Nanobodies. inspired by nature

Transcription

1 Nanobodies inspired by nature ANNUAL REPORT 2010

2 Content 01 Introduction Letter to the Shareholders 05 Highlights The Nanobody product engine Products in the clinic 17 Pre-clinical development Partners, operations and 03 investor information Partnering strategy 23 Operational performance 24 Key performance indicators 25 The shares in Glossary Corporate governance and financial review 27 1 Content Ablynx Annual Report 2010

3 01 Introduction 2 Introduction Ablynx Annual Report 2010

4 Letter to the Shareholders Dear Shareholders, 2010 was another important year for Ablynx, in which we further demonstrated our transformation from a technology platform company to a product focused organisation. In addition to developing our own internal product pipeline, we made considerable progress in our collaborative programmes. We signed an important new deal with Merck Serono, we continued to invest in our Nanobody technology and we carried out a successful Secondary Public Offering raising 50 million. We have created a critical mass in terms of people, technology, product candidates and development capabilities, to ensure continued progress in the years ahead. In 2010, we expanded our internal product pipeline, including the nomination of two clinical development candidates, the start of a new Phase II programme and the progression of the ongoing Phase II and Phase I studies. At the end of 2010, we had more than 25 projects in the R&D pipeline, including those that are partnered, and there were five Nanobodies in clinical development. In the past year, we continued to demonstrate the unique Nanobody technology advantages as we generated functional Nanobodies against ion channels and GPCRs, target classes that are challenging to address with conventional antibodies. Furthermore, we advanced into pre-clinical development the first Nanobody (anti-rsv) designed to be administered via the pulmonary route rather than by injection. During the year, the Phase II study being performed by Pfizer with an anti-tnfα Nanobody (ATN-103) continued, as did our own Phase II study in ACS with an anti-vwf Nanobody (ALX-0081). The Pfizer study is due to generate potential proof-of-concept data in the second quarter of 2011 and our ALX-0081 study is now on track to generate potential clinical proof-of-concept data in the second half of Importantly, in September we opened the first clinical centre for our Phase II study in the orphan disease TTP, using an antivwf Nanobody delivered both intravenously and subcutaneously (ALX-0081 plus ALX-0681), which should take about two years to complete. The anti-vwf Nanobody approach in the treatment of TTP has the potential to be first-in-class and could offer significant benefits to patients. The Phase I study with our anti-rankl programme (ALX- 0141) in healthy post-menopausal women, which was initiated at the end of 2009, made good progress with positive preliminary data being published in the third quarter of ALX appears to show a more potent effect than we had anticipated and we are continuing the Phase I follow-up, with final results expected in the first half of Pfizer also started a Phase I trial with a second anti-tnfα Nanobody (PF ) which employs a different half-life technology compared to ATN-103. The start of this trial resulted in a $3 million milestone payment to us. 01 Three pre-clinical development programmes were progressed during the year. We filed an IMPD for an anti-il-6r Nanobody (ALX-0061) in December and in March 2011 we initiated a Phase I/II trial in patients with active rheumatoid arthritis. Preparations for Phase I trials for our anti-rsv (ALX-0171) and anti-cxcr4 programmes (ALX-0651) proceeded well and both these studies are anticipated to begin in All three programmes are a good illustration of the wide applicability, competitive differentiation and advantages of Nanobodies in indications as diverse as inflammation, viral infection and cancer. Edwin Moses 3 Introduction Ablynx Annual Report 2010

5 Letter to the Shareholders In addition to Pfizer, our other collaborations continued to proceed encouragingly. As part of our Strategic Alliance with Boeh ringer Ingelheim, we received a total of 11 million in technical milestones alone during the year for successes in three different programmes including the first under this agreement to enter pre-clinical development. In our Alzheimer s collaboration with Boehringer Ingelheim, we received a 2 million milestone payment as they selected a Nanobody candidate for further development. We signed a second agreement with Merck Serono, on a single target with an up-front payment of 10 million. Critically, and for the first time in any of our collaborations, we retain responsibility for running the programme through to the generation of the IMPD/IND package, at which point Merck Serono will pay a further 15 million if they choose to proceed with the IMPD/IND filing. We then have the option to remain responsible for 50% of the development costs in return for 50% of any profits, or to convert the deal to a classic milestone and royalty arrangement. This new type of deal structure is designed to build on the respective strengths of both parties and we are very excited about the potential it offers. In the summer, we were pleased that Novartis exercised their rights to license Nanobodies, for further development and commercialisation, against two complex targets, which had been discovered as part of our collaboration which began in During the year, we have continued to aggressively invest in our product portfolio and technology as well as expanding the capabilities of our organisation by growing to 262 people and moving into a 8,000m 2 state-of-the-art facility. As a result of good financial management, a Secondary Public Offering that raised 50 million, and the earning of multiple different payments from our collaborators, we have ended the year with a very healthy cash position of million. This cash position helps to support our strategy of taking multiple programmes forward in parallel and to mitigate the natural risks of attrition, and allows us to choose to partner programmes at their optimal value inflection point, or as in the case of our TTP programme, to consider taking the product independently through to commercialisation. We believe that the Nanobody technology platform is an extremely productive product engine which could generate a series of best-in-class and first-in-class drugs. In the next three years, we expect at least eight Nanobody programmes to produce potential clinical proof-of-concept data. This exceptional asset base already establishes Ablynx as one of the leading biotechnology companies and we have every intention of continuing to rapidly build on the progress made so far. Finally, I would like to thank all our staff, investors and other key stakeholders for their continued dedication, commitment and enthusiasm. We are all proud to be guardians of this fabulous Nanobody technology and want to continue to aggressively exploit it to provide fulfilling employment opportunities, to generate significant value for shareholders and to improve the lives of patients with many different serious diseases. Edwin Moses Chief Executive Officer and Chairman 01 4 Introduction Ablynx Annual Report 2010

6 Highlights 2010 Building critical mass Internal pipeline maturing Continued recruitment for the Phase II trial in ACS/PCI with an anti-vwf Nanobody, ALX-0081 Initiated a single blinded, randomised Phase II study for TTP patients, with an anti-vwf Nanobody (ALX-0081/ALX-0681) Announced positive interim safety data for the Phase I study with ALX-0141, a Nanobody targeting RANKL Filed an IMPD to enable the start of a Phase I/II study with ALX-0061, a Nanobody targeting IL-6R, in patients with rheumatoid arthritis (RA) Selected for pre-clinical development, the first Nanobody against a GPCR, ALX-0651 (anti-cxcr4) Selected for pre-clinical development, the first Nanobody to be delivered via the pulmonary route, ALX-0171 (anti-rsv) Reported the successful generation of functional Nanobodies against ion channels Announced new in vivo data on pulmonary and needle-free administration of Nanobodies Increased staff numbers by 14% to 262 Moved into a 8,000m² state-of-the-art facility on the Technologiepark in Ghent, Belgium Progressed five Nanobody programmes in the clinic (two licensed to Pfizer) Maintained > 25 programmes in the R&D pipeline Established the potential for eight clinical proof-of-concepts in the next three years Strong financial position Successfully completed a Secondary Public Offering (SPO), raising 50 million Finished the year with million in cash, cash equivalents, restricted cash and short term investments Managed net cash burn to only 23.6 million Increased revenues by 6% to 31.4 million New partnerships and progress in existing collaborations Pfizer completed recruitment for its lead anti-tnfα Nanobody, ATN-103, in Phase II in patients with RA Pfizer initiated a long-term safety study with ATN-103 in RA patients, which is an open label extension of the Phase II trial with ATN-103 Received a $3 million milestone payment from Pfizer for the initiation of Phase I with a second anti-tnfα Nanobody, PF Boehringer Ingelheim started pre-clinical development with a lead Nanobody selected from its single target collaboration in Alzheimer s disease, which triggered a 2 million milestone payment to Ablynx Received a total of 11 million in milestone payments as part of the Strategic Alliance with Boehringer Ingelheim Entered into a second collaboration with Merck Serono, for a single inflammatory disease target, with an up-front payment of 10 million and a potential 15 million IND acceptance fee Received a 1 million payment as Novartis exercised their rights to license two Nanobodies for further development and commercialisation 01 Received total grants of 2.6 million from the Flemish agency for Innovation and Technology (IWT) and the Portuguese government 5 Introduction Ablynx Annual Report 2010

7 The Nanobody product engine 02 6 The Nanobody product engine Ablynx Annual Report 2010

8 Products in the clinic Ablynx has a broad portfolio of Nanobody-based therapeutics which are being developed in-house and in collaboration with pharmaceutical partners. To maximize the chances of overall success and to mitigate the risks that are inherent to drug development, Ablynx aims to maintain an extensive product portfolio targeting a range of therapeutic areas including haematology and thrombotic disorders, inflammation, viral infections, musculoskeletal diseases and oncology. The Nanobody platform is a very powerful product engine. At the time of its IPO in November 2007, Ablynx promised to deliver five IND s (or IND equivalents) in five years. By the end of 2011, Ablynx expects to have exceeded this promise and to have submitted five IND s in four years. On 31 December 2010, Ablynx had more than 25 programmes in research and development, including its partnered programmes, and there were five Nanobodies in clinical development. Two Nanobodies are on track to reach potential clinical proof-of-concept during ATN (TNFα) ALX-0081 (vwf) ALX-0081/ALX-0681 (vwf) Inflammation Haematology/ Thrombosis Haematology/ Thrombosis ALX-0141 (RANKL) Musculoskeletal PF (TNFα) NAME INDICATION DEVELOPMENT STAGE ALX-0061 (IL-6R) ALX-0651 (CXCR4) ALX-0171 (RSV) BI 2 BI 2 Inflammation Inflammation Oncology Respiratory Oncology Alzheimer s Various projects in multiple diseases 3 1 partnered with Pfizer 2 partnered with Boehringer Ingelheim 3 both partnered and own projects 02 DISCOVERY PRE-CLINICAL PHASE I PHASE II PHASE III MARKET Start Phase I in 2011 Phase I data in 2011 Potential PoC in The Nanobody product engine Ablynx Annual Report 2010

9 Products in the clinic ATN-103 and PF Anti-TNFα Nanobodies in rheumatoid arthritis Inflamed joints ATN-103 and PF are being developed by Pfizer as part of the exclusive license agreement with Ablynx for Nanobodies targeting TNFα. ATN-103 is initially being developed to treat rheumatoid arthritis (RA). To date, Ablynx has received $10 million in milestone payments as part of this collaboration progress ATN completed enrolment of 312 RA patients in Phase II - started a long-term safety study in patients with RA PF nd anti-tnfα Nanobody entered Phase I in healthy volunteers About TNFα and the interaction with the Nanobody Tumour necrosis factor (TNF, cachexin or cachectin and formerly known as tumour necrosis factor-alpha) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulates the acute phase immune reaction. Tumour necrosis factor promotes the inflammatory response, which, in turn, causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and psoriasis. Both ATN-103 and PF block the TNFα pathway and subsequently the inflammatory response. AML SSZ, gold MTX, LEF Higher-level immune regulation and immune senescence APC T cell B cell RF ACPA T REG Nature Reviews Rheumatology GM-CSF TNF IL-1 IL-6 IL-17 Osteoblast Osteoclast Synovial inflammation Extracellular matrix proteins Destructive changes Systemic inflammation Temperature ( C) Time 8 The Nanobody product engine Ablynx Annual Report 2010

10 Products in the clinic ATN-103 and PF About rheumatoid arthritis and the medical need RA is a chronic, progressive inflammatory disease of the joints and surrounding tissues that is associated with pain, irreversible joint destruction and systemic complications such as fatigue and anaemia. Although the cause of rheumatoid arthritis is still unidentified, it is known that various inflammatory factors play a significant role, including TNFα, interleukin-1 (IL-1) and interleukin-6 (IL-6). Various RA treatments are available, including non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. However, while these types of drugs treat the symptoms of RA, they do not modify the disease itself. Traditional small molecule disease modifying anti-rheumatic drugs (non-biological DMARDs) are widely prescribed and have the potential to reduce or prevent joint damage, and preserve joint integrity and function. The American College of Rheumatology recommends non-biological DMARDs for use in RA, either as monotherapy or combination therapy with biological DMARDs, with the latter being dominated by anti-tnfα drugs. Despite the success of these TNFα blockers, there is a clear need for new, differentiating anti-tnfα drugs, including products with a more convenient dosing regimen. RA in the seven major markets Prevalence million people in million people expected by 2019 Market size sales of the five 3 anti-tnfα blockers of $18.4 billion 1 Datamonitor, 2010 Nanobody advantages The Nanobody s specific characteristics could potentially result in a superior product in the anti-tnfα space. Its small size and format could lead to better tissue penetration, its pharmacokinetics, combined with its pharmacodynamic properties, could result in lower dosing frequency, and the product s stability potentially enables routes of administration other than injection. The Nanobody s ease of manufacturing offers the potential for relatively low cost of goods compared with conventional antibodies. Project status In the summer of 2009, Pfizer completed single ascending dose Phase I studies with 144 healthy volunteers for ATN-103 in the US, the rest of the world and Japan. In September 2009, multiple dose Phase II trials in the US, the rest of the world and Japan for ATN-103 were initiated in patients with RA. The Phase II trials include two randomised, double blind studies in patients with active RA on a treatment background of methotrexate, and who either receive subcutaneous injections of ATN-103 every four or every eight weeks, or placebo. The primary endpoint is the clinical response (ACR 20) at week 16. ACR 20 is a complex composite endpoint requiring a 20%, or more, improvement of several parameters, including tender joint count, swollen joint count and three of the following five ACR core set measures: patient-assessed global assessment, physician-assessed global assessment, pain, disability and level of acute-phase reactant. The trials completed enrolment of 312 patients in September 2010 and are expected to generate potential clinical proof-of-concept data during the second quarter of In February 2010, before the Phase II study enrolment was finished, Pfizer initiated a long-term safety study with ATN- 103, which is an open label extension of the Phase II trial in rheumatoid arthritis, and which will investigate the safety profile of ATN-103, administered subcutaneously every four weeks, for up to 48 weeks. In addition to the progression with the lead candidate ATN- 103, Pfizer started a single ascending dose Phase I trial with a second anti-tnfα Nanobody, PF in October 2010 in healthy volunteers, which is expected to generate safety data during the second half of The Nanobody product engine Ablynx Annual Report Company data 3 Enbrel, Humira, Cimzia, Simponi, Remicade

11 Products in the clinic ALX-0081 and ALX-0681 Anti-vWF Nanobodies in haematology and thrombotic disorders 1 2 1) Small bleeding lesions under the skin 2) platelet string formation caused by UL-vWF in plasma of TTP patients Structure of ALX-0081 ALX-0081 and ALX-0681 are the same Nanobody targeting von Willebrand factor (vwf), delivered through an intravenous and a subcutaneous route respectively. The anti-vwf Nanobody is being developed in two indications: high risk ACS patients undergoing a percutaneous coronary intervention (PCI) and thrombotic thrombocytopenic purpura (TTP), a rare blood disorder progress ALX-0081 further advanced the Phase II study in high risk ACS patients undergoing a PCI procedure ALX-0081/ALX-0681 initiated a Phase II study in patients with TTP About vwf and the interaction with the Nanobody von Willebrand factor is a blood glycoprotein involved in haemostasis, a complex procedure which causes the bleeding process to stop. Its primary function is binding to other proteins, and it is important in platelet adhesion to wound sites. It acts at an early stage in the blood clotting cascade in the arteries (high shear area) by controlling platelet adhesion and aggregation. Importantly, vwf is not involved in the mechanism of thrombus formation in the veins where, due to the lower velocity blood flow, the platelets are able to bind directly to the exposed collagen. Ablynx s anti-vwf Nanobody selectively inhibits the interaction of vwf with the GPIb receptors on platelets in areas of high shear (arteries) and represents a potential novel antithrombotic agent in cardiovascular diseases. vwf is also implicated in thrombotic thrombocytopenic purpura (TTP), a rare disease where precursors of vwf (ultralarge vwf multimers) are present in the blood of patients and lead to blood clot formation and potentially life-threatening pathologies. Under normal circumstances, ultra-large vwf (UL-vWF) is rapidly processed into smaller sized multimers through enzymatic cleavage by the enzyme ADAMTS13. In patients with TTP, processing of UL-vWF into smaller sized multimers is impaired due to a lack of functional ADAMTS13. UL-vWF can readily bind platelets in the absence of collagen, leading to the formation of the characteristic string-like clots found in the blood of this patient population. The anti-vwf Nanobody inhibits the platelet binding on the UL-vWF and thus has the potential to prevent the formation of the string-like clots in small blood vessels. ACS and the Nanobody interaction High shear Endothelium Subendothelium ULvWF multimers Endothelium vwf 02 platelet recruitment at high shear platelet string formation Area of vascular damage TTP and the Nanobody interaction platelet recruitment inhibited by Nanobody platelet string formation inhibited by Nanobody 10 The Nanobody product engine Ablynx Annual Report 2010

12 Products in the clinic ALX-0081 and ALX-0681 About acute coronary syndrome and the medical need Arterial thrombosis is the formation of a blood clot within an artery and it usually affects patients who have atherosclerosis. In those patients, the artery wall thickens as a result of the build-up of plaques that can eventually lead to clot formation within the lumen of the artery. This, at worst, can cause blockage of the vessel, resulting in insufficient blood supply to tissues and organs. The narrowing of the vessel in the coronary arteries can lead to a set of signs and symptoms, referred to as acute coronary syndrome (ACS), including unstable angina and myocardial infarction. In the Western world, percutaneous coronary intervention (PCI) is rapidly becoming the standard procedure of care in ACS. This procedure involves surgically widening of the arteries using either a small balloon or a stainless steel tube (stent). Currently, GPIIb/IIIa inhibitors such as ReoPro are often added to standard anti-thrombotic therapy 1 to improve inhibition of arterial thrombosis in high risk patients undergoing a PCI procedure. However, published reports state that the addition of ReoPro results in a two- to three-fold increase in the risk of clinically significant bleeding 2. Hence, there remains a high unmet medical need for safer anti-thrombotics for high risk patients undergoing PCI procedures. A Nanobody based product targeting vwf, which selectively inhibits vwf-mediated platelet adhesion and aggregation in areas of high shear, may provide a highly potent anti-thrombotic drug with a favourable safety profile that could contribute significantly to the prophylactic and therapeutic treatment of patients with, or at risk of, arterial thrombus formation. However, this disease area is increasingly challenging from a commercial and clinical development viewpoint and hence Ablynx continues to review its options here. About thrombotic thrombocytopenic purpura and the medical need Thrombotic thrombocytopenic purpura (TTP) is a rare disorder of the blood-coagulation system, causing extensive microscopic thromboses in small blood vessels throughout the body. It is a life-threatening disorder characterised by thrombocytopenia, haemolytic anaemia and microvascular thrombosis (most frequently cardiac or cerebral) causing variable degrees of tissue ischemia and infarction. TTP exists in two forms: a congenital and an acquired form, with the latter accounting for >90% of the patients. ACS in the seven major markets Prevalence ACS million people in million people expected by 2014 PCI procedures 3-2 million in million expected by There are currently no drugs specifically approved for the treatment of TTP. The predominant treatment is multiple plasma exchanges for acquired TTP and plasma transfusions for congenital TTP, which require lengthy hospital stays, and which can often be associated with clinical complications. Despite these procedures, mortality due to TTP remains high at 8-30% 4. Ablynx s anti-vwf Nanobody could be the first drug specifically approved for the treatment of acquired TTP. It received Orphan Drug designation from both the EMA (EU) and the FDA (US) in May TTP in the seven major markets Prevalence in acquired TTP 5 about 10,000 acute events annually Treatment cost 5 current cost of plasma exchange and hospitalization is estimated to be in the range 18-50K (depending on complications) 11 The Nanobody product engine Ablynx Annual Report Plavix, heparin, aspirin 2 Thomson Pharma 3 SDG Life Sciences (Unit of IMS) April Allford et al Infusion Pharma Consulting Feb 2010

13 Products in the clinic ALX-0081 and ALX-0681 Nanobody advantages The bivalent format of the anti-vwf Nanobody results in considerably increased potency compared with the monovalent Nanobody. The anti-vwf Nanobody is highly selective, has a fast onset of action, is quickly cleared from the body, and has a pharmacological behaviour that is well-predicted from the preclinical animal models. It is available in two forms of administration: subcutaneous and intravenous (ALX-0681 and ALX- 0081). ACS project status ALX-0081 is currently in Phase II clinical development. The study was initiated in September 2009 as a randomised, open label study in patients with high risk of coronary arterial clot formation undergoing a PCI procedure. These patients have a background treatment with the standard anti-thrombotic therapy and, in addition, are randomly assigned to receive either ALX-0081 administered as an intravenous bolus every six hours over 24 hours, or ReoPro administered as an intravenous bolus followed by 12 hours of continuous infusion. The primary endpoint is the number of bleeding events and the goal is to show a significant reduction (40%) in these events for ALX-0081 compared to ReoPro. The publication of Phase II data is on track for the second half of TTP project status In September 2010, the first clinical centres were opened for the Phase II trial with ALX-0081/ALX-0681 in patients with acquired TTP. In this trial, patients receive either placebo, or an intravenous bolus with ALX-0081 as adjunct to plasma exchange, followed by placebo or subcutaneous daily injections of ALX-0681 for the duration of plasma exchange plus 30 days. The primary endpoint is the time to response, based on normalisation of the platelet count and the goal is to demonstrate a significant reduction in this time. Final Phase II results are expected during the first half of The Nanobody product engine Ablynx Annual Report 2010

14 Products in the clinic ALX-0141 Anti-RANKL Nanobodies in diseases characterised by unwanted bone loss Normal bone Osteoporosis Structure of ALX-0141 ALX-0141 is a bivalent bi-specific construct composed of two Nanobodies targeting Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL) linked to a Nanobody that binds to human serum albumin, which may also lead to preferential targeting of inflamed tissue and cancerous regions. ALX-0141 is currently in a Phase I clinical trial in healthy post-menopausal women progress ALX announced positive interim Phase I data - progressed Phase I in 42 healthy post-menopausal women About RANKL and the interaction with the Nanobody RANKL is a key mediator of bone resorption (break up of bone) and an essential regulator of the generation and activation of osteoclasts, the cells involved in the breakdown of bone. Bone remodelling is a highly co-ordinated lifelong process. However, in certain diseases, the refilling of cavities created by osteoclasts is incomplete, resulting in a net loss of bone mass. Postmenopausal osteoporosis, cancer-related bone loss and other conditions are associated with an increase in the rate of bone remodelling, leading to accelerated bone loss and increased risk of fractures. ALX-0141 inhibits bone resorption by targeting and binding to RANKL and thereby preventing RANKL from binding to receptors on the surface of osteoclasts. The Nanobody product has the potential in treating diseases characterised by unwanted bone loss such as osteoporosis, chronic inflammation and cancer, or treatment related bone loss. CFU-M 2 Hormones Growth factors Cytokines 1 Osteoprotegerin 2 Colony forming cells Osteoblasts Bone formation Preosteoclast 02 The role of RANKL in bone resorption RANKL RANK OPG 1 Osteoclast formation, function and survival inhibited Bone resorption inhibited 13 The Nanobody product engine Ablynx Annual Report 2010

15 Products in the clinic ALX-0141 About bone loss and the medical need Osteoporosis is a disease of the bones that leads to an increased risk of fracture. In patients with osteoporosis, the bone mineral density is reduced, bone micro-architecture deteriorates, and the amount and variety of proteins in the bone is altered. Osteoporosis takes a huge personal and economic toll on affected patients. For women, gradual bone loss is accelerated after the menopause and is referred to as primary type 1 or postmenopausal osteoporosis. Primary type 2 or senile osteoporosis occurs after the age of 75 and is seen in both females and males at a ratio of about 2:1. Non-age related osteoporosis may also occur. For instance, in patients who receive the so called hormone-ablative therapy for their cancer (i.e. prostate cancer and breast cancer), bone resorption is accelerated and can result in severe signs of treatment induced osteoporosis and is also characterised by an increased fracture risk. In addition, cancer patients in whom the cancer has spread to the bones often experience bone deterioration or bone loss. Osteoporosis in the seven major markets Prevalence million people in people expected by 2020 Market size 1 - $7 billion in $9 billion in 2020 Another group of patients who are often affected by severe bone loss are patients with rheumatoid arthritis. Bone erosions are one of the characteristics of advanced disease and quite often significantly affect the quality of life of these patients. Current treatments for bone loss can either inhibit bone degradation through the use of bisphosphonates and selective oestrogen receptor modulators, or promote bone building by the use of parathyroid hormones and analogues. Oral bisphosphonates are by far the leading treatment class. However, their use is associated with unpleasant gastric side effects and they require a complicated dosing schedule. Denosumab has a new mode of action and is the first anti- RANKL humanized monoclonal antibody on the market. It is approved for the treatment and prevention of osteoporosis in post-menopausal women, and the treatment and prevention of bone loss in women and men receiving hormone therapy for either breast or prostate cancer. Denosumab was recently approved in the US for the prevention of skeletal-related events in patients with bone metastasis from solid tumours. Bone metastasis in the seven major markets Prevalence 2 - about 270,000 patients in about 283,000 patients in 2018 Market size 2 - $1.4 billion in $2.1 billion in Nanobody advantages The bivalent formatting of ALX-0141, together with its relatively small size and its albumin targeting half-life extension technology may result in a number of potential product advantages, including increased potency, improved tissue distribution, and selective targeting of inflamed and cancerous regions. In addition, the Nanobody is very stable and can be formulated in high concentrations for subcutaneous administration (up to 140mg/ml has already been achieved) without the formation of aggregates. With its size of 41kD, the Nanobody is about 1/3 rd of the size of a conventional monoclonal antibody, and on a molar basis, three times more Nanobody can be administered per dose, which could result in a convenient dosing and scheduling opportunity for ALX-0141 in all relevant indications. ALX-0141 is manufactured at high titres in a microbial production system, which could result in a relatively low cost of goods compared with conventional antibodies. Project status ALX-0141 is currently in Phase I clinical trials, involving 42 healthy post-menopausal women, to assess the product s safety, pharmacological profile and biologically effective dose. ALX-0141 was administered at six different dose levels, ranging from mg/kg to 1 mg/kg. Interim data demonstrated that ALX-0141 is well tolerated and no serious adverse events occurring in the first 120 days following the drug administration. Following single doses of 0.1 mg/kg to 1mg/kg, subjects showed statistically significant suppression of the bone biomarker CTX-1, even at the nine month follow-up in the highest dose group. This compares favourably with denosumab which demonstrated significant inhibition of the bone biomarker, serum NTX, at nine months, and only for the highest dose level of 3mg/kg. 14 The Nanobody product engine Ablynx Annual Report Datamonitor, July Datamonitor, March 2008

16 Products in the clinic ALX-0061 Anti-IL-6R Nanobodies in rheumatoid arthritis Inflamed joint Structure of ALX-0061 ALX-0061 is a half-life extended monovalent Nanobody that interacts with the interleukin-6 receptor (IL-6R) and neutralises pro-inflammatory activity in the IL-6 pathway. The Nanobody is half-life extended using an anti-human serum albumin Nanobody which may also lead to preferential targeting of inflamed tissue progress ALX generated encouraging pre-clinical data - filed an IMPD in December About IL-6R and the interaction with the Nanobody Interleukin-6 (IL-6) is a cytokine with a wide range of biological activities. Dysregulated production of IL-6 and IL-6R has been implicated in the pathogenesis of many diseases, including RA, multiple myeloma, autoimmune diseases and prostate cancer. High concentrations of both the ligand and receptor have been documented in the serum and synovium (i.e. the thin layer of tissue that covers the joint from the inside) of RA patients, and are believed to play a pivotal role in inflammation, swelling, joint damage and destruction of cartilage. ALX-0061 potently inhibits the interaction of the IL-6 receptor with its ligand, thereby neutralising pro-inflammatory activity in the IL-6 pathway. The IL-6 pathway is also an important mediator of anaemia and fatigue, as well as cardiac events and mortality, which are systemic implications of RA. As such, inhibition of the IL-6 pathway not only blocks the specific local inflammatory response but also has the potential to significantly improve general health and the overall quality of life of patients with RA. 02 Biological activities of interleukin-6 proliferation mesangial cells proliferation plasmacytoma cells B-cells plasma cells differentiation T-cells differentiation cytotoxic T-cells proliferation growth inhibition keratinocytes breast carcinoma cells growth inhibition melanoma cells IL-6 APP expression hepatocytes regeneration PC12-cells stem cells hematopoiesis 15 The Nanobody product engine Ablynx Annual Report 2010

17 Products in the clinic ALX-0061 About rheumatoid arthritis and the medical need There are several cytokines involved in the inflammatory process, including TNFα, IL-1 and IL-6. Currently, the preferred biologic disease-modifying anti-rheumatic drugs (DMARDs) are TNFα inhibitors. It is estimated that this drug class will remain the first line biologic in RA, based on significant clinical experience with these therapeutic agents. However, physicians are increasingly looking for drugs with alternative mechanisms of action, as up to 30% of patients do not tolerate or adequately respond to their anti-tnfα treatment 1. Even those patients who do respond, can become resistant over time, requiring them to shift to a different TNFα blocker or a biologic DMARD with a different mechanism of action. RA in the seven major markets Prevalence million people in million people expected by 2019 Market size 1 increased use of non-tnfα blockers in patients from 14% in 2010 to 36% in Datamonitor, 2010 According to Datamonitor, it is anticipated that there will be an increased use of non-tnfα biologics across the seven major markets. TNFα inhibitors are likely to remain the dominant biologic class but there will be considerable opportunity for products with alternative mode of actions, such as Actemra (the only anti-il-6r drug on the market), to gain access to a greater number of patients who have not been treated with a biologic yet. Nanobody advantages ALX-0061 potently neutralises the pro-inflammatory activity in the IL-6 pathway. Compared to conventional antibodies that target IL-6R, the Nanobody may offer an improved safety profile as a result of its binding mode (no potential for unwanted cross-linking of receptors) and its lack of an Fc function. Importantly, ALX-0061 incorporates albumin targeting as a means of half-life extension which may facilitate targeting to inflamed tissues. Thanks to its small size, the Nanobody could achieve improved tissue penetration. ALX-0061 is manufactured in a relatively low cost microbial system. Project status The pre-clinical studies with ALX-0061 showed that the Nanobody selectively and potently binds to both the soluble and membrane-bound form of IL-6R, and that it has a favourable PD, PK and safety profile. Based on the promising pre-clinical data, Ablynx initiated a Phase I/II trial directly in RA patients with active RA in March This study will investigate the safety, PK, PD and efficacy of single and multiple intravenous administrations of ALX-0061 in up to 72 patients in a number of centres in Europe The Nanobody product engine Ablynx Annual Report 2010

18 Pre-clinical development In addition to focusing on the rapid development of its clinical pipeline, Ablynx continues to invest both on its own and with partners in a significant number of discovery and pre-clinical programmes covering a range of therapeutic indications. The next programmes which are anticipated to enter Phase I trials in 2011 are an anti-cxcr4 Nanobody (ALX-0651) for use in stem cell mobilisation, and an anti-rsv Nanobody (ALX-0171) for treatment of pulmonary respiratory syncytial virus (RSV) infections. ALX-0651 will be the first Nanobody targeting a GPCR to enter the clinic and ALX-0171 will be the first Nanobody which will be delivered via the pulmonary route to start clinical trials. In total, Ablynx has more than 25 programmes in its R&D pipeline of which the majority are wholly owned. Haematology/ Thrombotic disorders Immunology/ Infection/ Inflammation Musculoskeletal Neurology Pulmonary disease Oncology Various ALX-0081 (vwf) ALX-0681/0081 (vwf) ATN-103 (TNFα) PF (TNFα) ALX-0061 (IL-6R) ALX-0141 (RANKL) ALX-0171 (RSV) ALX-0651 (CXCR4) TARGET SELECTION LEAD IDENTIFICATION LEAD OPTIMIZATION 02 PRE-CLINICAL PHASE I PHASE II PHASE III REGISTRATION Ablynx-led programme Partner-led programme The three Merck Serono programmes are in co-discovery and co-development with Ablynx 17 The Nanobody product engine Ablynx Annual Report 2010

19 Pre-clinical development ALX-0651 Anti-CXCR4 Nanobodies in stem cell mobilisation Haematopoietic stem cells Structure of ALX-0651 ALX-0651 is expected to be the first Nanobody against a GPCR (CXCR4) to enter clinical trials. This is a biparatopic Nanobody, targeting two different epitopes on the same protein. GPCRs comprise a target class that has proved very challenging to address with conventional antibodies, but the unique physical characteristics of Nanobodies have already allowed Ablynx to generate functional blockers for a number of different GPCRs progress ALX initiation of pre-clinical development - Phase I study preparation About CXCR4/CXCL12 and stem cell mobilisation CXCR4 is a chemokine receptor specific for the ligand CXCL12 (SDF-1), a potent chemo-attractant. Constitutive expression of CXCL12 by bone marrow stromal cells is critical for the recruitment and retention of haematopoietic stem cells to the bone marrow. The key role of CXCR4 in stem cell mobilisation has been clinically validated by the small molecule antagonist plerixafor, (Mozobil ). Mozobil was approved in the USA in December 2008 where it is indicated for use in combination with G-CSF (granulocyte colony stimulating factor) to mobilise haematopoietic stem cells to the bloodstream for collection and subsequent autologous transplantation in patients with non-hodgkin s lymphoma and multiple myeloma. Mozobil was approved in Europe in July 2009 as combination therapy with G-CSF for haematopoietic stem cell mobilisation and subsequent autologous transplantation in patients with lymphoma and multiple myeloma whose cells mobilise poorly. Blocking CXCR4 effectively releases the lock and allows stem cell release Cells are locked in bone marrow under control of stromal cells and extracellular matrix proteins Erythrocytes (Red blood cells) Myeloid progenitor cell Multipotent stem cell 02 Role of CXCR4 in stem cell mobilisation Hematopoietic stem cell Inside the patient Pluripotent stem cell Leukemia patient (HSC) Bone marrow G-CSF + Mozobil (HSC) (HSC). mobilisation. engraftment Transplant into the patient Bone marrow ALX-0651 (HSC) (HSC) 18 The Nanobody product engine Ablynx Annual Report 2010

20 Pre-clinical development ALX-0651 Medical need in stem cell mobilisation and transplantation Successful bone marrow transplantation requires the infusion of a sufficient number of haematopoietic stem cells capable of trafficking to the marrow cavity and regenerating a full array of haematopoietic cell lineages in a timely way. These stem cells can come from the patient (autologous), from a donor (allogenic), or from umbilical cord blood. Haematopoietic growth factors such as G-CSF or chemotherapeutic agents are currently frequently used to stimulate the mobilisation of stem cells into the peripheral blood for ease of collection (as compared with harvesting from the bone marrow). However, the patients currently need to undergo multiple mobilisation procedures to achieve the target number of cells (i.e. the required response), which is associated with increased hospital stays and related costs. Therefore, there is a need for new therapies with improved pharmaco-economics that could have the potential for shorter dosing regimens, fewer apheresis procedures, and improved transplant engraftment, resulting in lower drug costs and reduced time spent in the hospital. ALX-0651 is currently being developed to address this need. Opportunity beyond stem cell mobilisation CXCR4 is a widely expressed chemokine receptor in cancer, having been described in over 23 different tumour types. The role of CXCR4 in metastatic spread of tumours to distant organs such as the liver, lung, lymph nodes and bone marrow that constitutively express CXCL12 has been demonstrated in numerous in vivo models for cancer, including breast, lung, ovarian, prostate and melanoma. There is some evidence of a role for CXCR4 in tumour cell proliferation and survival, and in helping mediate resistance to cytotoxic drugs. In addition, the CXCL12: CXCR4/CXCR7 axis has also been shown to promote angiogenesis, the formation of new blood vessels within a tumour, which is essential for tumour growth and tumour invasion. Targeting the CXCL12: CXCR4/CXCR7 axis therefore represents an attractive therapeutic opportunity within the oncology setting, beyond stem cell mobilisation. Nanobody advantages By constructing a biparatopic molecule, Ablynx has been able to significantly increase the potency compared with a monovalent Nanobody. ALX-0651 has been shown to be very selective for CXCR4, which should provide a positive benefit in terms of safety. The relatively short half-life of this Nanobody should ensure that it has the preferred characteristics of rapid, transient and controllable stem cell release, whilst limiting unwanted side effects such as long lasting increase of leukocytes. Project status Ablynx has demonstrated in vivo proof-of-concept in a haematopoietic stem cell model, where a single, intravenous administration of ALX-0651 resulted in rapid mobilisation of stem cells. Ablynx is on track to file an IMPD during the first half of 2011 to enable the start of a Phase I clinical trial in healthy volunteers. The trial will assess the product s safety and biological effectiveness and will comprise a single ascending dose and multiple dose study, administered both subcutaneously and intravenously The Nanobody product engine Ablynx Annual Report 2010