What is Multiple Sclerosis? Disease Modifying Therapies. Best of all. Why is treatment so important? Outline and Expectations.

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1 What is Multiple Sclerosis? Disease Modifying Therapies for Relapsing Remitting MS Jeanie Lynn Cote, MD Chronic, auto immune disorder. As a consequence of immune attacks, there is loss of myelin (fatty protective covering on nerve fibers) and over time destruction of neurons. This can produce an array of symptoms based on the areas of involvement. MRI will show accumulated lesions and global volume loss over time. Leading cause of disability in working aged. Why is treatment so important? Though study designs and specific results vary, in general disease modifying therapies (DMT s) Decrease the number of relapses Prolong time to the next relapse Delay disability progression Decrease new lesion formation on MRI Decrease brain volume loss* Best of all We have options! Many FDA approved DMTs Even more are coming Outline and Expectations The DMTs Discuss Clinical trial results Dosing Side effects Baseline and surveillance needs Touch upon upcoming treatments Recognize the available treatments for RRMS including generic and trade names and how supplied Be aware of common and more serious side effects Know what surveillance is required based on the treatment used Injections Interferons (5) Glatiramer Acetate Oral Teriflunomide Infusions Natalizumab Novantrone* 1

2 Injection Treatments Interferons Beta 1a (2) Beta 1b (2) Pegylated beta 1a Glatiramer Acetate Interferon 1993: Betaseron (250 mcg SQ, EOD) 1996: Avonex (30 mcg IM, weekly) 2002: Rebif (22 or 44 mcg SQ, TIW) 2009: Extavia (250 mcg SQ, EOD) 2014: Plegridy (125 mcg SQ, every 2 weeks) Seems to modify cytokines towards anti inflammatory production (IL 10, IL4), inhibits release of inflammatory cytokines, enhances regulatory T cell function. Interferon Will focus on trial data for IFN B 1a PRISMS 22 mcg, 44 mcg IFN B 1a (Rebif) and placebo Decreased relapse rate (27 and 32% respectively) Reduction in moderate to severe types of relapses Decrease in median MR lesion load and active T2 lesion (greater in 44 mcg dose) EVIDENCE IFN β 1a 44 μg s.c. t.i.w. vs IFN β 1a 30 μg i.m. q.w aka Rebif vs Avonex Overall, more apt to remain relapse free and with fewer new lesions with higher more frequent dosing. Interferon Side effects Injection site reactions including necrosis Flu like side effects Depression, suicidal ideation Hepatotoxicity Decreased counts Less common: Allergic reaction, thrombotic microangiopathy, thyroid abnormalities, seizure* Baseline CBCPD and LFTs Repeat at 1, 3 and 6 months after starting, and periodically thereafter. Copaxone (1996) Glatopa (2015) Glatiramer Acetate Subcutaneous Injection 20 mg daily 40 mg three times per week (2014) Polymer of four amino acids found in MBP Mechanism unknown, however does appear to shift T cells from pro inflammatory Th1 cells to regulatory Th2 cells Glatiramer Acetate Numerous trials Lowers relapse rate relative to placebo (~ 1/3). Lower rate of lesion formation (both T2 and Gd+). Delayed time to next relapse. PreCISe Early treatment can delay conversion to clinically definite MS (CDMS) by 45 % Study patients had CIS with 2 or more T2 lesions 2

3 Glatiramer Acetate Side Effects Injection Site Reaction Lipoatrophy Post injection flushing / chest pain / tachycardia / anxiety / itching / SOB. 16% Lasts minutes Serious allergic reaction rare Teriflunomide Oral Treatments Monitoring: No routine labs required. Gilenya (2010) 0.5 mg capsule daily Binds to the Sphingosine 1 P receptor. Prevents egress of lymphocytes from lymph nodes, reducing the number of lymphocytes in peripheral blood. FREEDOMS Comparison of 0.5 mg, 1.25 mg and placebo ARR.16,.18 and.4 respectively Relapses were reduced by about half on treatment Reduced risk of disability progression propor on of pa ents disease free over 2 years 30% reduction of brain volume loss. Decreased T2 and Gd+ lesions TRANSFORMS compared to weekly IFN beta 1a Needed to have 1 relapse in last year, or 2 in last 2 years More effective in reducing ARR, rate of lesion development, lower rate of brain atrophy Compared with interferon beta 1a, after switching to fingolimod there were no significant changes in EDSS Side effects Decrease in heart rate / AV conduction Macular edema Headache, nausea, GI upset, aches, LFT abnormalities PRES reported Decrease in PFTs reported Infection (including herpes) 3 Cases of PML 3

4 Prior to starting VZV IgG CBCPD and CMP EKG Baseline eye exam (OCT) Baseline skin exam* First Dose Monitoring 6 hours of monitoring after the first dose. EKG and vitals are tracked Additional observation needed if at 6 hours: PR <45 bpm Nadir has not yet occurred ECG shows new onset second degree or higher AV block May need repeated if doses skipped, based on how long someone has been on treatment. After starting CBCPD and CMP every six months Repeat eye exam at 3 4 months Periodic MR surveillance Aubagio (2012) Teriflunomide 7 or 14 mg daily tablets Pyrimidine synthesis inhibitor, however the exact mechanism is unknown. Appears to affect production of T and B cells. Teriflunomide TEMSO 7 mg and 14 mg of teriflunomide vs placebo Reduced ARR by ~30 % 14 mg risk of sustained disability progression ~ 30 % 40 to 67% in lesion volume compared to placebo Number of Gd+ lesions were reduced with both doses, and trend toward greater effect was observed with the higher dose Teriflunomide Side effects Hepatotoxicity Teratogenicity (X) Decreased WBC / infection Headache, diarrhea, nausea, alopecia Peripheral neuropathy One case of Klebsiella PNA ILD theoretical 4

5 Before starting CBCPD, LFTs, HCG TB testing Teriflunomide Monitoring ALT monthly for 6 months LFTs and CBCPD q6 month thereafter Rapid Elimination Activated Charcoal Cholestyramine Tecfidera (2013) 240 mg capsule, twice daily Dimethyl ester of fumaric acid. Shifts cytokine balance towards an anti inflammatory / Th2 state. Activates anti oxidant pathways to reduce oxidative stress. DEFINE Comparing BID and TID dosing to placebo BID ARR by ~ 50% at one year risk of sustained disability progression ~ 38 % CONFIRM Comparing 2 doses of Tecfidera, Copaxone and placebo Not designed to compare the effectiveness of Tecfidera to Copaxone. Significant reduction in disease activity on MR. relapse rates % for Tecfidera compared to placebo. If curious, Copaxone decreased rates ~ 29% compared to placebo. ENDORSE (Extension Study) Evaluating long terms safety and efficacy 2014: Case of PML in MS after 4 yrs of treatment Prolonged lymphopenia may have contributed Side effects Lymphopenia GI upset Flushing Anaphylaxis Pre testing CBCPD, HCG Surveillance CBCPD every 6 months, with particular attention to the lymphocyte count 5

6 Infusions Natalizumab (Tysabri) (Lemtrada) Mitoxantrone (Novantrone) Tysabri (2004) Natalizumab 300 mg IV infusion, monthly Must be TOUCH registered Monoclonal antibody, alpha 4 integrin inhibitor. Prevents migration of leukocytes across vascular endothelium to parenchyma. Natalizumab AFFIRM Reduced risk of disability progression over 2 years by 42% 54% Decreased ARR by 68% during a period of 2 years. 83 % reduction in the accumulation of new or enlarging T2 hyper intense lesions 92 % fewer Gd+ lesions Natalizumab (Tysabri) Side effects / risks Well tolerated Occasional headache / fatigue post infusion. More rarely HSV and VZV Meningitis / encephalitis Hepatotoxicity Allergic reaction / hypersensitivity PML Monitoring includes JCV Ab q 6 months. LFTs as indicated Progressive Multi Focal Leukoencephalopathy Opportunistic viral infection of the brain (JCV) Neuropsychiatric changes and evolving focal neurologic symptoms Progress over days to weeks May include progressive weakness on one side of the body, clumsiness, disturbance of vision, changes in thinking, memory or orientation leading to confusion and personality changes. PML MRI Single or multifocal lesions, large or confluent Indistinct borders Grey and white matter No mass effect No enhancement Most commonly subcortical WM, cerebellar hemispheres, cerebellar peduncles, brain stem Hyperintense on T2/FLAIR, hypointense on T1. JCV PCR in CSF 6

7 Natalizumab associated PML Risk influenced by: JCV status Duration of treatment Previous immunosuppression Natalizumab associated PML Management includes PLEX Improves survival Accelerates drug clearance and immune reconstitution Tysabri Exposure No prior Prior immunosuppresion immunosuppression 1 24 months < 1 / 1,000 1 / 1, months 3 / 1,000 (1:333) 12 / 1,000 (1:83) months 6 / 1,000 (1:140) 13 / 1,000 (1:75) Caution for IRIS PML and 3 post marketing reports of PML in patients on Not previously on Natalizumab One after ~ 2.5 years Another with probable PML after 4 years 3 rd with concomitant history of Crohn s and past chemo exposure Lemtrada (2014) Annual IV infusion Year 1: 5 daily infusions Year 2: 3 daily infusions *Herpetic prophylaxis for 2 mo or CD4 > 200 cells/ml CD52 directed monoclonal antibody (Ab), which binds to T and B lymphocytes, NK cells, monocytes and macrophages. Following binding there is Ab dependent cellular cytolysis and complement mediated lysis. CARE MS I 2 year trial Compared to IFN Beta 1 a (Rebif) in treatment naïve patients ARR of.18 vs 0.39 for Rebif (~ 50% reduction) 60% in severe relapses requiring steroids Significant decrease in frequency of Gd+ lesions 15% on Lemtrada vs 27% on Rebif Care MS II Compared to INF Beta 1 a (Rebif) In patients who had prior relapse on an injectable ~ 50 % improvement in ARR 65% relapse free at 2 years (47% with Rebif) Subset highly active disease, 24% relapse free at 2 years Decrease in brain volume loss Decrease in lesion formation in mean disability score (slight worsening on Rebif) Extension: 70% of EDSS stable to improved at year 3 7

8 Side Effects Other autoimmune disorders Thyroid (34%) Immune thrombocytopenia (ITP, 2%) Anti glomerular basement membrane disease (0.3%) Other cytopenias (0.2%) Infusion reactions Anaphylaxis, Headache, fatigue, rash etc. Increased risk of malignancy, including thyroid, melanoma, lymphoproliferative disease Infections Herpes, Nasopharyngitis, UTI, URI, flu, fungal (Candida, listeria) Pre testing Skin exam Thyroid function Blood count Renal function UA with cell counts VZV IgG (and provide vaccine if needed 6 weeks prior) Tb screening per local guidelines (per insert) Consider Hep B / C screening in high risk patients Surveillance is for 48 months following the last dose Annual skin exam Thyroid studies q3 month Monthly CBCPD Monthly S Cr Monthly UA with counts Annual HPV screening Mitoxantrone Novantrone (2000) RRMS and SPMS IV infusion provided q 3 months Lifetime dose limit of 140 mg/m2 Single dose is 12 mg/m2 Cardiac disease, liver failure and leukemia Rarely used today Other / Emerging Therapies Rituximab Ocrelizumab Ofatumumab Daclizumab 8