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Involving all stakeholders
- 1. Academic and patient representatives perspective on drug development for rare diseases Annemieke Aartsma-Rus & Elizabeth Vroom June 2018
- 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?
- 4. Annemieke Aartsma-RusDepartment of Human Genetics4 Duchenne Muscular Dystrophy
- 7. Annemieke Aartsma-RusDepartment of Human Genetics7 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
- 8. Annemieke Aartsma-RusDepartment of Human Genetics8 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
- 9. Annemieke Aartsma-RusDepartment of Human Genetics9 Dystrophin exons
- 10. Annemieke Aartsma-RusDepartment of Human Genetics 10 Duchenne: reading frame disrupted
- 11. Annemieke Aartsma-RusDepartment of Human Genetics11 Exon 48-50 deletion Disrupted reading frame Exon 46 Exon 47 Exon 51 Exon 52? Protein translation truncated prematurely Dystrophin not functional
- 12. Annemieke Aartsma-RusDepartment of Human Genetics 12 Becker: reading frame maintained
- 13. Annemieke Aartsma-RusDepartment of Human Genetics13 Becker: reading frame maintained Protein translation continues Dystrophin partly functional Exon 46 Exon 47 Exon 52 Exon 53 Reading frame not disrupted
- 14. Annemieke Aartsma-RusDepartment of Human Genetics14 Duchenne vs Becker
- 15. Annemieke Aartsma-RusDepartment of Human Genetics15 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
- 16. Annemieke Aartsma-RusDepartment of Human Genetics 16 AONs • Modified pieces of RNA/DNA • Many different modifications possible • We use 2’-O-methyl phosphorothioate • Transfection needed in cell culture • Saline injection possible in mouse
- 17. Annemieke Aartsma-RusDepartment of Human Genetics17 Step 1: DMD cells start making dystrophin 5247 525147 M NT 51 -RT HC0h 4h 8h 16h24h48h NT 48 post transfection MANDYS1 DYS2MANDYS1
- 18. Annemieke Aartsma-RusDepartment of Human Genetics18 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
- 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 Genetics 24 Considerations for AON delivery • AONs very small (~8-12 kDa) • Filtered out by kidney • Phosphorothiate modification • Serum protein binding • Less clearance by kidney • Uptake by liver • Uptake muscle poor, heart very poor
- 25. Annemieke Aartsma-RusDepartment of Human Genetics25 Systemic studies in mdx mice WT Mice Mdx Mice AON levels in muscle and Liver Gastrocn.
- 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. Annemieke Aartsma-RusDepartment of Human Genetics 27 Ready for trials???? • Limited natural history data • Limited outcome measures •No biomarkers • Preclinical studies not standardized • Rare disease multiple trials sites needed? • Care standards • Trial sites where? • Personalized approach • Registries needed
- 28. Annemieke Aartsma-RusDepartment of Human Genetics 28 Infrastructure needed for clinical trials • Natural history data • Outcome measures • Biomarkers • Rare disease multiple trials sites needed • Care standards • Expert centers for DMD • Personalized approach • Registries to identify eligible patients
- 29. 29|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 – Kevin Flannigan Vice Chair – Jan Kirschner Executive Committee Supported by academic advisory board (“task force”) of NMD leaders
- 31. Clinical research Recruitement Interactions with Industry Selection of Centers Trial Design Regulatory Ethics
- 32. Outcome measures Patient Reported Outcome Measures Development of PUL Ask the patients! Clinically meaningful Development of PROM
- 33. Interactions with Industry ‘Early access to medicines in Europe: Compassionate use to become a reality’ Eurordis ‘Code of Practice between patient organisations and the healtcare industry’ Eurordis Community Advisory Board Eurordis
- 34. Meanwhile: trials were initiated Annemieke Aartsma-Rus • Dose escalating study (0.5 – 6 mg/kg/week for 4 weeks (April 2008) • Dystrophin restored in 10/12 patients • All patients then enrolled in an open label extension study (July 2009) • 6 mg/kg drisapersen per week for 72 weeks • Then 8 weeks break • Then cycles of 8 weekly doses, 4 week break • Treated for almost 4 years Goemans et al, NEJM 2011, 364: 1513-22
- 35. 6 Minute walk test • Global measure of function arising from cardio respiratory field • Captures clinically meaningful aspect of day-to-day life of ambulant DMD • Precedent of regulatory approval obtained based on 6MWD in NMD • Modified, standardized procedure described for DMD (C.McDonald, 2010)I • Is currently used as (primary) endpoint in therapeutic trials
- 36. Annemieke Aartsma-Rus 36 Distancewalked(m) Weeks in extension study intermittent PRO051-02 / DMD114673 Efficacy
- 37. Drisapersen - skin reactions
- 38. Open Label Extenion Trial Drisapersen Annemieke Aartsma-Rus • Side effects observed • Local injection site reactions • Proteinuria (reversible during breaks) • Thrombocytopenia seen for some patients • Seen in all phase 2/3 trials drisapersen • 6 minute walk distance maintained for >3.5 years in 8/10 ambulant patients • Very encouraging results but no placebo group
- 39. Placebo-controlled trial drisapersen Annemieke Aartsma-Rus • 54 patients • Early stage of disease (able to rise from floor in < 7 sec) • Steroid treated • Treatment for 48 weeks with 6 mg/kg drisapersen subcutaneous or placebo • Weekly injections (18 patients) • Intermittent regimen (17 patients) • Placebo (18 patients)
- 40. Primary Endpoint: Change from Baseline (95% CI) in 6MWD (m), ITT Population Visit Comparison Treatment Difference P-value Week 25 (Primary) Weekly vs Placebo 35.09 0.014 Intermittent vs Placebo 3.51 0.801 Week 49 (Secondary) Weekly vs Placebo 35.84 0.051 Intermittent vs Placebo 27.08 0.147
- 41. Placebo-controlled trial drisapersen Annemieke Aartsma-Rus • 51 patients • Early stage of disease (rise from floor <15 seconds) • Steroid treated • Treatment for 24 weeks with 3 or 6 mg/kg drisapersen subcutaneous or placebo • 24 week wash out
- 43. Placebo study drisapersen Annemieke Aartsma-Rus • Phase 3 (48 weeks) • Patients 5-16 years old (186) • Global study • 6 mg/kg/week or placebo
- 44. Primary Endpoint: 6MWD Adjusted Mean Change from Baseline (95% CI) in 6MWD (m) – Primary MMRM analysis ITT Population Treatment difference = 10.3m, p-value = 0.415 at Week 48 Curves offset for visualization 4.7m 4.8m 1.8m - 52.7 m - 42.3 m
- 45. Annemieke Aartsma-Rus What we know now
- 46. Annemieke Aartsma-Rus Pane et al.2014 Influence of age Blue: below 7 Red: above 7
- 47. Annemieke Aartsma-Rus Influence of disease stage Green: baseline >350 m Orange: baseline <350 m Pane et al.2014
- 48. Annemieke Aartsma-RusDepartment of Human Genetics48 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
- 49. Annemieke Aartsma-RusDepartment of Human Genetics49 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
- 50. Annemieke Aartsma-RusDepartment of Human Genetics50 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
- 51. EMA ‘Drugs are approved on data not on emotions’ Have arguments included in the discussion No drama Patients included in scientific committees More (real life) data needed Strict conflict of interest rules
- 52. Annemieke Aartsma-RusDepartment of Human Genetics52 Road to success: communication Free copy available on Researchgate
- 53. Outcome measures Patient Reported Outcome Measures Burden Ask the patients! Clinically meaningful Validation
- 54. EMA - CHMP Signed by 65 Muscle organisations and Eurordis Collective letter (incl data) for example on patient preferences Members from all countries Input via patient representatives in committees Distributed Among all members by EMA
- 55. Newborn Screening Market approval Clinical Trial Regulation Funding research Standards of Care/Centers of Care Reimbursement
- 56. Duchenne Data platform Underutilisation of data About patients for patients Q and A Data now in silo’s Conversation /chat bot PROM’s Wearables
- 58. Care Standards of care Certification Q and A Implementation Family guides Animations Education
- 60. Include patients and PO’s at an early stage!
- 61. Annemieke Aartsma-RusDepartment of Human Genetics61 Others are following example
- 62. Annemieke Aartsma-RusDepartment of Human Genetics62 Current situation • No functional data available yet • Approval based on minute increases in dystrophin • Clear room for improvement • Evaluation EMA pending
- 63. Annemieke Aartsma-RusDepartment of Human Genetics63 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
- 65. Thank you!