Workshop II. How to manage highly active MS patients in practice?

Transcription

1 Workshop II How to manage highly active MS patients in practice?

2 Gavin Giovannoni Department of Neurology Institute of Cell and Molecular Science Queen Mary University London & Barts and The London NHS Trust London, UK Declared receipt of 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, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck, Novartis, Pfizer, Roche, Sanofi- Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals

3 Workshop II How to manage highly active MS patients in practice? Gavin Giovannoni Barts-MS Barts and The London School of Medicine and Dentistry Queen Mary University London

4 Learning objectives Describe the mechanisms of action of induction treatments Define the long-term benefit of induction based on the evidence currently available

5 Important questions for patients to consider before starting a DMT 1. What is MS? 2. Are you sure that you have MS? 3. What type of MS do you have? 4. What prognostic group do you fall into? 5. What is the risk of you not being treated with a DMT? 6. Do you have active MS? 7. Are you eligible for treatment with a DMT? 8. Do you understand the difference between the treatment strategies of maintenanceand-escalation and induction therapy? 9. Do you understand the concepts of treat-2-target or no evident disease activity (NEDA)? 10.What about pregnancy? 6 DMT, disease-modifying therapy; MS, multiple sclerosis

6 What prognostic group do you fall into? Good prognosis Young Female sex Unifocal onset Isolated sensory symptom (optic neuritis, sensory) Full recovery from attack Long interval to second relapse No disability after 5 years Normal MRI/low lesion load No Gd-enhancing, posterior fossa and spinal cord lesions No baseline brain atrophy Biomarkers ( ve OCBs, normal CSF neurofilament levels, high vd3 levels) CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; OCB, oligoclonal band Poor prognosis Older age of onset Male sex Multifocal onset Efferent system affected (motor, cerebellar, bladder) Partial or no recovery from a relapse High relapse rate in first 2 years Disability after 5 years Abnormal MRI with large lesion load Gd-enhancing, posterior fossa and spinal cord lesions Baseline brain atrophy Biomarkers (OCBs, raised CSF neurofilament levels, low vd3 levels) Adapted from Miller DH, et al. Lancet Neurology 2005:4;281 8

7 What is active MS? Inactive MS: no relapses or MRI activity in the last 24 months 2001 Clinical Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months 2009 Clinical and MRI 2014 Clinical or MRI

8 Am I eligible for treatment? Inactive MS: no relapses or MRI activity in the last 24 months 2001 Clinical Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months Rapidly-evolving severe MS (RES); two disabling attacks in a 12-month period and MRI evidence of activity during this period 2009 Clinical and MRI Natalizumab Fingolimod Treatment No treatment 2014 Clinical or MRI

9 Aim of treatment Inactive MS: no relapses or MRI activity in the last 24 months (NEDA) 2001 Clinical 2009 Clinical and MRI Active MS: relapses in the last 12 or 24 months and/or MRI activity in the last 12 months Highly active MS: relapses in the last 12 months and MRI activity in the last 12 months Rapidly-evolving severe MS (RES); two disabling attacks in a 12 month period and MRI evidence of activity during this period Clinical or MRI

10 Do you understand the difference between maintenance escalation and a pulsed immune reconstitution therapy (PIRT)? 3rd-line X 3rd-line y 1 st -line A 1st-line E 1 st -line B 1st-line D 2nd-line M 2nd-line N 1 st -line C

11 BARTS-MS T2T-NEDA algorithm Define the individual s MS Choose a therapeutic strategy Personalization: MS prognosis based on clinical and MRI indices Lifestyle and goals Shared goals for therapy Patient s preferences? Your choice? Only one licensed induction therapy at present Yes Maintenance-escalation Choose therapy A B C Initiate or Switch or Escalate Rx Rebaseline Monitoring Treatment failure? No Pulsed immune reconstitution therapy Choose therapy X Z Y Complete course / Re-treat Rebaseline Monitoring Yes Breakthrough disease Rebaselining: IFNβ, natalizumab, fingolimod, teriflunomide, Dimethyl fumarate, 3 6 months Glatiramer acetate, 9 months Alemtuzumab, 24 months Individual measures: Evidence of disease activity? Tolerability/safety? Adherence? Drug or inhibitory markers, e.g. NAbs? T2T, treat-to-target; IFNβ, interferon-beta; NAbs, neutralizing antibodies; Rx, treatment

12 Rebooting or reconstituting the immune system Genes Environment Multiple Sclerosis

13 What is PIRT? Pulsed immune reconstitution therapy (PIRT) is by definition given as a short course, i.e. intermittently and not continuously PIRT has the ability to induce long-term remission and in some cases the possibility of a cure Please note that a PIRT is not given continuously Additional courses of the therapy are only given if there is a recurrence of inflammatory activity* *Inflammatory activity in MS typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and/or Gd-enhancing lesions) GD, gadolinium

14 What is maintenance therapy? Maintenance therapy is by definition given continuously, without an interruption in dosing Although it has the ability to induce long-term remission it cannot result in a cure Please note that maintenance therapy is given continuously A recurrence of, or ongoing, inflammatory activity* while on therapy is an indication of suboptimal response *Inflammatory activity in MS typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and/or Gd-enhancing lesions)

15 Maintenance therapy vs PIRT Maintenance therapy Continuous treatment Low to very high efficacy Reversible Perceived to be lower risk Cumulative, or increased, risk with time Examples Laquinimod, GA, IFNβ, 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 No potential for a cure Rebound SPMS and progressive brain atrophy PIRT Short-courses or pulsed therapy High to very high efficacy Irreversible Perceived to be higher risk Frontloading of risk or reduced risk with time Examples Mitoxantrone, cladribine, alemtuzumab, anti-cd20 (?), HSCT-BMT Breakthrough disease Marker for retreatment NEDA unreliable to assess efficacy Rebound activity Less likely Unlikely to be life-threatening Pregnancy Potentially curative? year experiment The following may not be licensed for MS in your country: laquinimod, daclizumab, mitoxantrone, cladribine, anti-cd20 therapies, BMT. GA, glatiramer acetate; HSCT-BMT, hematopoietic stem cell transplantation bone marrow transplantation; IFNβ, interferon beta; SPMS, secondary progressive multiple sclerosis

16 Can we define a cure for MS? Survival analysis pulsed immune reconstitution therapy or PIRT No secondary progression MS is an autoimmune disease hypothesis REMISSION CURE Environ -ment Genes year experiment Multiple Sclerosis

17 Case study 1

18 25-year-old woman with RRMS 2011 Optic neuritis MRI+ve Patient case scenario provided by Professor Gavin Giovannoni

19 25-year-old woman with RRMS 2011 April 2015 May 2015 Optic neuritis MRI+ve Brain stem INO Spinal cord triparesis IV methylprednisolone IV methylprednisolone EDSS = 5.0 EDSS, Expanded Disability Status Scale; INO, internuclear ophthalmoplegia; IV, intravenous Patient case scenario provided by Professor Gavin Giovannoni

20 25-year-old woman with RRMS 2011 April 2015 May 2015 Optic neuritis MRI+ve Brain stem INO Spinal cord triparesis IV methylprednisolone IV methylprednisolone EDSS = 5.0 Natalizumab or Alemtuzumab? EDSS, Expanded Disability Status Scale; INO, internuclear ophthalmoplegia; IV, intravenous Patient case scenario provided by Professor Gavin Giovannoni

21 25-year-old woman with RRMS 2011 April 2015 May 2015 June 2015 Optic neuritis MRI+ve Brain stem INO Spinal cord triparesis JCV+ve (index = 1.6) IV methylprednisolone IV methylprednisolone EDSS = 5.0 Natalizumab or Alemtuzumab? EDSS, Expanded Disability Status Scale; INO, internuclear ophthalmoplegia; IV, intravenous; JCV, JC virus Patient case scenario provided by Professor Gavin Giovannoni

22 25-year-old woman with RRMS What would you do? Patient case scenario provided by Professor Gavin Giovannoni

23 25-year-old woman with RRMS 2011 April 2015 May 2015 June 2015 Sept 2015 Optic neuritis MRI+ve Brain stem INO IV methylprednisolone Spinal cord triparesis IV methylprednisolone JCV+ve (index = 1.6) Severe spinal cord relapse, paraparesis, loss B&B, pressure sore Anti-AQ4 ve IV methylprednisolone IV methylprednisolone 2 EDSS = 5.0 EDSS = Natalizumab or Alemtuzumab? Natalizumab or Alemtuzumab? Pressure sore Urinary catheter AQ4, Aquaporin-4; RRMS, relapsing-remitting multiple sclerosis Patient case scenario provided by Professor Gavin Giovannoni Haines JD, et al. Mt Sinai J Med 2011;78:231 43; Münzel EJ, et al. Drugs 2013;73:

24 25-year-old woman with RRMS 2011 April 2015 May 2015 June 2015 Sept 2015 Optic neuritis MRI+ve Brain stem INO IV methylprednisolone Spinal cord triparesis IV methylprednisolone JCV+ve (index = 1.6) Severe spinal cord relapse, paraparesis, loss B&B, pressure sore Anti-AQ4 ve IV methylprednisolone IV methylprednisolone 2 EDSS = 5.0 EDSS = Natalizumab or Alemtuzumab? Natalizumab or Alemtuzumab? Natalizumab Patient case scenario provided by Professor Gavin Giovannoni Haines JD, et al. Mt Sinai J Med 2011;78:231 43; Münzel EJ, et al. Drugs 2013;73:

25 Switching from natalizumab to alemtuzumab Option 1: Immediate switch (high risk if carry-over PML develops) Natalizumab Asymptomatic PML? LP-JCV DNA & MRI Alemtuzumab Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity) Natalizumab Asymptomatic PML?* LP-JCV DNA & MRI 3 6 MONTH WASHOUT * For this option the shorter the washout the more important the screen for asymptomatic PML ** PML screening and baseline MRI studies use different scans, hence the need for both Rebaseline MRI** Alemtuzumab Option 3: Bridging (low risk; mainly related to using a low efficacy bridging agent and using alemtuzumab after the bridging agent) Natalizumab Asymptomatic PML? LP-JCV DNA & MRI 6 12 MONTHS Oral bridging agent (Teriflunomide, DMF or Fingolimod) Rebaseline MRI Alemtuzumab DMF, dimethyl fumarate; LP, lumbar puncture; PML, progressive multifocal leukoencephalopathy

26 25-year-old woman with RRMS 2011 April 2015 May 2015 June 2015 Sept 2015 Optic neuritis MRI+ve Brain stem INO IV methylprednisolone Spinal cord triparesis IV methylprednisolone JCV+ve (index = 1.6) Severe spinal cord relapse, paraparesis, loss B&B, pressure sore Anti-AQ4 ve IV methylprednisolone IV methylprednisolone 2 EDSS = 5.0 EDSS = Natalizumab or Alemtuzumab? Natalizumab or Alemtuzumab? Natalizumab Feb 2016 Alemtuzumab EDSS = 6.0 Patient case scenario provided by Professor Gavin Giovannoni Haines JD, et al. Mt Sinai J Med 2011;78:231 43; Münzel EJ, et al. Drugs 2013;73:

27 Case study 2

28 38-year-old woman with RRMS Teacher

29 38-year-old woman with RRMS Glatiramer acetate 3 years (good adherence) Relapse with a mild left sensory loss Referred to me for a second opinion Teacher

30 38-year-old woman with RRMS Switched to interferon-beta (IM IFNbeta-1a; Mild persistent flu-like side-effects and lymphopenia 12/12 NAb screen negative Volunteers for new research programme, which included an MRI protocol Teacher IM, intramuscular

31 38-year-old woman with RRMS Forced to retire due to cognitive impairment and severe fatigue Developed depression and anxiety She becomes an expert patient Widely read Internet savvy Regular follower of Teacher

32 Unemployment Kobelt, et al. J Neurol Neurosurg Psychiatry 2006;77:918 26

33 38-year-old woman with RRMS

34 38-year-old woman with RRMS Teacher?

35 38-year-old woman with RRMS

36 38-year-old woman with RRMS Teacher What would you do if this was you? Would you risk the wrath of the NICE inspectors? NICE, National Institute for Health and Care Excellence

37 38-year-old woman with RRMS Teacher Natalizumab vs Fingolimod

38 Bermel RA, et al. Ann Neurol 2013;73:95 103

39 Predictors of long-term outcome in MSers treated with interferon beta-1a Treatment vs Natural history OR, odds ratio Bermel RA, et al. Ann Neurol 2013;73:95 103

40 Case study 3

41 EDSS 17-year-old girl, presents with myelitis Jun 2000 Myelitis Feb st -year university L-optic neuritis IFN-beta Jun 2000 IFN-beta

42 EDSS 17-year-old girl, presents with myelitis Jun 2000 Feb 2001 Myelitis 1 st -year university L-optic neuritis IFN-beta Jan 2002 Oct 2003 Clumsy left hand Pins & needles in legs Mar 2004 R-optic neuritis Dec 2007 Brainstem syndrome; diplopia and ataxia How are you going to manage her? Jun 2000 IFN-beta

43 EDSS 17-year-old girl, presents with myelitis Jun 2000 Feb 2001 Myelitis 1 st -year university L-optic neuritis IFN-beta Jan 2002 Oct 2003 Clumsy left hand Pins & needles in legs Mar 2004 R-optic neuritis Dec 2007 Brainstem syndrome; diplopia and ataxia Jan 2008 Cervical cord relapse weak L arm with pain 6.0 Jun 2000 IFN-beta

44 EDSS 17-year-old girl, presents with myelitis Jun 2000 Feb 2001 Myelitis 1 st -year university L-optic neuritis Jan 2002 Oct 2003 Clumsy left hand Pins & needles in legs Mar 2004 R-optic neuritis Feb 2008 to May 2014 Bladder dysfunction Depression, anxiety, fatigue NEDA (no evident disease activity) Mild urinary frequency No depression, anxiety, fatigue IFN-beta Dec 2007 Brainstem syndrome; diplopia and ataxia Jan 2008 Cervical cord relapse weak L arm with pain Reduced mobility Jan 2008 Natalizumab Fully mobile Residual deficits: Walking distance >500m Unable to run Exercise induces intermittent sensory symptoms in L arm Mild urinary frequency 6.0 Jun 2000 IFN-beta Natalizumab May 2014

45 MRI progressive brain atrophy MRI progressive brain atrophy Dec 2007 Jul 2010 Jul 2013 Is this patient in long-term remission?

46 EDSS 17-year-old girl, presents with myelitis Jun 2000 Feb 2001 Myelitis 1 st -year university L-optic neuritis Jan 2002 Oct 2003 Clumsy left hand Pins & needles in legs Mar 2004 R-optic neuritis Feb 2008 to May 2014 Bladder dysfunction Depression, anxiety, fatigue NEDA (no evident disease activity) Mild urinary frequency No depression, anxiety, fatigue IFN-beta Dec 2007 Brainstem syndrome; diplopia and ataxia Jan 2008 Cervical cord relapse weak L arm with pain Reduced mobility Jan 2008 Natalizumab Fully mobile Residual deficits: Walking distance >500m Unable to run Exercise induces intermittent sensory symptoms in L arm Mild urinary frequency JCV positive - index Jun 2000 IFN-beta Natalizumab May 2014

47 Switching from natalizumab to alemtuzumab Option 1: Immediate switch (high risk if carry-over PML develops) Natalizumab Asymptomatic PML? LP-JCV DNA & MRI Alemtuzumab Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity) Natalizumab Asymptomatic PML?* LP-JCV DNA & MRI 3 6 MONTH WASHOUT * For this option the shorter the washout the more important the screen for asymptomatic PML ** PML screening and baseline MRI studies use different scans, hence the need for both Rebaseline MRI** Alemtuzumab Option 3: Bridging (low risk; mainly related to using a low efficacy bridging agent and using alemtuzumab after the bridging agent) Natalizumab Asymptomatic PML? LP-JCV DNA & MRI 6 12 MONTHS Oral bridging agent (Teriflunomide, DMF or Fingolimod) Rebaseline MRI Alemtuzumab Giovannoni et al. Pract Neurol Oct;16(5):

48 EDSS 17-year-old girl, presents with myelitis Jun-2000 Feb yr girl, myelitis 1 st -yr University L-optic neuritis Jan Clumsy left hand Oct-2003 Pins & needles in legs Feb-2008 to May-2014 NEDA (no evident disease activity) Bladder dysfunction Mild urinary frequency Feb-2001 IFN-beta Mar-2004 R-optic neuritis depression, anxiety and fatigue No depression,anxiety or fatigue Dec 2007 Brainstem syndrome; diplopia and ataxia Reduced mobility Fully mobile Jan 2008 Cervical cord relapse weak L arm with pain Jan-2008 Natalizumab Residual deficits: Walking distance >500m Unable to run Exercise induces intermittent sensory symptoms in L arm Mild urinary frequency 6.0 Jun-2000 IFN-beta Natalizumab May-2014

49 Switching from natalizumab to alemtuzumab Option 1: Immediate switch (high-risk if persistent lymphopenia occurs) Fingolimod Treat with alemtuzumab before lymphocyte counts normalize Alemtuzumab Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity) Fingolimod Only treat with alemtuzumab once lymphocyte counts normalize* 2 to 6 12 MONTH WASHOUT Alemtuzumab * What constitutes a normal level post-fingolimod needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below Option 3: Bridging (low risk; mainly related to MS rebound as a result of using a low efficacy bridging agent after fingolimod) Fingolimod 3-12 MONTHS Bridging agent (IFN-beta, GA, teriflunomide or DMF) Only treat with alemtuzumab once lymphocyte counts normalize* * What constitutes a normal level in this situation needs to be defined; I would be reluctant to give alemtuzumab to anyone with a total lymphocyte count below Alemtuzumab Giovannoni et al. Pract Neurol Oct;16(5):

50 BartsMS blog

51 Natalizumab Continuous treatment (monthly infusions) Very high efficacy; high NEDA rates, significant proportion of subjects improve Prevents end-organ damage (reduced brain atrophy at year 2) Reversible treatment effect Infusion reactions uncommon No short-term generalized immunosuppression Reduced immune surveillance increases risk of CNS infections; in particular PML if JCV-seropositive Breakthrough disease Re-baseline at 3 6 months Neutralizing antibodies to natalizumab reduce efficacy and cause infusion reactions Suboptimal or failure to respond NEDA reliable metric for efficacy Rebound activity Pregnancy Highly likely, can be life threatening Not recommended, natalizumab crosses placenta and has transient effects in baby No secondary autoimmunity No obvious secondary malignancy risk Monitoring: yes, blood and liver function tests early on, anti-natalizumab antibodies, JCV serology and annual MRI No potential for a cure Rebound Alemtuzumab Short-course pulsed therapy (2 5 annual cycles of treatment) Very high efficacy; significant proportion of subjects improve Reported NEDA rates low, but not measured in correct epoch Prevents end-organ damage (reduced brain atrophy at year 2) Irreversible treatment effect Infusion reactions the norm Short-term generalised immunosuppression (8 12 weeks post infusion) Low risk of CNS and other infections after immune system reconstitution Breakthrough disease Re-baseline at 24 months Antibodies to alemtuzumab are transient and don t appear to inhibit activity of drug Marker for retreatment NEDA unreliable to assess efficacy Rebound activity Less likely, unlikely to be life-threatening Pregnancy Fine once immune system reconstituted Potential for autoantibodies to cross placenta, for example neonatal hyperthyroidism Secondary autoimmunity; ~50% of patients with long-term follow-up mainly thyroid related Potential, but undefined, secondary malignancy risk Monitoring: yes, monthly blood and urine tests for secondary autoimmunity and annual MRI Potentially curative Long-term remission established in about 50% of treated patients Ongoing year experiment, analogous to BMT