new perspectives

From research to application ThromboGenics corporate highlights 2013 ThromboGenics corporate highlights 2013 4 Chairman Dr. Staf Van Reet 2013, a year of great importance

We continue to believe that, in time, JETREA® will be recognized as 22 the new standard of care. Prof. Dr. Peter Stalmans The ‘watchful waiting’ approach has much more disadvantages than initially thought. 8 CEO Dr. Patrik De Haes A challenging and promising future

2013 has been a challenge for sure, but also a great source of pride 41 for us, as we look back at a pool of Prof. Dr. close to 7,000 patients treated with our product. Marc de Smet ThromboGenics can have a major impact on the lives of diabetes patients. 27 33 Prof. Dr. Peter Kaiser Clara Eaglen, RNIB Summary A good patient Not having to undergo selection will surgery makes a huge dramatically raise difference for the anatomical and VMT patients. functional success rates of JETREA®.

4 Chairman Dr. Staf Van Reet 8 CEO Dr. Patrik De Haes 12 About ThromboGenics 18 JETREA®

26 JETREA® in the US

32 JETREA® in Europe

37 JETREA® in the rest of the world

38 Research and development 46 48 48 Our organization Prof. Dr. Koen Kas Our organization 56 Shareholder information Promising new data on People behind treating children’s brain the success of tumor. ThromboGenics. 4 Foreword of the Chairman THROMBOGENICS corporate highlights 2013 5

A YEAR OF GREAT IMPORTANCE Foreword of the Chairman

Dear reader,

Since its creation in 1998, ThromboGenics has successfully tackled numerous challenges. As someone who has been lucky enough to be a part of its story since 2006, I can confirm that it has been a truly exciting experience. The last twelve months have been a game-changing period, culminating in the recent decision by the Board to explore further strategic options for the Company.

As the newly appointed Chairman of the Board, I look forward to 2014 with confidence as I know that the ThromboGenics team will relish the next step in our corporate development, much as they have done in each of the past 15 years.

Following the successful clinical development of JETREA®, we have seen one important milestone after another during the last 18 months. The most important of these was the approval of JETREA® by the Food and Drug Administration (FDA) in the US (October 2012) and by the European Commission (EC) in Europe (March 2013). The importance of these achievements by the ThromboGenics team should not be underestimated given the very different approaches of the FDA and the EC. Other countries in the rest of the world have followed this lead with Canada granting JETREA® its first approval outside the US and Europe.

These regulatory approvals led to the commercial introduction of JETREA® for the treatment of symptomatic Vitreomacular Adhesion (VMA) or symptomatic Vitreomacular Traction (VMT) on both sides of the Atlantic during 2013.

In Europe this novel product has already received a number of positive endorsements. The National Institute for Health and Care Excellence (NICE) in the United Kingdom and the German Gemeinsamer Bundesausschuss (G-BA) emphasized in their health technology assessments that JETREA® offered real value to patients, including patients’ quality of life, especially when used for the earlier treatment of this progressive disease. These very positive evaluations of JETREA® highlight the value of this novel product for both patients and payers, and has created a strong platform from which to build the product’s sales.

These positive reimbursement decisions and value assessments have strengthened our confidence in the intrinsic potential of the product to bring meaningful benefit to patients. We continue to believe that, in time, JETREA® will be recognized as the new standard of care. 6 Foreword of the Chairman

Ensuring that JETREA® will meet success in each country is a complex operation with many requirements. It requires the sales teams and market access specialists to work together to ensure that they meet the needs of each country, as they all have their own particular systems and preferences. The reason why we chose to partner with Alcon is that it already has high-performing organizations in place in each of the over 40 markets worldwide where we intend to make JETREA® available in the years ahead.

Given the more homogeneous nature of the US market, ThromboGenics decided to use its own organization to commercialize JETREA®. The sales development of this novel product has been slower than anticipated, and it has become clear that we are doing more than introducing a new drug – we are in fact looking to establish a totally new standard of care for the earlier treatment of patients with symptomatic VMA.

Our US team remains focused on educating ophthalmologists and retinal specialists on the opportunity and important benefits that this groundbreaking treatment delivers. Over the coming years we believe that continued education, including further characterizing the efficacy and safety profile of JETREA®, combined with a marketing approach that focuses on highlighting its clear patient benefits, will help us realize the full potential of JETREA®.

One of the more important developments at ThromboGenics has been the shift from a university originated research and development company to the market oriented company in which we operate today. As we shift to a more commercially focused organization, we intend to continue to invest in fundamental research and in leveraging our proven capabilities to bring products to market. It is central to our future strategy that we continue to leverage all of our current capabilities and expertise on both sides of the Atlantic.

The growing importance of the US to ThromboGenics has been reflected at Board level, as we have been much honored to welcome Dr. David Guyer as our newest member. His proven skills and experience as a dedicated ophthalmic entrepreneur is and will be of great value for the Company, as we look to maximize the value of our business in the US.

The arrival of Dr. Guyer also helps us to fill the gap left by the recent retirement of ThromboGenics´ founder Professor Doctor Désiré Collen. His contribution to the successful development of ThromboGenics and the life sciences industry in general cannot be over-estimated. The importance of his work led him to gain great acclaim from the international community, and this was reflected in his receiving the international Lifetime Achievement Awards from both the leading pharmaceutical publication, Scrip and the Belgian- American Chamber of Commerce (BelCham).

The Company takes pride in its founder receiving these awards, as this reminds the whole ThromboGenics team of the significant progress that we have made. It gives us confidence that we can continue to produce many important achievements in the future.

Dr. Staf Van Reet Chairman of the Board of Directors THROMBOGENICS corporate highlights 2013 7

“We continue to believe that, in time, JETREA® will be recognized as the new standard of care.”

Chairman Dr. Staf Van Reet 8 Foreword of the CEO THROMBOGENICS corporate highlights 2013 9

A CHALLENGING AND PROMISING FUTURE Foreword of the CEO

Dear reader,

For ThromboGenics, the year 2013 was first and foremost the year of the commercial introduction of JETREA®. The launch of our flagship product in the United States in January was our most important event of the past year. Soon after, we landed our EC approval for JETREA® which was the starting signal for market introductions in Europe, and further approvals in the rest of the world. A Belgian biotechnology company introducing its own product in the US market by itself is unique. 2013 has been a learning year. It has been a challenge for sure, but also a great source of pride for us, as we look back at a pool of close to 7,000 patients treated with our product. We have done everything to make this product introduction a success, and this will remain our most important focus for 2014.

2013 also made it very clear how revolutionary JETREA® is for the treatment of patients suffering from symptomatic Vitreomacular Adhesion (VMA) and Vitreomacular Traction (VMT). For more than twenty years, the normal approach to treatment was waiting until the patient’s condition had worsened enough to justify an eye operation. JETREA®, which offers an earlier treatment option, has radically changed that, and has already brought relief to many patients.

As much as JETREA® is a great opportunity for the patient, it is clearly also a game-changer for the treating specialists. When pioneering a new treatment method such as JETREA®, it is very important to also focus on bringing new insights to treating specialists, in our case the retinal specialists and surgeons in the United States. Should they stick to ‘watchful waiting’ as before, or can they start treating patients at an earlier stage? The broad range of strongly held opinions put forward by the retina community and by the wider ophthalmology community has set a number of additional tasks and challenges for ThromboGenics.

Clinical ophthalmology is a domain of two specialties in the US. On the one hand we find the first-line ophthalmologists, on the other hand the retinal specialists and surgeons. Our sales force has focused on the retinal specialist and surgeons in 2013 and we intend to continue this approach.

Meanwhile, we have also learned a lot about the referral networks that lead to patients being evaluated at these retina clinics where they receive any retina-related treatment. 10 Foreword of the CEO

We know that the referral process for patients suffering from retina-related diseases will typically start at the level of the general ophthalmologists, who are highly experienced in identifying the first symptoms of various retina-related diseases. If ThromboGenics is to gain access to the opportunity to treat patients at an earlier stage of VMA/VMT, it is very important that general ophthalmologists understand the various stages of this disease and know how JETREA® can provide a treatment solution before the disease worsens to the point where a vitrectomy is the only solution. For this reason, the Company has decided to accelerate its efforts to educate the broader ophthalmology community. The combination of these necessary educational efforts and collecting validated clinical data needed to support this process, takes time. Our number one challenge for 2014 remains maximizing the sales of JETREA®.

In the United States, we are currently working with our own reinforced commercial team. In Europe and the rest of the world, we are supporting our partner Alcon to help them unlock the opportunity for JETREA® to identify and treat more and more eligible patients. As a world leader in the field of eye care and as the second largest division of Novartis, Alcon is ThromboGenics’ ideal partner, with whom we are happy to share our expertise.

Last year, thanks to a joint effort with Alcon, JETREA® was successfully introduced in a number of markets outside the US. It was first introduced in the United Kingdom and Germany, and then JETREA® soon became available in Ireland, Denmark, Norway, Sweden, Finland, and the Benelux. In most of these countries, the drug is also reimbursed. In certain countries including France, Belgium, Spain and Italy, we are presently negotiating the reimbursement levels ahead of gaining what we anticipate will be actual reimbursement. Given the robust recommendations that JETREA® has received so far, we feel confident that the introduction and endorsement of the product in the rest of Europe will follow swiftly.

Outside Europe, JETREA® has been launched in Canada. In Japan, the process towards gaining approval has started. In Japan, a so-called bridging study is needed to generate further supportive efficacy and safety data based on clinical use in the local population. While JETREA® is slowly but surely taking its rightful place in the treatment of symptomatic VMA/VMT, ThromboGenics remains ambitious in other areas as well. We want to further deepen our core expertise in developing innovative ophthalmic medicines for the treatment of disease of the back of the eye. This is why we are continuing to invest in new developments. We are not only looking at new formulations and indications for JETREA®, but also at entirely new treatments.

Our focus for the development of new innovative ophthalmic medicines is for the treatment of diabetic related eye diseases; this is driven by the next strategic direction for our Company. Diabetes is a global pandemic and has an important detrimental impact on the health of the eye, leading to poor vision and, in more severe cases, blindness. To further extend our pipeline of ophthalmic products, focused on diabetes-related eye diseases, we are also looking to leverage third party technologies for accelerating internal developments. The partnerships with Bicycle Therapeutics and Eleven Biotherapeutics are examples of this. It is our intention to continue with this approach as we develop a portfolio of potential new products.

Finally, in our search to improve the treatment of cancer, we see promise in the potential of anti-PlGF (TB-403) for the treatment of medulloblastoma, the most common brain tumor in children. In 2014, we will look at how we can best maximize this oncology asset, without losing our focus on ophthalmology.

Patrik De Haes, MD CEO THROMBOGENICS corporate highlights 2013 11

“2013 has been a challenge for sure, but also a great source of pride for us, as we look back at a pool of close to 7,000 patients treated with our product.”

CEO Dr. Patrik De Haes 12 about thrombogenics

I

about Thrombogenics THROMBOGENICS corporate highlights 2013 13

Innovative ophthalmic medicines

ThromboGenics is an integrated 1998 (Dec) biopharmaceutical company focused on D. Collen founds ThromboGene Ltd (later ThromboGenics Ltd) in Ireland for R&D of cardiovascular/oncology I developing and commercializing innovative programs in-licensed from KU Leuven/ VIB. Financed primarily with t-PA royalty ophthalmic medicines. rights (€71 million over the next 7 years).

1998 The Company’s lead product, JETREA® (ocriplasmin), has been approved by the US Food and Drug Administration for the treatment of symptomatic VMA Research on treatment of ischemic stroke by N. Nagai and D. Collen in and was launched in the United States in January 2013. Earlier, in March 2012, CMVB / KU Leuven leading to the about ThromboGenics had signed a strategic partnership with Alcon (Novartis) concept of recombinant microplasmin. for the commercialization of JETREA® outside the US. In March 2013, the European Commission approved JETREA® in the European Union for the 2000 treatment of symptomatic VMT, including when associated with macular holes of a diameter less than or equal to 400 microns. Since that March 2013 Production of microplasmin for stroke Thrombogenics treatment by Y. Laroche and D. Collen approval, Alcon has introduced JETREA® in the UK, Germany, the Benelux in CMVB / KU Leuven in collaboration countries and the Nordic region, triggering a €45 million milestone payment with Thromb-X / ThromboGenics Ltd. to ThromboGenics. JETREA® was approved in Canada in August 2013 for the treatment of symptomatic VMA. This was the innovative drug’s first approval in a market outside the US and Europe. 2001

Preclinical development of microplasmin ThromboGenics has a strong commitment to research and development on for PVD (posterior vitreous detachment) in collaboration with M. de treatments for diabetes related eye diseases such as Proliferative Diabetic Smet, A. Gandorfer, J.M. Stassen, M. Trese, Retinopathy (PDR) and Diabetic Macular Edema (DME). The Company is G. Williams and NuVue. also further exploring anti-PIGF (Placental Growth Factor), formerly referred to as TB-403, for the treatment of ophthalmic and oncology indications. 2004

ThromboGenics is headquartered in Leuven, Belgium, with commercial Clinical development of ocriplasmin operations in New Jersey, USA and a branch in Dublin, Ireland. It employs for symptomatic VMA (Vitreomacular Adhesion), directed by S. Pakola. around 190 people globally (including third party partners). The Company is listed on the NYSE Euronext Brussels exchange under the symbol THR. More information is available on www.thrombogenics.com. 14 about thrombogenics

Mission (Jul) 2006 ThromboGenics is dedicated to developing and commercializing new IPO of ThromboGenics NV on Euronext Brussels (€35 million raised). pharmacologic treatments that address important unmet clinical needs in ophthalmology and oncology.

(Aug) 2006 By delivering on this goal ThromboGenics intends to assist clinicians around the world to continually improve treatment for patients with sight threatening C. Buyse joins ThromboGenics as CFO. In the following years the Company will raise ophthalmic disorders and cancer. €204 million through four successive private placements to enable the further development of microplasmin / ocriplasmin / JETREA® As part of its corporate evolution, ThromboGenics has been building a team among other projects. consisting of scientists, sales and marketing experts with deep commercial ophthalmic and retina experience. Investing in this capability will generate the best returns for our shareholders and place the Company in a strong (Feb) 2007 position to achieve its goal of becoming a major global ophthalmic player. P. De Haes joins as COO. Central to ThromboGenics achieving its corporate goals is pioneering research and development, which has played a crucial role in ThromboGenics’ success 2008 to date. Today, the Company has highly qualified research personnel focused on developing new treatments for both ophthalmic and cancer indications. P. De Haes appointed CEO of ThromboGenics NV.

2009 Corporate objectives and strategy Following successful completion of the Phase II MIVI trials, the MIVI-trust pivotal Phase III trials Continuing as a leading global ophthalmology company are carried out both in the US and in Europe. ThromboGenics is well positioned to continue to be a leading global ophthalmology company developing and commercializing innovative 2011 therapies for significant back of the eye diseases with a high unmet medical need. The MIVI-Trust Phase III program is completed successfully and published in the New England ® Journal of Medicine in August 2012. Commercializing JETREA in the US via our own commercial organization The US launch of JETREA® was a major corporate milestone for 2012 ThromboGenics. The Company’s 91-person commercial organization (employees and third party partners) is now focused on building the sales The Company obtains pre-marketing approval for JETREA® by the FDA in the US, where it of this innovative new product for the treatment of symptomatic VMA. will be marketed by ThromboGenics, Inc. For The permanent J-Code for JETREA®, which became effective recently, will marketing in the rest of the world, JETREA® is out-licensed to Alcon. streamline the reimbursement process for retina practices and instill higher reimbursement confidence.

ThromboGenics is confident that JETREA® will enjoy significant success in the US, given the benefits it delivers and the already high awareness the product enjoys with the retina community. THROMBOGENICS corporate highlights 2013 15

Supporting Alcon to successfully commercialize JETREA® outside the US The approval of JETREA® in Europe and Canada, followed by launches in the 2013 (Jan) UK, Germany, the Benelux countries, the Nordic region and recently Canada US launch of JETREA®. The Company obtains mark the start of Alcon bringing JETREA® to patients around the world who a positive CHMP opinion for JETREA® for the could benefit from the first pharmacological treatment for symptomatic treatment of Vitreomacular Traction (VMT), including when associated with macular hole of VMA/VMT. diameter less than or equal to 400 microns.

The recent positive reimbursement guidance by NICE in the UK, the very positive value assessment of G-BA and IQWiG in Germany and CADTH in 2013 (March) Canada will result in JETREA® being reimbursed for a broad range of patients European Commission approves JETREA® with symptomatic VMA/VMT. (ocriplasmin) in the European Union for the treatment of Vitreomacular Traction (VMT), including when associated with macular hole ThromboGenics and Alcon will continue to work on clinical studies and of diameter less than or equal to 400 microns. approval for JETREA® in the rest of the world. In Japan, Alcon has started its ThromboGenics NV enters the BEL20 Index. first clinical study with JETREA® outside the US and Europe.

Working with Alcon to extend the clinical utility of JETREA® 2013 (Apr) A key element of ThromboGenics’ strategic alliance with Alcon relates to the ThromboGenics’ JETREA® launched in future development of JETREA®. Both companies are working on a plan that the UK by partner Alcon, first market in EU will cover the development of new formulations of the product as well as clinical trials for a number of new indications. 2013 (May)

The investment needed to develop the use of JETREA® will be shared equally JETREA® launch in Germany in private and with Alcon. public market by partner Alcon. Launch of JETREA® in Denmark and Sweden by Alcon.

Raising awareness of symptomatic VMA/VMT ThromboGenics, in conjunction with Alcon, is supporting medical education 2013 (Aug) efforts to increase the awareness of symptomatic VMA/VMT as an important JETREA® was approved in Canada in August unmet medical need. 2013 for the treatment of symptomatic Vitreomacular Adhesion. This was the first approval of this innovative drug in a market Building a broader global ophthalmology franchise outside the US and Europe. ThromboGenics is already building its presence in ophthalmology beyond JETREA®. To achieve this, the Company needs to access novel ophthalmic medicines that will help expand its ophthalmology franchise. The Company 2013 (Nov) intends to source these products from its own research, via joint development/ In November 2013, JETREA® was launched in licensing deals or possibly acquisitions. Canada by Alcon.

2014

Permanent J-Code for the reimbursement of JETREA® in the US became effective.

18 jetrea®

II

JETREA® THROMBOGENICS corporate highlights 2013 19

The year of the commercial launch

About JETREA®

JETREA® (ocriplasmin) is a truncated form of human plasmin. The drug is indicated for the treatment of symptomatic VMA in the US and for the II treatment of VMT in Europe, including when associated with macular hole of diameter ≤ 400 microns. JETREA® is a selective proteolytic enzyme that cleaves fibronectin, laminin and collagen – three major components of the vitreoretinal interface that play an important role in VMA/VMT.

JETREA® has been evaluated extensively in the US and Europe. A multi- center, randomized and double-masked Phase III trial involving 652 patients ® with symptomatic VMA/VMT was conducted in both the US and Europe. JETREA Both studies met the primary endpoint of resolution of VMA at day 28. 72% of JETREA® patients who achieved resolution of VMA/VMT and macular holes by Day 28 did so within seven days.

The Phase III program found that 26.5% of patients treated with ocriplasmin saw resolution, compared with 10.1% of patients receiving placebo. The % program also showed that the drug was well tolerated with most adverse ® events being transient and mild. 72of JETREA patients who achieved resolution of VMT and macular holes by Day 28, did so within seven days. Symptomatic VMA/VMT ThromboGenics’ extensive clinical development program has shown that JETREA® could play an important role in the treatment of symptomatic VMA and VMT. If left untreated, this progressive eye disease generally leads to significant visual distortion, deterioration in visual acuity, or even central blindness. 20 jetrea®

Symptomatic VMA/VMT is caused by traction resulting from a persistent attachment of the vitreous (jelly-like material in the center of the eye) to the macula at the back of the eye. The macula provides central vision that Mechanism is needed for everyday tasks such as driving, reading and recognizing faces. Symptomatic VMA/VMT can cause symptoms such as distorted or decreased of action vision. When the disease progresses the traction may eventually result in the formation of a hole in the macula (called a macular hole). Normal Separation (PVD) Vitreous remodelling A unique mechanism of action leads to progressive liquefaction with age. Up till now, the only treatment option for patients with symptomatic VMA/ VMT was the surgical separation of the vitreous from the retina, called a vitrectomy. This procedure holds several risks and can lead to complications such as bleeding, pain, post-operative inflammation or irritation. Because of this, it is usually only undertaken when the patient’s vision has deteriorated significantly. This approach is called ‘observation’ or ‘watchful waiting’ until a patient becomes a candidate for surgical treatment and repair of the retina. However, for many patients this is not a suitable option, as irreversible damage to the retina may have already occurred.

JETREA® is the first pharmacological option for treating symptomatic VMA and VMT. It is administered as an intravitreal injection: a unique mechanism of action. The technique has become routine practice among VMA retina physicians over recent years, and is easy to administer. JETREA® breaks Incomplete separation can cause Vitreomacular down the protein fibers which cause the abnormal traction between vitreous Adhesion (VMA), and macula that causes VMA/VMT. By dissolving these proteins, JETREA® that results in traction, leading to visual releases the traction, and helps to complete the detachment of the vitreous disturbance. from the macula. JETREA® can also be used when VMT has progressed and caused a small hole in the macula (central part of the light-sensitive layer at the back of the eye). If the treatment is successful, the symptomatic VMA/ VMA RESOLVED VMT will not recur. Ocriplasmin injected intravitreally acts by weakening and breaking The availability of JETREA® will allow physicians to treat patients with these the protein fibers that symptoms much earlier than the current situation. Successful treatment can are causing the adhesion and separates the lead to improvements in patients’ vision and their ability to carry out normal vitreous body from the daily activities. Furthermore, it stops further progression of this disease. retina, which relieves the traction and resolves the symptoms. THROMBOGENICS corporate highlights 2013 21

Better diagnosis through OCT The introduction of optical coherence tomography (OCT), a non-invasive imaging technique that can deliver instant real-time high-resolution images of eye tissue, is expected to be an important factor in the uptake of JETREA®. The technique is leading to better diagnosis of patients with symptomatic VMA/ VMT and macular hole, resulting in wider recognition and understanding of the role of VMA/VMT in the progression of eye disease and visual impairment among the retinal community. Nearly every ophthalmologist in the US now has access to OCT.

“Correct interpretation of Optical Coherence Tomography (OCT) imaging of the eye is crucial too”, explains Dr. Kaiser, who is also founding director of the Digital OCT Reading Center at the Cleveland Clinic, one of the leading OCT reading centers in the world. Optical Coherence Tomography is a non-invasive imaging technique. “It allows us to have an accurate diagnosis of patients with symptomatic VMA, which results in better understanding of the progression of this eye disease and will lead to better treatment with JETREA®.”

A truly innovative product After two pivotal Phase III trials with ocriplasmin for symptomatic VMA including macular hole, JETREA® became the first and currently only drug approved for VMA treatment. Recent market research conducted by ThromboGenics shows that there are no similar products under regulatory review or in clinical development for this indication. Given its potential clinical benefits and the size of the patient population it is targeting, this means JETREA® could represent a significant commercial opportunity.

For the moment, the product has to be kept frozen and has to be diluted before use. In collaboration with its partner Alcon, ThromboGenics will start the development of a pre-diluted formulation of JETREA®, in order to make the product ‘ready to use’ for physicians. It will also continue research on a new room temperature-stable formulation of JETREA®. 22

“The ‘watchful waiting’ approach has many more disadvantages

than initially thought”

Prof. Dr. Peter Stalmans

stresses the importance Large-scale study of treating VMA/VMT Prof. Stalmans carried out a study with a number of his own patients. “Between the completion of the clinical studies on JETREA® in 2010 early and the commercial launch of the product in 2013, I naturally saw a lot of patients with VMT in my practice. I recommended that they should wait until JETREA® was launched. This provided us with a very interesting database of patients with the condition left untreated for Before JETREA® hit the market in 2013, the only way to up to three years. We were able to do this study with 428 patients, treat symptomatic VMA/VMT was surgery. With this new or the equivalent of 556 eyes, since some people had both eyes product, the disease can for the first time be treated in a affected.” more simple way. “But more importantly, we can start treatment much earlier, thanks to JETREA®”, says Prof. The average follow-up period for the examined patients is 1.2 Peter Stalmans of the ophthalmology department at UZ years. The study was the first of this magnitude on this disease. Leuven. He was the first to demonstrate, through his large- “The previous principal publication was a study dating back to scale study, the importance of early treatment. 1996 – an eternity in terms of research – and it only covered a few dozen patients”, explains Prof. Stalmans. “So this research was on a The operation to treat patients with symptomatic VMA or VMT, completely different scale.” The results of that study were surprising, called a vitrectomy, comes with a number of risks and difficulties to say the least. for the patient, like having to stay in the hospital for one or two days and not being able to work for about a week. “That is why, Progressive condition in most cases, doctors waited until the affliction had progressed to “We have shown that VMT only heals spontaneously within one year an advanced stage where the patient’s vision had deteriorated so in 22% of the cases. That is a lot less than the 50% figure retina badly that the operation was then justified: the so-called ‘watchful specialists like myself had in mind. Nor does the disease remain as waiting’ approach”, says Prof. Peter Stalmans, ophthalmologist and stable as previously thought: in the patients studied we observed a vitreoretinal surgeon at UZ Leuven. “Up till now, many specialists significant decrease in eyesight. Moreover, we had to perform surgery believed that VMA/VMT healed spontaneously in 50% of cases, and in 26% of these patients because their situation deteriorated. This that the disease remained stable for a long time if left untreated. I too means VMT is definitely a progressive condition, which only heals was convinced of that.” spontaneously in 1 in 5 cases.” THROMBOGENICS corporate highlights 2013 23

“VMT is definitely a progressive condition, which only heals spontaneously in 1 in 5 cases”

“The results of the study have changed our understanding of the condition. They could create a turnaround in the way VMA/VMT is being treated. I myself was greatly surprised by the results. In the past few months, I have presented our findings to international meetings of retinal surgeons such as Euretina in September 2013, and found the same reaction with my colleagues. Thanks to this research, we’ll also be able to provide better information to our patients on the chances of healing.”

Selection of patients The fact that JETREA® offers the possibility to treat symptomatic VMA/VMT with a simple injection makes it a patient relevant value adding alternative for the classic ‘watchful waiting’ approach. “This allows us to treat patients showing very early symptoms who still have good vision. The research with my patients demonstrates that this approach has a lot of advantages for the patient: not only is the procedure far simpler, it can also provide a better and earlier cure.”

Like his colleagues in the US (see interview with Dr. Peter Kaiser, p.27), Prof. Stalmans emphasizes how important it is to select the right patients for treatment with JETREA®. “In the clinical efficacy study of JETREA®, a very wide inclusion of patients, stages and forms was allowed to determine who benefitted most of the product. There are a number of patient indications and parameters that can be determined through OCT and which indicate if the product will work better or worse. From late June 2013 to early February 2014, I have recommended the product to patients with good indications, resulting in dozens of injections. And even though there are always patients with lesser parameters who also want to try the product, I achieved a success rate of more than 70%. This is much higher than the percentages shown in clinical studies”, says Prof. Stalmans.

Further research into the best patients to be treated with JETREA® will be important to encourage greater use of the product and with even better results in practice, Prof. Stalmans agrees. “Within one or two months, we’ll be starting new studies in collaboration with Alcon, to collect certain new data on subgroups. In the United States, ThromboGenics is conducting similar studies.” 24 jetrea®

Global overview: approval and reimbursement status

Since the product was approved in the US, Europe and Canada, JETREA® has been launched in 13 countries and is reimbursed in 11 countries.

JETREA®: JETREA®: JETREA®: Approved & reimbursed Approved Clinical study started THROMBOGENICSTHROMBOGENICS corcorporateporate hhighighlliightsghts 2013 25

Global overview: approval and reimbursement status

ThromboGenics Dublin (IE)

ThromboGenics Headquarters - Leuven (BE)

ThromboGenics Iselin (USA) 26 jetrea®

JETREA® in the US

ThromboGenics launched JETREA® in the US via its own commercial organization on January 14, 2013. The introduction offers physicians an option to treat patient earlier until the point there is no other active treatment option available than surgery.

A specific disease code (ICD-9-CM) recognizing VMA in the US was added in October 2011. This made it easier to gain reimbursement for JETREA® from US healthcare payers. In January 2014, a permanent J-Code (J7316) for JETREA® became effective, which will lead to automatic reimbursement in the US.

High value healthcare service

A year after the US launch of JETREA® as a treatment option for patients with symptomatic VMA, more and more physicians are convinced that the product provides a valuable clinical alternative to surgery. But JETREA® also holds an important economic value: it can help downsizing the costs of treating VMA, as surgery is more complicated and in many countries even more expensive.

Dr. Wade Aubry is a consultant on market access and reimbursement strategy for several large biotechnology and pharmaceutical companies. He also advised ThromboGenics on the market access strategy for JETREA®, prior to the launch in January 2013. As a former National Medical Advisor for the Blue Cross Blue Shield Association and Senior Advisor for the California Technology Assessment Forum, Dr. Aubry notices that “healthplans are increasingly interested in value, and not only in the clinical value.”

“Simpler preventive approaches are increasingly viewed as having greater value since they prevent costly surgeries, hospitalizations and complications. In the past, US health plans haven’t always made explicit coverage decisions based on the costs, but they are moving in that direction now. There is a lot of interest in trying to incentivize high value services and disincentivize low value services. The latter would be services that maybe treat the same condition, but cost more or have disadvantages compared to their alternatives.” In that view, JETREA® could be perceived as a ‘high value service’ for treating VMA. There is a high likelihood that the product will offset surgery: surgery has a THROMBOGENICS corporate highlights 2013 27

“A good patient selection will dramatically raise the anatomical and functional success rates of JETREA®”

Dr. Peter K. Kaiser believes in the continued rollout of JETREA® in clinical practice in the US

The first reaction of physicians to JETREA® success in their patients with symptomatic Vitreomacular Adhesion (VMA) is vital for the perception of the drug in the ophthalmic medical world. One of these dedicated pioneers in the US is Dr. Peter K. Kaiser, Professor of Ophthalmology of the Cole Eye Institute at the Cleveland Clinic, Ohio. “If ThromboGenics hadn’t pushed JETREA® forward, there would be no other option for VMA patients than to wait or to have surgery, which isn’t without risks”, he says.

Since the launch of JETREA® in the US in the beginning of 2013, more and more physicians are starting to use the product to treat patients with symptomatic VMA. One of the first believers in ThromboGenics’ revolutionary product in the US is Dr. Peter Kaiser, expert on retinal diseases at the Cleveland Clinic. “We have treated about 40 patients since JETREA® became available in the US. Our success rates with those patients are high, so we have a very positive opinion of the drug in our clinic.” 28

The first reactions of US patients treated with the drug are also Cleveland Clinic are already much higher than the 26.5% in the very positive: “One of the first patients I treated with JETREA® JETREA® clinical study. That is because we are very careful to choose was even crying when I saw her a week after the injection because the right patients for the product. We know there are certain she had gotten her vision back”, says Dr. Kaiser. “She was a female baseline features that predict a positive outcome. Treating only these patient who already had serious vision loss in her other eye patients will dramatically increase success rates and convince those because of a macular hole. She was terrified of surgery and had physicians who are still waiting to use JETREA®.” never undergone surgery. In November 2012, before the launch of JETREA®, she started to show symptoms in her good eye too. I Dr. Kaiser stresses the importance of further research into the explained that she would need surgery or would go blind. But the outcomes of treatment with JETREA®. ThromboGenics is currently patient absolutely refused surgery, because she was terrified. Finally, working on building a global patient registry to gather data on the I advised her to wait for the launch of this novel drug. When we saw use of the drug. “In the US, ThromboGenics has a patient registry her again one week after treatment with JETREA® for her follow- study in the works and the company’s partner Alcon recruited up, the OCT showed resolution of the traction and her vision had their first patients in a registry outside the US. The global patient already improved.” registry will definitely help to establish the role of this new drug in actual clinical practice, and as part of a new standard of care for Early treatment of VMA vitreomacular interface diseases.” According to Dr. Kaiser, JETREA® offers the opportunity to treat patients with VMA earlier, which may translate into better visual The Cleveland Clinic, where Dr. Kaiser is staff member, also is outcomes. “Up until now we only had two ways to deal with gathering data on their patients treated with JETREA®. “We are vitreomacular interface disorders. We could either sit there and very involved in doing prospective clinical research and follow-up wait and watch, which really wasn’t all that great for the patient. Or on patients. We keep all the patients treated with the new drug in a we could do surgery, but that is not without its risks. That is why database so we can evaluate the successes and failures. We want to physicians would wait until there were considerable symptoms and know why the drug didn’t work or did work in a given patient, so loss of vision before they would proceed to a vitrectomy surgery. that we can learn and improve our successes in the future. We share Now, with JETREA®, we have the possibility to treat patients earlier”, that information with ThromboGenics. The company has been very he says. “We think treating patients with VMA early is very useful, good at getting actual users of the drug together to talk about best because if you don’t treat it and wait to do surgery, often times the practices.” disease will progress to a macular hole. So in that case the patient would go from having a minor problem to having a major problem.” biography

The ophthalmic medical community is obviously very excited to • Recognized by the American Academy of Ophthalmology and now have a pharmaceutical treatment for vitreomacular interface American Society of Retina Specialists with Achievement and diseases. But there still are retinal physicians who prefer to watchful Senior Achievement Awards, and listed in the ‘Best Doctors in waiting and then do surgery, because they are used to it. “The America’ list. reasoning is that surgery can release the vitreomacular traction in • Staff member of the vitreoretinal faculty of the Cole Eye Institute almost 100% of cases, whereas JETREA® doesn’t show that kind of in the Department of Ophthalmology at the Cleveland Clinic, success rate. Of course, these physicians are not taking into account since 1997. the considerable risks of doing surgery. Not to mention the costs, • Founding Director of the Digital Optical Coherence Tomography downtime, follow-up visits and other difficulties for a patient who (OCT) Reading Center at the Cole Eye Institute, one of the undergoes surgery.” leading OCT reading centers in the world. • Actively involved in retinal clinical research and study chairman New data of numerous, major international clinical trials and principal To further establish the drug as a new treatment option in clinical investigator in multiple other trials. practice, Dr. Kaiser is convinced that the continued investment of ThromboGenics in the educational process on the treatment of symptomatic VMA will pay off. “The key is to get higher success rates than the overall phase 3 trial results. Our results at the THROMBOGENICS corporate highlights 2013 29

higher cost, including hospitalization and several days of downtime from work. “We still need to look further into the offsets on a longer-term basis: the clinical effects and costs”, says Dr. Aubry. “But there is a good argument and good evidence to show that JETREA® works as intended, that it improves health outcomes and that it’s a valuable alternative to surgery. It addresses an unmet need for an effective nonsurgical treatment for VMA and a valuable option for patients, because for a lot of patients surgery is a procedure that they would not prefer to undergo.”

Biography Dr. Wade Aubry Dr. Wade Aubry is a nationally recognized and experienced Medicare and Blue Cross Blue Shield medical director, health care consultant, health policy researcher, and clinician. He has extensive background in technology assessment, Medicare coverage decisions, procedure coding and quality measurement. As Senior Medical Director at Quorum Consulting in San Francisco, he advises biotechnology, pharmaceutical and medical device/diagnostics companies on strategy, product development, clinical research planning, coding, commercialization and reimbursement strategy. “We advised ThromboGenics before the launch of JETREA®. We were involved in reviewing the evidence, advising on appropriate indications, how it might be covered in the health plans, etc. ThromboGenics has done a lot of preparation prior to the launch, which benefited the launch of the product.”

Reimbursement

The permanent J-Code (J7316) for reimbursement, which became effective in January 2014, was an important facilitator for the US physicians, patients and payers. “The J-Code is like a general agreement that this product is a valuable addition to treatment options, and that it is payable”, says Dr. Aubry. “Having a permanent code facilitates billing and reimbursement, which is obviously important for the Company, but also for patients, payers and physicians. The latter can now skip a previously cumbersome administrative process.” The automatic reimbursement process will be an important facilitator for the uptake of JETREA® by physicians in the US. “The J-Code coming out is huge, because that makes the chance of a problem with billing go down dramatically”, says Dr. Peter Kaiser of the Cole Eye Institute in Cleveland (REad the full interview with Dr. Peter Kaiser, p.27). “It will definitely change the selection of treatment options for physicians who were up until now sitting on the sidelines and waiting for new evolutions. No doctor wants to be stuck with the bill for the drug if the insurance company is not going to pay for it. The J-Code will definitely change everything, because the drug will now be reimbursed quicker.” 30 jetrea®

Technology assessments

In terms of coverage decisions, the technology assessment of the Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) on ocriplasmin was of major importance to US payers. The BCBSA TEC Program is an Evidence-Based Practice Center (EPC) of the Agency for Healthcare Research & Quality (AHRQ).

“One of the main reasons is that the TEC assessments are rigorous, based on scientific evidence. The Blue Cross Blue Shield Association performs about 12-15 technology assessments a year, which are made public and published online. Those assessments have an enormous influence on BCBS payers, which make up a huge percentage of the US insured population: approximately one in every three Americans is insured by BCBS. The AHRQ on the other hand is a federal government agency which contracts with its network of EPCs to produce technology assessments and comparative effectiveness reviews. All commercial health plans look at BCBSA TEC assessments and AHRQ- sponsored technology assessments when available. The favorable BCBSA TEC assessment technology on JETREA® had a big influence on coverage decisions of payers”, says Dr. Aubry.

About Blue Cross Blue Shield The Blue Cross and Blue Shield Association is a national federa- tion of 37 independent, community-based and locally operated Blue Cross and Blue Shield health insurance companies. Operating and of- fering healthcare coverage in all 50 states, the District of Columbia and Puerto Rico, the 37 Blue Cross and Blue Shield companies cover over 100 million Americans, which is about one third of the population. Nationwide, more than 96% of hospitals and 92% of professional providerscontract with Blue Cross and Blue Shield companies. “The BCBS Association has a number of initiatives for trying to maintain and improve the quality and reduce the cost of healthcare in the US. The individual plants of BCBS have quality initiatives, they promote evidence-based medicines and cover services based on the scientific evidence that they improve health-out- comes to patients”, says Dr. Wade Aubry, who formerly served as Senior Vice President and Chief Medical Officer for Blue Shield of California, National Medical Advisor and Chairman of the TEC Medical Advisory Panel for BCBSA, and Senior Medical Advisor for the Californian Tech- nology Assessment Forum.

THROMBOGENICS corporate highlights 2013 31

Educational process and patient registries

It is clear that it will take time and continued investment in medical The ORBIT study will recruit education to establish JETREA® as a treatment for patients suffering from the earlier symptoms of symptomatic VMA/VMT. To achieve this goal, the ThromboGenics team will develop programs with retina physicians on the importance of recognizing metamorphopsia (distorted vision) – a point at which early treatment has real preventive benefits for patients. Pro- 1,500 active treatment with is designed to stop patients’ deterioration in visual patients with symptomatic VMA patients across acuity, which is often occurring during the period of watchful waiting. Early treatment could stop the progression of the disease altogether, and therefore offer important benefits to a patient’s quality of life.

Appropriate patient selection is, in any phase (mild – moderate – severe), 120 retina centers in the US critical to achieving the best results with JETREA®. Experience has shown that physicians’ success rates with this innovative new product improve as they treat more patients. In order to help retina physicians best define the most suitable patients for this treatment, we are encouraging more peer-to-peer communications about their experiences.

ThromboGenics has initiated a registry of all patients treated with JETREA® in the US. The registry will provide data on the status of the patient’s condition at the time they received the treatment and its outcome. The study is called the Ocriplasmin Research to Better Inform Treatment (ORBIT). It will recruit 1,500 patients with symptomatic VMA patients across 120 retina centers in the US. The ORBIT study assesses clinical outcomes and safety of JETREA® administered in a real-world setting for the treatment of symptomatic VMA by assessing both anatomical and functional outcomes. 32 jetrea®

JETREA® in Europe

In Europe, JETREA® received approval by the European Medicines Agency (EMA) in March 2013. The product was approved for all patients in the European Union for the treatment of Vitreomacular Traction (VMT), including when associated with a macular hole of diameter less than or equal to 400 microns. ThromboGenics and Alcon estimate that 250,000 to 300,000 patients in Europe alone suffer from this condition. Following the approval in the European Union, ThromboGenics received a €45 million milestone payment from its partner Alcon.

The product has since then been launched in several countries in the EU: the United Kingdom, Germany, Finland, Denmark, Norway, Sweden, France, Ireland and the Benelux. Following the launch, healthcare authorities in the UK, Germany and recently France confirmed that JETREA® demonstrates significant therapeutic benefits, especially for patients suffering from mild and moderate symptoms of VMT. They also highlight the benefits of treating VMT with JETREA® at an early stage. This positive guidance in several European countries will lead to its reimbursement for several patient types.

The United Kingdom

In April 2013, JETREA® was launched in the UK, its first market in Europe. The first sale by Alcon triggered a €45 million milestone payment to ThromboGenics.

The launch was followed by a single technology appraisal (STA) by the National Institute for Health and Care Excellence as part of the process to gain reimbursement when used by the UK National Health Service (NHS). The appraisal committee considers evidence submitted by the manufacturer and makes a judgment on whether or not the technology should be recommended as a clinically and cost-effective use of NHS resources, or whether it should only be recommended for specific subgroups of patients. This process also takes into account testimony from clinical experts, patient groups and physicians. THROMBOGENICS corporate highlights 2013 33

“Not having to undergo surgery makes a huge difference for VMT patients”

Clara Eaglen of the Royal National Institute of Blind People stresses the impact of JETREA® on patients’ lives

The Royal National Institute of Blind People (RNIB), the leading charity for people with sight loss in the UK, asked several patients with symptomatic VMT and/or macular hole how their disease was treated before JETREA® was launched and what the impact was on their lives. “They all agreed that the worst parts of their treatment were the ‘watch and wait’ procedure and having to posture for several days after a vitrectomy”, says Clara Eaglen, Policy and Campaigns manager at the RNIB. “JETREA® can resolve both those issues.”

For a selection of approved new medicines by the EMA, the National Institute for Health and Care Excellence (NICE) in the United Kingdom investigates the cost-effectiveness of the product and whether it can be used and reimbursed in the National Health Service of England and Wales. “In the appraisal process of new treatments, NICE seeks opinions from clinicians, health economists and patients. With the RNIB, we make sure that NICE understands the importance of certain new drugs for those patients”, clarifies Clara Eaglen. “It is crucial that patients’ voices are heard during 34

the appraisal process: in many cases they have no treatment for riskier than an injection, and avoiding the need to posture were two their condition, or are confronted with new treatments that imply main advantages we spoke of in our reports”, confirms Clara Eaglen. massive changes for them. That is why it is really important to “But we also see other advantages to JETREA®: the fact that a patient show what the new drug really means to the patient and what the can be treated as a day case with a one-off injection means that there emotional impact is. Sometimes patients’ testimonials can really is minimum disruption to the patient’s life. It is also possible to try sway the decisions of NICE.” the intravitreal injection with ocriplasmin first and keep surgery as a second, more drastic option. Most patients we spoke with had Surgery and posturing noticeably better vision within three months after treatment with “For JETREA® we really wanted to show the negative emotional JETREA®. Finally, knowing there is a well-established technique in place impact of the existing treatment on the patients’ lives: the fact that really encouraged patients.” In its final guidance, IN CE recommended most of them had to wait to see the disease progress and then reimbursement of JETREA® for the treatment of a broad range of undergo surgery”, explains Clara Eaglen. The RNIB spoke to several VMT patients, from early stage to later stage, or with a full thickness patients with symptomatic VMT and/or macular hole on how their macular hole. The institute also recommended the reimbursement disease was treated and what the impact was on their life. “One of JETREA® to treat patients with early symptoms of VMT such as elderly female patient spoke about the surgery she had and the metamorphopsia. The guidance also allows the clinicians to be posturing she had to do afterwards. For her, having to lie down for innovative in the way they treat the patient. Because ocriplasmin can five days was incredibly traumatic: it gave her massive back ache and be administered at any moment, from diagnosis to vitrectomy, the had a big impact on her husband, who had to care for her the entire clinician can discuss with the patient the optimal time to perform week. It was a very traumatic time for her and many other problems the injection. “The final guidance was published in October 2013, so were accumulating because of the posturing she had to do. For by January 2014 it should be adopted by the NHS and the product several other patients, the surgery and posturing were described as should be available to everybody. As with every new treatment, RNIB the worst parts of their treatment. They all agreed that they would contacts commissioners and hospital trusts across the country to much rather prefer a simple injection.” seek evidence that the product is funded and available to all. If any problems are encountered, RNIB will send a representative to the Watch and wait commissioning group or hospital trust to secure a solution which will In the patients’ testimonials to the RNIB, another big issue was the ensure patients can access the new treatment”, says Clara Eaglen. ‘watch and wait’ procedure. Because a vitrectomy is not without any risks, most physicians prefer to wait to do surgery until the patient About the RNIB was at a more advanced stage of the disease, whilst having to endure distressing symptoms. “All the patients we spoke with agreed that The Royal National Institute of Blind People (RNIB) is the leading they had a lot of anxiety, not knowing what was going to happen to UK charity offering information, support and advice to almost them. They really didn’t like the thought of just being left to see what two million people with sight loss. The RNIB is a membership would happen to their eye condition. Most patients obviously like to organization with over 10,000 members who are blind, partially know which disease they’ve got, how to resolve it and when that’s sighted or who are the friends and family of people with sight loss. going to take place. It worries VMT patients every single day that their The main activities include: vision is getting worse: the longer it takes, the more anxious they • Campaigning to ensure proven treatments for sight-threatening get because they are constantly aware of a sight loss problem. With conditions are available on the NHS. JETREA®, most treated patients know in about seven days whether • Offering emotional and practical support, products to make life the treatment has worked and that means a lot to them”, says Clara easier, and advice about money, eye health and local services. Eaglen. • Improving educational opportunities for blind and partially sighted children and adults, including those with complex needs. Advantages • Enabling people with sight loss to retain and gain jobs. In their reports to the NICE appraisal committee for JETREA®, the • Working with transport operators, retailers and banks to enable RNIB stressed the fact that JETREA® could offer an alternative to more people with sight loss to travel, shop and run their own ‘watch and wait’ followed by a vitrectomy in some patients, and also finances. the fact that the product offers a solution for earlier treatment of • Influencing partners across the world to make computers, symptomatic VMT. “Avoiding the need for vitrectomy, which is much television, mobile phones and satellite navigation systems easier. THROMBOGENICS corporate highlights 2013 35

In October 2013, the final guidance of NICE recommended that JETREA® should be reimbursed within the NHS in England and Wales. In this guidance, NICE recommends reimbursement for treatment of a broad range of VMT patients, from early-stage to late-stage. Patients with epiretinal membranes (ERMs) are excluded. It also recommended reimbursement of JETREA® for patients suffering from VMT with macular hole of diameter less than or equal to 400 microns. A further important element of the guidance was its view that JETREA® should be reimbursed for the treatment of patients with metamorphopsia (blurred vision), since the impact of metamorphopsia on a patient is considered equal to the loss of 2 lines in visual acuity.

Following this final guidance, JETREA® is now reimbursed in the UK. The Department of Health allows NHS organizations up to three months to put in place the systems needed to reimburse recommended treatments from the date the final guidance is issued.

Germany

In May 2013, JETREA® became available in Germany’s private and public market. After the launch, the German Institute for Quality and Efficiency in Health Care (IQWiG) confirmed that JETREA® demonstrates major added The mild to moderate VMT population, as referred to by G-BA in its final assessment, value in VMT patients with mild and moderately severe symptoms compared represents with existing comparative treatment. IQWiG is an independent federal organization that evaluates a drug’s quality and efficiency, which makes a recommendation to the German Federal Joint Committee (G-BA).

The Federal Joint Committee (G-BA) followed this recommendation in its % final Early Benefit Assessment in October 2013 in which G-BA confirmed that JETREA® generates considerable patient-relevant benefits. The mild to 94of the total patient population covered by the approved label. moderate VMT population, as referred to by G-BA in its final assessment, represents the vast majority (94%) of the total patient population covered by the approved label. G-BA is the highest decision-making body of the joint self- government of physicians, dentists, hospitals and health insurance funds in Germany. Since the introduction of the early benefit assessment procedure in Germany in January 2011, G-BA has assessed more than sixty innovative new drugs. JETREA® is to date one of only six innovative medicines appraised by G-BA to provide sustained and large improvements in the therapy benefits for patients. In its assessment, G-BA particularly considered the potential improvement in visual acuity and the avoidance of surgery in the back of the eye as beneficial for patients.

Based on G-BA’s positive assessment, Alcon is currently negotiating the future German reimbursement price for JETREA® which will become effective as of May 01st, 2014. 36 jetrea®

Nordic countries

Following the introduction of JETREA® in Germany, Alcon launched the product in Denmark and Sweden by the end of May 2013, followed soon after by Finland and Norway.

France

The Transparency Commission (‘Commission de la Transparence’ or CT) of the French National Health Authority (‘Haute Autorité de Santé’ or HAS) issued a positive opinion for the reimbursement and hospital listing of % JETREA® by the French National Health Insurance in January 2014. The CT recommends JETREA® for the treatment of adult patients with VMT, 85of the European patient population covered by including when associated with macular hole of diameter less than or equal the approved label from EMA have symptoms that don’t require a vitrectomy to 400 microns, for whom symptoms do not require immediately a vitrectomy at the earlier stage of this disease. Those patients represent the vast majority (85%) of the total patient population covered by the approved label from EMA in March 2013.

The CT assessment recognizes the medical benefit (‘Service Médical Rendu’ or SMR) of JETREA®, indicating that the product is eligible for reimbursement in France. The assessment underlines the absence of clinically relevant alternatives to JETREA® in the proposed reimbursed indication. The CT assessment further highlights the importance of treating VMT early, starting from the diagnosis or when the patient first experiences metamorphopsia or other symptoms.

Pricing and reimbursement negotiations will now begin with the Economic Committee of Healthcare Products (‘Comité Economique des Produits de Santé’ or CEPS) in France.

Belgium

In Belgium, JETREA® is available since June 2013. Professor Dr. Peter Stalmans, who was also involved in the clinical study of JETREA®, is one of the first surgeons to use the product to treat his patients in the University Hospitals in Leuven (read the full interview with Prof. dr. Stalmans, p.22). “We still have to wait until the RIZIV decides to reimburse JETREA® in Belgium. However, since the launch I’ve treated already several dozen patients. As soon as the product is agreed for reimbursement, it will be used even more.” THROMBOGENICS corporate highlights 2013 37

JETREA® in the rest of the world

Canada

Canada was the first market outside the US and Europe where JETREA® ThromboGenics and Alcon estimate that was approved. Health Canada approved the drug for the treatment of up to symptomatic VMA in August 2013 and Alcon launched the product in November 2013. Canada was also the first market outside the US and Europe where the product was launched. ThromboGenics and Alcon estimate that up to 15,000 people each year are affected by symptomatic VMA in Canada. 15,000 people each year are affected by symptomatic VMA in Canada. In December 2013, JETREA® received a positive Common Drug Review (CDR), which is carried out by the Canadian Agency for Drugs and Technologies in Health (CADTH). This is a pan-Canadian process for drugs conducting objective, rigorous reviews of the clinical and patient evidence, and also cost-effectiveness. CDR provides a formulary listing recommendations to Canada’s publicly funded drug plans (except Quebec). To date, only 30% of all first-in-class products have received a positive CDR listing recommendation. To date, only JETREA® is already covered by most of the major private payers in Canada.

Japan %

In Japan, Alcon has started its first clinical study with JETREA® outside the US 30of all first-in-class products has received a positive CDR listing recommendation and Europe. This clinical bridging study is recruiting a total of 168 patients with symptomatic VMA, including those associated with macular hole. It is a randomized, double blind, multicenter study with patients receiving either ocriplasmin or a sham injection. The study is due to complete in 2014. The results from the study are expected to form part of the regulatory submission that will be made to the Japanese Ministry of Health, Labour and Welfare to gain approval to market ocriplasmin in Japan. 38

III

Research and development THROMBOGENICS corporate highlights 2013 39

Beyond JETREA®

Ongoing dedication to developing and commercializing new pharmacologic treatments that address important unmet clinical needs in ophthalmology and oncology.

Milestone: Commercialized: US (directly)/ ex-US with Alcon

Go

Clinical Phase III

Milestone: Prevention of progression Clinical to proliferative DR (< 2014) Phase II

Milestone: Evaluations Clinical Milestone: Milestone: planned in oncology Phase I Pre-clinical Pre-clinical

POC

JETREA® JETREA® Bicycle Eleven TB-403 (ocriplasmin) (ocriplasmin) Therapeutics Therapeutics (anti-PIGF) - - - - - Symptomatic Diabetic Eye Diabetic Eye Diabetic Eye Oncology VMA/VMT Disease Disease Disease 40 Research and development

Diabetic eye diseases: fighting a worldwide problem

As a worldwide leader in ophthalmology, ThromboGenics continuously researches drugs that address unmet medical needs. In that field, the Company explicitly focuses on the prevention and treatment of diabetic eye diseases such as Proliferative Diabetic Retinopathy (PDR) and Diabetic Macular Edema (DME). Those diseases have a very direct impact on the + % patient’s quality of life. “Type II diabetic patients often develop DME: the retina thickens causing vitreous traction with central vision loss. Type I patients often develop an abnormal growth of blood vessels. That can lead 50of the population in the Middle East develops diabetes to PDR, resulting in bleeding inside the eye or even detachment of the retina. If this is not treated correctly, it can ultimately lead to blindness”, explains Professor Dr. Marc D. de Smet of the university of Amsterdam.

According to the Professor, ThromboGenics has significant potential in fighting diabetic eye diseases: “Diabetes is a worldwide problem of pandemic proportions and some eye diseases are directly related to it. ThromboGenics can play an important role in the prevention and early treatment of those complications.”

Globally, 350 million people are estimated to suffer from diabetes (World Health Organization). As it is a growing problem worldwide, several markets could be targeted. “In the Middle East, for example, more than 50% of the population develops diabetes. In certain parts of Africa, this number is 30% and increasing. Because of the growing problem with obesity in the United States, many Americans develop diabetes too. Depending on the health care system and how much the government spends on awareness and prevention, these diabetics are often unaware of the risks of related eye diseases or do not have access to care. If diabetes is managed correctly from the beginning, the development of eye diseases can be avoided, which is one of the reasons why Courtesy of FIT in many European countries, the number of people with diabetic eye disease is lower”, says Prof. de Smet.

Diabetic Macular Edema: research on new treatment options

An estimated 30% of all patients suffering from diabetes for over 20 years are at risk of developing Diabetic Macular Edema (DME). As for the treatment of DME, the most common option is currently to use laser therapy, steroids, anti-VEGF therapy or a combination of those. “A drug is injected inside the eye to try and limit the amount of fluid that accumulates inside THROMBOGENICS corporate highlights 2013 41

“ThromboGenics can have a major impact on the lives of diabetes patients”

Professor Dr. Marc D. de Smet on JETREA®’s next target indication

One of the major future challenges for the medical world will be the growing number of people with obesity worldwide. As a consequence, more and more people are suffering from diabetes. “It is a growing problem, which has in fact already reached pandemic proportions”, confirms Dr. Marc de Smet, Professor of ophthalmology at the University of Amsterdam, who also heads MIOS S.A., a specialised eye clinic in Lausanne, Switzerland. He is a specialist in medical and surgical eye care, with a strong focus on retinal diseases. “As more and more people suffer from diabetes worldwide, the number of people with eye diseases such as Proliferative Diabetic Retinopathy (PDR) will also rise”, he states.

Prevention of PDR With the prevention of PDR expected to be the next JETREA® target indication, ThromboGenics could play a huge role in the prevention and early treatment of this eye disease. Currently, there is no approved drug available. “Once a patient has developed a diabetic eye disease, it means that he or she has had untreated or poorly treated diabetes for many years. It is very important to correctly and aggressively treat diabetes from early on: once you have PDR, there is currently no treatment to reverse the symptoms, only surgery can help. However, surgery is very complex and can only be executed by

Courtesy of FIT 42

a qualified retinal surgeon. A drug that would allow patients to avoid “Companies like ThromboGenics such surgery would have an enormous impact.” are very important for the “JETREA® has that potential”, states Prof. de Smet. “The use of medical world. In the United JETREA® in the prevention of PDR could offer a simpler and early- stage therapeutic solution. ThromboGenics’ research on new States, as well as elsewhere, indications for JETREA® is already at an advanced stage: clinical studies could start, in order to prove that the product can be used funding for research in to prevent the development of certain membranes causing blindness. biopharma and ophthalmology The key is to notice if somebody is at risk as early as possible and try to prevent the disease from progressing and causing loss of vision. is decreasing. That is why If ThromboGenics can prove that JETREA® is able to prevent the progression to PDR, this would have a major impact on improving partnerships between the health of diabetes patients.” researchers, universities and

Target markets companies like ThromboGenics “The United States is an interesting market to target with the will be extremely important possible next indication of JETREA®. Their healthcare system is more complex and there are many diabetic patients with Proliferative for our future health” Diabetic Retinopathy (PDR). JETREA® is already in use for the treatment of Symptomatic VMA in the United States, which makes this a win-win situation for a company like ThromboGenics: they can both extend the action of their current drug and study a second Professor Dr. Marc D. de Smet patient population using the same type of physician. Of course the developing world would benefit enormously as well from a quicker, cheaper and easier treatment and prevention of PDR, instead of trying to find enough highly trained physicians to treat the disease in its severe stages.”

Biography

• Specialist in medical and surgical eye care, with particular emphasis on retinal diseases and ocular inflammation. • More than 20 years of experience in the field. • Chairman of the department of Ophthalmology at the University of Amsterdam. • Authored or co-authored 20 book chapters and over 150 articles in peer-reviewed journals. • Involved in the field of pharmacologic vitreolysis for more than 10 years. • Consultant to the pharmaceutical industry, advises ThromboGenics. THROMBOGENICS corporate highlights 2013 43

the retina. The problem is that these treatments often have to be repeated several times, several times a year. Some patients have to keep using the anti-VEGF injections for the rest of their lives, and unfortunately there are some indications that this prolonged use might cause other complications”, says Prof. de Smet. ThromboGenics also started research on new treatment options for patients with DME. “The research is still in an early stage, but the An estimated strategy for ThromboGenics in this area is to research new drugs that can work better or faster, or require fewer injections than what is currently being done”, according to Prof. de Smet. The commitment regarding DME is highlighted by two partnerships. ThromboGenics entered into a collaboration and license % agreement with Bicycle Therapeutics, to develop and commercialize novel drugs inhibiting a specific target for the treatment of DME. ThromboGenics 30of all patients suffering from diabetes for intends to develop therapeutics based on Bicycle’s bicyclic peptides. These over 20 years are at risk of developing DME. can inhibit a target involved in vascular permeability. A selective inhibition of this target would offer a new approach with the potential to improve the treatment of DME. ThromboGenics and Bicycle will collaborate on the preclinical development of these inhibitors. ThromboGenics has gained an exclusive license from Bicycle Therapeutics to undertake clinical development and commercialization of identified drug candidates.

About Bicycle Therapeutics Bicycle Therapeutics has developed a proprietary bicyclic peptide based technology that enables the discovery of a new class of drug candidates (‘bicycles’) providing antibody-like affinity and selectivity in a much smaller chemically synthesized molecule. Bicycle peptides are short peptide sequences constrained by a chemical scaffold core to form a structure with two loops of amino acids. This structure offers high stability and a high affinity binding to targets. The company is applying the technology to drug discovery projects in areas including oncology and ophthalmology and additional therapeutic areas through selected collaborative discovery partnerships with pharma companies. Bicycle’s technology is based on the work performed at the MRC Laboratory of Molecular Biology in Cambridge by the scientific founders of the company, Prof. Christian Heinis and Sir Gregory Winter. The company is funded by Atlas Venture, Novartis Venture Fund, SVLS, SR One and Astellas Venture Management. For more information visit www.bicycletherapeutics.com.

In May 2013, ThromboGenics also announced it would use Eleven Biotherapeutics’ own AMP-Rx protein design technology to create a new therapeutic with improved pharmaceutical and therapeutic benefits. ThromboGenics will have the exclusive license to all future developments and the commercialization of this novel protein. In exchange, Eleven Biotherapeutics will receive an undisclosed upfront payment and is eligible to receive undisclosed payments for development, regulatory and sales milestones as well as royalties on potential future sales commensurate with industry standards. 44 Research and development

Courtesy of FIT About Eleven Biotherapeutics Eleven Biotherapeutics creates novel and differentiated biotherapeutics: first-of-a-kind protein-based drugs with significantly improved physical, pharmaceutical, and therapeutic benefits. The company’s AMP-Rx™ product engine brings capabilities beyond conventional approaches for making protein therapeutics, opening up new territory for the products to have novel structures, enhanced biophysical properties, and more effective targeting in disease pathways. Eleven’s success is built on designing proteins ‘fit for purpose’ that are rationally designed to have ideal therapeutic characteristics and result in best-in-class biotherapeutic products for a wide range of diseases. The Cambridge, Massachusetts- based company was founded in 2010 by life science investors Flagship Ventures and Third Rock Ventures and world-renowned scientific experts. For more information, visit www.elevenbio.com.

Oncology: new findings show promise for treating children’s brain tumor

In February 2013, ThromboGenics and co-development partner BioInvent International AB had a paper published in the prestigious journal ‘Cell’. The paper highlighted the potential of TB-403 to improve the treatment of medulloblastoma, the most common brain tumor in children. The publication highlights for the first time a new mechanism of action, showing that placental growth factor (PlGF) plays a vital role in the brain and that its expression is required for the growth and spread of medulloblastoma. This paper is reporting the findings of new pre-clinical research performed at the Massachusetts General Hospital in Harvard (Boston), in collaboration with the team of Prof. Peter Carmeliet. The novel positive findings in this paper provide evidence that could warrant further development of TB-403 as one of the first targeted therapies to treat this childhood cancer. TB-403 is a monoclonal antibody against PlGF, a naturally occurring protein that belongs to the family of vascular endothelial growth factors (VEGF) which promote the formation of blood vessels. TB-403 was in-licensed by ThromboGenics from the Flanders Institute for Biotechnology (VIB), where the therapeutic potential of anti-PlGF agents to treat cancer was first developed by Prof. Peter Carmeliet at the University of Leuven, Belgium.

About BioInvent BioInvent International AB, listed on the NASDAQ OMX Stockholm (BINV), is a research-based pharmaceutical company focused on discov- ery and development of innovative antibody-based drugs against cancer. The company’s pipeline currently includes three product candidates for the treatment of cancer. THROMBOGENICS corporate highlights 2013 45

The molecule TB-403 has the potential to be developed as one of the first targeted therapies to treat medulloblastoma.

Courtesy of FIT 46

“Promising new data on treating children’s brain tumor”

Prof. Dr. Koen Kas elaborates on novel findings in ThromboGenics’ oncology research

Courtesy of FIT THROMBOGENICS corporate highlights 2013 47

In oncology, ThromboGenics is investigating the potential Clinical study in preparation of the antibody TB-403 to improve the treatment of During the past year, ThromboGenics has set the ambition to do medulloblastoma, a brain tumor in children. “Currently, all the preparatory work in 2014 for a clinical study of anti-PlGF in there is no treatment for this form of children’s cancer”, medulloblastoma. The further investigation of those initial positive states Prof. Dr. Koen Kas, Chief Scientific Officer Oncology findings will be followed up by a spin-off initiative in the making. “We at ThromboGenics. will try to explore whether anti-PlGF can serve as a treatment for any other tumors that occur in children as well”, says Prof. Kas. “However, ThromboGenics’ oncology story initially started in the labs of we remain very cautious and do not want to give false hope. We Professor Peter Carmeliet at the Flemish institute of biotechnology are currently focusing on defining so-called ‘biomarkers’, which are VIB. “In those labs Professor Peter Carmeliet discovered the certain substances in the body of a patient that can give an indication completely new PlGF (Placental Growth Factor) molecule, which if the antibody will work or not. It will be very important to select in plays an important part in the development of blood vessels”, Prof. advance the patients for whom a candidate drug could be useful. This Kas clarifies. applies to all new treatments that are currently being investigated.”

ThromboGenics acquired the rights to this molecule in 2004. “PlGF A second oncology program on which ThromboGenics focused initiates a mechanism inside a tumor that allows it to signal its in 2013, investigates an antibody against a specific molecule that environment to keep blood vessels growing towards the tumor so is being secreted by tumor cells. “It concerns anti-PDGF (Platelet it can keep expanding. Together with our Swedish co-development Derived Growth Factor), a new antibody we have patented. Today, partner BioInvent, ThromboGenics developed antibodies in the past we are making selections within the pre-clinical group to detect few years that block the functioning of PlGF.” (For more on this, read: what would be the most appropriate tumor indication to treat with ‘New findings show promise for treating children’s brain tumor’, p.44). this antibody”, says Koen Kas.

Tumors in children “In the meantime, it has been shown that PlGF is also involved in Biography another tumor-formation mechanism, namely how tumor cells can stay in a sort of survival mode. This mechanism was shown at the • Chief Scientific Officer of Oncology at ThromboGenics NV. University of Harvard for medulloblastoma, a specific and rare type • Prof. Kas founded Pronota NV in 2004 and served as its Chief of brain cancer in children. ThromboGenics was able to confirm Science Officer. Koen Kas served as Director of Drug Discovery their research data in two independent studies”, says Prof. Kas. at the Belgian-Dutch functional genomics company Galapagos These data were published in the prestigious journal ‘Cell’. Genomics. He set up and headed the cancer drug discovery program at Tibotec. He served as Director of Pronota NV. “The publication highlights for the first time that the antibody • He is a guest professor at the University of Ghent, Belgium. He previously developed for PlGF has in fact the potential to be a has been professor at the University of Leuven and lecturer at future cure for a rare form of childhood cancer for which there is Harvard University, Boston, USA since 1999. no treatment today. 60 to 70% of children with medulloblastoma • Prof. Kas held postdoctoral research at a number of prestigious are able to survive, thanks to irradiation and a surgical brain institutes. He received his PhD degree in Biomedical Sciences intervention, but not with the same quality of life. For 30 to 40% of from the University of Antwerp, where he also obtained a degree these children there are no chances of survival.” in Business Administration. 48 Our organization

IV

Our organization THROMBOGENICS corporate highlights 2013 49

People behind the success of ThromboGenics

IV Our people ThromboGenics employees come from a wide variety of backgrounds. Despite working in different positions, everyone at the Company is striving towards the same goal: making ThromboGenics a global leader in providing cutting-edge medicines for the treatment of important eye diseases.

The Company’s success to date has been due to its ability to react quickly to the challenges and also the opportunities affecting its business. All staff members are driven by the feeling that their work is connected to the corporate Our strategy and that their contribution can make a real impact. As a result, the Company ensures that all employees have the resources and support they require to remain engaged and succeed in their roles. Most members of this international team hold a Masters or PhD degree. ThromboGenics values organization diversity and is committed to providing equal employment opportunities for all its employees.

ThromboGenics has grown considerably since it relocated from university labs to the BioIncubator Park in Leuven, Belgium in 2009. The Company’s global headcount grew to close to 200 (including third party partners) by the end of 2013. The team is equally distributed between the Leuven headquarters and the New Jersey office, whereas the number of home-based employees in Europe has slightly increased. ThromboGenics intends to continue strengthening the team with the right people having the right attitude and mix of skills, as this is fundamental to the Company achieving its strategic goals. 50 Our organization

Board of Directors

Diversity and accomplishment are the hallmarks of ThromboGenics’ Board of Directors. In choosing Board members for ThromboGenics, we have invited people who are able to make active contributions to the direction of our Company as we embark on the commercialization of promising therapies in several areas. The ThromboGenics Board of Directors influences our Company’s daily activities with broad views on the life sciences, informed by years of experience in a wide range of disciplines.

Recently, ThromboGenics appointed Dr. David Guyer to its Board of Directors. He has decades of success in the ophthalmology space, in both drug development and commercialization, particularly in the US, which will be extremely valuable to ThromboGenics.

Dr. Staf Van Reet – Chairman Dr. Staf Van Reet was formerly Managing Director of Janssen Pharmaceutica NV, Head of R&D of the Janssen Group and a member of the Group Operating Committee of the pharmaceutical sector of Johnson & Johnson. From 2000 to 2004, he was Vice President of the J&J Development Corporation, J&J’s venture arm. He was co-founder of Movetis NV and Chairman of its Board of Directors until November 2010, when the Company was acquired by Shire sarl. Currently, Dr. Van Reet is Chairman of the Board of Directors of Actogenix NV and a director of Biocartis S.A., Therasolve NV and VIB (the Flemish Institute of Biotechnology). He holds a Masters and PhD degree in Bio-engineering Sciences from the University of Leuven (Belgium) and studied law at the University of Antwerp (Belgium). He is a qualified Belgian and European Patent Agent. THROMBOGENICS corporate highlights 2013 51

Dr. Patrik De Haes – Chief Executive Officer Dr. Patrik De Haes has over 25 years of experience in the global healthcare industry, covering product development, marketing and general management. Before joining ThromboGenics as CEO in 2008, he was Head of Roche’s Global Insulin Infusion business. Prior to this, he was President and CEO of Disetronic Medical Systems Inc., a medical device company based in Minneapolis, USA. He also led the global development and commercialization of the first biotech product at Sandoz Pharma (now Novartis) in Switzerland. Dr. De Haes holds a degree in Medicine from the University of Leuven. He was also elected as Chairman of FlandersBio as of May 2012.

Chris Buyse – Chief Financial Officer Chris Buyse has more than 20 years’ experience in international company finance, including establishing and running best financial practices. Before ThromboGenics, as CFO of the Belgian biotechnology company CropDesign, he coordinated its acquisition by BASF in early 2007. Chris Buyse has also been Finance Director of WorldCom/MCI Belux, a European subsidiary of one of the world’s largest telecom companies, and CFO and interim CEO of Keyware Technologies. He has held financial positions at Spector Photo Group, Suez Lyonnaise des Eaux and Unilever. Chris holds a Master Degree in Economics from the University of Antwerp and an MBA from the Vlerick School in Ghent. In 2012, Chris Buyse was named CFO of the year by Trends Business Magazine.

Luc Philips Luc Philips (Lugost BVBA) holds a degree in commercial and financial sciences. He was CFO of the KBC Group until April 2011. He has held senior management and board positions at KBC Group, KBC Verzekeringen and KBC Bank, and was Managing Director of Almanij. Luc Philips is non-executive director of KBL European Private Bankers, serves as independent Director and Chairman of Whitewood Capital REIM and is an independent Director of PMV Infrastructure Fund. He also serves on the Board of Directors of W&K, the University College for Science and Arts, associated with the University of Leuven.

Thomas Clay Thomas Clay is Vice-President of East Hill Management Company, LLC. He also serves as a Director of The Clay Mathematics Institute, Inc. and of Golden Queen Mining Co. Ltd. Thomas is a graduate, magna cum laude, of Harvard College and of Oxford University.

Jean-Luc Dehaene Jean-Luc Dehaene has held several ministerial posts. He was Prime Minister of Belgium from 1992 to 1999. He has been chairman of Dexia NV since 2008 and is a Member of the European Parliament. Jean-Luc Dehaene studied law and economic sciences in Namur and Leuven, Belgium. 52 Our organization

Patricia Ceysens Patricia Ceysens is a member of the Flemish Parliament. Since June 2009, she is President of the Commission Economy, Innovation, Science Policy, Employment and Social Economy in the Flemish Parliament. In April 2011, she founded the start-up WeWatt. She has held high-level ministerial positions including Minister of Economy, Foreign Affairs and E-government (June 2003-2007) and Flemish Minister of Economy, Enterprise, Science, Innovation and Foreign Trade (October 2007-June 2009). Patricia graduated from law school at KU Leuven. She also obtained a degree in marketing management from CMO (now Syntra). She has been a barrister since 1988 and specialized in intellectual property rights.

Dr. David Guyer Dr. Guyer is a long standing member of the US retina community and is currently the Co-Founder and Chief Executive Officer of Ophthotech Corporation and also serves as Chairman of its board of directors. Ophthotech Corporation is a public biopharmaceutical company focusing on discovering, developing and commercializing first-in-class therapies for the treatment of major ophthalmic diseases. Dr. Guyer is also on the Boards of Allocure and Panoptica. He co-founded and served as CEO and a Director of Eyetech Pharmaceuticals, Inc. – part of OSI Pharmaceuticals since 2005 –, where he led the company through private, public and corporate financings, and oversaw the rapid development and successful commercialization of Macugen®.

Dr. Guyer has also had a successful career in academic medicine as Professor and Chairman of the Department of Ophthalmology at New York University School of Medicine. He received his Bachelor of Science (B.S.) degree from Yale College summa cum laude and his medical degree (M.D.) from Johns Hopkins Medical School. He completed his ophthalmology residency at Wilmer Ophthalmological Institute at Johns Hopkins Hospital and a retinal fellowship at the Massachusetts Eye and Ear Infirmary at Harvard Medical School. THROMBOGENICS corporate highlights 2013 53

“ThromboGenics has made significant progress in recent years, leading to the introduction of JETREA® in the US early in 2013. I am happy to be joining the board of this dynamic company as it works to create a new treatment paradigm for VMA patients.”

Dr. David Guyer 54 Our organization THROMBOGENICS corporate highlights 2013 55

Board Committees

The Board of Directors has established an Audit Committee and a combined Nomination and Remuneration Committee. The Board of Directors appoints the members and the chairman of each committee, which consists of at least 3 members. Since 2012 the composition of the committees has been as follows:

Audit Committee Luc Philips, chairman; Staf Van Reet; Thomas Clay and Jean-Luc Dehaene.

Nomination and Remuneration Committee Staf Van Reet, chairman; Jean-Luc Dehaene and Patricia Ceysens.

Extended executive team

The primary strength of our ThromboGenics Extended Executive Team is that it combines the weight of Big Pharma experience with the agility of New Pharma decision making and action. Successfully launching new products requires a special skill set, which many of our team members have acquired earlier in their careers.

Our leadership team has respectable backgrounds in research, clinical development, commercialization, and financing that pave the way to long-term success. Our current management also serves as our Extended Executive Committee, which is responsible for the Company’s vision and strategy. Our Extended Executive Committee meets regularly to plan and oversee the implementation of ThromboGenics’ policies.

The members of the extended executive team are: Chris Buyse*, Lene-Rose Arfelt, Wouter Piepers, Ove Pedersen, Laurence Raemdonck*, David Pearson*, Patrik De Haes*, Koen Kas, Andy De Deene*, Chris Jaeggi, Keith Steward*, Paul De Nijs*, Aniz Girach*, Rosemarie Corrigan, Claude Sander.

* Members of the executive team 56 Our organization

V

Shareholder information THROMBOGENICS corporate highlights 2013 57

Key investor information

Listing

ThromboGenics’ shares are listed on the Eurolist by NYSE Euronext Brussels under the symbol THR. Since 2009, ThromboGenics has been included in the V NEXT 150 Index, which comprises mid- to large-capitalization stocks on the Euronext exchange. As of 24 December 2012, ThromboGenics’ shares became part of the STOXX Europe 600 Index. This index represents large, mid and small capitalization companies across 18 countries in Europe.

Investor relations

Shareholder Our investor relations policies include: • Providing reliable, accurate, and valuable information in a timely manner to help shareholders make informed decisions • Providing full transparency information • Operating within the Company’s policies and adhering to the relevant security laws and regulations • Having a pro-active on-going dialogue with the investment community • Providing access to the senior management team on a consistent basis

ThromboGenics establishes Level 1 ADR Program for US investors

At the end of September 2013, ThromboGenics announced that it had established a sponsored Level 1 American Depositary Receipt (ADR) program. Trading of the ADRs commenced on September 30, 2013 on the US over the counter (OTC) market under the ticker TBGNY. 58 Shareholder Information

ThromboGenics’ ADRs are US dollar negotiable certificates with each ADR representing half of one ordinary share of the Company. J.P. Morgan has been appointed as the depositary bank for the ThromboGenics’ ADR program.

ADR effective date September 30, 2013 Local ISIN BE0003846632

Symbol TBGNY Country of incorporation Belgium

Traded OTC Industry Biopharmaceutical

Ratio 2 ADRs / 1 Ordinary Share Depositary JPMorgan Chase Bank, N.A.

CUSIP 886003 10 2 Custodian BNP Paribas, Belgium

Shareholding structure

As of 31 December 2013, ThromboGenics has a total number of 36,094,349 outstanding shares and a total number of 766,500 outstanding warrants.

The free float amounts to 81,8%. The shareholding structure can be summarized as follows:

Thomas Clay 6.1% The Clay Mathematics Institute 3.0%

Landon Clay 3.3% Public 81.8%

Biggar Ltd 5.8%

Paying agent services

KBC Bank acts as the company’s paying agent. The paying agent will not charge shareholders with respect to payments of dividends, the exercise of subscription rights and other events concerning ThromboGenics’ shares. THROMBOGENICS corporate highlights 2013 59

Financial calendar

Monday, March 17, 2014 Full Year Results 2013

Tuesday, May 6, 2014 General Shareholders Meeting 2014

Thursday, May 22, 2014 Business Update Q1

Thursday, August 28, 2014 Half Year Results 2014

Thursday, November 6, 2014 Business Update Q3

Registered office

ThromboGenics Nv Gaston Geenslaan 1

B-3001 Leuven, Belgium

T +32 (0) 16 75 13 10

F +32 (0)16 75 13 11

[email protected]

Investor relations contact

ThromboGenics Nv Gaston Geenslaan 1

B-3001 Leuven, Belgium

[email protected]

[email protected]

www.thrombogenics.com Contact details

ThromboGenics

Wouter Piepers, Global Head of Corporate Communications/IR +32 16 75 13 10 +32 478 33 56 32 [email protected]

Chris Buyse, CFO +32 16 75 13 10 [email protected]

Glossary

AMD Age-related Macular Degeneration CEO Chief Executive Officer Anti­-PIGF Anti-Placental growth Factor CFO Chief Financial Officer BLA Biological license application COO Chief Operating Officer DME Diabetic Macular Edema MIVI Microplasmin for vitreous injection DR Diabetic Retinopathy CMVB Center for Molecular and Vascular Biology EMA European Medicines Agency CADTH Canadian Agency for Drugs and Technologies in Health FDA Food and Drug Administration OCT Optical Coherence Tomography FTMH Full-Thickness Macular Hole BCBSA Blue Cross Blue Shield Assocation ICD­-9-­CM international Classification of Diseases, 9th edition, Clinical Modification TEC Technology Evaluation Center MAA Marketing Authorization Application EPC Evidence-based Practice Center Metamorphopsia Distorted vision AHRQ Agency for Healthcare, Research and Quality Ocriplasmin Formerly known as microplasmin, commercialized as JETREA® ORBIT Ocriplasmin Research to Better Inform Treatment PVD Posterior Vitreous Detachment EU European Union PDR Proliferative Diabetic Retinopathy STA Single Technology Appraisal R&D Research & Development NHS UK National Health Service Symptomatic VMA Symptomatic Vitreomacular Adhesion NICE National Institute for Health and Care Excellence VA Visual Acuity ERM Epiretinal membrane VMA Vitreomacular adhesion IQWiG German Institute for Quality and Efficiency in Health Care CHMP Committee for Medicinal Products for Human Use G-BA German Federal Joint Committee VMT Vitreomacular traction CT French Transparancy Commission TB-403 also known as anti-Placental Growth Factor (anti-PlGF) HAS French National Health Authority US United States SMR Medical benefit UK United Kingdom ASMR Improvement in medical benefit tPA Tissue plasminogen activator CEPS Economic Committee of Healthcare Products VIB ‘Vlaams Instituut voor Biotechnologie’ Flanders Institute RIZIV Belgian Government for Health Insurance for Biotechnology WHO World Health Organization VEGF Vascular Endothelial Growth Factor www.cantilis.be