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Guillaume Gerardi Paul Hermant Marion de Jalras Laurent Equipart Ablynx This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques et Biologiques de Lille The opinions expressed are our own and not necessarily those of Ablynx Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion Ablynx • drug discovery and development company based in Ghent, Belgium • Ablynx is a spin-off of the Flanders Interuniversity Institute for Biotechnology (VIB) and the Vrije Universiteit Brussel (VUB). • Ablynx is based on the research of Prof. Dr. R. Hamers, S. Muyldermans and was co-founded and seed-financed (€ 2M) by GIMV and Biotech Fund Flanders in 2001. Ablynx • Engaged in the discovery and development of Nanobodies® • 25 projects in the pipeline • 5 Nanobodies in clinical development : 4 Phase II & 1 Phase I • Two products achieved clinical proof-of-concepts in RA • Partnerships with Boehringer Ingelheim, Merck Serono, Novartis and Merck & Co • >250 employees Executive Management Chairman and Chief Executive Officer Chief financial officer Chief Business Officer Chief Medical Officer Chief Scientific Officer Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion Once upon a time… Conscientious students in Brussels in the late 1980s Discovery of a new form of immunoglobulin In the 1980s, several teams tried to miniaturize antibody to get recognition molecules more compact and solid But it is difficult: when we begin to reduce the size of molecules, undermines cohesion between the heavy chain and light chain compounds which are recognition sites. -Too large, complex, weak, difficult to produce in bacteria. -Do not lend themselves to applications in biotechnology -Immune response. Ideally, to have molecules with antibody specificity, but without their complications Work on camel antibodies Let’s go to Morocco… It was still necessary to verify that antibodies have an comparable efficacy than their heavier cousins. So they had to work on life camels. The first camel was stolen so researchers asked for help to Cheikh Mohammed bin Rashid Al Maktoum . The supply of blood serum of camelids was assured and discovery of the properties on “Heavy Ig” Technology Recognising uncommon or hidden epitopes Nanobodies recognize variable epitopes and recognised conserved epitopes inacessible to conventional Ab’s. Cavity binding-enzyme and receptors Because of their small size: -Nanobodies are able to act as inhibitors to enzymes through binding with active sites that are too small for mAbs to access. - Nanobodies can access enzymes is that the CDR3 loops are more flexible and can penetrate more deeply into binding sites. Exceptional drug format These formats are easy to construct and the modular proteins can often be expressed at high levels in bacteria or yeast. As a result of this formatting flexibility, the range of therapeutic applications for Nanobodies appears to be beyond that possible for conventional antibodies and antibody fragments. Alternative route of administration Antibodies can only be administered via injection or SC Nanobodies can be administered via injection, pulmonary, intranasal, oral and should be administered via transdermal and ocular Tailored Half Life Unmodified Nanobodies have a half-life in serum of a few hours This is ideal for many acute indications but if a longer circulating half-life is required (e.g. for chronic diseases) Nanobodies can be modified to extend their half-life NExpedite® = based on small (<3kD) peptides specific for human serum albumin. These peptides can be easily fused to Nanobodies Beyond antibodies and small molecules Production To reduce the risk of immunogenicity, Ablynx routinely humanizes its Nanobodies Cheaper, shorter and more resistant Monoclonal antibodies are produced from mammalian cells Nanobodies are made from micro-organisms (bacteria, yeasts) Nanobodies are robust to changes in temperature and pH Monoclonal antibodies are sensitive and must be used quickly Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion Ablynx’s pipeline www.ablynx.com Fully owned Ablynx’s pipeline Orphan disease – TTP Thrombotic Thrombocytopenic Purpura Thrombotic Thrombocytopenic Purpura (TTP) Production of Auto-Ab against ADAMTS13 Orphan disease ( 11 - 12 / 106) Current therapies for TTP Not any specific therapy Use of immunosuppresive therapies • Corticosteroid • Rituximab (Rituxan or MabThera) Estimated potential market of TTP Not any specific therapy difficult to estimate the number of patients seeking treatment in a given year 2012 Based on prevalence : ≈11000 patients (USA + UE + JAP) If similar to other orphan therapies, Ablynx will be able to charge between $75,000 and $100,000 per treatment. Potential to generate $250 million with only 33% market penetration Caplacizumab Anti-vWF Nanobody First in class Bivalent Nanobodies Phase I complete and promising & Phase II in process Challenges of clinical development in acquired TTP Europe; North-America; Israel; Australia 40 sites participate worldwide Pivotal study for MAA in Europe [Potential launch in 2015] In-house discussion for FDA to BLA Clinical trial Phase I Phase I Product Anti-wVF Daily treatment Population Healthy volunteers Number of subjects Regimen/dose Status 36 Single dose and multiple dose Subcutaneous (SC) 2 to 12mg Complete Clinical trial Phase II Exclusion criteria: -Severe infection/sepsis -Pregnancy -Bone Marrow Transplantation -Know congenital TTP Inclusion criteria: Patients with acquired TTP requiring Plasma EXchange (PEX) Possible concurrence Glenmark Pharmaceuticals GBR 600 : Monoclonal antibody “Neutralization” of overactive/over expressed vWF Preclinical studies show good tolerance in baboon But not any actual CT No information in their annual report Did they stop the development of GBR-600? Glenmark website To conclude on Caplacizumab « Advantages » of an orphan disease Not any specific treatment Actually, Ablynx seems to be alone on this part of the market. Rheumatoid arthisis Rheumatoid arthritis ≈1% of the world’s population & Autoimmune disorder Current opinion in pharmacology ,Volume 1, Issue 3, 1 June 2001, Pages 307–313 Actual therapies First line : MTX ± TNFα inhibitors Small molecules (ex : Sulfasalazine IL1 & TNFα inhibitor) : Generics ++ Biologics : Humira Adalimumab Cimzia Certolizumab Remicade Infliximab Cours DCEM3 Enbrel etanercept Simponi Golimumab TNFα inhibitors Estimated global market of RA These 5 drugs : $27 billion in 2012, and the market is expected to continue to grow. Humira : the top selling drug in 2012 : $9.5 billion Market held by some big pharma companies Very competitive but very lucrative market Cours 4A & www.evaluatepharma.com ALX-0061 Pre-clinical Anti-IL6R Bivalent Nanobodies Phase I -Rapid and dose-proportional decrease of biomarker (CRP) -Correlation between CRP and improvement of disease activity 3mg/kg is optimal biologically active dose Phase II Results of the Phase II Marker of efficacy ACR20 100% ACR50 75% ACR70 63% Other No tachyphylaxis All patients continued the study until week 24. Up to 75% of patients in DAS28* remission No progression Direct concurrence Tocilizumab Actemra in US RoActemra in UE IL6-R inhibitor : The drug was approved with the support of five Phase III clinical trials. A relative success, but surely a little part of the market FDA : January 2010 EU : January 2009 Sales in m$ 1000 900 800 700 600 500 400 300 200 100 0 Tocilizumab Roche website | www.evaluatepharma.com 2010 382 2011 698 2012 898 To conclude on ALX-0061 A very competitive market but very lucrative A « new » target An important part to establish efficacy will be to conduct a head-to-head comparison trial with Actemra Ablynx’s should be prepare to act in a hard fight. Reminder : RA & TNFα Ozoralizumab ATN-103 Anti-TNFα Nanobody Anti-TNF α Trivalent Nanobodies 2% positive for neutralizing Anti-Drug-Antibodies (nADAs) Ablynx regained worldwide rights from Pfizer ATN-0103 : Phase 2 trial Ablynx’s poster : A novel individualised treatment approach […]with RA on a background of MTX & Ablynx annual report 2012 Direct concurrence Humira Adalimumab Remicade Infliximab Enbrel etanercept Simponi Golimumab All these are Anti-TNFα antibodies ≈25 b$ in 2012 To conclude on Ozoralizumab • A very competitive market but very lucrative • Already targeted cytokine by highly used Mab • Also in competition anti-TNFα small molecule such as sulfazalazine ? 1. Compare Ozoralizumab head-to-head to TNFα inhibitors in trials ? 2. Try to include Ozoralizumab into an already approved therapeutic strategy? Bone loss Bone loss Khaler C = Calcium R = Renal failure A = Anemia B = Bone lesions Actual therapie for bone loss 1. 2. 3. 4. 5. 6. 7. Biphosphonate Estrogen Estrogen + Progesterone SERMs PTH Calcitonins Monoclonal Antibodies Estimated actual market of bone loss Bone loss market – Sales in m$ (non exhautive) 1600 1400 1200 1000 800 600 400 200 0 2010 Fosamax MERCK 926 Boniva ROCHE 974 Actonel SANOFI 1247 2011 855 787 1053 1487 613 1013 199 178 1333 950 203 351 189 2012 676 345 769 1288 590 1073 209 172 1258 1151 472 748 168 www.evalutatepharma.com Zometa Reclast NOVARTIS NOVARTIS 1511 579 Premarin WYETH 1040 Vivelle-dot Estraderm Evista NOVARTIS NOVARTIS ELI LILLY 189 181 1315 Forteo ELI LILLY 830 Prolia AMGEN 33 Xgeva AMGEN 8 Miacalcic NOVARTIS 181 Anti-RANKL Nanobody ALX-0141 Anti-RANKL Bivalent Nanobodies Pre-clinical models ALX-0141 performed well compared to denosumab Phase I results Well tolerated No serious adverse events Decrease the bone biomarker CTX-1 CTX-1 is a biomarker for the bone resorption Phase II Osteoporosis Randomized Controlled vs Denosumab First skeletal event 400 patients WW study (6 years) Patients with bone metastases Patients with RA and joint replacement Open label Open label Progression of metastasis Join healing stability 60 patients 20 patients EU study (18 months) EU study (18 months) Direct concurrence Prolia & Xgeva Denosumab ; Anti-RANKL antibody 800 As Prolia : June 2010 (post menopausal) AS Xgeva : November 2010 (cancer related) 700 600 500 400 300 200 With a relatively high success 100 0 2010 2011 2012 Amgen website & evaluatepharma.com Prolia AMGEN 33 203 472 Xgeva AMGEN 8 351 748 To conclude on bone loss A very competitive market A market which interest and held by some big pharma firms So… An important part of establishing efficacy will be to conduct a head-to-head comparison trial with Xgeva Ablynx should seek to a new partner for this program To resume on Ablynx pipeline Product Disease Target Phase Efficacy Competitive firms Our opinion on this product 2 Glenmark ? Roche Caplacizumab TTP vWF ALX-0061 RA IL6-R 2 Ozoralizumab RA TNFα 2 ALX-0141 Bone loss RANKL 2 Abbott J&J Pfizer Amgen Amgen Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion Ablynx’s business strategy to generate revenue through collaborations with large pharmaceutical partners relating to the development of novel Nanobodies To allow the company to manage the risks associated with such programs. In parallel, Ablynx continues to advance its own Nanobody therapeutic programmes with the goal of building a unique proprietary pipeline. Boehringer Ingelheim Collaborations The most important for Ablynx : 11 programs January 2007 • First collaboration for the development of nanobody therapeutics alzheimer’s disease September 2007 • Second agreement : strategic alliance to discover develop and commercialize up to 10 nanobody therapy programs March 2012 • The strategic alliance with BI has been extended through September of 2014. More than € 79 million since 2007 Merck Serono Collaboration co-discovery and co-development partner since September 2008 2008 • Two disease targets, one in immunology and one in oncology €10 million ($13 million) upfront payment to Ablynx • The first pre-clinical candidate : ALX-0761, the treatment of autoimmune diseases. €1 million ($1.3 million) milestone payment to Ablynx. Merck Serono Collaboration 2010 New partnership to include Nanobodies against an inflammatory disease target. 2011 Third collaboration agreement : Two targets in osteoarthritis 2012 Selection of a second pre-clinical candidate : ALX-0751 in oncology Novartis Collaboration 2008 Collaboration agreement • The deal includes R&D payments, licence fees, milestones and royalties. July 2010 • license, development and commercialization agreements were signed for two targets €1 million in upfront fees and license payments to Ablynx. April 2012 • TAS266 (anti-Death Receptor 5), entered Phase I clinical development in cancer patients. receipt of a €400,000 Merck and co October 2012 • Develop and commercialize Nanobody candidates against a voltagegated ion channel, with the option to develop Nanobodies against a second non-disclosed target €6.5 million upfront payment and a €2 million fee for research funding • Ablynx : discovery of Nanobody candidates • Merck : research, development, manufacturing and commercialisation of any Nanobody product resulting from the collaboration. Pfizer November 2006 • exclusive research and license agreement announced with Wyeth (acquired by Pfizer in 2009) • Pfizer obtained global exclusive rights to develop and commercialise Nanobodies against TNFα November 2011 Ablynx regains worldwide rights from Pfizer to develop and commercialise anti-TNFα Nanobodies Three-pronged approach to balancing risk and reward Fully Funded + Milestones and Royalties Co-discovery/ Co-development Wholly-owned clinical assets • • • • • TNFa (ozoralizumab) – Ph II vWF (caplacizumab) – Ph II IL-6R (ALX-0061) – Ph II RANKL (ALX-0141) – Ph II RSV (ALX-0171) – Ph I €160M in non-dilutive cash from collaborators received to date and 18 Nanobody candidates selected Future collaboration ? 25 Février 2013 Ablynx and Spirogen collaboration to evaluate the potential of novel toxinNanobody drug conjugates in cancer Spirogen's proprietary cytotoxic drugs, pyrrolobenzodiazepines (PBD) Nanobodies generated using Ablynx’s proprietary technology platform Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion Balance sheet overview 140000 120000 100000 80000 60000 40000 20000 0 2008 2009 2010 2011 2012 Non current assets Current assets Total 5001 4277 10319 11979 12304 121522 97645 121070 86550 62691 126523 101922 131389 98529 74995 Equity attribuable to equity holders 93870 76126 100790 58630 31722 non current liabilities 3 1134 1752 927 current liabilities Total Total equity and liabilities 32650 25796 29465 38147 42346 32653 25796 30599 39899 43273 126523 101922 131389 98529 74995 BFR & FRNG 100,000,000.00 80,000,000.00 60,000,000.00 40,000,000.00 20,000,000.00 0.00 -20,000,000.00 FRNG BFR 2008 88,869,000.0 -5,001,000.0 2009 71,849,000.0 -4,277,000.0 2010 90,471,000.0 -10,319,000. 2011 46,651,000.0 -11,979,000. 2012 19,418,000.0 -12,304,000. Total revenues Total expenses 35000 80000 30000 70000 25000 60000 20000 50000 15000 40000 30000 10000 20000 5000 0 Total 10000 2008 16755 2009 29683 2010 31432 2011 21869 2012 26,727 0 Total 2008 37336 Revenues 30000 25000 20000 15000 10000 5000 R&D Grants Total 2008 15557 1198 16755 2009 28068 1615 29683 2010 29169 2263 31432 2010 57394 2011 66730 2012 56,277 Expenses 35000 0 2009 51844 2011 19861 2008 21869 2012 25,645 1,082 26,727 80000 70000 60000 50000 40000 30000 20000 10000 0 R&D General & Adm Total 2008 29889 7447 37336 2009 42800 9044 51844 2010 48512 8882 57394 2011 56307 10423 66730 2,012 46,868 9,409 56,277 LoY & YeC 160000 140000 120000 100000 80000 Loss of the year Cash at year end 60000 40000 20000 0 2006 2007 20082009 2010 2011 2012 2013 2014 2015 NYSE euronext End of the collaboration with Pfizer 48 millions of shares Put on sale of new shares 48M x 7,20 = 284,680,000 x 2/3 = 230,400,000€ Presentation of Ablynx Their technology Pipeline & concurrence Partnerships Financial analysis SWOT & Our opinion -STechnology > Mab Low cost Wide range of therapeutic’s target New way of administration for biologics Financial power (partnerships) P1 trial : Good results -ONew markets opened 2 products potentially first-in-class New ways of administrations -WPharmacokinetics difficulties Proprietary pipeline No P2 trials fully finished Financially dependent There making economies on R&D research -TPharmacokinetic unpredictable Lack of experience with these kind of products (AE, Immunogenicity,…) Loss of partnerships (ex: Pfizer) Loss of Patent ! Too much explored areas Our opinion Merci de votre attention Guillaume Gerardi Paul Hermant Marion de Jalras Laurent Equipart