ThromboGenics NV: from an Academic Research Lab to a Biopharmaceutical CompanyDésiré Collen, Founder & Chairman of ThromboGenics NV

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1. Intellectual Property

2. A business environment with adequate incentives by the authorities

3. Smooth arms length interaction with academia

4. Focussed and flexible programs for translational research

5. Money

Important assets for Biopharmaceutical developments.

2

ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PAII. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical 

developmentV. 1998‐on Thromb‐X NV and microplasmin for strokeVI. 2001‐on Thromb‐X NV and microplasmin for sVMAVII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III 

developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin 

(ocriplasmin) for sVMA

IX. Conclusions

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ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PA• Agreement wit LRD VZW (1976)• Research on the regulation of fibrinolysis• Patent application t‐PA (1980)• Agreement with Genentech (1980‐1983)• First patient treated with melanoma t‐PA in 1981• Royalty return (1987‐2005)• Litigation jury verdict

II. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical developmentV. 1998‐on Thromb‐X NV and microplasmin for strokeVI. 2001‐on Thromb‐X NV and microplasmin for sVMAVII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMAIX. Conclusions

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5

t‐PAuPA

Activator SKSak

Plasminogen  Plasmin

α2  Antiplasmin

Fibrin   FDP

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Regulation of fibrinolysis: plasminogen activator as a thrombolytic agent

D. Collen

Pathobiology of the Endothelial Cell    pag. 183‐189     1982

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April 15 – thrombotic mass in the iliofemoral vein, protruding in the vena cava and occluding renal vein

May 8 – After tPA therapy: normal patency of renal vein and normal contrast dilution in open iliofemoral vein

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ROYALTY PAYMENTSYear Amount1988 $ 1,284,748.951989 $ 4,963,631.641990 $ 6,690,485.431991 $ 7,343,577.831992 $ 7,192,340.001993 $ 7,051,826.001994 $ 8,849,114.001995 $ 10,747,815.001996 $ 11,941,598.001997 $ 11,654,568.001998 $ 10,904,669.001999 $ 9,187,963.002000 $ 9,843,898.002001 $ 7,602,610.002002 $ 4,618,915.002003 $ 6,214,312.002004 $ 6,856,777.002005 $ 7,203,827.002006 $ 3,509,526.00

Total $ 143,662,201.85

Donations to DCRF (± 50%)

Sale (675 MBF)/Donation (600 MBF) to Collen Trust/Biggar

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ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PA

II. 1988‐on D. Collen Research Foundation, VZW for academic research• Constitution of DCRF (1988)• Co‐financing 9th floor GHB (1992)• Expansion of CMVB• Development of VIB‐programs (1994) 

III. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical developmentV. 1998‐on Thromb‐X NV and microplasmin for strokeVI. 2001‐on Thromb‐X NV and microplasmin for sVMAVII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMAIX. Conclusions

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Center for Molecularand Vascular BiologyDirectorH.R. Lijnen, Ph.D.

Katholieke Universiteit Leuven, BelgiumCampus Gasthuisberg

KU LEUVEN ThromboGenicsThromboGenics N.V.

ChairmanD. Collen, M.D., Ph.D.

9th floor

Vesalius Research CenterDirectorP. Carmeliet, M.D., Ph.D.

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ThromboGenics’ Relationship With KULeuven, the VIB, and the IWT

KUL, VIB

Vesalius Research Center, VIB and Center for Molecular and Vascular Biology, KULeuven

200 Researchers

€ 20 million annual budget

Provides Basic Scientific Research

ThromboGenics R&D ThromboGenics

Licenses and DevelopsKey Proprietary Technologies

Develops programs through (earlypilot) clinical trials

Speed/flexibility, cost control

Commercialises Cardiovascular and Ophtalmic Products

Conducts Clinical Trials

Raises Funds

Experienced Management Team

Total 130 people

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ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PAII. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMI

IV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical development• Constitution of TG Ltd• Financing of TG Ltd• Development of project portfolio

V. 1998‐on Thromb‐X NV and microplasmin for strokeVI. 2001‐on Thromb‐X NV and microplasmin for sVMAVII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMAIX. Conclusions

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ROYALTY PAYMENTSYear Amount1988 $ 1,284,748.951989 $ 4,963,631.641990 $ 6,690,485.431991 $ 7,343,577.831992 $ 7,192,340.001993 $ 7,051,826.001994 $ 8,849,114.001995 $ 10,747,815.001996 $ 11,941,598.001997 $ 11,654,568.001998 $ 10,904,669.001999 $ 9,187,963.002000 $ 9,843,898.002001 $ 7,602,610.002002 $ 4,618,915.002003 $ 6,214,312.002004 $ 6,856,777.002005 $ 7,203,827.002006 $ 3,509,526.00

Total $ 143,662,201.85

Donations to DCRF (± 50%)

Sale (675 MBF)/Donation (600 MBF) to Collen Trust/Biggar

Development of Capital of ThromboGenics Ltd

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ThromboGenics Ltd portfolio

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microplasmin

microplasmin

Staphylokinase

Anti‐PlGFAnti‐FVIII

ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PAII. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical 

development

V. 1998‐on Thromb‐X NV and microplasmin for stroke• Stroke infarct size in gene‐targeted mice• Patent for compounds that reduce α2 –antiplasmin• Microplasmin• Patent for recombinant microplasmin• Phase II study in stroke

VI. 2001‐on Thromb‐X NV and microplasmin for sVMAVII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMAIX. Conclusions

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Microplasmin for treatment of stroke

Clinical Phase IIa

Objectives - Safety and efficacy

- > 4 to 12 hours after event

- 1 application

- Dose ranging

Protocol - Multi-center

- Double masked- Placebo controlled

Results Presented at World Stroke Congress (Sep 2008)

-Well tolerated

- Promising preliminary findings on reperfusion and secondary markers of neurovascular protection

Future ThromboGenics will make no further investment in microplasmin for stroke indication without a partner

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ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PAII. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical 

developmentV. 1998‐on Thromb‐X NV and microplasmin for stroke

VI. 2001‐on Thromb‐X NV and microplasmin for sVMA• Letter from Dr. M. de Smet, 25 MAY 2001• Prospectus IPO 2006: Clinical development outlined

VII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMAIX. Conclusions

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THROMBOGENICS NVProspectus for IPO – June 2006 page 79‐80 

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ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PAII. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical 

developmentV. 1998‐on Thromb‐X NV and microplasmin for strokeVI. 2001‐on Thromb‐X NV and microplasmin for sVMA

VII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developments• Portfolio• Financing rounds• Clinical trials with ocriplasmin in sVMA• ThromboGenics highlights

VIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMAIX. Conclusions

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Focus R&D activities to maximize investment (2006)

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Cardiovascular disease

Development Phase I Phase II Phase IIIDiscovery

CLINICAL

DRUG CANDIDATE INDICATION

Microplasmin Eye disease - Vitrectomy

Microplasmin

Microplasmin

Microplasmin

Staphylokinase

Anti-factor VIII (TB-402)

Anti-PIGF (TB-403)

PIGF

Anti-GPIb (6B4)

Anti-VPAC

Diabetic retinopathy

Stroke Intravenous / Intra-arterial

Peripheral vascular disease (DVT/PAOD)

Acute myocardial infarction

Deep vein thrombosis

Atrial fibrillation

Cancer

Age related macular degeneration

Coronary artery disease, Peripheral arterial occlusive disease

Acute coronary syndrome,Thrombotic thrombocytopenic purpura

Thrombocytopenia

Visual disorders

PRECLINICAL

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To Date over 800 Patients were Treated with Ocriplasmin in 8 Clinical Trials

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20042004 20052005 20062006 20072007 20082008 20092009 20102010 20102010

Completed trialsOngoing trials

Out of the microplasmin‐treated patients 44% achieved Macular Hole closure at one month

FTMH closure (%

)

(n=32) (n=57)

43.9

12.5

***

0

10

20

30

40

50

60

(n=26) (n=46)

52.1

15.4

***

0

10

20

30

40

50

60

All Patients Patients withoutprotocol violations

Placebo Microplasmin***P≤0.00531

Guarantee Financial Resources to Achieve Corporate Goals – since IPO raised a total of > €340M

• Pre‐IPO capital rounds (71 mio € from DCRF/DC) and 14 mio €from Easthill

• IPO 2006 (€35M)• Out‐licensing TB‐403 to Roche 2008: upfront payment of €30M• Private placement 2007 (€23M)• Private placement 2009 (€43M)• Private placement 2010 (€56 M)• Private placement 2012 (€78 M)• Partnership with Alcon 2012: upfront payment of €75M

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ThromboGenics Highlights

• Lead product Ocriplasmin– Positive Phase III clinical trials– Submission to the EMA and FDA – Anticipated approval  and commercial launch end of 2012/begin 2013

• Market capitalization >€1 B 

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Management adopting a “Common Sense”Approach to ensure a Successful Launch of Ocriplasmin

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• Stepwise expansion of organizational struture

• Profiles with big pharma experience and a good sense of 

entrepreneurship

• Matrix structure /flat structure

• Empowerment of the employees

Board of Directors of ThromboGenics NV, 2012

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ThromboGenics NV: Development Stages

I. 1976‐on Research at CMVB‐KUL leading to t‐PAII. 1988‐on D. Collen Research Foundation, VZW for academic researchIII. 1990‐on Thromb‐X NV to develop Staphylokinase for AMIIV. 1997‐on ThromboGenics Ltd (Ireland) to optimize financing of clinical 

developmentV. 1998‐on Thromb‐X NV and microplasmin for strokeVI. 2001‐on Thromb‐X NV and microplasmin for sVMAVII. 2006 ThromboGenics NV: IPO for financing of phase II/phase III developmentsVIII. 2006‐2012 ThromboGenics NV progressive prioritization of microplasmin (ocriplasmin) for sVMA

IX. Conclusions

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1. Intellectual Property

• Of vital importance but …

2. A business environment with adequate incentives by the authorities

• Major efforts by the (Flemish) government ofessential importance

3. Smooth arms length interaction with academia

• Via VIB and tech transfer depts of universities

4. Focussed and flexible programs for translational research

• Pragmatic changes of orientation

5. Money

• t-PA royalties as seed money

Important assets for Biopharmaceutical developments.

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