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Clinical Research Strategies in MSA

JiePieAward , Brussels October 2nd, 2014. Clinical Research Strategies in MSA. Gregor K. Wenning MD PhD MSC Division of Neurobiology Department of Neurology & Neurosurgery Medical University Innsbruck AUSTRIA florian.krismer@i-med.ac.at. EMSA Sites 10 / 2014.

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Clinical Research Strategies in MSA

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  1. JiePieAward, Brussels October 2nd, 2014 Clinical Research Strategies in MSA Gregor K. Wenning MD PhD MSC Division of Neurobiology Department of Neurology & Neurosurgery Medical University Innsbruck AUSTRIA florian.krismer@i-med.ac.at

  2. EMSA Sites 10 / 2014 24 Study Sites in 12 EU Countries + Israel www.emsa-sg.org

  3. EMSA Registry Köllensperger et al., 2010

  4. EMSA Registry 436 consecutivepatientsrecruited Meanageatdiseaseonset: 57.8 years Baseline disease duration: 5.8 years 68.2% MSA-P Symptomatic autonomic failure in 99% Urinary incontinence in 83% Orthostatic dysregulation in 75% Parkinsonism in 87% Ataxia in 63% Köllensperger et al., 2010

  5. EMSA Registry Pharmacological Treatment Autonomicfailure Orthostaticsymptomstreated in 27% Midodrine – 69% Fludrocortisone– 25% Urinarydysfunctiontreated in 19% Tolterodine – 52% Oxybutinin – 45% Parkinsonism L-Dopa – 73% (beneficialresponse in 38%) DA – 29% MAO-B inihbitors – 11% Under-Treatment Köllensperger et al., 2010

  6. Progression ofmotorimpairment Progression of non-motor impairment Progression of global disability WorseningofHr-QoL Progression ofsurrogatemarkers Trial considerations

  7. UPDRS III progressionin MSA-P H&Y H&Y H&Y Annual UPDRS-III increase in PD: 1.5% ranging from 0.6-4.5 Mean UPDRS-III change: 10.8 (95%CI 8.5 – 13.1) H&Y 3 (n=22): 13.1 (95%CI 10.9 – 15.3) H&Y  4 (n=12):6.5 (95%CI 2.1 – 10.9) Olanow 1995; Louis 1999; Goetz 2000; Jankovic 2001 Seppi K et al, 2005

  8. EMSA – Natural History Wenning et al.2013

  9. EMSA - Natural History Wenning et al., 2013

  10. EMSA – Natural History Wenning et al., 2013

  11. EMSA – Natural History Clinical Milestones UMSARS Progression Per Protocol Analysis Wenning et al., 2013

  12. EMSA supportedsample sizecalculationfortrials 30% effectsize  159 patients per group (80% power) 30% effectsize  186 patients per group (80% power) Wenning et al., 2013

  13. Lowerbaselineimpairment Seppiet al, 2005 Absent L-Doparesponse Wenning et al, 2013 Short diseaseduration Seppiet al, 2005; Geser et al, 2006; Wenning et al, 2013 Cerebellarfeaturesatbaseline Geseret al, 2006 Factorsassociatedwith rapid progressionofmotorimpairment in MSA

  14. Progression of motor impairment Progression of non-motor impairment Progression of global disability Worsening of Hr-QoL Progression of surrogate markers Trial considerations

  15. Progression of self perceived dysautonomia in MSA6 months

  16. Progression of motor impairment Progression of non-motor impairment Progression of global disability Worsening of Hr-QoL Progression of surrogate markers Trial considerations

  17. H&Y stageswithin 1 yearofmotoronset H&Y I H&Y II H&Y III PD MSA DLB PSP Cases (%) MSA DLB PD CBD PSP N = 18; 13; 11; 15; 24 H&Y progression in pathologicallyconfirmedparkinsoniandisordes H&Y progression N = 81 Median H&Y III latency in MSA: 43 months (6 – 100) Median H&Y IV latency in MSA: 56 months (6 - 118) Mueller et al., 2000

  18. PROGRESSION IN MSA Disability-milestones • approx. 50-60% ofpatientswheelchair-boundat 5 years • Survival rate at 5 yearsapprox. 84% • Survival rate at 10 yearsapprox. 40% Wenning et al. 1994, N=100; Watanabe et al. 2002, N=230

  19. Progression of motor impairment Progression of non-motor impairment Progression of global disability Worsening of Hr-QoL Progression of surrogate markers Trial considerations

  20. - N = 115 pts. from EMSA-SG NH Study - Impairment in all EQ-5D and SF-36 domains - Significant impairments also relative to PD ! (except pain) - Autonomic dysfunction (COMPASS), motor impairment (UMSARS) and depression (BDI) closely associated with poor Hr-QoL - CAVE: No change in SF-36, scores in sample of 27 MSA pts. from 4 EMSA-SG centres over 6 mths (Köllensperger et al, 2006) Health-related Quality of Life in MSA(Schrag et al, 2006)

  21. Progression of motor impairment Progression of non-motor impairment Progression of global disability Worsening of Hr-QoL Progression of surrogate markers Trial considerations

  22. SURROGATE ENDPOINTS IN MSA Considerations • DopamineD2R  DA-D2R-Imaging (IBZM-SPECT, • Raclopride-PET) • Striatalglucosemetabolism FDG-PET • Dopaminetransporter DAT-SPECT (beta-CIT, FP-CIT) • Striatal LD metabolism F-DOPA-PET • Activatedmicroglia PK11195-PET • Basal gangliaatrophy MRT, MRV • Putaminaldiffusivity DWI (ADCs) • CSF/Plasma Biomarkers

  23. CompletedInterventional Trials

  24. rhGH Trial: Negative- trophicfactorsupport - Holmberg et al. 2007, Aberg et al. 2000

  25. Minocycline (MEMSA): Negative- microglial de-activation - CD11b + Cresylviolet PK11195-PET Stefanova et al. 2007, Dodel et al. 2010

  26. Riluzole (NNIPPS): Negative- anti-glutamatergicefficacy - Scherfler et al. 2005, Diguet et al. 2005, Bensimon et al., 2009

  27. MSA MSA+R 2.5 MSA MSA+R 2.5 Rasagiline: Negative- neuronal protection - Stefanova et al. 2008, Poewe et al. 2012 (Poster 1182)

  28. MesenchymalStem Cells - cellreplacement - Lee et al2012

  29. Intravenousimmunoglobulins- Immunomodulation -

  30. OngoingInterventional Trials

  31. Rifampicin- α-synucleinclearance - Ubhi et al. 2008

  32. Fluoxetine- trophicfactorrestoration - Ubhiet al. 2012

  33. Future MSA TrialsTargets • ToxicalphaSynucleinspecies („prion-like“) • Oligodendroglia versus neurons • Oxidative stress (CoQ 2 mutations) • Neuroinflammation

  34. Future MSA TrialsDesign • Placebo-controlledvs open label • Parallel groupvscrossover • Large versus small • Other?

  35. Future MSA TrialsPopulation • MSA-P • MSA-C • MSA-AF (OH, UGF, both) • Early, mid-stage • Large size(>200)

  36. Future MSA TrialsEndpoints • Motor • Autonomic • Cognitive • Psychiatric • QoL/pharmacoeconomics

  37. Future MSA TrialsLogistics • Funds EU (7FP/Horizon 2020), NIH • Academic networks EMSA, US-ADRC, JAMSA • Registries EMSA-R, GLOMSAR Important: Support by national MSA groups incl. UK MSA Trust, Belgian/Dutch/French/German MSA Societies, US MSACoalition, US MSA Awareness, US Fight MSA Initiative

  38. Division ofNeurobiologyDepartment ofNeurologyMedical University Innsbruck

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