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Translational research
- 1. Translational research: what, why, how and with whom?? Annemieke Aartsma-Rus March 2018 PARIS
- 2. Annemieke Aartsma-RusDepartment of Human Genetics2 Outline talk Use therapy development for DMD as a showcase • Patient community involvement • The need for timely tool development • The importance of involving all stakeholders • The importance of good communiciation • Bilateral education trilateral education • Can we learn from our mistakes?
- 3. Annemieke Aartsma-RusDepartment of Human Genetics3 Duchenne Muscular Dystrophy
- 4. Annemieke Aartsma-RusDepartment of Human Genetics4 Steps towards a marketed drugs • Fundamental research • Proof-of-concept studies • Pre-clinical studies • Clinical trials • Marketing authorization (regulators, EMA) • Health insurance/implementation • Post marketing studies (MEB)
- 5. Annemieke Aartsma-RusDepartment of Human Genetics5 Duchenne Muscular Dystrophy
- 6. Annemieke Aartsma-RusDepartment of Human Genetics6 Step 1: Fundamental research ($$) • DMD patients lack dystrophin protein • BMD patients have altered dystrophins • Acts as shock absorber • Connects muscle cytoskeleton to connective tissue • Functional domains located at beginning and end
- 7. Annemieke Aartsma-RusDepartment of Human Genetics7 Splicing Exons Introns 1 3 5 6 7 Gene (DNA) RNA copy (pre mRNA) messenger RNA 1 - - - - - - - - - 79 dystrophin protein Splicing 2 4 3 4 5 6 7 1 2 1 2 3 4 5 6 7 8
- 8. Annemieke Aartsma-RusDepartment of Human Genetics8 Dystrophin exons
- 9. Annemieke Aartsma-RusDepartment of Human Genetics9 Exon 48-50 deletion Disrupted reading frame Exon 46 Exon 47 Exon 51 Exon 52? Protein translation truncated prematurely Dystrophin not functional
- 10. Annemieke Aartsma-RusDepartment of Human Genetics10 Becker: reading frame maintained Protein translation continues Dystrophin partly functional Exon 46 Exon 47 Exon 52 Exon 53 Reading frame not disrupted
- 11. Challenges for DMD therapy 22-mrt-1811 Insert > Header & footer
- 12. Annemieke Aartsma-RusDepartment of Human Genetics12 Duchenne vs Becker
- 13. Annemieke Aartsma-RusDepartment of Human Genetics13 Exon skipping to restore reading frame Exon 52Intron 51Intron 47/50Exon 47 Exon 51 Intron 52AON Exon 46 Exon 47 Exon 52 Reading frame restored Partially functional dystrophin
- 14. Annemieke Aartsma-RusDepartment of Human Genetics14 Idea Experiments $$$
- 15. Annemieke Aartsma-RusDepartment of Human Genetics15 Step 1: DMD cells start making dystrophin 5247 525147 M NT 51 -RT HC0h 4h 8h 16h24h48h NT 48 post transfection MANDYS1 DYS2MANDYS1
- 16. Annemieke Aartsma-RusDepartment of Human Genetics16 Mutation specific approach hotspot Dystroglycan domain Exon All mutations Deletions 51 14% 21% 45 9.0% 13% 53 8.1% 12% 44 7.6% 11% 50 3.8% 5.6% 43 3.1% 4.5% 8 2.0% 2.9% Bladen et al, Hum Mut 2015
- 17. Annemieke Aartsma-RusDepartment of Human Genetics17 Communication • Not applicable to all patients • Patient education • Explain how approach works •www.exonskipping.nl •www.dmd.nl/gt/dance • Realistic expectations • Slows down disease progresion • Not a cure
- 18. Annemieke Aartsma-RusDepartment of Human Genetics18 Is this what patients want?
- 19. Annemieke Aartsma-RusDepartment of Human Genetics19 Therapeutic development
- 20. Annemieke Aartsma-RusDepartment of Human Genetics20 Step 2: first clinical trial
- 21. Annemieke Aartsma-RusDepartment of Human Genetics21 Clinical development
- 22. Annemieke Aartsma-Rus Department of Human Genetics22
- 23. Annemieke Aartsma-RusDepartment of Human Genetics23 Step 3: mouse models • No animal model is perfect – that does not mean they are not useful • Spontaneous mutation in mouse dystrophin • No dystrophin production • Dystrophic muscles • Milder phenotype • Test systemic delivery
- 24. Annemieke Aartsma-RusDepartment of Human Genetics24 Systemic studies in mdx mice WT Mice Mdx Mice AON levels in muscle and Liver Gastrocn.
- 25. Annemieke Aartsma-RusDepartment of Human Genetics25 Delivery routesAONTissueLevels(ug/g)
- 26. Annemieke Aartsma-RusDepartment of Human Genetics26 Step 4: Systemic efficacy trials How are drugs approved? • For rare diseases European Medicines Agency (EMA) approves drugs • Regulators base approval on benefit/risk analysis • Need to show ‘clincial benefit’ for patients • Need tools • Outcome measures • Natural history data
- 27. 27|TREAT-NMD BioBank Patient Registries Care & Trial Site Registry Outcome Measures Standards of Diagnosis & Care TACT Website & Communications Joint Research Standard Operating Procedures Three year work plan www.treat-nmd.eu Action Plan 3 year plan Milestone-driven approach Maintains network momentum & establish new goals Website & Communication Extensive website 250,000 annual page hits 70,000 visitors annually Monthly newsletter sent to 3,500 recipients Proven communication platform Secretariat - Kate Bushby Volker Straub Funding – EC (operating grant) TACT TREAT-NMD Advisory Committee for Therapeutics, Expert multidisciplinary body Independent and objective guidance on advancing new therapies for neuromuscular diseases Chair – Dominic Wells Funding - US (Dept of Defense) Joint research Regular meetings to consolidate efforts and jointly tackle common problems Topics based on necessity, hosting to be rotated between partners Leads - Eric Hoffman Annemieke Aartsma-Rus Filippo Buccella Funding - COST SOPs Unified experimental protocols improve the comparability of studies Drawn up by a group of independent researchers (listed in each protocol) Approx 40 sops updated regularly EuroBioBank Unique network of 18 members Stores & distributes 440,000 quality DNA, cell and tissue samples Leads - Marina Mora Lucia Monaco Marco Crimi Funding - Fondazione Telethon Patient Registries Standardized genetic & clinical core data for trial recruitment Interface can vary between countries whilst still able to share core data Ethical & governance best practice >10,000 DMD patients across 30 countries Leads - Jan Verschuuren Hugh Dawkins Funding - AFM & EC (operating grant) Care & Trial Site Registry Information about each registered trial site kept in one location for ease of comparison Addresses organisational difficulties of identifying appropriate sites when setting up a trial Coordinated by University Medical Center Freiburg Outcome measures Tests to decide whether treatment being tested in a trial is having any effect Vital to use the correct outcome measure to prove if a treatment works Working to harmonise the use of most appropriate outcome measures for different diseases Lead - Eugenio Mercuri Funding - Telethon & Parent Organizations Standards of Diagnosis & Care International consensus publication recommended standards of care DMD-SMA-CMD-LGMD Family guides in 25 different languages translations verified Printed booklets or download from website Leads - Thomas Sejersen Kathy North 2007-2011 EU funded Network 2012 onwards Alliance funded through multiple streams with global partners & membership Governance Chair – KevinFlanigan Vice Chair – Filippo Buccella Executive Committee Supported by academicadvisory board (“task force”) of NMD leaders
- 28. Annemieke Aartsma-RusDepartment of Human Genetics28 Trials were initiated (2008-2010) • Subcutaneous delivery • 2a: Dose escalation (n=12) • 2b: Dose regimen (n=51) • 2b: Dose comparison (n=51) • 3: Efficacy study (n=186) • Open label extension study for each • Primary endpoint: 6 minute walk test
- 29. Annemieke Aartsma-RusDepartment of Human Genetics29 Side effects observed • Local injection reactions • Known effect of subcutaneous delivery of PS AONs • Intraveneous delivery: no injection reactions • Proteinuria (reversible during treatment breaks) • Thrombocytopenia in some patients
- 30. Drisapersen - skin reactions
- 31. Annemieke Aartsma-RusDepartment of Human Genetics31 Open label study after dose escalation
- 32. Annemieke Aartsma-RusDepartment of Human Genetics32 Phase 2b. Dose regimen study
- 33. Annemieke Aartsma-RusDepartment of Human Genetics33 Phase 2b. Dose comparison
- 34. Annemieke Aartsma-RusDepartment of Human Genetics34 Phase 3. Efficacy study
- 35. Annemieke Aartsma-RusDepartment of Human Genetics35 What we know now Blue: below 7 Red: above 7
- 36. Annemieke Aartsma-RusDepartment of Human Genetics36 In hindsight • Information too limited to allow set up ideal trial • Limited information on 6MWT • Variation • Progression in different age ranges • Power calculations impossible • Selection of ideal cohort impossible • Difficult to pick up minor treatment effect
- 37. Annemieke Aartsma-RusDepartment of Human Genetics37 Is this the end? • Phase 3 population more advanced disease • See more response in younger patients • See more response in early stage patients • Open label studies: effect clearer after 2 years • Applied for FDA approval: not granted • EMA application withdrawn • Limited benefit vs side effects • Exon 44, 45 and 53 skipping programms stopped • Focus on next generation AONs
- 38. Annemieke Aartsma-RusDepartment of Human Genetics38 Collateral benefits
- 39. Anna MayhewDepartment of Human Genetics39 PUL test: developed WITH patients
- 40. Annemieke Aartsma-RusDepartment of Human Genetics40 Trilateral education • Regulators are no experts in any rare disease • DMD field no expert in regulatory affairs • Stakeholder meetings organized to learn each others language and perspective and plan for future • Patients/parents • Academics • Regulators • Industry
- 41. Annemieke Aartsma-RusDepartment of Human Genetics41 Road to success: communication Free copy available on Researchgate
- 42. Annemieke Aartsma-RusDepartment of Human Genetics42 Others are following example
- 43. Annemieke Aartsma-RusDepartment of Human Genetics43 Lessons learned by the field • Have natural history data available (especially for your outcome measures) • Suboptimal trial design can lead to false negative results (especially for low effective drugs) • Develop outcome measures in parallel with therapeutic approach and involve patients • Involve all stakeholders from an early stage • Learn each other’s language
- 44. Annemieke Aartsma-RusDepartment of Human Genetics44 Retrospective analysis
- 45. Annemieke Aartsma-RusDepartment of Human Genetics45 Current situation • No functional data available yet • Approval based on minute increases in dystrophin • Clear room for improvement • Evaluation EMA pending
- 46. Acknowledgements Exon Skip group Annemieke Aartsma-Rus Pietro Spitali Maaike van Putten Linda Switzar Silvana Jirka Svetlana Pasteuning Monika Hiller Julie Rutten Gido Gravesteijn Maurice Overzier Christa Tanganyika-de Winter Laura van Vliet Margriet Hulsker Joke Boertjes-van der Meulen Nisha Verwey Gert-Jan van Ommen Department of Neurology/Radiology Erik Niks Jan verschuuren Hermin Kan Zaida Koeks Nathalie Doorenweerd Melissa Hooijmans BioMarin Nederland Judith van Deutekom Nicole Datson Annemieke Aartsma-RusDepartment of Human Genetics 46