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Kristen Niedbalski, PharmD, BCGP January 8th, 2020 ▪ Kristen Niedbalski, PharmD, BCGP: Declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holding, and honoraria 1. Describe the disease courses/phenotypes of progressive forms of (MS) 2. Identify the new drug therapy options that have entered the U.S. drug market, since 2017, for the treatment of progressive MS 3. Describe treatment options for progressive MS 4. Given a patient case, select appropriate drug therapy for treatment of active progressive MS 5. Monitor for the adverse effects and contraindications of drug therapy for progressive MS 6. Discuss clinical studies that led to approval of siponimod and 1. Describe the disease courses/phenotypes of progressive forms of MS 2. Identify the new drug therapy options that have entered the U.S. drug market, since 2017, for the treatment of progressive MS 3. List the adverse effects and contraindications of drug therapy for progressive MS SR is 42 year old female who was diagnosed with RRMS at age 31. Her relapses have remained consistent with periods of recovery over the years; however, her disability has progressed in the past 12 months, leading her to visit her neurologist’s office to discuss her current symptoms of increased bladder incontinence, numbness and tingling in her left hand and foot, blurred vision in her right eye, decreased cognition and balance, and now walks with a walker. She also complains that spasticity in her legs prevents her from wanting to leave the house because she is afraid of falling. Current Meds: ▪ Rebif 44mcg three times weekly ▪ Lisinopril 10mg qd ▪ Loratadine 10mg qd ▪ Escitalopram 20mg qd ▪ Baclofen 10mg tid ▪ Vitamin D 2000 units qd After SR sees her neurologist, he changes her diagnosis to SPMS and wants to make a change to her drug therapy. She is Genotype *2/*2 for CYP2C9 and she is afraid of needles. Should the neurologist: 1. Switch Rebif to 3.5mg/kg over 2-year treatment course 2. Switch Rebif to Ocrelizumab 300mg on day 1 followed by 300mg 2 weeks later then 600mg every 6 months 3. Switch Rebif to Siponimod 0.25mg on days 1 and 2, 0.5mg on day 3, then 0.75mg on day 4, then 1.25mg on day 5, then 2mg daily beginning day 6 4. Stop drug treatment for MS and switch to palliative care and physical therapy to increase her abilities and regain mobility BD is 75 year old male with a 29 year history of RRMS. Early in his diagnosis he had frequent relapses; however, in the past few years he has had progression of disability with decreasing relapses. His last relapse was 5 years ago; however he continues to progress in severity of bowel and bladder incontinence, pain and spasticity in his lower limbs, dysphagia, worsened cognition, diplopia, and vertigo. He now requires a caretaker at home for dressing and personal care and has restricted mobility to a wheelchair. Current Meds ▪ Glatiramer 20mg SQ qd • Amantadine 100mg bid ▪ Baclofen 20mg tid • Oxybutynin 10mg tid ▪ Gabapentin 800mg tid • ▪ Valsartan 80mg qd Sertraline 50mg qd ▪ HCTZ 25mg qd • Vitamin D 5000 units qd ▪ Rosuvastatin 10mg qd • Aspirin 81mg qd After BD sees his neurologist, he changes his diagnosis to SPMS and wants to make a change to his drug therapy. He is Genotype *2/*2 for CYP2C9. Should the neurologist: 1. Switch glatiramer to Cladribine 3.5mg/kg over 2-year treatment course 2. Switch glatiramer to Ocrelizumab 300mg on day 1 followed by 300mg 2 weeks later then 600mg every 6 months 3. Switch glatiramer to Siponimod 0.25mg on days 1 and 2, 0.5mg on day 3, then 0.75mg on day 4, then 1.25mg on day 5, then 2mg daily beginning day 6 4. Stop drug treatment for MS and switch to palliative care and physical therapy to increase his abilities and regain mobility There are effective drug treatment options that are approved for ALL SPMS phenotypes that reduce the frequency and severity of MS relapses and disease progression Cladribine is an approved 1st line therapy option for SPMS Immunosuppressant therapies may diminish the therapeutic effect of vaccines Central Nervous Systen and Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multiple_sclerosis_ms/article.htm Central Nervous Systen and Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multip le_sclerosis_ms/article.htm Now called Primary Progressive with Central Nervous Systen and active disease Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multi ple_sclerosis_ms/article.htm MS Phenotypes. Digital Image, National Multiple Sclerosis Society, https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS GRAPH OF SPMS CLINICAL COURSE. DIGITAL IMAGE. EASYBIB. APRIL 2018 HTTP://WWW.CLEVELANDCLINICMEDED.COM/MEDICALPUBS/DISEASEMANAGEMENT/NEUROLOGY/MULTIPLE_SCLEROSIS/ MS DISEASE COURSE. DIGITAL IMAGE. BRAIN DIRECT. 9/2016. HTTPS://WWW.SCIENCEDIRECT.COM/ SCIENCE/ARTICLE/PII/S221103481630102X

Treatment options for SPMS based on phenotype

Treat with DMT

Treat with DMT

No approved drug therapy, DMT treatment can continue if necessary but continue only if risk outweighs benefit

No approved drug therapy, DMT treatment can continue if necessary but continue only if risk outweighs

Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. benefit UpToDate Inc. https://www.uptodate.com (accessed on 8/31/2019.) ▪Ocrelizumab (Ocrevus, approved March 2017)

Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪ Recommended: ▪ Continuing same disease-modifying therapy (DMT) used during RRMS phase ▪ Switching to a different DMT ▪ Not recommended: ▪ Glucocorticoid monthly pulses, cyclophosphamide,

Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. UpToDate Inc. https://www.uptodate.com (accessed on 8/31/2019.) ▪ MABs: ▪Alemtuzumab (Lemtrada) ▪ : ▪ (Tysabri) ▪ beta-1a (Avonex, Rebif) ▪Ocrelizumab (Ocrevus, 2017) ▪Interferon beta-1b (Betaseron, ▪ Fumaric Acid Derivatives Extavia) ▪ (Tecfidera) ▪ 1 phosphate receptor modulators: ▪ (Vumerity, 10/2019) ▪ (Gilenya) ▪ (Copaxone) ▪Siponimod (Mayzent, 3/2019) ▪ (Aubagio) ▪ Cladribine (Mavenclad, 3/2019)

***Note that although all on this list are approved, Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. UpToDate Inc. https://www.uptodate.com the bolded are evidence based treatments ▪The likelihood of future relapse should be assessed by: ▪Patient age ▪Disease duration ▪Relapse history ▪MRI-detected activity ▪Discontinuation of DMT may be advised in patients who do not have ongoing relapses and have not been ambulatory for at least two years

Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis A Rae-Grant, GS Day et. Al. Neurology Apr 2018, 90 (17) 777-788; DOI: 10.1212/WNL.0000000000005347

▪ Class: Sphingosine 1-phosphate ▪ Approved for clinically isolated syndrome (CIS), RRMS, and active SPMS in adults ▪ Requires 5-day dose titration and genotyping for CYP2C9 prior to initiation to determine the optimal dosage ▪ First-dose monitoring recommended for patients with sinus bradycardia, 1st or 2nd degree AV block, or a history of MI or heart failure ▪ Test patients for to varicella zoster virus before initiation ▪ Baseline labs/tests: CBC, EKG, LFT’s and bilirubin, ophthalmic evaluation of fundus and macula ▪ Use caution in patients with history of anti-neoplastic, immunosuppressive, or immune-modulating therapies (additive effects) Siponimod [package insert]. East Hanover, New Jersey: ; 2019 ▪Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator ▪Binds with high affinity to S1P receptors 1 and 5 ▪Blocks the capacity of to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood ▪ The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of migration into the central nervous system. Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Fingolimod Siponimod Notes MOA (S1P receptors ) Receptors 1,3,4,5 Receptors 1,5 Cardiac AE are most risky for first 24 hours First dose cardiac All patients Patients w/certain At home or MD office, free to patient monitoring pre-existing cardiac conditions Available generic ***Yes No ***Just announced not available in US yet Pharmacogenomic No (1 strength) Yes (2 strengths) Dosing PML cases reported Yes (low risk) **No **PML has not been reported for siponimod but counsel pts to monitor for symptoms Half life 6 to 9 days; prolonged ~30 hours Important for family planning by ~50% in patients with mod/severe hepatic impairment Complete drug 2 months 7 days Time required to wait after drug d/c before elimination beginning family planning

Proven Efficacy in *No- studied in PPMS Yes- studied in *Fingolimod failed to slow disease Progressive MS (INFORMS) SPMS (EXPAND) progression in PPMS Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 Siponimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 Fingolimod phosphate binds to S1P receptors 1, 3, 4, and 5

G Comi, Hans-Peter Hartung, Heinz S. Wiendl Published in Drugs 2017 DOI:10.1007/s40265-017-0814-1 Siponimod Binds with high affinity to S1P receptors 1 and 5

G Comi, Hans-Peter Hartung, Heinz S. Wiendl Published in Drugs 2017 DOI:10.1007/s40265-017-0814-1 ▪ First-dose 6-hour monitoring is recommended for patients with certain preexisting cardiac conditions, including: ▪Sinus bradycardia (HR <55 bpm), ▪First- or second-degree (Mobitz type 1) ▪AV block ▪History of MI or heart failure ▪ For these patients, administer the first dose and doses following therapy interruption (≥4 days) in a setting in which resources to appropriately manage symptomatic bradycardia and other conduction abnormalities are available Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 ▪Metabolism: Extensively metabolized to inactive metabolites via CYP2C9 (79.3%) and CYP3A4 (18.5%) ▪Changes in the amino acid sequence of CYP2C9 can affect both the activity and substrate specificity of CYP2C9 ▪CYP2C9*1 allele encodes the wild-type protein ▪Both CYP2C9*2 and CYP2C9*3 have variant alleles are associated with significantly reduced activity ▪Enzyme activity ranked greatest to least: ▪CYP2C9*1 > CYP2C9*2 > CYP2C9*3

Marion Funk, Georg Endler, Renate Freitag, Johann Wojta, Kurt Huber, Christine Mannhalter, Raute Sunder-Plassmann DOI: 10.1373/clinchem.2004.038034 Published November 2004 ▪CYP2C9 Genotype *1/*3 or *2/*3: ▪Maintenance: 1 mg once daily, beginning on Day 5 ▪CYP2C9 Genotype *1/*1, *1/*2, or *2/*2: ▪Maintenance: 2 mg once daily, beginning on Day 6 ▪ Missed dose: ▪ If treatment is interrupted for ≥4 consecutive daily doses after completion of initial titration, reinitiate treatment with Day 1 of the titration regimen, including first-dose monitoring when appropriate ▪ No dosage adjustment required for renal or hepatic impairment ▪ No geriatric dosing

Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Dosage Cost per unit Storage Storage # Tabs per (AWP) requirements- requirements container opened un-opened container container 0.25mg $72.74 20°C to 25°C Refrigerator #28 (68°F to 77°F) [for between 2°C to up to 1 month 8°C (36°F to 46°F). 2mg $290.96 20°C to 25°C Refrigerator #30 (68°F to 77°F) for between 2°C to up to 1 month 8°C (36°F to 46°F). Starter --- 20°C to 25°C Refrigerator #12 Pack(0.25mg) (68°F to 77°F) for between 2°C to up to 1 week after 8°C (36°F to opening the 46°F). blister. Store in original container. Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Siponimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪CYP2C9 *3/*3 genotype ▪History in past 6 months of MI, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, class III, IV heart failure ▪Mobitz type II second-degree, 3rd degree AV block, or sick sinus syndrome, unless patient has functioning pacemaker ▪The label advises against starting siponimod treatment after

Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 More common >10%: ▪Cardiovascular: (13%) ▪Central nervous system: (15%), falling (11%) ▪Hepatic: Increased serum transaminases (≤11%)

Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Less Common 1% to 10%: ▪ Cardiovascular: Peripheral edema (8%), bradycardia (4% to 6%), first degree atrioventricular block (5%), second degree atrioventricular block (<2%) ▪ Central nervous system: Dizziness (7%), seizure (2% to <5%) ▪ Gastrointestinal: Nausea (7%), diarrhea (6%) ▪ Hematologic & oncologic: Lymphocytopenia (<5%) ▪ Hepatic: Increased serum bilirubin (≤10%), increased serum alanine aminotransferase (6%), increased serum aspartate aminotransferase (1%) ▪ Infection: Herpes virus infection (5%), herpes zoster infection (<5%) Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 Less Common 1% to 10%: ▪ Neuromuscular & skeletal: Limb pain (6%), asthenia (<5%), tremor (<5%) ▪ Ophthalmic: Macular edema (2% to <5%) ▪ Respiratory: Reduced forced expiratory volume (<5%) ▪ Frequency not defined: ▪ Dermatologic: Facial swelling ▪ Infection: Infection ▪ <1%, post marketing, and/or case reports: Malignant melanoma, meningitis (cryptococcal), testicular neoplasm (seminoma), varicella zoster infection (meningitis)

Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 ▪Fingolimod was the 1st sphingosine 1-phosphate receptor modulator, on the market since 2010, and therefore has had more patient experience to see adverse effects and monitoring pearls may be applicable to siponimod therapy ▪Disseminated cryptococcal infections ▪Progressive multifocal leukoencephalopathy (PML) ▪Discontinuation of therapy ▪Neurotoxicity

Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪Progressive multifocal leukoencephalopathy (PML) ▪Cases of John Cunningham (JC) virus have been reported with fingolimod ▪Monitor for signs of PML: ▪Progressive weakness on one side of the body ▪Clumsiness of limbs ▪Vision disturbances ▪Mental status changes

Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪Discontinuation of therapy: ▪Cases of rebound syndrome (clinical and radiological signs of severe exacerbation beyond what was expected) ▪Due to residual pharmacodynamic effects following treatment discontinuation (e.g., decreased peripheral lymphocyte counts) ▪Use caution for 3 to 4 weeks after the last dose of therapy

Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪Neurotoxicity: ▪Posterior reversible encephalopathy syndrome (PRES) ▪Monitor for signs/symptoms of PRES (e.g., behavioral changes, cognitive deficits, cortical visual disturbances, any other neurological cortical symptom/sign, or symptoms/signs suggestive of increased intracranial pressure) ▪Symptoms are usually reversible, but may evolve into ischemic stroke or cerebral hemorrhage ▪Delayed diagnosis and treatment may result in permanent neurological sequelae. Discontinue use if PRES is suspected

Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪Test patients for antibodies to varicella zoster virus before initiation and if negative vaccinate prior to treatment ▪The use of live attenuated vaccines should be avoided during treatment and for 4 weeks after stopping treatment ▪Vaccinations may be less effective if administered during treatment. Treatment discontinuation 1 week prior to and until 4 weeks after a planned vaccination is recommended

Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 ▪Siponimod may cause fetal harm (Animal data) ▪DMT’s are generally not initiated during pregnancy ▪Females of reproductive potential should use effective contraception during therapy and for 10 days after the last siponimod dose ▪It is not known if siponimod is present in breast milk

Siponimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪EXPAND was a randomized, double-blind, placebo- controlled study in 1651 patients with SPMS ▪The inclusion criteria were: ▪Documented evidence of progression in the 2 years prior to enrollment ▪No evidence of relapse in the 3 months prior to study enrollment ▪An expanded disability status scale (EDSS) score of 3.0-6.5 at study entry Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 EDSS Scale PictoGraph. Digital Image. Twitter #expandeddisabilitystatusscale. https://twitter.com/hashtag/expandeddisabilitystatusscale ▪Patients were randomized 2:1 to receive either once-daily siponimod 2 mg or placebo ▪Evaluations were performed at screening, every 3 months, and when relapses occurred ▪MRI evaluations were performed at screening and every 12 months ▪The median follow-up duration was 21 months (maximum of 37 months)

Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 ▪The primary end point was the time to 3-month CDP ▪Two key secondary end points: ▪Time to 3-month confirmed deterioration by ≥20% from baseline in the T25-FW test ▪Change from baseline in T2 lesion volume ▪Additional end points included: ▪Annualized relapse rate (relapses/year) ▪MRI measures of inflammatory disease activity

CPD=Confirmed disability progression T25-FW = timed 25-foot walk test Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 ▪ Results Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 ▪ Results Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 ▪ Results ▪ US FDA and EMA Accepted Applications for for the Treatment of Relapsing Forms of Multiple Sclerosis, June 06, 2019 ▪ Ozanimod is an oral, S1P receptor modulator that binds with high affinity selectively to S1P subtypes 1 (S1P1) and 5 (S1P5) ▪ Studied against weekly intramuscular interferon beta-1a (Avonex®) ▪ FDA has set its action date as March 25, 2020 ▪ Me too drug? US FDA and EMA Accept Applications for Ozanimod for the Treatment of Relapsing Forms of Multiple Sclerosis. Celgene. June 6, 2019. https://ir.celgene.com/press-releases- archive/press-release-details/2019/US-FDA-and-EMA-Accept-Applications-for-Ozanimod- for-the-Treatment-of-Relapsing-Forms-of-Multiple-Sclerosis/default.aspx

▪Drug class: ▪CD20-directed cytolytic ; ▪Approved in 2017 for ▪CIS ▪RRMS ▪Active SPMS ▪PPMS in adults ▪When initiating ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive following ocrelizumab therapy, consider potential for increased immunosuppressive effects Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪MOA: ▪The precise mechanism by which ocrelizumab exerts its therapeutic effects in MS is unknown ▪Presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes ▪Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 Ocrevus MOA. Digital Image. Genentech. https://www.gene.com/media/product-information/ocrevus B-cell-depleting Monoclonal Antibodies in Neurology

B-cell-depleting monoclonal antibodies in neurology. mAb, monoclonal antibody; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder. Daniel H Whittam et al. Pract Neurol 2019;19:5-20 https://pn.bmj.com/content/19/1/5 ▪History of life-threatening infusion reaction to ocrelizumab ▪Active hepatitis B virus (HBV) infection

Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪Dosing: ▪Initial dose: ▪300 mg intravenous infusion ▪Followed two weeks later by a second 300 mg intravenous infusion ▪Subsequent doses: single 600 mg intravenous infusion every 6 months ▪No dosage adjustment required for renal or hepatic impairment ▪No geriatric dosing Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪Monitor for infusion reactions during infusion and observe for at least one hour after infusion is complete ▪If infusion reaction occurs, interrupt infusion, discontinue or decrease the rate, depending on the severity of the reaction

Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪Dosing: ▪Premedicate ▪ Methylprednisolone (100 mg IV) 30 minutes prior to each infusion ▪An antihistamine (e.g., diphenhydramine) 30 to 60 minutes prior to each infusion ▪May also consider premedication with acetaminophen ▪Assess for infection and delay administration for active infection

Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪Missed doses: ▪If a dose is missed: ▪Administer as soon as possible (do not wait until the next scheduled dose) ▪Then adjust the dose schedule to administer the next sequential dose 6 months after the missed dose was administered ▪Doses must be separated by at least 5 months

Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 More common >10%: ▪Dermatologic: ▪Skin infection (14%) ▪Hematologic & oncologic: ▪Decreased serum immunoglobulins (≤17%, IgM most affected), decreased neutrophils (13%) ▪Respiratory: ▪Upper respiratory tract infection (40% to 49%) ▪Miscellaneous: ▪Infusion related reaction (34% to 40%)

Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 Less common 1% to 10%: ▪Cardiovascular: Peripheral edema (6%) ▪Central nervous system: Depression (8%) ▪Gastrointestinal: Diarrhea (6%) ▪Infection: Herpes virus infection (5% to 6%) ▪Neuromuscular & skeletal: Back pain (6%), limb pain (5%) ▪Respiratory: Lower respiratory tract infection (8% to 10%), cough (7%) ▪<1%, post marketing, and/or case reports: Antibody development, malignant neoplasm of breast Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪Hepatitis B virus screening in all patients (HBsAg and anti-HBc measurements) prior to therapy initiation ▪Test to screen for chronic or unresolved HBV infection ▪HBsAg-negative/anti-HBc-positive patients should be monitored for HBV reactivation with HBV DNA and ALT testing approximately every 3 months during treatment

Ocrelizumab. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪Hepatitis B reactivation ▪Herpes infection ▪Infection ▪Infusion reactions ▪Malignancy ▪Progressive multifocal leukoencephalopathy

Ocrelizumab. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪ Immunosuppressants may diminish the therapeutic effect of vaccines ▪ Live-attenuated or live immunizations: ▪Administer at least 4 weeks prior to treatment initiation ▪Not recommended during treatment or after discontinuation until B-cell repletion ▪ Inactivated immunizations: ▪Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant ▪If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation Ocrelizumab. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪Information related to the use of ocrelizumab in pregnancy is limited ▪Transient peripheral B-cell depletion and lymphocytopenia have been observed in infants born to mothers who received similar agents ▪Females of reproductive potential should use effective contraception during therapy and for 6 months after the last ocrelizumab infusion ▪It is not known if ocrelizumab is present in breast milk

Ocrelizumab. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 Ocrelizumab vs Placebo in PPMS (ORATORIO) Montalban et. al. METHODS: • Phase 3 trial with 732 randomly assigned PPMS patients • IV ocrelizumab (600 mg) or placebo (2:1 ratio) • Every 24 weeks for at least 120 weeks and until a prespecified number of CDP events had occurred • Primary end point : • Percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis • Patients had EDSS range of 3-6.5

N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21 Ocrelizumab vs Placebo in PPMS (ORATORIO) Montalban et. al. Inclusion Criteria: • Age 18 to 55 years with PPMS Dx • EDSS range of 3-6.5 at screening • Pyramidal functions component of the Functional Systems Scale ≥ 2 (range 0 - 6, higher scores= ↑disability) • Duration of MS Sx: • <15 years in patients with an EDSS score of >5.0 at screening • <10 years in patients with an EDSS score of <5.0 at screening • Documented elevated IgG index or at least one IgG detected in CSF fluid

N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21 Pyramidal functions component of the Functional Systems Scale ≥ 2 (range 0 - 6, higher scores= ↑disability)

Functional Systems Scores. National Multiple Sclerosis Society. https://www.nationalmssociety.org/For-Professionals/Researchers/Resources-for- Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and-Expanded-Disab Ocrelizumab vs Placebo in PPMS (ORATORIO) Montalban et. al. RESULTS: ▪Week 12 ▪ The percentage of patients with CDP (HR 0.76; 95% CI 0.59-0.98; P=0.03) ▪ 32.9% with ocrelizumab ▪ 39.3% with placebo ▪Week 24 ▪ The percentage of patients with CDP (HR 0.75; 95% CI, 0.58-0.98; P=0.04) ▪ 29.6% with ocrelizumab ▪ 35.7% with placebo

N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21 Ocrelizumab vs Placebo in PPMS (ORATORIO) Montalban et. al. RESULTS: ▪Week 120 ▪ Performance on the timed 25-foot walk worsened (P=0.04) ▪ 38.9% with ocrelizumab ▪ 55.1% with placebo

▪ Total volume of brain lesions on T2-weighted MRI (P<0.001) ▪ decreased 3.4% with ocrelizumab ▪ increased by 7.4% with placebo ▪ Percentage of brain-volume loss (P=0.02) ▪ 0.90% with ocrelizumab ▪ 1.09% with placebo ▪ There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey

N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21 B-cell-depleting Monoclonal Antibodies in Neurology

B-cell-depleting monoclonal antibodies in neurology. mAb, monoclonal antibody; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder. Daniel H Whittam et al. Pract Neurol 2019;19:5-20 https://pn.bmj.com/content/19/1/5 ▪ Approved 4/2019 for RRMS and active SPMS ▪ Drug class: Antineoplastic Agent, ; Antineoplastic Agent, Antimetabolite (Purine Analog); Immunosuppressant Agent ▪ Because of its safety profile, is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS ▪ Black box warning for MALIGNANCIES and RISK OF TERATOGENICITY ▪ Most common AE: (incidence > 20%) are upper respiratory tract infection, headache, and lymphopenia ▪ MOA: cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes ▪ Not approved for use beyond 2 years of treatment with 2 years off Cladribine [package insert]. Darmstadt, Germany: Merck; 2019 ▪ Approved 10/2019 for CIS, RRMS, and active SPMS in adults ▪ Drug class: Fumaric acid derivative (second in class) ▪ “Claims” fewer GI side effects than dimethyl fumarate ▪ Twice daily oral dosage on empty stomach (if taken with food must be <30g fat & <700 calories) ▪ May administer aspirin (non-enteric coated ≤325 mg) 30 minutes prior to reduce the incidence and severity of flushing ▪ Not recommended in moderate/severe renal impairment; can cause hepatic injury, lymphopenia, severe infection, PML ▪ Most common AE: Cardiovascular: Flushing (40%); Gastrointestinal: Abdominal pain (18%), diarrhea (14%), nausea (12%); Infection: Infection (60%; similar to placebo) Gastrointestinal: Vomiting (9%), dyspepsia (5%) ▪ Alcohol interacts Risk category X (avoid combination) → decreases active metabolite ▪ Not preferred agent for females who plan on stopping therapy to become pregnant ▪ MOA: activates Nrf2 pathway → decreased oxidative stress → decreased inflammation Diroximel fumarate [package insert]. Cambridge, MA: Biogen; 2019 ▪Siponimod ▪$8700 per 30 days for 2mg daily ▪$104,400 per year ▪Ocrelizumab ▪$78,000 per year ▪Cladribine ▪Average adult weight 89kg needs 311.5mg ▪ $138,162 per year ▪Diroximel fumarate ▪$88,000 per year (WAC) Siponimod, Cladribine, Ocrelizumab. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 https://www.nationalmssociety.org/About-the-Society/News/FDA-Approves-Oral-Vumerity%E2%84%A2-(Diroximel-Fumarate), Emerging therapies in multiple sclerosis

Ann Indian Acad Neurol. 2019 Apr-Jun; 22(2): 131–136. doi: 10.4103/aian.AIAN_345_18 SR is 42 year old female who was diagnosed with RRMS at age 31. Her relapses have remained consistent with periods of recovery over the years; however, her disability has progressed in the past 12 months, leading her to visit her neurologist’s office to discuss her current symptoms of increased bladder incontinence, numbness and tingling in her left hand and foot, blurred vision in her right eye, decreased cognition and balance, and now walks with a walker. She also complains that spasticity in her legs prevents her from wanting to leave the house because she is afraid of falling. Current Meds: ▪ Rebif 44mcg three times weekly ▪ Lisinopril 10mg qd ▪ Loratadine 10mg qd ▪ Escitalopram 20mg qd ▪ Baclofen 10mg tid ▪ Vitamin D 2000 units qd MS Phenotypes. Digital Image, National Multiple Sclerosis Society, https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS After SR sees her neurologist, he changes her diagnosis to SPMS and wants to make a change to her drug therapy. She is Genotype *2/*2 for CYP2C9 and she is afraid of needles. Should the neurologist: 1. Switch Rebif to Cladribine 3.5mg/kg over 2-year treatment course 2. Switch Rebif to Ocrelizumab 300mg on day 1 followed by 300mg 2 weeks later then 600mg every 6 months 3. Switch Rebif to Siponimod 0.25mg on days 1 and 2, 0.5mg on day 3, then 0.75mg on day 4, then 1.25mg on day 5, then 2mg daily beginning day 6 4. Stop drug treatment for MS and switch to palliative care and physical therapy to increase her abilities and regain mobility BD is 75 year old male with a 29 year history of RRMS. Early in his diagnosis he had frequent relapses; however in the past few years he has had progression of disability with decreasing relapses. His last relapse was 5 years ago; however he continues to progress in severity of bowel and bladder incontinence, pain and spasticity in his lower limbs, dysphagia, worsened cognition, diplopia, and vertigo. He now requires a caretaker at home for dressing and personal care and has restricted mobility to a wheelchair. Current Meds ▪ Glatiramer 20mg SQ qd • Amantadine 100mg bid ▪ Baclofen 20mg tid • Oxybutynin 10mg tid ▪ Gabapentin 800mg tid • Sertraline 50mg qd ▪ Valsartan 80mg qd • Vitamin D 5000 units qd ▪ HCTZ 25mg qd ▪ Rosuvastatin 10mg qd • Aspirin 81mg qd MS Phenotypes. Digital Image, National Multiple Sclerosis Society, https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS After BD sees his neurologist, he changes his diagnosis to SPMS and wants to make a change to his drug therapy. He is Genotype *2/*2 for CYP2C9. Should the neurologist: 1. Switch glatiramer to Cladribine 3.5mg/kg over 2-year treatment course 2. Switch glatiramer to Ocrelizumab 300mg on day 1 followed by 300mg 2 weeks later then 600mg every 6 months 3. Switch glatiramer to Siponimod 0.25mg on days 1 and 2, 0.5mg on day 3, then 0.75mg on day 4, then 1.25mg on day 5, then 2mg daily beginning day 6 4. Stop drug treatment for MS and switch to palliative care and physical therapy to increase his abilities and regain mobility There are effective drug treatment options that are approved for ALL SPMS phenotypes that reduce the frequency and severity of MS relapses and disease progression Cladribine is an approved 1st line therapy option for SPMS Immunosuppressant therapies may diminish the therapeutic effect of vaccines ▪ Earlier treatment with a DMT in progressive MS can help to slow disability and prevent relapses ▪ Siponimod and ocrelizumab are two new options available to treat progressive forms of MS, with ocrelizumab being the first and only drug to show efficacy in PPMS in slowing disease progression ▪ Both siponimod and ocrelizumab target b-lymphocytes with differing mechanisms ▪ Although serious adverse effects have been observed with both siponimod and ocrelizumab, safety profiles are favorable compared to other options available when treatment escalation is required ▪ Vaccine response may be diminished and live vaccines should be avoided for patients on immunosuppressant therapies For further questions you may contact presenter at [email protected] ▪ Central Nervous Systen and Demyelination. Digital Image. Medicine Net. https://www.medicinenet.com/multiple_sclerosis_ms/article.htm ▪ MS Phenotypes. Digital Image, National Multiple Sclerosis Society, https://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS ▪ Graph of SPMS Clinical Course. Digital Image. Easybib. April 2018 http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclero sis/ https://www.sciencedirect.com/science/article/pii/S221103481630102X ▪ MS disease course. Digital image. Brain direct. 9/2016. https://www.sciencedirect.com/ science/article/pii/S221103481630102X ▪ Siponimod [package insert]. East Hanover, New Jersey: Novartis; 2019 ▪ G Comi, Hans-Peter Hartung, Heinz S. Wiendl Published in Drugs 2017 DOI:10.1007/s40265-017-0814-1 ▪ Marion Funk, Georg Endler, Renate Freitag, Johann Wojta, Kurt Huber, Christine Mannhalter, Raute Sund er-Plassmann DOI: 10.1373/clinchem.2004.038034 Published November 2004 ▪ Lancet. 2018 Mar 31;391(10127):1263-1273. doi: 10.1016/S0140-6736(18)30475-6. Epub 2018 Mar 23 ▪ Ocrevus MOA. Digital Image. Genentech. https://www.gene.com/media/product-information/ocrevus ▪ EDSS Scale PictoGraph. Digital Image. Twitter #expandeddisabilitystatusscale. https://twitter.com/hashtag/expandeddisabilitystatusscale ▪ Siponimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪ Fingolimod. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪ Ocrelizumab. In: Lexicomp Online Database. Hudson (OH): Lexicomp Inc: 2019 ▪ Ocrelizumab [package insert]. South San Francisco: Genentech; 2017 ▪ N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21 ▪ Cladribine [package insert]. Darmstadt, Germany: Merck; 2019 ▪ Diroximel fumarate [package insert]. Cambridge, MA: Biogen; 2019 ▪ Ann Indian Acad Neurol. 2019 Apr-Jun; 22(2): 131–136.doi: 10.4103/aian.AIAN_345_18 ▪ Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis A Rae- Grant, GS Day et. Al. Neurology Apr 2018, 90 (17) 777-788; DOI: 10.1212/WNL.0000000000005347 ▪ Olek MJ, Mowry E. Treatment of progressive multiple sclerosis in adults. Post TW, ed. UpToDate Inc. https://www.uptodate.com ▪ B-cell-depleting monoclonal antibodies in neurology. mAb, monoclonal antibody; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder.Daniel H Whittam et al. Pract Neurol 2019;19:5-20 https://pn.bmj.com/content/19/1/5 ▪ US FDA and EMA Accept Applications for Ozanimod for the Treatment of Relapsing Forms of Multiple Sclerosis. Celgene. June 6, 2019. https://ir.celgene.com/press-releases-archive/press-release-details/2019/US-FDA-and-EMA- Accept-Applications-for-Ozanimod-for-the-Treatment-of-Relapsing-Forms-of-Multiple-Sclerosis/default.aspx ▪ Functional Systems Scores. National Multiple Sclerosis Society. https://www.nationalmssociety.org/For- Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Functional-Systems-Scores-(FSS)-and- Expanded-Disab ▪ https://www.nationalmssociety.org ▪ http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Bro chure-The-MS-Disease-Modifying-Medications.pdf ▪ https://www.uptodate.com/contents/treatment-of-progressive-multiple-sclerosis-in-adults ▪ Disease-Modifying Treatment in Progressive Multiple Sclerosis. Curr Treat Options Neurol. 2018 Apr 7;20(5):12. doi: 10.1007/s11940-018-0496-3. ▪ Emerging Therapies for Progressive Multiple Sclerosis. https://practicalneurology.com/articles/2019-feb/emerging-therapies-for-progressive- multiple-sclerosis ▪ Ann Indian Acad Neurol. 2019 Apr-Jun; 22(2): 131–136. doi: 10.4103/aian.AIAN_345_18 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472227/ ▪ https://mymsaa.org/ ▪ https://www.mscare.org/ ▪ Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomized, double-blind, placebo-controlled trial. Lancet. 2016 Mar 12;387(10023):1075-1084. doi: 10.1016/S0140-6736(15)01314-8. Epub 2016 Jan 28.