Nanobodies® – creating better medicines JP Morgan Healthcare conference San Francisco – 15th January 2015 Nanobodies® Inspired by nature Forward looking statements Certain statements, beliefs and opinions in this presentation are forward-looking, which reflect the Company or, as appropriate, the Company directors’ current expectations and projections about future events. By their nature, forward-looking statements involve a number of risks, uncertainties and assumptions that could cause actual results or events to differ materially from those expressed or implied by the forward-looking statements. These risks, uncertainties and assumptions could adversely affect the outcome and financial effects of the plans and events described herein. A multitude of factors including, but not limited to, changes in demand, competition and technology, can cause actual events, performance or results to differ significantly from any anticipated development. Forward looking statements contained in this presentation regarding past trends or activities should not be taken as a representation that such trends or activities will continue in the future. As a result, the Company expressly disclaims any obligation or undertaking to release any update or revisions to any forward-looking statements in this presentation as a result of any change in expectations or any change in events, conditions, assumptions or circumstances on which these forward-looking statements are based. Neither the Company nor its advisers or representatives nor any of its parent or subsidiary undertakings or any such person ’ s officers or employees guarantees that the assumptions underlying such forward-looking statements are free from errors nor does either accept any responsibility for the future accuracy of the forward-looking statements contained in this presentation or the actual occurrence of the forecasted developments. You should not place undue reliance on forward-looking statements, which speak only as of the date of this presentation. www.ablynx.com 2 Corporate snapshot Corporate • Drug discovery and development company in Ghent, Belgium • >300 employees Technology • Pioneer in next generation biological drugs – Nanobodies® • >500 granted and pending patents Products • >30 programmes – six at the clinical development stage • Three clinical proof-of-concepts (POCs) • >10 new clinical programmes possible over the next 3 years Partners • AbbVie, Boehringer Ingelheim, Eddingpharm, Merck & Co, Merck Serono and Novartis Financials • >€200M in cash expected end 2014 www.ablynx.com 3 2014 – an exciting year for Ablynx! 5 clinical trial read outs – including clinical proof-of-concept (POC) for caplacizumab in TTP 4 clinical trials initiated – including 2 partnered programmes Further validation of the platform through immune-onco deal with Merck & Co focusing on multi-specifics – €20M upfront, €10.7M in research funding and up to €1.7Bn in future milestones plus royalties Expansion into Asia through 2nd licensing deal with Eddingpharm for the development and commercialisation of ozoralizumab (anti-TNFa) in Greater China Further strengthened the financial position through an oversubscribed private placement of new shares raising €41.7M A multi-asset clinical development company with a powerful discovery platform www.ablynx.com 4 Fully owned Proprietary and partnered programmes Therapeutic area Product name Target Haematology caplacizumab vWF ALX-0171 RSV Respiratory Discovery Pre-clinical Phase I Phase II Phase III Filing Various Oncology/ Immuno-oncology Various Inflammation/ Immunology/Infection Various Ocular Various Inflammation/ Immunology ALX-0061 IL-6R ALX-0761 IL-17A/F ozoralizumab TNFα Greater China RANKL Greater China Partnered Various Oncology/ Various ALX-0751 Immuno-oncology Various Bone disorders ALX-0141 Neurology Various CXCR2 Respiratory Other www.ablynx.com Various Validated targets (clinic) 1st in class 5 What are Nanobodies? Nanobodies® Inspired by nature Nanobodies – derived from heavy-chain only antibodies Camelid heavy-chain only antibodies are stable and fully functional Nanobodies represent the next generation of antibody-derived biologics VH VHH CH1 VHH VL CL CH2 CH3 Conventional antibodies www.ablynx.com 12-15kDa Ablynx’s Nanobody CH2 CH3 Heavy chain only antibodies • small • robust • sequence homology comparable to humanised/human mAbs • easily linked together • nano- to picomolar affinities • intractable targets • multiple administration routes • manufacturing in microbial cells 7 Nanobody platform – competitive advantages Alternative delivery routes Mix and match e.g. targeting different checkpoint inhibitors with a single Nanobody construct Customised half-life extension Weeks/days/hours Inhalation Needle-free Albuminbinding Nanobody Fc Challenging and intractable targets Nanobodies against ion channels and GPCRs Nanobodies can reach conserved cryptic epitopes Oral-to-topical Ocular Cell killing Cell / tissue-homing Cell specificity Immune cell retargeting www.ablynx.com PEG Nanobody-drug conjugates Tissue-specific targeting 8 Pipeline value drivers Nanobodies® Inspired by nature Leading programmes in the clinic Proprietary Programme (target) Indication Caplacizumab (vWF) First-in-class orphan drug Thrombotic thrombocytopenic Novel mode of action purpura Inhibition of microthrombi formation ALX-0171 (RSV) Respiratory syncytial virus infection Key differentiating features First-in-class addressing high unmet need Inhaled Nanobody delivered to infection site Highly potent trivalent construct Stage Start Phase III mid2015: results expected end 2017 Phase IIa infant study initiated: results expected H2 2015 Partnered Programme (target) Indication ALX-0061 (IL-6R) RA, SLE ALX-0761 (IL-17A/F) Psoriasis www.ablynx.com Partner Key differentiating features Stage Best-in-class opportunity Monovalent interaction; strong affinity and preferential binding to soluble IL-6R Start Phase IIb/a (RA; SLE) in 2015 RA results exp. 2016 Potent neutralisation of both IL-17A and IL-17F POC achieved in primate CIA* model Phase Ib ongoing in psoriasis patients: results exp. 2015 * Collagen induced arthritis model 10 caplacizumab – anti-vWF • First-in-class bivalent Orphan Drug Status • Developed for the treatment of acquired thrombotic thrombocytopenic purpura (TTP) • Phase III study to start in 2015 • Peak sales potential €300-400M* Nanobody with Nanobodies® Inspired by nature * US, EU, Japan, other markets (Brazil, Canada, Russia, Mexico, Australia) What is the basis of TTP? caplacizumab blocks the platelet – ULvWF interaction Caplacizumab binds to A1 domain of vWF and thereby inhibits platelet string formation ADAMTS13 activity is impaired Ultra-Large (UL) vWF multimers Platelet string formation in patients with TTP endothelium Ex vivo assay for platelet string formation Fluorescence microscopy image of platelets adhering to UL-vWF in plasma of TTP patients Without treatment, fluorescently labelled platelets adhere to UL-vWF, observed as string-like structures ULvWF Caplacizumab inhibits the formation of platelet strings and potentially the associated microvascular thrombi in many organs ULvWF and anti-vWF Nanobody www.ablynx.com 12 Acquired TTP – significant unmet medical need Severe fatigue, headache, coma, abdominal pain, weakness, nausea, bizarre behaviour, vertigo, seizures Sudden onset Healthy person Daily PE in hospital until recovery of platelet count Emergency Potentially life threatening rare disorder of the blood coagulation system • • incidence of 11.3 per million2 ~10,000 acute events annually in US and Europe Extensive microscopic thrombi formed in small blood vessels throughout the body High unmet medical need • no approved medicinal product for treatment available • standard of care is plasma exchange (PE) plus immune suppressants • mortality remains high (10-20%)1 and ~ 36% of patients have relapses2 • major morbidities after first TTP episode such as neurocognitive impairment www.ablynx.com 1 Scully et al, Br J Haematology, 2012 2 George et al, 2008 13 Caplacizumab – strong Phase II clinical proof-of-concept Primary endpoint Secondary endpoint Safety www.ablynx.com • patients treated with caplacizumab achieved confirmed platelet normalisation at more than twice the rate of the group treated with placebo • this effect was statistically significant (p = 0.013) • 71% less patients with an exacerbation • 76% more patients in complete remission • no deaths in the caplacizumab arm compared to 2 deaths in the placebo arm • increased bleeding tendency, which is believed to be manageable • overall, caplacizumab has an acceptable safety profile 14 Caplacizumab – current status and next steps Confirmed clinical activity and good safety profile in the clinic Data from TITAN study, including post hoc analysis, presented at ASH 20141 Consultation with regulatory authorities in US and EU in Q1 2015 • explore possibility to file dossier for approval (2017 expected) based on TITAN study Various partnering scenarios currently being evaluated Preparations progressing to start Phase III trial in mid-2015 In 2015, caplacizumab will be the first Nanobody to enter Phase III clinical development www.ablynx.com 1Oral presentation availabe on Ablynx website 15 ALX-0171 – anti-RSV • First-in-class trivalent Nanobody for the treatment of respiratory syncytial virus (RSV) infection in infants • Delivered through inhalation • First-in-infant Phase IIa initiated in Q4 2014 • Opportunity in a multi-billion dollar market Nanobodies® Inspired by nature RSV infection in infants – high unmet medical need Leading cause of infant hospitalisation and primary viral cause of infant death • ~300,000 children* (< 5 years) hospitalised per year in 7 major markets1,2 • increased medical cost in the 1st year following RSV infection3 • prolonged wheezing and risk for asthma development4 No widely accepted drug available to treat RSV infections • Synagis® used as prophylaxis in high-risk pre-term infants only ($1.1bn sales in 2013) Evolves to distressing symptoms Symptomatic treatment including inhaled corticosteroids & bronchodilator 8-20% hospitalised * Extrapolation based on estimated US prevalence www.ablynx.com 1 Hall et al, NEJM ,2009; 2 Lee et al, Human Vaccines 2005; 3Shi et al, J Med Econ, 2011; 4 Sigurs et al, Thorax, 2010; Krishnamoorthy et al, Nature Medicine 2012 17 ALX-0171 – key milestones achieved In vitro studies demonstrated • potent anti-viral effect against recent clinical RSV isolates • 10,000 fold reduction in viral titres and superiority over palivizumab (Synagis®)1 Daily inhalation of ALX-0171 for 3 consecutive days (starting 3 days after infection) in neonatal lamb model for infant RSV demonstrated • marked reduction in viral titres, lung lesions and symptoms of illness (malaise)2 with %% ofla mlambs re  1 ≥ 1 s c o score b s w ith G e n e r a l illn e s s s c o r e -1 “Malaise score” 100 RSV vehicle RSV ALX-0171 R S V V e h ic le Vehicle R S V A L X -0 1 7 1 M o c k V e h ic l e M o c k A L X -0 1 7 1 80 60 40 20 0 1 2 3 4 5 6 D a y s p o s t in f e c t io n Days post infection Well tolerated in multiple Phase I clinical studies in adults www.ablynx.com Oral presentations – 1Vaccines of the World (Oct 2013) and 2 RSV Symposium (Nov 2014) – available on Ablynx website (pipeline section) 18 ALX-0171 – first-in-infant inhalation study Infants aged 3 to <24 months who are hospitalised for RSV infection >20 EU centres and additional centres in Southern Hemisphere (risk mitigation) Open-label lead-in N=5 Review by DMC* Inhaled ALX-0171 once/day Randomisation Custom-developed infant inhalation device (vibrating mesh) ALX-0171 N=20 Inhaled ALX-0171 once/day or placebo 2:1 3 consecutive days Placebo N=10 3 consecutive days Primary endpoint: Safety and tolerability of ALX-0171 Secondary endpoints: Centres opened for recruitment Dec 2014 Results expected H2 2015 www.ablynx.com * Data Monitoring Committee Clinical effect (feeding, respiratory rate, wheezing, coughing, general appearance) PD (viral load), PK (ALX-0171 systemic concentration) and immunogenicity 19 ALX-0171 – current status and next steps Strong therapeutic effect demonstrated in a neonatal animal model for infant RSV infection Well tolerated in multiple Phase I studies in adults First-in-infant Phase IIa study initiated in Europe with the potential to extend to the Southern Hemisphere as risk mitigation With ALX-0171, Ablynx could potentially achieve its fourth clinical proofof-concept for Nanobodies, and its first for an inhaled Nanobody www.ablynx.com 20 ALX-0061 – anti-IL-6R • Monovalent half-life extended Nanobody • Best-in-class potential for the treatment of auto-immune disorders • Global licensing agreement with AbbVie • Phase IIb studies in RA and Phase IIa study in SLE to start in 2015 • Opportunity in multi-billion dollar markets Nanobodies® Inspired by nature ALX-0061 – compelling Phase IIa results in RA patients ACR50 score as potential differentiating factor 100 % of patients 83 80 71 58 60 63 40 29 20 0 All unmodified ALX-0061 at week 24 (N=24) ACR20 ACR50 ACR70 DAS28 remission Boolean remission • Treatment was highly efficacious and was well tolerated at all doses • No increase in adverse events upon extension of treatment • No anti-drugs antibodies were reported www.ablynx.com 22 ALX-0061 – global licensing deal with AbbVie Global exclusive licensing deal with AbbVie signed in September 2013 following compelling Phase IIa proof-of-concept results with ALX-0061 in February 2013 Economics Ablynx • • $175M upfront at signing in September 2013 $665M total potential milestones plus double-digit royalties • perform and fund Phase I study with subcutaneous formulation (started 2014) perform and fund Phase II studies in RA and SLE (start 2015) • AbbVie Commercialisation www.ablynx.com • • pay a fee for each indication if they exercise the right to license ALX-0061 after completion of the Phase II studies responsible for Phase III development and registration • • AbbVie is responsible for global commercialisation Ablynx retains option to co-promote ALX-0061 in the Benelux RA: rheumatoid arthritis SLE: systemic lupus erythematosus 23 ALX-0061 – key milestones in clinical development 2014 2015 2016 2017 2018 2019 Phase I sc study results announced 23 Oct 2014 ALX-0061 showed >80% bioavailability after sc injection Phase IIb RA combination study with MTX Phase IIb RA monotherapy study top line results potentially continues development in RA Phase II in SLE top line results potentially continues development in SLE www.ablynx.com 24 Partnerships Nanobodies® Inspired by nature Partnerships – broad platform exploitation and value creation Global licensing deal for ALX-0061 (anti-IL-6R) in RA and SLE: $175M upfront and total potential value of $840M plus royalties Strategic discovery alliance (8 pre-clinical programmes on-going) – focus on bispecifics - 2 programmes could enter the clinic in 2015 4 deals: 10 programmes (1 Phase Ib) on-going in inflammation, immunology, oncology, immune-oncology, neurology and osteoarthritis 2 discovery deals: ion channel deal in neurology; immune-onco deal (focus on multispecifics) with €20M upfront, €10.7M research funding and total potential milestones of up to €1.7bn plus royalties 2 licensing deals in Greater China for ALX-0141 (anti-RANKL) in bone disorders and ozoralizumab (anti-TNFα) in inflammation Target based discovery deal >€335M in non-dilutive cash received from collaborators to date ~€3Bn in potential future milestones plus royalties www.ablynx.com 26 Financials and shareholder structure Nanobodies® Inspired by nature Financial summary €M 2012 2013 First 9 months 2014 Revenue 26.7 35.9 35.2 Operating Result (29.8) (17.7) (11.7) Cash Position(1) 62.8 200.4 221.5 Anticipated net cash burn for 2014: €30M - €35M (1) cash, cash equivalents, restricted cash and short-term investments at the end of the period www.ablynx.com 28 Shareholder structure Investors Abingworth (UK); 9.08% Boehringer (DE); 3.97% Geography Aviva (UK); 3.84% Other/nonspecified 26% US 26% Perceptive Advisors (US); 3.85% France 2% Fidelity Management Research LLC (US); 3.35% Other/nonspecified institutional and retail investors; 75.92% www.ablynx.com UK 18% Benelux 28% • Ordinary shares listed on Euronext Brussels (ABLX BB) • Sponsored level I ADRs on the US OTC market (ABYLY US) • 54M shares outstanding • 3M outstanding warrants • Free float is ~90% 29 Outlook Nanobodies® Inspired by nature Potential value drivers in 2015 Developing the pipeline • • • Caplacizumab (vWF): confirm the regulatory pathway; start Phase III in acquired TTP ALX-0061 (IL-6R): start two Phase IIb’s in RA and a Phase IIa in SLE Partnered programmes: potential start of three Phase I’s Programme read outs • • • ALX-0171 (RSV): potential POC from Phase IIa in hospitalised infants with RSV infection Commercial • Caplacizumab (vWF): determine partnering strategy • Potential milestone payments from ongoing partnerships • Continuing discussions on partnering various assets ALX-0761 (IL-17A/F): expect Phase Ib results in psoriasis patients Technology: results from various feasibility studies across multiple applications An important year ahead! www.ablynx.com 31 Later stage clinical data expectations 2018 2017 2016 2015 ALX-0061 Phase IIb ALX-0171 Paediatric (RA) Phase IIb (RSV) AbbVie have option to Wholly-owned license worldwide ALX-0171 Infant Phase IIa (RSV) Wholly-owned 2014 caplacizumab Phase II (TTP) Wholly-owned www.ablynx.com ALX-0761 Phase Ib (severe psoriasis) Licensed to Merck Serono (worldwide)  caplacizumab Phase III (TTP) Wholly-owned ALX-0061 Phase IIa (SLE) AbbVie have option to license worldwide Results from various patient studies with partners ALX-0141 and ozoralizumab Phase I/II in China Licensed to Eddingpharm (China) ALX-0761 Phase IIa (severe psoriasis) Licensed to Merck Serono (worldwide) 32 Nanobodies® – creating better medicines JP Morgan Healthcare conference San Francisco – 15th January 2015 Nanobodies® Inspired by nature