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

1. 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

2. 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

3. 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

4. The Netherlands: “Waterstasis”
4

5. The Surgeon: “Hemostasis”
5

6. 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

7. The Coagulation Cascade
7

8. 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

9. 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

10. Fibrocaps Application Techniques
Air-powered Fibrospray Device
Direct from the vial
Rigid nozzle
Flexible nozzle
Rapid Clot Formation
CONFIDENTIAL
10

11. Fibrocaps Delivery System
Fibrospray Delivery
Device
Air Handling Equipment
Regulator
Fibrocaps vial
Umbilical
Air
Filter
Air Supply
from the OR
11

12. 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

13. 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

14. FC-002 US & FC-002 NL:
Phase 2 Randomized, Controlled Trials
of Fibrocaps in Surgical Bleeding

15. 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

16. Surgical Indications Included
16

17. Phase 2 Clinical Trial Sites

18. 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

19. 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

20. 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

21. 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

22. 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)

23. 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

24. FC-002 Time to Event (ITT)
Parameter
Statistic
Log-Rank test
p-value
<0.0001
Wilcoxon test
p-value
<0.0001

25. 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)

26. 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

27. 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

28. 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

29. 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

30. 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