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    Seminario iv Seminario iv Presentation Transcript

    • PROGRAMA DE ESTRATÉGIA EM P&D DE MEDICAMENTOS PARA FARMANGUINHOS
    • ESTRATÉGIA NA PROTEÇÃO DE RESULTADOS
    • Custos de desenvolvimento de uma droga • Custos podem alcançar US$ 800 milhões para uma droga • O prazo de desenvolvimento aproximado é de 15-16 anos • 75% deste custo é atribuído às taxas de falha • 90% de todas as drogas desenvolvimento não chegam ao mercado
    • Onde, como e quando investir nossos recursos de forma satisfatória?
    • Alocação de Recursos
    • Alocação de tempo (em anos)
    • TIME DegreeofInterest Idea Research Proof Of Concept Demonstration Pre-production Success in market Academic interest Commercial interest After Chisholm O Enigma
    • Quem tem interesse em preencher o gap? TIME DegreeofInterest Academic interest Commercial interest
    • O desafio: ausência de valor para preencher o gap! TIME DegreeofInterest After Chisholm
    • 138 318 802 1318 0 200 400 600 800 1000 1200 1400 $million 1975 1987 2001 2006 Year Estimated full cost of bringing a new chemical or biological entity to market ($ million – year 2005 $) Source: J.A. Di Masi and H.G. Grabowski, ‘The Cost of Biopharmaceutical R&D: Is biotech Different? Managerial and Decision Economics 28 (2007): 469-479  São 15 anos para desenvolver uma nova droga  De cada 5-10,000 moléculas sintetisadas & separadas por sua atividade, apenas 250 chegam ao pré-clinico, apenas 5 chegam a pesq. Clínica e apenas 1 alcança o mercado  Custo de P&D em 2006: $ 1.318 bilhões  Apenas 2 de 10 drogas disponíveis comercialmente produzem retorno que correspondam aos custos de P&D  Fármacos são geralmente baratos e fáceis de copiar – empresas de genéricos acessam mercados maduros desenvolvidos pelo 1o. Entrante, sem custo de entrada Desenvolvimento de drogas é caro e arriscado
    • Drug Discovery Pipeline Target Identification and Validation Assay Development Lead Generation Hypothesis Generation Candidate Development Commercialization Phase III Submit Global Launch Global Optimization Lead Optimization First Human Dose Phase IA Phase IB/II Compound patent filed at Lead Op Subsequent patents filed over 10-15 years
    • Função das Patentes na Inovação Competitiva
    • Product A 75 80 85 90 95 00 A B C D E F G JHI K L M Q R N O P Basic patent/product lifecycle Patent filings leading to granted patents
    • Classe de compostos, sais, formas cristalinas, usos (1o uso e subsequentes), formulações, processo de obtenção, métodos de purificação, rotas de administração, perfis de liberação e combinações Tipos de Patentes que refletem o processo de P&D
    •  O escritório Europeu conduz um dos exames mais rigorosos  Estatísticas de 2005: 128,754 depósitos 163,144 buscas empreendidas 104,433 exames  Apenas 53% das patentes foram concedidas  O prazo médio de aprovação é de 44.3 meses  Um portfólio de patentes de um produto pode ter entre 20 e 40 patentes Obter uma Patente não é um processo trivial
    •  No USPTO  Estatísticas de 2005: 417,508 depósitos 207,867 depósitos (nacionais) 143,806 depósitos estrangeiros  Apenas 48% das patentes foram concedidas  O prazo médio de aprovação é de 35 meses Obter uma Patente não é um processo trivial
    • Obter uma Patente não é um processo trivial INPI
    • Obter uma Patente não é um processo trivial Tempo médio 8,1 anos com tendência de redução para 6 anos
    • Competition in Therapeutic Innovation • The first mover is rarely the most successful • The period of exclusivity for first movers is shrinking
    • The period of exclusivity for first entrants to a therapeutic class is decreasing (US data) Source: DiMasi & Paquette (2004) 1.2 3 4.1 7.2 10.2 7.7 1.8 2.8 5.1 5.9 8.2 7.2 1995-98 (n=18) 1990-94 (n=15) 1985-89 (n=14) 1980-84 (n=5) 1970s* (n=9) 1960s (n=8) First-in-ClassApprovalPeriod Years Mean Median
    • Without patents there would be no innovation • Given the costs & risks of drug development, without a period of exclusivity against copyists there would be no investment in pharmaceutical innovation • Pharma do not seek therapeutic area exclusivity (anti-virals, antibiotics) Patent protection promotes therapeutic & innovative competition
    • Compound differentiation • New drugs tested against “gold standards” • Patent competition drives improvements: Increased Efficacy Decreased Side-effects Decreases ADRs Decreased drug-drug interactions Decreased dosing Specialised drug delivery systems • Patients benefit from a range of products with differing characteristics
    • Quarterly Enalapril Sales in the UK 0 5,000 10,000 15,000 20,000 25,000 Q TR SEP 1992 Q TR M AR 1993 Q TR SEP 1993 Q TR M AR 1994 Q TR SEP 1994 Q TR M AR 1995 Q TR SEP 1995 Q TR M AR 1996 Q TR SEP 1996 Q TR M AR 1997 Q TR SEP 1997 Q TR M AR 1998 Q TR SEP 1998 Q TR M AR 1999 Q TR SEP 1999 Q TR M AR 2000 Q TR SEP 2000 Q TR M AR 2001 Q TR SEP 2001 Q TR M AR 2002 Sales(£million) Protection Expiry Source: IMS Health MIDAS database
    • Changing face of Innovation • The Past….Large Corporate R&D facilities Secretive smart scientists, low level of collaboration Closed Innovation • The Present…..leaner business units Increased levels of collaboration More outsourcing, more partnerships Open Innovation
    • “Closed” Innovation “Open” Innovation “No matter who you are, most of the smartest people work for someone else” Bill Joy, Sun Microsystems
    • Changing Landscape of I.P • More small companies owning & licensing basic IP • Many companies not in manufacturing, only generating technology/IP • More patent aggregators, who take on patents from universities & small companies • Patents used as bargaining chips
    • Patent strategy and biotechnology • Biotech industry (and sometimes universities) use broad and basic and research-tool patents in marketing to Pharma and seek “reach-through royalties,” to obtain a share of the ultimate rent.
    • Observations on the Academic IP
    • Technology Strategy • Must concentrate on seeking competitive advantage, not on scientific interest • Must be consistent with overall strategy – e.g. R&D programs shouldn't focus on product performance if the firm is pursuing a cost leadership strategy • Shouldn't focus exclusively on product design or manufacturing technology if this means ignoring other areas of the firm (info systems, materials handling, office automation) • Must recognize risk/return tradeoffs • Must be consistent with industry/product lifecycle
    • Sustainability of the technological lead • Depends on: – Faster, more successful innovation than competitors • managing internal vs external sources • scale and scope economies in R&D • superior technological skills – Slowing the rate of diffusion to competitors • preventing reverse engineering • restricting technology transfer • obtain/enforce IP • loyalty of employees, non-disclosure agreements etc • vertical integration – Lock-in of customers • building in buyer switching costs • control of standards
    • Mechanisms undermining first- mover advantage • Free-riding by late-comers • First-mover locked in to the wrong strategy • Competition
    • Free-riding Latecomers can use the first-mover’s investments in: • R&D • moving down the learning curve • employee training • infrastructure development • obtaining regulatory approval • finding, educating customers & suppliers
    • Lock-in to the wrong strategy • ex ante choices may prove to be wrong ex post • First mover can be locked in to the wrong technology or marketing strategy because of – incumbent inertia • sunk costs: plant and equipment, marketing and distribution channels, advertising and reputation • reluctance to cannibalize existing product lines – organizational inflexibility • organizational routines • corporate culture doesn't prize innovation • doctrinal views about the world • internal political dynamics – established relations/contracts with other organizations
    • R&D Budgeting • Technology strategy usually implemented by R&D budgeting decisions – How much to spend? – Where to spend it?
    • Where do R&D budgets go? Breakdown for US manufacturing • long run v. short run 25:75 • fundamental v. incremental 8:92 • product v. process 65:35 • basic v. applied v. development 5:25:70 – “basic” means advancement of knowledge without specific commercial objectives – “applied” means research with specified commercial objectives – “development” means embodiment of research results into products/processes
    • R&D Budgeting: General Considerations • R&D is an investment, not an expense – evaluate R&D projects like any other investment project? • R&D budgeting decisions entail making trade-offs against competing uses of funds – should R&D always over-ride other claimants? • Continuing commitment to high levels of R&D spending often distinguishes leaders from followers – can a firm become a technology leader just by increasing R&D/Sales ratio? • Adoption of a formal budgeting process often marks start-up companies’ transition to “adolescence” • Can the firm find a project selection process which promotes innovative success?
    • Industry Practice in R&D Project Selection • Diversity: no standard practice – most firms use home grown techniques • Ambivalence towards quantification – many R&D managers are predisposed by background to seek objective quantitative criteria for decision-making, but the weakness of available techniques and complexity of problems make them reluctant to give these a dominant role • Some lessons: pay close attention to the process -- who should be involved? what weight should be placed on various inputs? how should conflicts be resolved?
    • Some Analytical Techniques for R&D Project Selection • index models: compare probability-weighted benefit/cost ratios • discounted cash flow models: recognize impact of distribution of costs and benefits over time, incorporate appropriate risk premium • portfolio models: risk and return tradeoffs. CAPM ??? • scoring/profile models: compare projects against checklist of desired characteristics • real options: “financial engineering at Merck”, recognize option value of continued funding, use Monte Carlo simulations to bound likely returns
    • Example: pharmaceutical R&D portfolios • Typical firm runs 8-10 major research programs • Discovery phase: $2m-$25m / year • Development phase: $50m+ / year • Manager’s problem: – How much to spend on each program? – How to select new projects? – How to know when to stop projects?
    • Why is this tough? • Very risky: – 10,000 candidate molecules – 10 go into development phase – 1 makes it to the market place • Hard to measure performance • Spillovers: project successes are correlated • Economies of scope and scale
    • Implications for real life R&D strategy • In head-to-head competition: – Try not to enter a race you aren't sure of winning: if you have to work too hard to win, it wasn't worthwhile – Have eyes in the back of your head: be well- informed of your competitor's position, and let them know it
    • Effective strategies answer three key questions: How will we Create value? How will we Capture value? How will we Deliver value?
    • • How will we create value? – How will the technology evolve? – How will the market change? • How will we capture value? – How should we design the business model? – Where should we compete in the value chain? – How should we compete if standards are important? • How will we deliver value? – How do we manage the core business and growth simultaneously? – How do we use our strategy to drive real resource allocation?
    • Outline: • Why do I need an innovation strategy? • How will we create value? • How will we capture value? • How will we deliver value? • Doing strategy in practice
    • Why have a strategy?
    • The Timing and Impact of Management Attention Phases Influence High Low ACTUAL ACTIVITY MANAGEMENT PROFILE Acquisition Investigation Basic Building Production Manufacturing ABILITY TO INFLUENCE OUTCOME
    • Why is it so hard to kill project #26? • It’s a “good” project! • Good managers can meet stretch goals (and I’m a good manager) • Making difficult decisions takes time & energy It’s very hard to kill projects without a strategy
    • Reasons to have a strategy: 2. To be able to change it
    • Simple molecules <1nm IBM PowerPC 750TM Microprocessor 7.56mm×8.799mm 6.35×106 transistors semiconductor nanocrystal (CdSe) 5nm 10-10 10-510-9 10-7 10-610-8 10-4 10-3 10-2 m Circuit design Copper wiring width 0.2m red blood cell ~5 m (SEM)DNA proteins nm bacteria 1 m Nanometer memory element (Lieber) 1012 bits/cm2 (1Tbit/cm2) SOI transistor width 0.12m diatom 30 m
    • Inventors Authors Universities Governments Companies Traditional IP Stakeholders New Stakeholders are focusing on IP
    • Regulators Companies Start-ups Universities Technology Transfer Companies VCs Investors GovernmentsBanks Financial New IP Stakeholders + New interests = More confusion and disputes Multiple Inventors Authors Indigenous Populations
    • E.g., Pharma Industry Requires Strong IP Protection Source: Boston Consulting Group: “A Revolution in R&D” 2001 • 70% of R&D Costs Are Incurred before Clinical Trials • Cannot raise money without IP and cannot afford to get IP wrong! Stage of Development $165 $205 $40 $120 $90 $260 $165 $410 $530 $620 $880 $0 $100 $200 $300 $400 $500 $600 $700 $800 $900 Target ID 1 yr Target Validation 2 yrs Screening 1.1 yrs Optimization 2 yrs Pre-clinical 1.6 yrs Clinical 7 yrs DollarsinMillions Stage Cost Cumulative Cost $370 Biology 3 years Chemistry 3.1 years Development 8.6 years = TOTAL 14.7 years
    • The Increased Visibility Of IP: What Is At Stake? The value of IP is growing but cannot be accurately forecast in an increasingly global and technological world. Our valuation methodologies and laws are inefficient. This will lead to more IP disputes “It is estimated that by 2007, as much as 90% of the value of the world’s top 2000 enterprises will consist of intellectual property” Building and Enforcing Intellectual Property Value, An International Guide for the Boardroom 2003 PriceWaterhouseCoopers “How appropriate is our system – developed for a world in which physical assets predominated – for an economy in which value increasingly is embodied in ideas rather than tangible capital?” Alan Greenspan April 4, 2003
    • What is the nature of an IP asset? • Bundles of national and territorial rights • Rights to exclude others (NB, not to practise) • Rights considered as property (financial assets), which can be pledged and securitized THE CHALLENGE = How to convert national, legal « rights to exclude » into global, commercial revenue-generating assets?
    • Invention Protection of invention Transfer of technology Entrepreneur Start-up creation Seed funding Business plan Proof of concept Development of technology / product First round financing Management/Structure of company Strategic partnerships More rounds of financing Company grows Traditional Thinking: IP is done at the beginning Product development Sales & markets Regulatory strategy & clinics EXIT TO SUCCESS!
    • EXIT TO SUCCESS! Invention Protection of invention Transfer of technology Entrepreneur Start-up creation Seed funding Business plan Proof of concept Development of technology / product First round financing Management/Structure of company Strategic partnerships More rounds of financing Company grows But, IP is important throughout IP + Money = O2: Lifeline of the company Product development Sales & markets
    • Possible Revenue-Generating Strategies Using IP • Sell Products: Usually a “one-way” street, with all IP rights exhausted (internationally or domestically) (e.g., INTEL) • License/Rent Product: Better to retain rights & maintain some control (e.g., transgenic mice, software: restrict access to source code & use) • Sale of IP: a) Assignment of IP assets: May be simplest (e.g., 3M Post-It) b) License of IP Assets: How? • M&A: Sell company including the IP in it (e.g., a holding entity) • Joint Ventures: Alliances that pool their IP resources into a new company (e.g., Nanonics) • Franchise: Package concept (e.g., McDonalds): what is the IP bundle (TM + © + Know-How + patents)? Quality Control and brand management issues? • Create Market: Offer for free and then charge using installed base (e.g., Skype) • Open Source/Freeware/Shareware & then charge for improvements (e.g., .php) • Covenant not to sue? (e.g., Two start-ups to avoid depleting resources) • IP Holding companies? Who should hold IP? Tax and financing issues: inter- company pricing and royalty considerations.
    • San Francisco (CN), February 24, 2012 Verinata Health and Stanford University sued Sequenom, in a dispute to determine who owns the rights to a noninvasive prenatal test that uses DNA sequencing to search for abnormal fetal chromosomes. The context: a case study Patent Fight Over Fetal DNA Sampling
    • • Verinata has just completed clinical trials of the test for aneuploidy, a genetic defect. – The most common birth defect associated with aneuploidy is Down syndrome. – Verinata claims the new test is more accurate than the maternal serum screening tests now available and less dangerous to the fetus than amniocentesis. – Verinata licensed-in this technology from Stanford University. – The company has spent "tens of millions of dollars in the research, evaluation, and development”. Patent Fight Over Fetal DNA Sampling
    • • Sequenom has a patent (licensed-in) for "Non-Invasive Prenatal Diagnosis," which was issued in 2001 (the so-called '540 patent). – in 2010 Sequenom's lawyers sent a letter alleging that "'the practice of non-invasive prenatal diagnostics, including diagnosis of the Down Syndrome and other genetic disorders, using cell- free nucleic acids in a sample of maternal blood infringes' the '540 patent.“ – Verinata's predecessor, Artemis Health, responded by stating that Sequenom's infringement claims were "unsupported by the patent". Patent Fight Over Fetal DNA Sampling
    • • Verinata says that: – since then, "Sequenom has repeatedly stated to the public that anyone who performs a non-invasive prenatal test using cell- free DNA circulating in the blood of a pregnant woman would infringe the '540 patent. – these statements, which misrepresent the scope of the '540 patent, are intended to broadly convey that: – no one other than Sequenom has the freedom to perform non-invasive prenatal testing under the '540 patent – with the goal of deterring potential competitors from entering the market and deterring doctors and healthcare providers from using anyone other than Sequenom for those services." Patent Fight Over Fetal DNA Sampling
    • NOW… • Verinata seeks declaratory judgment that its test does not infringe on Sequenom's patent. • And it claims that Sequenom itself infringes on Verinata's patents for determining chromosomal abnormalities (two patents), by manufacturing and marketing its test. – Sequenom's infringement of both patents has been "deliberate and willful, warranting increased damages and attorney's fees," Verinata says. – Verinata and Stanford University seek declaratory judgment that both patents have been infringed, a permanent enjoinder from further infringements, damages and treble damages. Patent Fight Over Fetal DNA Sampling
    • Patent Fight Over Fetal DNA Sampling The Message • The key point is not the patents as a way to block competitors – Few SMEs can afford litigation to enforce anyway – Few SMEs care about controlling a monopoly! • The patents protection (strength) of the actual business (product) is essential • Freedom to operate is the key (this is the real value of your patents)
    • Translational Application of Novel Withanolides for the Treatment of Advanced and Drug-Resistant Cancers Mark S. Cohen, MD, FACS Associate Professor of Surgery and Pharmacology University of Kansas Medical Center Barbara N. Timmermann, PhD University Distinguished Professor and Chair Dept. of Medicinal Chemistry, The University of Kansas
    • Portfolio of Novel Compounds • We have identified many of the important anticancer activities of the withanolide, Withaferin A. • Our strong medicinal chemistry team has recently identified 40 natural and semi- synthetic withanolide analogs from the local Physalis plant – Unique properties through structure-activity relationships (SAR) – Each has a unique anticancer activity profile
    • Benefits of Novel Withanolides Novel Withanolides from Physalis Potent, highly selective anticancer activity, orally bioavailable Induces apoptosis, cell cycle shift to G2M (potential radiosensitizer) and down- regulates several key signaling pathways(RET, BRAF, mTOR, notch, BRCA, HSF-1) in melanoma, breast CA, thyroid CA, Head and Neck CA, and leukemias Low Toxicity Profile, clean hERG and AMES Standard Chemotherapy Potent, majority given i.v. which are often non-selective, resistance is common (imatinib, cisplatin) Targeted agents as monotherapies have problems with resistance through alternative survival pathways Systemic toxicities common (often dose- and treatment-limiting) Novel withanolides effectively treat resistant cells and can synergize with imatinib or cisplatin to decrease dose/toxicity
    • Natural withanolide X001 inhibits notch signaling in breast cancers (even triple-negative tumors) Novel withanolides induce apoptosis, shift the cell cycle to G2M, and inhibit key signaling pathways in multiple cancer cell-lines
    • Withanolides are highly effective vs. MTC in vivo ________
    • Withanolides Effectively Treat Melanomas in vivo with Reversal of Metastatic Disease Balb-C mice injected with aggressive B16F10 murine melanoma cells develop metastatic disease in controls (top right figure) but treatment with low dose WA(2.5 mg/kg/d) results in partial response (top left) with prevention of metastases or complete response with high dose treatment (5mg/kg/d) with reversal and cure of metastatic disease (right bottom figure). Graph shows complete tumor response in 60% of low dose and 80% of high dose treated mice sustained even 5 weeks after treatment ceased. 2.5mg/kg/d Control Pre-treatment After 5mg/kg/d x 3 wks
    • Market Analysis • Melanoma, head & neck CA, ALL, glioblastoma, MTC, breast, pancreatic CA • 350k patients/year in US, 2.5M worldwide Potential Cancers for Withanolide Treatment • Orphan indication • US market of 20K pts/year • Currently PEGylated IFN is $20K per course, Yervoy is $120K per patient and Zelboraf is $112k/year Current Novel Melanoma Therapies •$50k per complete course of therapy due to superior safety & efficacy • Withaolides are safer than other cytotoxics and targeted agents • Can synergize with either cytotoxics, BRAFi or other TKIs for combo therapy • Phase 1 human trial anticipated for 2014 Melanoma Treatment with Withanolides 2018 2019 2020 2021 2022 Market share 5% 15% 30% 40% 50% # of courses of therapy 1,000 3,000 6,000 8,000 10,000 Revenue @ $50k per $50M $150M $300M $400M $500M
    • Business Development Strategy • IP – University has both composition of matter and method-of- use patents filed for novel withanolides from Withania and Physalis (licensing arrangement for partner/start up) • Capitalization – $150K grant from Inst. for Advancing Medical Innovation – Seeking additional $5M to get orphan status, IND, and complete phase 1 data in melanoma • Development Model – Start-up to move lead withanolide (already identified for potency in melanoma/ pathway specificity and solubility by SAR) through Phase I and then partner with larger pharma company to reach market – Early partnership/licensing opportunity with pharma company
    • Withanolide Development Milestones
    • Reasons to Invest in Novel Withanolides• Strong Scientific Validation – In vitro / in vivo anticancer mechanism, potent efficacy, low tox – Orally bioavailable analogs with enhanced solubility and potency for cancers (melanoma, thyroid, ALL) • Solid IP portfolio – 40 novel anticancer compounds with composition of matter and method-of-use patents filed (licensing arrangement for partner/start up) • Accelerated Market Entry Timeline – Orphan drug pathway in advanced melanomas, GLP scalability to start human Phase I in 2014, potential
    • Summary • Strong I.P essential & is the foundation of any technology driven organisation • Portfolios of multiple patents held by different parties do not impede innovation • There would be no competitive therapeutic innovation without patents • To be successful in taking new medicines into the clinic we need to dramatically increase our partnering activity to drive innovation through new business models