Progressive MS Research Update

1. Progressive MS Research Update David E. Jones, MD Director, MS Center

2. Multidisciplinary Symptom Mgmt Community Involvement Comprehensive MS Center MS Specialists Research Comprehensive Care of MS

3. History of Multiple Sclerosis • Saint Lidwina of Schiedam • A Dutch nun from 1400’s with intermittent pain, leg weakness, vision loss • Augustus Frederick d’Este • Grandson of King George III whose diary (1822-1846) describes episodes of LE weakness, dizziness, bladder dysfunction, clumsiness • Jean-Martin Charcot • Clinicopathological treatise of patient with dysarthria, ataxia, and tremor in 1868

4. Multiple Sclerosis • Likely, a chronic, inflammatory condition of the CNS likely induced by an environmental trigger in a genetically susceptible patient • “Neurological lesions disseminated in time and space” without an alternative explanation for symptoms

5. Clinical MRI Paradox 36yo woman Avid hiker, recently completed PhD EDSS 2.0 42yo woman Cane and bilateral MAFO EDSS 6.0

6. Regeneration Degeneration Inflammation Time Onset of Disease Immunopathogenesis of RRMS Early inflammation lead to demyelination and axonal loss; this may be what drives degeneration. A C B Compston A, et al. Lancet. 2008;372:1502-1517; Kuhlmann T, et al. Brain. 2002;125:2202-2212; Paolilo A, et al. J Neurol. 2004;251:432-439.

7. Subtypes of MS 1. Relapsing-remitting 2. Primary-progressive Increasing disability Increasing disability Time Time 3. Secondary-progressive 4. Progressive-relapsing Increasing disability Increasing disability Time Time Lublin FD, Reingold SC. Neurology. 1996;46:907-911.

8. Relapsing Remitting MS • RRMS • 85% of patients with MS start with a relapsing remitting course • Exacerbations / Flares / Relapses • Rapid onset of new symptoms • Association with gadolineum enhancement on MRI • May improve resolve over weeks to months (remission) • Steroids (iv) speed up the improvement and likely delay future events • Pseudo-exacerbation • Previous symptoms can reoccur / worsen in setting of infection, heat, stress • Inflammation plays a big role, but there is evidence of degeneration / atrophy in RRMS • Treatment delays progression into SPMS

9. Progressive MS • Degeneration plays more of a role in progressive MS • Secondary Progressive Multiple Sclerosis (SPMS) • Currently felt to be about 30% of MS patients • Always follows relapsing-remitting MS (RRMS) • Transition from episodic flares to slow, gradual worsening of symptoms independent of flares • Often occurs 10-20 years after beginning of MS (highly variable) • Primary Progressive Multiple Sclerosis (PPMS) • ~10% of multiple sclerosis patients • Gradual worsening of symptoms without preceding flares • Can have mild fluctuations in symptoms • Rare cases of PPMS will have occasional relapse (PRMS) • 85% predominance of spinal cord symptoms (myelopathy) • Slow worsening of gait is the most common presentation • Sex ratio 1:1 • Later onset of symptoms (~45yo)

10. Treatment of Progressive MS • All of our therapies work on the inflammatory component of the disease; however, progressive MS is felt to be more degenerative. • None of the currently approved medications have been proven to alter the course of progressive MS • Failed trials in PPMS • Rituxan (OLYMPUS) – possible response if <50yo, have relapses, or enhancing lesions • Copaxone • Mitoxantrone • Trials suggesting effects in disease transitioning to SPMS • Betaseron (European trial) • Mitoxantrone • Failed trials in SPMS • Betaseron (North American trial) • Dirucotide (MBP 8298)

11. Treatment of Progressive MS • My approach • Assess for amount of inflammation • Gad-enhancing lesions, positive spinal fluid, response to iv corticosteroids • If evidence of inflammation, consider off-label immunosuppressive drugs (Rituxan, Cellcept) • Occasional pulses of steroids is another approach • Steroids come with risks

12. Natalizumab (Tysabri) • Monoclonal Ab to VLA-4 • Disrupts interaction with VCAM-1 • Reduces ability of WBCs to cross the BBB • Efficacy (vs placebo) • Reduces relapses by 67% • Reduces disability progression by 42-54% • Reduces enhancing lesions by 92% • Reduces black holes by 76% Polman NEJM 354; 2006.

13. Natalizumab (Tysabri) • Improvement in Disability (EDSS) • 29.6% of patients had sustained improvement in physical disability (vs 18.7% placebo) • Improvement in Disability (MSFC) • Improvement in 25 foot walk speed • Improvement in 9 hole PEG test • Improvement in cognitive function (PASAT) • Improvement in quality of life (QOL) • Both physical and mental components

14. Progressive Multifocal Leukoencephalopathy (PML) • Rare, opportunistic infection of brain myelin caused by JC virus • Dysarthria, ataxia, cognitive impairment, cortical blindness • Symptoms progress over 1-3 months • JC virus is latent in many people (kidneys, bone marrow) • 50% in recent studies (old studies suggesting 80% included BKV) • Can reactivate in AIDS, CLL, organ transplant patients • No proven treatment, can be fatal • AIDS patients can reverse infection if immune system restore

15. PML with natalizumab

16. PML with natalizumab • As of December, 2011 • 95,300 patients exposed, 55% of which in the US • As of March, 2012 • 212 reported cases of PML with natalizumab, 38% in US • 46 deaths; others with varying degrees of disability • 10% mild, 50% moderate, 40% severe disability • 42% of cases were previously treated with immunosuppressant • Per TYGRIS, 14% of US patients and 24% of EU patients previously on IS • Novantrone 17 • Imuran 5 • Methotrexate 5 • Cellcept 5 • JC virus antibody assay • 59/59 patients with serum collected before PML (or even starting natalizumab) were JCV positive

17. PML with Natalizumab

18. Natalizumab (Tysabri) • ASCEND SPMS • Ongoing clinical trial of Tysabri in SPMS • Rationale - CXCL13 • May be a marker for SPMS • May be involved in SPMS • Is reduced by natalizumab

19. S1P Activation Proliferation anddifferentiation Lymphatic sinus Afferent lymphatic vessel Sinus-lining endothelium Activated T cells S1P1 receptor Naïve T cell Efferent lymphatic vessel Lymph node S1P1downregulation Sinus-lining endothelial cellbarrier enhancement Reduced T cell egress Fingolimod Fingolimod (Gilenya) • First approved oral DMT disease for MS • MOA – traps ~70% of circulating immune cells in LN Horga Expert Rev Neurother 8;2008.

20. Fingolimod (Gilenya) • TRANSFORMS – fingolimod vs. IM interferon-beta (Avonex) • 52% reduction in ARR; 80-83% of patients relapse free • No difference in disability (only 12 month trial) • 2 deaths (herpetic infection), 15 cardiac conduction abnormalities, 8 macular edema, 3 melanoma • FREEDOMS 1 – EU fingolimod vs placebo • 54-60% reduction in relapses • 30-32% reduction in sustained disability (24 month trial) • No significant difference in infection or malignancy, 3 cases macular edema, few asymptomatic cardiac conduction abnl • FREEDOMS 2 – US fingolimod vs. placebo • 48% reduction in ARR • 17-28% reduction in SAD (NS) • 74% reduction in new T2; 70% reduction in Gd+ Cohen NEJM 2010; Kappos NEJM 2010.

21. S1P Bronchial smooth muscle Vascular smooth muscle • Angiogenesis (S1P1) • Vasodilation (S1P1, 3) • Barrier decrease (S1P2–3) • Barrier enhancement (S1P1) • Airways hyperactivity (S1P1–3) Vascular endothelium Atrial myocytes Retina • Vasoconstriction, blood pressure increase (S1P1–3) • Heart-rate reduction and regulation (S1P1, 3) • Swelling(S1P2) Fingolimod (Gilenya) Brinkmann Pharmacol Ther 115;2007.

22. Recent changes with fingolimod (Gilenya) • Defined patient selection: • Appropriate - no pre-existing CV conditions, baseline EKG OK, no meds to lower HR • Caution – h/o CAD/CHF, CVD, HR-lowering drugs, recurrent syncope, severe OSA, mild dysryhthmias • Avoid – recent CAD/CHF, CVD, Class 1a or III antiarrhythymics, QTc > 500, Mobitz II or greater AV block • Monitoring: • Hourly 6 hours; ECG before and after • Overnight with caution or with symptoms during monitoring

23. Fingolimod (Gilenya) • INFORMS clinical trial in PPMS • Potential role in repair of myelin • S1P receptors in oligodendrocyte progenitor cells (OPCs) • In vitro studies suggest can stimulate OPCs, inducing production of myelin

24. Dimethyl fumarate (BG00012) • Presented to FDA 2/12 • MOA • Cytokine shift to more anti-inflammatory, Th2 cytokine milieu • May be neuroprotective (activation of nrf2/keap1 antioxidant pathway) • Phase II data • 69% reduction in Gad lesions • DEFINE study • 2 year, placebo-controlled, Phase 3 study of BG12 240mg bid and tid in patients with RRMS (n=1,011) • 54% reduction in relapses in bid group • 38% reduction in disability progression • 85% reduction in new MRI lesions; 90% reduction in gad

25. Dimethyl fumarate (BG00012) • CONFIRM trial • 2 yr Phase 3 study of BG12 bid and tid vs Copaxone vs placebo • 44% reduction in ARR in bid dose, 51% reduction in tid dose, 29% reduction in Copaxone group (vs placebo) • 65-7( % reduction in Gd+; 71-73% reduction in new T2 • Disability chg NS (very little progression in placebo group) • Safety • Seemingly few issues; available for psoriasis (Fumaderm) in Germany since 1994 • Flushing, especially first month (aspirin may reduce) • GI side effects, including diarrhea initially • Given potential “neuroprotection”, may be reasonable to study in progressive MS

26. Laquinimod • MOA • Unclear; suspect shift in cytokine milieu to Th2; may be neuro-protective • ALLEGRO: 2 year, placebo-controlled, Phase 3 study of laquinimod 0.6mg in pts with RRMS (n=1,106) • Efficacy • 23% reduction in relapses; 36% reduction in disability progression • Reasonable MRI data • Safety data appears promising • Reversible LFT elevations; back & abdominal pain • BRAVO: 2 year, comparator (placebo or Avonex), Phase 3 study of laquinimod 0.6mg in pts with RRMS (n=1,331) • Efficacy • 21% reduction in ARR (after correcting for randomization “dissimilarity”) - NS • 34% reduction in SAD; 28% reduction in brain atrophy • Pooled analysis • 21% reduction in ARR; 34% reduction disability; 30% reduction in atrophy • Would be reasonable to study in progressive forms of MS

27. Rituximab / Ocrelizumab • MOA • Humanized anti-CD20 monoclonal antibody; depletes B cells • Efficacy • HERMES Phase 2trial of rituximab in RRMS showed >50% reduction in relapses; 91% reduction in Gd+ • 96 week trial of OCR (600 and 2000mg) vs placebo or Avonex in 220 patients with RRMS; 73-80% reduction in ARR; 89-96% reduction in T2 lesions at 24 weeks • No gad or new T2 lesions weeks 24-96 • 67.3% of patients free of clinical activity at 96 week • 78-80% of patients relapse free • Ofatumumab (human) forms of rituximab • 99% reduction in Gad lesions • ORATORIO • Trial in PPMS

28. Anti-LINGO • Myelin-producing cells (oligodendrocytes) are dying in evolving MS lesions • One of the key causes of axon loss is myelin damage • Is it possible to make more oligodendrocytes? • Oligodendrocyte Precursor Cells (OPCs) are not rare in MS lesions, are sitting at the periphery • LINGO is a molecule that keeps OPCs quiet • Anti-LINGO molecule is under development • Entering Phase II

29. Stem Cells • Autologous hematopoietic stem cell transplantation (AHSCT) • “Treat MS by resetting the immune system” • Remove immune stem cells from bone marrow • Obliterate immune cells with high dose chemotherapy / radiation • Replace stem cells to reset immune system • This is treatment for RRMS • Replacement of oligodendrocytes (myelin) • Potential problem – tumor formation • Replacement of neurons • Problem – creation of neural networks • Adult human mesenchymal stem cells • International MSCT Study Group • Cells may be anti-inflammatory, promote repair, and potentially secrete substances that help protect axons / neurons

30. Low Dose Naltrexone (LDN) • Excitement at “grass roots” level • Opioid agonist, increased β-endorphins • ? Placebo effect • Compounding pharmacy • Studies • 17 patients with MS • Self-reported decreased disease activity • 35 patients with PPMS (open-label) • Improved fatigue and depression • 80 patients with MS (randomized) • Improved QOL, pain, cognition • My take – probably safe, may offer symptomatic benefit Cree, B. et al. Ann Neurol 2010,

31. And The Bizarre … • Chronic Cerebrospinal Venous Insufficiency (CCSVI) • Reports from Italy suggested abnormalities in venous drainage of the brain in patients with MS • Zivadinov - >500 ultrasounds • Approx. 55% of MS patients with CCSVI, 45% of pts with OND • 22% of healthy controls with CCSVI • Most recent papers - no CCSVI • No data to suggest CCSVI causes MS • Studies of interventions correcting these narrowings have been initiated • “Liberation therapy” • Thus far, no positive data to support this practice • Recent FDA warnings

32. Treatment of Progressive MS • There is even more hope … • In NY database of MS patients, up to 25% of patients with PPMS do not require a cane at 20 years. • There are significant benefits of attainable with appropriate multidisciplinary management of symptoms in a comprehensive MS center

33. Physical Therapy / Exercise • Randomized trial of efficacy of resistance training in RRMS • Exercise group • 15% improvement in strength • 21% improvement in functional status • Mild improvements in mood, fatigue, QOL • Biopsy – increase in size of muscle fibers • Obvious benefits of physical therapy in MS in other trials

34. Fatigue • Most common (and frequently most disabling) symptom of MS • Physical lassitude that hits “like a Mack truck” and feels like “carrying weights” • Compounded by increased energy expenditure needed to compensate for motor disability • Potential confounders, especially if “sleepiness” • Obstructive sleep apnea • Physical deconditioning • Drug side effects • Frequent nocturia • Depression • Treatment • Non-pharmacological • Maintain appropriate sleep • Energy conservation – pacing, planning activities • Mild exercise to prevent physical de-conditioning • Pharmacologic • Amantadine, Provigil, stimulants, l-carnitine?

35. Abnormal Mobility • Goal - safely maximize independence • Ambulatory patients • Strengthening • Treat spasticity • Treat foot drop • Modified ankle-foot orthosis (MAFO) • Peroneal stimulators - WalkAide, Bioness • Assistive devices • Ampyra • Non-ambulatory patients • Scooter, wheelchair to maintain independence • Augment ability to transfer • Transfer boards, Hoyer lift, grab bars • Meticulous skin care

36. Spasticity • “Velocity-dependent resistance to muscle stretch” • Complications of spasticity • Limitations in ability to walk / transfer • Pain, muscle spasms • Increased fatigue • Joint changes • Pressure sores • Benefits • Compensation for weakness • Exacerbating factors • Stress, infection, pain, temperature changes • Treatment is multifactorial • PT / OT - ROM / stretching, strengthening • Meds - baclofen, Zanaflex, BOTOX • Baclofen pump

37. Neurogenic Bladder • 2 basic problems • Failure to store – spastic bladder • Urgency, frequency, incontinence • Treatment • Timed void, pelvic floor therapy • Avoid bladder irritants (caffeine, alcohol) • Anticholinergics - Detrol, Ditropan, etc. • Failure to empty – atonic bladder or spastic sphincter • Hesitancy, retention, UTIs, incontinence • Treatment • Double voids, pelvic-floor therapy • Clean intermittent catheterization • Flomax? • Combination –> detrusor-sphincter dyssynergia

38. Sexual dysfunction • Lack of desire (Libido) • Psychological issues, including altered identity roles • Physical factors, including fatigue, bowel/bladder dysfunction, pain • Lack of arousal • Women • Diminished sensation in pelvic floor may cause decreased arousal • Vibrators, EROS device, “bag of frozen peas” • Lack of lubrication • Lubricants • Men • Erectile dysfunction • Phosphodiesterase inhibitors – Viagra, Cialis, Levitra • Caverject, prostheses • Anorgasmia • Psychological factors • Fatigue • Can respond to stimulants, alpha agonists

39. Neuropsychiatric Issues • Depression in MS • Situational stressors AND neurotransmitter deficiencies • More common in MS than in other neurological diseases • Requires multi-disciplinary care • Psychologist • Psychiatrist • Activating antidepressants (Effexor, Prozac, Wellbutrin) • Memory issues • Difficulty with processing speed, multi-tasking, rapid word retrieval, problem solving, and maintaining attention • Fatigue, depression, medications can worsen • Pseudobulbar affect • Spontaneous, inappropriate expression of emotion (laughter, crying) • Can respond to TCAs, SSRI • Neudexta

40. Pain in MS • Common causes of primary MS pain • Parathesias, including Lhermitte’s symptom • Most common type of pain in MS • Ephatic transmission between denuded axons • Often, responds to anticonvulsants • Often, lack of response to typical analgesics (i.e., narcotics) • Trigeminal neuralgia • Spasticity is painful! • Secondary MS pain • Osteoarthritis / joint pain can be attributed to abnormalities of gait • Musculoskeletal pain, skin breakdown, compression fractures • Psychiatric / emotional component to pain, especially chronic • Duloxetine (Cymbalta) is approved for depression and neuropathic pain • Role for PT / OT, acupuncture, massage, exercise (yoga, aqua)

41. Conclusions • Relapsing multiple sclerosis has an inflammatory component which has been amenable to anti-inflammatory therapies • Progressive MS may be more degenerative, a process that we do not understand as much • Some of the drugs in development offer hope of neuroprotection • Care of the MS should be multidisciplinary with some focus on symptomatic management