Nanobodies creating better medicines Corporate presentation November 2015
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 Corporate snapshot CORPORATE Platform technology and late-stage clinical development company 350 employees in Ghent, Belgium TECHNOLOGY Pioneer in next generation antibody-derived drugs Nanobodies >500 patent applications and granted patents PRODUCTS >30 wholly-owned and partnered programmes 1 Phase III and 4 Phase II studies ongoing in-house First potential product approval in 2018 PARTNERS AbbVie, Boehringer Ingelheim, Eddingpharm, Genzyme, Merck &Co., Inc., Merck KGaA, Novartis, Novo Nordisk and Taisho Pharmaceutical > 380M cash received; > 7Bn in potential milestones + royalties FINANCIALS 262M in cash at 30 September 2015 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) 54.5M shares outstanding 2.9M outstanding warrants Total shares outstanding by investor % of institutional shareholders by geography (representing 68% of total S/O) Other institutional and retail investors, 66% Abingworth Management Limited and Abingworth LLP (UK), 6% Boehringer Ingelheim (DE), 4% Aviva Investors (UK), 5% Perceptive Advisors (US), 4% Polar Capital Funds Plc (UK), 3% FMR LLC (US), 5% Taube Hodson Stonex Partners LLP (UK), 4% Oppenheimer Funds, Inc. (OFI) (US); 3% Scandinavia 2% Benelux 30% France 3% Other 3% UK 27% US 35%
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 HH V L Ablynx s Nanobody C H 2 C L C H 2 small and robust easily linked together C H 3 C H 3 sequence homology comparable to humanised/human mabs nano- to picomolar affinities challenging and intractable targets Conventional antibodies Heavy chain only antibodies multiple administration routes manufacturing in microbial cells 6
7 Ablynx s drug discovery engine Rapid generation of high quality biologics Immunise llamas with antigen and/or Wide range of highly diverse Nanobodies with 0.1-10nM affinities Formatted Nanobodies Use proprietary synthetic Nanobody phage libraries Cloning and production in microbial systems ~12-18 months
8 Ablynx s Nanobodies Competitive advantages Mix and match Targeting different pathways at once with a single Nanobody construct, e.g. multiple checkpoint inhibitors Challenging and intractable targets Nanobodies can reach conserved cryptic epitopes Nanobodies against ion channels and GPCRs Alternative delivery routes Inhalation Oral-to-topical Needle-free Ocular Cell- /tissue-homing Cell specificity Immune cell recruitment Tissue-specific targeting Customised half-life extension Fc Nanobodydrug conjugates High-yield, highconcentration, low-viscosity, microbial production Weeks/days/hours Cell killing Manufacturing Albuminbinding Nanobody Ag-1 Ag-1 Ag-2
Broad product pipeline
FULLY OWNED PARTNERED 10 Hybrid business model fuels the pipeline >30 programmes in development Therapeutic area Product name Target Discovery Pre-clinical Phase I Phase II Phase III Filing Clinically validated targets First-in-class Haematology Respiratory caplacizumab ALX-0171 vwf RSV Oncology/ Immuno-oncology Various Inflammation/ Immunology Various Ocular Various Other Various Inflammation/ Immunology ALX-0061 ALX-0761 ozoralizumab IL-6R IL-17F/IL-17A TNFα Greater China Japan Various Oncology/ Immuno-oncology Various VEGF/Ang2 Bone disorders ALX-0141 RANKL Greater China Neurology Various CXCR2 Other Various
Key value drivers
Immuno-oncology (I/O) Changing the cancer treatment paradigm Huge market potential Proven substantial survival impact Market expected to grow to >$43bn by 2020* I/O drugs expected to treat 60% of cancers* Multiple targets Increasing number of targets Combination therapies are the next generation Multi-specific Nanobodies 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 12
Anti-tumour activity Immuno-oncology therapies Best results when used in combination Sustained response Time course (months) Source: Prof Dr Omid Hamid (MD), Chief, Translational Research and Immunotherapy The Angeles Clinic & Research Institute (2014) 13
Multi-specific Nanobodies Major immuno-oncology collaboration with Merck & Co., Inc. Merck & Co., Inc. is a leader in the field heavily investing in I/O R&D pipeline (~80% of total R&D budget*) anti-pd-1 drug, Keytruda, approved for the treatment of advanced melanoma and metastatic NSCLC sales of Keytruda estimated to reach $6Bn by 2020** >160 clinical studies for Keytruda across more than 30 tumor types as a monotherapy and in combination Collaboration with Merck & Co., Inc. signed Feb 14 and expanded in July 15 targeting multiple immune-checkpoint modulators up to 17 Nanobody programmes with a focus on multi-specific combinations 33M up-front with potentially up to 5.7Bn in future milestones plus royalties first in vivo pre-clinical milestone ( 3.5M) achieved with a bi-specific Nanobody in Oct 2015 *Bryan Garnier Oct 2015 **Leerink August 2015 14
Product pipeline Leading products in the clinic PROPRIETARY Programme (target) Indication Key differentiating features Stage Caplacizumab (vwf) Thrombotic thrombocytopenic purpura First-in-class orphan drug Novel mode of action Inhibition of micro-clot formation Phase III on-going and MAA filing in H1 2017 in EU for conditional approval ALX-0171 (RSV) Respiratory syncytial virus infection First-in-class addressing high unmet need Inhaled Nanobody delivered to infection site Highly potent trivalent construct First-in-infant Phase IIa study on-going: results expected in H1 2016 PARTNERED 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 studies (RA; SLE) on-going; RA results expected in H2 2016 15 15
16 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 Planning to file for conditional approval in Europe (H1 2017) and BLA submission in USA (2018) Ablynx to lead commercialisation in Europe and USA Peak sales potential of 300M- 400M 1 1 US, EU, Japan, other markets (Brazil, Canada, Russia, Mexico, Australia)
17 Caplacizumab mode of action Stops formation of micro-clots Caplacizumab blocks the platelet ULvWF interaction Ultra-Large (UL) vwf multimers endothelium ADAMTS13 activity is impaired Platelet string formation in patients with TTP Caplacizumab binds to A1 domain of vwf and thereby inhibits platelet string formation Ex vivo assay for platelet string formation Fluorescence microscopy image of platelets adhering to UL-vWF in plasma of TTP patients 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
18 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 recovery of platelet count + immune suppressants attp is caused by impaired activity of ADAMTS13 (<10% than that in normal plasma 1 ) extensive micro-clot formation in small blood vessels throughout the body subsequent tissue ischemia and damage to vital organs Ultra-rare indication with an incidence of ~11/million 2 High unmet medical need with no approved therapeutic drug currently available mortality high (10-20%) 3 and ~ 36% of patients relapse 2 major morbidities, including brain, cardiac and renal damage 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 19 Caplacizumab proven clinical benefit Strong clinical proof-of-concept in TITAN Phase II study Study design Study results PE Placebo N=39 30 days 30 days Time to platelet normalisation Median days (95% CI) No prior PE Caplacizumab 3.0 (2.7, 3.9) N = 34 Placebo 4.9 (3.2, 6.6) N = 35 1:1 Median days (95% CI) One prior PE 2.4 (1.9, 3.0) N = 2 4.3 (2.9, 5.7) N = 4 75 subjects PE Caplacizumab N=36 30 days 30 days Primary endpoint: time to confirmed normalisation of platelet count Secondary endpoints: exacerbations; relapses; PE parameters; mortality; major clinical events Number of subjects Caplacizumab Placebo Subjects with exacerbation within 30 days after stopping daily PE 3 (8%) 11 (28%) Deaths 0 2 Primary endpoint met (p=0.005) 40% reduction in time to platelet normalisation = faster reversion of thrombocytopenia 71% fewer patients with exacerbations = potential prevention of further organ damage
RANDOMISATION Caplacizumab Phase III study Double-blind placebo controlled study (Q3 2015 to Q4 2017) Exacerbation restart daily PE and open label caplacizumab 1:1 30 days Daily PE Placebo* N=46 TREATMENT PERIOD** FOLLOW-UP PERIOD (4 weeks) Daily PE 30 days 92 subjects Caplacizumab* N=46 Potential extension of blinded study drug if relapse, restart daily PE and open label caplacizumab Primary endpoint: time to confirmed normalisation of platelet count Secondary endpoints: exacerbations/relapses; mortality rate; severe morbidity; organ damage biomarkers (troponin, creatinine, LDH); PE parameters; days in ICU/hospital; AEs; PD; PK; immunogenicity * iv bolus (10mg) followed by daily sc (10mg) ** incl. corticosteroids at start of daily PE until underlying disease activity resolved 20
Caplacizumab positioning New standard of care in attp Future standard of care based on three pillars Caplacizumab Daily PE Immunosuppression Treatement duration Immediate inhibition of platelet aggregation, micro clot formation and small blood vessel occlusion Protection during the acute phase of the disease Prevention of organ damage Remove ULvWF & auto-antibodies Replenish ADAMTS13 Reduce activity of immune system to resolve underlying cause of attp Reduction in exacerbations Caplacizumab could become the first approved product for the treatment of attp 21 21
ALX-0171 Wholly-owned anti-rsv Nanobody First-in-class trivalent Nanobody, delivered by inhalation Developed for the treatment of respiratory syncytial virus (RSV) infection in infants 3 Phase I studies in 106 subjects* successfully completed First-in-infant Phase IIa on-going with results expected in H1 2016 Opportunity in multi-billion dollar market * Of whom 24 adults with hyper-reactive airways 22
23 RSV infection in infants High unmet medical need Leading cause of infant hospitalisation and primary viral cause of infant death ~65% of infants are infected in their first year of life ~300,000 children* (< 5 years) hospitalised per year in 7 major markets 1,2 ; ~500-4,500 deaths per year in the US ~2.1 million outpatient visits annually in the USA among children <5 years of age increased medical cost in the first year following RSV infection 3 prolonged wheezing and increased risk of asthma development 4 No current treatment options 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 * Extrapolation based on estimated US prevalence 1 Hall et al, NEJM, 2009; 2 Lee et al, Human Vaccines, 2005; 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 24 ALX-0171 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 ) 1 daily inhalation of ALX-0171 for 3 consecutive days in neonatal lamb model for infant RSV demonstrated markedly reduced signs and symptoms of illness ( Malaise Score ) 2 and viral lesions 100 Malaise score 60 Lung viral lesions (day 6 post infection) 80 Control 50 60 40 20 0 0 1 2 3 4 5 6 ALX-0171 40 30 20 10 0 Control ALX-0171 RSV infection Treatment ALX-0171 or formulation buffer 1 Vaccines of the World (Oct 2013) 2 RSV Symposium (Nov 2014) presentations on http://www.ablynx.com/rd-portfolio/clinical-programmes/alx-0171/
RANDOMISATION ALX-0171 First-in-infant inhalation study on-going Infants aged 3 to <24 months who are hospitalised for RSV infection Study centres in Europe and Asia-Pacific region Custom-developed infant inhalation device (vibrating mesh) ALX-0171 N=20 Open-label lead-in N=5 Review by DMC* 2:1 Inhaled ALX-0171 once/day or placebo 3 consecutive days Inhaled ALX-0171 once/day 3 consecutive days Placebo N=10 Primary endpoint: Safety and tolerability of ALX-0171 Results expected H1 2016 Secondary endpoints: Clinical effect (feeding, respiratory rate, wheezing, coughing, general appearance) PD (viral load), PK (ALX-0171 systemic concentration) and immunogenicity * Data Monitoring Committee 25
ALX-0061 Anti-IL-6R Nanobody partnered with AbbVie Half-life extended Nanobody Best-in-class potential for the treatment of auto-immune disorders Global licensing agreement with AbbVie 2 Phase IIb studies in RA with results expected H2 2016; Phase II study in SLE with results expected in 2018 Opportunity in multi-billion dollar markets RA: rheumatoid arthritis SLE: systemic lupus erythematosus 26
% of patients ALX-0061 Compelling Phase IIa results in RA patients 100 ACR50 score as potential differentiating factor 80 60 83 71 58 63 40 29 20 0 All unmodified ALX-0061 at week 24 (N=24) ACR20 ACR50 ACR70 DAS28 remission Boolean remission Data published 13 February 2013: press release available on Ablynx s website 27
ALX-0061 Global licensing 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 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 Commercialisation AbbVie is responsible for global commercialisation Ablynx retains option to co-promote ALX-0061 in the Benelux 28 28
ALX-0061 Key data points 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 combination and monotherapy studies in RA Top line results potentially continues development in RA Phase II RA OLE study Phase II study in SLE Top line results potentially continues development in SLE 29
Outlook
31 Long term value creation Potential clinical and regulatory key events Clinical study results Key regulatory events 2 2016 ALX-0171 Infant Phase IIa (RSV) Wholly-owned ALX-0061 Phase IIb combination therapy (RA) AbbVie have option to license worldwide ALX-0061 Phase IIb monotherapy (RA) AbbVie have option to license worldwide ALX-0761 Phase Ib POC (psoriasis) Licensed to Merck KGaA (worldwide) 2017 Caplacizumab MAA filing EU + Phase III results (TTP) Wholly-owned ALX-0171 Infant Phase IIb (RSV) Wholly-owned ALX-0141 and ozoralizumab Phase I/II in China Licensed to Eddingpharm (China) ALX-0761 Phase IIa (psoriasis) Licensed to Merck KGaA (worldwide) 2018 Caplacizumab conditional approval EU and BLA filing in US Wholly-owned ALX-0061 Phase II (SLE) AbbVie have option to license worldwide Results from various patient studies with partners
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