Treatment of MS Alina Webber Neurology R 3

Treatment of MS Alina Webber Neurology R 3

Outline • • Overview of MS Acute treatment (relapse) Long term management MS and Lifestyle

MS (A brief overvveiw) • Figure. A: RRMS is characterized by acute attacks with full recovery or with partial recovery. B: SPMS starts with a RR course followed by a progressive phase. C: PPMS is characterized by progression from onset of disease without acute relapses. D: PRMS is characterized by progression from onset of disease with acute relapses. Data from Lublin F, et al. [2]

Pathogenesis of MS T cells, B cells and antigen-presenting cells (APCs), including macrophages, enter the central nervous system (CNS), where they secrete certain chemicals known as cytokines that damage the oligodendroglial cells. Lymphocytes diapedese into the CNS through use of a surface receptor known as alpha 4 integrin. This step is impeded by antibodies specific for alpha 4 -integrin or by interferon-beta (IFN-beta). Once the blood–brain barrier is breached, other inflammatory cells accumulate in the white matter. Inside the brain, T cells and accompanying macrophages and microglial cells release osteopontin (OPN), interleukin-23 (IL-23), IFN-gamma and tumour-necrosis factor (TNF), all of which damage the myelin sheath. Also, the presence of OPN might lead to the attraction of T helper 1 (TH 1) cells. T-cell activation can be blocked by altered peptide ligands (APLs), such as copaxone, or by statins. Concomitantly, B cells (plasma cells) produce myelinspecific antibodies, which interact with the terminal complex in the complement cascade to produce membrane-attack complexes that further damage oligodendroglial cells. DNA vaccination can be used to tolerize T- and B-cell responses to myelin. Lawrence Steinman & Scott Zamvil. Nature 2003

Good to know when talking about MS trials… • • EDSS Mc. Donald Criteria Poser Criteria Dinner tomorrow?

EDSS (Expanded Disability Status Scale) EDSS steps 1. 0 to 4. 5 refer to people with MS who are fully ambulatory. EDSS steps 5. 0 to 9. 5 are defined by the impairment to ambulation. (FS = functional systems: cerebellar, bladder, brainstem, sensory, motor… ) 0. 0: Normal Neurological Exam 1. 0: No disability, minimal signs on 1 FS 2. 0: Minimal disability in 1 of 7 FS 3. 0: Moderate disability in 1 FS; or mild disability in 3 - 4 FS, though fully ambulatory 4. 0: Fully ambulatory without aid, up and about 12 hrs a day despite relatively severe disability. Able to walk without aid 500 meters 5. 0: Ambulatory without aid for about 200 meters. Disability impairs full daily activities 6. 0: Intermittent or unilateral constant assistance (cane, crutch or brace) required to walk 100 meters with or without resting 7. 0: Unable to walk beyond 5 meters even with aid, essentially restricted to wheelchair, wheels self, transfers alone; active in wheelchair about 12 hours a day 8. 0: Essentially restricted to bed, chair, or wheelchair, but may be out of bed much of day; retains self care functions, generally effective use of arms 9. 0: Helpless bed patient, can communicate and eat 10. 0: Death due to MS Kurtzke JF. Neurology. 1983; 33: 1444 -52.

Mc. Donald Criteria • • • Origianlly devised in 2001 by Dr. Ian Mc. Donald. They made use of MRI, and were intended to replace old Poser and Schumacher criteria. Recent update and change to criteria in 2010 (out of criticism that non-caucasion pts did not fit the origincal criteria

A Historical note: Poser Criteria • Replaced Shumaker criteria for diagnosis of MS. • Clinically definite MS – 2 attacks and clinical evidence of 2 separate lesions – 2 attacks, clinical evidence of one and paraclinical evidence of another separate lesion • Laboratory supported Definite MS – 2 attacks, either clinical or paraclinical evidence of 1 lesion, and cerebrospinal fluid (CSF) immunologic abnormalities – 1 attack, clinical evidence of 2 separate lesions & CSF abnormalities – 1 attack, clinical evidence of 1 and paraclinical evidence of another separate lesion, and CSF abnormalities • Clinically probable MS – 2 attacks and clinical evidence of 1 lesion – 1 attack and clinical evidence of 2 separate lesions – 1 attack, clinical evidence of 1 lesion, and paraclinical evidence of another separate lesion • Laboratory supported probable MS – 2 attacks and CSF abnormalities SCHUMACKER et al. Ann N Y Acad Sci. 1965 Mar 31; 122: 552– 568 Poser CM, Paty DW, Scheinberg L, et al. (March 1983). Annals of Neurology 13 (3): 227– 31

Steroids, and acute MS

Treatment of the acute attack • History: • First RCT in 1970’s: adrenocorticotropic hormone (ACTH) was given IM. (Rose et al, 1970) • n~200 • Shortened recovery time, but 4 weeks post treatment there was no clinical difference. • Prominent SE’s (Na retention, hyperglycemia, Psych disorders) was what prompted trials of synthetic corticosteroids with a short half life. • 1992: Several RCTs emerged with methylprednisolone (but the duration and dose of treatment varied from 500 mg IV QD x 3 days to 1000 mg IV QD x 10 days. Some trials showed benefit of PO methylprednisolone (500 mg PO QD x 5 d) (Meyers 1992, medlink)

Current Protocol? • MOST COMMON CURRENT PROTOCOL: 3 -7 day course of IV methylprednisolone (500 -100 mg IV QD) with OR without a short taper • Methyprednisolone reduced the risk of worsening or not improving within 5 weeks. No long term benefits, however, just a quicker recovery. • Why not PO glucocorticoids? • Barnes, Lancet 1997: RCT, n~80 acute MS relapses: • Methlprednisolone 48 mg PO x 7 d, then 24 mg PO x 7 d, then 12 mg PO x 7 d. • Vs. 1000 mg IV methylpred x 3 days. • No statistical difference in EDSS at 4 weeks. • The authors concluded that oral steroids was a better regime in terms of cost, pt preference….

So, why not PO steroids? • • The Optic Neuritis Treatment Trial (ONTT) 314 patients. Random assignment to: • PO prednisone 1 mg/kg/d x 14 days, with a 4 day taper • IV methyprednisolone 250 QID x 3 days, PO pred 1 mg/kg/d x 11 days, four day taper. • PO placebo x 14 days • Primary outcome: visual acuity, contrast sensitivity • IV methylpred accelerated recovery, but 1 year outcomes were the same. • IV methypred reduced the risk of conversion to MS (7. 5% vs. 14. 7 and 16. 7% • Oral pred arm had a significantly higher 2 year risk of recurrent optic neuritis in both eyes (30% vs 13 and 16%). At 10 years this risk remained. Beck et al. Am J Ophthalmol. 2004

Steroids continued • Oral regimes are often used for MS exacerbations without optic neuritis. • No good theoretical evidence as to why PO glucocorticoids would do this. • SE’s of short term IV methyprednisolone: • Relatively few • Mental status changes • Unmasking of infection • GI disturbances • Decreased bone density if repeated Tx: yearly bone density scans recommended in pts with repeated treatments.

Other options for acute MS? • PLEX: plasma exchange vs. plasmapheresis? The difference? • Plasma exchange: removal of plasma and replacement with fluids • Plasmapheresis: the removal of plasma (aphaeresis is removal in greek) • The two are often used synonymously in medical literature. • Up to date uses them synonymously: (“Complications of therapeutic plasma exchange” article) Buskard, Can Med Assoc J. 1978

PLEX • May be beneficial in acute severe MS attacks that do not respond to glucocorticoids. • One trial: 22 pts with CNS demyelinating disease (12 MS pts total) assigned to PLEX vs sham. – Moderate to greater improvements (42% PLEX, 6% sham). • A later trial: 116 MS pts: results were that PLEX led to faster improvement in exacerbations that sham. (Note: no long term benefits) • This let the AAN to include PLEX into the guidelines for a possible adjunctive treatment of relapsing MS. Weiner, Neurology. 1989

Disease Modifying Treatment • • Avonex (interferon beta 1 a) Betaseron (interferon beta 1 b) Extavia (Interferon beta-1 b) Rebif (interferon beta 1 a) Copaxone (Glatiramer acetate) Tysabri (natalizumab) Mitoxantrone

Interferons • Pharmacology: Cytokines that mediate antiviral, antiproliferative and immunomodulatory activities in response to viral infections and other biological inducers. • Interferon beta binds to human cells, leads to ifn gene production… exact mechanism not understood, but there are some ideas: • Modulates plasma cell Ig. G synthesis • Decreases antigen presentation in microglia • Anti inflammatory effects via T cells (regulates migration, downregulates adhesion molecules…

The Interferons • History • Landmark paper in the 1980’s (Jacobs et al, 1986) showed for the first time that interferon beta, when intrathecally administered, could improve MS exacerbations. • In 1987 a trial of IV interferon gamma was performed (n=18). (Panitch et al). – The results? A dramatic increase in the relapse rate of patients treated with interferon gamma! – Yet the important discovery that activating the peripheral immune system with peripheral drug administration can change the course of a CNS disease.

History continued • The first approved med by the FDA was interferon beta 1 b in 1993. • In double blind placebo studies, interferon beta 1 b: – Decreases relapses by 34% at 2 years – Decreased T 2 lesion burden at 5 years – Slowed disease progression The IFNB Multiple Sclerosis Study Group. Neurology. Apr 1993; 43(4): 655 -61

Interferon beta-1 a • Interferon beta 1 a had similar efficacy: • 301 patients initially – Exacerbation rate decreased 29% – Disease progression was slowed (progression in 29% of patients on interferon vs 34% in the placebo group). – Decrease in the mean MRI lesion volume and number of enhancing lesions. – The Multiple Sclerosis Collaborative Research Group (MSCRG). Ann Neurol. Mar 1996; 39(3): 285 -94 • Dosing? Evidence of Interferon Dose-response: European North American Comparative Efficacy (EVIDENCE) trial – Relapses occurs less frequently with higher doses, and MRI lesions were reduced with higher doses – Neutralizing antibodies occurred more with higher doses, and this did affect the outcome in pts with neutralizing Abs.

Options for interferons: Brand (Generic Name) Frequency Route of Delivery Once a week Intramuscular (into the muscle) 30 mcg injection Every other day Subcutaneous (under the skin) injection 250 mcg Extavia (interferon beta 1 b) Every other day Subcutaneous (under the skin) injection 250 mcg Rebif (interferon beta 1 a) Subcutaneous Three times a week (under the skin) injection Avonex (interferon beta 1 a) Betaseron (interferon beta 1 b) Usual Dose 44 mcg

Side Effects of Interferons SE Beta-1 b Once every weekly other beta-1 a day 3 x/week management beta 1 a tolerability Local Skin reactions 85% 15% 46% Transient 50% dose Good reduction, or improve injection technique Fever 49% 23% 35% Tylenol, NSAIDS, pentoxyphilline Good Flulike Sx. 52% 61% 56% Tylenol, NSAIDS, pentoxyphilline Good Leuko or thrombocyt openia 40% 8% 20% Transient 50% dose reduction Good Increased liver enzymes 19% 10% 20% Transient 50% dose reduction Good (disappear within months.

Interferon Beta SE’s continued… SE Beta-1 b Once every weekly other beta-1 a day 3 x/week management beta 1 a tolerability Depression 16% 10% 24% Anti-depressants Poor Skin Necrosis 5% 0% 2% Improve injection technique, stop treatment Poor Thyroid alterations 1 -2% Transient 50% dose reduction Good

Other SE’s worth mentioning (that didn’t fit neatly into my table): • Neutralizing antibodies to interferon beta (NAbs) • May effect clinical and MRI efficacy. • Whether or not NAbs are detrimental to initial treatment response is unclear (studies yield mixed results) • NAbs have been more consistantly shown to have a detrimental effect in the long term (3 -4 years) • NAbs occur with a lower frequency in IM interferon 1 A (2 -6%). • Sub. Q interferon beta 1 a (12 -25%) • Interferon beta 1 b (22 -38%)

Monitoring guidelines: – CBC, Chem 7, LFTS at 1, 3, and 6 months. TSH should be checked every 6 months if Hx. Thyroid dysfunction – Psych sx (depression, SI) – Pregnancy test – CXR – EKG

Glatiramer acetate Copaxone is a random polymer of four amino acids found in myelin basic protein, namely glutamic acid, lysine, alanine, and tyrosine. The mixture is antigenically similar to myelin basic protein, a component of the myelin sheath of nerves

Glatiramer acetate (copolymer 1) • Mechanism of action – unclear of the exact mechanism, but: – Experimental models: binds to MCH molecules and competes with myelin antigens for their presentation to T cells. – Induces T helper 2 type suppressor cells to the CNS, these cells express anti-inflammatory granules.

History: • Benefits of Glatiramer acetate first established in a double blind trial of RRMS pts (n=251) (Johnson et al 1995) – At two years, significantly lower relapse rate (29%) – Slowed EDSS progression – No MRI outcome in initial trial. – Other studies, including a 2007 trial which showed similar results and a reduction of MRI activity – • two doses were tested as well (20 and 40 mg). The higher dose was more effective • (Cohen et al, 2007)

SE’s of Copaxone: Frequency Local skin reactions 90% Pain 64% Erythema 57% Pruritis 38% Necrosis 0% Lipoatrophy 45% Systemic reactions 15% Dyspnea 13% Flushing 8% Chest Pain 10% Palpitations 5% Management Tolerability Transient, no treatment Good

Side effects • Generally well tolerated • Short lived skin reactions are most common • Localized lipoatrophy has been reported in up to 45% of pts in some studies, mainly women. • May occur within months of therapy. • Disfiguring, permanent

Monitoring: No routine tests recommended

Fingolimod

Before I talk about Fingolimod, the following was stolen shamelessly from Medscape’s latest CME quiz on Oral MS treatment (An okay video, but sponsored by Novartis):

What factor(s) go into selecting the optimal therapy, both injectable and oral, for patients with RRMS? a) Efficacy, cost, convenience, monitoring, tolerability, and safety b) Burden of therapy c) Safety and efficacy d) Cost, convenience, monitoring, tolerability, and safety

Answer: • Efficacy, cost, convenience, monitoring, tolerability, and safety

Which of the following treatment approaches is best supported by a currently available evidence base in a patient with highly active RRMS who shows breakthrough disease after taking interferon-beta for 6 months? a) Switching to natalizumab b) Switching to fingolimod c) Continuing with interferon-beta for another 6 months and then switching to fingolimod d) Continuing with interferon-beta until steroids can no longer control motor symptoms and then switching to either fingolimod or natalizumab

Answer: A wide body of evidence supports an early switch in RRMS to fingolimod in pt’s with highly active disease and show signs of disease progression while on interferon beta therapy. Little data is available on the benefits of switching to tysabri

For patients with no history of cardiovascular disease and who are considering starting fingolimod, guidelines from the European Medicines Agency (EMA) recommend that they should have their heart activity monitored: a) Before the first dose of fingolimod and continuously overnight after the first dose b) Periodically during the first 6 weeks of therapy c) Never, only patients with a history of cardiovascular disease are at risk of cardiac side effects d) Before the first dose and continuously for at least the first 6 hours thereafter

Answer: The EMA (European Medicines Agency) recommends all patients starting fingolimod should have their heart activity monitored BEFORE the 1 st dose, and continuously for 6 hours. EXTEND monitoring by 2 hours in pts whose HR is lowest 6 h post first dose, or overnight if cardiac problems are clinically significant.

Fingolimod • An Sphingosine 1 -Phosphate (S 1 P)-receptor modulator, derived from a fungal metabolite • Reduces circulating WBCs by sequestering lymphocytes in lymph nodes, preventing them from becoming active. • Originally developed as an antirejection drug, not marketed for this. Now under investigation as a potential CHF/antiarrythmic med.

History: • FREEDOMS trial – N-1272, RRMS patients (0. 5 or 1. 25 mg PO QD) • 24 months: – The annual relapse rate was 0. 18, 0. 16, and 0. 4 (0. 4 was placebo). – Incidence of serious infections was similar. – Macular edema occurred in 7 pts on the high dose group. • TRANSFORMS trial – N = 1200, RRMS pts (0. 5 mg or 1. 25 mg PO QD vs interferon beta-1 a • Relapse rate lower in fingolimod group ( 0. 2, 0. 16 and 0. 33) • MRI favored fingolimod • No change in disease progression • More serious adverse effects in fingolimod groups: (2 serious disseminated infection: 1 herpes, 1 VSV. 12 patients developed skin or breast ca, 19 developed bradycardia or AV block)

SE’s • • • Risk of Herpes virus infections Macular edema Fatal tumor development Headache (25%) Diarrhea (12%) Elevated LFTs (14%) Flu like sx (13%) Cardio: HTN, bradycardia Heme: Lymphopenia, leukopenia

Monitoring: • Before initiation: – CBC, LFTs, – EKG – Optho exam – Varicella serology and vaccination Hx. (Fingolimod should not be started one month after vaccination – Derm exam – r/o precancerous lesions

Monitoring: • First dose; – BP, cardiac monitor x 6 hr (exxtend for 2 more hours if lowest HR at 6 hr post dose), and overnight if cardiac sx. • During Tx: – Avoid live vaccines – Optho exam at 3 mo, and routinely if diabetic or hx uveitis – LFT follow up – Pulmonary Function tests if clinically indicated

Tysabri (Natalizumab) • Tysabri is a monoclonal antibody directed against alpha 4 integrins, specifically the very late antigen 4 (VLA-4) and vascular-cell adhesion molecule 1 (VCAM-1) and lymphocyte functionassociated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1) interactions, respectively • Alpha-4 integrin is expressed on the surface of inflammatory lymphocytes and monocytes and may play a critical role in adhesion to the vascular endothelium.

• Mechanism of action and significance? – Rituximab, Natalizumab, and Efalizamab all inhibit the lyphocytes from binding to the endothelium in a similar manner, and all three are associated with rare cases of PML.

Tysabri: • Two key trials: AFFIRM and SENTINEL – results pooled in a 2011 review: – Significantly reduced the risk of having a relapse during two years of Tx (57%) – Reduced the risk of progression of sx (RR = 0. 74) – NNT to prevents one exacerbation in 2 years was 4. – 83% reduction in MRI plaques – Increased proportion of relapse free patients (32%)

Side effects: Tysabri AFFIRM study ENTINEL study Flu-like syndrome 22% 24% Infections 13% 15% Allergic reactions 7% -- GI disorders 8% 12% Menstrual disorders 5% 18% Chest discomfort 4. 5% <1% Vertigo 6% -- Anxiety -- 12% Tremor 1% 5% Depression 19% 21% Local Bleeding 3% -- Insomnia -- 17% PML -- <1%

Clinical use • AAN guidelines recommend Tysabri be reserved for selected RRMS pts who have failed therapies because of: – Continued disease activity – Medication intolerance (should try both interferons AND copaxone before determining treatment failure/intolerance) – Aggressive initial disease course (debatable*) • Not to be used with beta interferon or other immunosuppresants b/c of PML risk. • Drug Holiday? – NOT recommended (gr 2 C evidence), but a reasonable option for pts who are more concerned about PML.

Monitoring on Tysabri • Before initiating: Leukocyte counts, initial brain MRI, JC serology for risk stratification • Clinical evaluations every 6 months • Monitor for: – hepatotoxicity – hypersensitivity reactions 1 hr post infusion – Consider antibody testing to tysabri if drug holiday (higher risk of allergic rxn) • US: tysabri can only be given in select centers. Manditory patient registry (US) with checklist that asks about PML symptoms.

Mitoxantrone • An antineoplastic drug with long lasting immunosuppressive effects. • Approved for both RRMS and progressive forms of MS (Note: in progressive MS other meds are otherwise used off label) • AAN 2003 Guidelines: because of cardiac toxicity, and limited benefits in small trials, mitoxantrone should be limited to patients who have failed otherapies.

Nausea Frequency 76% Alopecia 61% Menstrual disorders (secondary amenorrhea) Urinary tract infection 60% (10%) Leukopenia (granulocytop enia) 19% (6%) 32% Side Effects: Management Give always intravenous antiemetics before infusions Transient, no treatment (hormonal replacement) Antibiotics (check white blood cell count) White blood cell count 3 to 6 days before and every 10 days after infusions (50% dose reduction in neutrophil count less than 1500 mm 3 Tolerability Good (may be irreversible) Good

SE Frequency Management Tolerability Increased liver enzymes 15% Good Cardiac toxicity 2% Usually transient, 50% dose reduction if greater than 5 -fold baseline Echocardiogram every 6 months or above 100 mg cumulative dose; stop if left ventricular ejection fraction drops by 10% or below 50% Acute leukemia Exceptional May occur even after stopping treatment May progress even after stopping treatment

Multiple other trials for disease modifying drugs with no evidence, or further evidence needed: • • • • Alemtuzumab Azathioprine CCSVI treatment Cladribine Cyclophosphamide Daclizumab Dalfampridine Fumarate Glucocorticoids in combination therapy Intravenous immune globulin Laquinimod Ocrelizumab Rituximab Statins Stem cell transplantation Teriflunomide

Since the first disease modifying treatment came out in 1993, there are now 7 drugs that are FDA approved for use in MS Brand (Generic Name) Frequency Route of Delivery Usual Dose Avonex® (interferon beta-1 a) Once a week Intramuscular (into the muscle) injection 30 mcg Betaseron® (interferon beta-1 b) Every other day Subcutaneous (under the 250 mcg skin) injection Copaxone® (glatiramer acetate) Every day Subcutaneous (under the 20 mg (20, 000 mcg) skin) injection Extavia® (interferon beta-1 b) Every other day Subcutaneous (under the 250 mcg skin) injection Gilenya™ (fingolimod) Every day Capsule taken orally Rebif® (interferon beta-1 a) Three times a week Subcutaneous (under the 44 mcg skin) injection Tysabri® (natalizumab) Every four weeks IV infusion in a registered 300 mg infusion facility 0. 5 mg

Manufacturer/Distributor & Year of Health Canada Approval • Avonex® Biogen Idec Canada — 1998 Betaseron® Bayer Health. Care Pharmaceuticals, Inc. — 1995 Copaxone® Teva Neuroscience — 1997 Extavia® Novartis Pharmaceuticals Canada Inc. — 2009 Gilenya® Novartis Pharmaceuticals Canada Inc. — 2011 Rebif® EMD Serono Canada Inc. — 1998 Tysabri® Biogen Idec Canada Inc. — 2006

For interest’s sake: How much would you guess MS drug treatment costs per year, in Canada?

From MS Society Canada: • Cost of disease modifying therapy: $20, 000$40, 000 (dependant on the drug, the pharmacy, etc) • The amount of reimbursement varies between provinces.

A few small points on complementary tx

MS and Lifestyle • Diet – no recommendations • Vitamin D: • ? Linked to decreased incidence of MS • 1000 -2000 IU vitamin D/day for people who may be vit D deficient. • Exercise • Reduces fatigue, improved bladder and bowel function, strength and mood. • Acupuncture • Studies suggesting benefit, not cosidered to be a CAM to avoid MS Society Canada (2012)

Controversy and new directions Surgeons look over a balloon at the end of the wire, which is put through with a surgical catheter into the patient as part of MS treatment. (JOHN LEHMANN/THE GLOBE AND MAIL)

Commonly use CAM methods to avoid: • Removal of amalgam fillings • Some suggestions that mercury in dental fillings can cause or trigger MS – No evidence • Bee sting therapy • 24 week RCT showed no change in activity, disability or fatigue. No change in quality of life. MS Society Canada (2012)

Thanks!