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Annual International Society of Hematology 2013: Update on Novel Fibrin Sealants (paul frohna)
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Annual International Society of Hematology 2013: Update on Novel Fibrin Sealants (paul frohna)

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Dr. Paul Frohna's presentation on Phase 2 clinical trials with Fibrocaps, a novel fibrin sealant, being developed by ProFibrix, Inc. of Leiden, the Netherlands

Dr. Paul Frohna's presentation on Phase 2 clinical trials with Fibrocaps, a novel fibrin sealant, being developed by ProFibrix, Inc. of Leiden, the Netherlands

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    Annual International Society of Hematology 2013: Update on Novel Fibrin Sealants (paul frohna) Annual International Society of Hematology 2013: Update on Novel Fibrin Sealants (paul frohna) Presentation Transcript

    • Session 3-3: Hemostasis and Thrombosis Time:13:30-16:05, May 25,2013 (Saturday) Place: Yan An Hall, 2F, Hilton Hotel Chair: Paul Frohna, MD, PhD, PharmD San Diego, CA, USA 13:35-14:00 Title: Advances in Topical Hemostats for Surgical Bleeding: Phase 2 Experience with Fibrocaps, a Novel, Dry-Powder Fibrin Sealant Dr. Paul Frohna, Chief Medical Officer, ProFibrix, Inc., USA 14:00-14:25 Title: Gender-specific Association between Promoter Methylation of PLA2G7 and CDKN2B and the Risk of Coronary Heart Diseases Dr. Shiwei Duan, Professor, School of Medicine, Ningbo University, China 14:25-14:50 Title: Assessing Platelet Function During Cardiac Surgery Dr. David Harris, Consultant Anaesthetist, Hammersmith Hospital, UK 14:50-15:15 Title: Mechanism of Enhanced Fibrinolytic Activity by Enzamin Dr. Matsuo Osamu, Professor, Kinki University, Japan Title: Platelet Production and Release of MAPPs (Macromolecular Activators of Phagocytosis from Platelets) Dr. Haruhiko Sakamoto, Professor, Kagawa University, Japan 15:15-15:40 15:40-16:05 Title: DrugRelated Genetic Variant in Clopidogrel and Warfarin-treated Patients: A double-edged Sword between Thrombosis and Bleeding Dr. Yongfang Hu, Director, Peking University, China
    • Advances in Topical Hemostats for Surgical Bleeding: Phase 2 Experience with Fibrocaps, a Novel, Dry-Powder Fibrin Sealant Paul Frohna*, N Singla, NY Gupta, H Lockstadt, G Moneta, W Muir, A O-Yurvati, L Sher, C Verhoef and RJ Porte 2nd Annual International Symposium on Hematology 25 May 2013
    • Agenda 1. Hemostasis as a Clinical Problem 2. ProFibrix & Fibrocaps™ • Private Dutch Company with offices in the NL and US 3. Review of Phase 2 Clinical Trials Design and Results 4. Conclusions
    • The Netherlands: “Waterstasis” 4
    • The Surgeon: “Hemostasis” 5
    • The Surgeon: “Hemostasis” • Clinical Problem of Surgical Bleeding: • • • • Mild to moderate: small to medium sized vessels; oozing, large surface area; desire to avoid cautery Widespread usage of novel anticoagulants and antiplatelet agents creates difficult to control bleeding Use of topical hemostats since the mid 1940s, but were made by surgeons for each patient Most of the available hemostats must be thawed and/or reconstituted, which delays the time from shelf to patient 6
    • The Coagulation Cascade 7
    • Today’s Clinical Toolbox to Stop Bleeding Topical Hemostats (Mild or moderate bleeding) • Category • Approved Products – Fibrin Sealants—FGN + Thr – Evicel (Ethicon/J&J), Tisseel (Baxter) – Flowables—Thr + gelatin – Floseal (Baxter), Surgiflo (Ethicon/J&J) – Fibrin Patch—FGN + Thr – Tachosil (Takeda/Baxter) – Thrombins—bovine, human plasma-derived, recombinant – Thrombin-JMI (Pfizer), Recothrom (Bristol-Myers Squibb) Injectable Hemostats (Severe bleeding) • Clotting Factor Concentrates: • – Plasma Fibrinogen – Plasma Transfusion – Cryoprecipitate Approved Products – Riastap/Haemocomplettan (CSL) – Blood banks – Blood banks CONFIDENTIAL 8
    • Fibrocaps (Fibrin Sealant) Manufacturing CSL Behring Proprietary Information Fibrogen raw materials Nova Laboratories “Open” Information Spray-dried Fibrinogen Fibrocaps Powder Plasma Fractionation (US Sites) Thrombin Raw materials Spray-dried Thrombin 1:1 Fibrinogen & Thrombin Blend Ready to use Stable at room temp
    • Fibrocaps Application Techniques Air-powered Fibrospray Device Direct from the vial Rigid nozzle Flexible nozzle Rapid Clot Formation CONFIDENTIAL 10
    • Fibrocaps Delivery System Fibrospray Delivery Device Air Handling Equipment Regulator Fibrocaps vial Umbilical Air Filter Air Supply from the OR 11
    • Scientific Advisory Board • Professor Robert Porte, MD, PhD Professor of Surgery, HPB Surgery and Liver Transplantation University Medical Center Groningen, the Netherlands • NavYash Gupta, MD, FACS Chief, Division of Vascular Surgery NorthShore University Health System, Chicago, IL • Grant V. Bochicchio MD, MPH Chief, Acute and Critical Care Surgery Washington University School of Medicine, St. Louis, MO USA • William D. Spotnitz, MD, MBA University of Virginia Health System, Charlottesville, VA 22908 USA • Neil Singla, MD CEO, Lotus Clinical Research, Pasadena, CA 91105 USA • Kenneth Renkens, MD, FACS Indiana Spine Group, Indianapolis, IN USA
    • Fibrocaps Clinical Development Plan • Mild-Moderate surgical bleeding with a broad label claim that allows it to be used in any type of surgery • Defined regulatory pathway • FIH study in liver surgery (2009-2010) • Safety, dosing, method of application and efficacy • Phase 2 in 3 different surgical indications (2011) • Safety data to enable Phase 3 (80-100 subjects treated) • Efficacy to support “Go” decision for Phase 3 • Phase 3 randomized, controlled trial in 4 indications • 4 independently-powered trials running in parallel • Efficacy and safety that support US and EU filings and proposed label text
    • FC-002 US & FC-002 NL: Phase 2 Randomized, Controlled Trials of Fibrocaps in Surgical Bleeding
    • FC-002 (US & NL) Study Design • Objective: Demonstrate Safety and Efficacy in 80-100 Treated Subjects with Mild to Moderate Surgical Bleeding to Enable Phase 3 • Design: Randomized (2:1), single-blind, controlled • Treatments: Fibrocaps + Gelatin vs. Gelatin alone – Up to 3 vials of Fibrocaps per patient • Efficacy Endpoints: 1°: Mean Time to Hemostasis (TTH) of Fibrocaps plus gelatin sponge, as compared to gelatin sponge alone 2°: Proportion of subjects achieving hemostasis at 3, 5 and 10 min • Safety: • • • Overall safety as determined by AEs, clinical labs and physical exams Proportion of subjects developing anti-thrombin antibodies Sites: 8 in the US and 5 in the NL CONFIDENTIAL 15
    • Surgical Indications Included 16
    • Phase 2 Clinical Trial Sites
    • Study Visit Schedule Visit 1 Visit 2 Visit 3 Visit 4 Days -30 to 1 Day 1 Day 2 16-48 hrs Day 29 ± 4 days ICF Signing Screening Procedures Surgery, Safety Treatment, TTH Evaluation and Safety (via phone for Evaluation outpts) Safety Evaluation 18
    • Treatment and Time to Hemostasis Treatment Re-Applied (as needed) Fibrocaps Application starts Light manual pressure applied with gauze when not assessing TTH Surgery, Randomize Patient, & Measure bleeding area 0 Gelatin Sponge Applied 1 2 3 4 5 min If Bleeding Continues, Use Other Interventions TTH Assessments q min until hemostasis or until 10 min elapse 19
    • Schedule of Assessments Visit 1 3 4 Screening Surgery Follow-up Follow-up Days -30 to 1 Event 2 Day 1 Day 2 Days 25 to 33 X X X Informed Consent b X Inclusion/ Exclusion Criteria X Xc Medical History X Xc Physical Examination, including Weight and Vital Signs d X Xe CBC with differential f X X X X X X Blood Chemistry Panel Coagulation Panel g h Pregnancy Test i X Immunogenicity Sample X X X Intra-operative Eligibility and Randomization X Treatment and TTH Measurement X Documentation of Surgical Procedure X Fibrospray Device Assessment Adverse Events j X k Concomitant Medications X X X X X X X
    • FC-002: Subject Disposition Total Population Consented N = 162 Not Eligible in Screening N=3 Planned for Surgery N = 159 Not Eligible during Surgery N = 33 Randomized N = 126 Fibrocaps + Sponge N = 86 Gelatin Sponge N = 40 Day 7 completed N = 83 Day 7 completed N = 40 Day 29 completed N = 82 Day 29 completed N = 40 Death: 1 Lost to FU: 2 Lost to FU: 1
    • FC-002: Population Demographics Statistic FCGS N = 86 GS N = 40 Total N = 126 Age (years) 0.157 Mean ± SD (N) Median,(min,max) Gender Male Female Ethnic Origin Asian Black White Other P-value 59.5±13.61 (86) 62.5,(25,82) 62.6±9.84 (40) 61.5,(35,81) 60.5±12.58 (126) 62.0,(25,82) 0.444 % (n/N) % (n/N) 58.1% (50/86) 41.9% (36/86) 50.0% (20/40) 50.0% (20/40) 55.6% (70/126) 44.4% (56/126) 0.128 % (n/N) % (n/N) % (n/N) % (n/N) 1.2% (1/86) 1.2% (1/86) 96.5% (83/86) 1.2% (1/86) 7.5% (3/40) 2.5% (1/40) 90.0% (36/40) 0.0% (0/40) 3.2% (4/126) 1.6% (2/126) 94.4% (119/126) 0.8% (1/126)
    • FC-002: Hemostasis Endpoints (ITT) Fibrocaps N = 86 Gelatin N = 40 P-value 2.0 ± 1.3 4.6 ± 3.1 <0.001 Hemostasis within 10 Min 100% (86) 80% (32) <0.001 Hemostasis within 5 Min 94% (81) 65% (26) <0.001 Hemostasis within 3 Min 80% (69) 42% (17) <0.001 Median TTH (Range) 1.5 (0.8,6.4) 3.8 (1.0,10.0) <0.001 Primary Restricted Mean TTH (min) Secondary Historical TTH data in Hepatic Resection: Evicel 5.3 min and Tachosil 3.9 min
    • FC-002 Time to Event (ITT) Parameter Statistic Log-Rank test p-value <0.0001 Wilcoxon test p-value <0.0001
    • Safety: Treatment Emergent AEs Fibrocaps N = 86 Gelatin N = 39 P-value Number of Subjects with ≥ 1 AEs, % (n) 90% (77) 82% (32) 0.259 Number of Subjects with ≥ 1 SAEs, % (n) 20% (17) 13% (5) 0.450 Highest Rank of Severity per Subject, % (n) Mild Moderate Severe Life Threatening Death Relationship by Subject, % (n) Not related Unlikely related Possibly related 0.989 18% (14) 61% (47) 16% (12) 3% (2) 3% (2) 19% (6) 63% (20) 19% (6) 0% (0) 0% (0) 0.259 66% (51) 33% (25) 1% (1) 78% (25) 22% (7) 0% (0)
    • Safety: Common (≥10%) AEs System Organ Class - Preferred Term, n (%) Fibrocaps Gelatin N=86 N=39 21 (24%) 21 (24%) 9 (10%) 9 (23%) 13 (33%) 2 (5%) 10 (12%) 7 (8%) 3 (8%) 5 (13%) 27 (31%) 13 (33%) 9 (10%) 1 (3%) 10 (12%) 4 (10%) Gastrointestinal disorders - Constipation - Nausea - Vomiting General disorders and administration site - Edema - Pyrexia Injury, poisoning and procedural complications - Procedural pain Metabolism and nutrition disorders - Hypokalemia Musculoskeletal and connective tissue disorders - Back pain
    • AEs of Interest (MOA, Device) Fibrocaps N = 86 Gelatin N = 39 1 0 1 1 1 1 0 1 0 1 1 0 0 1 1 1 1 1 1 N=42 0 0 0 1 0 3 1 0 0 0 N=16 0 0 0 Thromboembolic-associated AEs Acute coronary syndrome Arteriovenous fistula thrombosis Cardiac failure congestive Cerebrovascular accident Pulmonary embolism Deep vein thrombosis Surgical Site-related AEs Scrotal hematoma Wound complication Wound dehiscence Incisional drainage Wound drainage Post-procedural hematoma Post-procedural hemorrhage Air Emboli-associated AEs Acute Dyspnea Respiratory failure Hypotension
    • Phase 2 Safety Summary • Safety Monitoring Committee reviewed safety twice during the study and supported continuation of the trials • AE profiles were similar across studies and across treatment groups • No neutralizing anti-thrombin antibodies • AE profile is consistent with the surgical population and similar to published fibrin sealant and thrombin trials
    • A PHASE 3, RANDOMIZED, SINGLE-BLIND, CONTROLLED TRIAL OF TOPICAL FIBROCAPS™ IN INTRAOPERATIVE SURGICAL HEMOSTASIS http://www.clinicaltrials.gov/ct2/show/NCT01527357?term=fibrocaps&rank=2 29 CONFIDENTIAL
    • ProFibrix Clinical Trial Team • Clinical Operations Directors – Mary Jo Schreifels, US – Monique van Rij, EU • Clinical Project Manager – Beth Sleicher, US • Sr. Clinical Research Assoc. – Lisa Logue, US – Sandra Kohler, EU • Clinical Trial Assistant – Susan McMillen, US • Regulatory Affairs – Eliane Schutte – Linda Zuckerman – Sabrina Gu Independent Contractors • Biostatistics – Dan Gillen, PhD (Prof UC Irvine) • Data Management – Betty Lin – Brett Sellars • Medical Writing – Eilidh Williamson • Legal – Staci Severns