Workshop II How to Manage Highly Active MS Patients in Practice? Gavin Giovannoni

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

Learning objectives

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

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 maintenance- and-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 What prognostic group do you fall into?

Good prognosis Poor prognosis ▪Young ▪Older age of onset ▪Female sex ▪Male sex ▪“Unifocal” onset ▪“Multifocal“ onset ▪Isolated sensory symptom (optic neuritis, ▪Efferent system affected (motor, sensory) cerebellar, bladder) ▪Full recovery from attack ▪Partial or no recovery from a relapse ▪Long interval to second relapse ▪High relapse rate in first 2 years ▪No disability after 5 years ▪Disability after 5 years ▪Normal MRI/low lesion load ▪Abnormal MRI with large lesion load ▪No Gd-enhancing, posterior fossa and ▪Gd-enhancing, posterior fossa and spinal cord lesions spinal cord lesions ▪No baseline brain atrophy ▪Baseline brain atrophy ▪Biomarkers (−ve OCBs, normal CSF ▪Biomarkers (OCBs, raised CSF neurofilament levels, high vD3 levels) neurofilament levels, low vD3 levels)

CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; OCB, oligoclonal band Adapted from Miller DH, et al. Lancet Neurology 2005:4;281−8 What is active MS?

2001 Inactive MS: no relapses or MRI activity in the last 24 months 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 Am I eligible for treatment?

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

Natalizumab Fingolimod Treatment No treatment 2014 Clinical or MRI Aim of treatment

2001 Inactive MS: no relapses or MRI activity in the last 24 months (NEDA) 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. 2014 Clinical or MRI Do you understand the difference between maintenance escalation and a pulsed immune reconstitution therapy (PIRT)?

3rd-line 3rd-line X y

1st-line A 1st-line E

2nd-line 2nd-line 1st-line B 1st-line D M N

1st-line C BARTS-MS T2T-NEDA algorithm Personalization: • MS prognosis based on clinical and MRI indices • Lifestyle and goals • Shared goals for therapy Define the individual’s MS • Patient’s preferences? • Your choice? • Only one licensed Choose a therapeutic strategy induction therapy at present

Maintenance-escalation Pulsed immune reconstitution therapy Rebaselining: • IFNβ, natalizumab, fingolimod, Choose therapy Choose therapy teriflunomide, Dimethyl fumarate, 3–6 months • Glatiramer acetate, A B C X Z Y 9 months • Alemtuzumab, 24 months Initiate or Switch or Escalate Rx Complete course / Re-treat Individual measures: Rebaseline Rebaseline • Evidence of disease activity? • Tolerability/safety? • Adherence? Monitoring Monitoring • Drug or inhibitory markers, Yes No Yes e.g. NAbs? Treatment failure? Breakthrough disease

T2T, treat-to-target; IFNβ, interferon-beta; NAbs, neutralizing antibodies; Rx, treatment

Rebooting or reconstituting the immune system

Genes

Environ- ment Multiple Sclerosis 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

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)

Maintenance therapy vs PIRT

Maintenance therapy PIRT • Continuous treatment • Short-courses or pulsed therapy • Low to very high efficacy • High to very high efficacy • Reversible • Irreversible • Perceived to be lower risk • Perceived to be higher risk • Cumulative, or increased, risk with time • Frontloading of risk or reduced risk with time • Examples • Examples • Laquinimod, GA, IFNβ, teriflunomide, BG12, • Mitoxantrone, cladribine, alemtuzumab, fingolimod, natalizumab, daclizumab anti-CD20 (?), HSCT-BMT • Breakthrough disease • Breakthrough disease • Suboptimal or failure to respond • Marker for retreatment • NEDA reliable metric for efficacy • NEDA unreliable to assess efficacy • Rebound activity • Rebound activity • Highly likely • Less likely • Can be life-threatening • Unlikely to be life-threatening • Pregnancy • Pregnancy • No potential for a cure • Potentially ‘curative’? • Rebound • 15–20-year experiment • SPMS and progressive brain atrophy

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 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 Genes 15-20 year experiment Environ -ment

Multiple Sclerosis Case study 1 25-year-old woman with RRMS

2011

Optic neuritis

MRI+ve

Patient case scenario provided by Professor Gavin Giovannoni

25-year-old woman with RRMS

2011 April 2015 May 2015

Optic neuritis Brain stem Spinal cord INO triparesis MRI+ve

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

25-year-old woman with RRMS

2011 April 2015 May 2015

Optic neuritis Brain stem Spinal cord INO triparesis MRI+ve

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

25-year-old woman with RRMS

2011 April 2015 May 2015 June 2015

Optic neuritis Brain stem Spinal cord JCV+ve INO triparesis (index = 1.6) MRI+ve

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

25-year-old woman with RRMS

What would you do?

Patient case scenario provided by Professor Gavin Giovannoni

25-year-old woman with RRMS

2011 April 2015 May 2015 June 2015 Sept 2015

Optic neuritis Brain stem Spinal cord JCV+ve Severe spinal cord relapse, INO triparesis (index = 1.6) paraparesis, loss B&B, pressure MRI+ve sore IV methylprednisolone IV methylprednisolone Anti-AQ4 −ve

IV methylprednisolone IV methylprednisolone ×2

EDSS = 5.0 EDSS = 7.0 → 6.5

Natalizumab Natalizumab or or Alemtuzumab? Alemtuzumab?

Pressure sore Urinary catheter

Patient case scenario provided by Professor Gavin Giovannoni AQ4, Aquaporin-4; RRMS, relapsing-remitting multiple sclerosis Haines JD, et al. Mt Sinai J Med 2011;78:231−43; Münzel EJ, et al. Drugs 2013;73:2017−29 25-year-old woman with RRMS

2011 April 2015 May 2015 June 2015 Sept 2015

IV methylprednisolone IV methylprednisolone ×2

EDSS = 5.0 EDSS = 7.0 → 6.5

Natalizumab Natalizumab Natalizumab or or Alemtuzumab? Alemtuzumab?

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;73:2017−29 Switching from natalizumab to alemtuzumab

Option 1: Immediate switch (high risk if carry-over PML develops) Asymptomatic PML? LP-JCV DNA & MRI Natalizumab Alemtuzumab

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity) Asymptomatic PML?* Rebaseline LP-JCV DNA & MRI MRI** 3−6 MONTH Alemtuzumab Natalizumab 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

Option 3: Bridging (low risk; mainly related to using a low efficacy bridging agent and using alemtuzumab after the bridging agent) Asymptomatic PML? Rebaseline LP-JCV DNA & MRI 6−12 MONTHS MRI Natalizumab Oral bridging agent (Teriflunomide, DMF or Fingolimod) Alemtuzumab

DMF, dimethyl fumarate; LP, lumbar puncture; PML, progressive multifocal leukoencephalopathy 25-year-old woman with RRMS

2011 April 2015 May 2015 June 2015 Sept 2015

IV methylprednisolone IV methylprednisolone ×2

EDSS = 5.0 EDSS = 7.0 → 6.5

Natalizumab Natalizumab Natalizumab or or Alemtuzumab? Alemtuzumab? 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;73:2017−29 Case study 2 38-year-old woman with RRMS

Teacher 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 38-year-old woman with RRMS

• Switched to interferon-beta (IM IFNbeta-1a; www.msdecisions.org.uk) • 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 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 www.ms-res.org

Teacher Unemployment

Kobelt, et al. J Neurol Neurosurg Psychiatry 2006;77:918–26 38-year-old woman with RRMS 38-year-old woman with RRMS

Teacher

? 38-year-old woman with RRMS 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 38-year-old woman with RRMS

Teacher

Natalizumab

Fingolimod Bermel RA, et al. Ann Neurol 2013;73:95−103 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 Case study 3 17-year-old girl, presents with myelitis

Jun 2000 Myelitis Feb 2001 1st-year university L-optic neuritis

IFN-beta

Jun 2000 IFN-beta EDSS 17-year-old girl, presents with myelitis

Jan 2002 Clumsy Jun 2000 left hand Myelitis Oct 2003 Feb 2001 Pins & needles in legs 1st-year university L-optic neuritis Mar 2004 R-optic neuritis

IFN-beta Dec 2007 How are you going to Brainstem syndrome; manage her?

diplopia and ataxia

Jun 2000 IFN-beta EDSS 17-year-old girl, presents with myelitis

Jan 2002 Clumsy Jun 2000 left hand Myelitis Oct 2003 Feb 2001 Pins & needles in legs 1st-year university L-optic neuritis Mar 2004 R-optic neuritis

IFN-beta Dec 2007 Brainstem syndrome; diplopia and ataxia

Jan 2008 Cervical cord relapse weak L arm with pain

6.0

Jun 2000 IFN-beta EDSS 17-year-old girl, presents with myelitis

Jan 2002 Feb 2008 to May 2014 Clumsy Jun 2000 NEDA (no evident disease activity) left hand Myelitis Bladder dysfunction Oct 2003 Mild urinary frequency Feb 2001 Pins & needles in legs st 1 -year university Depression, No depression, anxiety, fatigue L-optic neuritis Mar 2004 anxiety, fatigue R-optic neuritis

IFN-beta Reduced mobility Dec 2007 Fully mobile Brainstem syndrome; diplopia and ataxia Residual deficits: Jan 2008 • Walking distance >500m Natalizumab • Unable to run Jan 2008 • Exercise induces intermittent Cervical cord relapse sensory symptoms in L arm weak L arm with pain • Mild urinary frequency

6.0

3.5 3.5

Jun 2000 IFN-beta Natalizumab May 2014 EDSS MRIMRI − progressive – progressive brain atrophy brain atrophy

Dec 2007 Jul 2010 Jul 2013

Is this patient in long-term remission? 17-year-old girl, presents with myelitis

JCV positive - index 2.9

6.0

3.5 3.5

Jun 2000 IFN-beta Natalizumab May 2014 EDSS Switching from natalizumab to alemtuzumab

Option 1: Immediate switch (high risk if carry-over PML develops) Asymptomatic PML? LP-JCV DNA & MRI Natalizumab Alemtuzumab

Giovannoni et al. Pract Neurol. 2016 Oct;16(5):389-93.

17-year-old girl, presents with myelitis

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

6.0

3.5 3.5 Natalizumab May-2014

EDSS Jun-2000 IFN-beta Switching from natalizumab to alemtuzumab

Option 1: Immediate switch (high-risk if persistent lymphopenia occurs) Treat with alemtuzumab before lymphocyte counts normalize Fingolimod Alemtuzumab

Option 2: Washout (intermediate risk; mainly related to rebound of MS disease activity) Only treat with alemtuzumab once lymphocyte counts normalize* 2 to 6 12 MONTH Fingolimod Alemtuzumab WASHOUT * 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 1.0 ×109

Option 3: Bridging (low risk; mainly related to MS rebound as a result of using a low efficacy bridging agent after fingolimod) Only treat with alemtuzumab once 3-12 MONTHS lymphocyte counts normalize* Fingolimod Bridging agent (IFN-beta, GA, teriflunomide or DMF) Alemtuzumab

* 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 1.0 × 109

Giovannoni et al. Pract Neurol. 2016 Oct;16(5):389-93.

BartsMS blog

www.ms-res.org Natalizumab Alemtuzumab • Continuous treatment (monthly infusions) • Short-course pulsed therapy (2−5 annual cycles of treatment) • Very high efficacy; high NEDA rates, significant proportion of subjects improve • Very high efficacy; significant proportion of subjects improve • Prevents end-organ damage (reduced brain atrophy at year 2) • Reported NEDA rates low, but not measured in correct epoch • Reversible treatment effect • Prevents end-organ damage (reduced brain atrophy at year 2) • Infusion reactions uncommon • Irreversible treatment effect • No short-term generalized immunosuppression • Infusion reactions the norm • Reduced immune surveillance increases risk of CNS infections; in particular • Short-term generalised immunosuppression (8−12 weeks post infusion) PML if JCV-seropositive • Low risk of CNS and other infections after immune system reconstitution • Breakthrough disease • Breakthrough disease • Re-baseline at 3−6 months • Re-baseline at 24 months • Neutralizing antibodies to natalizumab reduce efficacy and cause • Antibodies to alemtuzumab are transient and don’t appear to inhibit activity of drug infusion reactions • Marker for retreatment • Suboptimal or failure to respond • NEDA unreliable to assess efficacy • NEDA reliable metric for efficacy • Rebound activity • Rebound activity • Less likely, unlikely to be life-threatening • Highly likely, can be life threatening • Pregnancy • Pregnancy • Fine once immune system reconstituted • Not recommended, natalizumab crosses placenta and has transient • Potential for autoantibodies to cross placenta, for example neonatal hyperthyroidism effects in baby • Secondary autoimmunity; ~50% of patients with long-term follow-up − mainly thyroid related • No secondary autoimmunity • Potential, but undefined, secondary malignancy risk • No obvious secondary malignancy risk • Monitoring: yes, monthly blood and urine tests for secondary autoimmunity and annual MRI • Monitoring: yes, blood and liver function tests early on, anti-natalizumab • antibodies, JCV serology and annual MRI Potentially curative • • No potential for a cure Long-term remission established in about 50% of treated patients • • Rebound Ongoing 15−20 year experiment, analogous to BMT