PERSPECTIVES. Exploring novel treatments for diabetic eye disease

Transcription

1 PERSPECTIVES Exploring novel treatments for diabetic eye disease

2 Corporate Highlights 20 16

3 11 INTERVIEW PROF. SEHNAZ KARADENIZ, M.D. CHAIR OF THE IDF EUROPE REGION DR severely affects the life of people with diabetes 40 INTERVIEW PROF. PETER CARMELIET, M.D., PH.D. I see a promising future for anti-plgf 30 OASIS 2 YEAR FOLLOW-UP STUDY Confirmation of long-term efficacy and safety of JETREA 2

4 19 28 THROMBOGENICS RESEARCH&DEVELOPMENT Innovative pipeline targeting diabetic eye diseases INTERVIEW Notary Astrid De Wulf has successfully been treated with JETREA 04 EDITORIAL Crafting new avenues for treating diabetic eye disease 08 DIABETIC RETINOPATHY A vision threatening disease affecting 93 million adults worldwide 22 SYMPTOMATIC VMA/VMT Alternative treatment options in a changing standard of care 34 MEDULLOBLASTOMA Fighting brain cancer in children 43 ABOUT THROMBOGENICS & SHAREHOLDERS INFORMATION 3

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6 Editorial EDITORIAL CRAFTING NEW AVENUES FOR TREATING DIABETIC EYE DISEASE Dear Reader, In 2016, ThromboGenics unveiled a new and innovative drug development pipeline targeting novel treatments for tackling diabetic retinopathy, with or without diabetic macular edema. Diabetic retinopathy is a serious eye condition. Associated with diabetes, it is the leading cause of blindness in adults worldwide. Diabetes represents a global and growing health threat and it is well known that one in three persons with diabetes will develop some form of diabetic retinopathy as a direct consequence of their diabetes condition. In one out of ten, the disease will progress to the severe form, with the risk of vision loss as a result. Given this growing challenge of diabetes, it is clear that the unmet medical need is enormous. There is much work to be done. At ThromboGenics, we are committed to doing our part. Of course, maintaining overall good health is of utmost importance for managing or avoiding diabetes and potential eye disease as a direct consequence. But when health management or preventive measures prove to be insufficient or too late, early treatment must be the preferred next plan of attack. At this moment, there are few options available for early treatment. In most cases patients with diabetic retinopathy in its less or more severe form must wait until the indications become apparent, and even then treatment is usually if not always reduced to handling the symptoms. Depending on the treating physician or the patient s condition, this will mean laser therapy or repeated injections of anti-vegf. By then, often the eye has already been damaged. Moreover, the existing forms of treatment are fairly intensive and not every patient responds as well to them. It would therefore make a world of difference for patients if diabetic retinopathy could be treated at an earlier stage. That is the ambition and mission of ThromboGenics, an ambition and mission we began to implement last year. 5

7 ThromboGenics Perspectives 2016 CLINICAL RESEARCH - COMBATTING VISION LOSS IN DIABETES PATIENTS Our mission as a research and development company is to combat vision loss in persons with diabetes. In fulfilling this mission, we are currently recruiting patients in new clinical trials across the globe. Additional clinical studies are in the works for later this year and early next year. We are currently focusing our efforts on four promising molecules that could result in a new treatment for the various forms of diabetic retinopathy. Thanks to a dedicated and very experienced research and development team, and access to in- vitro and in-vivo preclinical evaluation models in-house, we have already made rapid progress. Phase II clinical trials are well underway for our molecules THR- 409 (ocriplasmin) and THR-317 (anti-plgf). For THR-409 (ocriplasmin), we are researching its potential to induce a total release of the vitreous gel from the retina (posterior vitreous detachment) as a way to definitively halt any further disease progression. Imagine the peace of mind this would bring to diabetic retinopathy patients, knowing that their disease would no longer progress to the more severe and blinding form. For THR-317 (anti-plgf), we are researching the antibody s potential for combatting diabetic eye disease hallmarks such as inflammation and the development of scar tissue at the back of the eye, symptoms for which no other available therapy has provided a solution. For the execution of these studies, we are partnering with experts and the global ophthalmology and diabetes community. We are very excited to see the great and growing interest they have in what we are doing, and we expect to be able to share the preliminary results of the these studies by early next year. GROWING INSIGHT INTO THE HALLMARKS OF DIABETIC EYE DISEASE In 2016, we also made significant progress with two other compounds in our R&D pipeline, and it is our intention to complete the preclinical phases in the course of the coming year. For these two new leads, we expect to be able to start 2 additional Phase I/II clinical trials later this year and early next year. Of course, it will not stop here. One of the absolute strengths of our company is the ongoing deepening of our insight into the mechanisms of diabetic eye disease. The team is continually searching for new, undiscovered research opportunities, which we explore further through our discovery pipeline for diabetic eye disease. We believe that this rich expertise and experience in drug development for the back of the eye, together with our capacity to screen and evaluate new molecules in-house, puts us in a unique position. ONCURIOUS: TARGETING NOVEL TREATMENTS FOR BATTLING PEDIATRIC CANCER As is sometimes the case, the diversity of the molecules being researched offer potential inroads for drug development in other new therapeutic domains. This is certainly the case for our anti-plgf molecule. In 2016, we began evaluating the potential of TB-403 as a novel treatment for medulloblastoma, a malignant brain tumor in small children. In order not to shift the focus of the organization away from ophthalmological clinical research, we decided to spin off this research and created a new company focused on oncology: Oncurious. We co-founded Oncurious together with VIB, the Flanders Institute for Biotechnology, a long-time research and collaboration partner of ThromboGenics. Meanwhile, the Oncurious team is recruiting patients in a US-based Phase I/IIa clinical study evaluating TB-403 for the treatment of medulloblastoma. To that end, the team is collaborating with the NMTRC (Neuroblastoma and Medulloblastoma Translational Research Consortium), a network of US hospitals specialized in clinical trials in pediatric cancer. The TB-403 program is jointly conducted with the Sweden-based Bio- Invent International which bears 50% of the research and development costs. Our aim is to create one more opportunity for young patients suffering from this very malignant disease. 6

8 Editorial MORE THAN 25,000 PATIENTS ALREADY TREATED WITH JETREA At ThromboGenics, we are also very proud of the fact that more than 25,000 patients worldwide have been treated with JETREA, the first product we developed. Now approved in 54 countries, the medicine is used for the daily treatment of patients suffering from symptomatic VMA/VMT. Of course, we remain disappointed concerning the slow pace at which the retina community is embracing JETREA as part of an extended toolkit for treating symptomatic VMA/VMT. At the same time, we are delighted to see that certain retina specialists have changed their standard of care and are offering JETREA as a preferred treatment for selected patients. These retina doctors have become real champions of and experts in the application of this novel product. In 2016, we made our US Commercial operations cash neutral, and we are continuing to examine how to broaden the current user base within such a breakeven scenario. At the same time, we remain committed to generating and distributing new real-world and clinical data to help the retina community better understand the JETREA risk/benefit profile, and to identify eligible patients. In the past year, the results of a 2-year Phase IIIb study (OASIS) were published. This randomized clinical trial confirmed much of the real-world and clinical data collected since the launch. When selecting patients according to specific criteria, the treatment may result in increased resolution rates with a consistent safety profile thereby avoiding major surgery with only one single injection. STRATEGIC, FOCUSED AND PRUDENT In the past year, our business strategy of a single major focus on diabetic retinopathy and a multiple shots on goal approach gradually revealed itself. Our enthusiasm about the growing opportunities for offering better treatments to people with diabetes is truly shared by the medical world, scientists, shareholders and other stakeholders. With this report, we not only wish to give you insight into our ongoing activities, we also hope to convey a bit of this enthusiasm that we experience daily. Thank you for your interest in and support for our company and our mission to improve the life of all in the world who live with diabetes. Yours truly, Patrik De Haes, M.D. CEO ThromboGenics NV Staf Van Reet, Ph.D. Chairman of the Board of Directors ThromboGenics NV What s more, the product will become even easier to administer in the near future. A new version of JETREA, which comes already diluted and therefore ready to use, has been approved by the Federal Drug Administration in the USA and will come on the market this year. 7

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10 DDiabetic retinopathy Diabetic retinopathy (DR) is a severe and degenerative eye disease that leads to vision loss and, in later stages, even blindness. It is a common complication that accompanies diabetes, a pandemic affecting 415 million adults worldwide. In the growing population of people diagnosed with diabetes, about 1 out of 3 will develop DR. ThromboGenics saw an unmet medical need for fighting this disease at an early stage and is currently researching innovative novel treatments, with a clear mission to combat vision loss in persons with diabetes.

11 A VISION THREATENING DISEASE AFFECTING 93 MILLION ADULTS* WORLDWIDE * Source:

12 DR SEVERELY AFFECTS THE LIFE OF PEOPLE WITH DIABETES Prof. Sehnaz Karadeniz, M.D. pleads for greater awareness of diabetes-related eye diseases An increasing population of people with diabetes worldwide suffer from diabetic retinopathy (DR), a common complication of diabetes that can lead to visual impairment and - in a severe stage - even blindness. Professor Sehnaz Karadeniz, M.D., ophthalmologist and Chair of the International Diabetes Federation Europe Region, pleads for greater awareness of this disease, since it affects people in their everyday activities. It would be better for people with diabetes if we could diagnose and treat DR at an early stage in order to prevent further vision loss. As an ophthalmologist and retina specialist at the Istanbul Florence Nightingale Hospital in Turkey, Sehnaz Karadeniz treats many people suffering from diabetic retinopathy. They come to us with complaints about visual impairment that affects their everyday lives. The symptoms make it difficult for them to drive a car, engage in their professional activities or even to cook or clean the house. QUALITY OF LIFE STUDY Sehnaz Karadeniz is also Chair of the International Diabetes Federation (IDF) Europe Region. Last year the IDF, in collaboration with the International Federation on Ageing (IFA) and the International Agency for the Prevention of Blindness (IAPB), published the findings of DR Barometer, a study conducted in 41 countries with 4,340 adults with diabetes and 2,329 healthcare professionals. The study provided new information about the experiences of living with, managing and treating DR. Interview with Prof. Sehnaz Karadeniz, M.D. International Diabetes Federation Chair Europe Region The numbers coming out of our study were significant: some 79% of people with diabetes surveyed, for example, said that their everyday activities are affected by diabetic retinopathy. A significant number also experienced psychological and emotional problems due to the disease. Unfortunately, in my experience as a doctor, these numbers are not surprising. Sehnaz Karadeniz stresses that these findings concern not only the most advanced stage of the disease, when blindness can occur. People with diabetes will experience a decreased quality of life even with moderate visual impairment. This differs from person to person, and depends on how he or she lives and works. People with 14/20 read further on page 12 11

13 ThromboGenics Perspectives 2016 vision can find that their everyday activities are highly affected by the disease, while those with greater vision loss may have fewer complaints. In any case, any form of visual impairment affects the lives of people with diabetes in a negative way. The main goal of conducting the DR Barometer study therefore was to create greater awareness of diabetic retinopathy among governments, health care professionals and people with diabetes worldwide. AN INSIDIOUS DISEASE Diabetic retinopathy is a common complication of diabetes, which is caused by high blood sugar levels. With 415 million adults worldwide living with diabetes in 2015 and an estimated increase to 642 million people by 2040, diabetes is a true pandemic. In this growing population, 1 out of 3 will develop DR. In addition, it is estimated that half of the people living with type 2 diabetes, nearly 200 million worldwide, are not even aware that they have the disease, says Sehnaz Karadeniz. This puts them at an even greater risk for complications like DR. When people with type 2 diabetes are diagnosed, they may have already had the disease for several years, so it is likely that they are also in some stage of DR. We are dealing with a population that is not aware that their eyes may already be affected, even though they do not yet show symptoms. DR is a degenerative disease that begins with moderate symptoms and progresses to a severe stage with advanced visual impairment and in some cases even blindness. In its moderate form, non-proliferative diabetic retinopathy (NPDR), it is very likely that the person will have no complaints about vision for several years. But as the disease progresses to its severe form, proliferative diabetic retinopathy (PDR), it causes more and more problems due to a proliferative growth of blood vessels. In addition to NPDR and PDR symptoms, all people with DR have an increased risk of developing diabetic macular edema (DME). DME occurs when fluid leaks into the macula (central part of the light-sensitive layer at the back of the eye). These leaks cause the macula to thicken and swell, progressively distorting vision: in some cases this can lead to a severe loss in central vision. This develops gradually, so people with diabetes may not be aware of any changes in their eye until their sight is affected and causes problems in their everyday life. read further on page 14 35% of people with diabetes worldwide will develop diabetic retinopathy 12

14 Interview with Prof. Sehnaz Karadeniz Diabetes, a worldwide pandemic Diabetes is one of the largest health emergencies of the 21st century. According to the 2015 edition of the International Diabetes Federation Atlas: Some 415 million people worldwide, or 8.8% of adults aged 20-79, are estimated to have diabetes. About 75% live in low- and middle income countries. If these trends continue, by 2040 some 642 million people, or one adult in ten, will have diabetes. The largest increases will take place in the regions where economies are moving from low-income to middle-income levels. Since it is a systemic disease, close monitoring of a person with diabetes blood sugar levels, blood pressure and other health parameters is crucial to prevent complications like diabetic retinopathy. But nearly half of people with type 2 diabetes are not aware that they have the disease, which puts them at greater risk for developing complications. More than 1 out of 3 people with diabetes eventually develops DR. (Source: International Diabetes Federation) Who is Professor Sehnaz Karadeniz? For the past 20 years, ophthalmologist Sehnaz Karadeniz, M.D., has been actively involved in the field of diabetes in a series of medical, scientific, and social projects at national and international levels. She teaches at the Ophthalmology Department of the Medical Faculty of Istanbul Science University and also works as an ophthalmologist at the Ophthalmology Dept. of the Istanbul Florence Nightingale Hospital. She is the Founding Member and Member of the Board of Trustees of the Turkish Diabetes Foundation (TURKDIAB) that was established in Since then, she has been actively involved in the social and scientific activities of the Foundation, and also has been voluntarily coordinating its international relations since In addition, she coordinates the DIABLIVA project of the Turkish Diabetes Foundation, an initiative that provides support for Turkish immigrants with diabetes. From , Dr. Karadeniz served as President of the Living with Diabetes Association, a nationwide patients organization, and from , as Board Member responsible for Association development. She joined the board of the International Diabetes Federation European Region (IDF Europe) in 2007, and has been the Chair of the IDF European Region since December She is also an EASD Council Member for the term. (Source: ) 13

15 ThromboGenics Perspectives 2016 For all of these reasons, DR often remains undetected at an early stage. Many people with diabetes only go to the doctor when they already have vision loss. The problem is that when they are already suffering from visual impairment due to diabetic retinopathy, the disease is most likely at a severe stage for which there presently is no treatment that can restore the vision already lost. We can only try to preserve their remaining vision. NEED FOR NOVEL TREATMENTS Sehnaz Karadeniz emphasizes that it therefore is very important to screen people with diabetes using regular eye examinations. Since there are currently no treatments to fight the disease in its non-severe form, our aim is to detect DR as early as possible, monitor the patient closely and intervene at the moment sight-threatening DR starts. Current treatments include laser therapy, injections with anti-vegf and in some cases cortisone. We mostly use injections with anti-vegf or, in a more severe stage of PDR, laser therapy. They are effective, but treat only some of the symptoms of the disease. The problem is also that many people with diabetes are diagnosed only in a later stage in which their vision can no longer be saved. Moreover, the present treatments are quite intensive: patients must undergo injections monthly or even every two weeks. We urgently need novel treatments to combat the disease at an earlier stage or in a simpler way. DR also generates several other complications like inflammation and fibrosis, which are not addressed by current treatments. People with diabetes therefore could benefit from new medicines to supplement those presently available. OPTIMISM ABOUT LONG-TERM SOLUTIONS As a healthcare professional, Sehnaz Karadeniz M.D. closely follows the research and new developments in the area of diabetic retinopathy. She is looking forward to the first results of the ThromboGenics studies on treating DR with ocriplasmin and anti-plgf. I think it would be wonderful if we could prevent DR, or at least slow its progression. Then perhaps we could treat people before DR reaches a vision-threatening stage. The search for novel treatments like those of ThromboGenics remains a major focus in the research. I hope that this new research will yield good results and solutions for the long term. In the end, we all have the same goal: preventing vision loss in DR patients on a worldwide scale. 14

16 Interview with Prof. Sehnaz Karadeniz IMPACT OF DIABETIC EYE DISEASES 38 % of patients says that long wait times for an appointment were a barrier to eye exams 20 % of respondents says their vision impairment due to DR or DME made it difficult to manage their diabetes About the International Diabetes Federation The International Diabetes Federation (IDF) is an umbrella organization of over 230 national diabetes associations in 170 countries and territories. It represents the interests of the growing number of people with and at risk of diabetes. The Federation has been leading the global diabetes community since The International Diabetes Federation is divided into seven regions: Africa (AFR), Europe (EUR), Middle East and North Africa (MENA), North America and Caribbean (NAC), South and Central America (SACA), South East Asia (SEA) and Western Pacific (WP). Its goal is to strengthen the work of the national diabetes associations and enhance collaboration between them. 69 % 79 % of respondents says their vision impairment due to DR or DMA made everyday activities difficult, such as driving, working and cooking or cleaning their home The Federation s activities aim to influence policy, increase public awareness, encourage health improvement, promote the exchange of highquality information about diabetes, and educate diabetes patients and their healthcare providers. The IDF is associated with the Department of Public Information of the United Nations and is officially represented in the World Health Organization (WHO) and the Pan American Health Organization (PAHO). (Source: of respondents with DME experiences days of poor physical and mental health (Source: 15

17 ThromboGenics Perspectives 2016 STOPPING THE PROGRESSION OF DIABETIC RETINOPATHY COULD BE A GAME-CHANGER Prof. Alan Stitt describes the irreversible impact of DR on vision Diabetic retinopathy (DR) is a degenerative disease. This means that once the first signs are present in a patient s eyes, its negative progression often continues, and may eventually lead to sight-threatening complications. Prof. Alan Stitt has studied the progression of DR for many years. Unfortunately this process is irreversible and can often cause significant vision loss in later stages of the disease. Professor Alan Stitt, McCauley Chair of Experimental Ophthalmology in the School of Medicine at the Queen s University in Belfast, has published more than 120 scientific papers on the pathogenesis of diabetic retinopathy and retinal angiogenesis. As an expert in the field, he is very clear about the unmet medical need for novel treatments to fight diabetic retinopathy in an early stage. Finding a way to begin the treatment of patients at the early stages of the disease, and to stop its progression to diabetic macular edema (DME), ischaemic maculopathy or proliferative diabetic retinopathy (PDR), really is the holy grail of the research into diabetic retinopathy. Because presently it is only possible to treat patients after their vision has already been affected. Interview with Prof. Alan Stitt Dean of Innovation & Impact, McCauley Chair of Experimental Ophthalmology DIFFERENT MANIFESTATIONS IN DIFFERENT PHASES In the severe phase of DR, called proliferative diabetic retinopathy (PDR), several complications occur in the patient s eyes. Manifestations in the final phase include an accumulation of problems such as micro-aneurisms, capillary non-perfusion, retinal hypoxia and pathological angiogenesis. This causes small blood vessels to penetrate the vitreous of the eye, which may result in hemorrhaging and scar formation. These scars can lead to detachment of the retina and severe loss of vision. 16

18 Interview with Prof. Alan Stitt According to Prof. Stitt, most patients visit an ophthalmologist only after they already have significant retinopathy and start to notice the first symptoms of visual impairment. But there are several other phases preceding vision loss, stresses Prof. Stitt. It all starts with the diagnosis of diabetes. With proper diagnosis, a degree of prevention is already possible at that early stage. There is evidence that some of the risks of the progression of DR can be offset with good glycemic control and close monitoring of blood pressure and blood lipids in patients. Unfortunately some type 2 diabetes patients are diagnosed quite late and some can already show evidence of DR, even if they don t have any vision complaints. We call this phase background retinopathy. Patients in this phase may progress further to non-proliferative diabetic retinopathy (NPDR). In this phase, there is already some inflammation of the retina, but generally NPDR is seen as the stage in which patients should be monitored very closely for progression to PDR and the need to begin treatment. Some patients also risk developing diabetic macular edema (DME), which is linked to a breakdown of the blood retinal barrier, which leads to an accumulation of fluid in the macular region of the retina and causes swelling and severe vision loss in the patient. INTRUSIVE THERAPIES Current treatments include anti-vegf injections, laser therapy and in some cases injections with steroids. All are combatting late-stage retinopathy with various degrees of success, but the problem is that the therapies are quite invasive. Anti-VEGF s are very effective for many patients with DME but the intra-ocular injections needs to be repeated regularly and unfortunately not all patients respond. Steroids are a viable option but they can cause cataracts and a rise in intra-ocular pressure while laser therapy is inherently destructive. Which is why patient organizations, scientists and healthcare professionals in the ophthalmology field are focused on research that can lead to new ways to treat diabetic retinopathy. All would benefit from innovative treatments that are easier to administer and capable of tackling DR in the earlier stages such as NPDR, thus stopping the disease from progressing. read further on page 18 Who is Prof. Alan Stitt? Professor Stitt was appointed to the McCauley Chair of Experimental Ophthalmology in Queen s University Belfast, in March For over 10 years he was Director of the Centre for Vision & Vascular Science (CVVS) and then the reconfigured Centre for Experimental Medicine. He is now Dean of Innovation and Impact within the Faculty of Medicine, Health and Life Sciences. He is internationally known for his research in ophthalmology. His academic attainment is reflected in his publication output which attracts a high degree of citation for his field. He has also earned significant prizes including a Royal Society Merit Award (2011), the Sir Jules Thorn Biomedical Science Award (2010) and the 5th Fincham Medal (2016)(City of London s Livery Companies) in recognition of research on diabetic retinopathy and neovascular events in diabetes. He contributes greatly to the academic community through undertaking editorial responsibility and editorial board membership for various journals, serving on advisory panels and presenting guest lectures across the world. Professor Stitt s research has focused on the pathogenesis of diabetic retinopathy and agerelated retinal disease and he established the role of advanced glycation endproducts (AGEs) and their receptors in the progression of these diseases. His work has uncovered several interrelated pathways involved in neuroglial and microvascular dysfunction in the diabetic and ageing retina. This research has led to the development and testing of several compounds that have progressed to clinical trials. For example, his recent work with GlaxoSmithKline (GSK) provided the necessary preclinical evidence to progress the LP-PLA2 enzyme inhibitor, darapladib, to an international Phase III clinical trial for diabetic macular oedema. (Source: Queen s University, Belfast) 17

19 ThromboGenics Perspectives 2016 PROMISING NEW COMPOUNDS ThromboGenics diabetic retinopathy research portfolio has been well received by the ophthalmology community. The company is studying 4 compounds. Some of them address the later stages of the disease and have the potential to supplement the benefits of treatments already in use. But ThromboGenics is also conducting promising research on various treatments that may be effective at earlier stages of the disease, confirms Alan Stitt. I m very excited about the clinical trial with anti-plgf. It has a lot of potential, especially for patients who do not respond to anti-vegf therapies. There is also considerable evidence in preclinical models that shows that anti- PlGF could stop the progression of DR at an earlier stage. Thus the therapy is definitely very promising. According to Prof. Stitt, the field of research into diabetic retinopathy is very vibrant. Many companies are increasingly interested in researching new treatment options. ThromboGenics has a unique position due to its strategic dedication to DR. The company is focusing its efforts and scientific knowhow on a range of defined retinal diseases, which puts them in my opinion in a strong position. It usually takes many years to build up core expertise in developing good research knowledge in both the pre-clinical and clinical arenas and ThromboGenics now offers advancements in both areas. The symptoms of DR People with diabetes have raised glucose levels in their blood, which causes changes in certain proteins and results in a series of problems in the back of the eye. In an early stage, the patient suffers from leaking blood vessels (hyperpermeability), causing inflammation in the back of the eye. This results in edema and the proliferation of new blood vessels (angiogenesis) in the vitreous or along the surface of the retina, eventually leading to permanent damage through the development of scar tissue (fibrosis). As the inflammation increases, the hyperpermeability deteriorates, causing new inflammation, more edema and more proliferation and scar tissue. This vicious circle continues and the disease progresses. Inflammation Permeability Neuro and vascular dysfunction Edema Leakage, occlusion & non-perfusion Angiogenesis Fibrosis Neurodegeneration 18

20 Innovative pipeline of novel medicines targeting diabetic eye disease INNOVATIVE PIPELINE OF NOVEL MEDICINES TARGETING DIABETIC EYE DISEASE ThromboGenics research and development in ophthalmology ThromboGenics continuously researches drugs that address unmet medical needs. With a growing global population suffering from diabetes and current treatment options insufficient, the company is explicitly focusing on the prevention and treatment of diabetic eye diseases like diabetic retinopathy (DR), with or without diabetic macular edema (DME), that have a very direct impact on the quality of life of people with diabetes. THR-409 FOR NON-PROLIFERATIVE DIABETIC RETINOPATHY (NPDR) ThromboGenics believes that through the application of multiple doses of ocriplasmin (THR-409), it can reduce the risk of a patient s disease progressing from NPDR to PDR by inducing total posterior vitreous detachment (PVD). Research has shown that the presence of PVD, where the vitreous membrane is separated from the retina, may prevent the growth of the new blood vessels that are responsible for proliferative diabetic retinopathy (PDR). They are no longer able to use the vitreous as scaffolding in order to grow along the surface of the retina or into the vitreous. This finding has been reinforced by the fact that PDR is rare in patients who suffer from posterior vitreous detachment. People with diabetes who progress to PDR run a high risk of experiencing severe vision loss or complete blindness. In January 2016, the company announced the start of its Phase IIa (CIRCLE) study with THR-409. The CIRCLE study is a Phase II, randomized, double-masked, sham-controlled, multi-center study that will evaluate the efficacy and safety of up to 3 intravitreal injections of either mg or half of the approved dose ( mg) of THR-409 in subjects with moderately severe to very severe NPDR, to induce total PVD and reduce the risk of the patient progressing to sight-threatening PDR. The primary clinical endpoint of the CIRCLE study is the percentage of patients with total PVD at the time of their visit one month after the third injection, as confirmed by both B-scan ultrasound and SD-OCT. The study has a number of secondary endpoints that are designed to provide further insights into ocriplasmin s potential to reduce the risk of NPDR progressing to PDR. THR-317 ANTI-PIGF ANTIBODY TO TREAT DIABETIC MACULAR EDEMA (DME) THR-317 is a disease modifying, anti-plgf antibody that has the potential to treat a broad range of people with latestage diabetic eye disease either alone or in combination with anti-vegf treatments. ThromboGenics is currently developing THR-317 for the treatment of diabetic macular edema (DME). Recently the first patients were enrolled in a phase II, single-masked, multi-center exploratory study evaluating the safety and efficacy of THR-317 for the treatment of diabetic macular edema (DME). The study will evaluate the safety of 3 intravitreal injections of 2 dose levels of THR-317 (4 mg or 8 mg). The trial will also assess THR-317 s ability to improve best-corrected visual acuity (BCVA) and to reduce central retinal thickness in subjects with DME. 19

21 ThromboGenics Perspectives 2016 The study plans to enroll a total of 50 patients over a period of approximately 12 months. The first results of the study are expected in Q ThromboGenics plans to evaluate THR-317 in additional DR indications if the current Phase II trial yields positive results. THR-687 FOR NON-PROLIF- ERATIVE AND PROLIFERA- TIVE DIABETIC RETINOPA- THY (NPDR AND PDR) The compound THR-687 (integrin antagonist) is a very promising product that has the potential to tackle the full spectrum of signs and symptoms of DR. Similar to ocriplasmin, research shows that THR-687 can generate PVD, preventing blood vessels from growing into the vitreous or along the surface of the retina, thus reducing the risk of patients developing sightthreatening PDR. Moreover, the molecule exhibits anti-dme compounds that reduce edema and therefore also stop the progression of inflammation and hyperpermeability. ThromboGenics has signed an exclusive global license agreement with Galapagos to develop and commercialize integrin antagonists for the treatment of diabetic eye disease. THR-149 TO TREAT DIABETIC MACULAR EDEMA (DME) Preclinical studies and clinical observations show that this molecule, a plasma kallikrein inhibitor, is able to decrease the edema in the back of the eye caused by inflammation. With less edema present in the eye, the inflammation and hyperpermeability stop deteriorating, thus halting the progression of DR. ThromboGenics intends to develop THR-149 in a sustained release dosage form, in order to generate a long-term effect in the back of the eye. Fewer treatments will be necessary, again lowering the burden on the patient. This compound emerged from the company s research collaboration with Bicycle Therapeutics. A quadrant for innovative compounds A quadrant of people with DR is used to determine which types could benefit from the novel compounds in the pipeline. 23.6% NPDR without DME 4.5% NPDR with DME 4.2% PDR without DME 3.0% PDR with DME Therefore, THR-687 could be used in the early treatment of patients with NPDR with or without DME, but also of PDR patients with or without DME. ThromboGenics believes that the compound has the potential to be developed into a very powerful product that offers all DR patients a better treatment that changes the progression of the disease. 35.4% Any DR* Moreover, the active mechanism of THR-687 is similar to ocriplasmin through pharmacological vitreolysis. Since ThromboGenics is a pioneer in this area, in particular the development and commercialization of JETREA, the company is able to use its experience to develop a product that covers the full spectrum of DR symptoms. *Any DR is defined as the presence of NPDR, PDR, DME or any combination thereof. ABBREVIATION(S) DR diabetic retinopathy NPDR non-proliferative diabetic retinopathy PDR proliferative diabetic retinopathy DME diabetic macular edema 20

22 Innovative pipeline of novel medicines targeting diabetic eye disease Ophthalmology portfolio Program Hallmarks of diabetic retinopathy Segment Inflammation Edema Angiogenesis Fibrosis Neurodegeneration THR-409 OCRIPLASMIN (1) THR-317 ANTI-PIGF (+) THR-687 INTEGRINE ANTAGONIST (2) THR-149 PLASMA KALLIKREIN INHIBITOR (1) prevention blood vessel ingrowth in vitreous (PVD) (2) neo-angiogenesis inhibition + prevention blood vessel ingrowth in vitreous (PVD) + level of therapeutic action 21

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24 S Symptomatic VMA/VMT Prior to the launch of JETREA only one treatment option was available to patients suffering from symptomatic vitreomacular adhesion/ traction (svma/vmt). If left untreated, this progressive eye disease generally leads to significant visual distortion or even central blindness. Treatment consisted of observation, followed by surgical separation of the vitreous from the retina. With JETREA, an innovative medicine developed by ThromboGenics, selected patients can now also be treated earlier on with a simple injection.

25 ALTERNATIVE TREATMENT OPTIONS IN A CHANGING STANDARD OF CARE

26 GOOD PATIENT SELECTION GUARANTEES BETTER TREATMENT RESULTS Prof. Peter Stalmans, M.D. on the regular use of JETREA to treat patients Peter Stalmans, M.D., Ph.D. vitreoretinal surgeon at the Ophthalmology Department of University Hospital Leuven (UZ Leuven), treats approximately 1 patient per month with JETREA. He stresses that good patient selection is crucial to obtaining the best results with this innovative product. Suitable referral by ophthalmologists can improve the success rates drastically. At University Hospital Leuven (Belgium), Peter Stalmans, M.D., Ph.D. sees an average of 3 patients per week with symptomatic VMT. Until a few years ago, patients had to undergo eye surgery (vitrectomy) after a period of watchful observation. Since the introduction of JETREA, he is able to offer them the treatment option of a single injection with this novel drug. Interview with Prof. Peter Stalmans, M.D. When JETREA was introduced to the market in 2013, Prof. Stalmans treated the first 40 svmt patients in Belgium to be administered this innovative product. The fact that we paid extra attention to selecting the right patients was crucial in obtaining these positive results. Our 10 years expertise in the field of svmt helped us define the right patient profile for treatment with JETREA. Ophthalmology Department, University Hospital Leuven TRIALS CONFIRM IMPORTANCE OF PATIENT SELECTION Thorough patient selection, for example using advanced diagnostic technology such as SD-OCT, continues to enhance the success rate of JETREA when treating patients with symptoms of svmt. Studies such as OASIS and OVIID, conducted in the US and Europe, monitored the long-term progress of patients who received a JETREA injection. The results confirm that with proper patient selection, 1 in 2 will be cured of the disease with a single injection. read further on page 26 25

27 ThromboGenics Perspectives 2016 Who is Professor Peter Stalmans? Peter Stalmans, M.D., Ph.D. is a staff member of the Ophthalmology Department at University Hospital Leuven (UZ Leuven) and Associate Professor at the KU Leuven. After completing his residency-in-training at the Ophthalmology Department of University Hospital Leuven, he worked for a year as a vitreoretinal fellow at the Rotterdam Eye Hospital. In 2000 he joined the staff of University Hospital Leuven and in 2001 he became an associate professor at KU Leuven. Prof. Stalmans is a member of the AAO, ARVO, EVER, the Belgian Society of Ophthalmology, ASRS, EVRS, and EURETINA, and he organized the international Leuven Retina Meeting in 2011, 2013, 2015 and He has presented at various national and international meetings. Prof. Stalmans was the principal investigator of the phase II ocriplasmin clinical trial and coordinating investigator of the MIVI TRUST phase III trials (MIVI 6 and MIVI 7). His professional interests include vitreoretinal surgery, surgical instruments and device development, and pharmacological vitreolysis. In the OVIID study for example, a phase IV trial with 466 patients at 87 locations worldwide, patients were required to visit a central reading center before they could receive the injection. This has resulted in increased outcomes, explains Prof. Stalmans. DISEASE AWARENESS AND CORRECT DIAGNOSIS When treating his patients, Prof. Stalmans pays considerable attention to a correct diagnosis. It is very important to always determine whether patients really suffer from vitreomacular traction in their retina, and not fibrosis. These two diseases can be confused. A patient with fibrosis won t benefit from treatment with JETREA. But when I diagnose VMT in patients, I always recommend treatment with JETREA as an alternative to a vitrectomy, says Stalmans. Most patients prefer to avoid an eye operation, because it can lead to complications such as bleeding, pain, post-operative inflammation and irritation. 26

28 Interview with Prof. Peter Stalmans It is also important that patients are able to detect the symptoms themselves and that svmt can be diagnosed in an early phase. Thanks to the introduction of JETREA, patients and ophthalmologists are now much more aware of the disease. Patients used to come to me after they were already suffering from serious complications such as a macular hole. Now we are able to detect the symptoms in an early phase and start treatment immediately to halt the progression of the disease, thus increasing the patient s chances of recovery. This is thanks to the efforts of ThromboGenics in introducing a new standard of care for symptomatic VMT. Innovative robot-assisted system injects JETREA to dissolve blood clots This past year, ThromboGenics also supplied the new pre-diluted version of JETREA (approved by the FDA in 2016) to the Ophthalmology Department of University Hospital Leuven for use in a trial on dissolving blood clots in the microscopic veins of the eye. The Ophthalmology Department collaborated with the KU Leuven Mechanical Engineering Department to develop an innovative robot-assisted system to locally administer the ocriplasmin in the retinal veins. This collaborative project was started to treat a condition called Retinal Vein Occlusion (RVO). Patients suffering from RVO exhibit full or partial blockage of the veins that drain the retina, due to the formation of clots. Until now, there was no treatment to dissolve these blood clots, explains Prof. Peter Stalmans. There was no needle thin enough to pierce such microscopically small vessels (100 micrometers). Moreover, the needle needs to remain stable in the vein for several minutes in order to inject the fluid that dissolves the clots. This level of stability is simply not possible with human hands. The team worked 7 years to develop a needle small enough and a robot-assisted system to stabilize the needle once it enters the vein. Ocriplasmin proved to be effective at dissolving the blood clots. The product was originally tested to treat thrombosis, so it has the right properties. Moreover, JETREA has already been approved for injection in the eye. Therefore we were happy to partner with Thrombo- Genics and use JETREA in the phase I trial with the robot-assisted needle system. 27

29 ThromboGenics Perspectives 2016 IN MY CASE, IT HAS BEEN A WONDER MEDICINE Notary Public Astrid De Wulf had her eye condition treated with JETREA as an alternative to surgery Astrid De Wulf was suffering from acute loss of vision after a holiday. She was soon diagnosed with symptomatic vitreomacular traction (svmt) and was facing major eye surgery. Luckily, I had heard of ThromboGenics and their new product. A simple injection with JETREA cured me of the disease. Astrid De Wulf, a Belgium-based notary public, suddenly found herself having difficulty reading when she returned to work after February vacation. It was hard to put into words what was wrong. It felt like trying to read through a glass jar. All the letters were more rounded and I couldn t read numbers properly. Up until my vacation, I could read perfectly well, so the sudden symptoms came as a big shock. I was beside myself with worry. Astrid consulted an eye doctor and was diagnosed with svmt, symptomatic vitreomacular traction. I was told that there was nothing to be done and that I would have to see an eye surgeon. My whole world kind of collapsed. I had so many unanswered questions. I got in touch with an eye surgeon who told me I would most likely need surgery. The surgeon explained the procedure, a vitrectomy. It s a fairly major surgery, and not without risk to my eyes. That s why I wanted to see if there were no alternative forms of treatment. On the Internet, I read about research and an innovative new treatment with just one simple injection. That s how I came into contact with ThromboGenics, the company that developed the product JETREA and put it on the market. Astrid was referred to Prof. Peter Stalmans, M.D., of the Ophthalmology Department at the University Hospital Leuven. He confirmed the diagnosis and was able to treat her with JETREA. My eye was anesthetized with eyedrops, and I was given the injection. The treatment was so quick that I barely noticed a thing. And it completely resolved my vision problems. I regained my vision and I ve been able to get back to work without any problems. In my case, it s been an absolute wonder drug. 28

30 In my case, it has been a wonder medicine Thanks to a simple injection, I now have my vision back (Astrid De Wulf)

31 ThromboGenics Perspectives YEAR FOLLOW-UP STUDY CONFIRMS LONG-TERM EFFICACY AND SAFETY OF JETREA OASIS trial evaluates 220 svma/vmt patients after treatment With JETREA, retina physicians for the first time have an alternative treatment available for symptomatic VMA/VMT. Some 25,000 patients worldwide have already been treated since the introduction of this novel medicine. Results of new phase III studies confirm that the drug safely and efficiently combats this severe eye condition over the long term. Symptomatic VMA/VMT is a progressive eye disease caused by traction from 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 the central vision needed for everyday tasks such as driving, reading and recognizing faces. Therefore, the disease can cause serious visual impairment and even blindness in patients, thus severely affecting their everyday lives. As the disease progresses, the traction may eventually result in the formation of a hole in the macula (a macular hole). NEW TREATMENT OPTION The innovative drug JETREA (ocriplasmin) was developed to improve patient s lives by offering a better and simpler treatment option for this severe eye condition. Previously, the only therapy was watchful observation of the disease, followed by eye surgery to separate the vitreous from the retina (vitrectomy). This procedure involves several risks and can lead to complications such as bleeding, pain, post-operative inflammation or irritation. Because of this, the operation is usually only done when the patient s vision has deteriorated significantly. This approach involves observation or watchful waiting until a patient becomes a candidate for surgical treatment and repair of the retina. For many patients this is not a suitable option, since irreversible damage to the retina may have already occurred. Since the introduction of JETREA, more than 25,000 patients worldwide have benefited from the new treatment option. Data from new studies that monitored patients for a long period after receiving an injection confirm that the novel drug offers them a safe and successful new standard of care for treating symptomatic VMA/VMT. STUDIES PROVE JETREA IS SUCCESSFUL AND SAFE The OASIS study (Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion including Macular Hole) was completed this past year. The goal of this phase IIIb trial was to further evaluate the long-term efficacy and safety of a single injection of mg of ocriplasmin in patients with symptomatic vitreomacular adhesion (VMA, US) and vitreomacular traction (VMT, outside the US), including a macular hole. 220 patients were monitored for a period of 24 months after receiving an injection with JETREA. 30

32 2 year follow-up study confirms long-term efficacy and safety of JETREA The study results show that almost half of the patients treated with JETREA were cured of symptomatic VMA/VMT on day 28 post-injection. Moreover, the safety profile of this 24-month follow up study was consistent with the drug s overall safety profile as contained in the approved label. This proves that the drug is a successful alternative for physicians in treating patients with symptomatic VMA/VMT and in improving their vision by halting the further progression of this disease. EASY TO ADMINISTER JETREA is the first pharmacological treatment for symptomatic VMA/ VMT and it is easy to administer as an intravitreal injection. The technique has become routine among retina physicians in recent years. The OASIS trial demonstrates the long-term efficacy and safety of ocriplasmin, providing improved resolution of symptomatic VMA compared with previous phase 3 trials with no additional safety signals identified. (Journal of the American Academy of Ophthalmology) A new version of JETREA, which comes pre-diluted and therefore ready to use, has been approved by the Federal Drug Administration in the USA and will come on the market this year. 31

33 ThromboGenics Perspectives 2016 NEW TREATMENT OPTION IN A CHANGING STANDARD OF CARE First-in-Class treatment for symptomatic VMA/VMT JETREA is the first product developed and brought to market by ThromboGenics. Now approved in 54 countries, the medicine is used daily to treat patients suffering from symptomatic VMA/VMT. More than 25,000 patients worldwide have been treated with JETREA. ThromboGenics pioneered the pharmacological vitreolysis drug category with JETREA and was the first to bring it to market. JETREA is the world s only approved pharmacological vitreolysis treatment for symptomatic VMA/VMT. Pre viously, the only treatment option for patients with this severe eye condition was observation, followed by surgical separation of the vitreous from the retina in a procedure called a vitrectomy. The company remains committed to assisting physicians in their efforts to enhance patient awareness of the options available for treating symptomatic VMA/VMT. UNIQUE MECHANISM OF ACTION JETREA is administered as an intravitreal injection, a unique procedure that has become routine for retina physicians and is easy to perform. The product breaks down the protein fibers that create the abnormal traction between the vitreous and the macula that causes VMA/VMT. By dissolving these proteins, JETREA releases the traction and facilitates the detachment of the vitreous from the macula. JETREA can also be used in advanced stages of VMA/VMT in which a small hole is present in the macula (the central part of the light-sensitive layer at the back of the eye). If the treatment is successful, symptomatic VMA/VMT will not recur. 32

34 New treatment option in a changing standard of care Patient journey Mechanism of action Patient experiences vision changes: metamorphopsia (blurreld vision) and/or macular hole (central blindness). The patient consults an ophthalmologist, who determines the patient is suffering from an early stage of VMA/VMT. The patient is diagnosed via optical coherence tomography (OCT), a non-invasive imaging technique providing instant real-time high-resolution images of eye tissue. The ophthalmologist refers the patient to a retina specialist, who discusses the treatment options with the patient. Normal Separation (PVD) Vitreous remodelling leads to progressive liquefaction with age. Symptomatic VMA Incomplete separation can cause Vitreomacular Adhesion (symptomatic VMA), that results in traction, leading to visual disturbance. Treatment options Observation: Watchful waiting until the patient s condition deteriorates to the point of becoming a candidate for surgical treatment and repair of the retina. For many patients this is not a suitable option, as irreversible damage to the retina may have already occurred. Injection with JETREA : JETREA is the first pharmacological option for treating symptomatic VMA/VMT. It is administered as an intravitreal injection and allows physicians to treat symptoms at an early stage. Successful treatment can improve patients vision and ability to carry out normal daily activities. It can also stop further progression of this disease. Symptomatic VMA resolved Ocriplasmin injected intravitreally acts by weakening and breaking the protein fibers that are causing the adhesion and separates the vitreous body from the retina, which relieves the traction and resolves the symptoms. Vitrectomy: Before JETREA, the only treatment option for patients with symptomatic VMA/VMT was surgical separation of the vitreous from the retina, called a vitrectomy. Vitrectomy is highly effective, but can lead to complications like bleeding, pain, post-operative inflammation or irritation. Because of this, it is usually only done when the patient s vision has deteriorated significantly. The alternative is observation or watchful waiting. 33

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36 A Alternatives for treating Medulloblastoma Medulloblastoma is a fast-growing, aggressive brain tumor that affects young children between 1 and 9 years of age. It accounts for almost 20% of all pediatric brain cancer: in the US alone, some 350 children are diagnosed with this cancer each year. Current treatments include chemotherapy and high doses of radiation. Cancer research company Oncurious, a joint venture between ThromboGenics and VIB, is currently studying alternative treatment options for children suffering from this disease.

37 FIGHTING BRAIN CANCER IN CHILDREN

38 CURRENT TREATMENTS SEVERELY AFFECT THE IQ OF YOUNG CHILDREN Giselle Sholler, M.D. MSC, talks about the unmet medical need in treating medulloblastoma As a pediatric oncologist at the Helen Devos Children s Hospital in Michigan (US), Giselle Sholler M.D. treats several young children each year who suffer from medulloblastoma. This very aggressive brain cancer affects children between 1 and 9 years of age. It presently can only be treated with chemotherapy and, in some cases, high doses of radiation. According to Dr. Giselle Sholler, there is a great medical need for alternative ways to treat medulloblastoma. Current treatments always start with the surgical removal of the tumor from the child s brain. This is followed by intense chemotherapy and, depending on the child s age, high doses of radiation. Radiotherapy severely affects the IQ of children as they grow, even after they have been cured of medulloblastoma. This usually results in the child s IQ decreasing after radiotherapy, which causes severe problems later in life, including significant learning difficulties. Consequently, radiotherapy is not used on children under 3 and is not recommended for children under 5. Interview with Dr. Giselle Sehnaz Sholler, Karadeniz M.D., MSC CHANCES OF SURVIVAL Unfortunately, these are the age groups often affected by medulloblastoma. These patients do receive chemotherapy, but this too is a very toxic treatment that is administered for approximately one year. Thus we hope to find novel treatments, especially for our youngest patients: not only to reduce the toxicity, but also to increase their chances of survival. Depending on the type of tumor, about 70 to 75% of all patients will be cured with chemotherapy and/or radiation treatment, but they will experience the side effects of the therapy for the rest of their lives. Some 20 to 25% will relapse. In this case, the outcome unfortunately is very poor. Most children who relapse don t survive. Chair of NMTRC This last group is the initial target group in the phase I/IIa clinical trial with the novel drug TB-403, which is currently being researched by Oncurious, a joint venture between ThromboGenics and VIB, a leading life science research institute in Flanders, Belgium. The trial is being conducted in partnership with the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC), of which Dr. Sholler is Chair. read further on page 38 37

39 ThromboGenics Perspectives 2016 PROMISING RESEARCH TB-403 is the antibody that combats placental growth factor (PlGF), which causes the brain tumor to develop in the child s brain. The molecule has the potential to stop the cells in the tumor from growing, explains Dr. Sholler. The results of the preclinical trial with TB-403 were very promising. We expect the drug to be much less toxic, thus it should be more tolerable for the patient. The purpose of the clinical phase I trial is to examine the safety of different doses. We have finished the first dosage level with 3 patients and the results are very promising. We will now be moving on to the second dosage level, says Dr. Sholler. A clinical phase II trial will follow the phase I trial. A total of 36 patients will be enrolled. It is very important to find novel treatments that can avoid radiation therapy, especially for our youngest patients The NMTRC is recruiting patients for this clinical trial. We have opened the study to many of our patient centers for children who have relapsed from medulloblastoma. Since the outcome for these patients is very poor, many of the families are willing to participate in the study. It is not likely to cause significant side effects and it gives their child an option when no other treatment is possible. The ultimate aim is to be able to treat not only patients relapsing from medulloblastoma, but also to use the drug in the future as an upfront alternative treatment. It would be a great benefit if the high doses of chemotherapy presently administered after surgery could be reduced. This severely affects the children s lungs, liver, kidney and heart. 38

40 Interview with Giselle Scholler, M.D. About the NMTRC The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) is a group of 25 universities and children s hospitals, headquartered at the Helen Devos Children s Hospital, that offers a nationwide network of childhood cancer clinical trials. These trials are based on the work of a group of closely collaborating researchers who are linked with laboratory programs developing novel therapies for high-risk neuroblastoma and medulloblastoma. The NMTRC s mission is to facilitate a national collaborative effort on the part of researchers, oncologists and family advocates in order to develop new therapies for children with relapsed neuroblastoma and medulloblastoma, with the goal of improving the quality of life and survival of children with neuroblastoma and medulloblastoma. (Source: nmtrc.org) Who is Giselle Sholler? Dr. Sholler received her M.D. from New York Medical College at Valhalla, NY. She was a resident in pediatrics and subsequently a fellow in pediatric hematology/oncology at Brown University, before coming to international prominence for her work with relapsed neuroblastoma at the University of Vermont. She then transferred her program to Helen DeVos Children s Hospital, Grand Rapids, MI. She is now Haworth Director of the Innovative Therapeutics Clinic focused on early phase clinical trials for pediatric cancers. Here she sees patients as part of the NMTRC which she chairs. Dr. Sholler s lab research at HDVCH, where she runs the Neuroblastoma Translational Research Laboratory, is focused on identifying new therapies for children with neuroblastoma. (Source: nmtrc.org) 39

41 ThromboGenics Perspectives 2016 I SEE A PROMISING FUTURE FOR ANTI-PLGF Peter Carmeliet, M.D., Ph.D. on the potential of TB-403 Prof. Peter Carmeliet, M.D., Ph.D., is Head of the Laboratory of Angiogenesis and Vascular Metabolism at the VIB-KU Leuven (Center for Cancer Biology, CCB) and Chief Scientific Strategy Advisor at Oncurious, which researches innovative medicines for the treatment of pediatric brain tumors. As the phase I/IIa clinical trial with TB-403 (anti-plgf) as an alternative treatment for medulloblastoma continues, he is enthusiastic about the initial results. The preclinical studies we have conducted with this antibody have already generated very promising data. These are the best results we have obtained to date with anti- PlGF, which is always an indication that the product potentially has a future as a new treatment and that further clinical trials are warranted, explains Peter Carmeliet. We expect the first results by the end of this year. TB-403 (anti-plgf) has the potential to block the disease process without side effects on the healthy tissue Doctors and scientists from around the world closely following the evolutions of the clinical phase I/IIa study of Oncurious with TB-403 (anti-plgf) are interested in these initial data. Doctors are desperate to find novel ways to fight this aggressive form of brain cancer in children, says Dr. Carmeliet. I have spoken with pediatric oncologists from the Massachusetts General Hospital of Harvard, among others. They were very enthusiastic about the potential of the product as an alternative treatment for medulloblastoma. Interview with Prof. Peter Carmeliet, M.D., Ph.D. Head of the Laboratory of Angiogenesis and Vascular Metabolism at the VIB-KU Leuven and Chief Strategy Advisor at Oncurious NO SIDE EFFECTS ON HEALTHY TISSUE Dr. Carmeliet confirms that TB-403 is very attractive as an alternative to current treatments with chemotherapy and/or radiotherapy, which are very invasive in young children suffering from medulloblastoma. 40

42 Interview with Prof. Peter Carmeliet The most attractive characteristic of anti-plgf is that the compound can block the disease process without any side-effects on healthy tissue. He continues: The high toxicity of chemotherapy and radiation entails several negative side effects in the long term. After treatment, young children treated with radiotherapy may progressively lose 1 IQ unit per year for the rest of their lives, which has a dramatic effect on their development. I know very intelligent children who underwent similar treatments and could no longer learn simple words in French after their therapy. If we could give them another treatment option in the future, that would be great. Dr. Carmeliet and his research team at VIB (CCB, KU Leuven), in collaboration with Prof. Rakesh Jain from the Massachusetts General Hospital at Harvard (Boston), generated the first pre-clinical data on the therapeutic potential of human monoclonal antibodies against placental growth factor (PlGF) in the treatment of medulloblastoma. These data were published in the prestigious medical journal Cell. Based on the positive results, the anti- PlGF code-named TB-403 is now being further developed by Oncurious with Dr. Carmeliet in the position of Chief Scientific Strategy Advisor. Who is Peter Carmeliet? Peter Carmeliet M.D., Ph.D. (CCB, VIB-KU Leuven) is world-renowned for his research into blood vessel formation (angiogenesis), the neuro-vascular link (the fact that nerves and blood vessels follow the same pattern in the human body) and more recently the role and therapeutic potential of endothelial cell metabolism in angiogenesis. His research has provided groundbreaking insights into tumor development and the mechanism of Amyotrophic Lateral Sclerosis (ALS), a deadly disease that paralyzes the muscles. The significant impact of this research has been confirmed by an international study that placed Peter Carmeliet amongst the top 400 most influential scientists worldwide in biomedical research. (Source: flandersbio.be) About medulloblastoma Medulloblastoma is a fast-growing, malignant, primary brain tumor. It originates in the lower rear portion of the brain called the posterior fossa, which controls balance, posture, and complex motor functions such as speech and balance. It is the most common form of malignant brain tumor in children, accounting for 20% of all such brain tumors. In the EU and US, approximately 400 new patients are diagnosed annually, with boys affected twice as much as girls. The peak age of incidence is 3-5 years, and approximately 80% of patients are diagnosed before the age of 15. Current treatment consists of surgically removing as much of the tumor as possible, followed by craniospinal (brain and spine) radiation and/or chemotherapy generally in older children (>3 years). Although treatment improves survival rates, these regimens are highly toxic to the developing brains and are associated with significant morbidity. The prognosis is worse if the child is less than 3 years old, if not enough tumor was removed, or if there is any spread to other regions of the brain or body. With treatment, 60-65% of children with high-risk medulloblastoma, and 80-90% of those with the disease that has not spread, can be expected to be free of the disease within 5 years. However, treatment often results in significant neurocognitive impairment in children younger than 8. 41

43 ThromboGenics Perspectives 2016 INNOVATIVE MEDICINES FOR THE TREATMENT OF BRAIN TUMORS IN CHILDREN Oncurious: Cancer research and development Oncurious is an emerging cancer research company and a joint venture between ThromboGenics and VIB, a leading life science research institute in Flanders, Belgium. The company focuses on the development of innovative orphan drugs for the treatment of pediatric cancers. It initiated a phase I/IIa study this past year to evaluate safety and tolerability, and explore the preliminary efficacy of TB-403 for the treatment of relapsed or refractory medulloblastoma, a rare and life-threatening brain tumor that mainly affects children. THE POTENTIAL OF TB-403 IN TREATING MEDULLOBLASTOMA TB-403 is a humanized monoclonal antibody against placental growth factor (PlGF). PlGF is expressed in several types of cancer, including medulloblastoma. High expression of the PlGF receptor neuropilin 1 has been shown to correlate with poor overall survival. In a landmark paper published in 2013 in Cell by Prof. Rakesh Jain (Massachusetts General Hospital, Harvard, Boston, US) and Peter Carmeliet (VIB/KU Leuven, Belgium), the authors showed that blocking PlGF signaling in medulloblastoma mouse models resulted in tumor regression, decreased metastasis and improved survival. Treatment of PlGF with TB-403 in relevant medulloblastoma animal models has demonstrated beneficial effects on tumor growth (containment) and survival. The favorable safety profile of TB-403 has already been shown in clinical trials in patients with other diseases. In January 2016, the FDA completed the safety review of Oncurious Investigational New Drug (IND) Application and ruled that the proposed pediatric clinical investigation could proceed. This was a major milestone for Oncurious. In May 2016, Oncurious initiated the phase I/IIa clinical trial. In clinical phase I, the aim is to examine the safety and tolerability of different dosages. The preliminary efficacy of TB-403 will also be explored. PARTNERSHIP WITH NMTRC FOR RECRUITING PATIENTS For the clinical phase I/IIa trial with TB-403, Oncurious is partnering with BioInvent and the Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) in the US. The NMTRC is a group of 25 US academic medical centers, teaching hospitals and other entities whose goal is to facilitate and conduct collaborative research and investigations into new treatments for neuroblastoma, medulloblastoma and other pediatric cancers. Headquartered at the Helen Devos Children s Hospital in Grand Rapids, MI (USA), NMTRC is the key clinical trial partner for this Phase I/IIa study. The study aims to recruit a minimum of 27 patients, with reports on the initial results expected by the end of In January 2017, the European Commission confirmed the orphan drug designation for TB-403 for medulloblastoma. An orphan drug designation is given for medicines to be developed for the diagnosis, prevention or treatment of rare diseases that are life-threatening or very serious. Drug/ Target TB-403 Target Indication Preclinical Medulloblastoma Clinical Phase I Clinical phase I/IIa Clinical Phase II Clinical Phase III Go 42

44 About ThromboGenics & Shareholders information T About ThromboGenics & Shareholders information ThromboGenics is a global biotechnology company developing innovative treatments for diseases of the back of the eye, with a focus on diabetic eye disease. 43

45 ThromboGenics Perspectives 2016 ABOUT THROMBOGENICS INNOVATIVE OPHTHALMIC MEDICINES ThromboGenics is strongly committed to R&D on treatments for diabetes-related eye diseases like proliferative diabetic retinopathy (PDR) and non-proliferative diabetic retinopathy (NPDR) with or without diabetic macular edema (DME). A quadrant of groups of DR patients is used to determine which types could benefit from the novel compounds in the pipeline. The company s first product, JETREA (ocriplasmin), has been approved in 54 countries worldwide for the treatment of symptomatic VMA/VMT. OUR MISSION The ThromboGenics mission is to pioneer and deliver next-generation treatments offering the potential to prevent vision loss. We have pioneered the drug category of pharmacological vitreolysis with JETREA, the world s only approved pharmacological vitreolysis treatment currently available. We will develop other solutions and expand this category. With diabetes, a leading health challenge worldwide, we are committed to deliver new and innovative treatments to help tackle the growing number of diabetes related eye diseases. We want to provide solutions enabling vision preservation for all people equally. All our work is centred on the patient: when a treatment is good for a patient, eventually it will benefit all the company s stakeholders, internally and externally. Drug/Target Target Indication Preclinical Clinical Phase I Clinical Phase II Clinical Phase III Go Milestones JETREA (ocriplasmin) Symptomatic VMA/VMT Go Commercialized: US (directly)/ex-us with Alcon THR-409 (ocriplasmin) NPDR Clinical phase II Ocriplasmin for inducing total PVD and halt further progression from Diabetic Retinopathy (DR) to Proliferative Diabetic Retinopathy (PDR). THR-317 (anti-pigf) DME Clinical phase II A PlGF neutralizing monoclonal antibody is developed for DME and/or for use in combination therapy with current anti-vegf drugs for treatments of DME or DR. THR-687 (integrin anatagonist, lead) NPDR & PDR Pre-cl. Preparing start Phase I clinical trial - Integrin receptor antagonist for treatment of DR with and without DME. THR-149 (plasma kallikrein inhibitor) DME Pre-cl. Preparing start Phase I clinical trial a plasma kallikrein inhibitor to treat DME associated with DR. 44

46 About ThromboGenics OUR ORGANIZATION: THE PEOPLE BEHIND THE THROMBOGENICS SUCCESS ThromboGenics employs around 80 people worldwide. Most work at the company headquarters in Leuven (Belgium) or from our office in New Jersey (US). The large majority of this international team s members hold a Master s or PhD degree. EXECUTIVE MANAGEMENT Patrik De Haes, M.D. Chief Executive Officer Patrik De Haes, M.D. has over 25 years of experience in the global healthcare industry, in product development, marketing and general management. Before joining ThromboGenics as CEO in 2008, he was head of Roche s Global Insulin Infusion business. Before that Patrik 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. Patrik holds a degree in Medicine from the University of Leuven. Patrik De Haes M.D. CEO Dominique Vanfleteren Chief Financial Officer In January 2015, ThromboGenics appointed Dominique Vanfleteren as its new Chief Financial Officer (CFO). Dominique has over 25 years of experience in senior finance, operational, control and reporting roles in quoted international biopharmaceutical companies. Before joining ThromboGenics, Dominique spent 12 years at UCB, a global biopharmaceutical company, where he held a number of international managerial finance positions, the latest being CFO of UCB s Asia Pacific Operations, operating from Brussels and Shanghai. Prior to joining UCB, Dominique worked for GSK for 16 years. He held a number of senior finance positions in Brussels and London, the latest as Finance Director of GSK s Diversified Healthcare Services Europe. Dominique Vanfleteren CFO 45

47 ThromboGenics Perspectives 2016 Operations Management Team and Executive Committee Our leadership team s expertise and experience in research, clinical development, commercialization and financing ensure the long-term success of ThromboGenics. The Executive Committee sets the company s vision and strategy, while the broader Operations Management Team is responsible for planning and overseeing this strategy s execution. The members of the ThromboGenics Operations Management Team are Andy De Deene*, Claude Sander*, Dominique Vanfleteren*, Grégoire Franoux, Isabelle Decoster, Jean Feyen*, Johny Van Genechten, Lionel Moro, Marc Denayer*, Muriel Pasté, Ove Pedersen, Patrik De Haes*, Paul Howes*, Rosemarie Corrigan, Wouter Piepers, and Zoe Heineman. * Executive Committee member BOARD OF DIRECTORS The Company is led by a Board of Directors which is the Company s most senior administrative body. The Board of Directors decides upon the Company s values and strategy, upon its willingness to take risks and upon the general policy plan. The Board of Directors currently consists of nine members (from left to right on the picture): Paul G. Howes, Executive Director Emmanuèle Attout (Investea BVBA), Non-Executive, Independent Director Thomas Clay, Non-Executive Director Patrik De Haes (ViBio BVBA), Executive Director Luc Philips (Lugo BVBA), Non-Executive Director Staf Van Reet (Viziphar Biosciences BVBA), Non-Executive, Independent Director, Chairman David Guyer M.D., Non-Executive, Director Patricia Ceysens (Innov Activ BVBA), Non-Executive, Independent Director Baron Philippe Vlerick, Non-Executive, Independent Director (not on the picture) 46

48 Shareholders information SHAREHOLDERS INFORMATION LISTING ThromboGenics is listed on the Eurolist by Euronext Brussels under the symbol THR. Since 2009 it has been listed on the NEXT 150 Index, made up of mid to large capitalization stocks on the Euronext exchange. INVESTOR RELATIONS Our investor relations policy includes: 1. Providing reliable, accurate, and valuable information in a timely manner to help shareholders make informed decisions 2. Full transparency 3. Operating within the Company s policies and adhering to relevant security laws and regulations 4. Strengthening our dialogue with the investment community PAYING AGENT SERVICES KBC Bank acts as paying agent, meaning it does not charge shareholders for dividend payments, exercise of subscription rights, and other events concerning ThromboGenics shares. Shareholders should investigate what other financial intermediaries might charge for paying agent services. FINANCIAL CALENDAR 16 March 2017 Full Year Results May 2017 Annual Shareholders Meeting 11 May 2017 Business Update Q Sep 2017 Half Year Results Oct 2017 Business Update Q Providing access to the senior management team SHAREHOLDING STRUCTURE As of 31 December 2014, ThromboGenics has 36,094,349 outstanding shares and 691,000 outstanding warrants. (in per share) Value Thomas Clay 3.11% Landon Clay 6.20% Philippe Vlerick 6.44% Norges Bank 2.95% Public 81.30% 47

49 Global Head Office: ThromboGenics NV Gaston Geenslaan 1 B-3001 Leuven Belgium T +32 (0) F +32 (0) info@thrombogenics.com US Office: ThromboGenics inc. 101 Wood Avenue South, Suite 610 Iselin, NJ USA T F info@thrombogenics.com Contact Information Wouter Piepers Global Head of Corporate Communications & Investor Relations T +32 (0) F +32 (0) wouter.piepers@thrombogenics.com IR@thrombogenics.com Creation & Copywriting Cantilis 48