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Personalizing Disease-Modifying Therapy for Multiple Sclerosis in the Era of Expanding Treatment Options and Potential Biomarkers

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Personalizing Disease-Modifying Therapy for Multiple Sclerosis in the Era of Expanding Treatment Options and Potential Biomarkers Personalizing Disease-Modifying Therapy for Multiple Sclerosis in the Era of Expanding Treatment Options and Potential Biomarkers This symposium is neither sponsored nor endorsed by the Consortium of Multiple Sclerosis Centers. Disclosures Edward J. Fox, MD, PhD, has a financial Aaron Boster, MD, has a financial interest/relationship or interest/relationship or affiliation in the form of: affiliation in the form of: Consultant and/or Advisor for Biogen; Celgene Consultant and/or Advisor for Biogen; EMD Serono, Inc.; Corporation; EMD Serono, Inc.; F. Hoffmann-La Genentech, Inc.; Genzyme Corporation; and Novartis Roche/Genentech, Inc.; Novartis Pharmaceuticals Corporation Corporation; and TG Therapeutics, Inc Grant/Research Support from AbbVie; Biogen; Celgene Grant/Research Support from Biogen and Genentech, Corporation; Chugai Pharmaceutical; EMD Serono, Inc.; Inc. F. Hoffmann-La Roche/Genentech, Inc.; MedDay; Speakers Bureau participant with Genentech, Inc.; Novartis Pharmaceuticals Corporation; Sanofi Genzyme; Genzyme Corporation; and Medtronic, Inc. and TG Therapeutics, Inc. Speakers Bureau participant with Biogen; EMD Serono, Aaron Boster, MD, does intend to discuss either non- Inc.; F. Hoffmann-La Roche/Genentech, Inc.; and FDA-approved or investigational use for the following Novartis Pharmaceuticals Corporation products/devices: investigational serologic markers for MS prognosis and monitoring Edward J. Fox, MD, PhD, does intend to discuss either non-FDA-approved or investigational use for the following products/devices: investigational therapies for the treatment of MS. This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by educational grants from Biogen, Novartis Pharmaceuticals Corporation, and Sanofi Genzyme. Disclosures Content Reviewers Medical Director John Vester, MD, has no financial interests/relationships or PVI, PeerView Institute for Medical Education affiliations in relation to this activity. Tracy L. Greene, MSN, RN, FNP-C, Lead Nurse Planner, Kirk Tacka, PhD, has no financial interests/relationships or has no financial interests/relationships or affiliations in relation affiliations in relation to this activity. to this activity. Janice Trainor-Tellier, MSN, RN, has no financial interests/relationships or affiliations in relation to this activity. Teresa Haile, RPh, MBA, Lead Pharmacy Planner, has no financial interests/relationships or affiliations in relation to this activity. Patricia A. Ensor, RPh, MBA, has no financial interests/relationships or affiliations in relation to this activity. Other PVI associates who are in a position to have control over the content of this activity do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC/CNE/CPE activity during the past 12 months. The associates of the Medical Learning Institute, Inc., the accredited provider for this activity, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/MOC/CNE/CPE activity during the past 12 months. Introduction Edward J. Fox, MD, PhD Director, MS Clinic of Central Texas Central Texas Neurology Consultants Clinical Associate Professor University of Texas Dell Medical School Round Rock, Texas Go online to access full CME/MOC/CNE/CPE information, including faculty disclosures. Evolution of the MS Treatment Landscape Mitoxantrone, IV IFN β-1a, subQ natalizumab, IV 1990s 2000s 2010s IFN β-1b, subQ Fingolimod, oral IFN β-1a, IM Teriflunomide, oral GA, subQ Dimethyl fumarate, oral PEG IFN β-1a Alemtuzumab, IV Ocrelizumab, IV Siponimod, orala Cladribine, oralb aApproved in 2019 for the treatment of adults with relapsing forms of MS including CIS, RRMS, and active SPMS bApproved in 2019 for the treatment of adults with relapsing forms of MS, to include RRMS and active SPMS; because of its safety profile, use of cladribine 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 Selected Investigational Therapies for the Treatment of MS Diroximel fumarate Ozanimod Ponesimod Selective S1PR Oral fumarate Selective S1PR1,5 1 modulator modulator MD1003 Ublituximab Ofatumumab High-dose Chimeric Fully human biotin anti-CD20 mAb anti-CD20 mAb Clinical Challenges Associated With DMT Selection in Patients With MS • The multitude of available and emerging DMTs has made treatment selection for individuals with MS increasingly complex • Treatment selection must be personalized and based on a multitude of patient- and disease-specific factors • Importance of factors that drive treatment selection varies between practitioners and patients; careful consideration of the benefits and risks of individual therapies must be considered • Underscores the need for prognostic and monitoring biomarkers Moving On to This Morning’s Agenda First, we’ll review data on approved and selected emerging DMTs for the treatment of MS Then, we’ll discuss some of the practicalities of personalizing DMT selection in patients with MS Approved and Emerging DMTs for the Treatment of MS A Look at Current Evidence Edward J. Fox, MD, PhD Director, MS Clinic of Central Texas Central Texas Neurology Consultants Clinical Associate Professor University of Texas Dell Medical School Round Rock, Texas Go online to access full CME/MOC/CNE/CPE information, including faculty disclosures. Approved Injectable DMTs for RRMS1-12 Conversion Relapses MRI Endpoints Disability to CDMS Progressionb • All available • All available a formulationsa formulationsa • GA 20 mg • IFN β-1a IMa • IFN β-1a IMa • IFN β -1a subQa • IFN β -1a subQa • PEG IFN β -1aa • IFN β -1ba Head-to-head studies have shown similar efficacy between GA and IFN βs Laboratory monitoring: GA, none; IFN β: minimal (LFT, CBC, TSH) a Versus placebo. b Significant decrease in ≥1 phase 3 clinical trial. 1. Jacobs LD et al. N Engl J Med. 2000;343:898-904. 2. Kappos L et al. Neurology. 2006;67:1242-1249. 3. Comi G et al. Lancet. 2009;374:1503-1511. 4. Comi G et al. Lancet Neurol. 2012;11:33-41. 5. Johnson KP et al. Neurology. 1995;45:1268-1276. 6. Kahn O et al. Ann Neurol. 2013;73:705-713. 7. PRISMS Study Group. Lancet. 1998;352:1498-1504. 8. Jacobs LS et al. Ann Neurol. 1996;39:285-294. 9. IFNB Study Group. Neurology. 1993;43:655-661. 10. Calabresi PA et al. Lancet Neurol. 2014;13:657-665. 11. O’Connor P et al. Lancet Neurol. 2009;8:889-897. 12. Mikol DD et al. Lancet Neurol. 2008;7:903-914. Profiles of Established Oral DMTs for RRMS1-11 • Shown to significantly reduce relapses,a MRI endpoints,a disability progressionb • Key safety monitoring prior to treatment initiation and/or during treatment: First-dose cardiac monitoring, ophthalmologic examination, VZV, LFT, CBC, BP, Fingolimod skin examination, spirometric evaluationc • Shown to significantly reduce relapses,b MRI endpoints,b disability progressionb; also shown to delay conversion to CDMS in CIS • Key safety monitoring prior to treatment initiation and/or during treatment: Teriflunomide Negative pregnancy test, TB screen, LFT, CBC, BP • Shown to significantly reduce relapses,b MRI endpoints,b disability progressionb • Key safety monitoring prior to treatment initiation and/or during treatment: LFT, CBC Dimethyl Fumarate a Versus placebo and IFN β-1a IM. b Versus placebo in ≥1 phase 3 clinical trial. c When clinically indicated. 1. Kappos L et al. N Engl J Med. 2010;362:387-401. 2. Cohen JA et al. N Engl J Med. 2010;362:402-415. 3. Calabresi PA et al. Lancet Neurol. 2014;13:545-556. 4. Gilenya (fingolimod) Prescribing Information. http://www.pharma.us.novartis.com/product/pi/pdf/gilenya.pdf. Accessed May 18, 2019. 5. Miller A et al. Lancet Neurol. 2014;13:977-986. 6. Confavreaux C et al. Lancet Neurol. 2014;13:247-256. 7. O’Connor P et al. N Engl J Med. 2011;365:1293-1303. 8. Aubagio (teriflunomide) Prescribing Information. http://products.sanofi.us/aubagio/aubagio.pdf. Accessed May 18, 2019. 9. Gold R et al. N Engl J Med. 2012;367:1098-1107. 10. Fox R et al. N Engl J Med. 2012;367:1087-1097. 11. Tecfidera (dimethyl fumarate) Prescribing Information. http://www.tecfidera.com/pdfs/full-prescribing- information.pdf. Accessed May 18, 2019. Recent Updates on Established Oral DMTs for MS Management Fingolimod1 Phase 3b ASSESS study showed: • Fingolimod 0.5 mg significantly reduced relapse rates, NEL, and GEL vs GA 20 mg/d • AEs reported with fingolimod were consistent with the known safety profile • More discontinuations from the study drug were reported with GA due to IRAEs, consent withdrawal, and unsatisfactory therapeutic effects Teriflunomide2 Pooled analysis of patients receiving teriflunomide 14 mg (for up to 12 years) showed: • Overall ARR and yearly ARRs were low and stable • Disability status remained stable through year 12 • No new safety signals were reported; most AEs were mild to moderate in severity Dimethyl Fumarate3 Analysis of ENDORSE showed: • Clinical benefits of DMF on relapse activity and disability progression in newly diagnosed patients are maintained over 9 years 1. Cree BAC et al. 2019 American Academy of Neurology Annual Meeting (AAN 2019). Abstract S56.009. 2. Freedman M et al. 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS 2018). Abstract P1233. 3. Gold R et al. AAN 2019. Abstract P3.2-084. EXPAND: Randomized, Double-Blind, Placebo-Controlled Trial of Siponimod in SPMS1,a Endpoint PBO SIP P 3-month CDP 32% 26% .013 6-month CDP 26% 20% .0058 ARR 0.16 0.07 < .0001 Adjusted mean ∆ in T2LV, mm3 (baseline to 24 months) 940.4 162.9 < .0001 Adjusted mean ∆ in BV, % (baseline to 24 months) -0.84 -0.71 .020 • Lymphopenia, ↑ liver transaminase levels, bradycardia and bradyarrhythmia at treatment initiation, macular edema, hypertension, VZV reactivation, and convulsions occurred more frequently with siponimod than placebo • Initial dose titration mitigated cardiac first-dose effects a Siponimod titrated from 0.25 mg/d to the 2 mg/d maintenance dose from days 1 to 6.
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