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Reprogramming Mindsets:Innovation from Everyone, EverywhereDiscovery Summit, Cannes22nd March, 2012Paul Chapman
Overview    • The scale of the problem (really brief)    • Some basic ideas for addressing the problem    • Focus on centr...
Why Put A Man on The Moon?We choose to go to the moon. We choose to go to the moon… and do the other things, notbecause th...
How Is This Relevant to Discovery?Innovation is not a process you ensure with SOPs, it is what happens along theway to sol...
Many Projects Must Be Started    130    120                               Number of projects required to produce 5    110 ...
Our Humble Home: Takeda’s Shonan Research Center5
Vision for Innovative Culture Allow for decision-making                 VALUE ON                                   Offer p...
Allow for decision-   Drug Discovery Units                                making discretion at                            ...
Takeda Exploratory Challenge: Helping to Test New Ideas           Preparation Period   6/1                                ...
Support for the Awardees7/1                                 Check-in Period                    Basic concept              ...
Ideas Came from All Grades and Disciplines     Application       ApprovalHow many votesby Reviewer?         Job title   ≧ ...
Takeda Research Idea Pageant                                                                                              ...
Plan for Takeda Innovation Center                                Takeda Innovation Center     Shonan Incubation lab       ...
Central Nervous System Diseases Must Benefit from New     Discovery Paradigms     •   Psychiatric Disease (e.g., schizophr...
SCHIZOPHRENIA          Looking for new targets with Envoy Therapeutics14
Schizophrenia Treatments and Pipeline     •   Marketed products          –   Typical antipsychotics                 •     ...
Cognitive Impairment Associated with  Schizophrenia: Potential MOAs …but still with limited MOAs. How to break into entire...
Takeda’s Strategic Alliance with Envoy Therapeutics to                    Generate Truly Novel Schizophrenia Targets     1...
ALZHEIMER’S DISEASE         Looking for prevention with Zinfandel Pharmaceuticals18
Why Prevention Is Better than Treatment   By the time   cognitive   symptoms are   detected, brain   changes may be   insu...
Why a Prevention Trial Is More Challenging than a Treatment Trial•   Age of onset in non-familial (i.e., Late Onset AD) ra...
APOE e4 - a Susceptibility Gene Variant Associated with  Alzheimer’s Disease - 1993                                       ...
SNP and structural variants are prevalent in regions of the TOMM40 gene                                                   ...
People with One Form of The Gene Develop AD at aYounger Age Age of AD onset (years)                               82      ...
Is The Genetic Difference Associated with Alzheimer’s Disease?• Yes• Age of onset• Endo-phenotypes, including biomarkers  ...
We Can Use the Gene to Design a Better Clinical Prevention Trial           PGx-assisted AD prevention Trial DesignValidate...
Summary of Innovative CNS Collaborations     •   New medicines for schizophrenia and related psychiatric disorders        ...
Overall Summary     • Drug discovery was never easy, but it seems to be getting harder     • Partnerships are certainly re...
Discovery Summit 2012: Reprogramming Mindsets: Innovation from Everyone, Everywhere by Paul Chapman
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Discovery Summit 2012: Reprogramming Mindsets: Innovation from Everyone, Everywhere by Paul Chapman

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Discovery Summit 2012: Reprogramming Mindsets: Innovation from Everyone, Everywhere by Paul Chapman, SVP, GM Pharmaceutical Research Division, Takeda

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Discovery Summit 2012: Reprogramming Mindsets: Innovation from Everyone, Everywhere by Paul Chapman

  1. 1. Reprogramming Mindsets:Innovation from Everyone, EverywhereDiscovery Summit, Cannes22nd March, 2012Paul Chapman
  2. 2. Overview • The scale of the problem (really brief) • Some basic ideas for addressing the problem • Focus on central nervous system – Schizophrenia – Alzheimer’s disease1
  3. 3. Why Put A Man on The Moon?We choose to go to the moon. We choose to go to the moon… and do the other things, notbecause they are easy, but because they are hard, because that goal will serve to organizeand measure the best of our energies and skills, because that challenge is one that weare willing to accept, one we are unwilling to postpone….But if I were to say… that we shall send to the moon… a giant rocket more than 300 feet tall…made ofnew metal alloys…which have not yet been invented, capable of standing heat and stresses severaltimes more than have ever been experienced, fitted together with a precision better than the finestwatch… on an untried mission, to an unknown celestial body, and then return it safely to earth, re-entering the atmosphere at speeds of over 25,000 miles per hour, causing heat about half that of thetemperature of the sun…and do all this, and do it right, and do it first before this decade is out--then wemust be bold. John F. Kennedy, September 1962
  4. 4. How Is This Relevant to Discovery?Innovation is not a process you ensure with SOPs, it is what happens along theway to solving big problems; when you take on major challenges that we arewilling to accept; ones we are unwilling to postponeBut if I were to say that in spite of declining productivity across thepharmaceutical industry, in spite of an increasingly challenging regulatoryenvironment, patent expirations and declining revenues that we intend tocreate important new medicines with the potential to change the world – thenwe must be bold.
  5. 5. Many Projects Must Be Started 130 120 Number of projects required to produce 5 110 IND per year at industry standard PoS 100 90 80 70 60 50 40 30 20 …but how to 10 Modest increase in PoS across late stages dramatically reduces number of early projects required increase PoS? 0 Target Hit to Lead Safety and Toxicology IND identification and lead optimization screening4
  6. 6. Our Humble Home: Takeda’s Shonan Research Center5
  7. 7. Vision for Innovative Culture Allow for decision-making VALUE ON Offer performance feedback AGILE PROCESSESdiscretion at all levels of the quickly,PEOPLE continuously and organization DEVELOPMENT directly OPEN-MINDED Hire for and promote civility SUPPORTIVE Actively promote effective among CULTUREand teams to individuals THAT information-sharing and ENVIRONMENT prevent ENABLES negative feedback stripping of silos FOR INNOVATION loops DIFFERENTIATION
  8. 8. Allow for decision- Drug Discovery Units making discretion at all levels of the organizationFive DDUs Four are therapeutically aligned MD DDU Oncology DDU Fifth is dedicated to creating extra XV value through repositioning DDU ImmunologyFull alignment of resource & CNS DDU accountability DDUBudgets and FTE given to DDU HeadsAuthority to spend internal or external at DDU Heads discretionResource allocation in future years to be dependent on performance against DDU goals
  9. 9. Takeda Exploratory Challenge: Helping to Test New Ideas Preparation Period 6/1 Application Period 6/30Basic concept 34 Single Applications Target Value Anything OK Date Poster Presentation Award = JPY 5 MM + 365 days IT with Project Team (Form, Website & Announce) 8/21
  10. 10. Support for the Awardees7/1 Check-in Period Basic concept Entrepreneurship Mentor Planning (Gantt Chart with Criteria) Actual expense Management virtual Shonan Incubation Lab. Contract Performance evaluation 9/21
  11. 11. Ideas Came from All Grades and Disciplines Application ApprovalHow many votesby Reviewer? Job title ≧ Associate Director Principal Scientist Scientist Affiliation BRL DRL MCRL ONC CNS MD Staff 10/21
  12. 12. Takeda Research Idea Pageant Actively promote Design features of the Idea Pageant effective information-sharing ▪ Researchers (~1000 people including all PRD) will be involved in this project and stripping of silos ▪ Researchers to vote for the most promising and the least promising project in each categorized stages to obtain clinical POC (Proof of Concept) ▪ All projects will be ranked by the number of votes and the top project by stage will be announced to entire PRD What is the value of an Idea Pageant? ▪ Encourage the more information sharing across projects and enable researchers to understand the whole pipeline projects in PRD ▪ Identify the jewels projects and projects that need further support ▪ Invite healthy competition and improve transparency among project teamsKey visions fornew PRD
  13. 13. Plan for Takeda Innovation Center Takeda Innovation Center Shonan Incubation lab Multiple type lab (Shonan Research Center) (On-site or off-site of SRC) Takeda “Open” collaborations with academics Global Sites Internal entrepreneurs • 1 Oncology project (committed) • 2 Inflammation/Immunology projects (planned) • 1 Neuroscience project (planned) Outside of Shonan Center12
  14. 14. Central Nervous System Diseases Must Benefit from New Discovery Paradigms • Psychiatric Disease (e.g., schizophrenia, autism spectrum disorders) – Enormous unmet need • Medicines are available to treat some symptoms, but they are not consistently efficacious • Safety and tolerability concerns limit utility of even the best medicines • Many key features (e.g., negative or cognitive symptoms in schizophrenia) are totally unmet – Growing understanding of the diseases have not yet translated into treatment strategies based on biology • Neurodegenerative disease (e.g., Alzheimer’s, Parkinson’s) – Symptomatic treatments exist, but nothing slows progression – Leading hypotheses may be misleading – Clinical trials to test prevention or disease modification appear to be too difficult and/or too costly • As an industry we need solutions that address core issues13
  15. 15. SCHIZOPHRENIA Looking for new targets with Envoy Therapeutics14
  16. 16. Schizophrenia Treatments and Pipeline • Marketed products – Typical antipsychotics • • haloperidol chorpromazine • Clinical pipeline • trifluoperazine – Atypical antipsychotics • clozapine – 3 atypical • • • risperidone aripiperazole Iloperidone antipsychotics • Ziprazidone • • paliperidone lurasidone – 3 DA or DA+5HT • asenapine • quetiapine • • olanzapine melperone – 1 GlyT • sertindole • • amisulpride blonanserine – 1 mGluR – Others • None – 2 PDE10 …although new aspects of schizophrenia are also being addressed….15
  17. 17. Cognitive Impairment Associated with Schizophrenia: Potential MOAs …but still with limited MOAs. How to break into entirely new targets?16
  18. 18. Takeda’s Strategic Alliance with Envoy Therapeutics to Generate Truly Novel Schizophrenia Targets 1. bacTRAP mice that express Engineered Ribosomal Proteins-eGFP 2. “Transcriptonomic profile” exclusively from cells of interest 3. Generate target hypotheses from genes modified in cell-type and model-specific manner Whole Cortex Promoter of selected disease associated gene andribosome tag-eGFP segment is inserted into BAC DNA Some cell specific genes Some genes are ubiquitous not seen at all in bulk tissue Oligodendrocyte Lineage Cells in the Cortex Isolated mRNA that was expressed only by cells Biochemic Add test al function expressing the target protein molecules of target and cell Cells with target type is are highlighted in characteri Profile cultured tissue zed sections transcriptome Comparisons between: Mixture of mRNA/ribosome complexes Reference. Cell, 135, 738, 2008 naïve vs. drug treated, normal vs. diseased wild-type vs, KO animals…. 17
  19. 19. ALZHEIMER’S DISEASE Looking for prevention with Zinfandel Pharmaceuticals18
  20. 20. Why Prevention Is Better than Treatment By the time cognitive symptoms are detected, brain changes may be insurmountable Even “mild” symptoms are distressing and should be avoided 19
  21. 21. Why a Prevention Trial Is More Challenging than a Treatment Trial• Age of onset in non-familial (i.e., Late Onset AD) ranges from early 60s to 90s• Incidence of AD is relatively low in the general population – Approximately 6 per thousand person-years for people between the ages of 65 and 79 – Risk increases with age (about 70 per thousand person-years above the age of 90) but prevention trials with very old would still be challenging – Without a biomarker to enrich, the trial would require tens of thousands of person- years – Investigational drug must be “safe as water” in order to dose healthy elderly subjects• Choice between relatively simple treatment trial that is very likely to fail and very challenging prevention trial that has a higher probability of success unless• The trial makes use of a predictive biomarker to find people of any age who are at high risk 20
  22. 22. APOE e4 - a Susceptibility Gene Variant Associated with Alzheimer’s Disease - 1993 Mean age of onset genotype unaffected 1.0 ’ of Alzheimer’s Proportion of each 0.8 2/3 disease as a 0.6 3/3 2/4 function of the 0.4 inheritance of the 3/4 five common APOE 0.2 4/4 genotypes 0 60 65 70 75 80 85 Age at onsetCase Study: Takeda-Zinfandel collaboration
  23. 23. SNP and structural variants are prevalent in regions of the TOMM40 gene E1 E6 E7 E8 E9 0 rs8106922 SNP 95% “A” allele in clade A ” Coun 40 97% “G” allele in clade B ” 20 t 10 15 20 25 30 35 Length rs10524523 poly-T polymorphism poly-T SNP
  24. 24. People with One Form of The Gene Develop AD at aYounger Age Age of AD onset (years) 82 80 APOE3/4 AD patients AD Age of Onset (Years) 78 78 76 74 72 70 70 68 66 64 Very Long/Long p<0.03 P < 0.03 Short/Long Longer Form Shorter Form 523 genotype
  25. 25. Is The Genetic Difference Associated with Alzheimer’s Disease?• Yes• Age of onset• Endo-phenotypes, including biomarkers – Data predicts neuropsychological changes before recognizable disease – MRI gray matter density and thickness varies with 523 genotype before recognizable disease – Data supports ethnic differences in age of onset distributions for different ethnic groups
  26. 26. We Can Use the Gene to Design a Better Clinical Prevention Trial PGx-assisted AD prevention Trial DesignValidate PGx Test Clinical Trial Treatment High Risk Randomize Placebo 523 PGx Predictive Placebo TestSeparate clinical Low Randomizetrial of early cognitive Riskdysfunction Placebo
  27. 27. Summary of Innovative CNS Collaborations • New medicines for schizophrenia and related psychiatric disorders require a different way of finding and prioritizing targets – Unbiased explorations based on known biology – Bioinformatics to understand the relationships between presumed targets – Partnerships that bring this biology together with medicinal chemistry and pharmacology expertise should be very productive • New medicines for Alzheimer’s and related neurodegenerative disorders require a different way of designing and executing clinical trials – Many target ideas and opportunities (that look great in mice) – Progressive diseases almost certainly require early intervention – Partnerships that bring biomarkers or innovative trial designs should be very productive27
  28. 28. Overall Summary • Drug discovery was never easy, but it seems to be getting harder • Partnerships are certainly required to solve the most difficult problems • No single way of partnering is best; solutions must be tailored to institutions and disease areas28

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