Clinical Research Strategies in MSA Gregor K. Wenning MD PhD MSC Division of Neurobiology Department of Neurology & Neurosurgery Medical University Innsbruck

Clinical Research Strategies in MSA

Gregor K. Wenning MD PhD MSCDivision of NeurobiologyDepartment of Neurology & NeurosurgeryMedical University [email protected]

JiePieAward, BrusselsOctober 2nd, 2014

EMSA Sites 10 / 2014

24 Study Sites in 12 EU Countries + Israel

www.emsa-sg.org

EMSA Registry

Köllensperger et al., 2010

• 436 consecutive patients recruited

• Mean age at disease onset: 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%

EMSA Registry


Pharmacological Treatment

• Autonomic failure

• Orthostatic symptoms treated in 27%

• Midodrine – 69%

• Fludrocortisone – 25%

• Urinary dysfunction treated in 19%

• Tolterodine – 52%

• Oxybutinin – 45%

• Parkinsonism

• L-Dopa – 73% (beneficial response in 38%)

• DA – 29%

• MAO-B inihbitors – 11%

EMSA Registry


Under-Treatment

Trial considerations

• Progression of motor impairment

• Progression of non-motor impairment

• Progression of global disability

• Worsening of Hr-QoL

• Progression of surrogate markers

Male : female 13 : 21 Age (yrs) 64.0 ± 7.1 Age at symptom onset (yrs)

59.9 ± 6.6

Disease duration at baseline (yrs)

4.1 ± 3.1

Follow-up duration (months)

11.8 ± 1.4

UPDRS III progression in MSA-P

H&Y

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)

Seppi K et al, 2005

Annual UPDRS-III increase in PD: 1.5% ranging from 0.6-4.5

Olanow 1995; Louis 1999; Goetz 2000; Jankovic 2001


59.9 ± 6.6


4.1 ± 3.1


11.8 ± 1.4

H&Y


59.9 ± 6.6


4.1 ± 3.1


11.8 ± 1.4

H&Y

EMSA – Natural History

Wenning et al. 2013

Baseline

• Minimal Data Set

• Rating Scales (UMSARS, H&Y, S&E, EQ5D, ...)

• Red Flag Screen

6-Months



• Red Flag Screen

12-Months



• Red Flag Screen

18-Months



• Red Flag Screen

24-Months



• Red Flag Screen

EMSA - Natural HistoryN 141Diagnostic certainty

Possible (%) 19.9Probable (%) 77.3

SexFemale (%) 44.0Male (%) 56.0

AgeStudy entry (years, mean ± SD) 62.1 ± 7.7Disease-onset (years, mean ± SD) 56.2 ± 8.4Disease duration baseline (years, mean ± SD) 5.5 ± 3.8

Global disability scale (mean ± SD) 2.3 ± 0.7Schwab & England ADL (mean ± SD) 4.9 ± 2.2Hoehn & Yahr Parkinson (mean ± SD) 3.7 ± 1.0Symptomatic autonomic dysfunction (%) 96.5Parkinsonism (%) 90.8

Beneficial L-Dopa Response(%) 31.2Response duration (years, mean ± SD) 3.5 ± 2.7

Ataxia (%) 71.6

Wenning et al., 2013





0%

10%

20%

30%

40%

50%

60%

6-Months 12-Months 18-Months 24-Months

ADL MEPer Protocol Analysis

UMSARS Progression Clinical Milestones

EMSA supported sample sizecalculation for trials


30% effect size 159 patients per group (80% power)

30% effect size 186 patients per group (80% power)

Factors associated with rapid progression of motor impairment in MSA

• Lower baseline impairment Seppi et al, 2005

• Absent L-Dopa response Wenning et al, 2013

• Short disease duration Seppi et al, 2005; Geser et al, 2006; Wenning et al, 2013

• Cerebellar features at baseline Geser et al, 2006







Progression of self perceived dysautonomia in MSA

6 months







H&Y progression in pathologically confirmed parkinsonian disordes

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

N = 18; 13; 11; 15; 24

PD

MSADLBPSP

0

20

40

60

80

100

Cas

es (

%)

PD CBD DLB MSA PSP

Diagnosis

HY I

HY II

HY III

H&Y I

H&Y II

H&Y III

PD CBD DLB MSA PSP

Ca

se

s (

%)

H&Y stages within 1 year of motor onset H&Y progression

N = 81

PROGRESSION IN MSADisability-milestones

MEDIAN TIME TO years

Walking aids 3 – 5

Wheelchair 5 – 6

Bedridden state 8

Death 9.0 – 9.5

· approx. 50-60% of patients wheelchair-bound at 5 years· Survival rate at 5 years approx. 84% · Survival rate at 10 years approx. 40%

Wenning et al. 1994, N=100; Watanabe et al. 2002, N=230







Health-related Quality of Life in MSA(Schrag et al, 2006)

- 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)







• Dopamine D2R DA-D2R-Imaging

(IBZM-SPECT,

Raclopride-PET)• Striatal glucose metabolism FDG-PET • Dopamine transporter DAT-SPECT

(beta-CIT, FP-CIT)• Striatal LD metabolism F-DOPA-PET• Activated microglia PK11195-PET• Basal ganglia atrophy MRT, MRV• Putaminal diffusivity DWI (ADCs)• CSF/Plasma Biomarkers

SURROGATE ENDPOINTS IN MSAConsiderations

Completed Interventional Trials

rhGH Trial: Negative- trophic factor support -

Holmberg et al. 2007, Aberg et al. 2000

Study design: Double-blind RCT

Primary outcome: UPDRS (52 weeks)

N 43

Phase: Phase 2

PI: B. Holmberg

Current Status: Published

Study identifier: Not registered

Minocycline (MEMSA): Negative- microglial de-activation -

Stefanova et al. 2007, Dodel et al. 2010


Primary outcome: UMSARS II (48 weeks)

N 63

Phase: Phase 3

PI: W. H. Oertel


Study identifier: NCT00146809

CD11b + Cresylviolet

PK11195-PET

Riluzole (NNIPPS): Negative- anti-glutamatergic efficacy -

Scherfler et al. 2005, Diguet et al. 2005, Bensimon et al., 2009


Primary outcome: Survival

N 398

Phase: Phase 3

PI: P. N. Leigh



Rasagiline: Negative- neuronal protection -

MSA

MSA+R 2.5

MSA

MSA+R 2.5

Cytochrome c releaseCaspase activation

Opening of MPTP pore

Apoptosis -

-

- -


Primary outcome: ∆ UMSARS (48 weeks)

N 174

Phase: Phase 2

PI: W. Poewe

Current Status: Completed

Study identifier: NCT00977665Stefanova et al. 2008, Poewe et al. 2012 (Poster 1182)

Mesenchymal Stem Cells - cell replacement -

Lee et al 2012


Primary outcome: UMSARS (52 weeks)

N 27

Phase: Phase 2

PI: P. H Lee



Intravenous immunoglobulins- Immunomodulation -

Study design: Open label

Primary outcome: Safety

N 9

Phase: Phase 2

PI: P. Novak



Ongoing Interventional Trials

Rifampicin- α-synuclein clearance -

Ubhi et al. 2008


Primary outcome: ∆ UMSARS (52 weeks)

N 100

Phase: Phase 3

PI: P. Low, S. Gilman, D. Robertson

Current Status: Data analysis


Fluoxetine- trophic factor restoration -

Study design: Double-blind RCTPrimary outcome:

∆ UMSARS (52 weeks)

N 87Phase: Phase 2PI: O. RascolCurrent Status: Data analysisStudy identifier: NCT01146548

Ubhi et al. 2012

Future MSA TrialsTargets

• Toxic alpha Synuclein species („prion-like“)• Oligodendroglia versus neurons• Oxidative stress (CoQ 2 mutations)• Neuroinflammation

Future MSA TrialsDesign

• Placebo-controlled vs open label• Parallel group vs cross over• Large versus small• Other?

Future MSA TrialsPopulation

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

Future MSA TrialsEndpoints

• Motor • Autonomic• Cognitive• Psychiatric• QoL/pharmacoeconomics

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 MSA Coalition, US MSA Awareness, US Fight MSA Initiative

Division of NeurobiologyDepartment of Neurology

Medical University Innsbruck

Documents

Clinical Research Strategies in MSA Gregor K. Wenning MD PhD MSC Division of Neurobiology Department of Neurology & Neurosurgery Medical University Innsbruck