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MANAGING MULTIPLE SCLEROSIS EXAMINING ORAL TREATMENT OPTIONS AND SPECIALTY PHARMACY CONSIDERATIONS

May 10, 2021

© 2020. All rights reserved. No part of this report may be reproduced or distributed without the expressed written permission of PTCE. Faculty Information Aimee M. Banks, PharmD, BCPS, MSCS Clinical Pharmacist, Multiple Sclerosis Vanderbilt University Medical Center Nashville, Tennessee

Amanda Hickman, PharmD, MPH, MSCS Central Support Neurology Pharmacist Clinical Oversight Neurology Subcommittee Chair TrellisRx Atlanta, Georgia This activity is supported by educational grants from EMD Serono and Bristol Myers Squibb. What Is Multiple Sclerosis (MS)? “more than one” “skleros” (Greek for “hard”)

Immune- Neuro- Neuro- Chronic Disabling mediated inflammatory degenerative

Disorder of the CNS: brain, spinal cord, optic nerve

CNS, central nervous system. Mallucci G, et al. Prog Neurobiol. 2015;127-128:1-22; Compston A, et al. Lancet. 2008;372(9648):1502-1517; “Multiple.” In: Merriam-Webster. Accessed January 31, 2021. merriam-webster.com/dictionary/multiple; “Sclerosis.” In: Merriam-Webster. Accessed January 31, 2021. merriam-webster.com/dictionary/sclerosis Epidemiology of MS

≈2.8 million people worldwide • About 10k-12k new cases per year ≈1 million people in the United States • Prevalence is higher in the northern US Diagnosis often between 20-50 years of age • Peaks around 30 years of age Women are diagnosed 2x-3x as often as men • May be up to 4x as often MS is the most common cause of nontraumatic disability in young adults

Walton C, et al. Mult Scler. 2020;26:1816-1821; Wallin MT, et al. Neurology. 2019;92(10):1029-1040; Mallucci G, et al. Prog Neurobiol. 2015;127-128:1-22; Koch-Henriksen N. Lancet Neurol. 2010;9(5):520-532; Hirtz D, et al. Neurology. 2007;68(5):326-337; Ascherio A, et al. Ann Neurol. 2007;61(4):288-299; Hirtz D, et al. Neurology. 2007;68(5):326-337; Who gets MS? National Multiple Sclerosis Society. Accessed April 12, 2020. nationalmssociety.org/What-is-MS/Who-Gets-MS Risk Factors for MS

• Female sex • Caucasian and northern European Genetic • Family history • HLA-DRB1*15:01 haplotype

• Vitamin D deficiency • Smoking Environmental • Obesity • EBV infection • Geographic latitude EBV, Epstein-Barr virus. Ascherio A. Expert Rev Neurother 2013;13(12 suppl):3-9; Sawcer S, et al. Lancet Neurol. 2014;13(7):700-709; Who gets MS? National Multiple Sclerosis Society. Accessed April 12, 2020. nationalmssociety.org/What-is-MS/Who-Gets-MS Physiologic Processes

Ongoing demyelination

Immune dysregulation

Neuro-inflammation Axonal loss

Demyelination Neuro-degeneration

Lesion formation Progression

Impaired conduction

+/- clinical event/relapse

Part 1: Understanding Progression in MS. Multiple Sclerosis Association of America. Updated September 19, 2017. Accessed November 19, 2020. mymsaa.org/publications/understanding-progression-ms/part-i-understanding-progression/; Compston A, et al. Lancet. 2008;372(9648):1502-1517; Hersh CM, Fox RJ. Cleveland Clinic. Published April 2018. Accessed November 12, 2020. clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/ Physiologic Processes

Supplied by Steven Needell/SCIENCESOURCE.

Republished with permission of American Society of Neuroradiology from “Evaluation of Focal Cervical Spinal Cord Lesions in Multiple Sclerosis: Comparison of White Matter–Suppressed T1 Inversion Recovery Sequence versus Conventional STIR and Proton Density–Weighted Turbo Spin- Echo Sequences,” Sandarakumar DK, et al; Vol 27, No 9 © 2016; permission conveyed through Copyright Clearance Center, Inc.

Republished from Hunter SF. J Mult Scler 2016;3:180, under the terms of a Creative Commons Attribution License. Acute Demyelinating Event

Criteria Common Features Terminology

• Episode of neurologic • Onset in hours to days • First event: clinically isolated dysfunction • Peak in 2-3 weeks syndrome (CIS) • Absence of fever, infection • Improves with or without • Subsequent events: relapses • Lasts >24 hours treatment • Responds to corticosteroids

Optic Neuritis Spinal Cord Syndrome Brainstem Syndrome

• Unilateral • Partial transverse myelitis • Double vision • Reduced visual acuity (TM) • Nystagmus • Reduced color perception • Asymmetric limb weakness • Facial sensory loss • Painful eye movement • Positive Lhermitte’s sign • Trigeminal neuralgia • Retrobulbar neuritis • Sensory symptoms • Vertigo, ataxia • Sphincter symptoms • Slurred speech

Law LY, et al. Neurology. 2019;93(9):390-405; Brownlee WJ, Miller DH. J Clin Neurosci. 2014;21(12):2065-2071. Acute and Chronic Symptoms of MS

CNS Primary Symptoms Secondary Symptoms Location Brain or Fatigue, depression, Urinary tract infections brainstem cognitive impairment, Loss of muscle tone ataxia, tremor, Decreased bone density diplopia, nystagmus, vertigo

Optic Vision changes Tertiary Symptoms nerve Social isolation Spinal Bladder/bowel/sexual cord dysfunction, Vocational limitations weakness, spasticity Psychological effects Depression

Multiple Sclerosis Symptoms. Accessed November 17, 2020. www.healthnormal.com/ms-symptoms-signs-and-symptoms-of-multiple-sclerosis/; Compston A, et al. Lancet. 2008;372(9648):1502-1517; Maroney M, et al. Am J Manag Care. 2014;20(suppl 11):S220-S227. Phenotypes of MS . . Clinically Isolated . Relapsing/ . Secondary Primary Syndrome (CIS) Remitting MS Progressive MS Progressive MS (RRMS) (SPMS) (PPMS) . . . Initial clinical event Relapsing phase: Progression onset . Progression of without full acute deficits, is secondary to symptoms and diagnostic criteria worsening function relapsing/ disability from of definitive MS or remitting course onset Remitting Phase • Active or Inactive • Active or Inactive complete or partial Phases Phases recovery

30%-70% of 85%-90% initially Without DMT, 10%-15% of MS patients with CIS diagnosed with 50% within 10 y, patients have will develop RRMS RRMS >75% within 25 y PPMS

Lublin FD, et al. Neurology. 2014;83(3):278-286; Lublin FD. Eur Neurol. 2014;72(suppl):1-5; Lublin FD, et al. Neurology. 1996;46(4):907-911; Hauser SL. Am J Med. 2020;133(12):1380-1390.e2; Secondary Progressive MS SPMS. National MS Society. Accessed March 8, 2021. www.nationalmssociety.org/What-is-MS/Types-of- MS/Secondary-progressive-MS Phenotypes and Modifiers

Republished from: Types of MS. National MS Society. Accessed January 31, 2021. nationalmssociety.org/What-is-MS/Types-of-MS; Lublin FD. Eur Neurol. 2014;72(suppl):1-5 Defining Modifying Terms • MRI activity • Episode of neurological dysfunction • Gd+ enhancing lesions, or • “Exacerbation” or “attack” new or enlarging lesions* • Lasts >24 hours (often days to • Clinical activity = relapse weeks) • Approx. 1 clinical relapse • Not a pseudo-attack occurs for every 10-20 MS activity Relapse • Altered core body temp (Uhthoff’s subclinical brain lesions phenomenon) • Infection

• Sustained worsening and accrual of disability for at least Progression Worsening • Neurological exam has worsened 6-12 months (eg, increase in impairment or • Decline must be independent disability) of relapse or MRI activity • May be residual effects of a relapse

MRI, magnetic resonance imaging; Gd+ gadolinium positive; *Lesions typical of MS based on location/characteristics. Lublin FD, et al. Neurology. 2020;94:1088-1092; Thompson AJ, et al. Lancet Neurol. 2018;17(2):162-173; Lublin FD, et al. Neurology. 2014;83:278-286; Lublin FD. Eur Neurol. 2014;72(suppl 1):1-5; McDonald WI, et al. Ann Neurol. 2001;50(1):121-127; Joy JE, Johnston RB Jr. Institute of Medicine US Committee on Multiple Sclerosis: Current Status and Strategies for the Future; National Academies Press; 2001. 2, Clinical and Biological Features. MS Disease Course

Reprinted from: Fox RJ, Cohen JA. Cleve Clin J Med. 2001;68(2):157-171. Copyright © 2001 Cleveland Clinic Foundation. All rights reserved. Hersh CM, Fox RJ. Cleveland Clinic. Published April 2018. Accessed May 5, 2021. clevelandclinicmeded.com/medicalpubs/diseasemanagement/neurology/multiple_sclerosis/ Foundation for Diagnosis: Dissemination in Space (DIS) and Time (DIT) DIS: evidence of damage in at least 2 areas of the CNS DIT: evidence that damage occurred at different points in time

Clinical Radiographic Supportive Testing • Presentation *and* History • MRI imaging • CSF: OCBs, IgG index • Visual Evoked Potentials

Exclusion of mimics

NMOSD Neuro-sarcoidosis Infection Malignancy Migraine

CSF, cerebrospinal fluid; OCB, oligoclonal band; IgG, immunoglobulin G; NMOSD, neuromyelitis optica spectrum disorder; McDonald WI, et al. Ann Neurol. 2001;50(1):121-127; Polman CH, et al. Ann Neurol. 2011;69(2):292-302; Thompson AJ, et al. Lancet Neurol. 2018;17(2):162-173; Aliaga ES, Barkhof F. Handb. Clin Neurol. 2014;122:291-316. Summary of 2017 McDonald Criteria for Relapsing MS CLINICAL PRESENTATION ADDITIONAL CRITERIA TO MAKE MS DIAGNOSIS …in a person who has experienced a typical attack/CIS at onset 2 or more events and clinical or None. However, MRI is often obtained to stage the disease severity and exclude other historical evidence of 2 or more diagnosis. lesions in 2 or more CNS locations 2 or more events and clinical DIS shown by one of these criteria: evidence of 1 lesion • Additional clinical event implicating different CNS site • 1 or more symptomatic or asymptomatic MS-typical T2 lesions in 2 or more areas of CNS: periventricular, juxtacortical/cortical, infratentorial, spinal cord 1 event and clinical evidence of 2 or DIT shown by one of these criteria: more lesions • Additional clinical event • Simultaneous enhancing and non-enhancing symptomatic or asymptomatic MS-typical MRI lesions, or new T2 or enhancing lesion compared to baseline • CSF-specific oligoclonal bands 1 event and clinical evidence of 1 DIS shown by one of the required criteria (as above) lesion AND DIT shown by one of the required criteria (as above)

Revisions compared to previous criteria; CIS, clinically isolated syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; DIS, dissemination in space; DIT, dissemination in time; T2 lesions: hyperintense lesion on T2-weighted MRI; Adapted from Thompson AJ, et al. Lancet Neurol. 2018;17(2):162-173; Diagnostic Criteria. National Multiple Sclerosis Society. Accessed February 2, 2021. www.nationalmssociety.org/For-Professionals/Clinical-Care/Diagnosing-MS/Diagnosing-Criteria Summary of 2017 McDonald Criteria for Primary Progressive MS CLINICAL PRESENTATION ADDITIONAL CRITERIA TO MAKE MS DIAGNOSIS

…in a person with progression of disability from onset Progression from onset 1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse

AND

DIS shown by at least two of these criteria • 1 or more symptomatic or asymptomatic MS-typical T2 lesions in 1 or more areas of the brain (periventricular, juxtacortical/cortical, infratentorial) • 2 or more T2 spinal cord lesions • CSF-specific oligoclonal bands

Revisions compared to previous criteria; CSF, cerebrospinal fluid; DIS, dissemination in space; T2 lesions: hyperintense lesion on T2-weighted MRI; Adapted from Thompson AJ, et al. Lancet Neurol. 2018;17(2):162-173; Diagnostic Criteria. National Multiple Sclerosis Society. Accessed February 2, 2021. www.nationalmssociety.org/For-Professionals/Clinical-Care/Diagnosing-MS/Diagnosing-Criteria Factors for Aggressive Disease Highly Active Relapsing MS Poor Prognostic Signs • ≥2 relapses in previous 12 months • Age ≥40 years at onset • Severe relapse resulting in significant • Male gender increase in EDSS • African American • Incomplete recovery from significant relapse • Motor, sphincter, cerebellar, spinal cord • EDSS of ≥4 within 5 years of onset symptoms • Change in EDSS ≥2 points in previous 12 • Brainstem or spinal cord lesions at onset months • ≥2 attacks in first 2 years of onset • ≥2 Gd+ lesions ≥3 mm in size • Incomplete recovery from relapse • ≥3 T2 lesions on 2 consecutive MRIs 6-12 months apart • Early brain atrophy

EDSS, expanded disability status scale; Gd+ = gadolinium-enhancing. Menon, et al. Mult Scler. 2017;23(3);456-463; Menon, et al. J Neurol Neurosurg Psych. 2013;84(11):1192-1198; Rush, et al. Nat Rev Neurol. 2015;11(7):379-389; Ford CC, et al. CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis: CMSC DMT Guideline Writing Group. February 2019. Treatment Goals Address Modify Risk Modify the Treat Acute Factors Disease Symptoms Relapses Course

• Accelerate • Reduce CIS • Reduce MRI • Improve time to → RRMS activity quality of recovery • Reduce MS • NEDA or life • Minimize activity MEDA • Reduce residual • Slow • Reduce impact of deficits progression clinical disability activity • Relapse rates • Slow progression • Prolong time to disability RMS, relapsing MS; NEDA, no evidence of disease activity; MEDA, minimal evidence of disease activity. Ford CC, et al. CMSC Practical Guidelines for the Selection of Disease-Modifying Therapies in Multiple Sclerosis: CMSC DMT Guideline Writing Group. February 2019; Rosso M. JAMA Neurol. 2019;10.1001; Pierrot-Deseilligny C. Mult Scler Relat Disord. 2017;14:35-45; Stampanoni Bassi M. Mult Scler. 2019. Disease-Modifying Therapy (DMT) approved for the treatment of relapsing forms of MS to include: CIS, RRMS, and active SPMS

• Glatiramer • Teriflunomide • Natalizumab acetate • Fumaric acids • Alemtuzumab • Interferon-beta • S1P modulators • Ocrelizumab* • Cladribine • Ofatumumab Platform Monoclonal Oral Agents Therapies Antibodies

*Ocrelizumab is also approved for the treatment of primary progressive MS (PPMS). Oral DMTs, Part 1: S1P Modulators Sphingosine-1-Phosphate (S1P) Modulators Indication relapsing forms of MS to include CIS, RRMS, and active SPMS Mechanism inhibition of S1P receptors → sequestration of lymphocytes within lymph nodes → reduced peripheral circulation → reduced migration into the CNS Agent Fingolimod Siponimod Ozanimod Ponesimod Year of FDA approval 2010 2019 2020 2021 2018 (peds >10 y/o) Maintenance dose 0.5 mg once daily 1 mg* or 2 mg* once 0.92 mg once daily, 20 mg once daily, daily, after titration after titration after titration Pediatrics <40 kg: 0.25 mg once daily

Receptor subtypes S1P1 S1P3 S1P4 S1P5 S1P1 S1P5 S1P1 S1P5 S1P1 Half-life 6-9 days 30 hours 21 hours (11 days for 33 hours active metabolite) Drug interactions 4F2 2C9, 3A4 2C8 3A4, UGT1A1 Median decrease of ALC 60% 20%-30% 30% 70% Median recovery time to 30-60 days 10 days (up to 3-4 weeks) 30 days 4-7 days normal range ALC

CYP, cytochrome-P-450. *Dose is dependent on CYP2C9 genotype. Cohan S, et al. Biomedicines. 2020;8(7):227; D'Ambrosio D, et al. Ther Adv Chronic Dis. 2016;7(1):18-33; Gilenya. Prescribing information. Novartis; 2019; Mayzent. Prescribing information. Novartis; 2021; Zeposia. Prescribing information. Celgene; 2020; Ponvory. Prescribing information. Janssen; 2021. S1P Receptors’ Biological Roles

Cree BA, et al. “Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm.” Curr Opin Neurol. 2019; 32(3):365-377. journals.lww.com/co- neurology/Abstract/2019/06000/Current_therapeutic_landscape_in_multiple.9.aspx Republished with permission from Wolters Kluwer Health, Inc. Safety Fingolimod Siponimod Ozanimod Ponesimod

Contraindications Recent (within last 6 months) MI/UA/stroke/TIA, class III/IV CHF, decompensated HF with hospitalization; Mobitz type II 2nd or 3rd degree AV block, sick sinus syndrome (unless pacemaker)

QTc ≥500 ms; CYP2C9 Genotype *3/*3 Severe sleep apnea; --- class Ia, III antiarrhythmics MAO inhibitors

Common adverse effects Lymphopenia, LFT elevation, headache, HTN, upper respiratory infection

1st dose bradycardia, cough, Peripheral edema Orthostatic hypotension --- sinusitis, back pain, GI upset

Serious ADEs Infections (including zoster), bradyarrhythmia, macular edema, reduced FEV1

Serious infections (including Serious infections (including Serious infections (including PML, cryptococci) cryptococci) PML, cryptococci) Skin cancer Skin cancer Skin cancer Fetal harm Fetal harm Fetal harm Fetal harm Rebound relapse/disability

Gilenya. Prescribing information. Novartis; 2019; Mayzent. Prescribing information. Novartis; 2021; Zeposia. Prescribing information. Celgene; 2020; Ponvory. Prescribing information. Janssen; 2021; Kappos L, et al. Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 2019. Safety Fingolimod Siponimod Ozanimod Ponesimod First Dose Observation FDO required before initiation FDO required if: sinus FDO not required FDO required if: sinus (FDO) of therapy bradycardia, Mobitz type I bradycardia, Mobitz type I 1st or 2nd degree AV block, 1st or 2nd degree AV block, or history of MI or CHF or history of MI or CHF Dose titration --- Dose titration required (with Dose titration required Dose titration required (with or without FDO) or without FDO) Missed doses Repeat FDO if ≥14-day lapse Restart with titration (± FDO) Restart titration if ≥1 Restart with titration (± FDO) if ≥1 titration dose is missed titration dose is missed if ≥4 titration doses are or if ≥4-day lapse in missed or if ≥4-day lapse in maintenance dose maintenance dose Pregnancy/contraception 2-month washout 10-day washout 3-month washout 7-day washout

Other considerations Pediatric approval for ages 10 CYP2C9 genotype needed to Monitor for hypertensive 4-hour FDO (versus 6) years and older determine dose crisis Not recommended in Continuous FDO w/ ECG Refrigeration required before patients with moderate monitoring if certain conditions opening or severe hepatic or concurrent medications impairment Gilenya. Prescribing information. Novartis; 2019; Mayzent. Prescribing information. Novartis; 2021; Zeposia. Prescribing information. Celgene; 2020; Ponvory. Prescribing information. Janssen; 2021; Kappos L, et al. Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), 2019. Drug Interactions Fingolimod Siponimod Ozanimod Ponesimod Class Ia and III antiarrhythmics Drug InteractionsContraindicated Avoid Use caution Avoid Other antiarrhythmics Use caution Avoid Use caution Avoid QTc prolonging agents (citalopram, ciprofloxacin) Use caution Avoid Use caution Avoid HR-lower agents (beta blockers, verapamil, digoxin) Use caution Use caution --- Use caution Strong CYP3A4 inhibitors (ketoconazole) and inducers (carbamazepine) Use caution Use caution ------Moderate/strong CYP3A4 inducers (modafinil, efavirenz) --- Use caution, Avoid* ------CYP3A4 and CYP2C9 inhibitors (fluconazole) and inducers (rifampin, --- Avoid ------carbamazepine) CYP2C9 inhibitors and inducers --- Use caution ------Strong CYP3A4 and UGT1A1 inducers (rifampin, phenytoin, ------Avoid carbamazepine) MOA inhibitors (selegiline, linezolid) ------Contraindicated --- Strong CYP2C8 inhibitors and inducers (gemfibrozil, rifampin) ------Avoid --- BCRP inhibitors (cyclosporine) ------Avoid --- Adrenergic/serotonergic drugs (SSRIs, SNRIs, TCAs) & tyramine-rich foods ------Not recommended --- Immunosuppressive and immune-modulating agents Use caution Use caution Use caution Use caution Reduced effectiveness of vaccines during and after last dose Up to 2 months Up to 1 month Up to 3 months Up to 2 weeks *Drug interactions for moderate or strong 3A4 inducers vary based on CYP2C9 genotype (ie, genotype *1/*3 and *2/*3 who require 1-mg dose); Gilenya. Prescribing information. Novartis; 2019; Mayzent. Prescribing information. Novartis; 2021; Zeposia. Prescribing information. Celgene; 2020; Ponvory. Prescribing information. Janssen; 2021. Efficacy S1P Agent Fingolimod Siponimod Ozanimod Ponesimod

Trial FREEDOMS I/II EXPAND SUNBEAM, RADIANCE OPTIMUM Comparator placebo placebo IM IFN-b teriflunomide

Inclusion Relapsing MS: RRMS SPMS Relapsing MS: RRMS, active Relapsing MS: RRMS, active SPMS SPMS

McDonald Criteria 2005 2010 2010 2010 RRR of ARR 48%-54% 55% 38%-48% 31%

RRR of CDP NS to 30% 21-26% 31% (NS) 17% (NS)

RRR of MRI New/enlarging T2: 74% New/enlarging T2: 90% New/enlarging T2: 42-48% New/enlarging T2: 56% Outcomes Gad+ lesions: 70-79% Gad+ lesions: 88% Gad+ lesions: 53-63% Gad+ lesions: 59% Brain volume loss: 31-36% Brain volume loss: 31% Brain volume loss: 27-33% Brain volume loss: 66%

RRR, relative risk reduction; ARR, annualized relapse rate; CDP, confirmed disability progression; NS, not statistically significant; CUAL, combined unique active lesions; FSIQ-RMS, Fatigue Symptoms and Impact Questionnaire-Relapsing MS. Cohan S, et al. Biomedicines. 2020;8(7):227; Cree BA, et al. Curr Opin Neurol. 2019;32(3):365-377; Kappos L, et al. N Engl J Med. 2010;362(5):387-401; Calabresi PA, et al. Lancet Neurol. 2014;13(6):545-56; Kappos L, et al. Lancet. 2018;391(10127):1263-1273; Comi G, et al. Lancet Neurol. 2019;18(11):1009-1020; Cohen JA, et al. Lancet Neurol. 2019;18(11):1021-1033; Kappos L, et al. ECTRIMS 2019. Oral DMTs, Part 2: Fumaric Acid Derivatives and Cladribine Amanda Hickman, PharmD, MPH, MSCS Fumaric Acid Derivatives Dimethyl Fumarate (DMF) Monomethyl Fumarate (MMF) Diroximel Fumarate (DRF)

MOA Activate Nrf2 Pathway anti-inflammatory and cytoprotective action

Initiation: 120 mg BID X 7 days Initiation: 95 mg BID X 7 days Initiation: 231 mg BID X 7 days Administration Maintenance: 240 mg BID Maintenance: 190 mg BID Maintenance: 462 mg BID

Trial: 42% Trial: used DMF trial data Trial: 31% GI FAERS: 20% FAERS: No report FAERS: 30% Trial: 19% Trial: used DMF trial data Trial: 44% Side Effects Flushing FAERS: 15% FAERS: only 1 case reported (Flushing) FAERS: 22% Severe Lymphopenia: 2% Moderate Lymphopenia: 7.3% Other General Class Warnings: respiratory infections, PML, hepatotoxicity, hypersensitivity, proteinuria T1/2: 1 hour T1/2: 0.5 hour T1/2: 1 hour Pharmacokinetics No Hepatic or Renal Considerations* Not recommended in pregnancy or breastfeeding (presence in breastmilk hasn’t been studied) Contraindications/ • • Not recommended with live vaccines Interactions of note *DRF has inactive metabolite that is renally excreted, monitor Package Insert Bafiertam, Vumerity, Tecfidera;• Contraindicated Studies: ENDORSE, with ENVOLVE other fumaric-MS-1 acid derivatives moderate-severe renal impairment. Bafiertam SE; Vumerity SE; Tecfidera SE: FDA Adverse Events Reporting System (FAERS) Public Dashboard. December 30, 2020. Accessed February 28, 2021. Fumaric Acid Derivatives

SIDE EFFECTS BASED ON TRIAL DATA DMF DRF 94 84.6 44 42 31 19 16 6.3 PERCENT PERCENT OF PATIENTS

GI SE FLUSHING TOTAL SE DC'D DUE TO SE

Studies: ENDORSE and ENVOLVE-MS-1. Cladribine Metabolized to Cd-ATPDNA incorporation and cytotoxic effects MOA Action in MS hypothesized to be from B and T cell depletion. *Weight-Based Dosing 2 Course Regimen* Example: 75-kg patient = 131 mg/year = 65.5 mg/cycle70 mg (per dosing chart) 1.75 mg/kg/year divided between 2 cycles Administration No more than 20 mg/day Cycle 1 Cycle 2 Separate cycles by 23-27 days after day 5 Days 1-2: two 10-mg tablets PO daily Days 28-29: two 10-mg tablets PO daily Separate Courses by at least 43 weeks Days 3-5: one 10-mg tablet PO daily Days 30-32: one 10-mg tablet PO daily Lymphopenia (28%) Hematology Lymphopenia leading to discontinuation (8%) Leukopenia (7%) All Grade 3 Lymphopenia resolved within 1-2 months

Side ID Total ID SE: 47% Nasopharyngitis (16%) Influenza (10%) URTI (9%) UTI (7%) Bronchitis (5%) Effects

Other Headache (15%) Back Pain (10%) Pain in Extremities (6%)

Pharmacokinetics T1/2: 24 hours. No hepatic considerations. Mild renal impairment (CrCl 60-89 mL/min)25% increased exposure • Black box warning (BBW): Contraindicated in pregnancy…both men and women receiving cladribine must use contraception up to 6 months after the last dose of treatment. **Cladribine may reduce the effectiveness of oral contraceptives** Contraindications/ • BBW: malignancy…evaluate patient risks and history and adhere to routine screenings. Interactions of note • Cannot repeat cladribine within 2 years of second course. • ID screenings: TB, HBV, HCV, herpes viruses, vaccination for varicella zoster. • No vaccines <4 weeks before initiation and until CBC returns to normal. Mavenclad. Prescribing information. EMD Serono; 2019; Study: CLARITY. Efficacy Dimethyl Fumarate Therapy Diroximel Fumarate Cladribine Monomethyl Fumarate

Landmark Trial DEFINE CONFIRM EVOLVE-MS-1 EVOLVE-MS-2 CLARITY

Comparator Placebo Placebo, glatiramer acetate None DMF Placebo

Average Age: 38.1 years Average Age: 37.8 years Average Age: 41.9 years Average Age: 43.7 years Average Age: 37.9 years Population Average Years with MS: 5.6 Average Years with MS: 4.9 Average Years with MS: 7.6 Average Years with MS: 7.4 Average Years with MS: 7.9 Average EDSS: 2.4 Average EDSS: 2.6 Average EDSS: 2.7 Average EDSS: 2.7 Average EDSS: 2.8 Proportion of patients Annualized Relapse rate at 2 years: Number of days with IGISIS Annualized Relapse Rate Primary End relapsed at 2 years: Safety and Tolerability of ≥2: point (see below) DRF DRF: 1.4 DMF: 2.6 (see below) DMF: 27% Placebo: 46%

DMF: 0.17 DMF: 0.22 ARR DRF: 0.16 Not measured Clad: 0.14 Placebo: 0.33 Placebo: 0.36 Placebo: 0.40 GA: 0.29

Mean number of new or Mean number of new or enhancing enhancing lesions: lesions: Combined Unique lesions: MRI Not measured Not measured Clad: 0.43 Placebo: 1.72 DMF: 2.6 Placebo: 17 DMF: 5.1 Placebo: 17.4 GA: 8.0

Studies: DEFINE, CONFIRM, EVOLVE-MS-1, EVOLVE-MS-2, CLARITY. Oral DMTs, Part 2: Fumaric Acid Derivatives and Cladribine Fumaric Acid Derivatives Dimethyl Fumarate (DMF) Monomethyl Fumarate (MMF) Diroximel Fumarate (DRF)

MOA Activate Nrf2 Pathway anti-inflammatory and cytoprotective action

Initiation: 120 mg BID X 7 days Initiation: 95 mg BID X 7 days Initiation: 231 mg BID X 7 days Administration Maintenance: 240 mg BID Maintenance: 190 mg BID Maintenance: 462 mg BID

Trial: 42% Trial: used DMF trial data Trial: 31% GI FAERS: 20% FAERS: No report FAERS: 30% Trial: 19% Trial: used DMF trial data Trial: 44% Side Effects Flushing FAERS: 15% FAERS: only 1 case reported (Flushing) FAERS: 22% Severe Lymphopenia: 2% Moderate Lymphopenia: 7.3% Other General Class Warnings: respiratory infections, PML, hepatotoxicity, hypersensitivity, proteinuria T1/2: 1 hour T1/2: 0.5 hour T1/2: 1 hour Pharmacokinetics No Hepatic or Renal Considerations* Not recommended in pregnancy or breastfeeding (presence in breastmilk hasn’t been studied) Contraindications/ • • Not recommended with live vaccines Interactions of note • Contraindicated with other fumaric acid derivatives *DRF has inactive metabolite that is renally excreted, monitor moderate-severe renal impairment.

Package Insert Bafiertam, Vumerity, Tecfidera; Studies: ENDORSE, ENVOLVE-MS-1 Bafiertam SE; Vumerity SE; Tecfidera SE: FDA Adverse Events Reporting System (FAERS) Public Dashboard. December 30, 2020. Accessed February 28, 2021. Fumaric Acid Derivatives

SIDE EFFECTS BASED ON TRIAL DATA DMF DRF 94 84.6 44 42 31 19 16 6.3 PERCENT PERCENT OF PATIENTS

GI SE FLUSHING TOTAL SE DC'D DUE TO SE

Side ID Total ID SE: 47% Nasopharyngitis (16%) Influenza (10%) URTI (9%) UTI (7%) Bronchitis (5%) Effects

Other Headache (15%) Back Pain (10%) Pain in Extremities (6%)

Landmark Trial DEFINE CONFIRM EVOLVE-MS-1 EVOLVE-MS-2 CLARITY

Comparator Placebo Placebo, glatiramer acetate None DMF Placebo

DMF: 0.17 DMF: 0.22 ARR DRF: 0.16 Not measured Clad: 0.14 Placebo: 0.33 Placebo: 0.36 Placebo: 0.40 GA: 0.29

Studies: DEFINE, CONFIRM, EVOLVE-MS-1, EVOLVE-MS-2, CLARITY. The Role of Specialty Pharmacy: Empowering Patients With MS Amanda Hickman, PharmD, MPH, MSCS Audience Poll

In which setting do you primarily care for MS patients? A) Hospital System Specialty Pharmacy B) Traditional Specialty Pharmacy C) Retail Pharmacy D) Acute Care/Inpatient Pharmacy E) Other F) I don’t really see MS patients in my practice Audience Poll

Which do you think is the biggest role a specialty pharmacist plays in the care of MS patients? A) Benefit Expertise (insurance and affordability) B) Medication Access C) Medication Selection D) Clinical Outcomes E) Access to Health Care Specialty Pharmacy’s Wheelhouse

Improved Clinical Patient Outcomes Empowerment

Medication and Medication Practitioner Appropriateness Access

Medication Safety and Tolerability Burden of Multiple Sclerosis

This Photo by Unknown Author is licensed under CC BY-SA Burden of Multiple Sclerosis

Access to Specialists

Ability to This Photo by Unknown Author is licensed under CC BY-SA Work “…[MS] patients, their families and caregivers, employers, and the entire healthcare system carry substantial clinical and economic burdens associated with the disease over a period of many years.” (Owens, 2016) Cost of

Owens (2016) Medications Simacek (2018) Burden of Multiple Sclerosis

Access to MS Specialists Progression

Ability to Current This Photo by Unknown Author is licensed under CC BY-SA Work Disability

Family and Symptom Cost of Pill Management Burden Owens (2016) Life Plans Medications Rieckmann (2017) The Role of Specialty Pharmacy

Access to MS Specialists Progression

Ability to Current This Photo by Unknown Author is licensed under CC BY-SA Work Disability

Family and Symptom Cost of Pill Management Burden Owens (2016) Life Plans Medications Rieckmann (2017) The Role of Specialty Pharmacy

MS Pill Cost of Progression Burden Medications

Family and Life Plans

Access to Symptom Specialists Management The Role of Specialty Pharmacy  Overview of Adherence to Oral MS DMTs  Review of Counseling and Adherence for each Oral Category • S1P Modulators • Fumaric Acid Derivatives • Cladribine

 Improving Quality of Life • MS and Depression • Monitoring for Progression • Connection to Resources The Role of Adherence

Why Is It Important? The Role of Adherence

Why Is It Important?

DMT treatment = only scientifically recognized option for slowing MS progression. . All approved therapies have shown lower ARRs than placebo

National Multiple Sclerosis Society. Adherence. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Medications/Adherence Ivanova (2012) Johnson (2017) The Role of Adherence

What Is the Situation? • “Lack of adherence was significantly higher [55% adherent vs 70.8% and 93.3%] in patients receiving oral as compared to injectable DMTs, despite their reported ease of administration.” (Dionne, 2015) • “Results showed that one in five patients do not adhere to…oral maintenance [DMTs]…and one in four patients with MS discontinue…before 1 year.” (Nicholas, 2020) • “…69.1% of patients were classified as adherent using the…medication possession ratio (MPR) ≥80%.” (Johnson, 2017) (Ivanova, 2012) • Issues affecting DMT access led to about 1 in 5 patients going without medication. (Simacek, 2018) The Role of Adherence What Is the Situation? • “Lack of adherence was significantly higher [55% adherent vs 70.8% and 93.3%] in patients receiving oral as compared to injectable DMTs, despite their reported ease of administration.” (Dionne, 2015) • “Results showed that one in five patients do not adhere to…oral maintenance DMDs…and one in four patients with MS discontinue…before 1 year.” (Nicholas, 2020) • “…69.1% of patients were classified as adherent using the…medication possession ratio (MPR) ≥80%.” (Johnson, 2017) (Ivanova, 2012) • Issues affecting DMT access led to about 1 in 5 patients going without medication. (Simacek, 2018) The Role of Adherence What Is the Situation? • “Lack of adherence was significantly higher [55% adherent vs 70.8% and 93.3%] in patients receiving oral as compared to injectable DMTs, despite their reported ease of administration.” (Dionne, 2015) • “Results showed that one in five patients do not adhere to…oral maintenance DMDs…and one in four patients with MS discontinue…before 1 year.” (Nicholas, 2020) • “…69.1% of patients were classified as adherent using the…medication possession ratio (MPR) ≥80%.” (Johnson, 2017) (Ivanova, 2012) • Issues affecting DMT access led to about 1 in 5 patients going without medication. (Simacek, 2018) The Role of Adherence

Why Is It Important? DMT treatment = only scientifically recognized option for slowing MS progression.

Adherence to oral DMTs is still an area of impact where specialty pharmacy can help. The Role of Counseling

Why Is It Important?

This Photo by Unknown Author is licensed under CC BY-SA-NC

Corallo (2019) National Multiple Sclerosis Society. Adherence. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Medications/Adherence Rieckmann (2017) The Role of Counseling

Why Is It Important? Non-financial barriers to adherence: • Chronic medication treating a remitting disease

This Photo by Unknown Author is licensed under CC BY-SA-NC

Corallo (2019) National Multiple Sclerosis Society. Adherence. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Medications/Adherence Rieckmann (2017) The Role of Counseling

Why Is It Important? Non-financial barriers to adherence: • Chronic medication treating a remitting disease • Complexity of treatment Frequency of administration o This Photo by Unknown Author is licensed under CC BY-SA-NC o Pill burden

Corallo (2019) National Multiple Sclerosis Society. Adherence. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Medications/Adherence Rieckmann (2017) The Role of Counseling

Corallo (2019) National Multiple Sclerosis Society. Adherence. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Medications/Adherence Rieckmann (2017) The Role of Counseling Why Is It Important? Non-financial barriers to adherence: • Chronic medication treating a remitting disease • Complexity of treatment o Frequency of administration Pill burden o This Photo by Unknown Author is licensed under CC BY-SA-NC • Side effects and risks • Lack of perceived efficacy or need for treatment • Potential disabilities and symptoms from MS (including cognitive and physical) Corallo (2019) National Multiple Sclerosis Society. Adherence. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Medications/Adherence Rieckmann (2017) The Role of Counseling Pharmacist Counseling 11% Program DMT Discontinuation Rate

Control 23% Group DMT Discontinuation Rate

Phillips (2015) The Role of Counseling Medication Administration

Fingolimod Daily

Siponimod Daily

Ozanimod Daily

DMF Titration BID

MMF BID

DRF BID Cladribine Daily, complex regimen, short duration The Role of Counseling Medication Administration Reduces the need Fingolimod Daily for FDO Siponimod Daily

Ozanimod Daily

DMF Titration BID Reduces intensity MMF BID of side effects DRF BID Cladribine Daily, complex regimen, short duration

Phillips (2015) The Role of Counseling Medication Administration 1 mg dosing = four 0.25-mg Fingolimod Daily tablets/day Siponimod Daily

Ozanimod Daily

DMF Titration BID 2 tablets BID

MMF BID

DRF BID Cladribine Daily, complex Weight-based regimen, short duration dosing

Phillips (2015) The Role of Counseling Medication Administration Skip meals? Fingolimod Daily

Siponimod Daily Vegetarian or

Ozanimod Daily Vegan? DMF Titration BID Allergies? GI meds already available? MMF BID DRF BID Aspirin available? Cladribine Daily, complex regimen, short Contraindications? duration (bleed risk, DDIs)

Phillips (2015) The Role of Counseling Medication Side Effects and Risks Fingolimod

Siponimod Risk Ozanimod

DMF

MMF SE DRF

Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization. The Role of Counseling Medication Side Effects and Risks Fingolimod

Siponimod Risk Ozanimod

DMF

MMF SE DRF

Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization.

Rieckmann (2017) The Role of Counseling Medication Side Effects and Risks Fingolimod

Siponimod Risk Health Care Providers Ozanimod Risks and side effects are key details to treatment decision DMF making. MMF SE DRF

Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization.

Rieckmann (2017) The Role of Counseling Medication Side Effects and Risks Fingolimod

Siponimod Risk MS Patients Health Care Providers While side effects are a Ozanimod Risks and side effects are key concern, patients want more details to treatment decision DMF information on the efficacy making. and benefits of therapy. MMF SE DRF

Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization.

Rieckmann (2017) The Role of Counseling Medication Side Effects and Risks Fingolimod

Siponimod Risk Ozanimod

DMF

MMF SE DRF

Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization. The Role of Counseling Medication Side Effects and Risks • Cardio risk Fingolimod • Macular edema • Lymphocytopenia Siponimod Risk • PML Ozanimod • Rebound MS relapses DMF

MMF SE DRF

Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization. The Role of Counseling Medication Side Effects and Risks Fingolimod

Siponimod Risk Ozanimod

DMF

MMF SE • Lymphopenia DRF • Infections • PML Cladribine Risk Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization. The Role of Counseling Medication Side Effects and Risks Fingolimod • GI side effects Siponimod Risk  Take with food (proteins Ozanimod and good fats) DMF  Mixture of GI medications  Time and patience MMF SE • Flushing DRF  ASA • Infections Cladribine Risk • Lymphopenia/PML Risk = counseling is more risk heavy. SE = counseling is more SE heavy for minimization.

Phillips (2017) The Role of Counseling Medication Access and Affordability Fingolimod FDO

Siponimod FDO Resources for Affordability • Co-pay Programs Ozanimod • Grants DMF Generic is • Low-Income Subsidy Plans not LDD • Patient Assistance Programs LDD MMF • Local and National Organizations DRF

Cladribine Not First Line

Limited Distribution Specialty Drug List | 1199SEIU Funds. January 1, 2021. Accessed April 15, 2021. www.1199seiubenefits.org/wp-content/uploads/2021/01/Limited- Distribution-Specialty-Drug-List.pdf The Role of Counseling Medication Family Planning

Fingolimod

Siponimod Rebound relapse* Ozanimod Not Recommended DMF

MMF Short t1/2 DRF Cladribine 2 cycles over 2 Contraindicated years *Seen with fingolimod.

Langer-Gould (2019) Berenguer-Ruiz (2019) The Role of Counseling Medication Administration Side Effects Access and Family Planning and Risks Affordability Fingolimod Daily FDO Rebound Siponimod Daily Risk FDO exacerbation* Ozanimod Daily Not DMF Generic is Recommended Titration BID not LDD MMF BID SE LDD Short t1/2

DRF BID Cladribine Daily, complex Not First 2 cycles over 2 regimen, short Risk Contraindicated Line years duration *Seen with fingolimod. The Role of Empowerment

MS and Depression Monitoring for Progression Connection to Resources The Role of Empowerment MS and Depression Depression • A depressive change that affects day-to-day life, typically for more than 2 weeks

8% of US adults had at least 1 major depressive episode in 2017. of US adults will struggle with major depressive 20% disorder in their lifetime.

National Alliance on Mental Illness. Depression. Reviewed August 2017. Accessed April 15, 2021. www.nami.org/About-Mental-Illness/Mental-Health-Conditions/Depression Minden S. National Multiple Sclerosis Society. Depression & Multiple Sclerosis. 2019. Accessed April 15, 2021. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-Depression.pdf The Role of Empowerment MS and Depression Depression • A depressive change that affects day to day life, typically for more than 2 weeks

8% of US adults had at least 1 major depressive episode in 2017. of US adults will struggle with major depressive 20% disorder in their lifetime. of MS patients could be affected with major depressive 50% disorder. National Alliance on Mental Illness. Depression. Reviewed August 2017. Accessed April 15, 2021. www.nami.org/About-Mental-Illness/Mental-Health-Conditions/Depression; Minden S. National Multiple Sclerosis Society. Depression & Multiple Sclerosis. 2019. Accessed April 15, 2021. www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-Depression.pdf The Role of Empowerment MS and Depression

 There is a significant correlation between depression and nonadherence. • MS patients with psychiatric diagnoses are 5X more to have nonadherence tendencies. Impact likely

 MS patients diagnosed with depression report higher EDSS scores than those without depression.

Nicholas (2020), Ivanova (2012), Corallo (2019), Binzer (2019) The Role of Empowerment MS and Depression

Ask about mental health during assessments and check-ins. Incorporate tools such as PHQ-2 and PHQ-9 into Empower assessments. Be familiar with the mental health resources available to patients. Report concerns to the patient’s provider.

Spitzer RL, et al. Patient Health Questionnaire-9 (PHQ-9). Accessed April 15, 2021. www.apa.org/depression-guideline/patient-health-questionnaire.pdf The Role of Empowerment Monitoring for Progression

MS Exacerbation Pseudo-Exacerbation

New or Worsening Symptom Old symptoms

>24 hours, >30 days since last relapse <24 hours*

“Stress” No apparent cause Sickness, heat, exhaustion, emotional stress *unless cause is lasting >24 hours, such as infection

National Multiple Sclerosis Society. Managing Relapses. Accessed April 15, 2021. www.nationalmssociety.org/Treating-MS/Managing-Relapses National Multiple Sclerosis Society. Glossary. www.nationalmssociety.org/Glossary#P The Role of Empowerment Connection to Resources

Medication affordability resources

Support groups/national organizations Empower Resources available through your pharmacy

Communication with providers (holistic care) Conclusion

• Adherence to DMTs is still a vital tool Specialty Pharmacy can impact for maximized MS control through personalized counseling and support. • Specialty Pharmacy can also empower patients beyond the prescription through Quality of Life assessments (depression screening and MS progression management guidance) and connection to resources. Additional Resources

American Academy of Neurology www.aan.com Consortium of Multiple Sclerosis Centers www.mscare.org Multiple Sclerosis Association of America www.mymsaa.org Multiple Sclerosis Foundation www.msfocus.org Multiple Sclerosis International Federation www.msif.org Multiple Sclerosis Trust www.mstrust.org.uk National Multiple Sclerosis Society www.nationalMSsociety.org Additional Resources