Benefit Risk from a Healthcare Provider Perspectiive

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Benefit Risk from a Healthcare Provider Perspectiive

  1. 1. Disease Management Holistic Approach: Benefit Risk from HCP & Patient Perspective Gavin Giovannoni Barts and The London
  2. 2. Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni. Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.
  3. 3. How much of my time is taken up with DMTs?
  4. 4. 10% 60% 5% 15% 5% DMTs Symptomatic Diagnostic Admin Blog My clinical time
  5. 5. Epstein Bar Virus Genetics Vitamin D Smoking Risks Adverse events Differential Diagnosis MRI Evoked Potentials Lumbar puncture Blood Tests Diagnostic Criteria Cognition Depression Fatigue Bladder Bowel Sexual dysfunction Tremor Pain Swallowing SpasticityFalls Balance problems Insomnia Restless legsFertility Clinical trials Gait Pressure sores Oscillopsia Emotional lability Seizures Gastrostomy Rehab Suprapubic catheter Intrathecal baclofen Physio- therapy Speech therapy Occupational Therapy Functional neurosurgery Colostomy Tendonotomy Studying Employment Relationships Travel Vaccination Anxiety Driving Nurse specialists Family counselling Relapses 1st line 2nd line Maintenance Escalation Induction Monitoring Disease-free Disease progression DMTs Side Effects Advanced Directive Exercise Diet Alternative Medicine Pregnancy Breast Feeding Research Insurance Visual loss Palliative Care Assisted suicide Social services Legal aid Genetic counselling Prevention Diagnosis DMT Symptomatic Therapist Terminal CounsellingAn holistic approach to MS; beta ver. 3.2 Intrathecal phenol Fractures Movement disorders Osteopaenia Brain atrophy Hearing loss Tinnitus Photophobia Hiccoughs DVLA Neuroprotection Psychosis Depersonaliation Brain Health Cognitive Reserve Sudden death Suicide OCD Narcolepsy Apnoea Carers Respite Hospice Respite Dignitas Advanced Directive Rhiztomy Wheelchair Walking aids Blood/Organ donation Brain donation Exercise therapy NABs Autoimmunity Infections Outcome measures Web Resources Pathogenesis Double vision What is MS? NEDA T2T OCT Neurofilaments JCV status Pharma Anaesthesia
  6. 6. The hypothetical Ideal Reliable long-term efficacy Maintaining QOL Maintaining independence Maintaining the ability to work No issue for pregnancy/fertility Maximum reduction of MS disease activity Maximum tolerability Maximum safety Ease of use Minor impact on everyday life
  7. 7. Risks vs. Benefits
  8. 8. How bad is MS?
  9. 9. MS Infographic www.ms-res.org
  10. 10. Audience Response Question What proportion of MSers are unemployed by the time they need a walking aid (EDSS 6.0)? 1. <20% 2. 25-50% 3. 50-60% 4. >60% > 60%
  11. 11. Consequences of increasing EDSS scores: loss of employment1 0 10 20 30 40 50 60 70 80 90 Work Capacity by Disability Level 0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0 EDSS Score ProportionofPatients≤65YearsOld Working(%) The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger. 1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926; 2. Pfleger CC et al. Mult Scler. 2010;16:121-126. Spain Sweden Switzerland United Kingdom Netherlands Italy Germany Belgium Austria ~10 yrs2
  12. 12. The Gambler’s Dilemma
  13. 13. What about benign MS?
  14. 14. Audience Response Question What proportion of MSers have benign MS? 1. >50% 2. 40-50% 3. 30-40% 4. <30% Hospital-based populations (EDSS < 3.5) • 15 years ~30% • 25 years ~15% • 30 years ~5% • 50 years ~2.5% Community-based populations • 15 years ~45%
  15. 15. 163 patients with “benign” MS (disease duration >15 years and EDSS <3.5): 45% cognitive impairment 49% fatigue 54% depression What is benign MS?
  16. 16. Impact of MS: cognitive functioning in the CIS stage Feuillet et al. MSJ 2007 CIS Patients n = 40 57% 7% -20% 0% 20% 40% 60% Healthy Controls n = 30 p < 0.0001 Deficits were found mainly in memory, speed of information processing, attention and executive functioningPatients failing ≥ 2 cognitive tests
  17. 17. Audience Response Question Do you believe in the concept of a therapeutic window? 1. Yes 2. No 3. Maybe
  18. 18. Coles et al. J Neurol. 2006 Jan;253(1):98-108. Post-inflammatory neurodegeneration
  19. 19. Early vs. Late?
  20. 20. Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFN-1b trial Goodin et al. Neurology 2012;78:1315-1322.
  21. 21. Natalizumab STRATA: stable EDSS scores for up to 5 years *P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 1 Year 2 Years 3 Years 4 Years 5 Years Cessation/ Treatment Gap* Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab MeanEDSSScore n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393 21
  22. 22. Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7. Therapeutic Lag
  23. 23. Motor system to legs Cerebellar or balance systems BladderTherapeutic window 1 Therapeutic window 2 Therapeutic window 3 Upper limbs Sensory Cognition Vision Etc. Therapeutic window 4 Therapeutic window 5 Therapeutic window 6 Therapeutic window 7 Therapeutic window 8, etc…. Diagnosis of Progressive MS Effective DMTs could still target the remaining windows of therapeutic opportunity for individual neurological systems The Asynchronous Progressive MS hypothesis
  24. 24. Audience Response Question Do you believe in the concept of a therapeutic window? 1. Yes 2. No 3. Maybe No I think there are multiple windows
  25. 25. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University Early or late? 26 MonitoringTreatmentClinicalOccup&social
  26. 26. PML
  27. 27. 17%
  28. 28. 17% 85%
  29. 29. >800,000 SlideShare Views
  30. 30. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University Early or late? 34 MonitoringTreatmentClinicalOccup&social
  31. 31. Redefining our treatment target
  32. 32. No evident disease activity: NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target No evidence of disease activity defined as:1,2 × No relapses × No sustained disability progression × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions
  33. 33. Relapses Unreported relapses Clinical disease progression Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Spinal fluid neurofilament levels MS Iceberg Clinical activity Focal MRI activity Hidden focal and diffuse MRI activity Microscopic or biochemical pathology Biomarkers
  34. 34. 17yr female, diagnosed with CIS after presenting with myelitis 18yr, 1st year university diagnosed with MS after having L optic neuritis Abnormal MRI; >9 T2 lesions on brain MRI and spinal cord lesion at C5 2000 2001 clumsy left hand pins & needles in legs IFN-beta 2002 2003 R optic neuritis 2004 Bladder dysfunction Graduate trainee marketing Full time employment Off work ~3 months of the year Dec 2007 Brainstem syndrome; diplopia and ataxia ? glatiramer acetate Cervical cord relapse weak L arm with pain High lesion load with brain atrophy Gd-enhancing lesion of upper cervical cord Splits from her partner depression , anxiety and fatigue Reduced mobility Occupational health assessment natalizumab New partner New job junior management position Residual deficits: Normal walking 300m, unable to run & exercise. Intermittent sensory symptoms in L arm. Mild urinary frequency Jan 2008 JCV positive 3-monthly MRI monitoring ? fingolimod Oct 2013 Annual MRI monitoring JCV high positive Final year of school University Early or late? 39 MonitoringTreatmentClinicalOccup&social Dec 2007 Jul 2010 Jul 2013
  35. 35. Relapses Unreported relapses Clinical disease progression Subclinical relapses: focal MRI activity Focal gray and white matter lesions not detected by MRI Brain atrophy Spinal fluid neurofilament levels MS Iceberg Clinical activity Focal MRI activity Hidden focal and diffuse MRI activity Microscopic or biochemical pathology Biomarkers
  36. 36. End-organ damage
  37. 37. Rheumatoid arthritis End-stage joint disease
  38. 38. Control Multiple sclerosis
  39. 39. Brain atrophy occurs across all stages of the disease De Stefano, et al. Neurology 2010 n= 963 MSers
  40. 40. Treatment-effect on atrophy correlates with treatment-effect on disability Sormani et al. Ann Neurol 2014;75:43–49.
  41. 41. Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials (13,500 patients) Sormani MP et al. Ann Neurol. 2014;75:43-49.
  42. 42. -1.0% -0.8% -0.6% -0.4% -0.2% 0.0% Years 0-2 -0.82% -0.80% P=0.822† Placebo (N=315) Natalizumab (N=627) Year 0-1* Year 1-2 -0.40% -0.56% -0.43% -0.24% P=0.004† P=0.002† †Difference between treatments; ‡Change from baseline; Miller DH et al. Neurology 2007;68:1390-1401. AFFIRM Study: natalizumab and brain atrophy Mean(SE)percentagechangeinBPF
  43. 43. Fingolimod has an early and sustained effect on the rate of brain atrophy compared with placebo and IFNb-1a IM FREEDOMS, 2 years Fingolimod 0.5 mg (n = 356) Placebo (n = 329) *** * ** 60 12 24 Time (months) 0 -0.4 -0.8 -1.2 -1.6 -2.0 −38% vs placebo p<0.001 ChangeinmeanBVfrom baseline(%) TRANSFORMS, 1 year 0 12 Time (months) 0.0 -0.4 -0.6 -1.0 IFNb-1a IM (n = 359) Fingolimod 0.5 mg (n = 368) −40% vs IFNb-1a IM p<0.001 ***-0.2 -0.8 ChangeinmeanBVfrom baseline(%) ITT population with evaluable MRI images. Note: n numbers for FREEDOMS data reflect the number of patients with available data at 24 months. *p<0.05; **p<0.01; ***p<0.001 vs comparator; p-values are for comparisons over Months 0-6, Months 0-12, Months 0-24 BV, brain volume; ITT, intent-to-treat. Gilenya™ Prescribing Information 19 April 2012. Reproduced with permission. Kappos L et al. N Engl J Med 2010; 362: 387-401, and Cohen JA et al. N Engl J Med 2010; 362: 402-415. Copyright © 2011 Massachusetts Medical Society. All rights reserved
  44. 44. Reduction in brain atrophy on alemtuzumab
  45. 45. Alemtuzumab Improves Brain MRI Outcomes in Patients With Active Relapsing-Remitting Multiple Sclerosis: Three-Year Follow-up of the CARE-MS Studies Douglas L Arnold,1,2 Elizabeth Fisher,3 Jeffrey A Cohen,4 Frederik Barkhof,5 Krzysztof W Selmaj,6 David H Margolin,7 Jeffrey Palmer,7 Edward J Fox8 AAN 2014 Blitz S65-008 1NeuroRx Research, Montréal, Québec, Canada, and 2Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Québec, Canada; 3Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA; 4Cleveland Clinic, Cleveland, OH, USA; 5VU University Medical Centre, Amsterdam, Netherlands; 6Department of Neurology, Medical University of Łódź, Łódź, Poland; 7Genzyme, a Sanofi company, Cambridge, MA, USA; 8University of Texas Medical Branch, Round Rock, TX, USA
  46. 46. CARE-MS I & II Three-Year MRI Outcomes Change in Brain Parenchymal Fraction (BPF)  Alemtuzumab slowed brain volume loss over 3 years, as assessed by change in BPF  For both patient populations, the median percentage reduction in BPF observed in in Year 3 (0.19% and 0.10%, respectively) was smaller than that observed in Year 1 (0.59% and 0.48%) and Year 2 (0.25% and 0.22%) Percentage Change in BPF in Formerly Treatment-Naive Patients (CARE-MS I) Percentage Change in BPF in Patients Who Relapsed on Prior Therapy (CARE-MS II) MedianChangeFrom Baseline,%(95%CI) Year No. of Patients 371 367 351 323 % Change from Previous Year – –0.59% –0.25% –0.19% MedianChangeFrom Baseline,%(95%CI) Year 428 414 405 359 – –0.48% –0.22% –0.10% No. of Patients % Change from Previous Year 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 0 1 2 3 -1 .5 0 -1 .2 5 -1 .0 0 -0 .7 5 -0 .5 0 -0 .2 5 0 .0 0 AAN 2014 Blitz S65-008
  47. 47. CARE-MS I & II Three-Year MRI Outcomes Proportion of Patients Free of Gd Lesions, T2 Lesions, and MRI Activity  The majority of alemtuzumab-treated patients were free of MRI activity (absence of Gd-enhancing lesions and new/enlarging T2 hyperintense lesions) at Year 2 and Year 3 MRI activity-free: absence of both Gd-enhancing and new or enlarging T2 hyperintense lesions; CARE-MS=Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; CI=confidence interval; DMT=disease-modifying therapy; Gd=gadolinium; MRI=magnetic resonance imaging; Y=year No. of Patients 359370 336 356370 325 354369 326 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Gd-enhancing lesion-free New/enlarging T2 lesion-free MRI activity-free % MRI Activity Free in Treatment-Naive Patients (CARE-MS I) % MRI Activity Free in Patients Who Relapsed on Prior Therapy (CARE-MS II) No. of Patients 412421 364 405423 361 Gd-enhancing lesion-free New/enlarging MRI activity-free 402414 361 ProportionofPatients, %(95%CI) 0 20 40 60 80 100 Y1 Y2 Y3 Y1 Y2 Y3 Y1 Y2 Y3 T2 lesion-free  Patients were treated with alemtuzumab 12 mg at baseline and 12 months later  Re-treatment in Year 3 was administered upon recurrence of disease activity  18% of CARE-MS I patients and 20% of CARE-MS II patients were re-treated with alemtuzumab in Year 3; <3% were treated with another DMT in Year 3 AAN 2014 Blitz S65-008
  48. 48. NEDA Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337. Treat-2-target Brain volume loss should be included in our definition for NEDA No evidence of disease activity defined as:1,2 × No relapses × No sustained disability progression × No MRI activity × No new or enlarging T2 lesions × No Gd-enhancing lesions
  49. 49. Treating-2-target Choosing therapy X Y Z Define the Individual’s MS No Treatment failure?Yes • Patient’s preferences? • Your choice? Individual measures: • Evidence of disease activity? • Tolerability/safety? • Adherence? • Drug or inhibitory markers? Monitoring • MS prognosis • Life style and goals • Shared goals for therapy Rebaseline Rebaseline: • IFNβ, natalizumab, fingolimod, teriflunomide, DMF=3-6 months • Glatiramer acetate=9 months • Alemtuzumab=24 months DMF=dimethyl fumarate.
  50. 50. Pros and cons of maintenance vs. induction therapies Maintenance therapies • Continuous treatment • Low to very high efficacy • Reversible • Perceived to be lower risk • Examples • Laquinimod, GA, IFN-beta, teriflunomide, BG12, fingolimod, natalizumab, daclizumab • Breakthrough disease • Suboptimal or failure to respond • NEDA reliable metric for efficacy • Rebound activity • Highly likely • Can be life threatening • Pregnancy • Contra-indicated • No potential for a cure • Rebound • SPMS & progressive brain atrophy Induction therapies • Short-courses or pulsed therapy • Very high efficacy • Irreversible • Perceived to be higher risk • Examples • Mitoxantrone, cladribine, alemtuzumab, anti- CD20 (?), BMT • Breakthrough disease • Marker for retreatment • NEDA unreliable to assess efficacy • Rebound activity • Less likely • Unlikely to be life-threatening • Pregnancy • Strategy of choice • Potentially curative • 15-20 year experiment • BMT, alemtuzumab, cladribine
  51. 51. T2T - NEDA Zero Tolerance Treatment objectives in relapsing MS NEDA Reduced ongoing damage Treat Early
  52. 52. T2T - NEDA Zero Tolerance Functional Improvement Maintain reserve capacity Treatment objectives in relapsing MS NEDA Reduced ongoing damage Treat Early
  53. 53. T2T - NEDA Zero Tolerance Functional Improvement Maintain reserve capacity Treatment objectives in relapsing MS NEDA Reduced ongoing damage CNS Repair Healthy ageing Treat Early
  54. 54. T2T - NEDA Zero Tolerance Functional Improvement Maintain reserve capacity Treatment objectives in relapsing MS NEDA Reduced ongoing damage CNS Repair Healthy ageing Improved Quality of Life / Brain Health Treat Early
  55. 55. Audience Response Question Who is more risk averse? 1. MSers 2. Neurologists 3. Equally risk averse Neurologists
  56. 56. Risk acceptance of PML (Survey 2009) Putative risk rate to stop Tysabri treatment Heesen et al. (2010) MSJ
  57. 57. WWW.MS-RES.ORG
  58. 58. WWW.MS-RES.ORG
  59. 59. Audience Response Question Do you believe that we can cure MS? 1. Yes 2. No 3. Not sure
  60. 60. Possible cure The hypothetical Ideal Reliable long-term efficacy Maintaining QOL Maintaining independence Maintaining the ability to work No issue for pregnancy/fertility Maximum reduction of MS disease activity Maximum tolerability Maximum safety Ease of use Minor impact on everyday life
  61. 61. Survival Curves 85% 50% 30% 0% 15yrs 25yrs 40yrs 50yrs 100% Natural history
  62. 62. Survival Curves 85% 50% 30% 0% 15yrs 25yrs 40yrs 50yrs 100% Benign MS Natural history
  63. 63. Survival Curves 85% 50% 30% 0% 15yrs 25yrs 40yrs 50yrs 100% Benign MS Natural history Delayed onset of SPMS
  64. 64. Survival Curves 85% 50% 30% 0% 15yrs 25yrs 40yrs 50yrs 100% Benign MS Natural history Unrealistic expectation Delayed onset of SPMS
  65. 65. Survival Curves 85% 50% 30% 0% 15yrs 25yrs 40yrs 50yrs 100% Benign MS Proportioned of treated MSers are cured Natural history Unrealistic expectation Delayed onset of SPMS
  66. 66. Defining a cure: a working definition 85% 50% 30% 0% 15yrs 25yrs 40yrs 50yrs 100% Proportioned of treated MSers are cured Natural history A cure is NEDA (no evident disease activity) x 15 years
  67. 67. Audience Response Question Do you believe that we can cure MS? 1. Yes 2. No 3. Maybe Maybe The experiment is ongoing
  68. 68. Conclusions • MS is a bad disease • Mortality, disability, unemployment, divorce, cognitive impairment, etc. • Early highly-effective therapy is the only realistic option of preventing end-organ damage • Now an established treatment option in the EU • NEDA and T2T are current treatment target (zero tolerance) • Beyond NEDA we need to target end-organ damage (brain atrophy and CSF NF levels) • We need an acceptable working definition of an MS cure • NEDA x 15 years? • Only possible with induction therapies (alemtuzumab, cladribine, BMT) • Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment? • Can we cure MS? • Risks and benefits • Who should take the risks? • Who should make the decisions? • What is the role of the healthcare professional in decision-making?

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