A five-point bulleted summary of the lecture pdf presented below (9-Pelleymounter-B...). Each bullet point should be approximately 5-7 sentences and concisely and accurately describe a major aspect of the lecture. *****The full summary should be no longer than one-page long. The goal of the exercise is to recognize the most important aspects of each lecture and effectively communicate them. ***I HAVE PROVIDED AN EXAMPLE OF HOW THE FLOW OF THE SUMMARY SHOULD SOUND LIKE. PLEASE FOLLOW THAT EXAMPLE STRICTLY.(1B Summary Example)
PROMPT: PLEASE SUMMARIZE WEEK 10B Raddatz- BioSimilars and 9A Calvo- Patent Law A POWERPOINT ( PLEASE DO NOT COPY IT WORD FOR WORD. PLEASE PARAPHRASE AND PUT THE IMPORTANT CONTENT IN THE SUMMARY)
Also write a 2 paragraph summary regarding this prompts:
1.Based on your current knowledge of the drug discovery process, what single recommendation would you make to a mid- to large-sized pharmaceutical company to decrease risk and/or increase profitability. Please provide a brief rationale for your suggestion.
1. The landscape of clinical trials has changed drastically over the last decade. The protocols are becoming more complex, leading to increased workload, burden on patients, and longer treatment times. Additionally, there has been an increase in the number of Phase 3 projects terminated, resulting in increasing costs of drug development – which is an accumulation from preclinical studies, failures, salaries, and the profit that could have been earned if the drug was approved. 2. The launch of ClinicalTrials.gov in 2000 provided key insight into the evolution of clinical trials. With the requirement by ICMJE to report prospective registration of clinical trials as a precondition for publication, this ensured that not only “successful” trials are published. The details required on ClinicalTrials.gov have expanded overtime, such as reporting results and adverse events. As of 2016, over 200,000 trials are listed and conducted in 191 countries. 3. Phases of clinical drug development are categorized as I, II, III, and IV. Phase I studies typically involve healthy volunteers or patients and conducted to determine responses to drug in humans and animals. The goal is to assess safety, efficacy, tolerability, and PK/PD of the drug. In Phase II trials, the drug is being studied in patients with the target disease for the first time to assess dosing requirements and study efficacy. When the drug development process fails, it typically happens in Phase II. Phase III studies are done in a much larger scale to further establish safety and efficacy. Phase IV trials are also known as Post Marketing Surveillance Trial, which may be required by regulatory authorities or sponsors to monitor the safety of the new drug in large number of patients. 4. A good protocol is designed to answer research questions. A good research question is constructed with three key points in mind: feasibility, relevance, and justifiable costs. Regarding feasibility, one must consider whether there is sufficient patient population that can enroll in the study as well as whether the trial is manageable in scope. For relevance, one must determine if the trial will advance scientific knowledge, guide further research, or affect public policies. Lastly, is the study aligned with the therapeutic focus of the sponsor to justify the costs it will take the conduct the study? 5. There are three ethical principles in clinical research that must be taken into consideration. First, it is the principle of Respect for the Person. This principle has two moral requirements – acknowledging that individuals should be treated as autonomous beings capable of representing their own goals and interests and acknowledging that people who are not capable of self-determination must be protected. Second, beneficence notes that scientists must refrain from knowingly harming their research subjects. Lastly, justice refers to the principle that the benefits and burdens of research must be fairly distributed. Risk in The Business of Biopharmaceutical Discovery and Development James Samanen James Samanen Consulting 2-Mar-16 Numbered references in brackets from “The Structure and Business of Biopharmaceutical Companies including the Management of Risks and Resources”, James Samanen, Chapter 7 in "Introduction to Biological and Small Molecule Drug Research and Development: theory and case studies” edited by Stanley Roberts, C. Robin Ganellin and Roy Jefferis, Elsevier 2013. Outline 1. Introduction - The Business of Biopharmaceutical R&D 2. The Organization of Biopharmaceutical R&D 3. Success/Attrition and Risk 4. Resource – Who Does What When and Where 5. Managing the Flow of Work in Discovery and Development 6. Corporate Behaviors 7. Cost Reduction Experiments in the Business of Biopharmaceutical Discovery and Development There will be time for questions after each section Biopharmaceutical and Protein-Based Drugs • Biopharmaceutical companies – companies that specialize in protein-based drugs and – companies that pursue both types of agents – small molecule and protein-based drugs • Protein-based drugs – therapies based on protein agents, e.g. monoclonal antibodies, cytokines, tissue growth factors and therapeutic proteins 1. The Business of Biopharmaceutical R&D Topics A. It is Big Business B. The Successful Drugs Also Pay for the Failed Drugs C. Revenue Challenges D. Revenue Opportunities Top Industries in 2016 by Net Profit Margins • It’s big business Top Biopharmaceuticals Worldwide in 2015 WW Ranking (7) Drug 1 Humira 2 Harvoni 3 Enbrel Generic Name adalimumab Ledipasvir/Sofosbuvir Etanercept Type protein small molecule protein 4 Remicade Infliximab protein 5 6 7 8 9 10 11 Rituxan Lantus Avastin Herceptin Revlimid Sovaldi Advair/Seretide Rituximab protein Insulin glargine protein Bevacizumab protein Trastuzumab protein Lenalidomide small molecule Sofosbuvir small molecule Fluticasone/salmeterol small molecule 12 13 Crestor Lyrica Rosuvastatin pregabalin small molecule small molecule 14 15 16 17 18 19 20 Neulasta Gleevec Xarelto Copaxone Januvia Abilify Tecfidera pegfilgrastim Imatinib Rivaroxaban Glatiramer acetate sitagliptin Aripiprazole Dimethyl Fumarate protein small molecule small molecule protein small molecule small molecule small molecule 2015 Sales Est. in $ billions (7) $14.01 $13.86 $8.67 $8.36 Disease Indications Rheumatoid arthritis Infectious Diseases (HIV, Hepatitis etc.) Autoimmune diseases Psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis $7.15 Lymphomas, leukemias, transplant rejection, and autoimmune disorders $7.03 Diabetes $6.75 Various cancers $6.60 Breast cancer $5.8 Multiple myeloma 5.28 Hepatitis C viral infection $5.22 Asthma and COPD $5.01 High cholesterol and cardiovascular disease $4.84 Pain $4.72 Neutrophil stimulation after chemotherapy $4.66 Multiple cancers $4.35 Anticoagulant $4.02 Multiple sclerosis 3.86 Diabetes 3.8 Antidepressant $3.64 Neuroscience and Mental Health Successful Drugs Pay for the Failed Drugs • Successful drug - brings in considerably more revenue than the expenses from the discovery, development, manufacture and sales of the drug. – Good return on investment (ROI). • Most R&D projects fail • In any company, cost of R&D - paid for by drugs that bring in revenue for company. • R&D - the future - a lot at stake in the business of R&D Hypothetical Cash Flow versus Time Plot • Cash flow - the difference between revenue and expense +$ Revenues > Expenses Cash Flow Time -$ Revenues < Expenses After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Also in J.A. Vernon et al Quart. Rev. Econ. & Finan. 49 (2009) p. 1260-1274 Hypothetical Cash Flow versus Time Plot • Prior to Product Launch, there are no revenues, only expenses +$ Revenues & Expenses Cash Flow Expenses -$ After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Also in J.A. Vernon et al Quart. Rev. Econ. & Finan. 49 (2009) p. 1260-1274 Time Hypothetical Cash Flow versus Time Plot • After Product Launch, the company can begin to make money Launch +$ Revenues & Expenses Cash Flow Expenses -$ After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Also in J.A. Vernon et al Quart. Rev. Econ. & Finan. 49 (2009) p. 1260-1274 Time Hypothetical Cash Flow versus Time Plot • After Product Launch, the revenues may not by dramatic at first Launch +$ Revenues & Expenses Cash Flow Expenses -$ After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Also in J.A. Vernon et al Quart. Rev. Econ. & Finan. 49 (2009) p. 1260-1274 Time Hypothetical Cash Flow versus Time Plot • Eventually there are revenues – Hopefully Revenues exceed Expenses e.g. Augmentin Launch +$ Revenues & Expenses Cash Flow Expenses -$ After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Also in J.A. Vernon et al Quart. Rev. Econ. & Finan. 49 (2009) p. 1260-1274 Time Profit = Revenues - Expenses Hypothetical Cash Flow versus Time Plot • Competition from other similar drugs will over time reduce revenues Launch +$ Revenues & Expenses Cash Flow Expenses -$ After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Also in J.A. Vernon et al Quart. Rev. Econ. & Finan. 49 (2009) p. 1260-1274 Time Profit = Revenues - Expenses Hypothetical Cash Flow versus Time Plot • Profitability is challenged in a number of ways Launch +$ Revenues & Expenses Cash Flow Expenses -$ Extra Phase III Trials to Satisfy Regulatory Agencies After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Time Hypothetical Cash Flow versus Time Plot • Profitability is challenged in a number of ways Launch +$ Revenues & Expenses Cash Flow Expenses -$ Extra Phase III Trials to Satisfy Regulatory Agencies After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Phase IV Trials to expand indications Time Hypothetical Cash Flow versus Time Plot • Patents - filed and approved long before Launch Launch Patent Approval +$ Revenues & Expenses Cash Flow Expenses -$ After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Time Hypothetical Cash Flow versus Time Plot • Patents – provide Period of Exclusivity Loss of Patent Exclusivity Launch Patent Approval +$ Revenues & Expenses Cash Flow Expenses Time -$ 20 yrs After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Hypothetical Cash Flow versus Time Plot • Revenues decrease after loss of patent exclusivity Loss of Patent Exclusivity Launch Patent Approval +$ Revenues & Expenses Cash Flow Expenses Time -$ 20 yrs After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Hypothetical Cash Flow versus Time Plot • Generic Companies challenge patents early on - May lose exclusivity earlier than expected Loss of Patent Exclusivity Launch Patent Approval Generic Co. Litigation +$ Revenues & Expenses Cash Flow Expenses Time -$ 20 yrs After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Hypothetical Cash Flow versus Time Plot • Profitability is challenged in a number of ways Loss of Patent Exclusivity Launch Generic Co. Litigation +$ Revenues & Expenses Cash Flow Expenses -$ Extra Phase III Trials to Satisfy Regulatory Agencies After Rick Ng, Drugs, from Discovery to Approval, 2nd Ed. 2009, p. 11 Phase IV Trials to expand indications Time Hypothetical Cash Flow versus Time Plot • Desirable - volume under the cash flow positive curve is considerably larger than the volume under the cash flow negative curve – to make up for • expense of discovery and development of that drug and • other R&D expenses Challenges to Profitability • 2 of 10 marketed drugs return revenues that match or exceed R&D costs • Most projects fail • The successful drugs must pay for the cost of all projects that failed or have yet to succeed • In 2012 - true cost of a drug reaching market was estimated US$ 1.2 billion “$1.3 billion in 2013 – top 12 companies – $0.3 to $2.8 billion ” – Deloitte & Thomson Reuters “$2.56 billion in 2014” – 10 companies – Tufts Center for Drug Development Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA R&D Spend as Percent of Total Sales Has been Flat since 1993 25.00% Total R&D as Percentage of Total Sales If Sales Go Up R&D Spend Goes Up 20.00% 15.00% Total Series1 R&D as Percentage of Total Sales 10.00% 5.00% 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 0.00% Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA U.S. Sales from PhRMA Member Companies $200,000.00 $180,000.00 2007 last year of growth $160,000.00 $140,000.00 $120,000.00 $100,000.00 U.S. Sales $80,000.00 $60,000.00 $40,000.00 $20,000.00 $0.00 Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA Total Spend on R&D Slowed since 2007 R&D Expenditures $70.00 $60.00 $50.00 2007 last year of consistent annual growth $40.00 $30.00 R&D Expenditures $20.00 $10.00 $0.00 Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA Biopharmaceuticals spend more on R&D than any other Industry Generic Drugs vs. Branded Pharmaceuticals • Generic drugs by definition do not provide new therapies • The generic drug industry depends upon the branded pharmaceutical companies to create their business • 91% of all biopharmaceutical sales in 2015 were from generics, up from 49% in 2000. • Branded pharmaceutical companies lose at least $10 billion dollars in US sales each year to generics Pharmaceutical Research and Manufacturers of America (2015), Pharmaceutical Industry Profile 2015, Washington, DC: PHRMA U.S. Sales at Risk from Patent Expiration • 2012 was the worst year https://www.caseyresearch.com/articles/is-the-patent-cliff-a-lethal-blow-to-big-pharma? Generics Top all Sub-industries Who Pays the Drug Companies? • Government Health Plans – U.S. - Medicare – EU – administered by country, e.g. UK - National Institute for Health and Clinical Excellence ("NICE”) • Health Insurance Providers – Blue Cross/Blue Shield – Kaiser – Etc. • GOAL – Pharmacoeconomic Benefit – “Better” or “Only one of its kind” is a hard sell if it is expensive Branded Pharmaceutical Companies Strive to Find New Drugs & Markets • Working against relentless challenge of patent expirations, biopharmaceutical companies strive to find new drugs and new markets. • Where are the Opportunities? Where are the Opportunities? Expanding Markets – BRIC Countries • BRIC countries (Brazil, Russia, India and China) – Estimated to be over $130 billion dollars, – Collectively larger than Japan, and growing rapidly – China – now the second largest market in the world – Many drugs have yet to be marketed in these countries • The play is with generics – Huge risks also – these countries are not like US/Canada/EU – culture, patent protection, regulatory environment http://trade.gov/topmarkets/pdf/Pharmaceuticals_China.pdf Global Pharmaceutical Market Total Market 2012-2017 All Countries 5.3% North America 0.7 to 3.7% Europe -0.4 to 2.6% Asia/Africa/Australia 11.4 to 14.4% Japan 1.7 to 4.7% Latin America 10.0 to 13.0% http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/PressRoom/ Total_World_Pharma_Market_Topline_metrics_2012-17_regions.pdf U.S. and Foreign Sales from PhRMA Member Companies $350,000.00 $300,000.00 $250,000.00 $200,000.00 U.S. Sales $150,000.00 Foreign Sales Total Sales $100,000.00 $50,000.00 $0.00 Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA Where are the Opportunities? Biologics • Present new opportunities in challenging therapy areas. • On the rise as an important contributor to the biopharmaceutical pharmacopeia. • Long associated with the treatment of cancer and immunological disorders. – 43% of the drugs approved in these therapy areas from 1998-2008 were biologics [22]. • Now 80% (most!) of the therapy areas are now amenable to biologics Where are the Opportunities? New Science Epigenetics • Study of factors that modulate genetic transcription without changing the DNA or RNA of a cell. • Led to identification of at least two mechanisms which can be modified by drugs – DNA methylation and histone modification. • Drugs that involve these mechanisms have shown efficacy in cancer [24]. • Other indications are likely to emerge as well. Where are the Opportunities? New Science RNA interference (RNAi) • Short strands of RNA can bind to native RNA and interfere with gene expression[25]. • Challenge – create drugs that mimic RNA interference – develop formulations that allow for short strands of interfering RNA (siRNA) to get through the cellular and nuclear walls and deliver the interfering RNA into the nucleus. • Encouragement – RNAi formulation recently demonstrated success in human patients with solid tumor [26]. • Truly revolutionary use for RNAi - block transcription of abnormal proteins arising from abnormal genes. – Cardiac Amyloidosis, muscular dystrophy, etc. Where are the Opportunities? • Expanding Markets – BRIC Countries • Biologics • New Science – Epigenetics, Gene Therapy – RNA interference (RNAi) • Can expect other new opportunities to arise Other Ways to Increase Profitability Decrease Expenses • Profit = Revenue – Expenses • Lower expenses, increase profitability • Need to understand how the business of R&D is conducted 2. The Organization of Biopharmaceutical R&D Topics A. The Science of Biopharmaceutical R&D B. The Logical Biopharmaceutical R&D Process C. The Project Pipeline The Science of Biopharmaceutical R&D • To investors - all science prior to Phase III. – Little to quantify or predict prior to Phase III. • There’s so much research in Development we tend to divide R&D into Discovery and Development – D&D The Process of Biopharmaceutical R&D Logical Order • Organized by what happens first and what happens next in a logical sequence of events. • Manner in which a drug is discovered and developed will always be the same – Regardless of type of company or set of partnered companies and service organizations – E.g. computer assembly a) Install the components of a motherboard, b) install the components that connect to it, c) cover with casing. • What may change in biopharmaceutical R&D organization that supports the process Logical Process Eight Stages of Discovery and Development Logical Process Eight Stages of Discovery and Development 3-6 yr 6-7 yr 0.5-2 yr 10-15 yr Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA Target, Molecule, Indication Progression The Project Pipeline • Biopharmaceutical companies work to discover and develop more than one drug at a time • Each drug discovery or development effort - project. • Set of projects - portfolio • All projects - go through all of the stages of work • Portfolio of projects viewed by stages of work pipeline The Project Pipeline 3. Success/Attrition and Risk Topics A. Success Rates per Stage B. Reasons for Failure C. The Attrition-Based Pipeline D. The Sustainable Pipeline E. Risk – How it Influences POS, Cost, Value and Commitment F. The Increasing Cost of Success Stage-Related Success • Not all projects get approved to advance to the next stage • What are the Success Rates at each stage? Success Rates per Stage • Few studies • Success rates at any particular stage < 60% – Except Launch - 83% Brown, D. and Superti-Furga, G. (2003) Rediscovering the Sweet Spot in Drug Discovery, Drug Disc. Today, 8, 106-1077 * * 35.5% Tufts 2014 29% KMR 2014 Attrition = 1/Success • Attrition - inverse of Success • The overall success rate is 98% of projects fail from Target Discovery to Launch! – Yikes! Cost of Developing A Drug • Each drug that reaches market bears discovery and development costs of all other project failures. • Cost to develop a drug - estimated to be US$ 1.2 billion Revised from [37] - Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA • FDA - ten percent improvement in compound attrition would save $100 million per drug [35] Reasons for Failure Discovery • Reasons for attrition across the industry yet to be published • Data gathered and held in private industry consortiums Reasons for Failure Development • 69 % of attrition in Development arises from poor pharmacokinetics and lack of efficacy – Issues - arise in Development but can be prevented in Discovery [36] Khola, I., and Landis, J. (2004) Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Disc. 3, 711 How Do Companies deal with Risk? Discovery • At beginning stages of Discovery - scant evidence that proposed therapy might actually work. • Blockbusters that command billions of dollars in sales today - in with the pack of wild ideas at beginning. • Risk that proposed therapy might not come to fruition so pervasive in Drug Discovery, often not discussed as risk – it’s seen as “work”. • At beginning of Discovery - risk of failure in clinic is part of the aggregate risk that new project faces – Even though work to reduce the clinical risk won’t occur until candidate is identified. • Every experiment or trial performed along the way addresses a single component of aggregate project risk. How Do Companies deal with Risk? Development • In Development (esp. late stage) - a mounting body of evidence that proposed therapy might succeed. • Risk – less obvious – needs special formal attention. – Can be tightly managed. Risk is Related to the Probability of Failure D&D is the removal of Risk • At project start, risk that any aspect will succeed - unknown • All potential project risk - loaded at the beginning – Aggregate Project Risk • Each experiment – Designed to answer one question about whether target and related compounds will work against a disease. – Risk - any experiment will fail. – If successful - that particular risk is eliminated and probability of success (POS) is increased. Risk POS Time Project Risk vs. POS, Cost • As project team works to reduce Aggregate Project Risk – Project POS increases, and – Total project Cost increases, because of cost of work involved Cost Risk POS Time Project Risk vs. POS, Cost, Value • As the project team works to reduce risk, • The project POS increases, and • The total project cost increases, but • Because POS increases, “potential” value of project increases, Value Cost Risk POS Time Project Risk vs. POS, Cost, Value and Commitment • As the project team works to reduce risk, • The project POS increases, and • The total project cost increases, but • Because the POS increases, “potential” value of project increases, and • Corporate commitment increases. Commitment Value Cost Risk POS Time Goal to Reduce Risk & Increase Value • At each stage of Discovery and Development, work is performed to reduce aggregate project risk and increase “potential” value. Commitment Value Cost Risk POS Drug Discovery Target Discovery Target Selection Lead Discovery Drug Development Lead Optimization Candidate Selection Preclinical Evaluation POC Full Development Product Differentiation Registration & Launch Market Access Managing Risk & Value in Discovery & Development • In Discovery, risk is so obvious it’s often not discussed as such - its seen as regular “work”. • In Development (esp. late stage), risk is less obvious, so it needs special formal attention. In Development it can be tightly managed. Commitment Value Cost Risk POS Drug Discovery Target Discovery Target Selection Lead Discovery Drug Development Lead Optimization Candidate Selection Preclinical Evaluation POC Full Development Product Differentiation Registration & Launch Market Access Managing Risk & Value in Discovery & Development • Later - will see how these factors influence key behaviors within the organization of Discovery and Development. Commitment Value Cost Risk POS Drug Discovery Target Discovery Target Selection Lead Discovery Drug Development Lead Optimization Candidate Selection Preclinical Evaluation POC Full Development Product Differentiation Registration & Launch Market Access The Increasing Cost of Success • Branded pharmaceutical companies, unlike generics companies need to continuously find totally new drugs - Innovation • In 2012 - true cost of a drug reaching market was estimated US$ 1.2 billion Revised from [37] - Pharmaceutical Research and Manufacturers of America (2013), Pharmaceutical Industry Profile 2013, Washington, DC: PHRMA 4. Resource – Who Does What When and Where Topics A. Association of Resource with Stage – Matrix of Work, B. Overarching Organization – Business Units – Therapy Areas (TAs) – Non-aligned Resource – Platform Technologies Resource Who Does What, When, and Where Resource • Modern euphemism for employees • Huge part of biopharmaceutical R&D. • Who does what when – constant aspect of resource, dictated by the logical organization of biopharmaceutical R&D. • Where work gets done varies widely between companies Association of Resource with Stage Matrix of Work Various Disciplines • Different disciplines work at different and often multiple stages of Discovery & Development • Organized into Line Departments • Some are required at all stages – Human Resources, Finance, Corporate Intellectual Property, Licensing, Alliance Management, and Marketing Matrix of Work • The types disciplines that may be needed in a project at different stages • (Neither complete nor correct for any particular company) Association of Resource with Business Units Overarching Organization • Business Units – organization of line departments that perform stage-specific work on projects – have their own budgets – operate relatively autonomously of other business units – Most commonly divided into Discovery and Development – Occasionally certain critical therapy areas may be split out as separate business units, e.g. Cancer or Biologics. – May be subsidiaries, GSK examples: • Steifel Laboratories, a business unit focused on dermatology; • Sirtris, business unit focused on “sirtuins” (closed last year); • Domantis, a business unit focused on a unique type of protein that mimics antibody structure. Association of Resource Therapy Areas • Clusters of diseases for which the company is pursuing therapies, e.g. – Allergy & Respiratory; – Cardiovascular and Metabolic Diseases; – Inflammation; – Infectious Diseases; – Gastrointestinal; – Neuroscience (and pain); – Oncology; and – Ophthalmology • Most Discovery & Development is organized under Therapy Areas • Each Therapy Area has budgetary and resource control over the majority of resources within each Area. Association of Resource Therapy Areas • Resource within each Therapy Area is typically organized into line departments based on areas of expertise, e.g. – Medicinal Chemistry, – Biology, – Drug Metabolism and Pharmacokinetics (DMPK), – Formulations, – Toxicology (Safety), – Clinical, etc. Association of Resource Therapy Areas • Business Plan – Each TA usually has a 3-5 year business plan – Describes long term goals and how to achieve them • Formal Review at end of the period – Organization may make adjustments that could include • re-clustering of diseases in the TAs, and • initiating or eliminating work on certain diseases • Annual Review (Portfolio Review) – Each TA reviews its progress towards its annual goals and towards the completion of its business plan – Budget for next year - typically established Association of Resource Platform Technologies • For some areas of expertise it may be more economical or efficient to avoid the duplication of resource across Therapy Areas and Business Units. • Such areas of expertise may be organized as service organizations to the Therapy Areas • May work in all stages of Discovery & Development – Analytical Chemistry • May work in specific stages of Discovery & Development – Medicinal Chemistry – Discovery – Scale-up Chemistry - Development 5. Managing the Flow of Work in Discovery and Development Topics A. Project Management in Biopharmaceutical R&D B. Portfolio Management in Biopharmaceutical R&D C. Small Molecules vs. Protein-Based Drugs D. The Necessity of Standard Operating Procedures Project Management in Biopharmaceutical R&D • Project – a way of organizing resource – a group of individuals who are assembled to perform different tasks on a common set of objectives for a defined period of time – needs a leader who can define work objectives and criteria for success and recruit staff from all relevant areas of expertise • Project leader does not need to be an expert in all areas of work, but must be able to motivate and recognize talent and communicate with team member’s bosses Project Management Level of Authority • Level of authority depends on corporate commitment to the project, which derives from its potential value to the corporation Commitment Value Cost Risk POS Drug Discovery Target Discovery Target Selection Low Lead Discovery Drug Development Lead Optimization Preclinical Evaluation POC Candidate Selection Project Leader Authority Full Development Product Differentiation Registration & Launch Market Access High Portfolio Management in Biopharmaceutical R&D • The discipline of managing an entire portfolio of projects in company If one or more individuals manage these functions, the company practices portfolio management • • • • • • • • • • • • Categorize and provide portfolio views of projects Evaluate project progress against milestone criteria Select and approve projects for inclusion in the active portfolio Approve projects for advancement into the next stage Select and approve projects for removal from the active portfolio Identify and analyze portfolio risks Develop and monitor portfolio risk responses Prioritize projects Balance or align the project portfolio to current prioritization and strategy Develop and execute portfolio adjustment action plan Review and report portfolio performance with respect to prioritization and current strategy Review and report portfolio resource alignment with prioritization and strategy Portfolio Management in Biopharmaceutical R&D If no one manages these functions, the company is in trouble! • • • • • • • • • • • Categorize and provide portfolio views of projects Evaluate project progress against milestone criteria Select and approve projects for inclusion in the active portfolio Approve projects for advancement into the next stage Select and approve projects for removal from the active portfolio Identify and analyze portfolio risks Develop and monitor portfolio risk responses Prioritize projects Balance or align the project portfolio to current prioritization and strategy Develop and execute portfolio adjustment action plan Review and report portfolio performance with respect to prioritization and current strategy • Review and report portfolio resource alignment with prioritization and strategy How Do Small Molecule Drugs Differ from Protein-based Drugs? • Size Matters • Regulatory Differences • Properties • Managing Small Molecule & Protein-based Drug R&D in the Same Company Small Molecules vs Proteins Size Matters! Aspirin 21 atoms Antibody ~25,000 atoms Small Molecules vs Proteins Aspirin 180 da Antibody ~150,000 da Small Molecules vs Proteins Bicycle, ~20 lbs Business Jet, ~30,000 lbs Small Molecules vs Proteins Structure Small Molecule – any kind of chemical structure Proteins – macromolecular structures composed of polypeptides chains Biotechnology and Pharmaceuticals Vaccines Biotechnology Cytokines Biotherapies Protein-Based Drugs • Here, we focus on biotherapies regulated by Center for Drug Evaluation & Research – protein-based Vaccines drugs CBER Biotechnology CDER Cytokines Protein-Based Drugs Governance as of 2003 Some Early Examples of Protein-Based Drugs Insulin Glucagon Growth Hormone LH, FSH tPA EPO G-CSF Protein-Based Drugs Muromonab-CD3 - T cell CD3 Receptor Abciximab -GP IIb/IIIa Rituximab - CD20 Infliximab - TNF Trastuzumab - ErbB2 Interferons Interleukins TNF Small Molecules vs. Proteins Comparison of Properties Small Molecules Proteins MW Low molecular weight (>1000 Da). Preparation Chemical Synthesis Biologically produced-can be engineered Physicochemical Properties Mostly well defined Complex - tertiary structure - undergo post transcriptional modifications, e.g., glycosylation Route of Administration Oral administration usually possible Usually administered parenterally Rapidly enter systemic circulation through blood capillaries Reach circulation primarily via parenteral route: iv, direct; or sc via lymphatic system Distribution To any combination of organs/tissues/cells Usually limited to plasma and/or extracellular fluids Metabolism Metabolized typically by liver and gut CYPs into Catabolism by proteolytic degradation non-active and active metabolites to peptides and amino acids Serum half-life Short serum half-lives Typical Dosing Regimen Suitable for QD or BID dosing Relatively long serum half-lives Dosing usually far less frequent Small Molecules vs. Proteins Comparison of Properties Small Molecules Pharmacology Species Reactivity Antigenicity Clearance Mechanisms - Renal excretion - Hepatic - Target Mediated -Intestinal Drug-Drug Interactions Tends to interrupt ligand interaction with its receptor or enzyme Proteins May interact with receptor but the biologic may BE the ligand (hormone replacement therapy) or bind to the ligand, it may be a soluble receptor (decoy therapy) or may be an enzyme Generally active in multiple animal species Relevant and irrelevant animals-models Non-antigenic, but can show unpredictable Potential for antigenicity (with MW > hypersensitivity 10 kDa) Small molecules and therapeutic proteins do not share clearance mechanisms noncompeting, parallel Yes Yes Biliary excretion Peptidases Metabolism (P450, UGT, Sulfotransferases, etc.) Rare Yes CYP, UGT, etc. No, due to peripheral administration Often involves transporters Pharmacokinetic interactions due to Less common, less well-defined competing clearance mechanisms - Decreasing clearance if there is enzyme inhibition - Increasing clearance if there is enzyme induction Game Changing Properties • Biweekly to monthly dosing regimen of Proteinbased Drugs often feasible – Due to relatively long serum half-lives – Parenteral administration less of an issue – Superior to once/twice a day, w/wo meal dosing regimen of small molecules – Ensures patient compliance – protein-based drugs doing well in chronic illness markets, e.g. diabetes, rheumatoid arthritis • Fully human antibodies via transgenic mice and phage display technologies eliminates issue of antigenicity. PJ Carter “Potent antibody therapeutics by design” Nat. Rev. Immunol. 2006, 6, p343-357. Mode of Action Small Molecules vs. Protein-based Drugs • Both can be designed to interact with protein-based target • The pharmacology of protein-based drugs is considerably more diverse. • In lock-and-key model, the protein-based drug – could be the key, as in hormone replacement therapy, – could bind to the key (ligand binding) or – could be an extracellular portion of the receptor, as in decoy therapy, – can even have enzymatic activity, e.g. tissue plasminogen activator (t-PA). Big Pharma are taking an interest in Protein-based Drugs • Twelve top biopharmaceutical companies all have protein-based drugs in their late stage portfolios, ranging from 21-66% of their portfolios (avg. 39%). [22] WHY? • Rapid ascendency of protein-based drugs into top tier of sales • Protein-based drugs can be found in 80% of WHO therapy area classes [22] 7/10, 9/20 Protein-based Drugs in the Top Biopharmaceuticals in 2015 WW Ranking (7) Drug 1 Humira 2 Harvoni 3 Enbrel Generic Name adalimumab Ledipasvir/Sofosbuvir Etanercept Type protein small molecule protein 4 Remicade Infliximab protein 5 6 7 8 9 10 11 Rituxan Lantus Avastin Herceptin Revlimid Sovaldi Advair/Seretide Rituximab protein Insulin glargine protein Bevacizumab protein Trastuzumab protein Lenalidomide small molecule Sofosbuvir small molecule Fluticasone/salmeterol small molecule 12 13 Crestor Lyrica Rosuvastatin pregabalin small molecule small molecule 14 15 16 17 18 19 20 Neulasta Gleevec Xarelto Copaxone Januvia Abilify Tecfidera pegfilgrastim Imatinib Rivaroxaban Glatiramer acetate sitagliptin Aripiprazole Dimethyl Fumarate protein small molecule small molecule protein small molecule small molecule small molecule 2015 Sales Est. in $ billions (7) $14.01 $13.86 $8.67 $8.36 Disease Indications Rheumatoid arthritis Infectious Diseases (HIV, Hepatitis etc.) Autoimmune diseases Psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis $7.15 Lymphomas, leukemias, transplant rejection, and autoimmune disorders $7.03 Diabetes $6.75 Various cancers $6.60 Breast cancer $5.8 Multiple myeloma 5.28 Hepatitis C viral infection $5.22 Asthma and COPD $5.01 High cholesterol and cardiovascular disease $4.84 Pain $4.72 Neutrophil stimulation after chemotherapy $4.66 Multiple cancers $4.35 Anticoagulant $4.02 Multiple sclerosis 3.86 Diabetes 3.8 Antidepressant $3.64 Neuroscience and Mental Health Managing Small Molecule & Protein-based Drug R&D in the Same Company • There are differences between the progression of small molecules and proteins through the Discovery and Development stages Small Molecules Target Discovery Lead Discovery Lead Optimization Preclinical Similar Lower POS Longer CT Lower POS Longer CT Shorter CT Biologics Capitalization Costs Phase 1 Phase 2Launch Longer CT Higher Costs POS = Probability of Success; CT = cycle Time; • But both can be managed with the same milestones and stages • The differences can be dealt with at the project level • NO NEED TO HAVE SEPARATE SMALL MOLECULE AND protein-based DRUG DIVISIONS 6. Corporate Behaviors Topics A. In-house vs. In-License & In-house vs. Out-license B. Big vs. Small and the Tendency to Get Big C. Dealing with Patent Expirations D. The Sustainable Pipeline In-license • An asset may be brought into a company at any stage of Discovery & Development • Cost of In-licensing likely to be higher in later stages Out-License • It may be more attractive to out-license a project to get some value for the work – Insufficient Funds • No company can do it all • Need to make choices – Change in Strategy • “No longer doing Neuroscience” – Secondary indications • May involve disease areas that fall outside corporate strategy – Small Start-up Companies • May lack the funds to bring a drug through late stage clinical trials In-Licensing and Out-Licensing • Both of these functions tend to be managed by the same group 6. Corporate Behaviors Topics A. In-house / In-Licensing & In-house / Out-licensing B. Big vs. Small and the Tendency to Get Big C. Dealing with Patent Expirations D. The Sustainable Pipeline Big vs. Small • Big companies - sluggish behemoths • Small companies - agile but unstable. • Medium size – The best of both? – Unable to survive late stage failures of important development projects – Overly exposed to patent expiration of key products • Employee Perspective re. Individual Responsibility – Small >> Medium > Big Tendency to Get Big • Success in the clinic tends to bring considerable new revenue to the company. • Smaller companies tend to invest new revenue back into company either through increasing spend on R&D or through acquisitions. • Larger companies use acquisitions to fill gaps in pipeline or in corporate strategy and bring new revenues into company, and reduced impact of patent expirations [46]. • Since 1988 mergers and acquisitions among biopharmaceutical companies - 42 became 11 [46.] – Enrich banks and lawyers that participate in merger activities – Reduce competition and jobs [47, 48]. 6. Corporate Behaviors Topics A. In-house / In-Licensing & In-house / Out-licensing B. Big vs. Small and the Tendency to Get Big C. Dealing with Patent Expirations D. The Sustainable Pipeline Dealing with Patent Expirations • Patent exclusivity – 20 years – Most marketed drugs begin to suffer patent challenges from generic companies once they begin to make money – Companies will try to extend patent exclusivity • Patenting new formulations • Patenting new method of manufacture • Patenting new indications – If drug is a blockbuster, i.e. billions of dollars in sales, the company needs to plan ahead for the loss in revenue – Protein-Based Drugs are now susceptible to generic competition - biosimilars Top Biopharmaceuticals in 2015 – Not a stable list WW Ranking (7) Drug 1 Humira 2 Harvoni 3 Enbrel Generic Name adalimumab Ledipasvir/Sofosbuvir Etanercept Type protein small molecule protein 4 Remicade Infliximab protein 5 6 7 8 9 10 11 Rituxan Lantus Avastin Herceptin Revlimid Sovaldi Advair/Seretide Rituximab protein Insulin glargine protein Bevacizumab protein Trastuzumab protein Lenalidomide small molecule Sofosbuvir small molecule Fluticasone/salmeterol small molecule 12 13 Crestor Lyrica Rosuvastatin pregabalin small molecule small molecule 14 15 16 17 18 19 20 Neulasta Gleevec Xarelto Copaxone Januvia Abilify Tecfidera pegfilgrastim Imatinib Rivaroxaban Glatiramer acetate sitagliptin Aripiprazole Dimethyl Fumarate protein small molecule small molecule protein small molecule small molecule small molecule 2015 Sales Est. in $ billions (7) $14.01 $13.86 $8.67 $8.36 Disease Indications Rheumatoid arthritis Infectious Diseases (HIV, Hepatitis etc.) Autoimmune diseases Psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis $7.15 Lymphomas, leukemias, transplant rejection, and autoimmune disorders $7.03 Diabetes $6.75 Various cancers $6.60 Breast cancer $5.8 Multiple myeloma 5.28 Hepatitis C viral infection $5.22 Asthma and COPD $5.01 High cholesterol and cardiovascular disease $4.84 Pain $4.72 Neutrophil stimulation after chemotherapy $4.66 Multiple cancers $4.35 Anticoagulant $4.02 Multiple sclerosis 3.86 Diabetes 3.8 Antidepressant $3.64 Neuroscience and Mental Health $16.00 Changes in Rank Order Worldwide $14.00 $12.00 World-wide Sales ($ Billion) $10.00 $8.00 $6.00 $4.00 $2.00 $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Patent Expiration Humira - Protein 2016 Harvoni - Small 2028 Solvaldi - Small 2028 Remicade - Protein 2015 Rituxan - Protein 2015 Advair Seretide - Small 2010 Enbrel - Protein 2028 Lantus- Protein 2015 Avastin - Protein 2019 Herceptin - Protein 2019 Crestor - Small 2016 Abilify - Small 2015 Cymbalta - Small 2013 Spiriva - Small 2023 Gleevec - Small 2015 Xarelto - Small 2020 Lyrica - Small 2015 Neulasta - Protein 2015 Copaxone - Protein 2015 Revlimid - Small 2019 Januvia - Small 2017 Tecfidera - Small 2030 Nexium - Small 2014 (Lipitor - Small) 2011 Plavix - Small 2012 (Singulair - Small) 2012 Atripla - Small 2015 Diovan - Small 2017 $16.00 Changes in Rank Order Worldwide Humira - Protein Harvoni - Small Solvaldi - Small $14.00 Lipitor Patent Protection lost in2012 Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein $12.00 Lantus- Protein Avastin - Protein Herceptin - Protein World-wide Sales ($ Billion) $10.00 Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small $16.00 Changes in Rank Order Worldwide Humira - Protein Harvoni - Small Solvaldi - Small $14.00 Remicade - Protein Plavix Patent Protection lost in2012 Rituxan - Protein Advair Seretide - Small Enbrel - Protein $12.00 Lantus- Protein Avastin - Protein Herceptin - Protein World-wide Sales ($ Billion) $10.00 Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small $16.00 Changes in Rank Order Worldwide Humira - Protein Harvoni - Small Solvaldi - Small $14.00 Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein $12.00 Lantus- Protein Advair Patent Protection lost in2010! Herceptin - Protein $10.00 World-wide Sales ($ Billion) Avastin - Protein Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 $2.00 Advair • combines two lung remedies in one inhaler • Had been difficult to replicate Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small $16.00 Changes in Rank Order Worldwide Humira - Protein Harvoni - Small Solvaldi - Small $14.00 Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein $12.00 Lantus- Protein Avastin - Protein Herceptin - Protein World-wide Sales ($ Billion) $10.00 Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small $16.00 Changes in Rank Order Worldwide Humira - Protein Harvoni - Small Solvaldi - Small $14.00 $12.00 Two drugs from Gilead Sciences blasted onto the scene in 2014 and 2015 both containing sofosbuvir for Hepatitis C Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein Lantus- Protein Avastin - Protein Herceptin - Protein World-wide Sales ($ Billion) $10.00 Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small Changes in Rank Order Worldwide Solvaldi blasted onto Market in 2014 • $16.00 It’s a great drug – for Hepatitis C Viral Infection • Work nearly 90 percent of the time • $14.00 With few side effects • Needs to be taken in combination with other antivirals • $12.00 $1,000 per day for all 12 weeks of treatment • State Medicaid programs can't afford it Humira - Protein Harvoni - Small Solvaldi - Small Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein Lantus- Protein Avastin - Protein Herceptin - Protein World-wide Sales ($ Billion) $10.00 Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small Changes in Rank Order Worldwide Harvoni contains both sofosbuvir and ledipasvir • $16.00 It already contains another antiviral (more convenient) so it is displacing Solvaldi • $14.00 Because these drugs CURE Hep C, sales are dropping! • Unmet medical need is dropping Humira - Protein Harvoni - Small Solvaldi - Small Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein $12.00 Lantus- Protein Avastin - Protein 2016 World-wide Sales ($ Billion) $10.00 Herceptin - Protein Crestor - Small Abilify - Small Cymbalta - Small $8.00 2017 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 2020 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small $16.00 Changes in Rank Order Worldwide Humira - Protein Harvoni - Small Solvaldi - Small $14.00 Small molecule drugs can still have a big impact! Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein $12.00 Lantus- Protein Avastin - Protein Herceptin - Protein World-wide Sales ($ Billion) $10.00 Crestor - Small Abilify - Small Cymbalta - Small $8.00 Spiriva - Small Gleevec - Small Xarelto - Small $6.00 Lyrica - Small Neulasta - Protein Copaxone - Protein $4.00 Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small $2.00 (Lipitor - Small) Plavix - Small (Singulair - Small) $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Atripla - Small Diovan - Small $16.00 $14.00 Changes in Rank Order Worldwide Patent Expirations will always change the rank order $12.00 World-wide Sales ($ Billion) $10.00 By 2016 14/20 will lose US Patent Protection $8.00 $6.00 $4.00 $2.00 $0.00 2010 Sales Est. (4) 2011 Sales Est. (4) 2012 Sales Est. 2013 Sales Est. (1) 2014 Sales Est. (6) (2&3) 2015 Sales (7) Patent Expiration Humira - Protein 2016 Harvoni - Small 2028 Solvaldi - Small 2028 Remicade - Protein 2015 Rituxan - Protein 2015 Advair Seretide - Small 2010 Enbrel - Protein 2028 Lantus- Protein 2015 Avastin - Protein 2019 Herceptin - Protein 2019 Crestor - Small 2016 Abilify - Small 2015 Cymbalta - Small 2013 Spiriva - Small 2023 Gleevec - Small 2015 Xarelto - Small 2020 Lyrica - Small 2015 Neulasta - Protein 2015 Copaxone - Protein 2015 Revlimid - Small 2019 Januvia - Small 2017 Tecfidera - Small 2030 Nexium - Small 2014 (Lipitor - Small) 2011 Plavix - Small 2012 (Singulair - Small) 2012 Atripla - Small 2015 Diovan - Small 2017 Alfred Jacob Miller 17 of the Top 20 in 2015 will have fallen away by 2022 Opdivo - Protein Humira - Protein Harvoni - Small Solvaldi - Small Remicade - Protein Rituxan - Protein Advair Seretide - Small Enbrel - Protein Lantus- Protein Avastin - Protein Herceptin - Protein Crestor - Small Abilify - Small Cymbalta - Small Spiriva - Small Gleevec - Small Xarelto - Small Lyrica - Small Neulasta - Protein Eylea - Small Copaxone - Protein Revlimid - Small Januvia - Small Tecfidera - Small Nexium - Small (Lipitor - Small) Plavix - Small (Singulair - Small) Atripla - Small Diovan - Small Imbruvica - Small Keytruda - Protein Ibrance - Small Soliris - Protein Eliquis - Small Tecintriq - Protein Prolia - Protein Victoza - Small $16.00 World-wide Sales ($ Billion) $14.00 $12.00 $10.00 $8.00 $6.00 $4.00 $2.00 $0.00 2014 Sales Est. (6) 2015 Sales (7) 2022 Sales Est. (8) 6. Corporate Behaviors Topics A. In-house / In-Licensing & In-house / Out-licensing B. Big vs. Small and the Tendency to Get Big C. Dealing with Patent Expirations D. The Sustainable Pipeline Sustainable Pipeline Sustainable Pipeline - Maintains a steady flow of new products year-on-year 1. From Within – Attrition-Based Pipeline 2. By Any Means – In-licensing – Mergers and Acquisitions – Partnerships, Co-Development – Joint Ventures The Attrition-Based Pipeline • If a company wants its internal R&D to supply new drugs to market, year-on-year, it must account for attrition in its pipeline. • Make sure that each stage is at least larger than the subsequent stage by the percent attrition that typically occurs at each transition. The Attrition-Based Pipeline • A hypothetical pipeline, using industry attrition, that would provide one launch in a given year. Based on Brown, D. and Superti-Furga [19] The Attrition-Based Pipeline • A hypothetical pipeline, using industry attrition, that would provide one launch in a given year. Based on Brown, D. and Superti-Furga [19] 78% of the projects would Need to be in Discovery! The Attrition-Based Pipeline • A hypothetical pipeline, using industry attrition, that would provide one launch in a given year. Based on Brown, D. and Superti-Furga [19] 78% of the projects would Need to be in Discovery! Not Scalable! If 4 Launches were required the company would need to begin with 4 X projects in Target Discovery! Sustainable Pipeline Variants Sustainable Pipeline - Maintains a steady flow of new products 1. From Within – Attrition-Based – If you can’t scale your R&D pipeline for attrition, you may not be able to bring along a new product in some years 2. By Any Means – fill the gaps – In-licensing – Mergers and Acquisitions – Partnerships, Co-Development – Joint Ventures The Sustainable Pipeline From Within vs. By Any Means Top 12 companies in 2009 - “Self-Originated” Late Stage Project: 0-44% of portfolio (avg. 25%) Top 12 in 2009 Pfizer Roche Novartis Sanofi-Aventis GlaxoSmithKline Johnson & Johnson AstraZeneca Merck Eli Lilly Bristol-Meyers Squibb Takeda Amgen [41] Deloitte and Thomson Reuters, (2010) R&D Value Measurement, Is R&D Earning its Investment?, www.deloitte.com/assets/Dcom-UnitedKingdom/…/UK_LS_RD_ROI.pdf The Sustainable Pipeline Sustainable Pipeline - Maintains a steady flow of new products 1. From Within – Attrition-Based 2. By Any MeansOrder an Essay Now & Get These Features For Free:
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