to treatment discontinuation 7 (5.8) Resulting in death 1 (0.8) (0 8) 73
Slide 74: Gastrointestinal Toxicity
Gastrointestinal Toxicity Pooled Peri Post Category n (%) Category, N=121 N 121 N=121 N 121 N=121 N 121 Any gastrointestinal event 31 (25.6) 9 (7.4) 28 (23.1) Ulcers, gastritis, Ulcers gastritis 13 (10.7) 2 (1.7) 11 (9.1) perforations, bleeds Pancreatitis, cholecystitis 6 (5.0) 2 (1.7) 5 (4.1) 74
Slide 75: Bleeding
Bleeding • There is risk of bleeding during the procedure due to – Anticoagulation – Filter sequestration of platelets • There is an additional risk due to thrombocytopenia from melphalan- melphalan-induced bone marrow toxicity • PHP requires diligent reversal of anticoagulation, ti l ti close l mon
Slide 76: Overview of Bleeding Events
Overview of Bleeding Events Pooled Event, n (%) N=121 Bleeding AE* 16 (13.2) Grade 4 3 (2.5) Serious 10 (8.3) Leading to hospitalization 9 (7.4) ( ) Leading to treatment discontinuation 4 (3.3) Resulting in death** 1 (0.8) * omits 3 patients: Ph2 001- 001-006 urethral hemorrhage pre pre--PHP; Ph3 00
Slide 77: REMS
REMS 77
Slide 78: Learnings Incorporated into Training
Learnings Incorporated into Training • Risk of hepatic failure – Added diagnostic laparoscopy for patients with 50% of their li liver replaced l d by b tumor t • Risk of gastrointestinal toxicity – Exclude patients with prior surgeries that could potentially affect normal hepatic biliary/vascular an
Slide 79: Learnings Incorporated into Training (con't)
Learnings Incorporated into Training (con’t (con’t)) • Risk of hemorrhage – Added brain MRI to detect active intracranial metastases or brain lesions – Hormonal suppression in premenopausal women • Risk of thrombocytopenia – Can lead to bleeding – Managed with transfusions • Risk of anemia – Managed
Slide 80: Mitigating Consequences of Neutropenia
Mitigating Consequences of Neutropenia • Neutropenia and febrile neutropenia – Requires prophylactic growth factor support • New recommendation based on 20% risk of complicated neutropenia 80
Slide 81: Mitigating Risks of CV Complications
Mitigating Risks of CV Complications • Patient selection – NYHA classification 1 only – Normal baseline ECG ECG, echo and troponins • Pre Pre--procedural monitoring and management – Adequate fluid pre pre--load prior to balloon inflation – 12 12--lead ECG prior to hydration, morning of procedure – C
Slide 82: Elements of the ETASU Melblez Kit REMS
Elements of the ETASU Melblez Kit REMS • Medication guide, communication plan • Hospital qualification and certification – Appropriate equipment – Qualified procedure team • Prescriber certification – Interventional radiologist, surgical oncologist, anesthesiologist, perfusionist • Restricted distri
Slide 83: Elements of the ETASU Melblez Kit REMS – Training Program
Elements of the ETASU Melblez Kit REMS – Training Program • Mandatory training of entire procedural team • Based on experience gained in the development program • Education about risks, causes and management due to procedure and myelosuppression • Three Three--stage process: – Didactic classroom tra
Slide 84: Benefit/Risk Summary
Benefit/Risk Summary • Key Benefits – Compelling disease control in a rare, rapidly fatal disease p with limited treatment options and no approved pp therapies p – Consistent efficacy across subgroups – Primary efficacy supported by secondary endpoints – Overall survival analysis y confounded by y s
Slide 85: Clinical Perspective
Clinical Perspective 85
Slide 86: Melblez Kit for Ocular Melanoma
M lbl Kit Melblez for Ocular Melanoma FDA Oncologic Drugs Ad i Advisory Committee C itt Meeting M ti Delcath Systems, Inc. 86
Slide 87: Overall PFS by Baseline Extra-Hepatic Lesion Status
Overall PFS by Baseline Extra- Extra-Hepatic Lesion Status ITT (April 2010) Randomized Randomized Hazard Ratio to PHP to BAC Interaction Extra--hepatic lesions Extra N=44 N 44 N=49 N 49 Estimate (95% CI) p-value (0.17, % patients with PFS event 88.2 95.2 0.34 0.8821 0.68) Median PFS, months 6.54 1.7
Slide 88: PK Sampling Sites
PK Sampling Sites Post--filter Post Filters Systemic P -filter Pre- Pre filt Veno-veno Veno- Bypass Pump PK-2
Slide 89: Phase III – Mean Concentration – Time Profiles
Phase III – Mean Concentration – Time Profiles 12,000 Systemic y 10,000 Prefilter Postfilter Concentrration (ng/mL) 8 000 8,000 6,000 4,000 2,000 0 0 10 20 30 40 50 60 Time (min) PK-37
Slide 90: Systemic Exposure: Comparison with Published Data
Systemic Exposure: Comparison with Published Data 12000 L) (ng/mL /mL 10000 Concentratiion (ng 8000 High Dose Melphalan 6000 elphalan C 4000 IV bolus Me 2000 Systemic 0 0 20 40 60 80 100 120 140 160 180 200 Time (min) *192 mg/ mg/mm2 over ~34 min inf inf,, Nath 2010. ^IV bolus, Alberts, Alberts, 197
Slide 91: Exposure: Comparison with Published Data
Exposure: Comparison with Published Data 12000 L) ion (ng/mL 10000 8000 Melphalan Concentrat Pre--filter Pre High Dose Melphalan 6000 C 4000 IV bolus 2000 Systemic 0 0 20 40 60 80 100 120 140 160 180 200 Time (min) *192 mg/ mg/mm2 over ~34 min inf inf,, Nath 2010. ^IV bolus, Alberts, Alberts, 1979.
Slide 92: OS by Baseline Extra-Hepatic Lesion Status
OS by Baseline Extra- Extra-Hepatic Lesion Status ITT Ocular ((June 2012)) Randomized Randomized Hazard Ratio to PHP to BAC Interaction Extra--hepatic lesions Extra N=39 N=44 Estimate (95% CI) p-value 0.6040 Baseline extra- extra-hepatic lesions 16/16 (100.0) 15/18 (83.3) 1.15 (0.57, 2.35) Patients
Slide 93: BAC hPFS: Liver-directed Therapies vs. Systemic vs. No Therapy
BAC hPFS hPFS:: Liver- Liver-directed Therapies vs. Systemic vs vs. No Therapy TACE/SIRT Systemic No therapy py BAC BAC BAC N=15 N=24 N=10 Median hPFS, hPFS months 2 69 2.69 1 64 1.64 1 61 1.61 95% CI 1.38-9.30 1.28-2.92 1.35-2.30 P-value from log-rank test 0.46 Hazard ratio vs. no therapy 0.56 0.82
Slide 94: hPFS Before and After Crossover
hPFS Before and After Crossover (n=28) Investigator, g , ITT 40 30 hPFS on PHP 20 10 nths 0 Mon 10 20 hPFS on BAC 30 40 K-103
Slide 95: Troponin Perspective
Troponin Perspective • Cardiovascular sequelae have been minimal • There have been some cardiovascular events and, given the benefit of PHP, they are not disproportionally high • Troponins are not a specific marker for infarction – Elevated in marathon runners • Troponin elevations appeared commonly
Slide 96: Hypotension and Cardiac Events
Hypotension and Cardiac Events • EXAMPLE: Patient 600— 600—73 year year--old male – History of hyperlipidemia – No history of coronary artery disease • Hypertension • Dysrhythmia – Ocular melanoma – Perfusion #1 Dec. 17, 2008 – ECGs • Dec 16, ’08: (Pre Rx) Inverted “T” waves in lead III • Dec 17, af
Slide 97: Hypotension and Cardiac Events
Hypotension and Cardiac Events • EXAMPLE: Patient 600— 600—73 year year--old male – Diagnosis of MI on the basis of troponin! • ECG/Echo changes do not meet criteria for MI – Cycle 1 Dec 17, 2008; troponin elevated – Cycle 2 Jan 27, 2009; Fluid overload – Cycle 3 Mar 17, 2009; Fluid overload – Cycle
Slide 98: IVC Venogram
IVC Venogram • Turn off pump • Shoot IVC venogram • Back filling of hepatic p veins ‒ Left usually does not fill • No leak around cranial balloon into right g atrium • Shows isolation of hepatic venous return t PR-16
Slide 99: Reasons for Discontinuation by Cycle
Reasons for Discontinuation by Cycle Pooled, N=121 Cycle 1 2 3 4 5 6 Reason, n (%) N=116 N=92 N=60 N=26 N=6 N=3 All 24 ((20.7) 20.7)) 32 ((34.8) 34.8)) 34 ((56.7) 56.7)) 20 ((76.9) 76.9)) 3 ((50.0) 50.0)) 2 ((66.7) 66.7)) Death 0 0 0 0 0 0 PD 7 ((6.0) 6.0) 22 ((23.9) 23.9) 8 ((13.3) 13.3) 2 ((7.7) 7
Slide 100: Median hPFS (IRC) by # of Cycles Received
Median hPFS (IRC) by # of Cycles Received (April 2010) Median hPFS, Randomized to PHP Crossover to PHP Total PHP Months (95% CI) N=44 N=28 N=72 7.03 8.44 8.05 Overall (5.22, 9.66) (3.06, 11.17) (5.22, 9.72) 2.63 1.45 1.86 0 ((0.89,, 6.44)) (, ) ((0.89,, 6.44)) 5.72 12.12 10.05 1 (1.22, 10.05) (1.38,