Multiple Sclerosis Strategies for Initial Treatment Selection and Patient Engagement

Achieving New Treatment Goals in Multiple Sclerosis Strategies for Initial Treatment Selection and Patient Engagement

A CME/CE-certified Symposium held in conjunction with the 2018 Annual Meeting of the CMSC

This program was supported by an educational grant from Jointly provided by: In collaboration with: Sanofi Genzyme.

Program Faculty

Suhayl Dhib-Jalbut, MD Machteld E. Hillen, MD Professor and Chairman, Department of Neurology Associate Professor Rutgers NJ Medical School Director, Adult Neurology Clinic and Neurology Newark, NJ Residency Program Robert Wood Johnson Department of Neurology Medical School Rutgers NJ Medical School New Brunswick, NJ Newark, NJ

Community Manager Patient Advocate Alina Ahsan Laura Kolaczkowski Health Union, LLC MultipleSclerosis.net MultipleSclerosis.net Dayton, OH Philadelphia, PA

Disclosures

Program Faculty The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Suhayl Dhib-Jabut, MD – Consultant/Independent Contractor: Celgene; Grant/Research Support: Biogen, Teva Machteld E. Hillen, MD – Grant/Research Support: Genentech Alina Ahsan – Nothing to disclose Laura Kolaczkowski – Nothing to disclose

Non-faculty Content Contributors Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: Chad Williamson, MS, MBA, CMPP; Blair St. Amand; Lindsay Scott, PT, DPT, ATC: Nothing to disclose The planners, reviewers, and staff at the Consortium of Multiple Sclerosis Centers in a position to influence content have disclosed no relevant financial relationships.

Educational Objectives

At the conclusion of this activity, participants should be able to demonstrate the ability to: • Recognize the benefits of starting an optimal DMT early enough to achieve the new treatment goal of “no evidence of disease activity” (NEDA) • Apply current evidence to select a personalized disease-modifying treatment approach with appropriate modifications based on disease activity • Implement practical strategies for improving patient engagement in management plans

Multiple Sclerosis An Immuno-genetic Disease

Suhayl Dhib-Jalbut, MD

Multiple Sclerosis: An Immuno-genetic Disease

Genetic Predisposition Environmental Factors

Twins studies Demographics/Epidemics

HLA-DR2 (DRß1*1501) Microbial Agents (antigen presentation) EBV

IL-2Ra Vitamin D (regulatory T-cells) Smoking

IL-7Ra Salt (memory T-cells) Immune Dysregulation BMI GWAS (>100 alleles) MS Microbiome Images courtesy of Dhib-Jalbut S. 2013.

T- and B-cells Coordinate Immune Attack in MS T-cell immune functions B-cell immune functions

BBB = blood-brain barrier; CSF = cerebrospinal fluid; MMP-3 = matrix metalloproteinase-3; NK = natural killer; ROS = reactive oxygen species; Th = helper T; Treg = regulatory T

Claes N et al. Front Immunol. www.dx.doi.org/10.3389/fimmu.2015.00642. Accessed 11/8/17. Alvermann S et al. JAMA Neurol. 2014;71:905-912. Dittel BN et al. Brain Behav Immun. 2008;22:421-430. Severson C, Hafler DA. Results Probl Cell Differ. 2010;51:75-98.

MS Treatment Goals: No Evidence of Disease Activity (NEDA)

Machteld Hillen, MD

No Evidence of Disease Activity (NEDA)

• NEDD (No Evidence of Detectable Disease) replaced the term cure in oncology, and is used in other fields as well (rheumatology) • 2013 NEDA was proposed to replace the term Disease Free Activity (DFA), based on clinical-trial outcomes already in use • 15 years of NEDA was proposed as a definition for MS cure

Banwell B et al. Mult Scler Relat Disord. 2013;2:65-67.

NEDA-3 or NEDA • No clinical relapses • No EDSS progression (12 weeks or 6 months in some trials) • No MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions) • Adopted as a treatment target in 2013

EDSS = Expanded Disability Status Scale; Gd = gadolinium; MRI = magnetic resonance imaging, NEDA = no evidence of disease Giovannoni G et al. 2018. Mult Scler Relat Disord. 2018;20:228-230.

Related Terminology NEDA Definitions

Level Criteria NEDA–3 No clinical relapses + no EDSS confirmed disability progression + no MRI activity NEDA–4 NEDA–3 + annualized percentage brain volume loss ≤ -0.4% NEDA–5 NEDA–4 + CSF neurofilament MEDA Minimal evidence of disease activity e.g. using the Rio Score (Rio et al. 2006), Modified Rio Score (Sormani et al. 2013) NEPAD No evidence of progression or active disease NEDA–3 + no 12-week confirmed progression of ≥20% on the timed 25-foot walk test and on the 9-hole peg test

Lu G et al. Mult Scler Relat Disord. 2018;20:231-238.

NEDA at 10 Years Observational Study 91 patients, 55% (50/91) no progression, MRI 14% 33% (30/91) no relapse, 21% (19/91) no MRI, 9% (8/91) NEDA 24% MRI+ = 72/91 (79%) REL+ = 61/91 (67%) EDSS+ = 41/91 (45%) 34% 8/91 (9%) = NEDA 7% 31/91 (34%) = MRI+, REL+ and EDSS+ 22/91 (24%) = MRI+ and REL+ 8% 6/91 (7%) = MRI+ and EDSS+ 1% 1/91 (1%) = REL+ and EDSS+ 3% 13/91 (14%) = MRI+ only EDSS 7/91 (8%) = REL+ only 9% REL 3/91 (3%) = EDSS+ only EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging; NEDA = no evidence of disease; REL = relapse. De Stefano N et al. Neurology. 2015;85:1722-1723.

NEDA at 7 Years in CLIMB Observational Study of 219 Patients • NEDA at 1 year 46% (99/215), NEDA at 2 years 27.5% (60/218), NEDA at 7 years 7.9% (17/216) • 56.5% (117/207) had no progression, 24.2% (52/215) had no MRI activity, and 23% (49/213) had no relapse at 7 years • NEDA at 2 years has a positive predictive value, 78.3% of no disability at 7 years (better predictor than each indicator alone)

Rotstein DL et al. JAMA Neurol. 2015;72:152-158.

NEDA in Randomized Controlled Trials Post-hoc Analysis of NEDA-3 in Clinical Trials

Study Duration (years) Percent NEDA ADVANCE 1 34% peginterferon-ß*** 15% placebo AFFIRM 1 47% natalizumab*** 15% placebo SELECT 1 39% daclizumab*** 11% placebo FREEDOMS/FREEDOMSII 2 31% fingolimod*** 10% placebo AFFIRM 2 37% natalizumab*** 7% placebo DEFINE/CONFIRM 2 23% dimethyl fumarate*** 11% placebo TEMSO 2 23% teriflunomide 14 mg*** 14% placebo 18% teriflunomide 7 mg* CARE-MSIa 2 39% alemtuzumab** 27% interferon-ß CARE-MSIIa 2 32% alemtuzumab*** 14% interferon-ß OPERA Ia 2 48% ocrelizumab*** 29% interferon-ß OPERA IIa 2 48% ocrelizumab*** 25% interferon-ß P-value for study DMS vs comparator * <0.05; ** <0.01; ***P-value <0.001. a Pre-specified endpoint. Parks NE et al. J Neurol Sci. 2017;383:31-34.

NEDA and Interferon Beta-1a

• NEDA in SET Trial (CIS) – 40.1% at year 1 – 10.1% at year 4 • NEDA at ASA Trial (RRMS) – 20.4% at year 1 – 3.3% at year 4 – 0% at year 10

CIS = clinically isolated syndrome; RRMS = relapsed remitting multiple sclerosis Uher T et al. Multip Scler. 2017;23:242-252.

NEDA (DAFS) and First-line Agents (COMBIRX) Disease Activity-free Status at Years 3, 4, and 6 (PDE) • Interferon Beta-1a: NEDA at 3 years 20.5%, at 6 years 13.2% • Glatiramer Acetate: NEDA at 3 years 20.4%, at 6 years 18.8% • Both: NEDA at 3 years 32.1%, at 6 years 21%

Year 3: IFN+GA, P=0.002 35 IFN+GA vs IFN, P=0.001 Year 4: IFN+GA, P=0.014 IFN vs GA, P=0.81 IFN+GA vs IFN, P=0.033 30 Year 6: IFN+GA, P=0.10 32.1 IFN vs GA, P=0.88 IFN+GA vs IFN, P=0.018 25 IFN vs GA, P=0.38 20 25.1 21 15 20.5 20.4 18.8 16.1 16.8 IFN+GA 10 13.2 IFN 5 % Disease Activity Free Disease % GA 0 Year 3 (740) Year 4 (500) Year 6 (261) No PDE + No EDSS Worsening + No CUA DAFS = disease activity free status; EDSS = Expanded Disability Status Scale; GA = glatiramer acetate; INF = interferon; PDE = protocol-defined exacerbation; CUA = combined unique lesion activity Lublin FD et al. Multi Scler Relat Disord. 2017;18:95-102.

NEDA and Peginterferon Beta-1a (ADVANCE) NEDA at 2 Years: 16% in Delayed Treatment, 37% (Q 2 Week Dosing)

LOCF = last observed carried forward; MRI = magnetic resonance imaging; NEDA = no evidence of disease activity Arnold DL et al. BMC Neurology. 2017;17:29.

NEDA and NEDA-4 in Fingolimod FREEDOMS and FREEDOMS II NEDA at 2 years fingolimod: 31%, NEDA-4 at 2 years: 19.7%

CDP, confirmed disability progression; OR, objective response; CI, confidence interval; NEDA, no evidence of disease

Kappos L et al. Mult Scler. 2016;22:1297-1305.

NEDA (DAF) and Natalizumab (AFFIRM) NEDA at 2 Years: Natalizumab 37%, Placebo 7% Proportions of Patients without Disease Activity Over 2 Years Placebo Natalizumab Absolute Difference (95% CI) No relapse 130/300 (43%) 422/598 (71%) 27.3% (20.6-34.0%) No progression 205/286 (72%) 486/581 (84%) 12.0% (5.9-17.9%) No relapse and no progression 117/301 (39%) 383/596 (64%) 25.4% (18.7-32.1%) No gadolinium-enhancing lesions 164/290 (57%) 553/583 (95%) 38.3% (32.3-44.3%) No new or enlarged T2 lesions 44/296 (15%) 342/593 (58%) 43.4% (37.7-49.1%) No gadolinium-enhancing lesions and no 42/296 (14%) 342/593 (58%) 43.5% (37.9-49.1%) new or enlarged T2 lesions No gadolinium-enhancing lesions, no new 25/303 (8%) 244/600 (41%) 32.4% (27.4-37.4%) or enlarged T2 lesions, and no relapse No radiological or clinical activity 22/304 (7%) 220/600 (37%) 29.5% (24.7-34.3%) P<0.0001, natalizumab vs placebo, for all individual and combined disease measures. Havrdova E et al. Lancet Neurol. 2009;8:254-260.

NEDA (DAF) and Cladribine (CLARITY) 96 Week NEDA Cladribine:44% (3.5 mg), 46% (5.25 mg), and 16% placebo

100 P<0.0001 P<0.0001 P<0.0001

P<0.0001 P<0.0001 P<0.0001 80 266/395 283/406 60 208/384 222/396 178/402 189/411 145/373 40 Patients (%) Patients 86/360 20 60/379

0 Weeks 0-24 Weeks 0-48 Weeks 0-96 Placebo Cladribine 3.5 mg/kg Cladribine 52.5 mg/kg Giavannoni G et al. Lancet Neurol. 2011;10:329-337.

NEDA and Ocrelizumab in OPERA I and II 96 Week NEDA Interferon (INF) Beta-1a: 27.1% 96 Week NEDA Ocrelizumab: 47.7%

Havrdova E et al. Mult Scler J Exp Transl Clin. 2018;4:2055217318760642.

NEDA and Alemtuzumab (CARE-MS I)

CI = confidence interval; MRI = magnetic resonance imaging; NEDA = no evidence of disease activity Havrdova E et al. Neurology. 2017;89:1107-1116.

NEDA and Alemtuzumab (CARE-MS II)

CI = confidence interval; MRI = magnetic resonance imaging; NEDA = no evidence of disease activity Coles AJ et al. Neurology. 2017;89:1117-1126.

Autologous Stem Cell Transplant and NEDA NEDA at 2 Years 78%-83%, at 5 Years 60%-68%

NEDA ‐ no evidence of disease activity.

Sormani MP et al. Mult Scler. 2017;23:201-204.

Individualizing DMD Therapy in MS

Suhayl Dhib-Jalbut, MD

Existing and Emerging MS Therapies Cladebrine Approved Therapy Phase III completed In Phase III Other Approved Treatment Laquinomod MD1003 (Biotin) Dalfampridine Mastinib Dextromethorph- Ofatumumab IFNβ-1b Natalizumab anquinidine Ozaninod IFNβ-1a 2nd IFNβ-1b Pegylated IM injection Cladribine* Ponesimod IFNβ-1a Glatiramer Siponimod acetate Alemtuzumab Fingolimod Mitoxantrone Teriflunomide Ocrelizumab IFNβ-1a Dimethyl Laquinimod SC injection fumarate

1995 2000 2005 2009 2010 2011 2012 2013 2014 2015 2016 2017 Approval date *In March 2011, the FDA did not approve cladribine and requested Merck KGaA provide an improved understanding of its safety risks and overall benefit-risk profile. www.nationalmssociety.org/For-Professionals/Clinic-Care/Managing-MS/DiseaseModification.

MS Therapies

Cell migration inhibitors/ Lymphocyte Immunomodulators Remyelinators Lymphocyte sequesters depleters • Dimethyl fumarate • Natalizumab B- and T-cells • MD1003* • GA • Fingolimod • Alemtuzumab (high-dose biotin) • IFN-beta • Siponimod* • Daclizumab • Teriflunomide • Ozanimod* B-cells • Laquinamod* • Ponesimod* • Ocrelizumab • Mastinib* • Ofatumumab

*Investigational Multiple Sclerosis Association of America. Long-term treatments for multiple sclerosis. Updated April 13, 2018. Available from: https://mymsaa.org/ms-information/treatments/long-term. Accessed May 1, 2018.

Long-term Safety and Efficacy Studies (1)

Study Drug Findings References REVEAL Natalizumab Natalizumab superior Butzkeuven H et al. ECTRIMS 2017; Paris, vs Fingolimod France. Abstract P791. LONGTERMS Fingolimod Established safety and sustained Cohen J et al. ECTRIMS 2017; Paris, France. efficacy over 10 years Abstract P1879. TESMO & TOWER Teriflunomide Abortions and malformations Comi G et al. ECTRIMS 2017; Paris, France. similar to general population Abstract 742. Low-grade lymphopenia Vukusic S et al. ECTRIMS 2017; Paris, infrequent France. Abstract 205. TOPAZ Alemtuzumab Reported on safety and efficacy Singer BA et al. ECTRIMS 2017; Paris, at 7 years France. Abstract P736. Listeria meningitis (0.25%) Coles AJ et al. ECTRIMS 2017; Paris, France. Abstract P1188. Scolding N et al. ECTRIMS 2017; Paris, France. Abstract 203.

Long-term Safety and Efficacy Studies (2)

Study Drug Findings References EXTEND Daclizumab Sustained efficacy over 6 years. Kappos L et al. ECTRIMS 2017; Paris, France. Abstract 731. Recently withdrawn from market Cohan S et al. ECTRIMS 2017; Paris, France. Abstract 206.

OPERA I & II Ocrelizumab Reduced progression by 36% Kappos L et al. ECTRIMS 2017; Paris, France. Abstract relative to IFNB-1a at 96 weeks P654. CLARITY Cladribine Lymphopenia recovers after 1 year Giovannoni G et al. ECTRIMS 2017; Paris, France. Abstract extension 42% achieve NEDA P1143. Soelberg-Sorensen P et al. ECTRIMS 2017; Paris, France. Abstract P655. Cook S et al. ECTRIMS 2017; Paris, France. Abstract P666. SUNBEAM & Ozanimod Superior to IFNB-1a Comi G et al. ECTRIMS 2017; Paris, France. Abstract 232. RADIANCE ARR 38%-48% Arnold DL et al. ECTRIMS 2017; Paris, France. Abstract No 2nd degree AV block P1857. Cohen JA et al. ECTRIMS 2017; Paris, France. Abstract 280. Arnold DL et al. ECTRIMS 2017; Paris, France. Abstract P1857.

Making Treatment Decisions Considering the Benefits and Risks

Evidence-based Safety Tolerability approach

Convenience MOA Treatment decisions Monitoring Response Pregnancy issues Physician Patient experience Cost preference

The Treatment Scale

Benefit Risk

Clinical Prognostic Factors Favorable Unfavorable • Isolated sensory symptoms • Older male • Complete recovery from first • Motor, brain stem, and SC attack involvement • Long interval between attacks • High relapse rate in 2-5 years • Low MRI-lesion load after onset • Negative CSF OCB • High MRI-lesion load • Positive CSF OCB

CSF = cerebral spinal fluid; OCB = oligoclonal band; SC = spinal cord Montalban X. Presented at: ECTRIMS 2013, Copenhagen, Denmark; October 2-5, 2013 (Abstract #94).

Prognosis: Initial MRI

70 • T2 lesion numbers EDSS > 3 60 EDSS ≥ 6 • Median EDSS at 20 50 years = 6 for >10 T2 40 lesions 30

% patients % 20 • 3 or 4 Barkhof criteria 10

moderate correlation 0 with EDSS at 5 years 01-34-9≥10 # of brain lesions

EDSS = Expanded Disability Status Scale; MRI = magnetic resonance imaging Fisniku LK. Brain. 2008;131:808-817.

Choosing Therapy Aggressive Disease?

Yes No

Non- Safest Pregnancy JCV Ab+ JCV Ab- injectable

IFN Teriflunomide GA GA DMF Insurance ?Fingolimod Ocrelizumab Fingolimod ?Natalizumab Natalizumab Alemtuzumab* DMF?

Ab = antibody; DMF = dimethyl fumarate; GA = glatiramer acetate; INF = interferon; JCV = John Cunningham virus Image courtesy of Aaron Miller.

MS Therapies Natalizumab Dimethyl fumarate Fingolimod Alemtuzumab Rituximab* Ocrelizumab Teriflunomide

* Denotes off-label use. PML = progressive multifocal leukoencephalopathy Mills EA et al. Front Immunol. 2018;9:138.

JCV Antibody Status and Risk for PML

JCV antibody status

Negative <1/1,000 Positive Calculation based on 2 cases of JCV antibody–negative PML in patients exposed for at least 1 month of therapy as of September 3, 2013

PML risk estimate per 1000 pts (No prior IS use) Natalizumab Prior IS exposure Index Result Index Result Index Result Index Result Index Result use ≤0.9 ≤1.1 ≤1.3 ≤1.5 >1.5

1-24 months 0.1 0.1 0.1 0.1 1.0 1/1,000 (0-0.41) (0-0.34) (0.01-0.39) (0.03-0.42) (0.64-1.41)

25-48 months 0.3 0.7 1.0 1.2 8.1 13/1,000 (0.04-1.13) (0.21-1.53) (0.48-1.98) (0.64-2.15) (6.64-9.8)

49-72 months 0.4 0.7 1.2 1.3 8.5 9/1,000 (0-0.41) (0.08-2.34) (0.31-2.94) (0.41-2.96) (6.22-11.38)

IS = immunosuppressant; JCV = John Cunningham virus; PML = progressive multifocal leukoencephalopathy Natalizumab Prescribing Information. www.tysabri.com/content/dam/commercial/multiple-sclerosis/tysabri/pat/en_us/pdfs/tysabri_prescribing_information.pdf.

PML Management Strategies

• Plasma exchange (PLEX) • Switching from natalizumab to alternate DMTs with lower PML risk – No PML observed in patients after switching from natalizumab to alemtuzumab, fingolimod, or rituximab

Clifford D. ECTRIMS 2017; Paris, France. Abstract 202.

Criteria for Switching Therapy

• Relapse rates of either 1 per year or unchanged from pretreatment rates • Incomplete recovery from multiple attacks • Evolution of polyregional neurologic involvement • Recurrent brainstem or spinal-cord lesions • Cumulative loss of neurologic function sufficient to disrupt daily activities • Intolerability

Pardo G et al. Mult Scler. 2017;264:2351-2374.

Concerns With Switching Therapies

• Concerns about ongoing risk of PML after natalizumab in JC virus antibody + patients • Concerns about need for “washout period” • Concerns about lymphopenia • Concerns about post-natalizumab “rebound”

JCV = John Cunningham virus; PML = progressive multifocal leukoencephalopathy

ECTRIMS-EAN Clinical Practice Guideline on Pharmacological Management of MS • Treatment Initiation • Monitoring Treatment Safety – IFN or GA for patients with CIS or – Brain MRI (frequency adjusted based on abnormal MRI who do not fulfill MS criteria low- or high-risk PML – Early treatment initiation with DMTs in • Switching/Stopping Considerations active RRMS – Offer more efficacious drug to patients • Monitoring Treatment Response progressing on IFN or GA – Baseline and follow-up brain MRI – Continue DMT if patient is stable with no – Measurement of new or enlarging T2 safety or tolerability issues lesions supplemented by GdE lesions • Pregnancy – Advise women of childbearing age that CIS = clinically isolated syndrome; ECTRIMS-EAN = European Committee for Treatment and Research in Multiple Sclerosis-European Academy of Neurology; DMTs (except GA 20 mg/mL) are not DMT = disease-modifying therapy; GA = glatiramer acetate; recommended during pregnancy GdE = gadolinium-enhanced; INF = interferon; MRI = magnetic resonance imaging; Montalban X et al. Mult Scler. 2018;24:96-120.

Incorporating Biomarkers and Risk Factors into MS Management

Case Presentation

• A 25-year-old white female was diagnosed with MS 2 years earlier when she presented with optic neuritis and numbness below the mid-thoracic area. She was placed on interferon-beta 1a IM weekly injections. • She continues to have relapses and worsening symptoms.

Current MS Biomarkers in Clinical Use Biomarker Clinical Utility Neutralizing antibody to IFN-B Unresponsiveness JCV assay PML risk with natalizumab Anti-natalizumab Ab Unresponsiveness CD19 expression on B-cells Rituximab response CSF oligoclonal IgG bands MS Diagnosis/Prognosis Aquaporin-4 Ab Neuromyelitis optica Varicella Ab Risk of Varicella with fingolimod

Ab = antibody; CSF = cerebral spinal fluid; INF = interferon; JCV = John Cunningham virus Coyle PK. Mult Scler Int. 2017;2017:6198530.

Case (continued)

• Follow-up MRI showed 2 non-enhancing brain T2 lesions and a new enhancing spinal cord lesion between T1 and T4 • Serum NMO Ab titer was elevated

Neuromyelitis Optica

• Inflammatory demyelination of the optic nerves and spinal cord • Characterized by a specific IgG antibody marker (NMO antibody) • Target antigen is aquaporin-4, a water channel abundant in the CNS • Role of NMO Ab in pathogenesis remains uncertain

Pittock SJ. Semin Neurol. 2008;28:95-104. Lennon VA et al. Lancet. 2004;364:2106-2112.

Anti-MOG Antibodies Are Present in a Subgroup of Patients with a Neuromyelitis Optica Phenotype

anti-MOG = anti-myelin oligodendrocyte glycoprotein; NMO = neuromyelitis optica; AQP4 = aquaporin-4 Probstel AK et al. J Neuroinflammation. 2015;12:46.

NMO Pre- and Post-treatment Median Annualized Relapse Rates Pre- and Post-Tx Relapse Rates Change in EDSS with Treatment

Pre- and post-treatment median annualized relapse rates (ARR). The median ARR decreased from 1.17 to 0.25 on rituximab (P<0.01), 0.92 to 0.56 on azathioprine (P=0.475), 1.06 to 0.39 on mycophenolate (P<0.05), and 1.30 to 0.92 on cyclophosphamide (P=0.021). EDSS = Expanded Disability Status Scale; NMO = neuromyelitis optica Torres J et al. J Neurol Sci. 2015;351:31-35.

Optimizing Patient Engagement and Shared Decision-making

Machteld Hillen, MD

Patient Engagement Promotes . . . • Improved clinical outcomes (treatment adherence, faster recovery, and reduced mortality) • Reduced healthcare consumption (improved health service efficiency, fewer diagnostic tests and referrals, decreased use of health services, lower annual charges) • Improved service quality (improved communication and health literacy, greater confidence in treatment decisions, decreased malpractice claims, higher staff retention rates, improved patient satisfaction, reduced patient-physician discordance)

Rieckmann P et al. Mult Scler Relat Disord. 2015;4:202-218.

Where We Stand At Present

• About 60%-65% of patients with MS are adherent with treatment (mostly defined as 80% of days covered) • Poor compliance leads to greater healthcare costs (more clinic visits and hospitalizations) • Poor compliance may influence long-term disability

Burks J et al. Clinicoecon Outcomes Res. 2017;9:251-260. Tan H et al. Adv Ther. 2011;28:51-61. Locklear J et al. Neurology. 2015;84(supp 14). Gerber B et al. Mult Scler Relat Disord. 2017;18:218-224.

Ways to Achieve Patient Engagement • Establishment of an effective, caring, and mutually respectful patient–physician relationship • Shared decision-making (91% of MS patients prefer this) • Provide access to credible sources of accurate information • Prioritize patient-reported outcomes: increasing the importance placed on QoL and patient concerns • Promote patient empowerment through a sense of responsibility

Rieckmann P et al. Mult Scler Relat Disord. 2015;4:202-218. Colligan E et al. Mult Scler. 2017;23:185-190.

Shared Decision-making

• HCP incorporates the patient’s values and goals about their care, exploring their life experiences, psychosocial circumstances, and health status • HCP then has a discussion of all evidence-based treatment options that are in line with the patient’s goals, including the option not to treat, when appropriate • HCP partners with the patient to make a decision that is consistent with the patient’s personal situation

Colligan E et al. Mult Scler. 2017;23:185-190.

How to Promote Shared Decision-making

• Educational programs and information aids • Shared Decision-making Tools – Text, video, or web-based

Colligan E et al. Mult Scler. 2017;23:185-190.

Benefits of Shared Decision-making Tools

• Promotes patient autonomy, patient education, and patient- centered care • Increase patient’s knowledge and perception of risk • Patients select options that are congruent with their values • Decision aids reduce decisional conflict • Increase in patient satisfaction (not proven in MS) • ? Cost effectiveness (not studied in MS)

Colligan E et al. Mult Scler. 2017;23:185-190.

Limits of Shared Decision-making Tools

• Not shown to benefit adherence to therapy • Not shown to improve outcomes • Decision aids added some time to a patient visit (mean 2.55 minutes longer) • Not generalizable to patients who are illiterate or speak a different language • Insurance industry in the US determines to a large extent a patient’s options for treatment

Colligan E et al. Mult Scler. 2017;23:185-190.

Decision Points in the Course of MS that Lend Themselves to Shared Decision-making

• Whether to take steroids for an acute relapse • Which immunotherapy drug to take, if any • Whether to initiate disease-modifying drugs (DMDs) early in the disease course • Whether to have a child after being diagnosed with MS

Examples of Decision Aids

• https://www.mstrust.org.uk/understanding-ms/ms-symptoms-and- treatments/ms-decisions/decision-aid • https://decisionaid.ohri.ca/AZsumm.php?ID=1117

Patient Engagement and Shared Decision-making from the Patient Perspective

Alina Ahsan Community Planner Health Union

Barriers to Patient Engagement

Health Union’s Multiple Sclerosis In America survey showed that 25.8% of RRMS respondents (n= 3,559) rarely or never engage with their HCPs when experiencing a relapse • 57.9% did not consider their relapse to be severe enough • 30.9% felt their HCPs were unhelpful (during past relapses) or did not tell them they should contact them if they experienced a relapse • 25.6% felt treatment doesn’t work well/can’t tolerate • 24% prefer to manage alone

Nazareth T et al. Institutions: Mallinckrodt Pharmaceuticals, Bedminster, NJ; Health Union, Philadelphia, PA. Presented at: 7th Joint ECTRIMS-ACTRIMS Meeting October 25-28, 2017; Paris, France. P805.

Encouraging Adherence through Engagement (1)

• For SDM to occur, patients need to be informed and involved (to the level of their choosing) • Even when HCPs provide all of the information and options, patients may not be given time to process the information • After a conversation with their HCPs, patients forget 40%-80% of the information discussed • NEDA is often the goal for HCPs treating MS; for patients, stable disease does not always mean symptom-free • Focusing on patients’ goals for their treatment (often managing symptoms and fewer relapses) can be the key to improved patient engagement and adherence

HCP = healthcare provider; NEDA = no evidence of disease activity Kessels RP. J R Soc Med. 2003;96:219-222.

Encouraging Adherence through Engagement (2) HCP Strategies for Shared Decision-making 1. Explore all options 2. Identify biases and work to minimize them in patient interactions 3. Acknowledge and reveal experience with various procedures and treatments 4. Respect what matters most to the patient, including the risks and benefits associated with a variety of options

HCP = healthcare provider; NEDA = no evidence of disease activity Kessels RP. J R Soc Med. 2003;96:219-222.

Online Communities as Sources for Accurate Information • Directing patients towards online communities can empower them to connect with other patients like https://multiplesclerosis.net/livin https://multiplesclerosis.net/livin themselves, share experiences, and g-with-ms/the-neurological- g-with-ms/some-of-the-weirder- hear from experts and advocates exam-explained/ ms-symptoms/ • Offering them curated articles that explain common questions and misconceptions in a digestible form can help them more easily understand https://multiplesclerosis.net/livin https://multiplesclerosis.net/livin their diagnoses and options g-with-ms/lets-address- g-with-ms/multiple-sclerosis- elephant-room-depression/ 101-understanding-immune- system/

Perspectives from the Patient Laura Kolaczkowski

Question & Answer Session

Suhayl Dhib-Jalbut, MD Alina Ahsan Rutgers NJ Medical School Health Union, LLC Newark, NJ MultipleSclerosis.net Rutgers Robert Wood Philadelphia, PA Johnson Medical School New Brunswick, NJ Laura Kolaczkowski MultipleSclerosis.net Machteld E. Hillen, MD Dayton, OH Rutgers NJ Medical School Newark, NJ

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