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Home , Dimethyl fumarate, Diroximel fumarate, Fingolimod, Glatiramer acetate, Ozanimod, Ponesimod

6/16/2021

Outline Relapsing Remitting : ▪ Why should we treat MS Treatment Update ▪ Rational for early treatment goals ▪ Treatment consideration in clinical practice ▪ DMT overview Helena Bulka, DO Henry Ford Hospital June 18th , 2021

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Current Standard Treatment NEDA-4 Outcomes In MS

▪ Reduce relapses; extend time b/w relapses ▪ ▪ Reduce severity of relapse No relapse ▪ Prevent or reduce the number (lesion burden), size of ▪ No disability progression new lesions on MRI in order to prevent axonal damage ▪ No MRI activity in (CNS) and mitigate brain atrophy. ▪ Annualized Brain volume loss less than/equal to ▪ Prevent or extend the time to onset of secondary 0.4 progressive stage ▪ Extend time during which there is no evidence of disease activity (NEDA)

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NEDA in Clinical Studies

Neuroinflamation in neurological disease. Behav. Sci. 2019, 9(9), 99. Polmen et. Al. N Engl Med 2006: 354-899 Kappos et al N.Engl J Med 2010:362-387-401

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Choosing the Optimal Therapy selection: Factors to Individualized Treatment Regimen Consider

▪ Patient factors ▪ Disease factors ▪ Drug factors

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Identifying Active and Aggressive Neurofilament Light Protein Disease

Clinical Factors Paraclinical Factors ▪ Proposed biomarker for MS disease activity

• Male gender • High MRI lesion burden at ▪ Structural component of neurons and axons • Older age of onset presentation ▪ Released in CSF after axonal injury • African American/Hispanic • New T2 lesions in the first year of symptom onset − Elevated during relapse or active lesion • Onset with disabling symptoms; − Levels decrease with effective DMT cerebellar and spinal cord • Brainstem, Cerebellum or Spinal disease Cord lesions − Initial level in CSF may predict disease course • Poor recovery from relapses • Brain/spinal cord atrophy ▪ Studies have shown that it can be detected in • Multifocal involvement at onset serum and it does correlate to CSF levels • Early cognitive dysfunction

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FDA Approved disease modifying agents • The concept of MS immunopathogenesis forms the basis for understanding why many of the therapies Indication: have been developed and where or how in the ▪ Relapsing Remitting MS (RRMS) disease process they might make a difference. ▪ Clinically Isolated Syndrome (CIS) with high probability to develop clinical definitive MS ▪ Active Secondary Progressive MS (SPMS) ▪ Primary Progressive MS (PPMS)

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Cells, Molecules, and Therapies. Injectable Oral Intravenous Avonex ( beta- Aubagio () Ocrevus () 1a) Plegridy (pegylated Tecfidera (dimethyl Tysabri () interferon-1a) fumarate) Betaseron ((interferon Vumerity (diroximel Lamtrada () beta-1b) fumarate) Extavia (interferon beta- Bafiertam (monomethyl Novantrone 1b) fumarate) () Rebif (interferon beta 1a) Gilenya () Copaxone (glatiramer Mayzent () acetate) Glatopa (glatiramer Zeposia () acetate) Kesimpta (ofatumumab) Mavenclad ()

Buzzard. Int.J.Mol.Sci.2012,13,12665-12709

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Types of DMTs by Effects to Immune System DMT Overview Approved Emerging (beta 1a, beta 1b, pegylated) Type Therapies Therapies (Avonex, Rebif/Extavia, Betaseron, Plegridy) Immunomodulation IFNs, , dimethyl NA Effects on immune fumarate, , monomethyl fumarate, MOA Cells and mediators Safety issues teriflunomide • Activation of • migration of • ISR General Mitoxantrone, NA IFN on inflammatory cells • Cytopenias leukocytes through the BBB Immune-selective blockade Natalizumab NA • LFTs •  production of • Immune-selective- Fingolimod, Siponimod pro-inflammatory Hepatic injury sequestering Ozanimod Oponesimod • Depression Immune-selective-depleting Alemtuzumab, Ublituximab •  anti- • CHF Ocrelizumab inflammatory Cladribine • Seizures Ofatumumab cytokines

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Glatiramer acetate (Tecfidera), diroximel fumarate (Vumerity), (Copaxone, Glatopa) monomethyl fumarate (Bafiertam)

Effects on immune Effect on immune MOA cells and mediators Safety issues MOA cells and mediators Safety issues • ISR • MBP mimetic • Diverts T-cells • Activates nuclear •  • Severe and/or factor-like 2 (Nrf2) • Competes with response away • Post-injection count by 30% persistent from reaction ( flushing, • Protects against MBP chest , oxidative stress- • 6% lymph count lymphopenia to bind with •  production of palpitations, induced cellular <0.5x109/L • Flushing the MHC II pro-inflammatory anxiety, dyspnea, injury) cytokines (TH1) throat constriction, • Modulates • Pruritus, rash urticaria) immunes system • anti- (induces • GI symptoms • inflammatory Pregnancy Cat:B lymphopenia, alter (less with newer levels and fumarates) cytokines (Th2) inhibit inflammatory • PML pathways.

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Fumarates Monitoring

▪ Diroximel Fumarate (Vumerity) ▪ CBC and diff, CMP prior to initiation − Significantly fewer days with individual GI symptoms ▪ Every three months for first year then every 6 and Impact Scale (IGISIS) months. − Lower discontinuation rates ▪ Check baseline VZV IgG titer, hepatitis and TB status ▪ Monomethyl Fumarate (Bafiertam) − Active metabolite of Vumerity and Tecfidera − Lower GI side effects

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Teriflunomide (Aubagio) Effect on immune Monitoring MOA cells and mediators Safety issues ▪ CBC and diff, CMP prior to medication initiation. • Inhibits •  neutrophils and • Hepatic Injury proliferation of by • Teratogenicity ▪ Check baseline VZV IgG titer, hepatitis and TB activated T and 15% •  blood pressure status B lymphocytes • 12% with • Alopecia ▪ CBC with diff, LFTs (monthly for the first 6 • Inhibits lymphocytes • Interstitial lung months), patients must user reliable mitochondrial ,0.8x109/L disease dihydroorotate • contraception, wash out (if needed). dehydrogenase • GI symptoms ▪ Women who wish to become pregnant must • Latent TB stop therapy and undergo and accelerated • Neuropathy elimination procedure (cholestyramine or activated charcoal for 11 days)

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Fingolimod(Gilenya), siponimod( Mayzent), ozanimod (Zeposia), ponesimod (Ponvory) New S1P modulators Effects on immune MOA cells and mediators Safety issues • Shorter half life •  • S1P receptor •  circulating LFTs • modulator on lymphocytes by 20- • Hepatic injury Minimizes cardiac issues –does not bind to S1P3 with lymphocytes. 30% • Bradycardia high affinity also slow drug titration less cardiac effects Preventing egress -Next generation S1P receptor • Selective 1-phosphate (S1P)-1 and 5 form secondary modulators (selective affinity for S1P1 lymphoid organs to and S1P5 receptor) less prone to cause receptor. bradycardia due to utilization of drug peripheral circulation titration • May cross blood-brain-barrier and decrease production • S1P1 and S1P5 • of TNF alpha, IL-6, IL-17 by astrocytes and microglia, this •  blood pressure can lead to less demyelination modulation reduces (siponimod , • PRES ozanimod) accumulation of neurological impairment and slows • Pulmonary events • S1P1 modulator progression of brain atrophy. (ponesimod) • (HSV, Cryptococcus) • Skin cancer • PML

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Monitoring Ozanimod ▪ Contraindicated in patients taking MOA ▪ First dose cardiac monitoring-6 hours and post inhibitors EKG (fingolimod) , caution in patients taking beta- blockers and calcium channel blockers. ▪ Monoamine oxidase (MOA) is an that is responsible for breakdown of tyramine ▪ Contraindicated for all S1P modulators : − with history of MI, stroke, TIA in last 6months ▪ Ozanimod metabolites inhibit MOA that may − Decompensated heart failure in last 6 months result in higher levels of tyramine and − Mobitz type II block 2nd/3rd AV blocks hypertensive crisis − Sick sinus syndrome if no pacemaker ▪ Patients need to avoid food and beverages that − QTc interval > or = to 500 msec would result in a total of more than 150 mg daily of tyramine while on ozanimod.

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Monitoring Monoclonal

▪ ▪ Eye and skin examinations (macular edema and Natalizumab basal cell carcinoma) yearly − Target: CD49, a4-, leukocytes ▪ Varicella-Zoster Virus IgG prior to starting ▪ Alemtuzumab medication if negative vaccinate 2-4 weeks prior − Target CD52, T cells, B cells, APC to starting med, PFTs (if clinically indicated) ▪ Ocrelizumab ▪ EKG prior to starting treatment with all − Humanized mAb, Target CD20, mature B cells ▪ CBC with diff, LFTs every 6 months. ▪ Ofatumumab ▪ Treatment interruption >12-14 days need repeat − Humanized mAb, Target different site of CD20, of first dose observation (fingolimod) mature B cells

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Natalizumab Factors that Increase PML Risk

Effects on immune MOA system Safety profile • Anti-JCV positive status • Inhibits VLA-4 •  circulating • PML • Receiving an immunosuppressant ( such leukocytes as mitoxantrone, , • Hypersensitivity , cyclophosphamide, • Prevents except reactions mycophenolate motefil) prior to neutrophils receiving natilizumab leukocyte • Hepatic injury migration • Natalizumab treatment duration • Infections (HSV, (especially >2 years) across the • Titer index over 0.9 BBB meningitis, hep b) • Serum JV Ab check every 6 months (<2 yr tx); every 3 months > 2yrs of tx

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Alemtuzumab Safety Considerations with Alemtuzumab

Effects on immune Warnings Monitoring and Precautions

MOA system Safety issues • Infusion reaction • Restricted distribution under the REMS program monitoring • Infusion reactions – >90% of patients in clinical trials experienced • Targets CD52 on • Rapid  of infusion reactions, 3% serious: Rash, – Monthly blood tests • Thyroid dysfunction-36% , influenza-like symptoms: less – TSH every 3 months. lymphocytes circulating T and B commonly transient recurrence of previous Cells • ITP- !% one death in trial MS symptoms • Obtain thyroid function tests prior to initiating • Depletes T and treatment and every 3 months until 48 months after • Autoimmune thyroid disease (34%) B cells, • Long lasting effects • Glomerulonephritis-0.3% the last infusion. • Infections (herpes, fungal, • Autoimmune Thrombocytopenia (ITC) (2%) • Monitor CBC prior to treatment and monthly until 48 monocytes, on adaptive listeria, nocardia) • Glomerular nephropathies (0.3%) months after last infusion. immunity • Cancer Risk- thyroid, • Malignancies Melanoma (0.3%), Lymphoma • Monitor serum creatinine prior to treatment and melanoma and lymphoma. monthly and dendritic • Infections • Conduct baseline and yearly skin exams for cells • Pneumonitis melanoma • Delay treatment initiation in patients with active infections. • Do administer live viral

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Ocrelizumab Monitoring

Effect on immune MOA cells Safety issues ▪ Baseline Hepatitis screen, HIV, TB-quant, VZV • Targets CD20 • Depletion of pre- • Infusion IgG status, CBC and diff, cmp, monoclonal on B B cells, mature B reactions protein eval. lymphocytes cells and • memory B cells ▪ Yearly mammograms • Antibody and (URI, PML) − Increase risk of breast ca 1% cell mediated • Lymphoid stem cytotoxicity cells and plasma • Neoplasm? cells are • Breast unaffected

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Ofatumumab (Kesimpta) Cladribine (Mavenclad) Effect on immune MOA Effect on immune Safety issues MOA system Safety issues cells • Purine analog that • Depletes 80% of • Malignancy prevents DNA replication peripheral B cells, • Hematologic and reduces T and B-cells. • Targets CD20 on • Depletion of pre-B • Injection site reaction • 40-50% of total T- malignancies B lymphocytes cells, mature B cells • Headache • In cells phosphorylated cells. • Ovarian carcinoma into its toxic form by • Pancreatic carcinoma and memory B cells • Myalgia another enzyme • Also affects NK Cells • Antibody and • Malignant melanoma • Fever deoxycytidine kinase, cell mediated • Lymphoid stem cells (DCK ). (1.1% vs 0.5% ) cytotoxicity and plasma cells are • • Cells that have high • URI unaffected • Infection concentration of DCK ( T, • Headache • URI B and NK cells) • Lymphopenia • Hep B accumulate reactivation phosphorylated • Infections (TB, VZV, cladribine. • PML PML(none), liver problems and heart failure

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Cladribine • Tests prior to treatment • Monitoring • CBC and diff • Measure lymphocyte counts ▪ One or two pills depending on weight • TB status before each treatment • HIV status course and at 2 and 6 ▪ Two treatment weeks per year one month apart and repeated months after each treatment again on second year. • VZV status course • Vaccination ▪ • Absolute lymph count must 2 year treatment courses: 1.75 mg/kg/course divided into 2 recommended for VZV be > 800 cells/mm3 before treatment cycles IgG negative patients year 2 of treatment ▪ Not to exceed 3.5 mg/kg cumulative dosage • Pregnancy test • HSV prophylactic treatment if lymphocytes drop to 200 ▪ #mg tablet taken daily for 4 to 5 consecutive days, repeated • Precautions to prevent one month later for another week pregnancy must be - repeat cycle one year later. maintained for at least 6 months after treatment (of either partner)

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Mitoxantrone (Novantrone) Stem Cell Transplant Effects on immune MOA cells Safety Issues • Intercalates with • Reduction of • Menstrual disorders ▪ Autologous hematopoietic stem cell DNA causing leukocytes, • Blue/Green urine transplant(HSCT) strand breaks mainly • Hair loss • Immunosuppression followed by infusion of • Inhibits DNA neutrophils and • UTI/URI autologous stem cell repair via most lymphocyte • Mouth sores • “re-booting of immune system” subsets except for inhibition of • Irregular heart beat • Stem cells derived form bone marrow or blood are stored naïve and and the rest of the individual’s immune cells are depleted by topoisomerase II • activated T Cardiotoxicity-CHF; can chemotherapy then stem cells re-introduced. leading to happen years after cytotoxicity lymphocytes cessation of therapy • Potent durable benefits • Acute myeloid leukemia • Young, mild to mod disability and highly active MS benefit

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BEAT-MS Efficacy of DMTs for MS

▪ Best Available Therapies (BAT) versus Autologous Hematopoietic Stem Cell Transplant(AHSCT) for Multiple Sclerosis ▪ Comparing BAT vs AHSCT over 72 months in RRMS and continued MS disease activity despite treatment with DMTs ▪ BAT agents: natalizumab, alemtuzumab, ocrelizumab or ▪ Prospective 1:1 randomized controlled trial of 156 participants ▪ Age less than 55, EDSS less than 5.5 ▪ Primary Endpoint: MS release free survival

Pardo, Gabriel. MS Therapy: DMT1, AAN, 2018 Las Vegas, NV

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Safety and Effectiveness of DMTs. For RRMS Approaches to MS Treatment

▪ Escalation of chronic immunomodulatory/- suppressive treatment ▪ Induction and reconstitution , followed up by treatment of residual (innate) inflammation ▪ 3 principles: safety , efficacy and tolerability ▪ Optimize neurologic reserve, cognition and physical function by reducing disease activity

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Reasons to Consider Switching Temporal effect on the immune cell system

Treatment Near term Mid term Long Term Day to week Week to month Month to Year ▪ Breakthrough disease activity INF beta 1B Fingolimod Alemtuzumab - More than three lesions on MRI INF beta 1a Siponimod Ocrelizumab

-More than one relapse in first year of treatment Peginterferon Ozanimod Cladribine

-Disability progression with EDSS Glatiramer acetate Natalizumab Mitoxantrone • JCV ab seroconversion Dimethyl Fumarate Teriflunomide (w/o • Poor adherence accelerated elimination) • Teriflunomide (with Ofatumumab Intolerable and severe medication side- effects accelerated elimination)

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Pregnancy Considerations When to STOP DMT in MS

▪ Glatiramer acetate pregnancy Class B ▪ DISCO MS-PICORI study= DISCOntinuation of ▪ Interferons, FDA updated for Plegridy and Avonex in 4/2020 − No longer contains Pregnancy category C due to human pregnancy MS DMT registry. ▪ Randomized controlled prospective study for ▪ No washout period necessary for GA or interferons individuals with MS age 55 or older. ▪ Dimethyl fumarate and Tysabri no wash out period required ▪ Participants will be randomized to one of the 2 ▪ Must stop S1P modulators 3 months prior to conception groups: one continue with DMT and one ▪ Must stop Cladribine 6 months prior to conception discontinue . ▪ Must stop Ocrelizumab and ofatumumab 6 months prior to conception (12 months in Europe) ▪ Estimated completion by February 2022. ▪ Teriflunomide use accelerated elimination to lower serum levels to below 0.02 mg/L

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COVID-19 and MS COVID19 and Multiple Sclerosis • Recommendations from NMSS • SARS-CoV-2 triggers the innate immune system, on which DMTs • COVID-19 vaccine are inactive and safe have little effect • Most DMTs should be continued as they will not affect response to vaccine • DMTs should be continued • Some DMTs ( alemtuzumab, cladribine, B-cell depleting drugs) may decrease the mounted response to vaccine • Most DMTs do not increase risk of severe COVID-19 infection, with • some exceptions Coordinate timing of vaccine with timing of DMT • If not on DMT already ideal to start oral/infusions (DMTs) 2-4 weeks after second dose of • Possible: alemtuzumab, cladribine, ocrelizumab, rituximab vaccine • Having MS does not make it likely to become severely ill or die • If already on DMT for ocrelizumab or rituximab consider vaccine 12 weeks after last dose • alemtuzumab vaccinate 24 weeks post last dose • Susceptible to severe disease similar subgroups to those observed • ofatumumab no longer listing delay after last dose for vaccine , wait 2-4 weeks post with general population vaccine to resume next injection. • cladribine no longer listing ideal timing for vaccine while on medication but consider wait • >60, men, A.A or S. Asian, HTN, DM, heart/lung disease, obesity, 2-4 weeks post vaccine to resume patients with higher disability • For IV steroids consider vaccine 5 days after

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Conclusions References

• Trapp et al. Axonal transection in the lesions of multiple sclerosis. NEJM 1989, 338:278-85 • Polman et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. • Repertoire of DMTs for patients with RRMS has increased over the • AAN Neurol 2011;69:292-302 recent years • Wingerchuck and Carter. Multiple sclerosis: current and emerging disease-modifying therapies • and treatment strategies. Mayo Clinic Proceedings 2014;89:225-240 – MOA and duration of effect on immune system need to be • Kapos et al. Oral fingolimod (FTY720) for relapsing remitting multiple sclerosis. considered when selecting and changing DMTs • NEJM 2006; 355:1124-40. – • Kapos et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. Different routes of administration and dosing • NEJM 2010;362:387-401 – Different safety and efficacy profiles • Miller et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis • (TOPIC): a randomised, double-blind, placebo-controlled, phase 3. Lancet Neurol 2014;10:977-86 – Greater opportunities for individualized treatment • O’Connor et al. randomized trial of oral teriflunomide for relapsing multiple sclerosis. • NEJM 2011;365:1293-303 ▪ Treatment needs to fit the needs of a given patient and their • Gold et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. disease activity • NEJM 2012;367:1098-107 • Fox et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. − Adherence to treatment • NEJM 2012;367:1087-97 − Comorbidities, family planning, age, safety • Polman et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. • NEJM 2006;354:899-910 − Patient education • Millefiorini et al. Randomized placebo-controlled trial of mitoxantrone in relapsing-remitting • multiple sclerosis: 24-month clinical and MRI outcome. J Neurol 1997;244:153-9 − Mohamed AIJumah, Cladribine Tablets and Relapsing-Remitting Multiple Sclerosis: A Pragmatic Narritive Review of What Physicians Need to Know. Neurology and Therapy pp1-13

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References

• Miller at al. A controlled trial of natalizumab for relapsing multiple sclerosis. NEJM 2003;348:15-23 • Cohen et al. Alemtuzumab versus interferon -1aas first-line treatment for patients with relapsing- • remitting multiple sclerosis: a randomised control phase 3 trial. Lancet 2012;380:1819-28 • Coles et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: • a randomised controlled phase 3 trial. Lancet 2012;380:1829-39 • Wynn et al. in active relapsing multiple sclerosis (CHOICE study): a phase 2, randomized, • double-blind, placebo controlled, add-on trial with interferon beta. Lancet Neurol 2010;9:381-90 • Gold et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): • a randomised, double-blind, placebo-controlled trial. Lancet 2013;38:2167-75 • Kappos et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomized, • placebo-controlled, multicenter trial. Lancet 2011;378:1779-87 • Calabresi et al. Pegylated interferon -1 a for relapsing-remitting multiple sclerosis (ADVANCE): • a randomized, phase 3, double-blind study. Lancet Neurol 2014: 13:657-65 • Mancandi et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis. A phase II • trial. Neurology 2015; 84:981-88 • Ontaneda et al. Clinical trials in progressive multiple sclerosis: lessons learned and future • perspectives. Lancet Neurol 2015;14:208-223 • Buzzard al. What do effective treatments of Multiple Sclerosis tell us about the Molecular Mechanism Involved in Pathogensis.Int.J.Mol.Sci 2012,13,12665-12709

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