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MPS webinar master deck

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Innovation applications of microphysiological systems (MPS) have been growing over the past decade, especially with respect to the use of complex human tissues for assessing safety of drug candidates – but broad industry adoption of MPS methods has not yet become a reality.

This webinar addresses some recent advances in MPS development and begins to explore the barriers to increased incorporation of MPS to improve drug safety assessment and to provide safer, more effective drugs into the clinical pipeline.

Published in: Healthcare
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MPS webinar master deck

  1. 1. Pistoia Alliance Webinar Driving Toward Adoption of Microphysiological Systems in Drug R&D 30th April 2020 16.00 to 17.00 BST
  2. 2. ©PistoiaAlliance Agenda 2 Time (BST) Title Presenter 16:00 Housekeeping Zahid Tharia, Pistoia Alliance 16:05 Introduction Roger Frechette, Pistoia Alliance 16:10 Multi-Organ-Chips for Safety and Efficacy Assessment in Drug Discovery Reyk Horland, VP Business Development, TissUse 16:20 Organs-on-chips in the pharmaceutical industry: Current applications and future perspective Rhiannon David, Microphysiological Systems Scientific Lead, AstraZeneca 16:30 Driving Toward Adoption of Microphysiological Systems in Drug R&D David Jacobson-Kram ToxRox Consulting 16:40 Panel Moderator Mary Ellen Cosenza, Consultant, NDA Partners 17:00 Close
  3. 3. Introduction Roger Frechette, Pistoia Alliance
  4. 4. Multi-Organ-Chips for Safety and Efficacy Assessment in Drug Discovery Reyk Horland, VP Business Development, TissUse
  5. 5. www.tissuse.com Multi-Organ-Chips for Safety and Efficacy Assessment in Drug Discovery Pistoia Alliance Webinar Driving Toward Adoption of Microphysiological Systems in Drug R&D
  6. 6. 85 % failure rates of NCE from pre-clinic into clinic (46 % due to toxicity, 35 % due to lack of efficacy) Traditional Drug Testing Still Leads to Dramatic Failure Rates in Clinical Studies US$ 223 m* and precious time lost (*per failed NCE) Translation animal model to human only 8 % (oncology) 25–100 million vertebrate animals per year used (USA) Animal model: systemic but NOT human; 2D & 3D cell culture: human but NOT systemic Challenges Our solution - Pistoia Alliance MPS Webinar - Predict substance performance by targeted Multi-Organ-Chip (MOC) testing
  7. 7. Our Solution Approach: Testing the Patient Without the Patient We develop automated on-chip testing of human organ models to achieve highly relevant and accurate results: • Equip chips with indication-relevant organ models to measure safety/efficacy on whole organism before exposure • Eventually, equip chip with subunits of patient’s own relevant diseased organs to predict personalized treatment outcome Multi-Organ- (Human)-on-a-Chip: human AND systemic - Pistoia Alliance MPS Webinar -
  8. 8. Components of Our Solution - Pistoia Alliance MPS Webinar - Liver Intestine Kidney Brain Skeletal muscles Pancreas Adipose tissue Skin and Hair Thyroid Lung Bone-marrow Lymph node* Vasculature 3D Lung tumor Heart Your organ of interest 2. Multi-Organ-Chips & control units HUMIMIC Chip2 HUMIMIC Chip3 HUMIMIC Chip4 1. Organ models ?
  9. 9. The Multi-Organ-Chip (MOC) Features: • Size of a standard microscope slide • On-chip micro-pump enabling pulsatile flow • Suitable for iPSC-derived cells, primary cells, 3D tissues and cell lines • Compatible with life tissue imaging • Plug-in option for insert-based barrier models - Pistoia Alliance MPS Webinar - COMSOL Multiphysics® 5.2. Standard cell culture inserts (96-/12-/24-well format)
  10. 10. Subunits of healthy or diseased tissue – Primary or iPS cells – Cell lines – Recreating organ-level functions Organs on Chips Can Recreate Complex Biological Functions of Tissues - Pistoia Alliance MPS Webinar - Liver Intestine Kidney Brain Pancreas Skeletal muscles Adipose tissue Skin Hair Lung Bone-marrow Lymph node* Vasculature 3D tumor ? Your organs of interest Starting with organ models: *in collaboration with ProBioGen AG Heart
  11. 11. Bone marrow on-a-chip •Modelling the human hematopietic stem cell niche - Pistoia Alliance MPS Webinar -
  12. 12. TissUse bone marrow on-a-chip - Pistoia Alliance MPS Webinar - Human Bone marrow CD34+ cells hMSC - human mesenchymal stromal cells 7d static preculture
  13. 13. Creating a human bone marrow on-a-chip - Pistoia Alliance MPS Webinar - human MSCs (0.5 Mill MSCs, Day -7) Vimentin DAPI MSC culture Day 7 Fibronectin + DAPI SCF + DAPI
  14. 14. Creating a human bone marrow on-a-chip - Pistoia Alliance MPS Webinar - human MSCs (0.5 Mill MSCs, Day -7) human HSCs (5000 HSCs, Day 0) BFU-E CFU-E CFU-G Sieber et al: Bone marrow-on-a-chip: Long-term culture of human haematopoietic stem cells in a three-dimensional microfluidic environment. Tissue engineering and regenerative medicine 2017
  15. 15. Haematopeitic potential of the bone marrow chip - Pistoia Alliance MPS Webinar - bone-marrow repopulation of irradiated NOG mice Human cell engraftment (20 weeks after injection) Type Isolated HSCs Day 28 (n=7) BFU-E 9 9 ± 4 CFU-E 10 7 ± 2 CFU-G 9 23 ± 7 CFU-M 6 14 ± 5 CFU-GM 3 4 ± 2 CFU-GEMM 11 5 ± 2 colony-forming unit assays Bone marrow model optimised for prolonged maintenance of undifferentiated HSCs
  16. 16. HUMIMIC Starter Components of a qualified MPS-based assay - Pistoia Alliance MPS Webinar - Commercial Equipment European IQ, OQ, PQ standards Qualified Biological Models GCCP standards 1 2 Pamies et al. ALTEX 2018 Nr. of models R&D: 4 -12 Pharma: ≥ 24 Administration Exposure Dosing Controls: vehicle, non-specific binding Qualified Assay In process controls End point analyses GCCP standards
  17. 17. Our HUMIMIC AutoLab Will Further Increase Efficiency and Cost-Effectiveness of Our End-to-End-Solution • Automated chip operation (24 chips per robot) • Integrated cold storage for different liquids • Automatic media exchange, liquid sampling, microscopy, etc. • Robot facility with customized number of robots available - Pistoia Alliance MPS Webinar -
  18. 18. MPS-based assays in industrial adoption - Pistoia Alliance MPS Webinar - DMPK/Safety Disease modelling/Efficacy
  19. 19. www.tissuse.com TissUse GmbH Oudenarder Str. 16 13347 Berlin, Germany Phone: +49 (0)30 5130 264 00 E-Mail: reyk.horland@tissuse.com
  20. 20. Organs-on-chips in the pharmaceutical industry: Current applications and future perspective Rhiannon David, Microphysiological Systems Scientific Lead, AstraZeneca
  21. 21. Organs-on-chips in the pharmaceutical industry: Current applications and future perspective Rhiannon David Pistoia Webinar: Driving Toward Adoption of Microphysiological Systems in Drug R&D 30/04/2020
  22. 22. 22 Introducing the need for organs-on-chips Advancing pre-clinical safety assessment – Bone Marrow MPS Future challenges and closing remarks
  23. 23. 23 Introducing the need for organs-on-chips Advancing pre-clinical safety assessment – Bone Marrow MPS Future challenges and closing remarks
  24. 24. Why the interest in Microphysiological systems (MPS)? 24 The number of publications with ‘Organ-on-chip’ 42x Increase in 10 Years* Multiple cell types and organ systems; Less drug used compared to in vivo; Human cells/tissues for more relevant models *From Google Scholar 13 550 2009 2019 Their development and use is increasing A revolutionary tool to transform drug discovery?
  25. 25. ` MPS more precisely control cell culture 25 Multiple cell types allowing cell-cell interactions Matrices for maintenance of cell shape and architecture Mechanical forces Blood-like component Flow Immune component
  26. 26. Target identification & validation Lead Identification Lead Optimisation Preclinical Safety Clinical Assessment In vitro model In vitro patient In vivo patient 26 Today Future view Could MPS transform drug discovery? In vivo patient In vivo model
  27. 27. Target identification & validation Lead Identification Lead Optimisation Preclinical Safety Clinical Assessment 27 Opportunities for MPS to add value across the drug discovery pipeline Enhance target ID and validation using disease models Enhance compound progression using human MPS Improve in vivo study design and/or reduce the number of in vivo studies Human-follow up of clinical findings
  28. 28. MPS models at AstraZeneca 28
  29. 29. 29 Introducing the need for organs-on-chips Advancing pre-clinical safety assessment – Bone Marrow MPS Future challenges and closing remarks
  30. 30. Need for a Bone Marrow MPS 30 BONE MARROW TOX CHALLENGE SOLUTIONS A side-effect of oncology drugs that can limit efficacy Gap scheduling and drug combinations can overcome this Finding the right dose and schedule in the clinic is highly challenging BONE MARROW MPS W H Y W E N E E D A
  31. 31. 31 3D MICRO- ENVIRONMENT MEDIA + CYTOKINES RECIRCULATING FLUIDICS Ceramic scaffold mimics human BM pore size and structure and mesenchymal stem cell (MSC) growth is similar to in vivo CD34+ stem and progenitor cells added to MSC-coated scaffold. Cultured in serum-free, cytokine- containing media for differentiation into erythroid, myeloid and megakaryocyte lineages while maintaining stem cells Cells move from the scaffold into the media enabling repeat sampling from the same chip, increasing the power of the study and decreasing variability Key features of our Bone Marrow MPS Human BMScaffold Images provided by Stefan Sieber, TissUse GmbH
  32. 32. Experimental design 32 Spread experimental variables across all technical variables to ensure differences observed are drug-induced Technical Variables Control unit: Each controls 4 chips, have a total of 6 across 2 incubators Side of the Chip: Each chip has 2 circuits Operator: Each chip is maintained and sampled by different people Incubator: Chips are spread across 2 incubators Position of chip in incubator: Each controls 4 chips, have a total of 6 across 2 incubators
  33. 33. Cell differentiation in the BM MPS 33 14 days co-culture on chip Terminal differentiation of myeloid cells After 14 days culture on the chip Mid differentiation of erythroid cells 0 7 14 28 35 42 1 10 100 1000 10000 100000 1000000 Numberofcells Stem cells 0 7 14 28 35 42 1 10 100 1000 10000 100000 1000000 Numberofcells 21 Erythroid 0 7 14 21 28 35 42 1 10 100 1000 10000 100000 1000000 Numberofcells Myeloid Megakaryocytes 0 7 14 28 35 42 1 10 100 1000 10000 100000 1000000 Numberofcells 21
  34. 34. Testing capability for combinations and scheduling 34 Carboplatin mono Olaparib mono Carboplatin + Olaparib 2 x 21 day cycles (24h) (21d) Cell collection, staining and flow cytometry
  35. 35. Combination study: Results 35 Testing for an interaction effect: combination (CP+O) is tested against the combined effect of both monotherapies using negative binomial regression, *** = <0.001, ** = <0.01, * = <0.05. Erythroid Myeloid Megakaryocyte Vehicle 15M C P 5M O O + C P 10 100 1000 10000 100000 ** Cycle 1 (Day 21) Cycle 2 (Day 42) Vehicle 15M C P 5M O O + C P 0.1 1 10 100 1000 10000 Vehicle 15M C P 5M O O + C P 0.1 1 10 100 1000 10000 * + lower error bar missing due to negative error on log scale + ^ ^3 circuits have no cells detected Vehicle 15M C P 5M O O + C P 1 10 100 1000 10000 100000 Numberofcells ** Vehicle 15M CP 5M O O + CP 1 10 100 1000 10000 100000 NumberofCells *** ^^5 circuits have no cells detected ^ ^2 circuits have no cells detected Vehicle 15M C P 5M O O + C P 10 100 1000 10000 100000 + lower error bar missing due to negative error on log scale + + lower error bar missing due to negative error on log scale +
  36. 36. 36 Introducing the need for organs-on-chips Advancing pre-clinical safety assessment – Bone Marrow MPS Future challenges and closing remarks
  37. 37. 37 Challenges for adoption Choice of material for chip fabrication Cost vs relevance Chip platform Choice of cells, number of donors and replicates Clinical translation Acceptance by regulators Qualification of models
  38. 38. 38 0 0 .0 0 .5 1 .0 1 .5 1 0 1 5 2 0 2 5 3 0 D ru g A c o n c e n tra tio n D a y s DrugA(uM) Inlet O utlet F re s h m e d iu m Chip model 1 Chip model 2 Choice of material for fabrication
  39. 39. Clinical translation 39 MPS IN VIVO CLINIC
  40. 40. Acceptance by regulators 40 FDA signs collaborative agreement with CN Bio Innovations to use Organs-on-Chips to improve drug development and evaluation ” FDA signs collaborative agreement with Emulate Inc to use Organs-on-Chips as a toxicology testing platform for understanding how products affect human health and safety ”
  41. 41. Closing remarks 41 MPS provide an opportunity to be more mechanistic and predictive in our preclinical assessment MPS can be deployed at multiple points across the drug discovery process Emerging data build confidence that MPS add value in specified situations To move towards routine use, need to work with regulators and build understanding of translation
  42. 42. 42 Acknowledgements Conor Parks Kainat Khan Asli Akidil Benedicte Recolin Frida Gustafsson Surya Kotha Sinbad Sweeney Sonja Gill Ann Doherty Lorna Ewart Andy Mead Peter Newham Mark Anderton Model development and chip maintenance Modelling and statistics Jonathan Cairns Carmen Pin Chiara Fornari Stan Lazic Teresa Collins Flow Cytometry and Image Analysis Emilyanne Leonard Gareth Maglennon Annika Winter Leopold Koenig Stefan Sieber Hendrick Erfurth Thi Phuong Tao Reyk Horland Uwe Marx Model development
  43. 43. Confidentiality Notice This file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this file is not permitted and may be unlawful. AstraZeneca PLC, 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge, CB2 0AA, UK, T: +44(0)203 749 5000, www.astrazeneca.com 43
  44. 44. Driving Toward Adoption of Microphysiological Systems in Drug R&D David Jacobson-Kram ToxRox Consulting
  45. 45. DRIVING TOWARD ADOPTION OF MICROPHYSIOLOGICAL SYSTEMS IN DRUG R&D David Jacobson-Kram, Ph.D. DABT ToxRox Consulting, LLC McLean VA
  46. 46.  What information do we need microphyiometers to provide? Much of this information is currently derived from animal studies which we all want to reduce and eliminate. no footer My very spoiled dog Lucy
  47. 47. New chemical entity is synthesized, designed to have a specific biological effect Next step is to give it to humans in phase 1 tolerability trial no footer
  48. 48. PHASE 1 TRIALS  Phase 1 studies are generally performed using healthy volunteers.  Unlike taking an approved drug or participating in a late stage clinical trail, there is no risk benefit paradigm, only risk.  Because participants have nothing to gain aside from monetary compensation, bar for safety is very high. no footer
  49. 49. no footer USE OF PRECLINICAL TOXICOLOGY DATA Selection of safe starting dose. Identify target organs of toxicity. Identify safe stopping dose. Determine if toxicological responses reversible. Information is used in Informed and Investigator’s Brochure
  50. 50. TYPES OF PRECLINICAL AND NONCLINICAL TESTS no footer Pharmacology (mechanistic) Safety pharmacology General toxicology Genetic toxicology Pharmacokinetics ADME (absorption, distribution, metabolism and excretion) Reproductive toxicology Carcinogenicity
  51. 51. IMPORTANCE OF NON CLINICAL STUDIES DATA FROM PRECLINICAL STUDIES ARE USED TO ASSESS TOXICOLOGICAL RISKS THAT CANNOT, FOR PRACTICAL OR ETHICAL REASONS, BE EVALUATED IN HUMANS.  Teratogenicity: don’t want to deliberately expose pregnant women  Carcinogenicity: long latency period  Long term toxicities no footer
  52. 52. Panel Discussion Moderator Mary Ellen Cosenza, Consultant, NDA Partners
  53. 53. Get Involved! Emerging Science & Technology Roger Frechette roger.frechette@pistoiaalliance.org Membership: Beeta Balali-Mood beeta.balalimood@pistoiaalliance.orgbeeta.balalimood@pistoiaallian ce.or General Enquiries: Zahid Tharia – zahid.tharia@pistoiaalliance.org
  54. 54. Next Webinar How Can Federated AI/ML Support Genomics and Patient data Analysis to Enable Precision Medicine at Scale? Mon, May 4, 2020, 15:00 – 16:00 BST
  55. 55. info@pistoiaalliance.org @pistoiaalliance www.pistoiaalliance.org

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