focus on novel treatments to combat vision … · prof. alan stitt, mccauley chair of experimental...

Exciting milestones in the fight against vision loss

Developing novel drugs through collaboration and strong science

Unlocking global business opportunities for JETREA®

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FOCUS ON NOVEL TREATMENTS TO COMBAT VISION LOSS

PERSPECTIVES ‘17-’18TH

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FOCUS ON NOVEL TREATMENTS TO COMBAT VISION LOSS

“WE NEED THERAPIES FIGHTING DIFFERENT HALLMARKS SIMULTANEOUSLY”

Prof. Alan Stitt, McCauley Chair of Experimental Ophthalmology

"EXPANDING OUR HORIZON WITH NOVEL TREATMENTS TO COMBAT VISION LOSS"

Patrik De Haes, MD, CEO Thomas Clay, Chairman of the Board of Directors

“DEVELOPING NOVEL DRUGS THROUGH COLLABORATION AND STRONG SCIENCE”

Susan Schneider, MD, Chief Medical Officer Jean Feyen, PhD, Chief Scientific Officer, Andy De Deene, MD, Global Head of Development

“JOIN FORCES TO FIGHT EYE DISEASE IN DEVELOPING COUNTRIES”

Rajat Agrawal, MD, CEO of Retina Global

CONTENTS

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p. 4

p. 14 p. 17

“THROMBOGENICS REMAINS INNOVATOR IN NOVEL RETINAL THERAPIES”

Benjamin Yerxa, PhD, CEO of Foundation Fighting Blindness

“JETREA® HAS A GROUP OF VERY LOYAL USERS WORLDWIDE”

Vinciane Vangeersdaele, Chief Commercial Officer

“LOOKING AT THE FUTURE OF IMMUNO-ONCOLOGY THERAPY”

Prof. Massimiliano Mazzone, PhD Prof. Gabriele Bergers, PhD Prof. Jo Van Ginderachter , PhD

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EXPANDING OUR HORIZON

WITH NOVEL TREATMENTS

TO COMBAT VISION LOSS

5

Perspectives

The year 2017 was marked by some very exciting milestones for ThromboGenics. Regaining the global commercial rights to JETREA® was obviously one of the main highlights. The company also made important progress in its drug development pipeline targeting diabetic retinopathy, the leading cause of blindness in the adult working population worldwide.

“I’ve been on the Board of Directors for many years now, and I can’t remember a more vibrant and exciting time to be with the company than today,” confirms Thomas Clay, Chairman of the Board of Directors. The Chairman has been a ThromboGenics shareholder for many years and was appointed in June 2017 fol-lowing the retirement of Staf Van Reet.

CEO Patrik De Haes, MD, continues: “The deal with Novartis was one of the most important achievements of this past year. The Board of Directors supported us during the whole process, which really was a team effort.”

As part of the agreement, ThromboGenics received an equity investment of €10 million, and the company welcomed Novartis as a shareholder. “We will use this cash infusion to expand our inno-vative drug development pipeline targeting novel treatments for diabetic retinopathy (DR), with or without diabetic macular edema (DME). This eye condition associated with diabetes is the leading cause of blindness in the adult working population worldwide,” says Patrik De Haes.

3 shots on goal to combat vision loss in people with diabetesIn developing its pipeline of potential diabetes treatment innova-tions, ThromboGenics’ goal is to offer best in class breakthroughs to fight vision loss worldwide. The company’s multipronged

approach to developing treatments for diabetic retinopathy has resulted in three innovative compounds already being evaluated in a clinical study or entering the clinic soon.

Early in 2017, ThromboGenics initiated a Phase I/IIa clinical trial evaluating anti-PlGF (THR-317) in patients with DME. This study is now complete, with first results reported in the Spring of 2018. CEO Patrik De Haes: “We are researching this antibody’s potential as a combination therapy with anti-VEGF treatments. The current standard of care consists of repeated injections, making it fairly intensive for patients. Unfortunately, not all persons with DME or DR respond well to anti-VEGF therapy, so for them this novel drug could offer a promise of relief.”

The drug's potential benefits have already been validated in several publications, including Experimental Eye Research. This peer-reviewed journal published preclinical data from early research on THR-317. In their conclusion, the authors clearly con-firm that the compound’s efficacy is comparable to that of VEGF inhibitors and highlight its potential added ability to reduce inflam-mation and fibrosis. “We are very enthusiastic about publications like these from the scientific community. They validate the poten-tial of our drug development pipeline,” says Chairman Thomas Clay. And there’s more: new promising routes lie ahead with two compounds ready to enter Phase I clinical studies by mid-2018. Preclinical research on THR-687 (an integrin antagonist) yielded encouraging data showing this novel molecule's potential for treating a broad range of patients with diabetic retinopathy, with or without DME. “Our presentation of these preclinical results at the

6

Perspectives

annual European Association for Vision and Eye Research (EVER) meeting in September generated keen interest in the eye and retina community. The next step is to translate these promising preclinical data sets into a clinical trial,” says Patrik De Haes.

“We are also evaluating the molecule THR-149, a selective plasma kallikrein inhibitor, to treat DME associated with DR. We have already conducted toxicology studies with this compound and are now preparing its clinical development, to begin soon.”

Expanding the horizon“Deepening the company’s insights into back of the eye diseases and the hallmarks of diabetic retinopathy is an ongoing effort,” continues Thomas Clay. “ThromboGenics therefore aims to recruit international talent with extensive experience and a broad net-work in the eye community.”

Patrik De Haes confirms: “This is why we invested in our Science team this past year. We were happy to announce the appoint-ment of Susan Schneider, MD, as Chief Medical Officer. Dr. Schneider brings to our company nearly 15 years of experience in clinical drug development. She was attracted by our targets in this field and will be invaluable in shepherding them along the clinical pathway.”

ThromboGenics aims to remain a leader in the area of the retina. “We want to expand our horizon of novel new treatment options in the future. Our preclinical research team is constantly seeking new ways to add innovative targets to our discovery pipeline in diseases of the back of the eye,” says Patrik De Haes.

Global commercialization of JETREA®

Meanwhile, the company’s first developed product JETREA® is today approved for treating symptomatic VMA/VMT in over 50 countries. “We are proud that nearly 30,000 patients have been treated with JETREA® since its introduction in early 2013," says Patrik De Haes.

ThromboGenics will now ensure continued patient access to JETREA® either through direct commercial activities in selected core markets or via commercial arrangements with third parties. “We agreed with Novartis that our company is a better fit for build-ing a smaller but sustainable long-term business case,” explains Patrik De Haes. “This brought new responsibilities to our organi-zation. Our first priority now is continuity of care by ensuring that patients and physicians have timely access to JETREA®.”

“Over the next years, we will further promote its global business case aiming to make this drug a profitable product,” the CEO con-tinues. “To this end, we welcomed Vinciane Vangeersdaele to our Leadership Team as Chief Commercial Officer. She is setting up a dedicated commercial team to further capitalize the drug's opportunities worldwide.”

Oncurious: fighting childhood cancer and exploring new assets in immuno-oncology This past year saw another momentous agreement for ThromboGenics’ daughter company Oncurious, co-founded with VIB (Flanders Institute for Biotechnology). The team acquired exclusive licenses to a portfolio of unique next-generation immuno-oncology assets from VIB.

Patrik De Haes: “The compounds have an extraordinary scientific foundation of seminal work at the VIB-KULeuven labs of Professor Massimiliano Mazzone and Professor Gabriele Bergers and the VIB-VUB lab of Professor Jo Van Ginderachter. With these new assets, Oncurious will start preclinical programs targeting a broad spectrum of cancers. We expect this effort to generate valuable outcomes within a few years.”

“I’ve been on the Board of Directors for many years now, and I

can’t remember a more vibrant and exciting time to be with the company than today.”Thomas Clay, Chairman of the Board of Directors

Significant marketsThe Chairman continues: “All these programs were recognized this past year by scientists, retina specialists, our shareholders, and other stakeholders of the medical and eye community. Our promising landscape of next-generation treatments targets sig-nificant markets and confirms our unique position as a focused biotech company.”

“In fulfilling our mission, we keep reaching out to the broad eye community. It is vital that researchers, biotech companies and patient organizations join forces to offer better treatment options for vision problems and fight blindness worldwide,” the Chairman concludes.

Meanwhile, Oncurious continues the clinical study of the antibody TB-403 (anti-PlGF) for treatment of medulloblastoma. This is the most common life-threatening brain tumor in young children. The study is conducted in collaboration with Beat Childhood Cancer and aims to recruit 27 patients. In early 2017 the European Commission also confirmed orphan drug designation for TB-403 for medulloblastoma. This is a key validation of this drug's poten-tial and offers vital benefits, including protocol assistance and 10-year market exclusivity once the medicine is on the market in Europe.

“ThromboGenics remains the majority shareholder in Oncurious, focusing on generating value in the oncology segment that will then be invested in our drug development efforts,” confirms Thomas Clay.

“We focus our efforts and resources on finding novel treatments for vitreoretinal disorders. We plan to expand the horizon of treatments in the near future.” Patrik De Haes, MD, CEO

DIABETIC EYE DISEASE

Diabetes is a worldwide pandemic affecting 425 million adults*, causing a steady rise in diabetic eye disease. Some 1 of 3 people in this growing diabetes population will develop diabetic retinopathy (DR) with or without diabetic macular edema (DME). This severe and degenerative disease leads to vision loss, and in later stages even blindness. ThromboGenics saw an unmet medical need for fighting these disorders and is researching innovative treatments, with a clear mission to combat vision loss in persons with diabetes.

*Source: www.idf.org

“WE NEED THERAPIES FIGHTING

DIFFERENT HALLMARKS SIMULTANEOUSLY”

Interview Professor Alan Stitt

11Diabetic eye disease

Perspectives

Every person with diabetes is at risk of going blind. The two main causes are proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). From years of studying the progression of diabetic eye disease, Prof. Alan Stitt points to a need for better therapies compatible with the current standard of care.

PDR and DME are two manifestations of diabetic retinopathy (DR), and in many respects they stem from the same cause, explains Prof. Alan Stitt, Dean of Innovation & Impact and the McCauley Chair of Experimental Ophthalmology. “Diabetes causes damage to vascular cells in the retina. This progressive decline in vascular functions relates to depletion of blood vessels, causing a lack of nutrition and oxygen reaching the retina. This is known as ischemia, a kind of stroke, which can cause leakage and abnormal growth of blood vessels.”

Dysfunctional cellsIn the first case the patient develops DME, in the second PDR, but both conditions can also occur at the same time. What’s more, blood vessels in the retina are surrounded by glial cells protecting neurons and immune cells. DR also damages them. “All those blood vessels and cells act together as one unit. If one becomes dysfunctional, the whole unit becomes suboptimal. Much research thus focuses on trying to understand what causes dysfunction of this so-called neurovascular unit which eventually leads to loss of blood vessels and retinal neurons,” says Prof. Stitt. “Stopping the early damage to the neurovascular unit could halt the progression of DR to PDR with or without DME.”

The professor believes inflammation is probably behind much of the pathology in DR in a very chronic and progressive manner. “It is not the same as having an acute infection. Inflammation in DR is much more low-key, but over time it becomes a key factor in vascular dysfunction. Novel therapies fighting this inflammation could therefore offer benefits to diabetes patients.”

Who is Prof. Alan Stitt?Prof. Alan Stitt was appointed to the McCauley Chair of Experimental Ophthalmology in Queen's University Belfast in March 2001. For over 10 years he was Director of the Centre for Vision & Vascular Science (CVVS), then the re-configured 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 oph-thalmology. His academic strengths are reflected in his publication output, which has garnered numer-ous citations. He has been awarded leading prizes including the Royal Society Merit Award (2011), the Sir Jules Thorn Biomedical Science Award (2010), and the 5th Fincham Medal (2016) (from the City of London’s Livery Companies) in recognition of research on diabetic retinopathy and neovascular events in diabetes. He is a leading contributor to the academic community by assuming editorial responsibility, holding editorial board memberships for various journals, serving on advisory panels, and presenting guest lectures across the world.

Prof. Stitt’s research has focused on the pathogen-esis of diabetic retinopathy and age-related retinal disease, where he discovered the role of advanced glycation end products (AGEs) and their receptors in the progression of these diseases. His work has uncovered several inter-related pathways involved in neuroglial and microvascular dysfunction in the diabetic and ageing retina. This research has led to developing and testing several compounds that have progressed to clinical trials.

(Source: Queen’s University Belfast)

12 Diabetic eye disease

Perspectives

Hand in hand with current therapiesThe current standard of care for PDR and DME is repeated injec-tions with anti-VEGF medicines. “One result of a lack of oxygen in the retina is an upregulation of hypoxia mediated growth factor. This is an increase in the number of receptors in cells, making them more sensitive to a certain substance. The best known is vascular endothelial growth factor or VEGF,” explains Prof. Stitt. “It has been proven that if you block that growth factor using an anti-body, you can effectively prevent the vascular leakage causing DME. Anti-VEGF therapy is very effective but quite intrusive for patients. They must undergo repeated injections or the retinal edema will return. Some patients respond very late, some in a delayed manner and some not at all. This argues in favor of novel therapies that can conform to this current standard of care and improve the outcome for patients.”

ThromboGenics is researching a PlGF antibody (anti-PlGF, THR-317) for treating DME in persons with diabetes. “This is a very promising clinical study. It positions very nicely alongside anti-VEGF medicines and potentially can also have anti-inflamma-tory aspects and protect the neurons in the retina. That would be a major benefit for patients. It might also work for non-responsive patients, or could mean that patients need fewer injections.”

Precision medicineProf. Stitt sees a major opportunity in enabling diabetic retinop-athy to identify patients responding to anti-VEGF as opposed to non- or late responders. “Ophthalmology lags behind the cancer field in adopting a precision medicine approach. But research is ongoing, and if we could find a way to phenotype patients in a more detailed manner there may be an opportunity to treat non-responding patients with other medicines. For instance, anti-PlGF could potentially offer benefits for the non-responders.”

It is also hard to predict which patient will develop PDR and which will have DME. “There are hallmarks that indicate disease pro-gression, but PDR and DME are often driven by the same ones. Some patients will progress quickly, others very slowly if at all. So therapies that can stop the progression at a very early stage, or novel treatments tackling several hallmarks simultaneously, would also be very advantageous.”

Diabetes, a worldwide pandemicDiabetes is a worldwide pandemic and a leading health emergency of this century. The 2017 edition of the International Diabetes Federation Atlas puts the number of people living with diabetes at nearly half a billion.

This chronic disease occurs when the pancreas can no longer make insulin, or the body cannot make good use of the insulin it produces. This leads to higher glucose levels in the blood (hyperglycemia), eventually causing damage to several parts of the body and severe complications like diabetic eye disease.

Nearly half of people with type 2 diabetes are unaware they have it, putting them at greater risk for developing complications like diabetic eye disease. More than a third of those with diabetes eventually develop some form of visual disorder, like diabetic retinopathy (DR) and/or diabetic macular edema (DME).

Source: International Diabetes Federation Atlas, edition 2017

Diabetes by age (20-79 years)

327 million

20-64 years

98 million

65-79 years

438 million

20-64 years

191 million

65-79 years

2017

2045


Perspectives

New pathwaysProf. Stitt says the search for therapies to treat DR or DME could also unlock opportunities for other eye diseases. “Diabetes is a pandemic, but another global challenge is definitely the ageing popula-tion. People worldwide are living longer so they suffer increasingly from age-related eye diseases like age-related macular degeneration (AMD). It is proven that, similar to PDR, abnormal angiogenesis drives one sub-type of AMD, known as the ‘wet’ form. The larger proportion of AMD patients have the so-called ‘dry’ form which is sometimes called geographic atrophy. In this form of AMD, retinal tis-sue slowly wastes away due to cell degeneration. The anti-inflammatory and neuroprotective aspects of anti-PlGF could potentially have some efficacy in geographic atrophy. All these aspects could be interesting targets to research.”

Strategic focus of ThromboGenics“I believe ThromboGenics is well positioned to explore all these pathways and find innovative treatments for diseases affecting the back of the eye,” confirms Prof. Stitt. “The company has a strong strategic focus on the retina and long-standing core expertise in that area. It can screen drugs and look for their efficacy in its established preclinical programs. It also has good experience in clinical development, so it can efficiently move from pre-clinical evidence into early stage clinical trials. Its in-depth focus enables it to detect the added value and market position of new compounds,” concludes Prof. Stitt.

“DEVELOPING NOVEL DRUGS THROUGH COLLABORATION AND STRONG SCIENCE”

Interview - Susan Schneider, MD, Chief Medical Officer - Jean Feyen, PhD, Chief Scientific Officer - Andy De Deene, MD, Global Head of Development


Perspectives

A key strength of ThromboGenics is its collaborative mind-set. Its Science team displays this under the leadership of Susan Schneider, MD (Chief Medical Officer), Andy De Deene, MD (Global Head of Development) and Jean Feyen, PhD (Chief Scientific Officer). They guide development of the company’s innovative pipeline, driven by intensive research and based on solid scientific evidence.

“We work as a complimentary team, putting ThromboGenics in a unique position as a very agile biotech company,” says Susan Schneider, who joined the company’s leadership team in 2017. With nearly 15 years of experience in clinical drug development, she oversees the company’s global clinical and medical groups.

The exciting and innovative ThromboGenics’ pipeline persuaded Susan Schneider to join the team. “This is a small R&D company with big ambitions and various development opportunities for the future. We take a truly objective and scientific approach to understanding the retinal space and the underlying mechanisms of action in diabetic eye disease. That positions us well to address the pathophysiology at hand and to focus on developing impor-tant disease-modifying treatments. The close cross-functional interactions between our preclinical, clinical and medical teams clearly make that possible.”

Cross-functional development “Development is cross-functional,” agrees Andy De Deene. “Our approach is unique because all teams stay involved throughout the process. In the clinical phase Development works hard on the regulatory, quality and safety aspects to get approvals in several countries. But our ultimate goal is to bring new therapies to clinics, so the medical side is involved from the beginning and critical at the end. And we continually consult the Preclinical Research people along the way. In bigger companies these fields are typically divided.”

Jean Feyen confirms: “Throughout the development, even in phase II and III trials, we remain accountable for the research tar-gets we explored because every phase has preclinical aspects to address. This type of complimentary action lets us be fast and agile without sacrificing quality.”

Ophthalmology as science platformIn exploring innovative pathways to fight diabetic eye disease, ThromboGenics aims to understand key areas of unmet medical need. “We want to make a difference and to build on the insights and experience gained from developing ocriplasmin (JETREA®) for symptomatic VMA/VMT,” says Susan Schneider.

Jean Feyen confirms: “In the biotech field many companies have science platforms based on a certain technology, like antibodies. Ours is ophthalmology, and more specifically the retinal space. We have a wealth of knowledge and experience in understanding retinal diseases and patients' unmet medical needs. Susan now brings additional extensive ophthalmology clinical development expertise, so together we can to map the ThromboGenics medical scientific strategy for the future.”

For the past two years the Science team has been working hard on drug development targeting diabetic retinopathy (DR). This yielded one program in clinical development and two more for which clinical trials are targeted to be initiated in 2018.

“Complementary action between preclinical, clinical and medical

teams lets us be fast and agile without sacrificing quality.”Jean Feyen, PhD, Chief Scientific Officer


Perspectives

Understanding diabetic eye diseaseEveryone with diabetes eventually develops vision problems and is at risk of going blind. Diabetic eye disease results directly from chronic high blood glucose levels that damage the retina. Patients can develop diabetic retinopathy (DR), a progressive disease with potentially diabetic macular edema (DME) as a further complication. This is characterized by a swelling of the macula due to ischemia.

About 93 million adults worldwide are affected with DR, making it the leading cause of vision loss in the working population. One in ten persons with DR will develop its vision-threatening form. As it progresses DR can cause blurry vision, cloudy vision, or colors that look faded. If left untreated, DR can lead to blindness. These symptoms can greatly impair quality of life and daily activities like driving the car, working, or household chores.

The symptoms of diabetic retinopathy (DR)Patients with diabetes have raised glucose levels in their blood, causing changes in certain proteins and 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 causes edema and proliferation of new blood vessels (angiogenesis) in the vitreous or along the retina's surface, eventually leading to permanent damage through development of scar tissue (fibrosis).

As the inflammation intensifies the hyperpermeability worsens, causing new inflammation, more edema and more proliferation and scar tissue. As this vicious circle continues, the disease progresses.

The symptoms of diabetic macular edema (DME)DME occurs when fluid leaks into the macula (the central part of the light-sensitive layer at the back of the eye). These leaks cause the macula to thicken and swell, progressively distorting acute vision. In some cases this can lead to a severe loss in central vision.

Inflammation

Permeability

Neuro and vascular dysfunction

Edema

Leakage, occlusion & non-perfusion

Angiogenesis

Fibrosis

Neurodegeneration


Perspectives

Combination study with THR-317One of the compounds, THR-317, a placental growth factor anti-body, is being evaluated to potentially treat diabetic macular edema (DME) in persons with diabetes mellitus. “In preclinical models this compound has some distinct pharmacology features compared to the current standard of care with anti-VEGF therapy,” explains Jean Feyen. “Like anti-VEGF, anti-PlGF also affects the edema aspect of diabetic retinopathy.”

“But in addition, our research has shown a positive effect of anti-PlGF on inflammation, another key disease hallmark of DR. Moreover, our compound is neutral and perhaps even slightly beneficial for the neuronal compartment of the eye and inhibit collagen deposition in fibrotic eye lesions.”

ThromboGenics is initiating a phase II clinical study with THR-317 to investigate its efficacy and safety profile, in combination with anti-VEGF for the potential treatment of DME. “The phase I/IIa clinical study with THR-317 focused on assessing THR-317s safety and tolerability profile. We also want to see whether we can address additional components of diabetic eye disease, such as inflammation and/or neurodegeneration in this program”, says

“JOIN FORCES TO FIGHT EYE DISEASE IN DEVELOPING COUNTRIES”Rajat Agrawal, MD, CEO Retina Global

Retina Global's goal is to save the world from blindness, specifically related to retinal diseases. “This focus on the retina makes us unique as a global organiza-tion,” says Rajat Agrawal, MD, CEO. Retina Global concentrates its work in developing countries in Africa and Central and South America, and wants to par tner with research companies pursuing novel treat-ments to the best international standards.

“In those parts of the world there are many patients who lack access to routine retinal care,” Dr. Agrawal explains. “We aim to provide clinical care by sending retina specialists to Africa and Central and South America. But our bigger goal is to create a sustainable outcome. We want to train local people as retina spe-cialists and share their expertise with the next generation.”

Beyond doubt, the diabetic retinopathy (DR) pandemic is larger in the Third World. “Patients there often aren’t aware they have diabetes, let alone DR. Moreover, they often must travel far to clinics or medical centers and can’t take time off from their work because their whole family's income depends on it. That is why we often see patients an a very late and severe stage of DR.”

“If they do come at an early stage and the medicines are available, we try to treat them with anti-VEGFs. But this requires repeated injections and many times they're unable to return in time for those. For them, an innovative new treatment requiring fewer injections could be a god-send. That is why we're keenly interested in the clinical trials ThromboGenics has in the pipeline. We're eager to join forces with the industry and research community to fight retinal diseases globally.”

Dr. Agrawal sees it as vital for patient organizations like Retina Global and research companies like ThromboGenics to par tner for cl inical t r ials . “Many patients in the Third World have never been exposed to medication before. Such patients are ideal to explore in early clinical trials. If we work together we truly can make a difference in finding new treat-ments to the best international standards,” concludes Dr. Agrawal.

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Perspectives

Treating diabetic eye diseaseDR often goes undetected because people with diabetes experience no symptoms of vision loss in its early stages. Screening and diagnosis do not happen until there is already vision loss, meaning DR is possibly in its severe stage. Screening dia-betes sufferers regularly through eye examinations with ophthalmoscopy, optical coherence tomog-raphy (OCT), or retinal photography is therefore critical. Good management of diabetes is the key to preventing DR from progressing at a first stage.

There are currently no treatments to restore vision loss in persons with DR, but when it has reached its severe and sight-threatening phase there are some methods to preserve vision. Treatments include laser therapy, intravitreal injections with anti-VEGF and in some cases cortisone, or a vit-rectomy. These are effective in preventing further vision loss and stabilizing vision. But anti-VEGF treatment with repeated injections is fairly intrusive for persons with DR, and unfortunately not every patient responds well to the therapy.

ThromboGenics saw an unmet medical need for treating DR and DME, and is working on three novel disease-modifying medicines to this end. A PlGF antibody is being developed for treating DME, and might offer added value as a combination therapy with current anti-VEGF treatments for DME or DR. Two other molecules, integrin antagonist (THR-687) and a selective plasma kallikrein inhibitor (THR-149), will also enter clinical development shortly.

Susan Schneider. “That way we could potentially offer improved treatment outcomes for patients. Our focus on the patient helps to define our areas of concentration that, in turn, drive our drug development goals.”

Jean Feyen continues: “Our ultimate goal is to research and develop innovative therapies with disease-modifying activity. DR is a chronic and degenerative disease for which there is currently no adequate treatment. Anti-VEGFs are saving patients' vision, but they don’t cure the disease and require repeated injections in the eye. If we could modify the disease by combining current therapies and novel products with added benefits, this could potentially reduce the number of injections over time.”


Perspectives

Continued development of research targetsThe late-stage preclinical development with THR-149 and THR-687 is now being completed. “The results clearly support further progression in clinical trials, which we will initiate shortly,” says Jean Feyen. The compounds are two more shots on goal to treat DR. THR-149, a plasma kallikrein inhibitor, will be developed to treat diabetic macular edema. “With plasma kallikrein as a vali-dated target, this compound has a strong potential on the vascular leakage aspect of DR,” says Andy De Deene.

With THR-687, an integrin antagonist, ThromboGenics is aiming at a broader spectrum of DR hallmarks. “This compound could have positive effects on inflammation and edema, but also on neovascularisation. It's a powerful combination that could target both early- and later-stage DR.”

“THROMBOGENICS REMAINS INNOVATOR IN NOVEL RETINAL THERAPIES”Benjamin Yerxa, PhD, CEO of Foundation

Fighting Blindness

Foundation Fighting Blindness is a global nonprofit organization devoted to providing treatments, prevention and cures for blinding retinal diseases. CEO Benjamin Yerxa sees a huge medical need in neuroprotection and preventing degeneration of the retina.

“There is currently an explosion in R&D activities in the retinal space. Numerous potential new therapies are ready for trans-lation into clinical studies, making this a truly exciting time for the eye community,” says Benjamin Yerxa, CEO of Foundation Fighting Blindness.

With two new compounds entering clinical trials in 2018 and one already in clinical development, with its focus on diabetic retinopathy ThromboGenics contributes to these developmental evolutions in retinal disease. Benjamin Yerxa says the company has always been among the leaders in this area. “I think ThromboGenics is true to its nature, and that gives it serious credibility in the community. They've been working on novel treatments for retinal diseases for a

long time and remain an innovator. That sets them apart from many other companies and gives confidence for the future.”

Foundation Fighting Blindness is constantly looking for new research and develop-ment of novel therapies. It funds academic researchers to search for new discoveries or interventions based on the action mech-anism of diseases. The Foundation focuses on inherited and age-related retinal dis-orders, but Benjamin Yerxa also points to important synergies in researching genetic eye diseases and larger indications like diabetic retinopathy.

“The disease processes show similarities. If we could discover and develop a compound that is neuroprotective and helps prevent retinal degeneration, that would be helpful in inherited retinal diseases but also in DR and age-related retinal disorders.”

eye community

“CUTTING-EDGE RESEARCH CAN CHANGE PEOPLE'S LIVES”Jeff Todd, President & CEO Prevent Blindness US

Prevent Blindness has existed for more than a century with one clear mission: to prevent blindness and preserve sight. The organiza-tion focuses on eye health conditions in the US, working to improve both education and public policy.

“Partnerships with the industry and biotech companies like ThromboGenics are crucial to us,” says Jeff Todd, President & CEO. “It is vital that ophthalmologists, retina spe-cialists, patient organizations, R&D com-panies and the big pharma industry work together to have an impact on a large scale. It will take all of us to fight blindness and sight-threatening diseases.”

“Visual disorders have a large impact on the patient’s life,” he continues. “Not being able to drive a car or go to work makes them

lose their independence. That is definitely an aspect Prevent Blindness is strongly focusing on. We want to make sure people have a high quality of life, not impacted by visual problems.”

To fulfil its mission, Prevent Blindness wants to par tner with organizations that are trying to solve problems currently lacking a treatment or looking for ways to improve an existing one. “That is why we're so excited to partner with ThromboGenics. They have an innovative approach to new eye care research for conditions that presently have no known therapies. Their cutting-edge research can really improve and change people’s lives,” concludes Jeff Todd.

eye community


Perspectives

Addressing a sub-optimal response to current therapies“What’s important is that all our pathways are anti-VEGF inde-pendent,” adds Andy De Deene. “For example, we explore THR-317 also in combination with anti-VEGFs but they all can work independently. That is why we also focus on patient populations where anti-VEGFs don’t always work.”

Diabetes mellitus, as a systemic disease, is a pandemic globally and with that, an increase in the incidence of diabetic eye disease goes hand in hand. Diabetic retinopathy can result in vision loss and even blindness. “We believe that this is a growing area of unmet medical need in which new and innovative alternative and/or adjunctive treatments might be able to address its multifactorial nature and thus have the potential to improve outcomes,” says Susan Schneider.

“Developing innovative medicines doesn’t happen in isolation. We look for as many interactions as possible.”Andy De Deene, MD, Global Head of Development


Perspectives

Reaching out to the communityA vital success factor for the company’s clinical programs is its strong relationship with the ophthalmology community. “Interacting with scientists and clinical investigators is critical to us,” says Jean Feyen. “We're not going to cure eye diseases by ourselves as a company. We depend on a broad community of retinal specialists, scientific experts and patient advocacy organ-izations. Our goal is to a have highly productive drug discovery engine by integrating the knowledge in the field and selected scientific collaborations.”

ThromboGenics therefore consults regularly with various experts during the research and development process for all compounds. “They bring complimentary knowledge from which we learn and can apply to our programs. It's essential for us to stay scientifically sound and clinically relevant,” adds Susan Schneider.

“That is why we are excited and proud to see our preclinical work published in international peer-reviewed journals like Experimental Eye Research. It helps to illustrate the high quality of our science,” says Jean Feyen.

“Developing innovative medicines doesn’t happen in isolation. We look for as many interactions as possible that enable us to deliver innovative drugs. Regaining the global rights to JETREA® pushed us forward in that respect. We are now a true global player, giving us even more exposure to the medical community,” adds Andy De Deene.

“In the end, our primary focus is always on the patient,” says Susan Schneider. “Through insights gained from healthcare professionals advocacy groups and the patients themselves, we hope to continue to gain a sound and relevant perspective on this very important aspect of drug development. That way we keep optimizing our potential to provide the best possible therapies to treat debilitating eye diseases.”

Crossroads“In 2018 the team will be highly focused on operationalizing aspects of its rich development pipeline in diabetic eye disease, which includes initiating these clinical programs and enrolling the first patients in these clinical trials,” says Susan Schneider. “We will also continue to look to optimize our programs in a data driven and patient-centric way.”

Meanwhile, the company is already looking to the future, exploring unmet medical needs in the broader area of retinal vascular diseases and in additional areas of interest in back of the eye disorders. “We're at a crossroads: our rich DR portfolio is being developed but we also have some new targets being discov-ered. We intend to remain current with what’s happening in the ophthalmology space and in touch with the community to explore the best strategic paths moving forward to the future,” concludes Jean Feyen.

“It is critical to ThromboGenics that we remain scientifically sound and focused on true unmet medical need. We seek to truly understand the mechanisms of action underlying diabetic retinopathy (DR) and the multifactorial nature of diabetic eye disease.”Susan Schneider, MD, Chief Medical Officer


Perspectives

DISCOVERY AND PRECLINICAL

PIPELINEEXPANDING OUR HORIZONThromboGenics is continuously expanding its work in earlier-stage projects, searching for new pathways and compounds for developing next-generation treatments for back of the eye disorders, with a focus on diabetic eye disease.

Before a new medicine becomes available to the broad public, it goes through an exten-sive preclinical and clinical validation process.

ThromboGenics currently has 1 compound in clinical development and 2 more com-pounds for which clinical studies will start this year. Further new drug candidates are currently being progressed for the treatment of diabetic eye disease and one of these is expected to enter development in 2018.

NOVEL COMPOUND undisclosed

THR-149 (PLASMA KALLIKREIN INHIBITOR)Preclinical research targeting DR, DME

THR-687 (INTEGRIN ANATAGONIST)Preclinical research targeting DR

THR-317 (ANTI-PIGF)Clinical research targeting DR, DME

ANTICIPATED 2018


Perspectives

CLINICAL PHASE I CLINICAL PHASE II

THR-149 (PLASMA KALLIKREIN INHIBITOR)Preclinical research targeting DR, DME

THR-687 (INTEGRIN ANATAGONIST)Preclinical research targeting DR

THR-317 (ANTI-PIGF)Clinical research targeting DR, DME

ANTICIPATED H1 2018

ANTICIPATED H1 2018

ANTICIPATED MID 2018

JETREA®

GLOBAL BUSINESS

UNIT

Through an agreement with Novartis, ThromboGenics regained full global commercial rights to its product JETREA®, the first and only approved pharmacological treatment for symptomatic VMA/VMT. The Commercial Team is assuring continuity of care for patients and physicians and evaluating how best to capitalize on the global opportunities and untapped potential to commercialize JETREA® worldwide. First introduced in 2013, JETREA® has been approved in over 50 countries with nearly 30,000 patients being treated.

Chief Commercial Officer Vinciane Vangeersdaele is setting up ThromboGenics’ global business unit

“JETREA® HAS A GROUP OF VERY LOYAL USERS WORLDWIDE”

Interview Vinciane Vangeersdaele, Chief Commercial Officer

27JETREA®

Perspectives

Gaining the global rights to JETREA® from Novartis brought new responsibilities to ThromboGenics. Chief Commercial Officer Vinciane Vangeersdaele is setting up a full operational business unit to assure continuity of care for physicians and their patients. “Our flexible organization is a good fit to answer the specific needs of JETREA® users,” she notes.

Vinciane Vangeersdaele joined the ThromboGenics leader-ship team this past year. With extensive experience in com-mercializing pharmaceutical portfolios worldwide, including in ophthalmology, she was attracted by the company’s ded-icated strategy in back of the eye diseases. “Driving innova-tion allows us to actually change patients’ lives,” she says. “Our strong focus should enable us to truly make a difference in bringing value to end users.”

“In this respect the JETREA® business case intrigues me. There is a group of physician customers who have stayed very loyal to this innovative product over the years. By using it with the right selected patients they have witnessed its value in treating symptomatic VMA/VMT. They also continue to investigate the drug’s potential and publish those data. Since the OASIS study there have been a lot of real-life, evidence-based publications on JETREA®. This shows the continuous interest in our product.”

Real world evidenceVinciane Vangeersdaele says ThromboGenics is now investi-gating what drives retina specialists to use JETREA® for their patients. “That way we will show its potential with real world, user-based evidence. Over the years, users have continued to investigate and understand JETREA®. Real world evidence could help us further to understand if and how the drug stops the disease from progressing and preventing further vision loss in patients with sVMA/VMT.”

Symptomatic VMA/VMT: patient journeyThromboGenics 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. Previously, 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.

Patient journeyThe patient experiences vision changes: metamorphopsia (blurred vision) and/or a macular hole (central blindness).

The patient consults an ophthalmologist, who determines that 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 that can deliver 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.

Treatment options:

Observation: This is the process of ‘watchful waiting’ until the condition of the patient deteriorates until he or she is eligible for surgical treatment and repair of the retina. However, this is not a suitable option for many patients, since irreversible damage to the retina may have already occurred.

Injection with JETREA®:JETREA® is the first pharmacological option for treating sympto-matic VMA and VMT. It is administered as an intravitreal injection. The drug allows physicians to treat patients with the relevant symptoms in an early stage. Successful treatment can improve the patients’ vision and their ability to carry out normal daily activities. It can also halt the further progression of the disease.

Vitrectomy: Before JETREA®, the only treatment option for patients with symp-tomatic VMA/VMT was surgical separation of the vitreous from the retina, in a procedure called a vitrectomy. This entails several risks and can lead to complications such as bleeding, pain, post-opera-tive inflammation and irritation. Because of this, the surgery is usu-ally only performed after the patient’s vision has deteriorated sig-nificantly. This approach is called ‘observation’ or ‘watchful waiting’.

28 JETREA®

Perspectives

A key factor in producing strong outcomes with JETREA® is good patient selection. “This was clearly shown by the OASIS study with ocriplasmin, evaluating the drug in a two-year follow-up study. We want to build on these results to create a sustainable, long-term solution for physicians and their patients.”

JETREA® is now approved in over 50 countries and being used to treat some 30,000 patients. “In 18 countries the product is also reimbursed. With the evidence we've accumulated we're now also preparing a reimbursement dossier in Belgium. This will be a landmark event, ThromboGenics being a Belgian company,” says Vinciane Vangeersdaele.

Untapped opportunitiesRegaining the global commercial rights to JETREA® from Novartis brought new responsibilities. “We are now setting up a full operational business unit to meet all the requirements for com-mercializing this product on a global scale: regulatory, supply chain, legal and commercial, etc.”

“Our first priority is ensuring a smooth transition for physicians and patients. As a smaller organization we should be able to adapt resources more flexibly to answer specific market needs,” adds Vinciane Vangeersdaele.

Local commercial teams are being set up in identified key coun-tries. “We're focusing on the existing markets. The commercial team in the US will be reinforced. Their insights in building long-term customer relationships will be invaluable. Other best prac-tices from the past in countries like Germany, Italy or Canada will be leveraged more broadly.”

ThromboGenics will also launch the already diluted formulation (beyond the US at this moment) of JETREA® in the second part of 2018. “This will make our product easier to administer, providing a more easy to use, fast and efficient solution to professionals,” says Vinciane Vangeersdaele.

29JETREA®

Perspectives

JETREA® (ocriplasmin): a unique mechanism of actionJETREA® 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.

Normal Separation (PVD)Vitreous remodeling leads to progressive liquefaction with age.

Symptomatic VMAIncomplete separation can cause Vitreomacular Adhesion (symptomatic VMA), which results in traction and leads to visual impairment.

Symptomatic VMA resolvedOcriplasmin injected intravitreally acts by weakening and breaking down the protein fibers causing the adhesion, thus allowing separation of the vitreous body from the retina. This relieves the traction and resolves the symptoms.

30 JETREA®

Perspectives

Combining commercial and scientific know-howVinciane Vangeersdaele confirms the agreement with Novartis was a milestone for the company, not just for JETREA®. “We now truly have a global footprint. Commercializing the product world-wide will position us closer to our stakeholders, for both JETREA® and our drug development pipeline. Because in the end, we are offering solutions to the same population of physicians.”

Her ultimate aim is to bring market insights into early stages of the ThromboGenics clinical development portfolio. “I find it fas-cinating to work closely with the R&D department. The beauty of ThromboGenics is that we're a true biotech company that has commercialized its own product. This brings us closer to the end user and makes us truly understand what the market needs. Combining scientific and commercial know-how will bolster ThromboGenics’ strategy for the future.”

“TRAINING OPHTHALMOLOGISTS IS ESSENTIAL TO FIGHT BLINDNESS IN DEVELOPING COUNTRIES”Isabelle Verhaegen, Director of Light for the World

Since 2014, ThromboGenics has been supporting the Belgian branch of the European NGO Light for the World. It fights eye disease in Rwanda, Tanzania and Congo, providing organizational, technical and financial support to medical eye centers.

“Our key ambition is to put an end to avoidable blindness worldwide,” says Isabelle Verhaegen, Director of Light for the World. “Creating awareness of eye diseases really is key for developing coun-tries, such as in Africa. For example, most people with cataracts don’t know their vision problems can be easily treated. For diabetic retinopathy it's even worse: people often don’t even know they have diabetes, let alone that their disease can cause vision threatening disorders if left untreated.”

Light for the World supports local partner organizations in creating disease aware-ness among the population in Rwanda, Tanzania and Congo. “We also help local partners build and equip medical eye care centers, and with educating local doctors. We give scholarships to students wanting to study ophthalmology and send European specialists to train local doctors as eye specialists.” ThromboGenics has supported Light for the World since 2014. “With their funding we supported, for instance, the eye department of a hospital in Tanzania and gave a scholarship to a doctor to be trained as an ophthalmolo-gist,” says Ms. Verhaegen.

One problem developing countries face is insufficient equipment and knowledge to treat certain eye diseases. “For diabetic retinopathy that is definitely the case. There is often no access to the current standard of care. Moreover, patients must

keep returning for injections, another big obstacle for most of them. Finding treat-ments that are easier and less intrusive for patients would be a major benefit for Third World countries.”

“To f ight blindness globally all stake-holders must work together: nonprofit organizations like ourselves, big pharma industries, the medical and science community, and innovative R&D com-panies like ThromboGenics,” concludes Isabelle Verhaegen

eye community

ONCURIOUS CANCER

RESEARCH

Oncurious is a joint venture between ThromboGenics and VIB, the leading life science research institute in Flanders, Belgium. The company is focused on development of inno-vative medicines for treatment of a broad spectrum of can-cers. Its clinical trial with TB-403 (anti-PlGF) researches alternative treatment options for medulloblastoma, a rare life-threatening brain tumor in children. Moreover, the com-pany is currently developing a portfolio of next generation immuno-oncology assets.

Oncurious and VIB in a unique partnership to fight cancer

“LOOKING AT THE FUTURE OF IMMUNO- ONCOLOGY THERAPY”

Interview Prof. Massimiliano Mazzone, PhD Prof. Gabriele Bergers, PhD Prof. Jo Van Ginderachter, PhD

35

Perspectives

Oncurious

With the first generation of immuno-oncology therapies ready to hit the market, Oncurious and VIB are already looking at the future. Their partnership seeks to combine early-stage research on five novel assets. “Combining targets is a unique opportunity to offer improved next-generation immuno-oncology therapies.”

This past year Oncurious concluded an agreement with VIB to acquire exclusive licenses to a portfolio of five innovative immuno-oncology assets. Those unique new targets origi-nate from seminal work at the VIB-KU Leuven labs of Gabriele Bergers and Massimiliano Mazzone and the VIB-VUB lab of Jo Van Ginderachter.

“Our labs all have a different focus,” explains Jo Van Ginderachter. He is head of the Immunology labs at VIB and VUB, where his team researches immunotherapies for several diseases. The VIB-KU Leuven lab of Gabriele Bergers focuses on the vascular niches of tumors, and Massimiliano Mazzone and his team at the Angiogenesis lab of VIB and KU Leuven research inflammation and angiogenesis of tumors. “We now combine our expertise for one shared goal: to find next-generation therapies in immuno- oncology,” Jo Van Ginderachter explains.

Combinatory approach“In past years it has been proven that our immune system is indeed able to recognize cancer cells efficiently and perform anti-tumor activity,” says Jo Van Ginderachter. Several clinical trials of immuno-oncology therapies show excellent results and some of them are already on the market. “Those first-generation therapies, like checkpoint inhibitors that help the body recognize and attack cancer cells, have already proven successful in a sub-set of patients,” adds Gabriele Bergers.

But many cancer patients are still not responding to the first genera-tion of immunotherapies. “To give an example, melanomas immuno-therapy is currently first in line and works very well for some 30% of patients. But what about the other 70%? Even worse is the situation for colon and pancreas cancer where the response is close to zero,” explains Massimiliano Mazzone. “That is where we want to make a difference with our unique combinatory approach.”

Who is Prof. Gabriele Bergers?Gabriele Bergers is a Professor of Oncology at the University of Leuven and a group leader at the VIB-KU Leuven-Center for Cancer Biology in Leuven since 2016. She has been a Professor in the Department of Neurological Surgery, and a PI in the Brain Tumor Research Center (BTRC) at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco for more than 15 years and has remained associated with UCSF.

She had received her PhD in Genetics at the Institute of Molecular Pathology (IMP) and the University Vienna in Austria. She then moved to the US to pursue her postdoctoral studies on tumor angiogenesis in the laboratory of Dr. Douglas Hanahan at UCSF. She has made seminal dis-coveries about tumor niches regarding both the interactions among tumor cells, the vasculature, and inflammatory cell constituents in regulating neovascularization and invasion in various mouse models of brain, breast and pancreatic cancer and in revealing and understanding intrinsic and evasive resistance mechanisms of tumors to antiangiogenic therapy.

Prof. Bergers has received several awards for her research, including the Sidney Kimmel, the Program for Breakthrough Biomedical Research Award, the Sandler Opportunity and the Judah Folkman award. She has been an External Advisory Board member for various universities and pharmaceutical companies, and is currently on the Editorial Board of Science.

36

Perspectives

Oncurious

Gabriele Bergers continues: “We will combine our labs' different strategies to merge five innovative compounds into one R&D pipeline. Combinatorial treatment modalities can potentially have a much better effect and reach a majority of patients.”

The research team notes several possible combina-tions. “We will investigate whether our assets can be complementary and beat cancer cells in a unique way. But they also can potentially be combined with first-generation immunotherapies like checkpoint inhibitors and offer a better outcome for patients. They could even improve conventional chemother-apy, to better reach and attack the tumor.”

Tumor as a complex organJo Van Ginderachter explains this novel research of the VIB-Oncurious team as focusing on the ‘non-cancer’ part of tumors: “What has been partly overlooked in the past is that a tumor is a very com-plex organ, not just consisting of cancer cells but

About VIBVIB is a strategic research center in life sciences and biotech. The results of VIB’s top research are actively translated into added value for society. VIB unites the expertise of 75 research groups thematically organized into 8 research centers. VIB’s technology transfer team proactively trans-lates new biological findings into new economic activities, such as starting up new companies and partnerships with the biotech and pharmaceuti-cal industry. Since its foundation in 1996, VIB has created 20 start-up companies. VIB also engages actively in the public debate on biotechnology by developing and disseminating a wide range of science-based information about all aspects of bio-technology. VIB has a close partnership with five Flemish universities – Ghent University, KU Leuven, University of Antwerp, Vrije Universiteit Brussel and Hasselt University.

More information: www.vib.be.

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Perspectives

Oncurious

also containing normal cells and blood vessels. This ‘non-cancer’ part of a tumor is critical to supporting its growth, so it too can be interesting as a therapy target.”

“Conventional therapies like chemo and radiation often delay the disease instead of killing the tumor, which provides a long-term cure,” notes Massimiliano Mazzone. “The problem is that a tumor will always find other ways to grow, so often it is just a matter of time until the cancer returns. If you can use a positive force of cells that attack the cancer cells from within, you could actually remove the disease. That is the basic idea of immunotherapy: to use the body’s own immune cells to fight cancer.”

But a tumor's complex microenvironment influences immune cell activity. “A tumor can be compared to a normal functioning organ. It is programmed to survive so it will try to prevent immune cells from entering, for example by disguising itself,” says Jo Van Ginderachter. “Our goal is to find ways to work around that.”

Who is Prof. Van Ginderachter?Jo Van Ginderachter graduated as bio-engineer at Vrije Universiteit Brussel in 1995 and obtained his PhD in the lab of Cellular and Molecular Immunology at the same university in 2002 under the supervi-sion of Prof. Patrick De Baetselier, studying the impact of the innate and adaptive immune system on the growth and metastasis of mouse lymphoma models. He continued his postdoctoral training in Brussels funded by a competitive Prospective Research for Brussels grant, focussed on the identification of molecules on tumor-associated macrophages with a therapeutic potential. Jo Van Ginderachter became staff scientist in the Cellular and Molecular Immunology Lab in 2006, Assistant professor at VUB in 2010, Group Leader of the Myeloid Cell Immunology Lab at VIB in 2012 and Full Professor of Immunology at VUB in 2014. He is now heading the Cellular and Molecular Immunology Lab and program director of the Master of Sciences in Biomolecular Sciences at VUB.

He is an author of 88 scientific publications and 4 book chapters and is inventor on 5 patents. He is also member of the Board of the Belgian Immunological Society and Flanders Vaccine. The mission of his lab is to use the heterogeneity of myeloid cells (monocytes, macrophages, dendritic cells) as an in vivo sensor to track inflammatory responses and as a target for therapeutic inter-vention, not only in cancer, but also in liver and brain diseases.

Prof. Van Ginderachter became a laureate of the KVIV Student prizes and received the Rimaux-Bartier Donation of FWO. He is an external Advisory Board member of start-up companies, organizer of several international scientific meetings, editorial board member of the journal Cancer Research and is reviewer for a multitude of journals and granting bodies (Dutch Cancer Association, Italian Cancer Association, ERC etc).

“A tumor is in fact a very complex organ, containing not only cancer cells but also normal cells and blood vessels essential for tumor growth. We focus on that non-cancer part of the tumor.”Prof. Jo Van Ginderachter, PhD

Head, Laboratory of Cellular and Molecular Immunology, VUB (Vrije

Universiteit Brussel), Laboratory of Myeloid Cell Immunology, VIB

Center for Inflammation Research

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Perspectives

Oncurious

Trojan horse“In essence, we want to create an immunostimula-tory environment in which immune cells are able to attack cancer cells,” continues Gabriele Bergers. Her team is working on a concept to modulate the vascular system in the tumor. “We intend to create specialized blood vessels that enhance the infiltra-tion of immune cells into the tumor.”

“Another working part of a tumor is immunosuppres-sion by specialized cells that downregulate the func-tion of immune cells,” notes Jo Van Ginderachter. “Lowering that immunosuppressive activity can improve immunotherapy's working mechanism. That is what my lab is focusing on.”

Massimiliano Mazzone adds: “My team's contribu-tion is very similar. We see that tumors try to repulse the immune system, creating some type of barrier. We try to modify guidance cues and the ‘traffic lights’ inside the tumor to attract immune cells instead of repulsing them. Another way to attack tumors from the inside is reeducating specific cells called macrophages. These cells normally protect

Who is Prof. Massimiliano Mazzone?Massimi l iano (Max) Mazzone graduated in Medical Biotechnology at the Medical School of the University of Torino, Italy, and then performed his PhD in Cell Science and Technologies at the Institute for Cancer Research of Torino, under the supervision of Prof. Comoglio. In November 2006, he moved to Belgium as an EMBO-awarded postdoctoral fellow in the lab of Prof. Peter Carmeliet, at the University of Leuven, Belgium. Since September 2009, he is heading the Lab of Tumor Inflammation and Angiogenesis, at the Center for Cancer Biology, part of the VIB in Leuven, and he is Professor in Molecular Oncology at the University of Leuven.

Max Mazzone has contributed to the field of oncology under-standing the mechanisms of cancer metastasis and to vascu-lar biology identifying a new endothelial cell phenotype, the "phalanx" cell, which takes part in the formation of aligned blood vessels in perfused tissues. Since he is independent group leader, his team is focusing in studying the response of inflammatory cells to hypoxic conditions in order to restore blood flow and regulate favorably the immune response in conditions such as cancer and ischemic pathologies.

Prof. Mazzone got important national awards (the Belgian Royal Academy Prize, the Italian Lorini Award, and the AIRC Price for excellence in science, the EMBO Young Investigator Award, etc.) and international recognitions (ERC-starting grant, ERC-proof-of-concept, ERC-consolidator, EMBO, FEBS, Burgen Award, etc.). He is author in 95 papers, with an average impact factor in first or senior corresponding author research papers of 21; 8,000 total citations, and an H-index of 39. He is member of the boards of several peer-reviewd journals (such as Cancer Research), he is reviewer for almost 20 journals, and he has been so far invited to speak in more than 60 conferences (including GRC, Keystone, AACR, FEBS meetings, etc.). He currently holds an ERC-consolidator grant and EMBO Young Investigator Award.

“With our unique merged approach, we want to make a difference for patients who do not respond to the first generation of immunotherapies”Prof. Massimiliano Mazzone, PhD

Head, Laboratory of Tumor Inflammation and

Angiogenesis, VIB-KU Leuven Center for Cancer Biology

39Oncurious Cancer research

Perspectives

the body, but they're modified by the tumor to make it stronger. If we can reeducate them to their original function they will start to attack the cancer cells like a Trojan horse.”

Collaboration as strong added valueVIB Discovery Sciences will take the lead in these projects' pre-clinical development to create a new pipeline of next-generation immuno-oncology drugs. “The VIB research institute brings our labs together, yielding intense collaboration between our teams. That is a powerful added value to achieving progress in this field,” explains Jo Van Ginderachter.

“Our holistic approach looks at the concept of fighting cancer in a broad perspective. The preclinical research in these early-stage programs can lead to potential new drugs targeting a very broad spectrum of cancers. This is why the project is so exciting,” concludes Gabriele Bergers.

“Combined treatment models can potentially have a much

better effect and reach a majority of patients”Prof. Gabriele Bergers, PhD

Head, Laboratory of Tumor Microenvironment and Therapeutic

Resistance, VIB-KU Leuven Center for Cancer Biology

FIGHTING BRAIN CANCER IN CHILDREN

About medulloblastomaMedulloblastoma is a fast-growing, malignant, primary brain tumor. It originates in the lower rear portion of the brain called the posterior fossa that controls balance, posture, and complex motor functions like 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 some 400 new patients are diagnosed annually, with boys affected twice as much as girls. The peak age of incidence is 3-5 years, and about 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 crani-ospinal (brain and spine) radiation and/or chemo-therapy – 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.

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Perspectives

Oncurious

Oncurious is conducting a clinical phase I/IIa study with TB-403 (anti-PlGF) to treat medulloblastoma, a rare and life-threatening brain tumor that mainly affects young children. Patient recruitment is ongoing in partnership with Beat Childhood Cancer.

Medulloblastoma is the most common malignant brain tumor, accounting for 20% of all brain tumors in children. This very aggressive type of cancer affects mostly young children between 1 and 9 years of age. It presently can only be treated through surgery followed by chemotherapy, which is very toxic and administered for about one year. In some cases children must also undergo high doses of radiation. This severely affects the IQ of young children as they grow, even after they have been cured of medulloblastoma.

As both therapies have very negative side effects, Oncurious detected this unmet medical need and is researching TB-403 (anti-PlGF) to offer an innovative alternative treatment. This com-pound is the antibody that combats placental growth factor (PlGF), which causes the brain tumor to develop in the child’s brain.

Clinical trial ongoingPreclinical studies with TB-403 have already generated very promising data. The molecule has the potential to stop tumor cells from growing, thus blocking the disease process. It is expected to be much less toxic than chemotherapy, so it could offer an alterna-tive treatment option for children suffering from medulloblastoma without side effects on healthy tissue.

A phase I/IIa clinical trial with TB-403 is ongoing. The study aims to recruit 27 patients with relapsed or refractory medulloblastoma to examine the safety of different doses. The first two of a planned four patient groups have been recruited and the trial with the third dose level is under way. For recruiting patients Oncurious is part-nering with Beat Childhood Cancer. This is a collaboration of 25 universities and children’s hospitals, headquartered at the Helen Devos Children’s Hospital, which offers a nationwide network of childhood cancer clinical trials.

About Beat Childhood CancerBeat Childhood Cancer (formerly known as 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, Grand Rapids. MI, USA that offer a nationwide network of childhood cancer clinical trials. These trials are based on the research of a group of closely collab-orating investigators who are linked with laboratory programs developing novel therapies for high-risk neuroblastoma and medulloblastoma.

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Oncurious

Orphan drug designationIn early 2017, the European Commission confirmed orphan drug designation for the Oncurious com-pound TB-403 for medulloblastoma. This allows a pharmaceutical company to benefit from incentives from the European Union to develop a medicine for a rare disease, such as reduced fees and pro-tection from competition once the medicine is on the market.

TB-403 is being developed by Oncurious in con-junction with BioInvent International. In July 2017, ThromboGenics and BioInvent amended their long-standing monoclonal antibody development agreement. In the amended agreement, BioInvent assumes project lead for development of TB-403 in all oncology indications and will increase its share in the economic value of TB-403 from 40% to 50%. Both parties will continue to share equally the costs of developing TB-403 for oncology indications.

43About Thrombogenics

Perspectives

ABOUT THROMBOGENICSDelivering innovative treatments for vitreoretinal disorders, with focus on diabetic eye diseaseThromboGenics is a biopharmaceutical company focused on developing innovative treatments for vitreoretinal disorders (back of the eye disease), with a focus on diabetic eye disease.

The company’s pipeline of disease modifying drug candidates is targeting the key segments of the diabetic eye disease market. ThromboGenics is developing THR-317, a PLGF inhibitor in a Phase I/IIa clinical study for the treatment of diabetic macular edema.

ThromboGenics’ late preclinical pipeline consists of THR-149, a plasma kallikrein inhibitor, and THR-687, an integrin antagonist.THR-149 is expected to enter the clinic in H1 2018 and THR-687 around mid-2018.

Further new drug candidates are currently being progressed for the treatment of diabetic eye disease and one of these is expected to enter development in 2018.

ThromboGenics owns the global rights to JETREA® (ocriplas-min), the only pharmacological vitreolysis drug approved for the treatment of symptomatic vitreomacular adhesion (in the US) and vitreomacular traction (in Europe and elsewhere).

ThromboGenics is headquartered in Leuven, Belgium, and is listed on the NYSE Euronext Brussels exchange under the symbol THR. More information is available at www.thrombogenics.com

44 About Thrombogenics

Perspectives

Our missionWe aim 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 being 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.

Our organization: the people behind the ThromboGenics successThromboGenics employs around 75 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.


Perspectives

Executive management

Patrik De Haes, MD, Chief Executive OfficerDr Patrik De Haes has over 25 years of experience in the global healthcare industry, covering product development, marketing and general manage-ment. Before joining ThromboGenics as CEO in 2008, Patrik 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. Past Chairman of FlandersBio, Patrik is an active member of the local and regional biotech and lifesciences community in Belgium. Patrik is also Executive Chairman of Oncurious nv, an emerging oncology company co-created by ThromboGenics nv and VIB lIfesciences. Patrik holds a degree in Medicine from the University of Leuven.

Dominique Vanfleteren, Chief Financial OfficerIn January 2015, ThromboGenics appointed Dominique Vanfleteren as its new Chief Financial Officer (CFO).

Dominique has over 25 years of experience in senior finance, operational, con-trol 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 mana-gerial 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.

Management Team and Executive CommitteeOur leadership team’s expertise and experience in research, clinical devel-opment, commercialization and financing ensure the long-term success of ThromboGenics. The Executive Committee sets the company’s vision and strat-egy, while the full Management Team is responsible for planning and overseeing this strategy's execution.

The members of the ThromboGenics Management Team are Andy De Deene*, Claude Sander*, Dominique Vanfleteren*, Grégoire Franoux, Isabelle Decoster*, Jean Feyen*, Marc Denayer, Patrik De Haes*, Susan Schneider*, Vinciane Vangeersdaele*, and Wouter Piepers.

* Members of the Executive Committee


Perspectives

Board of DirectorsThe Company is led by a collegiate 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 six members.

Paul G. HowesNon-Executive Director

Thomas Clay, ChairmanNon-Executive, Independent Director

Emmanuèle Attout (Investea BVBA)Non-Executive, Independent Director

Patrik De Haes, MD (ViBio BVBA)Executive Director

David Guyer, MDNon-Executive Director

Baron Philippe VlerickNon-Executive, Independent Director


Perspectives

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:

• Providing reliable, accurate, and valuable information in a timely manner to help shareholders make informed decisions

• Full transparency• Operating within the Company’s policies and adhering to

relevant security laws and regulations• Strengthening our dialogue with the investment community• Providing access to the senior management team

Shareholding structureAs of 5 January 2018, ThromboGenics has a total number of 38,271,575 outstanding shares and a total number of 387,500 outstanding warrants.

Shareholder % of voting rightsMr Thomas M. Clay and entities controlled by him 8.78%Baron Philippe Vlerick and entities controlled by him 6.07%Novartis Pharma AG 5.69%Public 79,46%

Paying agent servicesKBC Bank acts as paying agent, meaning it does not charge shareholders for dividend payments, exercise of subscrip-tion rights, and other events concerning ThromboGenics’ shares. Shareholders should investigate what other financial intermediaries might charge for paying agent services.

Financial calendar

Date event15 Mar 2018 Full Year Results 20172 May 2018 Annual Shareholders’ Meeting9 May 2018 Business Update Q1 20186 Sep 2018 Half Year Results 201819 Oct 2018 Business Update Q3 2018


Perspectives

Contact information

Global Head OfficeThromboGenics NV Gaston Geenslaan 1 B-3001 Leuven Belgium T +32 (0) 16 75 13 10 F +32 (0) 16 75 13 11 [email protected]

US OfficeThromboGenics inc. 101 Wood Avenue South, Suite 610 Iselin, NJ 08830 USA T +1 732 590 2900 F +1 855 301 1600 [email protected]

Contact InformationWouter Piepers Global Head of Corporate Communications & Investor Relations ThromboGenics NV Gaston Geenslaan 1 B-3001 Heverlee Belgium T +32 (0) 16 75 13 10 M +32 478 33 56 32 F +32 16 75 14 66 [email protected] www.thrombogenics.com

Creation & CopywritingCantilis www.cantilis.be

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