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Treatement in progressive MS

1) Clinical trials in progressive multiple sclerosis (MS) face many challenges due to heterogeneity of the condition and unclear pathological mechanisms. 2) Current trials are exploring therapies targeting inflammation, neuroprotection, and repair, with mixed results. Adaptive trial designs may help overcome challenges. 3) Future research priorities include better defining MS phenotypes, identifying pathological drivers of progression, and developing biomarkers to aid trial design and measure treatment response. Several promising therapies are now in late-stage clinical testing.

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Clinical trials in secondary and primary progressive MS Current challenges and future directions Alan Thompson UCL and MSIF 16th State of the Art Symposium Lucerne January 2014
• Introduction • Challenges • Current activity • Future directions
Natural History RR-MS SP-MS Preclinical Relapses and Impairment MRI Activity Brain Atrophy 0 5-10 15-20+ Disease Duration (Years) 10 FDA-approved therapies 1 FDA-approved therapy (mitoxantrone - rarely used) SPMS (and PPMS) represents a significant unmet clinical need Why such failure with Prog MS?
Scalfari et al Neurology 2011 Development of secondary progression is the dominant determinant of long-term prognosis, independent of disease duration and early relapse frequency
Scalfari et al Neurology 2011 Onset of progressive phase determines disability
How the James Lind Alliance Works The JLA facilitates Priority Setting Partnerships. These bring patients, carers and clinicians together to identify and prioritise for research the treatment uncertainties which they agree are the most important. The JLA believes that: • Addressing uncertainties about the effects of treatments should become accepted as a much more routine part of clinical practice • Patients, carers and clinicians should work together to agree which, among those uncertainties, matter most and thus deserve priority attention • Prioritise the top 10 uncertainties… that they agree are most important.
The Top 10 1. Which treatments are effective to slow, stop or reverse the accumulation of disability associated with MS? i.e. TREAT PROGRESSION 2. How can MS be prevented? 3. Which treatments are effective for fatigue in people with MS? 4. How can people with MS be best supported to self-manage their condition? 5. Does early treatment with aggressive disease modifying drugs improve prognosis? 6. Is Vitamin D supplementation an effective disease modifying treatment for MS? 7. Which treatments are effective to improve mobility for people with MS? 8. Which treatments are effective to improve cognition in people with MS? 9. Which treatments are effective for pain in people with MS? 10. Is physiotherapy effective in reducing disability in people with MS?
1. Delayed Progression 2. Stabilised Progression 3. Improved Function 4. Recovered Function
WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS? 9 1 2 3 www.ms-res.org
Efforts Underway 2012 Global Progressive MS Portfolio Plus ~45 interventional clinical trials currently recruiting patients (www.clinicaltrials.gov) $85.5 M USD
• Introduction • Challenges • Current activity • Future directions
• Defining phenotype • Clarifying pathological mechanisms underpinning progression • Identifying targets • Outcomes/Biomarkers • Trial design Challenges
Defining Progressive MS • Neurologist – accumulation of disability, – gradual change over time (Progressive myelopathy) • Imager: – Progressive atrophy, expanding lesions – Reduced MTR, NAA, fractional anisotropy • Pathologist: – Axonal pathology – Oligodendrocyte pathology • Patient: – Loss of independence – Inability to work, worsening symptoms Progressive MS is defined differently from different perspectives
Multiple Sclerosis Phenotypes: Toward More Biologically-Relevant Definitions New York City – 26/27 October 2012 A Project of the International Advisory Committee on Clinical Trials in MS Sponsored by the National Multiple Sclerosis Society (NMSS) and the European Committee for Treatment and Research in MS (ECTRIMS)
Main conclusions • Relapsing/Remitting, Primary Progressive, Secondary Progressive • Active/in-active • Progressing/non-progressing • Terms => replace sustained with confirmed => selective use of term “Progressing”
Possible pathological correlates of progression  Slowly expanding pre-existing lesions  Persistent microglial activation  Compartmentalized inflammation  B cell/antibody involvement  Remyelination failure  Axonal/neuronal loss  Cortical/gray matter involvement  Changes in the NAWM
Key areas Inflammation White matter demyelination/remyelination Gray matter involvement Axonal loss
MRI in primary progressive MS Thompson et al. Ann Neurol 1991
Brain Enhancement • 42% patients with early PPMS (< 5 years) had at least one enhancing lesion on their baseline scan • Number of enhancing lesions associated with - younger age (r=0.5, p= 0.003) - higher T2 load (r= 0.5, p=0.02) - worse outcome!
Bradl and Lassmann, Semin Immunopathol 2009 Compartmentalized inflammation in progressive MS Inflammation behind a closed (repaired) blood–brain barrier
0 5 10 15 20 25 30 Years After MS Onset Pathologic Mechanisms in Early vs. Late MS
Key areas Inflammation White matter demyelination/remyelination Gray matter involvement Axonal loss
More extensive spinal cord demyelination in SPMS compared to PPMS Tallantyre et al., Brain 2009
Key areas Inflammation White matter demyelination/remyelination Gray matter involvement Axonal loss
Cortical demyelination is extensive in progressive MS RRMS SPMS/ PPMS Kutzelnigg et al., Brain 2005 Cortical lesion area forebrain (%) White matter lesion area (%) RRMS 2.96 10.3 PPMS 12.54 6.54 SPMS 13.29 24.13
High cortical lesion load at baseline High number of new CLs High rate of GM atrophy progression Characterize patients with disability progression after 5 yrs
Key areas Inflammation White matter demyelination/remyelination Gray matter involvement Axonal loss
Spinal cord axonal loss correlates with disease duration and disability Schirmer et al., Brain Pathol 2011
Tallantyre et al., Brain 2009 Greater axonal loss in PPMS spinal cord
Neurodegeneration in MS Inflammation Mitochondrial Injury / Energy Deficiency Functional Disturbance Tissue Degeneration Oligodendrocytes > thin axons > neurons > others) ROS / RNI production DNA Damage Microglia / Astroglia Activation Oxidative Burst PARP / AIF Trigger ? Trigger ? Cytokines ? Liberation of Free Iron from Cellular Stores Microglia activation due to pre-existing CNS damage
• Clinical • Imaging • OCT • CSF/Serum Outcomes/Biomarkers
MS Outcomes Assessments Consortium (MSOAC) – Collaboration of academic, industry, regulatory, and patient- advocacy representatives – Supported by the US National MS Society – Coordinated by the C-Path - a nonprofit, public-private partnership with the Food and Drug Administration (FDA), created in 2005 under the auspices of FDA's Critical Path Initiative. – Mission: to develop, gain regulatory approval, and support adoption of a new clinician-reported outcome measure for use in future MS clinical trials
Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
Natalizumab treatment of progressive multiple sclerosis reduces inflammation and tissue damage - results of a phase 2A proof-of-concept study ClinicalTrials.gov Identifier: NCT01077466 J. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1
Phase 2A study: CSF markers of axonal damage and demyelination (secondary endpoints) Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170. NIND Mean +/- 95% CI p=0.03 CSFNeurofilamentllightng/L p=0.048 CSFMBPng/ml NIND Mean +/- 95% CI
Clinical Trials Conventional trial design • Large numbers • Lengthy • Very expensive Targeting inflammation (largely) => Need to consider new trial designs => Need to focus on neuroprotection/repair?
Placebo Treatment A Placebo Treatment B Placebo Treatment C Moving to adaptive trials
The interim measure 0 0 6 12 18 24 30 36 MRI EDSS Interim Δ MRI Δ EDSS
• Introduction • Challenges • Current activity • Future directions
Previous trials
ProportionofPatients Rituximab Placebo Time to Confirmed Disease Progression (weeks) Time to Confirmed Disease Progression All Intent-to-Treat Patients (N=439) 0 12 24 36 48 60 72 84 96 108 10 20 30 40 50 HR: 0.77 (95% CI: 0.55 -1.09) p-value=0.1442
ProportionofPatients Rituximab Placebo Time to Confirmed Disease Progression (weeks) Time to Confirmed Disease ProgressionSubgroup Analysis 0 12 24 36 48 60 72 84 96 108 10 20 30 40 50 0 12 24 36 48 60 72 84 96 108 10 20 30 40 50 Age <51 Gd (+) at Baseline n=72 HR: 0.63 (95% CI: 0.34-1.18) p=0.1427 HR: 0.33 (95% CI: 0.14-0.79) p=0.0088 Age <51 Gd (-) at Baseline n=143
– Phenytoin Optic Neuritis Study (Phase II) – PROXIMUS Trial - oxcarbazepine in SPMS (Phase II) – INFORMS – fingolimod in SPMS (Phase III) – ASCEND – natalizumab in SPMS (Phase III) – ORATORIO – ocrelizumab (rituximab cousin ) in PPMS (Phase III) – EXPAND – siponimod (fingolimod cousin) in SPMS (Phase III) – MS Smart Trial – riluzole, amiloride, ibudilast in SPMS (Phase II) – SPRINT-MS – ibudilast in PPMS/SPMS (Phase II) – MS – STAT – high dose simvastatin – CUPID - cannabinoids – rituximab, mesenchymal stem cells, mastitinib, lipoic acid, erythropoietin, hydroxyurea, idebenone
48 Ocrelizumab in PPMS Phase III study (Oratorio) Design • Global, randomised, double-blind, placebo-controlled of 120 weeks duration Treatment • Ocrelizumab: 2 × 300 mg (600 mg) iv q24w v Placebo Target sample size • 630 patients (2:1 randomisation) Primary end point Time to sustained disability progression, with confirmation at least 12 weeks after initial disease progression Secondary end points • Time to confirmed disease progression, with confirmation at least 24 weeks after initial disease progression • Change from baseline to Week 120 in 25-foot Walk • Change from baseline to Week 120 in the total volume of T2 lesions
MS-STAT trial High dose oral Simvastatin in Secondary Progressive Multiple Sclerosis Jeremy Chataway for the MS-STAT Collaborators Lancet in press
• High-dose simvastatin (80mg) in SPMS • Established secondary progression (narrative/EDSS) for ≥ 2years • EDSS 4.0 (500m) - 6.5 (20m/2 sticks) – Relapse free/no corticosteroids >3 months – DMT >6months – Mitoxantrone >12 months – Never alemtuzumab/natalizumab
Outcomes • Primary – Volumetric MRI BBSI • Secondary – Disability (EDSS/MSIS-29v2/MSFC) – New and enlarging lesions T2 MRI – Relapses – Safety • Other* – Neuropsychology – Immunology/Proteomics
Baseline
Registered Year 2
Screening showing BBSI colour overlay
Primary outcome: BBSI change in whole brain volume (%/year) *Adjusting for minimisation variables and MRI site Mean (SD) placebo Mean (SD) simvastatin Difference in means (95% CI)* p-value Change WBV (%/year) 0.589 (0.528) 0.298 (0.562) -0.254 (-0.423 to -0.085) 0.003 Number patients evaluated 64 66
Change whole brain volume (%/yr)
Change in EDSS 0 to 24 months Change in EDSS from Baseline to 24 months
Cannabinoid trials N=657 CAMS 12 month follow-up (80%) Zajicek Lancet 2003; JNNP 2005
Aims of CUPID study • assess the value of Δ9-THC in slowing progressive MS over 3 yrs • assess the safety of Δ9-THC over the long-term. • improve research methodology; using new, patient-orientated methods.
CUPID (THC): EDSS progression over 3 years Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X. Treatment group Placebo Active 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 1200 P(EDSSprogression) Time to EDSS progression (days)
CUPID (THC): EDSS progression according to baseline EDSS score Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X. Baseline EDSS score 6.5 5 5.5 4.5 4 6 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 1200 P(EDSSprogression) Time to EDSS progression (days)
Log rank test P = 0.01 CUPID (THC): EDSS progression in patients with baseline EDSS <6 (post-hoc analysis) Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X. n = 110 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 1200 P(EDSSprogression) Time to EDSS progression (days) Treatment group Placebo Active
• Introduction • Challenges • Current activity • Future directions
Neuroprotection Repair/Remyelination Lifestyle Rehabilitation Enhancing plasticity
Kapoor et al. Lancet Neurol 2010; 9: 681–88.
Kapoor et al. Lancet Neurol 2010; 9: 681–88.
MS-STOP>>MS-SMART 4 arms [1 placebo + 3 active] Multiplex Phase IIb trial – 4*110=440 – allowing for drop-outs [10%+10%] – Primary outcome = SIENA PBVC – Gives 90% power for 35% treatment effect
Amiloride blockade of the acid-sensing ion channel is myelo- and neuro-protective in CNS inflammation Amiloride Amiloride Slide courtesy of M Craner
Amiloride treatment in primary progressive MS Atrophy rate reduced in amiloride treated (p = 0.018) Amiloride reduced rate of white and grey matter damage (p < 0.01) Slide courtesy of M Craner
Ibudilast trial (relapsing remitting MS) • Phosphodiesterase and MIF inhibitor • Placebo-controlled 2 year trial, mainly RRMS, 100 per arm • No effect on new Gd, T2 lesions or relapses • Significant decrease in – Brain atrophy (30%) – EDSS progression Barkhof et al Neurology 2010
 96-week, randomized, placebo-controlled phase II trial of ibudilast (PDE- and MIF-inhibitor) in SPMS/PPMS  Concurrent treatment with IFN-β1 or GA is allowed  Primary Outcome: whole brain atrophy (BPF)  Secondary Outcomes:  DTI (descending pyramidal tracts)  MTR (whole brain)  OCT (retinal nerve fiber layer)  Cortical atrophy (CLADA)  Standardized 3T imaging at all sites  EDSS, MSFC-4, PROs  Utilize NeuroNEXT, an US-based, NIH-funded Phase II clinical trial network Head-to-head comparison of imaging measures  Longitudinal validation to clinical outcomes Secondary and Primary pRrogressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis
Visual Outcomes in SPRINT-MS • Primary OCT outcome: mean change in peripapillary RNFL • Cirrus or Spectralis SD-OCT at all sites – 5 time points: Screening, W24, W48, W72, W96 – Acquisitions: Peripapillary/Optic Disc and Macular – Central OCT Reading Center (R. Bermel, Cleveland Clinic) • Exploratory outcomes: – ganglion cell layer thickness – total macular volume – macular RNFL • Correlation with visual acuity – 100% and 2.5% contrast
Acute neuroprotection
MSC Treatment of Multiple Sclerosis Reference Indication Patients MSC Source Connick 2012 SPMS 10 Autologous culture-expanded BM MSCs administered IV Karussis 2010 RR, SP, PP MS 15 Autologous culture-expanded BM MSCs administered IV and IT Liang 2009 PP MS 1 Allogeneic umbilical cord MSCs administered IV and IT after CTX Mohyeddin Bonad 2007 Treatment-refractory MS 10 Autologous culture-expanded BM MSCs administered IT Rice 2010 Chronic MS 6 Fresh BM cells enriched for MSCs Riordan 2009 Treatment-refractory MS 3 Autologous non-expanded adipose MSCs Yamout 2010 SPMS 10 Autologous culture-expanded BM MSCs administered IT
Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study Peter Connick, Madhan Kolappan, Charles Crawley,Daniel J Webber, Rickie Patani, Andrew W Michell,Ming-Qing Du, Shi-Lu Luan, Daniel R Altmann, Alan J Thompson, Alastair Compston, Michael A Scott, David H Miller, Siddharthan Chandran Lancet Neurology Feb 2012 10 patients with secondary progressive MS Studied visual system
Autologous mesenchymal stem cells in secondary progressive MS • 10 SPMS patients with previous optic neuritis • Studied pre- and post stem cell Rx • Significant improvement of visual acuity (unblinded) • Laboratory evidence for remyelination (blinded) – ↓VEP latency (p=0.016) & ↑optic nerve area (p=0.006) Connick et al Lancet Neurology 2012
• Constitution of IMSCT Study Group (Paris, March 2009) supported by CMSC ,Canadian MS Society and ECTRIMS • Consensus paper set the guidelines for phase I/II clinical trials of MSCT in MS • Consensus paper on the utilization of MSCs for the treatment of MS published in Mult. Scler. 2010
• Centralized protocol, inclusion / exclusion criteria and outcomes adopted by international clinical centers • Robust sample size (~160 subjects) to get conclusive data on the safety and efficacy of MSCT in MS. • Number of centers involved ( ≥10 ) • Duration of the study: two years (including enrollment) • Contract Research Organization (CRO) for data collection • Clinical Research Associate (CRA) to support coordination • Centralized MRI reading • Blinded centralized data analysis MESEMS Trial
Mission: To expedite the development of effective disease modifying and symptom management therapies for progressive forms of multiple sclerosis PROGRESSIVE MS ALLIANCE MANAGING MEMBERS
Initial discussions identified 5 priority areas:  Experimental Models  Target pathways and drug repurposing  Proof of concept trials (phase II)  Phase III clinical trials & outcome measures  Symptom management and rehabilitation
April - August 2012 November 2012 February 2013 Research community engagement – working groups to fill gaps, propose strategies and funding models First International Scientific Conference on Progressive MS Working groups present recommendations to Steering committee Timeline and milestones Sept 2013 First Request for Applications (RFA) by Alliance
Scientific Steering Committee * Alan Thompson, UK, Chair Giancarlo Comi, Italy , co-Chair * Timothy Coetzee, USA * Bruce Bebo, USA * Kathy Smith, USA Robert Fox, USA * Paola Zaratin, Italy Marco Salvetti, Italy Peer Baneke, MSIF * Dhia Chandraratna, MSIF * Ceri Angood, MSIF Nick de Rijke, UK * Susan Kolhaas, UK Raj Kapoor, UK Inga Huitinga, Netherlands Kim Zuitwijk, Netherlands * Karen Lee, Canada Anthony Feinstein, Canada
Countries actively involved in the Alliance
REQUEST FOR APPLICATIONS (RFA) CHALLENGES IN PROGRESSIVE MS AWARDS - encourage scientific innovation in: • Phenotype/Genotype and pathophysiological mechanisms • Development of new and existing pre-clinical models for progressive disease based on community consensus building • Discovery and validation of proof of concept biomarkers • Innovative designs for proof of concept trials of therapeutic agents or therapeutic strategies
2. INFRASTRUCTURE AWARDS - to develop enabling technologies and infrastructure for data sharing to: • promote and enhance data sharing and knowledge management • encourage collaboration among researchers • support one or more of the Alliance priority research areas Awards - €75,000 for 12 months REQUEST FOR APPLICATIONS (RFA)
REQUEST FOR APPLICATIONS (RFA) May 2014 July 2014 APPLICATIONS DUE 31 January 2013 PRE-APPLICATIONS DUE 15 January 2013 ANNOUNCEMENT OF DECISIONS START http://www.endprogressivems.org
2013 – 2021 PLAN 2013 – 2017 HORIZON 1 2017 – 2021 HORIZON 2/3 CHALLANGES AWARDS 2013 - 2016 INNOVATIVE OPERATIVE FUNDING MODELS TO ACELERATE RESEARCH COLLABORATIVE TEAM AWARDS 2014 - 2017 Long term commitment towards PMSA goal
Challenges ahead • Understand relevant aspects of human MS pathology – Validate a pre-clinical model that emulates human pathology – Develop high through-put screening tools • Validate a Phase II outcome biomarker – Use trials to advance methodology • Develop accepted clinical outcome measures • Not forget about symptomatic treatments • Expand international collaboration

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Treatement in progressive MS

  • 1.
    Clinical trials insecondary and primary progressive MS Current challenges and future directions Alan Thompson UCL and MSIF 16th State of the Art Symposium Lucerne January 2014
  • 2.
    • Introduction • Challenges •Current activity • Future directions
  • 3.
    Natural History RR-MS SP-MS Preclinical Relapses and Impairment MRIActivity Brain Atrophy 0 5-10 15-20+ Disease Duration (Years) 10 FDA-approved therapies 1 FDA-approved therapy (mitoxantrone - rarely used) SPMS (and PPMS) represents a significant unmet clinical need Why such failure with Prog MS?
  • 4.
    Scalfari et alNeurology 2011 Development of secondary progression is the dominant determinant of long-term prognosis, independent of disease duration and early relapse frequency
  • 5.
    Scalfari et alNeurology 2011 Onset of progressive phase determines disability
  • 6.
    How the JamesLind Alliance Works The JLA facilitates Priority Setting Partnerships. These bring patients, carers and clinicians together to identify and prioritise for research the treatment uncertainties which they agree are the most important. The JLA believes that: • Addressing uncertainties about the effects of treatments should become accepted as a much more routine part of clinical practice • Patients, carers and clinicians should work together to agree which, among those uncertainties, matter most and thus deserve priority attention • Prioritise the top 10 uncertainties… that they agree are most important.
  • 7.
    The Top 10 1.Which treatments are effective to slow, stop or reverse the accumulation of disability associated with MS? i.e. TREAT PROGRESSION 2. How can MS be prevented? 3. Which treatments are effective for fatigue in people with MS? 4. How can people with MS be best supported to self-manage their condition? 5. Does early treatment with aggressive disease modifying drugs improve prognosis? 6. Is Vitamin D supplementation an effective disease modifying treatment for MS? 7. Which treatments are effective to improve mobility for people with MS? 8. Which treatments are effective to improve cognition in people with MS? 9. Which treatments are effective for pain in people with MS? 10. Is physiotherapy effective in reducing disability in people with MS?
  • 8.
    1. Delayed Progression2. Stabilised Progression 3. Improved Function 4. Recovered Function
  • 9.
    WHAT ARE YOUR EXPECTATIONSOF A THERAPY FOR PROGRESSIVE MS? 9 1 2 3 www.ms-res.org
  • 11.
    Efforts Underway 2012 Global ProgressiveMS Portfolio Plus ~45 interventional clinical trials currently recruiting patients (www.clinicaltrials.gov) $85.5 M USD
  • 12.
    • Introduction • Challenges •Current activity • Future directions
  • 13.
    • Defining phenotype •Clarifying pathological mechanisms underpinning progression • Identifying targets • Outcomes/Biomarkers • Trial design Challenges
  • 14.
    Defining Progressive MS • Neurologist –accumulation of disability, – gradual change over time (Progressive myelopathy) • Imager: – Progressive atrophy, expanding lesions – Reduced MTR, NAA, fractional anisotropy • Pathologist: – Axonal pathology – Oligodendrocyte pathology • Patient: – Loss of independence – Inability to work, worsening symptoms Progressive MS is defined differently from different perspectives
  • 15.
    Multiple Sclerosis Phenotypes:Toward More Biologically-Relevant Definitions New York City – 26/27 October 2012 A Project of the International Advisory Committee on Clinical Trials in MS Sponsored by the National Multiple Sclerosis Society (NMSS) and the European Committee for Treatment and Research in MS (ECTRIMS)
  • 16.
    Main conclusions • Relapsing/Remitting,Primary Progressive, Secondary Progressive • Active/in-active • Progressing/non-progressing • Terms => replace sustained with confirmed => selective use of term “Progressing”
  • 17.
    Possible pathological correlatesof progression  Slowly expanding pre-existing lesions  Persistent microglial activation  Compartmentalized inflammation  B cell/antibody involvement  Remyelination failure  Axonal/neuronal loss  Cortical/gray matter involvement  Changes in the NAWM
  • 18.
    Key areas Inflammation White matterdemyelination/remyelination Gray matter involvement Axonal loss
  • 19.
  • 20.
    Brain Enhancement • 42% patientswith early PPMS (< 5 years) had at least one enhancing lesion on their baseline scan • Number of enhancing lesions associated with - younger age (r=0.5, p= 0.003) - higher T2 load (r= 0.5, p=0.02) - worse outcome!
  • 21.
    Bradl and Lassmann, SeminImmunopathol 2009 Compartmentalized inflammation in progressive MS Inflammation behind a closed (repaired) blood–brain barrier
  • 22.
    0 5 1015 20 25 30 Years After MS Onset Pathologic Mechanisms in Early vs. Late MS
  • 23.
    Key areas Inflammation White matterdemyelination/remyelination Gray matter involvement Axonal loss
  • 24.
    More extensive spinalcord demyelination in SPMS compared to PPMS Tallantyre et al., Brain 2009
  • 25.
    Key areas Inflammation White matterdemyelination/remyelination Gray matter involvement Axonal loss
  • 26.
    Cortical demyelination is extensivein progressive MS RRMS SPMS/ PPMS Kutzelnigg et al., Brain 2005 Cortical lesion area forebrain (%) White matter lesion area (%) RRMS 2.96 10.3 PPMS 12.54 6.54 SPMS 13.29 24.13
  • 27.
    High cortical lesionload at baseline High number of new CLs High rate of GM atrophy progression Characterize patients with disability progression after 5 yrs
  • 28.
    Key areas Inflammation White matterdemyelination/remyelination Gray matter involvement Axonal loss
  • 29.
    Spinal cord axonalloss correlates with disease duration and disability Schirmer et al., Brain Pathol 2011
  • 30.
    Tallantyre et al.,Brain 2009 Greater axonal loss in PPMS spinal cord
  • 31.
    Neurodegeneration in MS Inflammation Mitochondrial Injury/ Energy Deficiency Functional Disturbance Tissue Degeneration Oligodendrocytes > thin axons > neurons > others) ROS / RNI production DNA Damage Microglia / Astroglia Activation Oxidative Burst PARP / AIF Trigger ? Trigger ? Cytokines ? Liberation of Free Iron from Cellular Stores Microglia activation due to pre-existing CNS damage
  • 32.
    • Clinical • Imaging •OCT • CSF/Serum Outcomes/Biomarkers
  • 33.
    MS Outcomes AssessmentsConsortium (MSOAC) – Collaboration of academic, industry, regulatory, and patient- advocacy representatives – Supported by the US National MS Society – Coordinated by the C-Path - a nonprofit, public-private partnership with the Food and Drug Administration (FDA), created in 2005 under the auspices of FDA's Critical Path Initiative. – Mission: to develop, gain regulatory approval, and support adoption of a new clinician-reported outcome measure for use in future MS clinical trials
  • 35.
    Petzold et al.J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11. Spinal fluid neurofilament levels
  • 36.
    Natalizumab treatment of progressivemultiple sclerosis reduces inflammation and tissue damage - results of a phase 2A proof-of-concept study ClinicalTrials.gov Identifier: NCT01077466 J. Romme Christensen1, R. Ratzer1, L. Börnsen1, E. Garde2, M. Lyksborg2, H.R. Siebner2, T.B. Dyrby2, P. Soelberg Sørensen1 and F. Sellebjerg1
  • 37.
    Phase 2A study:CSF markers of axonal damage and demyelination (secondary endpoints) Romme Christensen J, et al. ECTRIMS 2012. Oral presentation 170. NIND Mean +/- 95% CI p=0.03 CSFNeurofilamentllightng/L p=0.048 CSFMBPng/ml NIND Mean +/- 95% CI
  • 38.
    Clinical Trials Conventional trialdesign • Large numbers • Lengthy • Very expensive Targeting inflammation (largely) => Need to consider new trial designs => Need to focus on neuroprotection/repair?
  • 39.
  • 40.
    The interim measure 0 06 12 18 24 30 36 MRI EDSS Interim Δ MRI Δ EDSS
  • 42.
    • Introduction • Challenges •Current activity • Future directions
  • 43.
  • 45.
    ProportionofPatients Rituximab Placebo Time to ConfirmedDisease Progression (weeks) Time to Confirmed Disease Progression All Intent-to-Treat Patients (N=439) 0 12 24 36 48 60 72 84 96 108 10 20 30 40 50 HR: 0.77 (95% CI: 0.55 -1.09) p-value=0.1442
  • 46.
    ProportionofPatients Rituximab Placebo Time to ConfirmedDisease Progression (weeks) Time to Confirmed Disease ProgressionSubgroup Analysis 0 12 24 36 48 60 72 84 96 108 10 20 30 40 50 0 12 24 36 48 60 72 84 96 108 10 20 30 40 50 Age <51 Gd (+) at Baseline n=72 HR: 0.63 (95% CI: 0.34-1.18) p=0.1427 HR: 0.33 (95% CI: 0.14-0.79) p=0.0088 Age <51 Gd (-) at Baseline n=143
  • 47.
    – Phenytoin OpticNeuritis Study (Phase II) – PROXIMUS Trial - oxcarbazepine in SPMS (Phase II) – INFORMS – fingolimod in SPMS (Phase III) – ASCEND – natalizumab in SPMS (Phase III) – ORATORIO – ocrelizumab (rituximab cousin ) in PPMS (Phase III) – EXPAND – siponimod (fingolimod cousin) in SPMS (Phase III) – MS Smart Trial – riluzole, amiloride, ibudilast in SPMS (Phase II) – SPRINT-MS – ibudilast in PPMS/SPMS (Phase II) – MS – STAT – high dose simvastatin – CUPID - cannabinoids – rituximab, mesenchymal stem cells, mastitinib, lipoic acid, erythropoietin, hydroxyurea, idebenone
  • 48.
    48 Ocrelizumab in PPMS PhaseIII study (Oratorio) Design • Global, randomised, double-blind, placebo-controlled of 120 weeks duration Treatment • Ocrelizumab: 2 × 300 mg (600 mg) iv q24w v Placebo Target sample size • 630 patients (2:1 randomisation) Primary end point Time to sustained disability progression, with confirmation at least 12 weeks after initial disease progression Secondary end points • Time to confirmed disease progression, with confirmation at least 24 weeks after initial disease progression • Change from baseline to Week 120 in 25-foot Walk • Change from baseline to Week 120 in the total volume of T2 lesions
  • 49.
    MS-STAT trial High doseoral Simvastatin in Secondary Progressive Multiple Sclerosis Jeremy Chataway for the MS-STAT Collaborators Lancet in press
  • 50.
    • High-dose simvastatin(80mg) in SPMS • Established secondary progression (narrative/EDSS) for ≥ 2years • EDSS 4.0 (500m) - 6.5 (20m/2 sticks) – Relapse free/no corticosteroids >3 months – DMT >6months – Mitoxantrone >12 months – Never alemtuzumab/natalizumab
  • 51.
    Outcomes • Primary – VolumetricMRI BBSI • Secondary – Disability (EDSS/MSIS-29v2/MSFC) – New and enlarging lesions T2 MRI – Relapses – Safety • Other* – Neuropsychology – Immunology/Proteomics
  • 52.
  • 53.
  • 54.
  • 55.
    Primary outcome: BBSIchange in whole brain volume (%/year) *Adjusting for minimisation variables and MRI site Mean (SD) placebo Mean (SD) simvastatin Difference in means (95% CI)* p-value Change WBV (%/year) 0.589 (0.528) 0.298 (0.562) -0.254 (-0.423 to -0.085) 0.003 Number patients evaluated 64 66
  • 56.
  • 57.
    Change in EDSS 0to 24 months Change in EDSS from Baseline to 24 months
  • 58.
    Cannabinoid trials N=657 CAMS 12month follow-up (80%) Zajicek Lancet 2003; JNNP 2005
  • 59.
    Aims of CUPIDstudy • assess the value of Δ9-THC in slowing progressive MS over 3 yrs • assess the safety of Δ9-THC over the long-term. • improve research methodology; using new, patient-orientated methods.
  • 60.
    CUPID (THC): EDSSprogression over 3 years Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X. Treatment group Placebo Active 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 1200 P(EDSSprogression) Time to EDSS progression (days)
  • 61.
    CUPID (THC): EDSSprogression according to baseline EDSS score Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X. Baseline EDSS score 6.5 5 5.5 4.5 4 6 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 1200 P(EDSSprogression) Time to EDSS progression (days)
  • 62.
    Log rank testP = 0.01 CUPID (THC): EDSS progression in patients with baseline EDSS <6 (post-hoc analysis) Zajicek J, et al. ECTRIMS 2012. Oral presentation 161X. n = 110 0.0 0.2 0.4 0.6 0.8 1.0 0 200 400 600 800 1000 1200 P(EDSSprogression) Time to EDSS progression (days) Treatment group Placebo Active
  • 63.
    • Introduction • Challenges •Current activity • Future directions
  • 64.
  • 65.
    Kapoor et al.Lancet Neurol 2010; 9: 681–88.
  • 66.
    Kapoor et al.Lancet Neurol 2010; 9: 681–88.
  • 67.
    MS-STOP>>MS-SMART 4 arms [1placebo + 3 active] Multiplex Phase IIb trial – 4*110=440 – allowing for drop-outs [10%+10%] – Primary outcome = SIENA PBVC – Gives 90% power for 35% treatment effect
  • 69.
    Amiloride blockade ofthe acid-sensing ion channel is myelo- and neuro-protective in CNS inflammation Amiloride Amiloride Slide courtesy of M Craner
  • 70.
    Amiloride treatment in primary progressive MS Atrophyrate reduced in amiloride treated (p = 0.018) Amiloride reduced rate of white and grey matter damage (p < 0.01) Slide courtesy of M Craner
  • 71.
    Ibudilast trial (relapsing remitting MS) •Phosphodiesterase and MIF inhibitor • Placebo-controlled 2 year trial, mainly RRMS, 100 per arm • No effect on new Gd, T2 lesions or relapses • Significant decrease in – Brain atrophy (30%) – EDSS progression Barkhof et al Neurology 2010
  • 72.
     96-week, randomized,placebo-controlled phase II trial of ibudilast (PDE- and MIF-inhibitor) in SPMS/PPMS  Concurrent treatment with IFN-β1 or GA is allowed  Primary Outcome: whole brain atrophy (BPF)  Secondary Outcomes:  DTI (descending pyramidal tracts)  MTR (whole brain)  OCT (retinal nerve fiber layer)  Cortical atrophy (CLADA)  Standardized 3T imaging at all sites  EDSS, MSFC-4, PROs  Utilize NeuroNEXT, an US-based, NIH-funded Phase II clinical trial network Head-to-head comparison of imaging measures  Longitudinal validation to clinical outcomes Secondary and Primary pRrogressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis
  • 73.
    Visual Outcomes inSPRINT-MS • Primary OCT outcome: mean change in peripapillary RNFL • Cirrus or Spectralis SD-OCT at all sites – 5 time points: Screening, W24, W48, W72, W96 – Acquisitions: Peripapillary/Optic Disc and Macular – Central OCT Reading Center (R. Bermel, Cleveland Clinic) • Exploratory outcomes: – ganglion cell layer thickness – total macular volume – macular RNFL • Correlation with visual acuity – 100% and 2.5% contrast
  • 74.
  • 75.
    MSC Treatment of Multiple Sclerosis ReferenceIndication Patients MSC Source Connick 2012 SPMS 10 Autologous culture-expanded BM MSCs administered IV Karussis 2010 RR, SP, PP MS 15 Autologous culture-expanded BM MSCs administered IV and IT Liang 2009 PP MS 1 Allogeneic umbilical cord MSCs administered IV and IT after CTX Mohyeddin Bonad 2007 Treatment-refractory MS 10 Autologous culture-expanded BM MSCs administered IT Rice 2010 Chronic MS 6 Fresh BM cells enriched for MSCs Riordan 2009 Treatment-refractory MS 3 Autologous non-expanded adipose MSCs Yamout 2010 SPMS 10 Autologous culture-expanded BM MSCs administered IT
  • 76.
    Autologous mesenchymal stemcells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study Peter Connick, Madhan Kolappan, Charles Crawley,Daniel J Webber, Rickie Patani, Andrew W Michell,Ming-Qing Du, Shi-Lu Luan, Daniel R Altmann, Alan J Thompson, Alastair Compston, Michael A Scott, David H Miller, Siddharthan Chandran Lancet Neurology Feb 2012 10 patients with secondary progressive MS Studied visual system
  • 77.
    Autologous mesenchymal stem cellsin secondary progressive MS • 10 SPMS patients with previous optic neuritis • Studied pre- and post stem cell Rx • Significant improvement of visual acuity (unblinded) • Laboratory evidence for remyelination (blinded) – ↓VEP latency (p=0.016) & ↑optic nerve area (p=0.006) Connick et al Lancet Neurology 2012
  • 78.
    • Constitution ofIMSCT Study Group (Paris, March 2009) supported by CMSC ,Canadian MS Society and ECTRIMS • Consensus paper set the guidelines for phase I/II clinical trials of MSCT in MS • Consensus paper on the utilization of MSCs for the treatment of MS published in Mult. Scler. 2010
  • 79.
    • Centralized protocol,inclusion / exclusion criteria and outcomes adopted by international clinical centers • Robust sample size (~160 subjects) to get conclusive data on the safety and efficacy of MSCT in MS. • Number of centers involved ( ≥10 ) • Duration of the study: two years (including enrollment) • Contract Research Organization (CRO) for data collection • Clinical Research Associate (CRA) to support coordination • Centralized MRI reading • Blinded centralized data analysis MESEMS Trial
  • 81.
    Mission: To expedite thedevelopment of effective disease modifying and symptom management therapies for progressive forms of multiple sclerosis PROGRESSIVE MS ALLIANCE MANAGING MEMBERS
  • 83.
    Initial discussions identified5 priority areas:  Experimental Models  Target pathways and drug repurposing  Proof of concept trials (phase II)  Phase III clinical trials & outcome measures  Symptom management and rehabilitation
  • 84.
    April - August2012 November 2012 February 2013 Research community engagement – working groups to fill gaps, propose strategies and funding models First International Scientific Conference on Progressive MS Working groups present recommendations to Steering committee Timeline and milestones Sept 2013 First Request for Applications (RFA) by Alliance
  • 85.
    Scientific Steering Committee * AlanThompson, UK, Chair Giancarlo Comi, Italy , co-Chair * Timothy Coetzee, USA * Bruce Bebo, USA * Kathy Smith, USA Robert Fox, USA * Paola Zaratin, Italy Marco Salvetti, Italy Peer Baneke, MSIF * Dhia Chandraratna, MSIF * Ceri Angood, MSIF Nick de Rijke, UK * Susan Kolhaas, UK Raj Kapoor, UK Inga Huitinga, Netherlands Kim Zuitwijk, Netherlands * Karen Lee, Canada Anthony Feinstein, Canada
  • 86.
  • 87.
    REQUEST FOR APPLICATIONS (RFA) CHALLENGES INPROGRESSIVE MS AWARDS - encourage scientific innovation in: • Phenotype/Genotype and pathophysiological mechanisms • Development of new and existing pre-clinical models for progressive disease based on community consensus building • Discovery and validation of proof of concept biomarkers • Innovative designs for proof of concept trials of therapeutic agents or therapeutic strategies
  • 88.
    2. INFRASTRUCTURE AWARDS- to develop enabling technologies and infrastructure for data sharing to: • promote and enhance data sharing and knowledge management • encourage collaboration among researchers • support one or more of the Alliance priority research areas Awards - €75,000 for 12 months REQUEST FOR APPLICATIONS (RFA)
  • 89.
    REQUEST FOR APPLICATIONS (RFA) May 2014July 2014 APPLICATIONS DUE 31 January 2013 PRE-APPLICATIONS DUE 15 January 2013 ANNOUNCEMENT OF DECISIONS START http://www.endprogressivems.org
  • 90.
    2013 – 2021PLAN 2013 – 2017 HORIZON 1 2017 – 2021 HORIZON 2/3 CHALLANGES AWARDS 2013 - 2016 INNOVATIVE OPERATIVE FUNDING MODELS TO ACELERATE RESEARCH COLLABORATIVE TEAM AWARDS 2014 - 2017 Long term commitment towards PMSA goal
  • 91.
    Challenges ahead • Understandrelevant aspects of human MS pathology – Validate a pre-clinical model that emulates human pathology – Develop high through-put screening tools • Validate a Phase II outcome biomarker – Use trials to advance methodology • Develop accepted clinical outcome measures • Not forget about symptomatic treatments • Expand international collaboration