Nanobodies creating better medicines Investor presentation February 2016
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. 2 2
Ablynx Powerful platform generating potentially innovative medicines CORPORATE Platform technology and late-stage clinical development company 350 staff in Ghent, Belgium TECHNOLOGY Pioneer in next generation antibody-derived drugs Nanobodies >500 patent applications and granted patents; critical know-how Validation through multiple partnerships with top tier pharma companies PRODUCTS ~40 wholly-owned and partnered programmes 1 Phase III and 4 Phase II studies ongoing in-house First potential launch in 2018 PARTNERS AbbVie, Boehringer Ingelheim, Eddingpharm, Genzyme, Merck &Co., Inc., Merck KGaA, Novartis, Novo Nordisk and Taisho Pharmaceuticals > 380M cash received; > 7Bn in potential milestones + royalties FINANCIALS 262M in cash at 30 th September 2015 277M raised in equity 100M of issued Convertible Bonds maturing in 2020 3
4 Ablynx Diversified shareholder base Ordinary shares listed on Euronext Brussels (ABLX) Sponsored Level I ADRs on the US OTC market (ABYLY) 54.8M shares outstanding 2.7M outstanding warrants Breakdown of share capital % of institutional shareholders by geography (representing 70% of total shares outstanding) 5.1% 5.0% 4.5% 4.4% 4.0% Perceptive Advisors (US) Fidelity Management Research (US) Aviva Investors (UK) Taube Hodson (UK) Abingworth Management (UK) Scandinavia 2% France 4% Other 5% US 35% 63.7% 3.9% 3.3% 3.1% 3.0% Boehringer Ingelheim (DE) JP Morgan Asset Management (UK) Oppenheimer Funds (US) Polar Capital Funds Plc (UK) Benelux 28% UK 27% Other shareholders
Strong performance in 2015 Excellent progress in all areas Development & Discovery Initiated Phase III study with caplacizumab (vwf) in acquired TTP Initiated 2 Phase IIb RA studies with ALX-0061 (IL-6R) (partnership with AbbVie) Initiated Phase II SLE study with ALX-0061 (IL-6R) (partnership with AbbVie) Completed recruitment for Phase I/IIa safety study in infants with ALX-0171 (RSV) Merck KGaA completed Phase Ib study in psoriasis patients with ALX-0761 (bi-specific IL-17A/F Nanobody) Achieved pre-clinical POC with bi-specific Nanobody programme in immuno-oncology (partnership with Merck & Co., Inc.) Initiated 4 new internal discovery programmes and ~10 new partnered programmes Financial & Commercial 100M raised through a 5-year Convertible Bond Expanded immuno-oncology collaboration with Merck & Co., Inc. to include a total of 17 programmes; 5.7Bn in potential milestones plus royalties Signed collaboration with Novo Nordisk to utilise multispecific Nanobodies in a specific indication; 5M upfront and 182M in potential milestones plus royalties Signed licensing deal with Taisho Pharmaceuticals to develop and commercialise ozoralizumab (TNFα) in Japan Extended the ion channel collaboration with Merck & Co., Inc. in Neurology Signed research collaboration with Genzyme to explore the potential of a Nanobody targeting an ion channel in Multiple Sclerosis Began to build a commercial organisation to support the launch of caplacizumab in EU and USA 5 5
Unique technology
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 C H 1 V H V HH 12-15kDa V L V HH Ablynx s Nanobody C H 2 C H 3 C L C H 2 C H 3 small and robust easily linked together sequence homology comparable to humanised/human mabs nano- to picomolar affinities Conventional antibodies Heavy chain only antibodies able to bind and block challenging targets multiple administration routes manufacturing in microbial cells 7
8 Ablynx s drug discovery engine Rapid generation of novel biologics Immunise llamas with antigen and/or Use proprietary synthetic Nanobody phage libraries Wide range of highly diverse Nanobodies with 0.1-10nM affinities Formatted Nanobodies Cloned into microbial systems and produced through fermentation ~12-18 months
9 Ablynx s Nanobodies Platform advantages Mix and match Multiple delivery routes Multi-specific Nanobodies that address different targets in a single drug molecule Inhalation Ocular Oral-to-topical High-yield, highconcentration, low-viscosity, microbial production Manufacturing Able to bind and block challenging targets Nanobodies against ion channels and GPCRs Customised half-life extension Hours/days/weeks Albuminbinding Nanobody Fc
Broad product pipeline
11 Hybrid business model fuels the pipeline ~40 programmes, 6 Nanobodies in clinical development Product Indication Target Pre-clinical Phase I Phase II Phase III Filing caplacizumab attp vwf ALX-0061 RA IL-6R RA SLE IL-6R IL-6R + ALX-0171 RSV RSV Up to 17 programmes Immuno-Oncology Various BI 836880 Oncology VEGF/Ang2 ozoralizumab RA RA TNFα TNFα Greater China Japan ALX-0141 Bone disorders RANKL Greater China ALX-0761 Psoriasis IL-17A/IL-17F ~ 15 whollyowned and partnered programmes Various
Key value drivers
Immuno-oncology (I/O) Changing the cancer treatment paradigm Huge market potential Market expected to grow to >$43bn by 2020* I/O drugs expected to treat 60% of cancers* Proven substantial survival impact Multiple targets Increasing number of targets Combination therapies are the future Multi-specific Nanobodies - the next wave! Bind multiple targets (2, 3, 4 or 5) with one Nanobody molecule Potential to increase efficacy and avoid escape mechanisms Technology allows rapid exploration of combinations Manufacturing simplicity and cost-effectiveness *BofA Merrill Lynch July 2015 Nature Reviews - 2012 13
14 Immuno-oncology (I/O) Multi-specific Nanobodies versus combination mabs One tri-specific Nanobody is 4x smaller than a mab More difficult for mabs to bind to different targets simultaneously mab 2 Tri-specific Nanobody mab 3 mab 1 mab Target 1 Target 2 Target 3 Multi-specific Nanobodies may block multiple targets simultaneously Target 3 Target 2 Target 1
Multi-specific Nanobodies Major immuno-oncology collaboration with Merck & Co., Inc. Merck & Co., Inc. leader in the field Heavily investing in I/O R&D pipeline (~80% of total R&D budget*) Keytruda approved in advanced melanoma (first line) and metastatic NSCLC Sales of Keytruda estimated to reach $6Bn by 2020** >160 clinical studies for Keytruda in >30 tumor types Merck & Co., Inc. and Ablynx in collaboration Targeting multiple immune-checkpoint modulators Up to 17 fully-funded Nanobody programmes; focus on multi-specific combinations 33M upfront; up to 5.7Bn in potential future milestones plus royalties First product could enter the clinic in 2017 First in vivo pre-clinical milestone ( 3.5M) achieved in October 2015 with a bi-specific Nanobody *Bryan Garnier Oct 2015 **Leerink August 2015 15
16 Proprietary tetravalent anti-gitr Nanobody Efficacy as monotherapy or in combination with anti-pd1 mab Tumour efficacy in a syngeneic mouse model Vehicle Irrelevant Nb + PD-1 mab GITR Nb GITR Nb + PD-1 mab GITR Nb PD1 mab CT26 colon carcinoma tumours were grown to 90 mm 3 in size prior to start of treatment (Day 0)
Proprietary tetravalent anti-gitr Nanobody Efficacy as monotherapy or in combination with anti-pd1 mab Individual tumor efficacy plots Vehicle 0/10 Reg Irr Nb + PD-1 mab 0/10 Reg GITR Nb 1/10 Reg GITR Nb + PD-1 mab 5/10 Reg CT26 colon carcinoma tumours were grown to 90 mm 3 in size prior to start of treatment (Day 0) Reg = regressed below baseline volume 17
Product pipeline Most advanced clinical programmes PROPRIETARY Programme (target) Indication Key differentiating features Stage Caplacizumab (vwf) Acquired thrombotic thrombocytopenic purpura First-in-class orphan drug Inhibits micro-clot formation More rapidly restores normal platelet counts Phase III on-going and MAA filing planned in H1 2017 in EU for conditional approval ALX-0171 (RSV) Respiratory syncytial virus infection Inhaled Nanobody delivered directly to infection site First-in-class therapeutic addressing high unmet medical need Completed recruitment of firstin-infant Phase I/IIa 35 patient safety study: results expected in H1 2016. Expansion study on-going in infants aged 1-5 months OPTION TO LICENSE Programme (target) Indication Key differentiating features Stage Partner ALX-0061 (IL-6R) RA, SLE Best-in-class opportunity Monovalent interaction; strong affinity and preferential binding to soluble IL-6R* 3 Phase II s (RA; SLE) ongoing; RA results expected in H2 2016 *Gottschalk et al, Frontiers in Immunology, Oct 2015 18 18
19 Caplacizumab Wholly-owned anti-vwf Nanobody First-in-class bivalent Nanobody with Orphan Drug Status and patent protection up to 2035 Developed for the treatment of acquired thrombotic thrombocytopenic purpura (attp) Phase II (75 patients) successfully completed; Phase III (92 patients) on-going with results expected by end of 2017 Planned filing for conditional approval in Europe (H1 2017) and BLA submission in USA (2018) Ablynx to lead commercialisation in Europe and USA Anticipated first launch in 2018 Peak sales potential of ~ 300M 1 1 US, EU, Japan, other major markets
20 Caplacizumab unique mode of action Rapidly stops formation of micro-clots Caplacizumab blocks the platelet ULvWF interaction ADAMTS13 activity is impaired Caplacizumab binds to A1 domain of vwf and thereby inhibits platelet string formation Ultra-Large (UL) vwf multimers endothelium Platelet string formation in patients with attp Ex vivo assay for platelet string formation Fluorescence microscopy image of platelets adhering to UL-vWF in plasma of an attp patient ULvWF Without treatment, fluorescently labelled platelets adhere to UL-vWF, observed as string-like structures ULvWF and anti-vwf Nanobody Caplacizumab inhibits the formation of platelet strings and potentially the associated microvascular thrombi in many organs
21 Acquired TTP (attp) Life-threatening ultra-rare acute blood clotting disorder episode diagnosis treatment attp patient Emergency Room ICU/haematology unit Sudden onset in otherwise healthy person (nausea, fever, coma,..) Initial diagnosis based on thrombocytopenia & haemolysis Plasma exchange until normalisation of platelet count + immune suppressants attp is caused by impaired activity of ADAMTS13 (<10% of that in normal plasma 1 ) extensive micro-clot formation in small blood vessels throughout the body leads to tissue ischemia and damage to vital organs Ultra-rare indication with incidence estimated at up to 11 per million 2 High unmet medical need with no approved therapeutic drug currently available high acute mortality (10-20%) 3, vast majority within 2 weeks post diagnosis, and ~ 36% of patients with recurrences 2 major morbidities, including brain (e.g. stroke), heart and kidney damage impacts life expectancy and quality of life 1 Scully et al, BJH 2012; 2 George et al, EJH 2008; 3 Allford et al, BJH 2003, Kremer Hovinga, Blood 2010; Benhamou, Haematologica 2012
RANDOMISATION Caplacizumab (anti-vwf) proven clinical benefit TITAN Phase II study achieved clinical proof-of-concept 75 subjects 1:1 30 days 30 days PEX Placebo N=39 30 days 30 days PEX Caplacizumab N=36 Primary endpoint: time to confirmed normalisation of platelet count Secondary endpoints: recurrences; PEX parameters; mortality; major clinical events Primary endpoint met with high statistical significance (p=0.005) - 40% reduction in time to platelet normalisation = faster reversion of thrombocytopenia and reduced use of plasma exchange (PEX) 71% fewer patients with recurrences during caplacizumab treatment - potential prevention of organ damage PEX = plasma exchange 22
RANDOMISATION Caplacizumab (anti-vwf) Hercules Phase III study (Q3 2015 to Q4 2017) Recurrence restart daily PEX and open label caplacizumab Daily PEX 30 days 1:1 Placebo* N=46 TREATMENT PERIOD** FOLLOW-UP PERIOD (4 weeks) Daily PEX 30 days 92 subjects Caplacizumab* N=46 Potential extension of blinded study drug if recurrence, restart daily PEX and open label caplacizumab Primary endpoint: time to confirmed normalisation of platelet count Secondary endpoints: recurrences; mortality rate; severe morbidity; organ damage biomarkers (troponin, creatinine, LDH); PEX parameters; days in ICU/hospital; AEs; PD; PK; immunogenicity * iv bolus (10mg) followed by daily sc (10mg) ** incl. corticosteroids at start of daily PEX until underlying disease activity resolved PEX = plasma exchange 23
Caplacizumab positioning Potential new component in standard of care for attp Future standard of care could be based on three pillars Caplacizumab Daily PEX Immunosuppression Treatement duration Rapid inhibition of platelet aggregation, micro-clot formation and small blood vessel occlusion Reduction in duration of PEX treatment Protection during the acute phase of the disease Prevention of organ damage Removal of ULvWF & auto-antibodies Replenishment of ADAMTS13 Reduces activity of immune system to resolve the underlying cause of attp Reduction in recurrences Caplacizumab may become the first approved product for the treatment of attp 24 24
Caplacizumab (anti-vwf) Potentially Ablynx s first marketed product Strategic opportunity Concentrated patient presentation Established KOL network and reference centres Modest commercial infrastructure requirements Retain direct control over commercialisation in EU5 and USA Contract sales, distributors and/or commercial partners in other territories Market potential No direct competition in attp Potential key component in future standard of care Orphan Drug status with patent protection to 2035 Peak sales potential in attp of ~ 300M Potential launch in 2018 25 25
ALX-0171 Wholly-owned anti-rsv Nanobody First-in-class trivalent Nanobody, delivered by inhalation Potential breakthrough for the treatment of Respiratory Syncytial Virus (RSV) infection in infants 3 Phase I studies in 106 adults* successfully completed First-in-infant Phase I/IIa safety results in H1 2016 Expansion cohort in younger infants within the Phase I/IIa safety study on-going during H1 2016 Phase II dose-ranging study to start in H2 2016 Opportunity in multi-billion dollar market * Including 24 adults with hyper-reactive airways 26
27 RSV infection in infants Leading cause of infant hospitalisation 60%-70% of children will have been infected by the age of 1 year 1 >3 million children (<5 years) hospitalised worldwide each year 1 3,000-8,500 deaths in infants <2 years globally p.a. 2 No specific treatment options currently available Synagis used as prophylaxis in high-risk pre-term infants only ($900M sales in 2014) Evolves to distressing symptoms Symptomatic treatment including inhaled corticosteroids & bronchodilator 8-20% hospitalised Long-term disease burden increased medical cost in the first year following RSV infection 3 prolonged wheezing and increased risk of asthma development 4 1 Nair et al, Lancet 2010; 2 Byington et al, Pediatrics 2014; 3 Shi et al, J Med Econ, 2011; 4 Sigurs et al, Thorax, 2010; Backman et al, Acta Pediatr, 2014
% of lambs with score 1 Mean % lung tissue with viral lesions ALX-0171 (anti-rsv Nanobody) Key milestones achieved Well tolerated in multiple Phase I clinical studies in adults Strong in vitro and in vivo study results potent anti-viral effect against recent clinical RSV isolates 10,000 fold reduction in viral titres and superiority in vitro compared with palivizumab (Synagis ) strong effect following daily inhalation for 3 consecutive days in neonatal lamb model for infant RSV 100 Malaise score - Lambs 60 Lung viral lesions - Lambs (day 6 post infection) 80 60 40 20 0 0 1 2 3 4 5 6 Control ALX-0171 50 40 30 20 10 0 Control ALX-0171 RSV infection Treatment ALX-0171 or formulation buffer Compelling pre-clinical proof-of-concept Vaccines of the World (Oct 2013); RSV Symposium (Nov 2014): presentations on Ablynx website: http://www.ablynx.com/rd-portfolio/clinical-programmes/alx-0171/ 28
RANDOMISATION ALX-0171 (anti-rsv Nanobody) First-in-infant Phase I/IIa safety study recruitment completed Infants aged 3 to <24 months who were hospitalised for RSV infection Study centres in Europe and Asia-Pacific region Adapted infant inhalation device (vibrating mesh) ALX-0171 N=20 Open-label lead-in N=5 Inhaled ALX-0171 once/day * Data Monitoring Committee 3 consecutive days Review by DMC* Results in H1 2016 2:1 Inhaled ALX-0171 or placebo once/day 3 consecutive days Placebo N=10 Review by DMC* Primary endpoint: Safety and tolerability of ALX-0171 Secondary endpoints: Clinical effect (feeding, respiratory rate, wheezing, coughing, general appearance) PD (viral load), PK (ALX-0171 systemic concentration) and immunogenicity 29
30 ALX-0171 (anti-rsv Nanobody) Next steps in clinical development Phase I/IIa expansion cohort Expansion of Phase I/IIa safety study ~10-18 hospitalised infants aged 1-5 months Generate additional data in younger children On-going Results: H2 2016 Phase II dose-ranging Clinical centres in EU, Asia-Pacific and USA ~100 hospitalised infants aged 1-36 months Primary endpoint: nasal viral load Secondary endpoints: clinical effect (e.g. feeding and respiratory parameters) and duration of hospitalisation Start: H2 2016 Target recruitment completion: end 2017
ALX-0171 (anti-rsv Nanobody) Innovative therapeutic approach with significant commercial potential Unique product Delivered via inhalation directly to the site of infection Highly potent and selective Neutralises broad range of RSV strains Compelling proof-of-concept in animal model of infant RSV Good safety profile demonstrated Data from first-in-infant Phase I/IIa safety study expected in H1 2016 Market potential Currently only prophylactic and symptomatic treatment options Vaccines and improved antibodies in development for prophylactic use, but with potential limitations Small molecule therapeutics in development but ALX-0171 appears to be the most advanced programme for the treatment of infant RSV infections ~34M infections/year resulting in ~3-4M hospitalisations/year globally 1 ; total estimated cost burden of ~$88Bn 2 1 Nair et al, Lancet 2010; 2 Novavax November 2015: estimated value of life lost, future health implications and lost earnings (both elderly and infant populations) 31 31
ALX-0061 Anti-IL-6R Nanobody partnered with AbbVie Half-life extended Nanobody Best-in-class potential for the treatment of autoimmune disorders Global licensing agreement with AbbVie 2 Phase IIb studies in RA on-going with results expected in H2 2016 Phase II study in SLE on-going with results expected in 2018 Opportunity in multi-billion dollar markets RA: rheumatoid arthritis SLE: systemic lupus erythematosus 32
% of patients The RA landscape ALX-0061 (anti-il-6r) has best-in-class potential ACR50 scores from various clinical studies 80 75 75 70 60 63 60 50 40 44 50 47 44 44 37 41 48 45 43 41 39 30 31 20 10 0 ALX-0061 1 Tocilizumab (Roche) 2 Sirukumab (J&J/GSK) 3 Sarilumab (Sanofi/Regeneron) 4 Clazakizumab (Alder) 5 Adalimumab (AbbVie) 6 1 PhIIa study (iv) (all responders): 1mg/kg Q4W; 3mg/kg Q4W; 6mg/kg Q8W; 2 Data extracted from OPTION (iv) (4 and 8 mg/kg), AMBITION (iv) (8 mg/kg) and ADACTA (iv) (8mg/kg) trials; 3 Phase II results ACR2011/EULAR 2012: 100mg Q2W; 100mg Q4W; pooled data; 4 Phase III TARGET trial (press release Nov 2015); 150 mg Q2W and 200 mg Q2W; 5 Phase IIb trial (ACR 2013), Q4W; 25 mg, 100 mg, 200 mg; 6 2003 FDA briefing document: DE19 confirmatory Phase II/III study: 20mg QW, 40mg Q2W +MTX 33
ALX-0061 (anti-il-6r Nanobody) Phase IIa RA study demonstrated best-in-class potential Highly efficacious ACR20, ACR50 and ACR70 scores of up to 100%, 75% and 63% First onset of remission as of week 2 Early signs of effect on bone oedema No disease progression as determined by MRI Convenient dosing Wide therapeutic window with potential to dose subcutaneously once a month Favourable safety profile No dose dependent increase in frequency or severity of adverse events 34
ALX-0061 (anti-il-6r Nanobody) Global licensing option deal with AbbVie Economics $175M upfront at signing in September 2013 $665M total potential milestones plus double-digit royalties Ablynx Perform and fund Phase I study with subcutaneous formulation (successfully completed in 2014) Perform and fund Phase II studies in RA and SLE (on-going) AbbVie Pays a fee for each indication if they exercise the right to license ALX-0061 after completion of the Phase II studies then responsible for Phase III development, registration and commercialisation 35 35
36 ALX-0061 (anti-il-6r Nanobody) Key data points in clinical development 2014 2015 2016 2017 2018 Phase I study subcutaneous (sc) ALX-0061 Phase IIb RA combination study Results announced 23 Oct 2014 ALX-0061 showed >80% bioavailability after sc injection Top line results Phase IIb RA monotherapy study Top line results potentially continues development in RA Phase II RA open label extension (OLE) study Phase II SLE study Top line results potentially continues development in SLE
Outlook
38 2016 an exciting year ahead Potential key events Clinical study results Results of first-in-infant Phase I/IIa safety study with ALX-0171 (RSV) (35 infants aged 3-24 months) Results from the expansion cohort of the first-in-infant Phase I/IIa safety study with ALX-0171 (RSV) (infants aged 1-5 months) Results from the Phase IIb RA combination therapy study with ALX-0061 (IL-6R) Results from the Phase IIb RA monotherapy study with ALX-0061 (IL-6R) Results from the Phase Ib study with ALX-0761 (IL-17A/F) in psoriasis patients (licensed to Merck KGaA) Building the pipeline Continuation of Phase III study with caplacizumab Continuation of Phase II study in SLE with ALX-0061 (IL-6R) Initiation of Phase II doseranging study with ALX-0171 (RSV) Initiation of up to 4 Phase I studies in partnered programmes Start of IND enabling studies with immuno-oncology programmes (partnered with Merck & Co., Inc.) Initiation and continuation of ~40 internal and partnered discovery and pre-clinical programmes Commercial Opt-in decision by AbbVie for global exclusive license of ALX-0061 in RA Continuing preparations for commercialisation of caplacizumab Expand existing collaborations and/or initiate new partnerships Payment to Ablynx of multimillions in up-fronts, FTE payments and milestones
39 Ablynx Investment thesis Unique and powerful validated technology platform which has been used to generate potential medicines in a wide range of therapeutic areas Very well funded hybrid business model which supports ~40 programmes, some together with pharmaceutical partners, offering a balanced range of risk and reward A number of short and medium term pre-clinical, clinical and commercial catalysts
Questions CONTACT DETAILS Investor Relations +32 9 262 00 00 investors@ ablynx.com www.ablynx.com