L/O/G/OL/O/G/O

Introduction of Rafugen BMP2

David Kim

R&BD of Korea Bone Bank Co LtdR&BD of Korea Bone Bank Co., Ltd.

ContentsContents

Introduction1

Safety & Efficacy2

3 Clinical Trial

Manufacturing Capacity4

1.Introduction

1 Market Analysis1.Market Analysis

1 Bone Morphogenic Protein (BMP2)1. Bone Morphogenic Protein (BMP2)

1 History of BMPs1.History of BMPs

2000~2002 11 FDA hBMP 2(INFUSE) f i l l l i l f i

2004. 4 : FDA-OP-1 putty(Stryker) for revision spinal fusion

2004. 5 : FDA- rhBMP-2(INFUSE) for treating acute open tibial shaft fractures

2001.10: FDA-Humanitarian device exemption (HDE) approval for rhOP-1

2002.11: FDA-rhBMP-2(INFUSE) for a single level spinal fusion

1990

1991: Elizabeth A. Wang: recombinant BMP-2

1991 : Orthopedic surgeons use DBM for commercial use

1992 : David C. Rueger : recombinant OP-1

1970

1980

1971 M h ll U i t d l th t f BMP’

1991: Elizabeth A. Wang: recombinant BMP 2

1960

1970

1965 Marshall Urist : discovery DBM can induce bone formation

1971 Marshall Urist : develop the concept of BMP’s

1960 U y

1 BMP animation1.BMP animation

1 Competitive Products1.Competitive Products

INFUSE Bone Graft(Medtronic)

OP-1 Implant(Stryker)

RafugenTM

(Korea Bone Bank)

ProteinrhBMP-2

(CHO cell expressed)rhBMP-7

(CHO cell expressed)rhBMP-2

(CHO cell expressed)

Collagen spongeCarrier Collagen powder Demineralized bone matrix Collagen gel, CMC

1.5 mg/mlConcentration 0.88 mg/ml 50 ug/ml

7-16 minutes

S i f i

Half-life 10-15 hours > 3 days

Long bone non unionsSpine fusions

(ALIF with LT-CAGE)FDA approval Long-bone non-unions

Spine posterolateral fusions

gSpine posterolateral fusions

Dental surgery

1 Spinal Fusion Case In USA1. Spinal Fusion Case In USA

(Source : Frost & Sullivan)

1 Pricing forecast for BMPs1. Pricing forecast for BMPs

( Source : Frost & Sullivan)

1 USA market size for BMPs1. USA market size for BMPs

(Source : Frost & Sullivan)

1 Competitive Products

Infuse – rhBMP-2 Medtronics

1.Competitive Products

OP-1 – rhBMP-7 Stryker

1 Rafugen BMP2 DBM Gel by KBB

A : Human DBM

1.Rafugen-BMP2-DBM Gel by KBB

A : Human DBM

(BMPs + TGF-, PDGF, FGF, VEGF, etc. in DBM)

0.25cc/0.5cc/1ccAt 37℃ for 16hr

B : rhBMP 2

Mixed Freeze-DryMix

3cc/5ccB : rhBMP-2 C : Carrier

(Package)

Used concentration of rhBMP-2: 50μg/ml: 50μg/ml

2.Product Safety & Efficacy Datay y

2 In vitro test – Rafugen BMP2 vs USA BMP2

Study group : Prof. Teoh in Singapore National University

2. In vitro test – Rafugen BMP2 vs. USA BMP2

mRNA expression

Alizarin red stain Control : Cells in general media OS : Cells in media with osteogenic supplementOS : Cells in media with osteogenic supplement OS(A) : Cells with USA R&D BMP2 OS(K) : Cells with KBB Rafugen BMP2

2 Subcutaneous transplantation study2. Subcutaneous transplantation study

Study group : Prof. Moon in Yonsei University Medical College

Rafugen-DBM (without BMP2) Rafugen-BMP-2-DBM

Animal : Rat Method : Subcutaneous transplantation after 4 weeks

f Topic : Ectopic bone formation

2 Spinal fusion study2 Spinal fusion study2. Spinal fusion study2. Spinal fusion study

Inha Univ. Hospital NeurosurgeryProf. Yoon Seunghwan

2 Spinal fusion study2. Spinal fusion study

Study group : Prof. Yoon in Inha University, Medical College

CT Scan resultsCT Scan results

Fusion (10ug)Control Fusion (10ug)Control

Rafugen BMP-2(10ug)

Rafugen BMP-2(50ug)

2 Ulna defect study – X-ray results2. Ulna defect study – X-ray results

2-27 Ulna defect study – X-ray results

Pi #3 D 58 (LT DBX RT R f ) 1W

2 27. Ulna defect study X ray results

Study group : Prof. Moon in Inha University, Medical College

Pig #3 : D-58 (LT : DBX, RT : Rafugen) – 1W

2 Ulna defect study – X-ray results

Pi #3 D 58 (LT DBX RT R f ) 4W

2. Ulna defect study X ray results

Pig #3 : D-58 (LT : DBX, RT : Rafugen) – 4W

2 Ulna defect study – X-ray results

Pig #3 : D-58 (LT : DBX, RT : Rafugen) – 8W

2. Ulna defect study X ray results

2 Ulna defect study – X-ray results

Pig #3 : D-58 (LT : DBX, RT : Rafugen) – 12W

2. Ulna defect study X ray results

2 Ulna defect study – X-ray results

Pig #3 : D-58 (LT : DBX, RT : Rafugen) – 16W

2. Ulna defect study X ray results

Pig #3 : D 58 (LT : DBX, RT : Rafugen) 16W

2 Calvarial defect study – CT scan2. Calvarial defect study – CT scan

Study group : Prof. Cho in Yonsei University, Dental College

Animal : Rat Method : Calvarial defect after

2 8 k2, 8 weeks Topic : New bone formation

2-13 Calvarial defect study – X-ray results2-13. Calvarial defect study – X-ray results

2 Calvarial defect study - Histology2. Calvarial defect study - Histology

MBCP particle alone

At 2 weeks (10)

At 8 weeks (10)At 8 weeks (10)

2 Calvarial defect study - Histology2. Calvarial defect study - Histology

MBCP particle + rhBMP-2(0.025mg/ml)

At 2 weeks (10)

At 8 weeks (10)

2 Calvarial defect study - Histology2. Calvarial defect study - Histology

MBCP particle + rhBMP-2(0.05mg/ml)

At 2 weeks (10)

At 8 weeks (10)

2-17 Calvarial defect study - Histology2-17. Calvarial defect study - Histology

MBCP particle + rhBMP-2(0.1mg/ml)

At 2 weeks (10)

At 8 weeks (10)At 8 weeks (10)

2-18 Calvarial defect study - Histology

MBCP particle + rhBMP 2(0 2mg/ml)

2-18. Calvarial defect study - Histology

MBCP particle + rhBMP-2(0.2mg/ml)

At 2 weeks (10)

At 8 weeks (10)

2 Dental study Only zirconia implant2. Dental study – Only zirconia implant

Study group : Prof.Han in Seoul National University, Dental College

Before implantation After rhBMP2, 0.05mg grafting

Group A : only Zirconia implant

Group B : Implant + DBM Gel

Group C : Implant + rhBMP2 + DBM Gel

After Zirconia implantation

2-23 Dental study – Only zirconia implant2-23. Dental study – Only zirconia implant

100x100x

Animal : Beagle dogs

12.5x

Animal : Beagle dogsMethod : Lower jawbone implantation for 3 weeks

2 24 Dental study Zirconia implant + DBM gel2-24. Dental study – Zirconia implant + DBM gel

100x100x

12.5xAnimal : Beagle dogsMethod : Lower jawbone implantation for 3 weeks

2-25. Dental study – Zirconia implant + DBM gel y p gwith BMP2

100x100x

12.5x

Animal : Beagle dogsMethod : Lower jawbone implantation for 3 weeks

Beagle dog dental implantation model – 3, 6 weeksBeagle dog dental implantation model 3, 6 weeks

After 3 weeks Bone remodeling area : Yellow & Red

After 6 weeks Group A Group B Group C

Seoul National Univ. Hospital DentalsurgeryProf. Han Jung seock

2-26 Dental study – New bone formation ratio2 26. Dental study New bone formation ratio

Group A : Only implant Group A : Only implant Group B : Implant + DBM Gel Group C : Implant + DBM Gel + rhBMP2

8090

100

50607080

A(%

)

A

20304050

BA A

BC

01020

3 wk 6 wk3 wk 6 wkTimes(weeks)

3.Clinical Trial

3 Clinical Trial3. Clinical Trial

Contents Company / Institute Nation State

1. Preclinical study to dental medical device YUMC Korea Completed

2. Preclinical safety test of rhBMP2 Chemon Co. Korea Completed

3. Preclinical effectiveness test of rhBMP2 IHU, YUMC, SNU, NUS Korea / Singapore Completed

4. Master cell characterization test Newlabs Co. (Charles River) Germany Completed

5. Virus clearance test to bioprocess Newlabs Co. (Charles River) Germany Completed

6. IRB approval for clinical study YUMC, KUMC Korea Completed

7. KGMP for clinical study KFDA Korea Completed

8. Clinical study to dental medical device YUMC, KUMC Korea Completed

9. KFDA final approval KFDA Korea On schedule

4.Manufacturing Capacityg p y

4 Manufacturing Capacity4. Manufacturing Capacity

1,000 Liter Bioreactor system1 Batch Final rhBMP2 Production : 25g (25milligram/Liter)

1cc Rafugen BMP2 DBM Gel = 500,000 ea x 50microgram

O1 Batch Operation Day : 40 Days

L/O/G/OL/O/G/O

Thank You!

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