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Advancing science, changing lives 1. Safe Harbor This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques of Lille.

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Presentation on theme: "Advancing science, changing lives 1. Safe Harbor This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques of Lille."— Presentation transcript:

1 Advancing science, changing lives 1

2 Safe Harbor This is an independent study performed by students from the Faculté des Sciences Pharmaceutiques of Lille. The opinions expressed are our own and not necessarily those of Elan Corporation plc. 2

3 Overview of the company Created on 18 December 1969 by Donald Panoz Became a public limited company in January 1984 Stock Exchange Listings – New York Stock Exchange (ELN) – Irish Stock Exchange (ELN.I) Elan Corp = 2 business units: Elan Drug TechnologyBioPharmaceuticals Science and clinical based Parkinson’s disease Alzheimer’s disease Multiple sclerosis Integrated technology Oral Controlled Release NanoCrystal technology 3 BioNeurology Elan website 28th Annual J.P. Morgan Healthcare Conference, on January 13, 2010

4 Locations and subsidiaries in 2009 Gainesville, GA Owned R&D manufacturing administration 89,000 sq. ft Bermuda Financial services company San Francisco, CA Leased R&D sales administration 334,000 sq. ft King of Prussia Leased R&D manufacturing, sales administration 113,000 sq. ft Dublin Leased Headquarters 41,000 sq. ft Athlone Owned R&D manufacturing administration 463,000 sq. ft Annual Report 2009 OCR NanoCrystal Others 4

5 Elan Drug Technology’s pipeline 5 Elan website

6 Elan BioNeurology’s pipeline Discovery Parkinson’s research Autoimmune research Pre-clinical AAB-002ELND007 Gamma secretase Phase I ELND006 Natalizumab (Myelome multiple) ELND004ELND002 Phase II Bapineuzumab SC ACC-001ELND005 Natalizumab SC Phase III Bapineuzumab IV LY450139 Marketed Tysabri (US/UE) Tysabri USPrialtAzactamMaxepime Alzheimer’s disease Multiple sclerosis Crohn’s disease Chronic pain Other 6 Elan website

7  History with Donald Panoz  NanoCrystal and Oral Controlled Release  Yesterday : Tricor, Skelaxin, Ritalin, Verelan  Today : Ampyra, Invega Sustenna, Zypadhera  Tomorrow ? Elan Drug Technology

8 Donald Panoz,, moves to Ireland and launches Elan Corporation. 1969 Elan opens a research and development center in Athlone, Ireland 1978 Elan floats its U.S. subsidiary on the NASDAQ 1984 Elan absorbs its U.S. subsidiary and launches a full public offering on the New York, London, and Irish Stock Exchanges. 1990 The company acquires a manufacturing operation in Lugano, Switzerland. 1993 The company acquires a manufacturing facility in Israel. 1995 New strategic direction as a full-scale pharmaceuticals company with the acquisition of Athena Neuroscience in the United States 1996 Elan acquires GWC Health and Neurex. 1998 Elan's stock collapses after the Securities and Exchange Commission launches an investigation into the company's accounting practices. AN 1792: meningo-encephalitis 2002 8

9 Business Overview 9 Expertise in drug formulation, development, scale-up & manufacture More than 30 products launched in 100+ countries 15 products in clinical development Extensive product development, scale-up and manufacturing capabilities in US and EU World’s leading drug delivery company 40 years of innovation and expertise in drug delivery Most successful drug delivery provider in US in recent times – 11 products launched since 2001 Robust drug delivery portfolio in the industry

10 Elan collaborative model 10 Elan website

11 What is Nanocrystal Technology ?  Technology using tiny drug particles in the nanometre scale  The drug size is reduced by a proprietary milling technique  GRAS stabilisers are absorded on the nanoparticle to afford agglomeration  GRAS stabilizers must be safe and are excipients commonly used in marketed products ( fat acid, polymers) 11 Objective: obtain a colloïdal dispersion Elan website

12 Effects of NanoCrystal on bioavailability 12 Nanocrystal technology is used:  For poorly water soluble drugs: ↑ solubility ↑ bioavailability  For moderately soluble drugs when high concentration is need in a low fluid volume Useful for all dosages forms both parenteral and solid,liquid oral dosage forms

13 Point on Oral Controlled Release 13 Avinza, Cardizem, Focalin, Ritalin, Verelan, Luvox, Zanaflex NaprelanVerelanAfeditab

14 Yesterday… 14 Trade nameGeneric nameIndicationTechnologyParteners Tricor® 145mgfenofibrateDyslipidemiaNanoCrystal Skelaxin®metaxolone Skeletal-muscular pain NanoCrystal Ritalin® / Focalin® Methylphenidrate/ Dexmethylphenidate Hyperactivity OCR (SODAS) Verelan®verapamilCardiac disorders OCR (CODAS)

15 Tricor® : what’s that? API: micronised fenofibrate (prodrug) Indications: Dyslipidemia type IIa, IIb, IV, III,V 2004: Tricor® 145 launched by Abbott and manufactured by Elan using NanoCrystal technology Could market lower dosage strength with 9% improve in bioavailability Minimised food effect:  Class formulation: 30-50% fasting Vs 60-90% while eating  Micronized formulation: bioavailability 100% without conditions. Patented formulation expiry on 9-Jan-2018 15

16 Today… 16 Trade nameGeneric nameIndicationTechnologyParteners Paliperidone palmitate SchizophreniaNanoCrystal Fosaprepitant dimeglutine Emetogenic chemotherapy NanoCrystal OlanzapineSchizophreniaNanoCrystal FampridineCardiac disorders OCR (MXDAS) 16

17 Ampyra® (Fampridine) : What is it ? FDA approval on 22 jan 2010 Indication : improved walking in patients with multiple Sclerosis Extended released tablets using Oral release technology MXDAS Mechanism = not fully elucidated => several hypotheses for Ampyra’s mechanism:  Fampridine is a broad spectrum potassium channeblocker  Fampridine increases conduction of action potentials in demyelinated axons through inhibition of potassium channels  Increase acetylcholine release at the neuromuscular junction 17 ®

18 Ampyra®: the deal 18 Elan and Accorda, a joint venture since 1998 for MS rest of the world marketing 16% of royalties for elan manufacture in Athlone’s facility Biogen paid: upfront: US$ 110 millions milestones: US$400 millions US$35.7millions from Accorda for the drug delivery

19 Ampyra®’s forecast sales 19 Represents the sales in U.S Ampyra will be launched in March 2010

20 … and tomorrow for Elan Drug Technology 20 Elan website

21 Elan BioNeurology  Yesterday : Azactam®/Maxipime®, Prialt®  Today : Tysabri ®  Tomorrow : Alzheimer Immunotherapy Program Research in Parkinson’s disease 21

22 Timeline of Elan’s marketed products Maxipime® (Cefepime) Azactam® (Aztreonam) Tysabri® (Natalizumab) Prialt® (Ziconotide) AIP Program 1996 1998 1995 2000 Beginning of a new business unit called Elan Biopharmaceuticals, then Elan BioNeurology 22 From 1969 to early 1990’s : Elan only worked in drug delivery domains Then, Elan’s activities widened with collaboration from research to market of drugs

23 Maxipime® (cefepime) : what’s that? Semi-synthetic forth-generation cephalosporin Mechanism of action : – Inhibits final transpeptidation of peptidoglycan synthesis in bacterial cell walls – inhibiting cell wall biosynthesis Broad spectrum activity Indications – respiratory tract infection – skin infections – urinary tract infections – febrile neutropenia – Intra-abdominal infections 23 The product was launched worldwide in 1995 Elan acquired US comarketing rights from BMS in January 1999 The basic U.S. patent for Maxipime expired in March 2007. Stop distributing Maxipime as of September 30, 2010. Thomson

24 Maxipime® (cefepime) revenues 24 - 78% Bristol-Myers Squibb Co Elan Corp plc USD (Millions) Annual report 2009 Thomson

25 Prialt® (ziconotide) 25

26 Prialt® (ziconotide) : what’s that? Member of the ω conotoxin family o 25 aminoacids and 3 disulfide bonds o prepared by chemical synthesis Targets N-Type voltage sensitive calcium channels = > diminished neurotransmitter release Pain Transmitting nerves Pain signal Ziconotide Calcium N-type calcium channel Intrathecal formulation 26

27 History of Prialt® (ziconotide) May 1993Neurex (now Elan) joined Warner-Lambert (now Pfizer) in a collaboration to cooperate in the development and commercialization of ziconotide for the treatment of brain ischemia early 1995phase II trials for the prevention of brain damage halted due to some patients experiencing hypotension. Neurex received permission from the FDA in May 1995 to resume these trials Aug. 19999th World Congress on Pain meeting in Vienna, Austria : results of a placebo controlled study into the use of intrathecal ziconotide in the treatment of chronic pain in opioid-resistant non-cancer patients May 200137th ASCO meeting in San Francisco : clinical data for chronic pain in cancer and AIDS patients 9 Jul. 2001Orphan designation granted by the European Commission Feb. 2002Elan had reached an agreement with the FDA and had agreed to conduct one additional phase III 2004Pain Management 2004 meeting in London, UK 4th annual conference on Ion Channels in Drug Discovery Development in Philadelphia, PA. Apr. 2005Lauch market in the USA Mar. 2006Eisai acquired the European rights to ziconotide from Elan Elan received ~ $60 million for the launch in key European markets +$40 million contingent on Prialt achieving revenue related milestones in Europe. 2016Expiration of fundamental U.S. patent covering the use of ziconotide 27 Thomson

28 Tysabri® (natalizumab) 28

29 Tysabri® (natalizumab) : what is it ? Humanized Monoclonal Antibody (recombinant IgG4) Targets selectively human α4-integrine Trade names : Tysabri®, Antegren® Integrines α-4 Expressed on cell membrane In association with β1 or β7 integrines Adherence molecules on activated T-cells, B-cells, monocytes, eosinophils, basophils, leukocytes, NK cells, dendritic cells, and vascular endothelium of some organs. Implicated in leukocytes homing to CNS and GIT 29 GASTROENTEROLOGY, 2009, Vol. 136, Issue 4, 1182-1197 M/S : medecine sciences, vol. 21, n° 10, 2005, p. 797-798. Drug Discovery Today Volume 12, Numbers 13/14 July 2007

30 Tysabri® dealings 1996 Elan was collaborating with Axogen on the development of natalizumab 1999 Elan acquired Axogen 23-Nov-2004 Initially approved by FDA for treatment of RRMS. August 2000 Elan entered into a worldwide exclusive collaboration with Biogen for the joint development, manufacture and commercialization of natalizumab. 30 Thomson

31 Tysabri®’s timeline 18 MONTHS 18-Feb-2005 Biogen learnt about 1 case of death to PML and 2 suspected cases of PML 25-Feb-2005 Voluntary suspension of Tysabri market Mar- 2006 REMS presented to FDA : advisory panel voted to support the drug’s return 05-Jun-2006 FDA approved a special restricted distribution program for Tysabri (TOUCH®) Jul-2006 Tysabri’s reintroduction to the market 23-Nov-2004 FDA approval for treatment of relapsing forms of MS 31 Drug Discovery Today Volume 12, Numbers 13/14 July 2007 Nature Biotechnology, Nov 2009,vol 27, Numero 11

32 Tysabri® and PML 25-Feb-2006: Confirmation of 3 cases of PML (initial trials: 3,417 patients)  2 patients during MS trial (SENTINEL) + 1 patient in trial for Crohn’s disease  All 3 were on combination therapy with another immunosuppressive drug  No patients on Tysabri alone developed PML Progressive Multifocal Leucoencephalitis = opportunistic disease  Agent = JC virus (Polyomavirus family)  infects oligodendrocyts => local demyelinisation => neurologic dysfunction  ~ 80% of population already met JCV before adult age => latent form (bone marrow and kidneys) Natalizumab + another immune drug  fixation of natalizumab on VCAM-1 and MAdCAM-1 of endothelial cells  inhibition of T-cells homing  uncontrolled replication of JCV in CNS 32 N Engl J Med 2006;354:924-33.

33 33

34 Consequences on the stock 34 25-Mar-2005 26,90 $ 28-Mar-2005 8,00 $ ELAN 28-Mar-2005 38,65 $ 25-Mar-2005 67,28 $ BIOGEN -50% -67% Yahoo finance

35 Tysabri®’s REMS: TOUCH® program 7-8 March 2006 : Risk Minimalisation Action Plan exposed to Peripheral and Central Nervous System Drugs Advisory Committee Meeting => Goals : o Warn patients about risk-benefit balance forTysabri use in treatment of MS patients. o Contraindicated in immunocompromised patients o Minimize health consequences of PML (death/disability) through early diagnosis Key elements of T ysabri O utreach: U nified C ommitment to H ealth program o Mandatory enrollment of prescribers, infusion sites, and afflilated central pharmacies o Controlled distribution to authorized infusion sites and pharmacies o Education program for health care providers and patients o Safety surveillance of PML, serious opportunistic infections, and deaths o Program evaluation of health outcomes, process compliance, and assessment of knowledge 35 Business Insights, 2009 « THE AUTOIMMUNE OUTLOOK TO 2013, Competitive landscape, pipeline analysis and growth opportunities » Joint Meeting of the Gastrointestinal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, 31-Jul-2007

36 The benefit Natalizumab versus β-IFN is: -Sligthly more effective (MRI data) -Twice as effective (relapse-rate data) - More effective (EDSS data) Many people strongly believe that Natalizumab is the most effective drug we currently have. Patients asked the right to choose and accept the risk Tysabri returned to the US market in July 2006 36

37 Top 5 Multiple Sclerosis Drugs in 2007 (m$) 37  Will Tysabri marketing setback affecting its own sales and Elan’s business ? N°5 !

38 Tysabri® sales rose, fell… then rise again! 38 Forecast Tysabri in-market net sales in 2013 : 1,3 b$ NB: Expected patent expiry by 2015 Life cycle management: natalizumab SC extension of indication to multiple myeloma Nature Biotechnology, novembre 2009, vol 27, numero 11 Business Insights, 2009 Natalizumab, Thomson 2009 28th Annual J.P. Morgan Healthcare Conference, on January 13, 2010

39 20052011 Injectables IV Teriflunomide Laquinimod FTY 720 Oral Cladribine Daclizumab Generic Mitoxantrone (oncology) (MS) Generic Mitoxantrone (oncology) (MS) Orals Tysabri IV 20062007 Copaxone Betaseron Avonex Novantrone Rituximab II - RRMS; III - PPMS Rituximab II - RRMS; III - PPMS Rebif 20102012 MLN1202 BG 12 Oral Fumarate Fampridine ambulation indication? Fampridine ambulation indication? MBP 8298 Filed approved In phase II In phase III SB683699 2013 Campath Existing and Emerging Therapies for MS 39

40 Alzheimer’s disease 40

41 Alzheimer Immunotherapy Program Research, develop and commercialize selective products Includes multiple compounds being evaluated for slowing the progression of Alzheimer's disease. Main product: Bapineuzumab The Alzheimer Immunotherapy Program 41

42 Two approaches for Alzheimer’s disease 42 Mécanismes Moléculaires dans les Démences Neurodégénératives Inserm-UM2-EPHE U710 La maladie d’Alzheimer : aspects moléculaires, diagnostiques et thérapeutiques Octobre 2009

43 Neuropsychopharmacology (2009) 34, 142–158; doi:10.1038/npp.2008.115 Figure 6

44 3 approaches in the Beta amyloid cascade 44 Three Approaches to Disrupting the Beta Amyloid Cascade Clearing existing beta amyloid from the brain Preventing aggregation of beta amyloid in the brain (ELND005) Preventing production of beta amyloid in the brain with secretase inhibitors

45 Tomorrow : AIP 45 Janssen Alzheimer Immunotherapy Bapineuzumab ACC-001 Follows-on 28th Annual J.P. Morgan Healthcare Conference, on January 13, 2010

46 BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37 $885 M 18,4% Elan's capital IP Elan (AIP) Estimated at $500 M $ 500 M 49,9% Janssen AI's capital Royalties Under conditions The Deal 46

47 The Deal 47 BioCentury, the Berstein report on biobusiness July 6, 2009 Page A22 of 37 Transaction J&J purchased 107.3 million Elan's shares at $8,241/share J&J also agreed not to acquire any more shares for the next five years The program will remain partnered with Wyeth, which was acquired by Pfizer Inc (01/2009, $68 billion) Royalties : ONLY after J&J has earned profits from the AIP equal to its $500 M Janssen AI: all annual in-market salesRoyalties for Elan $2 billion - $4 billion5 % $4 billion - $ 10 billion7 % > 10 billion9 %

48 Bapineuzumab (AAB-001) 48 Name: AAB-001 Other Name: Bapineuzumab Class: Humanized monoclonal antibody Therapeutic Applications: Mild to moderate AD Therapy Types: Protein : humanized monoclonal antibody against Aβ Mechanisms: Designed to bind and remove the Aβ peptide that accumulates in the brain Development Status: Fast Track status from FDA in U.S FDA Phase: Phase III Side Effects: – Passive immunotherapy will induce similar side effects is largely unknown. One report has shown that frequency and severity of cerebral microhemorrhage – Vasogenic edema Thomson

49 Bapineuzumab (AAB-001) : Phase III 49 DesignMulticentrique, randomized, double-blind, placebo- controlled, parallel-assigned trial, studies 4 studies : 2 with ApoE4 (+) & 2 withApo E4 (-) 2 US trials and 2 European phase III trial Safety ObjectiveThe safety and tolerability Estimated study Duration 18 Months Dosing0.5 mg/kg 1 mg/kg Source : DevelopmentFast Track designation from the FDA

50 Forecast sales and market share for bapineuzumab 50 2010 THOMSON REUTERS

51 Research on Parkinson’s disease Several active early discovery efforts in Parkinson’s disease The Michael J. Fox Foundation for Parkinson’s Research Program « Novel Approaches to Drug Discovery » In 2009, the program funded six research projects. 2006 : Michael J. Fox Foundation and Elan Commit up to $2 Million to Drive Novel Therapies for Parkinson's 51 The Michael J. Fox Foundation for Parkinson’s Research Since 2006, our efforts with the Michael J. Fox Foundation for Parkinson’s Research have included a grant program, “Novel Approaches to Drug Discovery,” designed to identify and fund promising projects, to help them advance more quickly from the lab to the clinic. With a strong focus on the development of disease-modifying therapies for Parkinson’s disease, Novel Approaches to Drug Discovery provides funding for projects of up to one year’s duration. Ideal proposals focus on efforts to develop promising biological targets into novel disease-modifying therapeutic strategies. Novel Approaches to Drug Discovery provides awardees from both academic and biotech institutions with a clear opportunity for follow-on funding and collaboration for further development. We have an option for a right of first negotiation for any promising approaches or materials that arise out of this program. In 2009, the program funded six research projects. Annual report 2009 MJFF website

52 Our opinion about Elan Corporation plc. Financial Analysis SWOT Would we join Elan? 52

53 Major owners of Elan Corp. at 22-Feb-10 53 Annual Report 2009

54 Total product revenue for 2009 54 724,3m$ 81,4m$ 16,5 m$ 13,2m$ 1,7m$ 61,6 m$ 34,9 m$ 32,6 m$ 22,1 m$ 106 m$ 18,7 m$ 0 m$ Annual Report 2009

55 Revenues from marketed products of BioNeurology 55 Annual Reports

56 Elan Drug Technology: total revenue 56 Annual Reports

57 Five years performance : EBITDA improvement 200520062007 20082009 57 Annual Reports

58 Operating margin 58 Annual Reports

59 2008 US$m 2009 US$m Assets Current Assets Cash and cash equivalents375.3836.5 Restricted cash and cash equivalents -- current20.216.8 Investment securities -- current30.57.1 Deferred tax assets -- current95.923.9 Other current assets240.1274.9 Total current assets762.01,159.2 Non-Current Assets Intangible assets, net553.9417.4 Property, plant and equipment, net351.8292.8 Equity method investment--235.0 Investment securities -- non-current8.18.7 Deferred tax assets -- non-current145.3174.8 Restricted cash and cash equivalents -- non- current 15.014.9 Other assets31.542.9 Total Assets1,867.62,345.7 Liabilities and Shareholders' Equity/(Deficit) Accounts payable, accrued and other liabilities334.8311.5 Long-term debt1,765.01,540.0 Shareholders' equity/(deficit)(232.2)494.2 Total Liabilities and Shareholders' Equity/(Deficit) 1,867.62,345.7 The consolidated Balance Sheet 59 Annual Report 2009

60 Elan’s debt 2005-2009 Due dates : November 2011:300 m USD December 2013: 615 m USD October 2016: 625 m USD Strong indebtedness => the success of AIP is essential Elan plc is restricted among various other things : Incur additional debt Enter into transactions with related parties Enter into some types of investment transactions; Engage in some asset sales or sale and leaseback transactions Pay dividends or buy back our ordinary shares Consolidate, merge with, or sell substantially all our assets to another entity Widen their capital 60 Annual Report 2009

61 61 Annual Report 2009

62 Five years performance : cost management Approximate 5 years change ↑ > 30% ↓ > 20%  Reduced SG&A and reinvest savings in R&D 62 28th Annual J.P. Morgan Healthcare Conference, on January 13, 2010

63 Number of employees in Elan corp. Year R&D activities Manufacturing and supply activities Sales and marketing activities General and administrative area Total 20054715833103651729 20064945433283691734 20075535472112991610 20086566011233071687 63 Annual Reports

64 Elan’s lawsuits 2002 Elan vs Wolf Popper LLP 2008 Elan vs Shareholders 2009 Elan/J&J vs Biogen 64

65 Evolution of the stocks 65 AN1792 + Wolf popper LLP Launch of Tysabri Tysabri withdrawal Results of Bapineuzumab Clinical Trial Yahoo finance

66 Elan Corp. Strengths Leadership position in drug delivery Tysabri, its key product, sustaining the revenue growth Strategic alliances bolstering the company’s business Weaknesses  Important endebtedness patent expiry and risk of generic competition Geographic concentration enhancing business risk Tysabri marketing restricted indications affecting Elan’s business Opportunities Focus on Alzheimer’s market, could be a source of revenues Benefits to accrue from growing incidences of neurological disorders Favorable demographic shift increasing Alzheimer drug market Threats Intense competition from Avonex, Rebif against Tysabri in the MS drug market. Patent expiries could affect company’s Revenues Legal proceedings could affect company’s Reputation Reimbursement policies could affect company’s product sale 66

67 Conclusion An important debt and short due dates. Cash flow left only for 12 months!… Tysabri revenues will not be enough. No more constant revenues from BioNeurology business unit. Elan depends on the success of the AIP, especially on bapineuzumab success. So ?… 67

68 Thanks for your attention! Any question? 68

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