Utah Medicaid Pharmacy and Therapeutics Committee Drug

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Agents for the Treatment of Multiple Sclerosis

Oral Medications: Cladribine (Mavenclad) Dalfampridine (Ampyra, generic) Dimethyl fumarate (Tecfidera) Diroximel fumarate (Vumerity) Fingolimod (Gilenya) Siponimod (Mayzent) Teriflunomide (Aubagio)

Subcutaneous and Intramuscular Medications: Glatiramer acetate (Copaxone, Glatopa, generic) Interferon beta-1a (Avonex, Rebif) Interferon beta-1b (Betaseron, Extavia) Peginterferon beta-1a (Plegridy)

Intravenous Medications: Alemtuzumab (Lemtrada) Mitoxantrone (generic) Natalizumab (Tysabri) Ocrelizumab (Ocrevus)

Report finalized October 2019 Report presented November 2019

Review prepared by: Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Joanne LaFleur, PharmD, MSPH, Associate Professor University of Utah College of Pharmacy

Executive Summary ...... 3 Introduction ...... 8 Table 1. Key Characteristics of Multiple Sclerosis Agents ...... 9 Table 2. Detailed Characteristics of Multiple Sclerosis Agents ...... 10 Methods ...... 13 Disease Overview ...... 14 Table 3. The 2017 revision of the 2010 McDonald Criteria for Diagnosis of Multiple Sclerosis...... 15 Guidelines Recommendations ...... 17 Table 4. Treatment Guideline Recommendations for Multiple Sclerosis in Adults ...... 18 Pharmacology & Special Populations ...... 20 Table 5. Mechanism of Action of Multiple Sclerosis Agents ...... 21 Table 6. Pharmacokinetic Parameters ...... 24 Table 7. Special Population Considerations ...... 25 Direct Comparative Evidence ...... 28 Figure 1. PRISMA Flow Chart for Publication Screening ...... 28 Figure 2. Systematic Reviews Included to Describe the Comparative Efficacy Among Disease-Modifying Agents ...... 29 Safety ...... 36 Table 8. Warnings and Precautions for Disease-Modifying Agents ...... 39 Table 9. Common Adverse Reactions and Monitoring Requirements ...... 42 Summary ...... 44 References ...... 45 Appendix A – Literature Search Strategies ...... 49 Appendix B – Included and Excluded References ...... 55 Appendix C – Evidence from Systematic Reviews of Multiple Sclerosis Agents ...... 59 Appendix D. Randomized Controlled Trials Included in the Selected Systematic Reviews for Multiple Sclerosis ...... 65

Executive Summary Introduction: Multiple sclerosis (MS) is an inflammatory, autoimmune disease of the central nervous system (CNS) characterized by demyelination and axonal damage. MS is classified into 3 main phenotypes including relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS), with RRMS being the most common. A clinically isolated syndrome (CIS) is the first neurological episode in patients not known to have MS. Disease-modifying therapies (DMTs) aim to reduce disease activity and progression of disability in patients with MS. Interferon (IFN) therapy and glatiramer acetate were the standard of care for treating relapsing forms of MS in the United States for more than 20 years. During the last decade, an increasing number of injectable and oral DMTs has been approved providing multiple treatment options for adults with MS. Currently, 14 DMTs and 1 non-DMT are available for the treatment of MS including oral DMTs (cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, siponimod, and teriflunomide), subcutaneous (SQ) and intramuscular (IM) DMTs (glatiramer acetate, interferon beta-1a, interferon beta-1b, and pegylated interferon beta-1a), intravenous (IV) DMTs (alemtuzumab, mitoxantrone, natalizumab, and ocrelizumab), and the oral non- DMT, dalfampridine. Each DMT is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with relapsing forms of MS including RRMS and active SPMS. In addition, each DMT except alemtuzumab, cladribine, and mitoxantrone is approved for patients with CIS. Ocrelizumab is the only agent approved for PPMS in adults. Fingolimod is the only agent approved for use in the pediatric population (10 years of age or older) with relapsing forms of MS. Due to safety concerns, labeling information for cladribine and alemtuzumab recommends their use only in patients who have had an inadequate response or are intolerant to other drugs indicated for the treatment of MS. The single, non-DMT, dalfampridine, is an oral medication approved for walking improvement in patients with MS. Interferons and the humanized monoclonal antibodies alemtuzumab, natalizumab, and ocrelizumab are biologic products produced by recombinant DNA techniques. Cladribine, dalfampridine, dimethyl fumarate, diroximel fumarate, fingolimod, glatiramer acetate, siponimod, teriflunomide, and mitoxantrone are synthetic drugs. For maintenance dosing, the oral DMTs may be administered once daily (fingolimod, siponimod, teriflunomide) or twice daily (dimethyl fumarate and diroximel fumarate). Cladribine administration includes 2 treatment courses 43 weeks apart. Regarding self-injectable DMTs, glatiramer acetate can be administered daily or 3 times weekly. The interferons are administered once weekly to every other day, with the exception of peg-interferon, administered once every 14 days. The intravenous DMTs are administered every 4 weeks (natalizumab), 3 months (mitoxantrone), or 6 months (ocrelizumab). Alemtuzumab is administered in treatment courses (3 to 5 days long), separated by 12 months apart. The recommended maintenance dosing frequency is twice daily for the non-DMT agent, dalfampridine. The 2018 American Academy of Neurology (AAN) guideline for the treatment of MS recommends offering treatment with DMT to patients with 1 demyelinating event and at least 2 brain lesions consistent with MS, and to patients with relapsing forms of MS who experienced recent relapses or magnetic resonance imaging (MRI) lesion activity. For people with CIS, clinicians may recommend close monitoring rather than starting DMT. Guideline authors provide a moderate recommendation for the use of alemtuzumab, fingolimod, or natalizumab in patients with highly active MS (though no standard definition is currently available for highly active MS). The risk-benefit balance associated with each treatment approach should be evaluated on an individualized basis. Treatment initiation with

natalizumab requires consideration of the John Cunningham virus (JCV) antibody status and the potential risk for progressive multifocal leukoencephalopathy (PML). A moderate recommendation is provided for use of ocrelizumab in ambulatory patients with primary progressive multiple sclerosis (PPMS). Mitoxantrone therapy should only be offered to MS patients when the benefits greatly outweigh the risks. DMTs are not recommended for use during pregnancy unless benefits of treatment outweigh potential risks. The 2 recently approved DMTs (diroximel fumarate and siponimod) are not included in the AAN guideline. The aim of this report is to provide evidence from systematic reviews (SRs) and randomized controlled trials (RCTs) of head-to-head efficacy and safety comparisons among the MS agents, at their FDA- approved dosages. Comparative Efficacy Evidence: Following a systematic literature search in Ovid-Medline and Embase for direct head-to-head comparisons, few comparative RCTs in patients with RRMS were identified. No comparative studies were identified for the targeted population of CIS, SPMS, or PPMS populations. Most RCTs included adult patients with RRMS, were of 2-year duration, and compared a DMT versus non-pegylated IFN beta formulations. Adult Population with Relapsing Forms of Multiple Sclerosis Fingolimod (Gilenya) versus IM Interferon Beta (Avonex) The single RCT for this comparison (TRANSFORMS study) in patients with RRMS demonstrated fingolimod was significantly better than IM IFN beta-1a for the reduction of relapses and MRI disease activity; however, no between-group differences were reported regarding disability progression. Teriflunomide (Aubagio) versus SQ Interferon Beta (Rebif) One RCT (TENERE study) in patients with relapsing MS showed teriflunomide 7 mg or 14 mg was similar to SQ IFN beta-1a 44 µg 3 times weekly for the primary composite endpoint of time to failure (ie, first occurrence of relapse or treatment discontinuation). In addition, teriflunomide 14 mg was similar to IFN for the endpoint of annualized relapse rate (ARR); however, AAR was significantly greater in patients receiving teriflunomide 7 mg compared to IFN. A significantly greater number of patients treated with IFN were relapse free compared to teriflunomide. IM versus SQ Interferon Beta (Avonex, Rebif, and Betaseron) A meta-analysis of RCTs comparing several interferon beta products (IM IFN beta [Avonex], SQ IFN beta- 1a 44 µg 3 times weekly [Rebif], and SQ IFN beta-1b 250 µg every other day [Betaseron]) in patients with RRMS showed no differences in ARR reduction. Additional outcomes reported among the individual RCTs indicated a significantly lower risk of relapses and new MRI lesions at year 1 with SQ IFN beta-1a 44 µg 3 times weekly compared to IM IFN beta-1a. A significantly greater effect in reducing the risk of relapses and MRI lesions, and delaying disease progression over 2 years was reported with SQ IFN beta- 1b 250 µg compared to IM IFN beta-1a. Glatiramer Acetate versus SQ or IM Interferon Beta Glatiramer acetate and SQ or IM IFN beta formulations (aside from the pegylated formulation) seem to be similarly efficacious in terms of relapse rate and MRI disease activity reduction for patients with RRMS. Specific differences between groups include a significantly higher risk of disease progression with SQ IFN beta-1b 250 µg (Betaseron) vs. glatiramer and a significantly greater reduction in ARR with glatiramer compared to IM IFN (Avonex). 4

Alemtuzumab (Lemtrada) versus SQ Interferon Beta (Rebif) Meta-analyses of RCTs in patients with RRMS demonstrated that alemtuzumab 12 mg IV was significantly more efficacious compared to SQ IFN beta-1a 44 µg 3 times per week at decreasing relapses, MRI disease activity, brain volume loss, and disability progression. Ocrelizumab (Ocrevus) versus SQ Interferon Beta (Rebif) Meta-analyses of RCTs in patients with relapsing MS showed ocrelizumab 600 mg IV was significantly more efficacious than SQ IFN beta-1a 44 µg 3 times per week in reducing relapses, MRI disease activity, brain volume loss, and disability progression. Pediatric Population with Relapsing Forms of Multiple Sclerosis Fingolimod (Gilenya) versus IM Interferon Beta (Avonex) One head-to-head RCT (PARADIGMS study) in patients 10 to 17 years of age with relapsing MS demonstrated a significantly greater reduction in relapses and MRI disease activity with fingolimod at the FDA-approved dosage compared to IM IFN beta-1a. Adverse Drug Reactions: Safety profiles differ among MS agents. All self-injectable medications (glatiramer acetate, interferon beta products, and peg-interferon beta), certain oral medications (dalfampridine, dimethyl fumarate, diroximel fumarate, fingolimod, and siponimod), and the IV medication, ocrelizumab, do not carry any black box warning (BBW). Interferon beta and glatiramer acetate have a well-characterized long-term safety profile. Among the oral medications, cladribine has a BBW concerning the risk of malignancy and teratogenicity and teriflunomide has a BBW regarding hepatotoxicity and embryofetal toxicity. Among the intravenously infused medications, alemtuzumab, mitoxantrone, and natalizumab carry serious risks and have BBWs in the prescribing information (autoimmune conditions, infusion reaction, stroke, and malignancies for alemtuzumab; cardiotoxicity and secondary leukemia for mitoxantrone; and progressive multifocal leukoencephalopathy [PML] for natalizumab). Risks associated with DMTs can be minimized by implementing measures at the time of MS diagnosis and monitoring the patient before, during, and after therapy. Risk Evaluation and Mitigation Strategy (REMS) programs are required for alemtuzumab and natalizumab because of safety concerns included in their corresponding BBWs. Further information regarding warnings, adverse events, and monitoring requirements are included in the safety section of the report. Summary: Evidence comparing DMTs at FDA-approved dosages is available only for patients with RRMS, and is limited to only a few comparisons versus IFN beta products. In the adult population with RRMS, head-to-head evidence demonstrated a significantly greater reduction in relapses and MRI disease activity with fingolimod versus IM IFN (Avonex), alemtuzumab versus SQ IFN beta-1a (Rebif), and ocrelizumab versus SQ IFN beta-1a (Rebif). In addition, alemtuzumab and ocrelizumab were more efficacious than SQ interferon beta-1a (Rebif) in decreasing the risk of disability progression. Teriflunomide 14 mg was similarly efficacious as SQ IFN beta-1a (Rebif) in reducing relapses; however, teriflunomide 7 mg performed worse than IFN for ARR. SQ IFN formulations (ie, SQ IFN beta-1a 44 µg 3 times weekly [Rebif] or SQ IFN beta-1b 250 µg [Betaseron]) were similarly efficacious or significantly better compared to IM IFN beta in terms of relapse rates and MRI disease activity. The 2 SQ INF formulations (Rebif and Betaseron) were similarly efficacious at reducing ARR. Glatiramer acetate was similarly efficacious or better compared to SQ or IM IFN beta formulations (aside from the pegylated IFN) with respect to clinical relapses, MRI disease activity, and disease progression. In the pediatric population with RRMS, fingolimod significantly reduced relapses and MRI disease activity compared to

IM IFN beta. In selecting therapies, the risk-benefit profile and patient tolerability for the potential risks should be considered. The Utah Medicaid Preferred Drug List (PDL) currently includes the self-injected medications Avonex (IFN beta-1a), Betaseron (IFN beta-1b), and Copaxone 20 mg (glatiramer acetate), and the oral medication Gilenya (fingolimod) as preferred products; step therapy is required for Gilenya (ie, patients must fail another preferred agent first). Other oral and self-injectable agents are non-preferred. The intravenous medications are not included in the PDL. Regarding the Medicaid fee-for-service (FFS) pharmacy claims data for 2019, utilization was highest for Copaxone SQ injection (glatiramer acetate), followed by Tecfidera capsules (dimethyl fumarate), generic glatiramer actetate, Gilenya (fingolimod), Avonex (IFN beta-1a IM injection), and Aubagio (teriflunomide). Medical FFS claims data for 2019 showed utilization for the monoclonal antibodies natalizumab, ocrelizumab, and alemtuzumab. No pediatric (< 18 years) FFS claims for the reviewed MS agents were identified in 2018 and 2019. Considerations for inclusion in the Utah Medicaid Preferred Drug List are listed below: 1. Adult patients with relapsing forms of MS: • AAN guideline recommendations: The 2018 AAN guideline recommends offering DMT treatment to patients with 1 demyelinating event and at least 2 brain lesions consistent with MS, and to patients with relapsing forms of MS who experienced recent relapses or magnetic resonance imaging (MRI) lesion activity. The selection of DMTs for patients with MS should consider drug characteristics (mechanism of action, route and frequency of administration, contraindications, risk-benefit profile, reproductive risk, monitoring requirements) together with patients’ preferences, concerns about medication adherence, comorbidities, as well as concerns regarding disease activity and long-term risk for disability and morbidity. For patients with highly active MS, the 2018 AAN guideline recommends alemtuzumab, fingolimod, or natalizumab therapy. This recommendation is based on subgroup analyses from phase 3 RCTs with these drugs compared to IFN beta therapy; no supportive subgroup analysis was described for ocrelizumab. However, a subgroup analysis in highly active MS patients receiving ocrelizumab was published in 2019 demonstrating a significantly greater benefit at reducing relapses, MRI outcomes, and confirmed disability progression with ocrelizumab compared to SQ IFN beta-1a (Rebif). Diroximel fumarate (Vumerity, approved by the FDA in October 2019) and siponimod (Mayzent, approved by the FDA in March 2019) are not included in the 2018 AAN guideline. • Head-to-head evidence in adult patients with RRMS showed that alemtuzumab, fingolimod, and ocrelizumab were more efficacious than specific formulations of IFN beta (Avonex or Rebif) at both reducing clinical relapses and MRI disease activity. Alemtuzumab and ocrelizumab were more efficacious at decreasing disability progression compared to SQ IFN beta-1a (Rebif). • Literature evidence describes different treatment strategies that can be used in clinical practice for treatment-naïve patients with relapsing MS. These include ‘tiered-escalation’ and ‘maximal efficacy’ strategies. The tiered-escalation approach consists of starting therapy with a modestly efficacious first-line DMT (interferon beta products, glatiramer acetate, teriflunomide, and possibly dimethyl fumarate) followed by the use of a highly efficacious second-line DMT

(alemtuzumab, cladribine, fingolimod, mitoxantrone, natalizumab, and ocrelizumab) if the first- line DMT fails. The ‘maximal efficacy’ approach consists of starting therapy with a highly efficacious, but potentially higher risk DMT. Some evidence has suggested that this last approach may help to better control relapsing activity and improve long-term patients´ outcomes (eg, disability progression and evolution to secondary progressive MS). Although it is unclear which patients will benefit most from the escalation or maximal efficacy approach, evidence suggests that some highly efficacious DMTs are often reserved to highly active MS patients (ie, patients with aggressive disease in terms of clinical relapses, MRI lesions, and presence of negative prognostic factors) due to the potential serious adverse effects associated with these agents (eg, progressive multifocal leukoencephalopathy [PML]). 2. Patients with primary progressive MS: The 2018 AAN guideline recommends ocrelizumab for PPMS. Ocrelizumab is the only DMT with demonstrated efficacy in this population, affecting approximately 15% of MS cases. 3. Pediatric population use: Fingolimod is the only DMT FDA approved in the pediatric population (≥ 10 years old) with relapsing forms of MS. A head-to-head trial in patients 10 to 17 years of age showed fingolimod was more efficacious than IM IFN beta-1a (Avonex) at both reducing clinical relapses and MRI disease activity. The prevalence of MS among the general pediatric population is low (3% to 5% of MS patients) and no pediatric FFS claims (<18 years) for the reviewed MS agents were identified in the Medicaid FFS population for 2018 and 2019. 4. Pregnancy: The 2018 AAN guideline states that DMTs should not be used during pregnancy unless benefits outweigh the potential risks. FDA prescribing information contraindicates cladribine and teriflunomide in pregnant women and does not recommend mitoxantrone during pregnancy. The remaining DMTs do not have a specific contraindication for pregnant women; however, there may be a potential fetal harm. 5. Dalfampridine: This agent is a non-DMT approved to improve walking in patients with MS. Identified clinical practice guidelines are DMT-focused and do not include dalfampridine. The Utah Medicaid P&T Committee may consider including at least 1 modestly effective DMT and at least 1 highly effective DMT to optimize the management of patients with MS, with considerations for limitations of use regarding the following drugs: • Cladribine: prescribing information indicates that, due to safety concerns, its use is generally reserved for patients who have had an inadequate response or are intolerant to other agents indicated for the treatment of MS. This agent may be considered non-preferred and require prior treatment with a preferred agent. • Alemtuzumab: prescribing information indicates that, due to safety concerns, its use is generally reserved for patients who have had an inadequate response to ≥ 2 agents indicated for the treatment of MS. This agent may be considered non-preferred and require prior treatment with 2 or more preferred agents.

• Mitoxantrone is associated with a high frequency of serious adverse events and should not be prescribed to people with MS unless the potential therapeutic benefits greatly outweigh the risks. This agent should be non-preferred and consideration of a prior authorization for use may be considered.

Introduction Disease-modifying agents (DMTs) aim to reduce disease activity and progression of disability in patients with multiple sclerosis (MS). Currently, 14 DMTs and 1 non-DMT are available for the treatment of MS including oral DMTs (cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, siponimod, and teriflunomide), subcutaneous (SQ) and intramuscular (IM) DMTs (glatiramer acetate, interferon beta-1a, interferon beta-1b, and pegylated interferon beta-1a), intravenous (IV) DMTs (alemtuzumab, mitoxantrone, natalizumab, and ocrelizumab), and the oral non-DMT, dalfampridine.1-18 Each DMT is FDA-approved for adult patients with relapsing forms of MS including relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). In addition, each DMT except alemtuzumab, cladribine, and mitoxantrone is approved for patients with clinically isolated syndrome (CIS). Ocrelizumab is the only agent approved for primary progressive MS (PPMS) in adults. Fingolimod is the only agent approved for the pediatric population (10 years of age or older) with relapsing forms of MS. Due to safety concerns, labeling information for cladribine and alemtuzumab recommends the use of these agents in patients who have had an inadequate response or are intolerant to other drugs indicated for the treatment of MS. DMTs differ in the mechanism of action, risk-benefit profile, route and frequency of administration, and monitoring requirements.1,2,4-19 Dalfampridine is an oral non-DMT approved for walking improvement in patients with MS.3 Table 1 includes key characteristics of these medications for the treatment of multiple sclerosis. Table 2 includes detailed information regarding FDA-labeled indications and dosing recommendations for each MS agent. Interferons and the humanized monoclonal antibodies alemtuzumab, natalizumab, and ocrelizumab are biologic products produced via recombinant DNA technologies. There are 2 forms of interferon beta (IFN beta) for the treatment of MS including IFN beta-1a and IFN beta-1b. IFN beta-1a is available as IM and SQ formulations (Avonex and Rebif, respectively). In addition, a pegylated form of IFN beta-1a is available as an SQ formulation (Plegridy). IFN beta-1b is available as SQ formulations (Betaseron and Extavia). Both SQ INF beta-1b contain the same active ingredient and are formulated as a lyophilized powder for reconstitution before SQ administration; they only differ in the package content. Cladribine, dalfampridine, dimethyl fumarate, diroximel fumarate, fingolimod, glatiramer acetate, siponimod, teriflunomide, and mitoxantrone are synthetic drugs.1-17 For maintenance dosing, the oral DMTs may be administered once daily (fingolimod, siponimod, teriflunomide) or twice daily (dimethyl fumarate and diroximel fumarate). Cladribine administration includes 2 treatment courses 43 weeks apart. Regarding self-injectable medications, glatiramer acetate can be administered daily or 3 times weekly. The interferons are administered once weekly to every other day, with the exception of peg-interferon, administered once every 14 days. The intravenous medications are administered every 4 weeks (natalizumab), 3 months (mitoxantrone), or 6 months (ocrelizumab). Alemtuzumab is administered in treatment courses (3 to 5 days long), separated by 12 months apart. The recommended maintenance dosing frequency is twice daily for the non-DMT agent, dalfampridine. Of the self-administered products (oral, IM, or SQ), fingolimod requires the patient to be monitored by a healthcare provider upon the first dose for 6 hours for bradycardia, and overnight monitoring if necessary. With siponimod, first-dose monitoring is only required for patients with significant cardiac history (see Table 2). Alemtuzumab and natalizumab are only available through Risk Evaluation and Mitigation Strategies (REMS) programs.1,2,4-18 The research objective of this report is to determine whether there are key efficacy or safety differences between the DMTs listed in Table 1 for the treatment of MS, at their FDA-approved dosages. The Utah

Medicaid Preferred Drug List (PDL) includes these products under the category ‘Multiple Sclerosis Agents’. Preferred products include the self-injectable medications Avonex (IFN beta-1a), Betaseron (IFN beta-1b), and Copaxone 20 mg (glatiramer acetate), and the oral medication Gilenya (fingolimod); step therapy is required for Gilenya (ie, patients must fail another preferred agent first). The remaining oral and injectable (SQ or IM) agents listed in Table 1 are included in the PDL as non-preferred. No MS agents requiring intravenous administration is listed on the PDL.20 Regarding the Medicaid fee-for-service (FFS) pharmacy data for 2019, utilization was highest for Copaxone SQ injection (glatiramer acetate), followed by Tecfidera capsules (dimethyl fumarate), generic glatiramer actetate, Gilenya (fingolimod), Avonex (IFN beta-1a IM injection), and Aubagio (teriflunomide). No pediatric (<18 years) claims for the reviewed MS agents were identified in 2018 or 2019. For Medicaid fee-for-service (FFS) medical claims data, there was utilization for natalizumab, ocrelizumab, and alemtuzumab (in order of highest to lowest claim numbers) in 2019; natalizumab use is not limited to MS as it is additionally approved for Crohn’s disease.

Table 1. Key Characteristics of Multiple Sclerosis Agents1-18 FDA-Approved Route Population Agent Indication Regarding of (per Labeled Recommended Dosage MS Admin. Indication) RRMS, SPMS 2 treatment courses: (inadequate 12 mg/day (5 days); after 12 Alemtuzumab (Lemtrada) IV Not specified response to ≥ 2 months 12 mg/day (3 days); agents for MS) additional courses if needed RRMS, SPMS 2 treatment courses (inadequate or Cladribine (Mavenclad) PO Adults (3.5 mg/kg) separated by 43 intolerable response weeks to other MS agents) To improve walking Dalfampridine (Ampyra) PO Adults Max. dose: 10 mg BID in MS patients Dimethyl fumarate (Tecfidera) CIS, RRMS, SPMS PO Adults MD: 240 mg BID Diroximel fumarate (Vumerity) CIS, RRMS, SPMS PO Adults MD: 462 mg BID Fingolimod (Gilenya) CIS, RRMS, SPMS PO ≥ 10 years MD: 0.25 mg or 0.5 mg QD Glatiramer acetate (Copaxone, MD: 20 mg/mL QD or CIS, RRMS, SPMS SQ Adults Glatopa) 40 mg/mL TIW Interferon beta-1a (Avonex) CIS, RRMS, SPMS IM Adults MD: 30 µg QW Interferon beta-1a (Rebif) CIS, RRMS, SPMS SQ Adults MD: 22 µg or 44 µg TIW Interferon beta-1b (Betaseron, CIS, RRMS, SPMS SQ Adults MD: 0.25 mg EOD Extavia) Mitoxantrone (Novantrone) RRMS, SPMS IV Not specified 12 mg/m2 every 3 months Natalizumab (Tysabri) CIS, RRMS, SPMS IV Adults 300 mg every 4 weeks CIS, RRMS, SPMS, Ocrelizumab (Ocrevus) IV Adults MD: 600 mg every 6 months PPMS Peginterferon beta-1a (Plegridy) CIS, RRMS, SPMS SQ Adults MD: 125 µg every 14 days Siponimod (Mayzent) CIS, RRMS, SPMS PO Adults MD: 1 mg or 2 mg QD Teriflunomide (Aubagio) CIS, RRMS, SPMS PO Adults MD: 7 mg or 14 mg QD Abbreviations: Admin., administration; BID, twice daily; CIS, clinically isolated syndrome; EOD, every other day; FDA, U.S. Food and Drug Administration; IV, intravenous; Max., maximum; MD, maintenance dosage; MS, multiple sclerosis; PO, oral; PPMS, primary progressive multiple sclerosis; QD, once daily; QW, once weekly; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; SQ, subcutaneous; TIW, three times per week

Table 2. Detailed Characteristics of Multiple Sclerosis Agents1-18 Generic Name Brand Name Preparations Labeled Indication Dosing Recommendations (Approval Date) Oral Medications Relapsing forms of MS in Assessments required prior to starting adults, including relapsing- treatment (eg, cancer, infection, remitting disease and active pregnancy, CBC, and liver enzymes) Mavenclad secondary progressive Tablet: 10 mg disease Cumulative dosage of 3.5 mg/kg Cladribine (also as generic IV Due to its safety profile, it is divided into 2 treatment courses Mavenclad solution; generally recommended (1.75 mg/kg per treatment course) (Mar 2019) however, not only after having an and separated by at least 43 weeks inadequate or intolerable indicated for MS) Each treatment course is divided into response to alternative MS 2 treatment cycles that are separated drugs, and is not for use for by 23 to 27 days CIS Max. dose: 10 mg twice daily Dalfampridine Ampyra and To improve walking in generic Ampyra adults with MS CrCl should be tested before initiating ER tablet: 10 mg (Jan 2010) treatment Tecfidera Relapsing forms of MS in Blood tests required prior to starting Dimethyl DR-capsule: adults, including clinically therapy fumarate 120 mg, 240 mg isolated syndrome,

(also available as relapsing-remitting disease, Tecfidera Start at 120 mg twice daily for 7 days, powder for and active secondary (Mar 2013) then 240 mg twice daily compounding) progressive disease Relapsing forms of MS in Blood tests required prior to starting Diroximel adults, including clinically therapy fumarate Vumerity isolated syndrome,

DR-capsule: relapsing-remitting disease, Start at 231 mg twice daily for 7 days, Vumerity 231 mg and active secondary then 462 mg twice daily (October 2019) progressive disease Patients >40 kg: 0.5 mg once daily Relapsing forms of MS in Pediatric patients ≤40 kg: 0.25 mg patients ≥ 10 years of age, once daily Fingolimod including clinically isolated Gilenya syndrome, relapsing- Capsule: 0.25 mg, Healthcare provider must monitor Gilenya remitting disease, and 0.5 mg (for at least 6 hours) and be able to (Sept 2010) active secondary treat symptomatic bradycardia with progressive disease the first dose Pre-initiation assessments required Relapsing forms of MS in (eg, CYP2C9 genotype; ophthalmic, adults, including clinically cardiac, and liver function Siponimod Mayzent isolated syndrome, evaluations; medication and Tablet: 0.25 mg, Mayzent relapsing-remitting disease, vaccination histories) 2 mg (Mar 2019) and active secondary Titration required for first 4 or 5 days progressive disease Maintenance dose: 2 mg once daily; for those with a CYP2C9 *1/*3 or

Table 2. Detailed Characteristics of Multiple Sclerosis Agents1-18 Generic Name Brand Name Preparations Labeled Indication Dosing Recommendations (Approval Date) *2/*3 genotype dosing is 1 mg once daily First-dose monitoring recommended for patients with sinus bradycardia, 1st or 2nd-degree (Mobitz type I) AV block, or history of MI or HF Relapsing forms of MS in adults, including clinically 7 mg or 14 mg once daily Teriflunomide Aubagio isolated syndrome, Pre-initiation assessments required Tablet: 7 mg, relapsing-remitting disease, Aubagio (eg, liver function, CBC, TB screening, 14 mg and active secondary (Sept 2012) pregnancy, and BP) progressive disease Subcutaneous and Intramuscular Medications

Copaxone, SQ administration: 20 mg/mL once Glatiramer Glatopa, and daily, or 40 mg/mL three times acetate generic weekly and at least 48 hours apart Copaxone, SQ, single-dose Glatopa prefilled syringes: The 20 mg/mL and the 40 mg/mL (Dec 1996) 20 mg/ml, products are not interchangeable 40 mg/ml

Avonex IM, single-use IM administration: may be titrated, vials, prefilled starting at 7.5 µg for the first week to syringe, or pen reduce flu-like symptoms Interferon autoinjector of Relapsing forms of MS in Maintenance dose: 30 µg once weekly beta-1a 30 µg per dose adults, including clinically Avonex isolated syndrome, SQ administration: titrate with 20% of Rebif (May 1996) relapsing-remitting disease, the prescribed dose 3 times weekly, SQ, single-dose and active secondary and increase over 4 weeks to targeted prefilled syringe Rebif progressive disease dose of either 22 or 44 µg 3 times per or autoinjector (Mar 2002) week 8.8 µg in 0.2 mL, and 22 µg or Analgesics and/or antipyretics on 44 µg in 0.5 mL treatment days may help reduce flu- like symptoms Betaseron and Interferon Extavia SQ administration: initiate at beta-1b SQ, single-use vial 0.0625 mg (0.25 mL) every other day, Betaseron containing 0.3 mg and increase over 6-weeks to 0.25 mg (Jul 1993) of lyophilized (1 mL) every other day. powder (optional Extavia Maintenance dose: 0.25 mg every autoinjector for (Aug 2009) other day Betaseron)

Table 2. Detailed Characteristics of Multiple Sclerosis Agents1-18 Generic Name Brand Name Preparations Labeled Indication Dosing Recommendations (Approval Date) SQ administration: titrate, starting Plegridy Relapsing forms of MS in with 63 µg on day one, 94 µg on day Peginterferon SQ, single-dose adults, including clinically 15, and 125 µg (full dose) on day 29 beta-1a prefilled pen or isolated syndrome, and every 14 days thereafter syringe as relapsing-remitting disease, Plegridy 125 µg/0.5mL, and active secondary Analgesics and/or antipyretics on (Aug 2014) 63 µg/0.5 mL, progressive disease treatment days may help reduce 94 µg/0.5 mL flulike symptoms Intravenous Medications IV infusion over 4 hours for 2 or more Relapsing forms of MS, treatment courses: the 1st course is including relapsing- 12 mg/day for 5 consecutive days, remitting disease and active followed by the 2nd course of secondary progressive 12 mg/day for 3 consecutive days 12 disease Alemtuzumab Lemtrada months after the first course Due to its safety profile, use Lemtrada IV, single-dose Subsequent courses, if needed: (May 2001) vial 12 mg/1.2 mL should generally be 12 mg/day on 3 consecutive days at reserved for patients who least 12 months after the last dose of have had an inadequate any prior treatment course response to ≥2 drugs indicated for MS Pre-medicate with CCS for the first 3 days of each treatment course For reducing neurologic disability and/or frequency of clinical relapses in 12 mg/m2 every 3 months patients with secondary Mitoxantrone Generic: (chronic) progressive, Should not receive a cumulative dose IV, multidose Novantrone- progressive relapsing, or greater than 140 mg/m2 vials DCN worsening relapsing- Assess baseline left ventricular 20 mg/10 mL, (Dec 1987) remitting MS; not indicated ejection fraction, cardiac risks, and 25 mg/12.5 mL, for primary progressive MS ECG prior to start of therapy; avoid 30 mg/15 mL Generic only Other indications include with neutrophil counts <1500 use in advanced hormone- cells/mm; monitor liver function refractory prostate cancer or in ANLL Relapsing forms of MS (as monotherapy) in adults, including clinically isolated syndrome, relapsing- Tysabri remitting disease, and Natalizumab IV, single-dose active secondary 300 mg IV infusion over 1 hour, every Tysabri vial progressive disease 4-weeks 300 mg/15 mL (Nov 2004) Consider expected benefit vs. risk of PML Other indications include Crohn’s disease

Table 2. Detailed Characteristics of Multiple Sclerosis Agents1-18 Generic Name Brand Name Preparations Labeled Indication Dosing Recommendations (Approval Date) Relapsing forms of MS in Starting dose: 300 mg, and a second adults, including clinically dose of 300 mg 2 weeks later. isolated syndrome, Subsequent doses: 600 mg every 6 Ocrelizumab Ocrevus relapsing-remitting disease, months IV, single-dose and active secondary Ocrevus vial progressive disease Pre-medicate with CCS and (Mar 2017) 300 mg/10 mL antihistamine Primary progressive MS in adults Pre-screening for hepatitis B required Abbreviations: AV, atrioventricular; ANLL, acute nonlymphocytic leukemia; BP, blood pressure; CBC, complete blood cell count; CCS, corticosteroid; CIS, clinically isolated syndrome; CrCl, creatinine clearance; DCN, discontinued; DR, delayed release; ER, extended release; HF, heart failure; IM, intramuscular; IV, intravenous; MI, myocardial infarction; MRI, magnetic resonance imaging; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy; SQ, subcutaneous; tab, tablet; TB, tuberculosis

Methods Literature Search

Search strategies were developed for OVID Medline and Embase. Strategies consisted of controlled vocabulary, such as Medical Subject Headings (MeSH), and keyword phrases. Two methodological filters were used, one for systematic reviews (SRs) and another for randomized controlled trials (RCTs). The Embase search excluded conference abstracts. Based on the literature searches described in the American Academy of Neurology (AAN) and the European Committee of Treatment and Research in Multiple Sclerosis/European Academy of Neurology (ECTRIMS/EAN) guidelines, an updated search for SRs was performed in Ovid Medline and Embase from January 2015 to September 2019. Following the identification of SRs including head-to-head RCTs (eg, Lucchetta 2018),21 an RCT search was performed in Ovid Medline and Embase from January 2017 to October 2019. The complete search strategies and terms are available in Appendix A. At the time of the literature search undertaking, diroximel fumarate (Vumerity) was not yet approved so was not included in the search strategy. Following its approval in October 2019, information for this medication was added based on the product labeling information.

Authors additionally screened the reference lists of related systematic reviews and other relevant websites for further information:

1. For guidelines addressing multiple sclerosis: websites of the American Academy of Neurology (AAN), the European Committee of Treatment and Research in Multiple Sclerosis (ECTRIMS), the European Academy of Neurology (EAN), the National Institute for Health and Clinical Excellence (NICE), and the Canadian Agency for Drugs and Technology in Health (CADTH)

2. For prescribing information package inserts: The Food and Drug Administration website (Drugs@FDA: FDA Approved Drug Products: https://www.accessdata.fda.gov/scripts/cder/daf/)

3. For evidence-based drug information databases: Micromedex, Lexicomp, and UpToDate

Screening

Two review authors screened titles and abstracts. Conflicts were resolved via discussion between reviewers. The full texts for all citations receiving 2 inclusion votes were retrieved; screening and inclusion were determined by the lead author. Figure 1 on page 28 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart22 for the review process.

Inclusion and Exclusion Criteria

Systematic reviews of RCTs and RCTs providing direct head-to-head efficacy or safety comparisons among the agents for MS were included. For product comparisons where a systematic review provided robust data, we examined only those trials or systematic reviews published after the search date of the robust systematic review. Network meta-analyses (NMA) including standard pairwise meta-analyses of an agent for MS vs. another were included; however, the indirect- or mixed-treatment effect summary outcomes from the NMA were not included.

Excluded references met the following exclusion criteria: 1) Review articles not using systematic review methodology, 2) Network meta-analyses including indirect comparisons only, 3) SRs comparing MS agents vs. placebo, or 4) Post hoc analyses, pilot studies, switching studies, and observational studies. A list containing the included and excluded references is provided in Appendix B. Disease Overview Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory, demyelinating disorder affecting more than 400,000 Americans.23 Disease progression can cause severe physical, mental, and emotional disability, significant work productivity loss, reduced quality of life, and increase in health-related costs.19,24 MS is more common in women and disease onset usually occurs between 20 to 40 years of age.25 Approximately 3% to 5% of patients have a disease onset in childhood (before the age of 18 years).26 MS is characterized by axonal demyelination in the central nervous system with histologic manifestations of focal leukocyte infiltration (mainly macrophages and lymphocytes) and plaque formation (ie, damaged areas in the brain and spinal cord detected by magnetic resonance imaging [MRI]). Acute plaques show oligodendroglia cell and axon damage, while chronic plaques display astrogliosis with less inflammatory cells than acute plaques.19 Primary symptoms of MS include visual disturbances such as blurred vision, muscle weakness, alteration of coordination and balance, gait disturbances, numbness, tingling, fatigue, pain, muscle spasms, speech problems, cognitive impairment, and depression.25,27 Some of the most relevant risk factor for developing MS relate to geography, age, environment stimuli, and genetics.27

The clinical course of MS is heterogeneous.27 Based on the 2013 revised Lublin criteria, MS can be classified into 3 clinical courses including relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), and primary-progressive MS (PPMS).28 Classification considers MRI disease activity, clinical disease activity (ie, relapses, also known as exacerbations or attacks), and disease progression to define the different clinical phenotypes of MS. The majority of patients (85%) experience RRMS, which is characterized by worsening episodes (relapses) followed by periods of full or partial recovery (remission).27 RRMS can be categorized as RRMS-active or RRMS-not active based on clinical relapses and brain imaging during the clinical assessment period.28 RRMS may or may not be accompanied by worsening of disability. RRMS typically begin with a single attack, also known as a clinically isolated

syndrome (CIS).27,28 Some people with CIS may not progress to MS.29 SPMS starts as RRMS and continues with a significant, gradual accumulation of disability.27,28 PPMS occurs in 15% of patients and is characterized by an absence of relapses prior to disease progression.27,28 Although there is clinical evidence of disease progression in SPMS and PPMS, patients may remain stable for periods of time (ie, absence of both disease activity and disability progression). During the time of the patient´s clinical assessment, SPMS and PPMS can be categorized as ‘active’ or ‘not active’ based on disease activity (relapses and/or lesions on MRI) and ‘progressing’ or ‘not progressing’ based on clinical evaluation of disease worsening (eg, increase in neurologic dysfunction or disability).28

Diagnosis of Multiple Sclerosis

The 2010 McDonald Criteria is commonly used in research and clinical practice to diagnose MS. These diagnostic criteria were revised in 2017 by the International Panel on Diagnosis of MS to incorporate clarifications, enable earlier diagnosis, and reduce misdiagnosis. The diagnosis of MS is based on clinical evaluation (symptoms/signs), imaging testing (presence of MRI lesions in brain and/or spine), and laboratory assessments (eg, cerebrospinal fluid abnormalities).29 A patient receives a diagnosis of MS if meets any of the 2017 McDonald Criteria scenarios shown in Table 3.29

Table 3. The 2017 revision of the 2010 McDonald Criteria for Diagnosis of Multiple Sclerosis29 Possible Clinical Presentation Scenario 1 ≥ 2 clinical attacks and ≥ 2 lesions with objective clinical evidence 2 ≥ 2 attacks and 1 lesion with objective clinical evidence (and clear evidence of a prior attack involving a lesion in a different anatomical location) 3 ≥ 2 attacks, 1 lesion with objective clinical evidence, AND “dissemination in space demonstrated by an additional attack implicating a different CNS site or by MRI” 4 1 clinical attack, ≥ 2 lesions with objective clinical evidence, AND “dissemination in time demonstrated by an additional clinical attack or by MRI OR demonstration of CSF-specific oligoclonal bands” 5 1 clinical attack, 1 lesion with objective clinical evidence, “dissemination in space demonstrated by an additional attack implicating a different CNS site or by MRI”, AND “dissemination in time demonstrated by an additional clinical attack or by MRI OR demonstration of CSF-specific oligoclonal bands” Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; MS, multiple sclerosis

Treatment Strategies for Multiple Sclerosis While the exact immunologic targets in MS associated with antibody-mediated destruction are not fully understood, a variety of immune-modulating or immune-suppressing treatments have been found to slow disease progression.19 Treatment of MS is a two-stemmed approach that includes management of relapses/disease progression and management of MS symptoms.27 DMTs listed in Table 1 are commonly prescribed to interfere with the clinical course of MS by reducing the number of relapses and delaying disease progression.19 Other therapies are prescribed for the management of MS symptoms, including dalfampridine for gait disturbances, steroids for inflammation in acute attacks, muscle relaxants and tranquilizers for spasticity, and antidepressant agents for depression.25 There are additional DMTs used off-label for the treatment of MS (eg, azathioprine, cyclophosphamide, mycophenolate mofetil, and rituximab).19 Clinically important outcomes of DMTs are that they modify clinical disease activity (ie,

relapse rates), disability, lesion development on MRI, brain volume loss, quality of life, or cognition; however, none of the available medications are curative.

The selection of DMTs for patients with MS should consider the benefits and risks of treatment, patient’s preferences, monitoring requirements, patient-specific factors, disease activity/severity, and concerns regarding long-term risk for disability and morbidity.19 Interferons and glatiramer acetate have been the standard of care for the treatment of MS in the United States for more than 20 years.30 These agents reduce the frequency of relapses compared to placebo and may decrease disease progression.30,31 Interferon beta and glatiramer have an established safety profile with limitations to use such as a short half-life, the formation of interferon neutralizing antibodies that decrease efficacy, and poor adherence due to frequent dosing regimens and adverse events.6-11,32 Some of the novel FDA- approved oral and injectable agents (eg, fingolimod, alemtuzumab, and ocrelizumab) seem to be more efficacious than older DMTs; however, their long-term safety profile is still uncertain and they may potentially cause severe adverse events and complications.33 Some severe adverse events reported with the newer agents include progressive multifocal leukoencephalopathy (PML) with dimethyl fumarate, fingolimod, and natalizumab; malignancy with alemtuzumab, cladribine, fingolimod, and ocrelizumab; serious autoimmune disorders with alemtuzumab, and hepatotoxicy with teriflunomide.1,2,4,5,14,15,17

Adherence to DMTs is key in the treatment of MS and may be influenced by the efficacy of DMT, adverse events, convenience, cognitive ability, and provider´s support.34 In addition, poor adherence to DMTs is related to a higher risk of relapses, hospitalization rates, emergency room visits, outpatient visits, and health care costs.32 Treatment adherence to injectable DMTs may be challenging due to the occurrence of injection-related adverse events such as physical or emotional fatigue and pain or discomfort at the site of injection.19 Regarding oral DMTs, short-term studies have suggested that patients adhere well to oral DMTs.32 A retrospective analysis using short-term pharmacy claims data for the period between October 2010 and February 2011 suggested that patients initiating fingolimod daily were more adherent to therapy compared to those initiating self-injected DMTs (ie, glatiramer acetate or the non-pegylated interferon betas).32,35 However, another retrospective analysis using pharmacy claims data for the period between January 2008 to September 2015 showed similar adherence between patients starting injectable DMTs (glatiramer acetate, non-pegylated interferon betas, and natalizumab) and those initiating oral DMTs (dimethyl fumarate, fingolimod, and teriflunomide).36

In clinical practice it seems that there are 2 philosophies for managing treatment-naïve patients with relapsing MS. These include ‘tiered-escalation’ (also known as ‘treat-to-target’) and ‘maximal efficacy’ (also known as ‘early intensive’) strategies.37 The tiered-escalation approach consists of starting therapy with a modestly efficacious first-line DMT (interferon beta products, glatiramer acetate, and teriflunomide) followed by the use of highly efficacious second-line therapies (alemtuzumab, cladribine, fingolimod, mitoxantrone, natalizumab, and ocrelizumab) if the first-line DMT fails.37-40 Dimethyl fumarate seems to be considered a moderately high-efficacy DMT that can be used first- or second- line.37,40 The ‘maximal efficacy’ approach consists of starting therapy with a highly efficacious, but potentially higher risk DMT (alemtuzumab, cladribine, fingolimod, mitoxantrone, natalizumab, and ocrelizumab).37-40 These DMTs are considered ‘high-efficacy’ based on relapse rate reductions compared to interferon beta formulations or placebo.40 Some evidence has suggested that the ‘maximal efficacy’ approach may help to better control relapsing activity and improve long-term patients´ outcomes (eg, disability progression and evolution to secondary progressive MS).37-39 Although it is unclear which patients will benefit most from the escalation or maximal efficacy approach, evidence suggests that

some highly efficacious DMTs are often reserved to highly active MS patients (ie, patients with aggressive disease in terms of clinical relapses, MRI lesions, and presence of negative prognostic factors) due to the potential serious adverse effects associated with these agents (eg, progressive multifocal leukoencephalopathy [PML]).27,37,38,41 Clinicians generally reserve mitoxantrone and alemtuzumab as last-line therapies to obtain rapid control of aggressive disease activity.38 In addition, there is clinical interest for studying early switching compared to delayed switching to highly efficacious DMTs in patients with suboptimal response to first-line agents.38,42 The 2018 AAN guideline and systematic review accompanying this guideline state suggestions for further research including 1) studies comparing the long-term efficacy of high-potency DMTs when used early in the disease course, 2) studies comparing maximal efficacy treatment approach versus escalation approach, and 3) studies evaluating switching versus continuing DMTs in patients with sustained disease activity.19,23

The non-DMT, dalfampridine, is the only agent approved for walking improvement in adult patients with MS.3 Data supporting its approval come from two 14-week randomized controlled trials comparing dalfampridine 10 mg twice daily versus placebo. In these studies, dalfampridine was more efficacious than placebo for the primary efficacy endpoint of walking speed, as measured by the Timed 25-foot Walk (T25FW). The proportion of patients experiencing faster walking speed was significantly higher with dalfampridine compared to placebo (Study 1: 34.8% vs. 8.3%; Study 2: 42.9% vs. 9.3%).3 The proportion of patients experiencing walking speed improvement of 10%, 20%, or 30% from baseline was significantly higher with dalfampridine compared to placebo. Regarding concomitant medications, 63% of patients were receiving IFN, glatiramer acetate, or natalizumab; however, the effect of walking improvement was independent of the concomitant use with these DMTs.3

Guidelines Recommendations Evidence-based guidelines for the treatment of patients with MS have been developed by several professional organizations including the American Academy of Neurology (AAN), the National Institute for Health and Clinical Excellence (NICE), and the European Committee of Treatment and Research in Multiple Sclerosis/European Academy of Neurology (ECTRIMS/EAN). Table 4 summarizes key treatment guideline recommendations for adults with MS.

When selecting a DMT, the 2018 AAN guideline for adults with MS strongly recommends that clinicians consider patient preferences in terms of drug safety and efficacy profile, route of administration, reproductive plans, lifestyle, and costs. Guideline authors state that an evaluation of patient preferences may increase adherence to DMT.19 Clinicians should inform patients that DMTs are prescribed to reduce relapses and new MRI lesion activity, and not for symptom improvement. Treatment with DMT should be offered to patients with 1 demyelinating event and at least 2 brain lesions consistent with MS and to patients with relapsing forms of MS who experienced recent relapses or MRI disease activity.19 Patients with clinically isolated syndromes (CIS) and relapsing forms of MS who have not experienced relapses in at least 2 years or new MRI activity may be monitored closely rather than initiating DMT.19

For therapy initiation, the AAN guideline provides a moderate recommendation for the use of alemtuzumab, fingolimod, or natalizumab in patients with highly active MS; though, no standard definition was provided for “highly active MS.”19 This recommendation is based on subgroup analyses from phase 3 trials with these drugs compared to interferon beta therapy; no supportive subgroup analysis in highly active MS patients was described for ocrelizumab. A risk-benefit balance of each

treatment approach should be evaluated on a case-by-case basis. Treatment initiation with natalizumab requires consideration of the anti-John Cunningham virus (JCV) antibody status and the potential benefits versus the potential risk of progressive multifocal leukoencephalopathy (PML). There is a weak recommendation for use of azathioprine or cladribine in patients with relapsing forms of MS who do not have access to approved DMTs. A moderate recommendation is provided for use of ocrelizumab in ambulatory patients with primary progressive multiple sclerosis (PPMS).19 Mitoxantrone therapy should not be offered unless the benefits greatly outweigh the risks.

Concerning switching treatment recommendations, the AAN guideline recommends changing to another DMT in patients experiencing 1 or more relapses, 2 or more unequivocally new MRI-detected lesions, or disability worsening on examination over a 1-year period of using and adhering to a DMT.19 In addition, a switching strategy may be considered if the route of administration, dosing frequency, or adherence to treatment are not appropriate. For instance, the guideline recommends switching to non-injectable or less frequent injectable DMTs in MS patients who do not tolerate discomfort or experience fatigue with injectable DMTs. Other switching considerations include risk for developing PML, presence of persistent natalizumab antibodies, development of a malignancy, serious infection potentially associated with DMT, and reproductive risks.19

MS patients should be caught up on immunizations at least 4 to 6 weeks before starting specific immunosuppressive/immunomodulating (ISIM) medications. Live-attenuated vaccines are not recommended for use in MS patients once on ISIM therapy. Prior to initiating ISIM therapy, patients should also be tested for latent infections (eg, tuberculosis and hepatitis) and treated if positive.43

Table 4. Treatment Guideline Recommendations for Multiple Sclerosis in Adults Professional Organization Recommendations and Guideline American Academy of Recommendations on starting DMTs:a Neurology (AAN) - Selection of DMTs in patients with MS is based on patients´ preferences, drug risk-benefit profile, route of administration, lifestyle, and cost Practice guideline - Offer DMT to patients who experienced a single clinical demyelinating event and recommendations ≥2 brain lesions characteristic of MS and to patients with relapsing forms of MS summary: Disease- with recent clinical relapses or MRI activity modifying therapies for - Alemtuzumab, fingolimod, or natalizumab should be prescribed for people with adults with multiple highly active MS, based on subgroup analyses from phase III studies (Level B) sclerosis, 201819 - Mitoxantrone should not be prescribed to people with MS unless the potential therapeutic benefits greatly outweigh the risks (Level B). Mitoxantrone is associated with severe adverse events: high risk of cardiomyopathy, ovarian failure, male infertility, chromosomal aberrations, and promyelocytic leukemia - Azathioprine or cladribine may be recommended for people with relapsing forms of MS who do not have access to approved DMTs (Level C) - Natalizumab treatment may be initiated in MS patients with a positive anti-JCV antibody above 0.9 only when there is a “…reasonable chance of benefit compared with the low but serious risk of PML” (Level C) - Ocrelizumab should be offered to people with PPMS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits (Level B) - DMTs should not be initiated during pregnancy unless the potential benefits of treating MS outweigh the potential risks to the fetus during pregnancy (Level B) See guidelines for switching and stopping recommendations

Table 4. Treatment Guideline Recommendations for Multiple Sclerosis in Adults Professional Organization Recommendations and Guideline European Committee of - Interferon or glatiramer acetate is strongly recommended for patients with CIS Treatment and Research and an abnormal MRI with lesions suggestive of MS who do not fulfil criteria for in Multiple MS Sclerosis/European - Early treatment with DMTs is strongly recommended for patients with active Academy of Neurology RRMS (ECTRIMS/EAN) - For active RRMS, selection of available agents (interferon beta-1b, interferon beta-1a [SQ or IM], peginterferon beta-1a, glatiramer acetate, teriflunomide, Guideline on the dimethyl fumarate, cladribine, fingolimod, daclizumab, natalizumab, pharmacological ocrelizumab and alemtuzumab) depends on patient characteristics and treatment of people with comorbidities, disease severity/activity, drug safety profile, accessibility to multiple sclerosis, 201844 therapy (consensus statement – evidence is insufficient to support a formal recommendation) - For active SPMS, interferon beta-1a (SQ), interferon beta-1b, mitoxantrone, ocrelizumab, or cladribine may be considered (weak recommendation) - For PPMS, ocrelizumab may be considered (weak recommendation) - A more efficacious drug should be offered to patients treated with interferon or glatiramer acetate who show evidence of disease activity. Selection of switching therapy should be based on patient characteristics and comorbidities, disease severity/activity, and drug safety profile (consensus statement – evidence is insufficient) - DMTs are not approved during pregnancy, except glatiramer acetate 20 mg/ml (consensus statement – evidence is insufficient) - For women planning a pregnancy and a high risk of disease reactivation, IFN or GA may be considered until pregnancy is confirmed. In some cases, continuing this DMT during pregnancy may be considered (weak recommendation) - For women with highly active disease who decide to become pregnant or have an unplanned pregnancy, natalizumab or alemtuzumab (with an interval of 4 months from the last infusion until conception) may be considered (weak recommendation) National Institute for - Alemtuzumab is recommended as an option, within its marketing authorization, Health and Care for treating adults with active RRMS. Excellence - Ocrelizumab is recommended for treating RRMS in adults with active disease (Recommendations are defined by clinical or imaging measures, only if alemtuzumab is contraindicated based on costs) or unsuitable (based on cost-effectiveness estimates) - Cladribine tablets are recommended for treating highly active MS in adults, only Disease-modifying if the person has: 1) rapidly evolving severe RRMS, that is, at least 2 relapses in therapies for multiple the previous year and at least 1 T1 gadolinium-enhancing lesion at baseline MRI sclerosis; last updated: 25 or 2) RRMS that has responded inadequately to treatment with DMT, defined as July 201945 1 relapse in the previous year and MRI evidence of disease activity - Dimethyl fumarate is recommended as an option for treating adults with active RRMS, only if the person does not have highly active or rapidly evolving severe RRMS - Interferon beta-1a is recommended for RRMS - Interferon beta-1b (Extavia) is recommended for RRMS if the person has had ≥ 2 relapses within the last 2 years or for SPMS with continuing relapses - Interferon beta-1b (Betaferon) is not recommended for MS, based on cost- effectiveness analyses and because it needs to be reconstituted before use - Glatiramer acetate is recommended for RRMS

Table 4. Treatment Guideline Recommendations for Multiple Sclerosis in Adults Professional Organization Recommendations and Guideline - Fingolimod is recommended as an option for the treatment of highly active RRMS in adults, only if patients have unchanged or increased relapse frequency, or ongoing severe relapses compared to the prior year despite treatment with interferon beta - Natalizumab is recommended for the treatment only of rapidly evolving severe RRMS - Teriflunomide is recommended as an option for treating adults with active RRMS, only if the patients does not have highly active or rapidly evolving severe Abbreviations: DMT, disease modifying therapy; JCV, JC virus or John Cunningham virus; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy; PPMS, primary progressive multiple sclerosis; RRMS; relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; a Levels of recommendation strength: • Level A (Strong recommendation): The agent MUST be recommended • Level B (Moderately strong recommendation): The agent SHOULD be recommended • Level C (Weak recommendation): The agent MAY be recommended

Pharmacology & Special Populations Disease modifying therapies have different immune system targets, which aim to decrease central CNS immune-mediated inflammatory processes and myelin damage.31 Mitoxantrone specifically inhibits topoisomerase II and interferes with DNA synthesis, especially in cells that rapidly divide (eg, immune cells).46 Interferons and glatiramer acetate have a pleiotropic immunomodulatory effect in the immune system.46 Dimethyl fumarate and diroximel fumarate are fumaric acid esters with neuroprotective and immunomodulatory effects.47 Teriflunomide and cladribine are cell-specific inhibitors of DNA synthesis that reduce the quantity of lymphocytes.31,46 Natalizumab, fingolimod, and siponimod cause peripheral sequestration of leukocytes reducing the number of immune cells entering the CNS.5,14,16,46 Alemtuzumab and ocrelizumab are monoclonal antibodies that deplete circulating immune cells (eg, T and B lymphocytes).46 Dalfampridine (a non-DMT agent) is a potassium channel blocker that is thought to prolong action potentials in demyelinated axons.3 Table 5 describes the specific mechanism of action of each agent approved for the treatment of MS. Table 6 summarizes select pharmacokinetic parameters for the agents approved for MS.

Table 5. Mechanism of Action of Multiple Sclerosis Agents1-18 Active Agent Brand Name Mechanism of Action Oral Medications Purine antimetabolite with cytotoxic and depletion effects on B and T Cladribine Mavenclad lymphocytes Dalfampridine Ampyra Potassium channel blocker Unknown. The active form (monomethyl fumarate) of dimethyl fumarate is thought to reduce cell damage from oxidative stress by Dimethyl fumarate Tecfidera activating the Nrf2 pathway.4 It is also believed to increase anti- inflammatory activity and block production of pro-inflammatory cytokines31 Unknown. The active form (monomethyl fumarate) of diroximel Diroximel fumarate Vumerity fumarate is thought to reduce cell damage from oxidative stress by activating the Nrf2 pathway18 S1P receptor antagonist that targets S1P receptors 1, 3, 4, and 5 to Fingolimod Gilenya decrease the exit of lymphocytes from lymph nodes5,31 S1P receptor antagonist that targets S1P receptors 1 and 5 to Siponimod Mayzent decrease the exit of lymphocytes from lymph nodes16,31 Teriflunomide Aubagio Pyrimidine synthesis inhibitor that blocks DNA synthesis31 Subcutaneous and Intramuscular Medications Copaxone, Unknown; it is thought to modify immune processes by inducing Glatiramer acetate Glatopa tolerance of myelin-reactive lymphocytes31 Avonex, Interferon beta-1a Unknown; it is thought that interferon beta affects the immune Rebif system by elevating the production of anti-inflammatory cytokine, Betaseron, Interferon beta-1b modifying the traffic of immune cells across the blood-brain barrier, Extavis modulating the “antigen-presenting function of dendritic cells,” and Peginterferon beta-1a Plegridy promoting the anti-inflammatory function of B cells31,46 Intravenous Medications CD52-directed cytolytic monoclonal antibody that depletes circulating Alemtuzumab Lemtrada lymphocytes31 Synthetic antineoplastic that interferes with DNA and RNA and inhibits Mitoxantrone Generic only topoisomerase II Integrin receptor antagonist that inhibits the action of the integrin Natalizumab Tysabri impeding the access of lymphocytes to the brain31 CD20-directed cytolytic monoclonal antibody that specifically depletes Ocrelizumab Ocrevus circulating B-cells31 Abbreviations: Nfr2, nuclear factor (erythroid-derived 2)-like 2; S1P, sphingosine 1-phosphate

A. Oral Medications2-5,16,17 Oral DMTs approved for the treatment of relapsing forms of MS include cladribine, dimethyl fumarate, diroximel fumarate, fingolimod, siponimod, and teriflunomide. Dalfampridine is an oral agent that improves walking in MS patients, and is not a DMT. The recommended maintenance dosing frequency is twice daily for dimethyl fumarate, diroximel fumarate, and dalfampridine and once daily for fingolimod, siponimod, and teriflunomide. Cladribine is administered as 2 treatment courses separated by 43 weeks. Half-lives range from 1 hour with dimethyl fumarate to 19 days with teriflunomide.

Cladribine is not recommended in moderate to severe renal or hepatic impairment. Diroximel fumarate is not recommended in patients with moderate to severe renal impairment. Dalfampridine is

contraindicated in patients with moderate to severe renal impairment and caution should be exercised in patients with mild renal impairment. Teriflunomide is contraindicated in patients with severe hepatic impairment. No dose adjustments are specified for dimethyl fumarate, fingolimod, and siponimod in patients with renal or hepatic impairment.

Regarding drug-drug interactions, cladribine should not be used in combination with immunosuppressive drugs, antiviral and antiretroviral drugs, and breast cancer resistance protein (BCRP) or equilibrative nucleoside transporter (ENT)/concentrative nucleoside transporter (CNT) inhibitors. The use of cladribine with hematotoxic drugs may increase the risk for hematologic adverse events and patients should be monitored.

Dalfampridine should be used with caution when combined with organic cation transporter 2 (OCT2) inhibitors (eg, cimetidine) due to a potential increase of dafampridine plasma concentrations that may increase the risk of seizures.

No drug-drug interactions with dimethyl fumarate are specified in the product labeling. Diroximel fumarate is contraindicated in patients taking dimethyl fumarate because both agents are metabolized to the same active metabolite (monomethyl fumarate).18

Patients receiving fingolimod and systemic ketoconazole should be monitored for an increased risk of adverse events. Live attenuated vaccines should be avoided during and for 2 months after discontinuing fingolimod treatment.

Use of siponimod is not recommended in combination with drugs that are moderate cytochrome P450 (CYP) 2C9 and moderate or strong CYP3A4 inhibitors (eg, fluconazole, a dual inhibitor, or drug combinations that have this effect) or in combination with drugs that are moderate CYP2C9 and strong CYP3A4 inducers (eg, rifampin or carbamazepine). Live attenuated vaccines should be avoided during and for 4 weeks after discontinuing siponimod treatment. Caution should be used when combining siponimod with immunosuppressive or immune-modulating therapies due to the potential risk for additive immunosuppressive effects.

Teriflunomide may interact with other drugs (eg, repaglinide, duloxetine, cefaclor, and rosuvastatin) because it is a CYP2C8 inhibitor, a weak CYP1A2 inducer, an organic anion transporter 3 (OAT3) inhibitor, a BCRP transporter inhibitor, and an organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) inhibitor. Teriflunomide may decrease the international normalized ratio (INR) when used in combination with warfarin. In addition, it may increase the plasma levels of ethinylestradiol and levonorgestrel when used concomitantly.

B. Subcutaneous and Intramuscular Medications6-12 Glatiramer acetate, interferon beta-1a (Rebif), interferon beta-1b (Betaseron and Extavia), and peginterferon beta-1a are administered subcutaneously. Interferon beta-1a (Avonex) is administered by intramuscular injection. The recommended maintenance dosing frequency is once daily or 3 times weekly for glatiramer, once weekly for Avonex, 3 times weekly for Rebif, every other day for Betaseron and Extavia, and every 14 days for peginterferon. Half-lives range from 8 minutes with interferon beta-1b to 78 hours with peginterferon. The pegylated form of interferon beta-1a (peginterferon) has a higher apparent mass compared to interferon beta-1a, contributing to its reduced clearance and longer half-life.12

No dose adjustments are recommended for glatiramer acetate or interferon beta formulations in patients with renal or hepatic impairment. No significant drug-drug interactions are specified in the prescribing information for glatiramer acetate and interferon beta products. C. Intravenous Medications1,13-15 Alemtuzumab, mitoxantrone, natalizumab, ocrelizumab are administered by intravenous infusion. The recommended maintenance dosing frequency is every 4 weeks for natalizumab, every 3 months for mitoxantrone, and every 6 months for ocrelizumab. Alemtuzumab is administered as 2 or more treatment courses separated by 12 months. Half-lives range from 75 hours with mitoxantrone to 26 days with ocrelizumab.

Mitoxantrone should not be used in patients with MS and hepatic impairment. Renal and hepatic dose adjustments are not necessary or not specified for alemtuzumab, natalizumab, and ocrelizumab.

There is limited information concerning drug-drug interactions with mitoxantrone. It is thought that mitoxantrone is a weak inducer of CYP450 2E1 enzyme. Natalizumab should not be used in combination with immunosuppressants or immune-modulating therapies. Caution should be exercised when combining ocrelizumab with immunosuppressive or immune-modulating therapies due to the potential risk for additive immunosuppressive effects. Ocrelizumab may decrease the efficacy of non-live vaccines when administered in combination; though its effect on the response to live or live-attenuated vaccines has not been evaluated.

Pregnancy and Fertility Concerns

Regarding use of DMTs during pregnancy, the 2018 AAN guideline states that DMTs should not be initiated during pregnancy unless the potential benefits of treating MS outweigh the potential risks to the fetus during pregnancy.19 DMTs differ in the degree of pregnancy risks; reproductive plans of women should be considered when selecting a DMT.19 Preclinical studies have shown fetal malformations with teriflunomide, fingolimod, dimethyl fumarate, and diroximel fumarate; embryotoxicity with alemtuzumab and teriflunomide; teratogenicity with cladribine and teriflunomide; and increased perinatal mortality with ocrelizumab.46 Mitoxantrone is a potential human teratogen and is not recommended during pregnancy.13 FDA package inserts specifically contraindicate cladribine and teriflunomide during pregnancy and in women of childbearing potential who do not take appropriate contraceptive precautions.2,17 Natalizumab may cause fetal harm based in animal data (fetal immunologic and hematologic effects) and may require discontinuation due to pregnancy planning.14,19 Although the use of interferon beta formulations during pregnancy are not associated with major birth defects based on animal data, this risk cannot be ruled out in humans and package inserts note potential fetal harm.8-12,46 No adverse effects during animal fetal development have been reported with glatiramer acetate although this agent should be used during pregnancy only if clearly necessary, according to the FDA product labeling.6,7,46 Specific FDA-labeled recommendations for pregnancy and breastfeeding are included in Table 7.

Regarding fertility, mitoxantrone may cause ovarian failure and male infertility. Teriflunomide reduced epididymal sperm count in animal studies.17,19

Table 6. Pharmacokinetic Parameters1-17 Active Agent Tmax Terminal Half-Life Maintenance Dosing Frequency

Metabolism Oral Medications

Cladribine 0.5 h 24 hours 2 courses of 1.73 mg/kg per dose, separated by 43 weeks; each course is divided into 2 cycles separated by 23 to 27 days 5.2 to 6.5 h Dalfampridine 3-4 h Twice daily Mainly via CYP2E1

Dimethyl 2 to 2.5 h 1 h (for MMF) Twice daily (for MMF) fumarate Esterases convert drug to active metabolite (MMF); tricarboxylic acid involved in metabolism of MMF (CYP system not involved)

Diroximel 2.5-3 h 1 h (for MMF) Twice daily fumarate (for MMF) Esterases convert drug to active metabolite (MMF); tricarboxylic acid involved in metabolism of MMF (CYP system not involved)

Fingolimod 12 to 16 h 6 to 9 days Once daily Phosphorylation, oxidation (mainly by the CYP 4F2 and other CYP4F isoenzymes), CYP3A4 may also be involved

Siponimod 4 h (range 30 h Once daily 3 to 8) Mainly via CYP2C9 (79.3%), and by CYP3A4 (18.5%)

Teriflunomide 1 to 4 h Median half-life was 18 and 19 days, Once daily respective to each dose CYP P450 and flavin monoamine oxidase enzymes Subcutaneous and Intramuscular Medications Glatiramer NR NR Once daily, or three times weekly acetate depending on the strength used

Avonex: Avonex: Avonex: once weekly Interferon beta- 15 h 1a Rebif: 69 h Rebif: three times weekly Rebif: NR 16 h

Interferon beta- NR 8 minutes to 4.3 h Every other day 1b NR

Table 6. Pharmacokinetic Parameters1-17 Active Agent Tmax Terminal Half-Life Maintenance Dosing Frequency

Metabolism

Peginterferon NR 78 h Every 14 days beta-1a Renally eliminated, primarily

Intravenous Medications

st Alemtuzumab Day 5 of 1 2 weeks 2 or more treatment courses: course and initial course on 5 consecutive NR day 3 of days; following courses on 3 2nd course consecutive days, 12 months after last dose of any proceeding course

Mitoxantrone NR 75 h (23 to 215 range) Every 3 months Unknown

Natalizumab NR 11 days Every 4 weeks Primarily by catabolism

Ocrelizumab NR 26 days Infusions at week 0 and 2, then every 6 months Primarily by catabolism Abbreviations: CYP, cytochrome P450; DR, delayed release; h, hour(s); IM, intramuscular; MMF, monomethyl fumarate; NR, not reported; SQ, subcutaneous; XR, extended release

Table 7 summarizes select special population considerations for the agents approved for MS.

Table 7. Special Population Considerations1-17 Generic Name Pregnancy Dose adjustments Pediatric Use Brand Name Breast feeding Dose adjustments not Pregnancy: may cause fetal harm; women of Safety and Alemtuzumab specified childbearing potential should use effective effectiveness birth control during is not and for 4 months after a treatment course established in patients <17 Lactation: lack of data on potential excretion years of age into human milk; drug was excreted into mice milk and was shown to decrease lymphocytes in offspring No dose adjustment Pregnancy: Contraindicated; last dose Safety and Cladribine needed with mild renal or should be taken at least 6 months before effectiveness hepatic impairment. Not going without use of effective contraception is not recommended in in persons with reproductive potential established; moderate to severe renal not Lactation: Contraindicated; animal studies or hepatic impairment recommended showed harm (eg, abnormal skeletal due to the risk development) in off-spring of malignancies

Table 7. Special Population Considerations1-17 Generic Name Pregnancy Dose adjustments Pediatric Use Brand Name Breast feeding Contraindicated in Pregnancy: may cause fetal harm based on patients with moderate or Safety and animal data severe renal impairment. effectiveness Dalfampridine Consider risk-benefits in is not Lactation: unknown whether drug passes patients with mild renal established into human milk impairment Hepatic or renal Pregnancy: may cause fetal harm based on Safety and Dimethyl impairment are not animal data effectiveness fumarate expected to affect is not Lactation: lack of data on the presence of exposure; thus, no dose established the drug or its active metabolite in human adjustments are necessary milk Not recommended in Pregnancy: may cause fetal harm based on Safety and Diroximel moderate to severe renal animal data effectiveness fumarate impairment. No dose is not Lactation: lack of data on the presence of adjustment needed with established the drug or its active metabolite in human mild renal impairment. milk Hepatic impairment is not expected to affect exposure Renal dose adjustments Pregnancy: May cause fetal harm based on Indicated for Fingolimod are not necessary animal studies; it takes about 2 months to patients ≥10 No dose adjustment is eliminate the drug. Patients with years of age needed in mild or childbearing potential should use effective for treatment moderate hepatic contraception to avoid pregnancy during of relapsing impairment; patients with and for 2 months after stopping treatment forms of severe impairment should multiple be closely monitored but Lactation: lack of data about the presence of sclerosis dose adjustments are not the drug or its active metabolite in human specified milk; drug is excreted into rat milk Effects of renal or hepatic Pregnancy: no adequate and well-controlled Safety and Glatiramer impairment on drug PK studies in pregnant women; studies in rats effectiveness acetate have not been determined and rabbits did not show adverse effects on is not offspring development established

Lactation: unknown whether drug passes into milk Effects of renal or hepatic Pregnancy: based on animal data, may cause Safety and Interferon impairment on the PK fetal harm effectiveness beta-1a have not been determined is not Lactation: unknown whether drug passes established into milk No doses adjustments Pregnancy: the majority of the observational Safety and Interferon specified for renal or studies did not identify an association with effectiveness beta-1b hepatic impairment major birth defects; however, studies in is not monkeys showed harm at doses >3 times established the expected human exposure Lactation: unknown whether drug passes into milk

Table 7. Special Population Considerations1-17 Generic Name Pregnancy Dose adjustments Pediatric Use Brand Name Breast feeding Drug PK in renal Pregnancy: potential teratogen; not Safety and Mitoxantrone impairment is unknown recommended during pregnancy since it effectiveness may cause fetal harm; use effective birth is not Patients with MS and control while taking the drug established hepatic impairment should ordinarily not be treated Lactation: should avoid while taking with mitoxantrone medication since the drug is excreted in high amounts into human milk Drug PK in renal or hepatic Pregnancy: based on animal data, may cause Safety and Natalizumab insufficiency has not been fetal harm effectiveness studied is not Lactation: detected in milk of monkeys; established however, the risk to offspring is unclear Dose adjustments not Pregnancy: based on animal data, may cause Safety and Ocrelizumab necessary in mild renal or fetal harm effectiveness hepatic impairment; effect is not of more severe Lactation: detected in human milk; however, established impairment on drug PK the risk to child is unclear has not been studied Renal or hepatic dose Pregnancy: based on animal data, may cause Safety and Peginterferon adjustments are not fetal harm effectiveness beta-1a specified; however, should is not monitor for adverse Lactation: unknown whether drug passes established reactions due to increased into milk drug exposure during severe renal impairment No dose adjustment Pregnancy: May cause fetal harm based on Safety and Siponimod needed with renal or animal studies. Patients with childbearing effectiveness hepatic impairment potential should use effective contraception is not to avoid pregnancy during and for 10 days established after stopping treatment.

Lactation: lack of data on potential excretion into human milk; drug is excreted into rat milk and was shown to cause harm

Contraindicated with Pregnancy: Contraindicated in patients of Safety and Teriflunomide severe hepatic childbearing potential not taking effective effectiveness impairment; no dose contraception; caused teratogenicity and is not adjustments are needed embryolethality in animal models at doses established with mild/moderate below the maximum recommended dosage hepatic or mild to severe Lactation: lack of data on potential excretion renal impairment into human milk; drug is excreted into rat milk and was shown to cause harm Abbreviations: MS, multiple sclerosis; PK, pharmacokinetics

Direct Comparative Evidence The literature search for systematic reviews identified 871 unique records, of which 9 SRs with head-to- head RCTs in RRMS met inclusion criteria for the qualitative synthesis. In addition, 2 analyses from phase 3 RCTs were identified. Most RCTs included adult patients with RRMS, were 2 years in duration, and compared a DMT versus interferon beta.1 In the pediatric population, there was only one study comparing IFN beta versus fingolimod. No head-to-head studies were identified for patients with CIS, SPMS, and PPMS. Figure 1 shows the PRISMA flow diagram for the review process.

Figure 1. PRISMA Flow Chart for Publication Screening

• Records identified in Ovid Medline: 181 SRs, 288 RCTs • Records identified in Embase: 302 SRs, 496 RCTs

Identification

Records after duplicates removed (356 SRs and 515 RCTs)

Screening Records excluded Records screened (871) (797)

Full-text articles excluded, Full-text articles assessed for with reasons eligibility (63) Eligibility (74) Wrong study design (27) More recent or more robust SR available (20) Duplicates (9) Publications included in qualitative Wrong comparator (5) Wrong intervention (1) synthesis

Included Data unavailable (1) (11 publications: 9 SRs and 2 analyses from phase 3 RCTs)

Abbreviations: RCT, randomized controlled trials; SRs, systematic reviews

To compare the efficacy of DMTs in patients with RRMS, several endpoints measuring disease activity (relapses and magnetic resonance imaging [MRI] lesions) and disease progression were used in clinical trials. These include 1) the annualized relapse rate (ARR; the average number of confirmed relapses during the treatment period per patient-year);19,48 2) the proportion of patients with at least 1 relapse at a specific time point (eg, over 1 or 2 years); 3) the mean difference in volume or number of gadolinium- enhancing lesions or new or enlarging T2 lesions assessed by MRI; 4) the proportion of patients with

new or enlarging T2 lesions on MRI; 5) brain atrophy measures (eg, changes in brain volume on MRI from baseline); and 6) the disability progression rate (ie, the proportion of patients with disability progression, defined as “…an increase in the Expanded Disability Status Scale (EDSS) of 1 point in those with a baseline EDSS less than or equal to 5.0, or an increase of 0.5 points in those with a baseline EDSS 5.5 or greater, sustained for 3 or 6 months, which was detected over a 2-year study period”).19,28 Head-to-head evidence was primarily extracted from the full 2018 AAN practice guideline developed by Rae-Grant et al and the systematic review supporting guideline recommendations.19,23 Additional systematic reviews and RCTs identified in the literature search were also summarized for each comparison.21,26,44,49,50 Appendix C includes the efficacy and safety results from SRs. Appendix D describes which RCTs were located in each included SR.

Figure 2. Systematic Reviews Included to Describe the Comparative Efficacy Among Disease-Modifying Agents Indication and Population Systematic reviews

FIN vs. IFN beta: Rae-Grant 2018

TER vs. IFN beta: Montalban 2018

IFN vs. IFN beta Relapsing-Remitting : Multiple Sclerosis - Rae-Grant 2018 Adults Melendez-Torres 2018

GA vs. IFN beta: Rae-Grant 2018 Montalban 2018 Comparative La Mantia 2016 Evidence for Multiple Sclerosis ALE vs. IFN beta: Rae-Grant 2018 Montalban 2018 Lucchetta 2018 Zhang 2017

OCR vs. IFN beta: Rae-Grant 2018 Montalban 2018 Lucchetta 2018

Relapsing-Remitting Multiple Sclerosis - Pediatrics FIN vs. IFN beta: Krupp 2019

Abbreviations: ALE, alemtuzumab; FIN, fingolimob; GA, glatiramer acetate; IFN, interferon; OCR, ocrelizumab; TER, teriflunomide

Adult Population with Relapsing Forms of Multiple Sclerosis

1. Oral Disease Modifying Therapies (Cladribine, Dimethyl Fumarate, Fingolimod, Siponimod, Teriflunomide)

Head-to-head evidence was available for fingolimod or teriflunomide versus interferon beta. No head- to-head RCTs comparing the different oral DMTs or comparing cladribine, dimethyl fumarate, or siponimod versus other DMTs were identified.

Fingolimod (Gilenya) versus Intramuscular Interferon Beta-1a (Avonex)

One head-to-head RCT (TRANSFORMS study) conducted by Cohen et al (2010)51 was obtained from the Rae-Grant 2018 SR. AAN guideline authors reported that fingolimob was significantly more effective compared to IM IFN beta-1a (30 µg weekly) in decreasing the proportion of people with at least 1 relapse at 12 months and annualized relapse rates (ARRs) in adults with RRMS.19 Confidence in this evidence was graded as ‘high’ by AAN guideline authors.19 Regarding MRI disease activity, fingolimod was more efficacious than interferon at decreasing the proportion of patients with new or enlarged T2 lesions at 12 months. Confidence in the evidence was graded as ‘moderate’.19 In terms of disability progression over 1 year, no between-group differences were reported; however, confidence in evidence was graded as ‘low’.19

Teriflunomide (Aubagio) versus Subcutaneous Interferon Beta-1a (Rebif)

The ECTRIMS/EAN guideline on the treatment of MS reported a 48-week RCT comparing teriflunomide 7 mg or 14 mg once daily versus SQ IFN beta-1a 44 µg (3 times weekly) in adult patients with relapsing forms of MS (Vermersch 2014 - TENERE study).44,52 Results showed no difference between either dose of teriflunomide and interferon for the primary composite endpoint of time to failure (ie, “first occurrence of confirmed relapse or permanent treatment discontinuation for any cause”). The percentage of patients failing treatment at week 48 was 37% for the IFN beta group, 36% for the teriflunomide 7 mg group, and 33% for the teriflunomide 14 mg group. Treatment failure was driven by treatment discontinuation rates in the IFN group, however, the number of confirmed relapses was lowest for the IFN group.52 Regarding the secondary endpoint of ARR, no difference was found between teriflunomide 14 mg and interferon; however, AAR was significantly greater in patients receiving teriflunomide 7 mg compared to interferon. Disability worsening was not measured.52 ECTRIMS/EAN guideline authors reported a significantly greater proportion of patients who were relapse free at week 48 with interferon compared to teriflunomide and a small between-group difference in terms of ARR at 48 weeks, based on low-quality evidence (TENERE study).44

2. Subcutaneous and Intramuscular Disease Modifying Therapies (Glatiramer Acetate, Interferon Beta Formulations, and Peginterferon Beta)

Evidence was identified comparing different formulations of interferon beta versus each other as well as glatiramer acetate versus interferon beta products; however, none involve comparison with peginterferon.

Intramuscular IFN beta-1a 30 µg (Avonex) vs. Subcutaneous IFN Beta-1a 44 µg (Rebif)

Rae-Grant et al (2018) included an RCT conducted by Panitch et al (EVIDENCE trial, 2002).53 This 48-week trial showed a significantly lower risk of relapses and new or enlarging T2-weighted lesions at year 1

with SQ IFN beta-1a 44 µg 3 times weekly compared to IM IFN beta-1a 30 µg weekly in adult patients with confirmed relapsing MS. Confidence in this evidence was graded as ‘moderate’ by AAN guideline authors.19 Specific outcomes measuring clinical relapses included number of patients relapse free, ARR, and time to first relapse. Results were significantly better with SQ IFN beta compared to IM IFN beta for each of these clinical relapse measures.54 Regarding time to progression confirmed at 3 and 6 months, no difference between groups was found; however, the study was not designed to identify differences for this specific outcome.53,54

The ECTRIMS/EAN guideline on the treatment of MS reported an RCT (Calabrese 2012) that compared glatiramer acetate vs. IFN-beta 1a 44 µg SQ vs. IM IFN-beta 1a 30 µg in patients with RRMS. This study was a 2-year, prospective, single-center, phase 4, randomized pilot study showing a significantly lower number of patients with new cortical lesions with SQ IFN-beta 1a compared to IM IFN-beta 1a at month 12 and 24.

Melendez-Torres et al (2018) conducted a meta-analysis (MA) comparing IM IFN beta-1a 30 µg once weekly vs. SQ IFN beta-1a 44 µg 3 times weekly in patients with RRMS. This MA included 3 RCTs (Calabrese 2012, EVIDENCE 2007, and Etemadifar 200654-56) and found no significant differences between groups in reducing ARR, with a trend toward favoring the subcutaneous IFN formulation.50 Results from 2 of the individual studies (Calabrese 2012 and EVIDENCE 2017) are described above. The third study, Etemadifar 2006, is a single-blinded RCT that showed significantly greater improvements with SQ IFN beta-1a 44 µg 3 times weekly compared to IM IFN beta-1a 30 µg once weekly in terms of the number of relapse-free patients and EDSS disability progression over 2 years.56 Intramuscular IFN beta-1a 30 µg (Avonex) vs. Subcutaneous IFN Beta-1b 250 µg (Betaseron)

Melendez-Torres et al (2018) performed a meta-analysis comparing IM IFN beta-1a 30 µg once weekly vs. SQ IFN beta-1b 250 µg every other day in RRMS patients. This MA included 2 RCTs (Durelli 2002 [INCOMIN study57] and Etemadifar 200656) and showed no differences in ARR between treatment groups. Additionally, the primary study, Etemadifar 2006, showed significantly greater improvements with SQ IFN beta-1b compared to IM IFN beta-1a in terms of the number of relapse-free patients and disability progression (as shown by EDSS score) over 2 years.56 The INCOMIN study demonstrated a significantly better response with the SQ formulation compared to the IM formulation regarding the number of patients free from relapses, number of patients without new T2 MRI lesions, and time to disease progression over 2 years.57

Subcutaneous IFN beta-1b 250 µg (Betaseron) vs. Subcutaneous IFN Beta-1a 44 µg (Rebif)

The MA by Melendez-Torres et al (2018) included 2 RCTs (Etemadifar 2006 and Singer 2012 [REFORMS study]58) that compared SQ IFN beta-1b 250 µg every other day vs. SQ IFN beta-1a 44 µg 3 times weekly in patients with RRMS. This MA showed no between-group differences regarding ARRs.50 The primary study, Etemadifar 2006, demonstrated no differences in terms of EDSS score and relapse rate at 24 months. The REFORMS study was designed to assess comparative safety but not efficacy.

Glatiramer Acetate versus Interferon Beta

Rae-Grant et al (2018)19 and Melendez-Torres (2018)50 identified 4 RCTs comparing glatiramer acetate 20 mg daily versus different formulations of interferon beta in patients with RRMS (Cadavid 2009, O’Connor 2009, Lublin 2013, and Mikol 2008). Below is a summary of the results for each comparison:

• Glatiramer Acetate versus SQ Interferon Beta-1b 250 µg (Betaseron) Two RCTs (Cadavid 2009 [BECOME study]59 and O’Connor 2009 [BEYOND study]60) compared glatiramer acetate 20 mg daily versus SQ IFN beta-1b 250 µg every other day in patients with RRMS. A meta- analysis of both RCTs reported no differences in terms of the proportion of patients with at least 1 relapse at 2 years.19 Confidence in this evidence was graded as ‘low’ by AAN guideline authors. Similarly, the MA of Melendez-Torres et al found no differences between groups for the endpoint of ARR.50 The BEYOND study demonstrated a significantly higher number of patients with confirmed disability progression over 2 years in the interferon group compared with glatiramer group; confidence in this evidence was graded as ‘moderate’ by AAN guideline authors.19

• Glatiramer Acetate versus SQ Interferon Beta-1a 44 µg (Rebif) Mikol et al (2008) conducted an RCT (REGARD study)61 in patients with RRMS to compare glatiramer acetate 20 mg daily with SQ IFN beta-1a 44 µg 3 times weekly. AAN guideline authors reported no between-group differences with respect to the proportion of patients with at least 1 relapse at 2 years and the proportion of patients with active T2 lesions on MRI at 2 years. Confidence in evidence was graded as ‘low’ by AAN guideline authors.19

The ECTRIMS/EAN guideline on the treatment of MS reported an RCT (Calabrese 2012) showing no significant differences between glatiramer acetate and SQ IFN beta 1a 44 µg at month 12 and 24 regarding the number of patients with new cortical lesions.55

The MA of Melendez-Torres et al included 2 RCTs (Calabrese 2012 and REGARD 2008) and found no differences between groups for the endpoint of ARR.50

• Glatiramer Acetate versus IM Interferon Beta-1a 30 µg (Avonex)

Lublin et al (2013) performed an RCT (CombixRx study62) in patients with RRMS. Glatiramer acetate 20 mg daily significantly reduced ARR at 36 months (primary endpoint) compared to IM IFN beta-1a 30 µg; however, no differences were reported in time to first exacerbation and percentage of patients with relapses at 36 months. For the endpoints of disease progression in EDSS at 6 months and MRI disease activity at month 36, similar results were reported between groups.62 AAN guideline authors reported no differences between glatiramer acetate and IM IFN beta-1a 30 µg once weekly in terms of the proportion of people with at least 1 relapse over 3 years and the proportion of patients with disability progression on EDSS over 3 years. Confidence in evidence was graded as ‘low’ by AAN guideline authors.19 The MA by Melendez-Torres et al included 2 RCTs (CombiRx and Calabrese 2012) and found no significant differences between groups for ARR (using random effects model to report a rate ratio); though the trend favored glatiramer acetate.50 Another MA conducted by Lucchetta et al (2018) included the same studies and showed a significantly greater reduction in the ARR with glatiramer compared to IM IFN (using the Poisson method to report a hazard ratio).21 Glatiramer Acetate versus Interferon Beta (All Non-Pegylated Formulations Combined)

The ECTRIMS/EAN guideline on the treatment of MS reported the results of several MAs comparing interferon betas altogether (excluding the pegylated form) versus glatiramer acetate. Results from 4 RCTs (Cadavid 2009, O’Connors 2009, Mikol 2008, and Calabrese 2012) were combined depending on the endpoints assessed. Based on low- to moderate-quality evidence, no significant differences were

found for all endpoints evaluated (ie, number of patients relapse free at 96-104 weeks, ARR at 96-104 weeks, new T2 white matter lesion at 104 weeks, number of new gadolinium lesions at 104 weeks, number of new cortical lesions at 48 weeks, discontinuations due to any reason at 48 and 96- 106 weeks, discontinuations due to adverse events at 48 and 96-104 weeks).44

The Cochrane review conducted by La Mantia 2016 included 5 RCTs (Cadavid 2009, O’Connors 2009, Mikol 2008, Lublin 2013, and Calabrese 2012) in their MAs.49 The main objective was to compare glatiramer acetate versus interferon beta at high frequencies and dosages (data for the comparison of glatiramer versus IM interferon beta was limited). Authors concluded that interferon beta formulations seem to be similarly efficacious to glatiramer acetate regarding the number of participants with relapse, risk of confirmed progression, time to first relapse, and number of patients treated with steroids.49 Evidence from only 1 study (Lublin 2013) showed a significantly lower relapse rate at 36 months with glatiramer acetate 20 mg daily compared to IM IFN beta-1a 30 µg weekly.49 Regarding MRI measures, no differences were reported in terms of new/enlarging T2 lesions or gadolinium-enhancing lesions at 24 months. Similar safety outcomes (eg, discontinuations due to adverse events) were reported between groups.49

3. Intravenous Disease Modifying Therapies (Alemtuzumab, Mitoxantrone, Natalizumab, and Ocrelizumab)

Evidence is only available for alemtuzumab or ocrelizumab versus SQ IFN beta-1a dosed 3 times weekly (Rebif). No head-to-head comparisons were identified for intravenous DMTs versus each other or versus other DMTs different from IFN.

Alemtuzumab (Lemtrada) versus Subcutaneous Interferon Beta-1a (Rebif)

Several SRs comparing alemtuzumab 12 mg with SQ IFN beta-1a 44 µg (3 times per week) in patients with RRMS were identified (Rae-Grant 2018, Montalban 2018, and Lucchetta 2018).19,21,44 Three head- to-head RCTs were obtained from these SRs: Coles 2008 (CAMMS223),63 Cohen 2012 (CARE-MS I),64 and Coles 2012 (CARE-MS II).65

Rae-Grant et al (2018) performed an SR to support the new 2018 AAN guideline recommendations on DMTs for the treatment of MS.19,23 A meta-analysis of 2 studies (CARE-MS I in treatment-naïve patients and CARE-MS II in patients who had an inadequate response to prior therapy) demonstrated alemtuzumab was significantly more effective compared to SQ IFN beta-1a 44 µg 3 times per week at decreasing the ARR and the patient proportion with at least 1 relapse at 2 years.19,23 Confidence in the evidence was graded as ‘high’ by AAN guideline authors. With respect to MRI disease activity, the CARE- MS I study demonstrated alemtuzumab was significantly more effective than IFN beta-1a (44 µg SQ 3 times weekly) at decreasing T2 lesion volume from baseline to 2 years and reducing the percentage of patients with new or enlarging T2 lesions at 2 years. In addition, the CARE-MS II study showed better efficacy with alemtuzumab compared to interferon at reducing brain volume loss, as measured by changes in brain volume on T1 from baseline to year 3. Confidence in the aforementioned evidence was graded as ‘moderate’ by AAN guideline authors. The CARE-MS II study showed no differences between groups when measuring the T2 lesion volume from baseline to 3 years; however, the confidence in evidence was graded as ‘very low’ by authors.19 Regarding disability progression, a meta-analysis of CARE-MS I and CARE-MS II studies showed alemtuzumab was more efficacious than SQ interferon at decreasing the proportion of patients with disability progression over 2 years. In the CARE-MS I study,

alemtuzumab significantly increased the proportion of patients with confirmed disability improvement at 2 years, as measured by the Expanded Disability Status Scale (EDSS).19 Confidence in the evidence was graded as ‘high’ by AAN guideline authors.19

The ECTRIMS/EAN guideline on the treatment of MS reported results of MAs combining the 3 RCTs available for alemtuzumab 12 mg vs. interferon (Coles 2008 [CAMMS223 phase 2 trial],63 Cohen 2012 [CARE-MS I phase 3 trial],64 and Coles 2012 [CARE-MS II phase 3 trial]). Alemtuzumab 12 mg was significantly better than SQ interferon in terms of number of patients relapse free at 104-156 weeks (MA of 3 RCTs) and 260 weeks (1 RCT), disability progression at 104-156 weeks (MA of 3 RCTs) and 260 weeks (1 RCT), and ARR at 2 to 3 years (MA of 2 RCTs). A significantly lower number of patients receiving alemtuzumab discontinued treatment for any reason or due to adverse events compared to interferon. MA of 2 RCTs regarding MRI measures indicated high heterogeneity. Individual studies showed fewer patients with new or enlarging T2 lesions in the group receiving alemtuzumab compared to the group treated with interferon; differences were significant in 1 RCT (Coles 2012) but not in the other (Cohen 2012).44 Lucchetta 2018 reported similar results regarding ARRs, confirmed disability progression at 6 months, and discontinuations due to adverse events.21

Zhang et al (2017) conducted a MA of 3 RCTs (CARE-MS I, CARE-MS II and CAMMS223) comparing alemtuzumab 12 mg/day and SQ IFN beta-1a 44 µg 3 times per week in patients with RRMS. Alemtuzumab was significantly more efficacious than IFN at reducing the risk of relapse (moderate quality evidence), the risk of worsening disability (low-quality evidence), and the risk of developing new T2 MRI lesions (low-quality evidence) after 24 and 36 months of treatment.66

An analysis of quality of life (QoL) outcomes in the phase 3 trials with alemtuzumab (CARE-MS I and CARE- MS II) was performed.67 QoL, as measured by different questionnaires, was significantly improved with alemtuzumab compared to SQ IFN beta-1a 44 µg. Improvements were observed at month 6 (first post- baseline assessment) and maintained till the end of study (2 years).67

Ocrelizumab versus Subcutaneous Interferon Beta-1a

Several SRs (Rae-Grant 2018, Montalban 2018, and Lucchetta 2018)19,21,44 identified 2 phase 3 RCTs (OPERA I and OPERA II68) comparing ocrelizumab 600 mg IV with SQ IFN beta-1a 44 µg (3 times per week) in patients with RRMS. Rae-Grant et al reported that ocrelizumab was significantly more efficacious than interferon for preventing relapses, reducing MRI disease activity, and decreasing the risk of disability progression, as measured by the ARR at 96 weeks, the proportion of patients with new or enlarging T2 lesions on MRI at 2 years, changes in brain volume on MRI from week 24 to 96, and disability progression confirmed at 3 and 6 months over 2 years.19 Confidence in the evidence was graded as ‘high’ by AAN guideline authors.19 Regarding the proportion of patients with disability improvement confirmed at 3 months, no differences were reported between groups; confidence in the evidence was graded as ‘low’ by AAN guideline authors.19 ECTRIMS/EAN guideline authors (Montalban et al) performed MAs of the 2 RCTs and reported similar results as Rae-Grant et al for the ARR outcome. With respect to the proportion of patients with disability improvement confirmed at 3 and 6 months, ocrelizumab was significantly better than interferon.

The MA by Lucchetta et al (2018), with 3 RCTs (a phase 2 RCT [Kappos 2011] and 2 phase 3 RCTs [OPERA I and OPERA II]), resulted in similar findings as Rae-Grant, favoring ocrelizumab for the ARR outcome and for confirmed disability progression at 3 and 6 months.21

Subgroup analyses from the pooled OPERA I and OPERA II populations were reported by Turner et al (2019).69 Pre-specified subgroups included: study (OPERA I vs. OPERA II), age (<40 vs. ≥40 years), sex, BMI, region, baseline EDDSS score, baseline gadolinium-enhancing T1 lesion status (0 vs. ≥1), and pre- treated patients with active disease (“pre-treated for ≥1 year with either ≥1 relapse in the year prior to randomization or ≥1 baseline T1 gadolinium-enhancing lesion”) or highly active disease (“≥1 relapse in the year prior to randomization and ≥9 T2 lesions or ≥1 T1 gadolinium-enhancing lesion at baseline”). Ocrelizumab remained significantly better than SQ IFN beta-1a 44 µg (3 times per week) in terms of ARR, disability progression, and MRI outcomes for most of the subgroups. For the subgroup of patients pre- treated with active or highly active disease, ocrelizumab compared to IFN significantly reduced ARR, T1 gadolinium-enhancing lesions, new or enlarging T2 lesions, and confirmed disability progression at 12 weeks (no significant differences at 24 weeks).69 Pediatric Population with Relapsing Forms of Multiple Sclerosis Fingolimod versus Intramuscular Interferon Beta-1a

Fingolimod is the only DMT approved for the treatment of pediatric patients with MS. A 2-year phase 3 RCT (PARADIGMS study70) was reported in an SR conducted by Krupp et al (2019).26 This RCT compared fingolimod 0.5 mg daily (0.25 mg daily for patients with body weight ≤40 kg) versus IM IFN beta-1a 30 µg once weekly in patients 10 to 17 years with relapsing MS. Fingolimod significantly reduced relapses and new or enlarged T2 MRI lesions at 2 years compared to IFN; however, more patients experienced serious adverse events with fingolimod (18 patients) versus IFN (7 patients).70

Safety Safety profiles differ among MS agents. The self-injectable medications, glatiramer acetate, beta interferons, and beta peg-interferon, do not carry any black box warning (BBW). Interferon beta products are associated with injection-site reactions (eg, inflammation and pain), influenza-like symptoms, depression, liver function abnormalities, and lymphopenia. Glatiramer acetate is primarily associated with injection-site reactions and chest pain. Among the oral medications, dalfampridine, dimethyl fumarate, diroximel fumarate, fingolimod, and siponimod do not carry a black box warning. Cladribine has a BBW concerning the risk of malignancy and teratogenicity associated with the use of this drug. Teriflunomide has a BBW regarding hepatotoxicity and embryofetal toxicity. Among the intravenously infused medications, alemtuzumab, mitoxantrone, and natalizumab carry serious risks and have BBWs in the prescribing information (autoimmune conditions, infusion reaction, stroke, and malignancies for alemtuzumab; cardiotoxicity and secondary leukemia for mitoxantrone; and progressive multifocal leukoencephalopathy for natalizumab). Ocrelizumab does not carry any BBW. Risks associated with DMTs can be minimized by implementing measures at the time of MS diagnosis and monitoring the patient before, during, and after therapy.46 Risk Evaluation and Mitigation Strategy (REMS) programs are implemented for alemtuzumab and natalizumab to warn healthcare professionals about the safety concerns included in their corresponding BBWs. Table 8 summarizes warnings and precautions. Table 9 contains common adverse drug reactions and monitoring requirements. Long-term safety profile in terms of risk of malignancies or infections is still uncertain, especially for newer DMTs.46 There are undefined risks of malignancy and infection with long-term use of some newer DMTs (alemtuzumab, cladribine, siponimod, fingolimod, and ocrelizumab). If a patient develops a malignancy or serious infection potentially linked to the use of DMTs, switching DMTs can be considered.19 Progressive multifocal leukoencephalopathy is a serious viral infection caused by the John Cunningham virus (JCV) that has been identified in patients receiving specific DMTs, particularly natalizumab.14,19,46 It usually occurs in immunocompromised patients and may lead to death and pronounced disability.14 Risk factors for developing PML include the presence of anti-JCV antibodies, longer duration of therapy, and prior use of immunosuppressive agents.14,19,46 The risk of PML is associated with the use of natalizumab (4 cases per 1,000 treated patients), fingolimod (rare reports), dimethyl fumarate (rare reports), ocrelizumab (risk potential is based on similarity to other anti-CD20 antibodies), and alemtuzumab (one case reported).19 The 2018 AAN guideline suggests switching to a DMT with a decreased risk for PML if patients are receiving natalizumab and become JCV antibody– positive (particularly if JCV antibody index is > 0.9).19

Safety concerns for each DMT as well as head-to-head safety evidence are described below: Alemtuzumab

Alemtuzumab may cause serious and life-threatening infusion reactions, autoimmune conditions such as immune thrombocytopenia or antiglomerular basement membrane disease, stroke, malignancies (eg, thyroid cancer, melanoma, and lymphoproliferative disorders), serious infections, and hyperthyroidism. All except hyperthyroidism and infections are black box warnings for alemtuzumab. PML has been reported in a patient with MS receiving alemtuzumab. This DMT is only available through a risk evaluation and mitigation strategies (REMS) program that aims to reduce infusion reactions and includes

monitoring requirements (eg, complete blood count and serum creatinine levels before and during treatment) as well as baseline and yearly skin examinations to monitor for melanoma.1,19

An MA of 3 studies (CARE-MS I, CARE-MS II and CAMMS223) showed a significantly lower risk of discontinuations due to AEs with alemtuzumab compared to SQ IFN beta-1a 44 µg 3 times weekly.19 Evidence comparing these agents regarding the risk of cancer, mortality, liver toxicity, serious infections, and immune thrombocytopenic purpura is very limited.19 Another MA of the same 3 studies reported similar risk of experiencing adverse events or serious adverse events between alemtuzumab and IFN (low to moderate quality evidence).66

Cladribine

Cladribine may increase the risk of malignancy and is contraindicated in pregnant women due to the risk of teratogenicity (black box warnings). Other warnings include hematologic toxicity (particularly lymphopenia), infections (eg, tuberculosis, hepatitis, and viral infections), graft-versus-host-disease with blood transfusion, cardiac failure, and liver injury.2,19 Due to its safety profile, cladribine is usually recommended for patients with an inadequate response, intolerance, or contraindication to other DMTs for the treatment of MS.2 Fumaric Acid Esters

Dimethyl fumarate and diroximel fumarate do not carry a BBW. Dimethyl fumarate can cause anaphylaxis and angioedema, progressive multifocal leukoencephalopathy (PML), lymphopenia, liver injury, and flushing.4 Cases of PML have been reported with the use of dimethyl fumarate, especially in patients with persistent lymphopenia.19 Clinical studies with diroximel fumarate in RRMS patients showed a safety profile that was consistent with that seen in clinical trials with dimethyl fumarate.18

Glatiramer Acetate

The use of glatiramer acetate is associated with post-injection reactions (eg, flushing, chest pain, tachycardia, anxiety, dyspnea, and urticaria) that are generally transient and manageable without treatment, as well as transient chest pain, lipoatrophy, and skin necrosis at injection sites. There is no BBW for glatiramer acetate.6,7,19

In one head-to-head clinical trial, no differences were observed between glatiramer and SQ IFN beta-1a 3 times weekly regarding discontinuations due to adverse events. Another RCT showed a significantly lower risk for injection site reactions but a significantly higher risk for influenza-like illness with SQ IFN beta-1b compared to glatiramer.19

Interferon Beta

Interferon beta products do not carry any BBWs.8-12 These agents are associated with post-injection flulike symptoms (eg, chills, fever, myalgia, and asthenia). Injection-site reactions may occur with SQ formulations of IFN beta and skin necrosis may occur with IFN beta-1b.19 Patients receiving IFN beta can develop neutralizing antibodies that may reduce drug efficacy.46 Other safety concerns associated with the use of IFN beta include the development of thrombotic microangiopathy (a rare but severe condition), elevated liver enzymes, depression, suicide, psychotic disorders, seizures, and development of autoimmune disorders (eg, autoimmune thyroid disease).8-12,46

In one RCT comparing SQ IFN beta-1a 3 times weekly with IM IFN beta-1a weekly, no differences were found regarding treatment discontinuations due to adverse events at 1 year.19

Mitoxantrone

Mitoxantrone may cause congestive heart failure, especially with cumulative doses of mitoxantrone.19 In addition, cases of secondary acute myeloid leukemia have been reported in MS patients receiving mitoxantrone. These are black box warnings for mitoxantrone.13,19

Natalizumab

Natalizumab includes a black box warning related to the risk of PML. Patients treated with natalizumab may experience anaphylaxis, herpes virus or other infections, and hepatotoxicity.14,19 Ocrelizumab

There are no BBWs for ocrelizumab. Infusion reactions, infections (eg, respiratory tract infections, herpes virus infection, and PML), and malignancies may occur with ocrelizumab therapy.15 No cases of PML has been reported in clinical trials with ocrelizumab; however, cases of PML have been reported with other anti-CD20 antibodies.15 Infusion-related reactions (eg, pruritus, rash, throat irritation, and flushing) were the most commonly reported adverse events in clinical trials with ocrelizumab. They were mild to moderately severe and reduced with adequate pretreatment.71

Two studies comparing ocrelizumab with SQ IFN beta-1a 3 times per week in patients with RRMS showed a significantly higher number of patients discontinuing treatment due to adverse events at 2 years and experiencing serious infections or infestation with interferon compared to ocrelizumab. Comparative evidence regarding the risk of malignancies or mortality was insufficient.19

Sphingosine 1-phosphate (S1P) receptor modulator

The use of fingolimod or siponimod is associated with bradyarrhythmia and atrioventricular conduction delays, infections (eg, herpes zoster, bronchitis, and pneumonia), PML, macular edema, posterior reversible encephalopathy syndrome (PRES), respiratory effects, elevation of liver enzymes, liver injury, fetal risk, severe increase in disability after discontinuing fingolimod or siponimod, increased blood pressure, and malignancies (eg, increased risk of cutaneous malignancy with fingolimod and case reports with siponimod).5,16,19 There are no BBWs for these 2 agents.5,16

In one head-to-head clinical trial, no differences were observed between fingolimod and IM IFN beta-1a in terms of discontinuations due to adverse events; however, the risk of neoplasm was significantly higher with fingolimod compared to IFN beta-1a.19 Teriflunomide

Black box warnings for teriflunomide include hepatotoxicity and embryofetal toxicity. Other warnings include anaphylaxis, increased blood pressure, decreased white blood cells and platelet count, risk of infections and malignancies, and peripheral neuropathy.17

An SR including 1 RCT (TENERE study) compared the liver safety profile of teriflunomide versus IFN beta- 1a 44 µg. A significantly higher incidence of liver adverse events (ie, alteration of liver function tests and

elevation of alanine aminotransferase [ALT]) was reported with IFN compared to teriflunomide. No cases of liver failure were found.72

Dalfampridine

Dalfampridine is a non-DMT that can cause seizures and anaphylaxis. The risk of seizures is increased with higher doses of dalfampridine. It is contraindicated in patients with a history of seizures.3 In clinical trials with dalfampridine, adverse events leading to treatment discontinuation more frequently than in the placebo arm included headache, balance disorder, dizziness, and confusional state.3

Table 8. Warnings and Precautions for Disease-Modifying Agents1,2,4-18 Agent Warnings and Precautions Oral Medications Warnings for Malignancy: cladribine (BBW, contraindicated with current malignancy) and sphingosine1- Oral phosphate receptor modulators, fingolimod and siponimod Medications Teratogenicity: BBW and contraindication for use in pregnancy for cladribine and teriflunomide Avoid use during pregnancy: applies to all products Progressive multifocal leukoencephalopathy: cases reported with fingolimod and dimethyl Cladribine fumarate; risk is extrapolated to siponimod and diroximel fumarate Dimethyl Leucopenia/lymphopenia: applies to all products fumarate Liver injury: applies to all products, but is a BBW for teriflunomide Diroximel Increased BP: fingolimod, siponimod, teriflunomide fumarate Hypersensitivity: dimethyl fumarate, diroximel fumarate, teriflunomide Fingolimod Infection risk: cladribine, fingolimod, siponimod, teriflunomide Siponimod Additional warnings for Sphingosine1-Phosphate Receptor Modulatorsa (siponimod and Teriflunomide fingolimod): Macular Edema Bradyarrhythmia and Atrioventricular Blocks Decreased pulmonary function Posterior Reversible Encephalopathy Syndrome: cases reported with fingolimod Severe increase in disability after stopping therapy: reported with fingolimod Contraindicated with CYP2C9*3/*3 Genotype: siponimod Additional warnings for Cladribine (Mavenclad) Breastfeeding: Contraindicated during treatment and for 10 days following last dose due to potential for serious adverse reactions in breastfed infant Vaccinations: Ensure patients are up-to-date with vaccinations; Administer anti-herpes prophylaxis in patients with lymphocytes < 200 cells per microliter Graft-versus-host-disease with blood transfusion Hematologic toxicity Additional warnings for Teriflunomide (Aubagio) Peripheral Neuropathy Subcutaneous and Intramuscular Medications Immediate Post-Injection Reaction (flushing, chest pain, palpitations, tachycardia, anxiety, Glatiramer dyspnea, throat constriction, and/or urticaria), usually self-limiting acetate Chest pain, usually transient

Table 8. Warnings and Precautions for Disease-Modifying Agents1,2,4-18 Agent Warnings and Precautions Modifies immune response: may underine body’s tumor surveillance function and defenses against infection Lipoatrophy and skin necrosis may occur: rotate injection sites Hypersensitivity: avoid with hypersensitivity to drug, mannitol, or any other ingredient in product Flu-like Symptoms: consider analgesics and/or antipyretics on injection days Warnings for interferon- Depression, Suicide, and Psychotic Disorders: increased frequency reported in clinical trials beta therapies Seizures: monitor with pre-existing seizure disorders, seizures were temporally associated with the use of beta interferons in clinical trials and in postmarketing reports Hepatic Injury: monitor liver function Decreased Peripheral Blood Counts: see product for specific cytopenia Thrombotic Microangiopathy: cases, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, have been reported, some of which were fatal Autoimmune Disorders: postmarketing reports of autoimmune disorders (including idiopathic thrombocytopenia, hyper- and hypothyroidism, autoimmune hepatitis, lupus erythematosus, retinal vascular disorders, Steven’s Johnson Syndrome) have been reported in post-marketing studies Anaphylaxis and Other Allergic-Reactions: avoid with allergy to natural or recombinant interferon beta, or any component of the formulation Congestive Heart Failure: monitor patients with pre-existing significant cardiac disease for worsening of cardiac symptoms Injection Site Reactions Intravenous Medications : autoimmunity, infusion reactions, stroke, and malignancies Alemtuzumab Black box warnings Immune Thrombocytopenia and Other Autoimmune Cytopenias: monitor complete blood counts (CBCs) with differential Glomerular Nephropathies: monitor serum creatinine levels, urinalysis, and urine protein to creatinine ratio Thyroid Disorders: monitor thyroid function Autoimmune Hepatitis: monitor liver function/enzymes Infections: Consider delaying initiation of treatment if active infection is present and until it is fully controlled; contraindicated with HIV infection Avoid live viral vaccines following a course of alemtuzumab Progressive multifocal leukoencephalopathy: one case has been reported

Mitoxantrone Black box warnings . Cardiotoxicity: congestive heart failure, potentially fatal, may occur; assess baseline left ventricular ejection fraction, cardiac risks, and ECG prior to start of therapy; avoid with left ventricular ejection fraction below 50% . Myelosuppression: primary neutropenia; avoid with neutrophil count less than 1,500 cells/mm3; blood and blood products may be needed . Secondary acute myeloid leukemia possible: has been associated with use of Topoisomerase II inhibitors, including mitoxantrone . Administration should be only by IV route and under supervision of a physician experienced with cytotoxic chemotherapy agents

Table 8. Warnings and Precautions for Disease-Modifying Agents1,2,4-18 Agent Warnings and Precautions Medullary hypoplasia at high doses Monitor CBC Monitor liver function Sulfite-related Anaphylaxis: contains sodium metabisulfite; this type of sensitivity is more frequent in asthmatics Cardiac effects: Functional cardiac changes including decreases in left ventricular ejection fraction (LVEF) and irreversible congestive heart failure is possible; avoid with left ventricular ejection fraction below 50% Fetal harm: avoid use during pregnancy

Natalizumab Black box warnings: Increases risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability; risk factors include longer duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies; monitor patients and consider expected benefits vs. risks o only available through a restricted distribution program (TOUCH® Prescribing Program) o contraindicated in patients who have had a PML infection previously Immunosuppression/Infections: may increase the risk; monitor for infections Herpes infections: life-threatening/fatal cases and blindness have occurred while receiving therapy Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, has occurred Hypersensitivity: serious reactions have occurred Infusion reactions: some have been life-threatening; for life-threatening reactions, immediately Ocrelizumab and permanently stop treatment Infections: Delay treatment if an active infection is present; contraindicated with hepatitis B infection Malignancies: may increase risk of malignancy, including breast cancer Avoid live-attenuated or live vaccines during treatment and after discontinuation, until B-cell repletion occurs Abbreviations: AV, atrioventricular; BBW, black box warnings; CBC, complete blood cell count; DDIs, drug-drug interactions; HF, heart failure; IV, intravenous; MI, myocardial infarction; TB, tuberculosis a Although case reports may not have been reported with siponimod for certain adverse effects, the product labeling warns of a potential class effect

Table 9. Common Adverse Reactions and Monitoring Requirements1-18 Agent Monitoring Most Common Labeled Adverse Reactions Brand Name Requirements/REMS27 Oral Medications CBC, LFTs, infections, Cladribine Occurring at an incidence >20%: upper respiratory tract infection, cancer screening, headache, and lymphopenia Mavenclad pregnancy test Occurring at an incidence >2% and greater than placebo: urinary Dalfampridine tract infection, insomnia, dizziness, headache, nausea, asthenia, back pain, balance disorder, multiple sclerosis relapse, paresthesia, CrCl Ampyra nasopharyngitis, constipation, dyspepsia, and pharyngolaryngeal pain

Dimethyl fumarate Occurring at an incidence ≥10% and ≥2% placebo: flushing, CBC, LFTs abdominal pain, diarrhea, and nausea Tecfidera

Diroximel Occurring at an incidence ≥10% and ≥ 2% greater than placebo for Fumarate dimethyl fumarate (dimethyl fumarate has the same metabolite as CBC, LFTs diroximel fumarate): flushing, abdominal pain, diarrhea, and nausea Vumerity CBC, ECG, varicella Fingolimod Occurring at an incidence ≥10% and greater than placebo: zoster antibody, blood headache, liver transaminase elevation, diarrhea, cough, influenza, pressure, ophthalmic Gilenya sinusitis, back pain, abdominal pain, and pain in extremity examination, LFTs CBC, ECG, varicella zoster antibody, blood Siponimod Occurring at an incidence of >10%: headache, hypertension, and pressure, ophthalmic Mayzent elevated transaminase examination, LFTs, CYP2C9 variants

CBC, LFTs, blood Teriflunomide Occurring at an incidence of ≥10% and ≥2% greater than placebo: pressure, pregnancy headache, diarrhea, nausea, alopecia, increase in ALT Aubagio test, TB test Subcutaneous and Intramuscular Medications

Glatiramer Occurring at an incidence of ≥10% and ≥1.5 times higher than The FDA does not acetate placebo: require regular o For the 20 mg/mL regimen: injection site reactions, monitoring of specific Copaxone, vasodilatation, rash, dyspnea, and chest pain parameters Glatopa o For the 40 mg/mL regimen: injection site reactions Occurring in at least 5% of patients on Avonex and more frequent compared to placebo: flu-like symptoms including chills, fever, Interferon myalgia, and asthenia Electrolytes, CBC, LFTs, beta-1a Most common adverse reactions in controlled clinical trials with thyroid function, depression Avonex, Rebif Rebif were injection site disorders, influenza-like symptoms, abdominal pain, depression, elevation of liver enzymes and hematologic abnormalities

Table 9. Common Adverse Reactions and Monitoring Requirements1-18 Agent Monitoring Most Common Labeled Adverse Reactions Brand Name Requirements/REMS27 Occurring in at least 5% and more frequent than placebo: injection Interferon Electrolytes, CBC, LFTs, site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, beta-1b thyroid function, Betaseron, neutropenia, increased liver enzymes, headache, hypertonia, pain, depression Extavia rash, insomnia, abdominal pain, and asthenia. Occurring with an incidence ≥10% and at least 2% more frequent Peginterferon Electrolytes, CBC, LFTs, than placebo: injection site erythema, influenza-like illness, pyrexia, beta-1a thyroid function, headache, myalgia, chills, injection site pain, asthenia, injection site depression Plegridy pruritus, and arthralgia Intravenous Medications CBC, thyroid function, antibodies to varicella zoster virus, HPV Occurring with an incidence of ≥10% and > interferon beta-1a: rash, screening, serum headache, pyrexia, asopharyngitis, nausea, urinary tract infection, creatinine, TB test prior Alemtuzumab fatigue, insomnia, upper respiratory tract infection, herpes viral to treatment, infusion infection, urticaria, pruritus, thyroid gland disorders, fungal reactions, skin exams, Lemtrada infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, urinalysis oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting REMS concerning autoimmunity, infusion reactions, and malignancies Occurring in > 5% of patients on either dose and numerically more frequent than placebo: nausea, alopecia, amenorrhea, upper

Mitoxantrone respiratory tract infection, urinary tract infection, stomatitis, CBC, ECG, LVEF, LFTs arrhythmia, diarrhea, constipation, back pain, sinusitis, headache, Generic only abnormal ECG, leukopenia, gamma-GT increased, SGOT increased, granulocytopenia, anemia, SGPT increased JCV antibody, infection, Occurring at an incidence ≥ 10% in MS patients: headache, fatigue, MRI for signs of PML, Natalizumab arthralgia, urinary tract infection, lower respiratory tract infection, LFTs gastroenteritis, vaginitis, depression, pain in extremity, abdominal Tysabri discomfort, diarrhea NOS, and rash REMS concerning the risk of PML In patients with relapsing MS and at an incidence ≥10% and > Rebif comparator: upper respiratory tract infections and infusion Infusion reactions, Ocrelizumab reactions hepatitis B screening before treatment Ocrevus In patients with primary progressive MS at an incidence ≥10% and >placebo: upper respiratory tract infections, infusion reactions, skin initiation infections, and lower respiratory tract infections Abbreviations: CBC, complete blood count; CrCl, creatinine clearance; CYP, cytochrome P450; ECG, electrocardiogram; FDA, U.S. Food and Drug Administration; HPV, human papillomavirus; JCV, John Cunningham virus; LFT, liver function test; LVEF, left ventricular ejection fraction; MS, multiple sclerosis; PML, progressive multifocal leukoencephalopathy; REMS, Risk Evaluation and Mitigation Strategy; TB, tuberculosis

Summary There are 2 primary clinical practice guidelines for the treatment of MS including the 2018 American Academy of Neurology (AAN) guideline and the 2018 European Committee of Treatment and Research in Multiple Sclerosis/European Academy of Neurology (ECTRIMS/EAN) guideline. In general, selection of DMTs in patients with relapsing forms of MS should be tailored based on risk-benefit profile, patients’ preferences, patient-specific factors, disease activity or severity, and concerns regarding long-term risk for disability progression. Guidelines specify some DMT preferences regarding certain subgroups of patients or types of MS. The AAN guideline specifically recommends alemtuzumab, fingolimod, or natalizumab therapy for patients with highly active MS (although no standard definition is currently available for highly active MS). Ocrelizumab is recommended by both guidelines for patients with primary progressive MS (PPMS). For patients with active secondary progressive MS (SPMS), the ECTRIMS/EAN guideline recommends subcutaneous interferon beta-1a or beta-1b, mitoxantrone, ocrelizumab, or cladribine. The AAN guideline does not provide specific recommendations for SPMS. Mitoxantrone is associated with a high frequency of severe adverse events and is not recommended by the AAN guideline unless the benefits outweigh the risks. AAN and ECTRIMS/EAN guidelines do not recommend the use of DMTs during pregnancy unless benefits outweigh the risks; however, the ECTRIMS/EAN guideline states that interferon, glatiramer acetate, natalizumab, and alemtuzumab may be used before or during pregnancy in specific situations. Siponimod and diroximel fumarate were recently approved by the FDA and are not included in the 2 primary guidelines. Dalfampridine is a non- DMT agent approved to improve walking in patients with MS; no clinical practice guidelines including recommendations for use of this agent are currently available. Moderate- to high-quality head-to-head evidence in the adult population with RRMS showed a significantly greater reduction in relapses and MRI disease activity with fingolimod versus IM IFN beta-1a 30 µg once weekly (Avonex), and alemtuzumab or ocrelizumab versus SQ IFN beta-1a 44 µg 3 times per week (Rebif). In addition, alemtuzumab and ocrelizumab were more efficacious than SQ IFN beta-1a 44 µg (Rebif) in decreasing the risk of disability progression. In the pediatric population (10 to 17 years of age), a significantly greater reduction in relapses and MRI disease activity was reported with fingolimod at the FDA-approved dosages compared to IM IFN beta-1a 30 µg once weekly (Avonex). Overall, treatment guidelines and routine clinical practice seem to be consistent regarding the selection of DMTs for relapsing MS, which should be individualized and tailored based on patients’ needs and drug characteristics. Modestly/moderately effective DMTs (interferon beta products, glatiramer acetate, teriflunomide, and dimethyl fumarate) and highly-effective DMTs (fingolimod, natalizumab, and ocrelizumab) may be considered first-line in treatment-naïve patients with relapsing MS depending on the treatment approach selected by the clinician (escalation or maximal efficacy). The place in therapy for the 2 recently approved DMTs (siponimod and diroximel fumarate) is somewhat unclear due to the very limited guidance available; however, based on the prescribing information, both agents may be used first-line in patients with relapsing form of MS. Based on AAN guideline recommendations or prescribing information, alemtuzumab, cladribine, and mitoxantrone are usually recommended second, third, or even last line due to safety concerns. The Utah Medicaid P&T Committee may consider including at least 1 modestly effective DMT and at least 1 highly effective DMT to optimize the management of patients with MS, with considerations for limitations of use regarding alemtuzumab, cladribine, and mitoxantrone.

References

1. LEMTRADA (alemtuzumab) [package insert]. Cambridge, MA: Genzyme Corporation; revised October 2019. 2. MAVENCLAD (cladribine) [package insert]. Rockland, MA: EMD Serono, Inc.; revised March 2019. 3. Dalfampridine [package insert]. Durham, NC: Accord Healthcare Inc.; revised April 2018. 4. TECFIDERA (dimethyl fumarate) [package insert]. Cambridge, MA: Biogen Inc.; revised July 2019. 5. GILENYA (fingolimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; revised August 2019. 6. COPAXONE (glatiramer acetate) [package insert]. North Wales, PA: Teva Pharmaceuticals USA, Inc.; revised July 2019. 7. GLATOPA (glatiramer acetate) [package insert]. Princeton, NJ: Sandoz Inc.; revised July 2019. 8. AVONEX (interferon beta-1a) [package insert]. Cambridge, MA: Biogen Inc.; revised July 2019. 9. BETASERON (interferon beta-1b) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; revised August 2019. 10. REBIF (interferon beta-1a) [package insert]. Rockland, MA: EMD Serono, Inc.; revised July 2019. 11. EXTAVIA (interferon beta-1b) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; revised August 2019. 12. PLEGRIDY (peginterferon beta-1a) [package insert]. Cambridge, MA: Biogen Inc.; July 2019. 13. Mitoxantrone [package insert]. Lake Forest, IL: Hospira, Inc.; revised April 2019. 14. TYSABRI (natalizumab) [package insert]. Cambridge, MA: Biogen Inc.; August 2019. 15. OCREVUS (ocrelizumab) [package insert]. South San Francisco, CA: Genentech, Inc.; revised July 2019. 16. MAYZENT (siponimod) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; revised March 2019. 17. AUBAGIO (teriflunomide) [package insert]. Cambridge, MA: Genzyme Corporation; revised September 2019. 18. VUMERITY (diroximel fumarate) [package insert]. Waltham, MA: Alkermes, Inc.; revised October 2019. 19. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease- modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788. 20. Utah Department of Health. Utah Medicaid Preferred Drug List (effective October 1, 2019). https://medicaid.utah.gov/pharmacy/PDL/files/Utah%20Medicaid%20PDL%20(10-01-19).pdf. Accessed October 25, 2019. 21. Lucchetta RC, Tonin FS, Borba HHL, et al. Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: A Network Meta-Analysis. CNS drugs. 2018;32(9):813-826. 22. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097. 23. Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: Disease- modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):789-800. 24. Campbell JD, Ghushchyan V, Brett McQueen R, et al. Burden of multiple sclerosis on direct, indirect costs and quality of life: National US estimates. Mult Scler Relat Disord. 2014;3(2):227- 236. 25. National Institute of Neurological Disorders and Stroke. Multiple Sclerosis Information Page. Definition and Treatment. https://www.ninds.nih.gov/Disorders/All-Disorders/Multiple- Sclerosis-Information-Page. Accessed October 21, 2019. 45

26. Krupp LB, Vieira MC, Toledano H, et al. A Review of Available Treatments, Clinical Evidence, and Guidelines for Diagnosis and Treatment of Pediatric Multiple Sclerosis in the United States. Journal of child neurology. 2019;34(10):612-620. 27. Bainbridge JL, Miravalle A, Wong PS. Multiple Sclerosis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. New York, NY: McGraw-Hill Education; 2017. 28. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286. 29. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173. 30. McGraw CA, Lublin FD. Interferon beta and glatiramer acetate therapy. Neurotherapeutics. 2013;10(1):2-18. 31. Tramacere I, Del Giovane C, Salanti G, D'Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015(9):Cd011381. 32. Yoon EL, Cheong WL. Adherence to oral disease-modifying therapy in multiple sclerosis patients: A systematic review. Mult Scler Relat Disord. 2019;28:104-108. 33. Rommer PS, Zettl UK, Kieseier B, et al. Requirement for safety monitoring for approved multiple sclerosis therapies: an overview. Clin Exp Immunol. 2014;175(3):397-407. 34. Higuera L, Carlin CS, Anderson S. Adherence to Disease-Modifying Therapies for Multiple Sclerosis. J Manag Care Spec Pharm. 2016;22(12):1394-1401. 35. Agashivala N, Wu N, Abouzaid S, et al. Compliance to fingolimod and other disease modifying treatments in multiple sclerosis patients, a retrospective cohort study. BMC Neurol. 2013;13:138. 36. Burks J, Marshall TS, Ye X. Adherence to disease-modifying therapies and its impact on relapse, health resource utilization, and costs among patients with multiple sclerosis. Clinicoecon Outcomes Res. 2017;9:251-260. 37. Cree BAC, Mares J, Hartung HP. Current therapeutic landscape in multiple sclerosis: an evolving treatment paradigm. Curr Opin Neurol. 2019;32(3):365-377. 38. Grand'Maison F, Yeung M, Morrow SA, et al. Sequencing of high-efficacy disease-modifying therapies in multiple sclerosis: perspectives and approaches. Neural Regen Res. 2018;13(11):1871-1874. 39. Maarouf A, Boutiere C, Rico A, Audoin B, Pelletier J. How much progress has there been in the second-line treatment of multiple sclerosis: A 2017 update. Rev Neurol (Paris). 2018;174(6):429- 440. 40. Fernandez O. Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS? Mult Scler Relat Disord. 2017;17:75-83. 41. Freedman MS, Comi G, De Stefano N, et al. Moving toward earlier treatment of multiple sclerosis: Findings from a decade of clinical trials and implications for clinical practice. Mult Scler Relat Disord. 2014;3(2):147-155. 42. Merkel B, Butzkueven H, Traboulsee AL, Havrdova E, Kalincik T. Timing of high-efficacy therapy in relapsing-remitting multiple sclerosis: A systematic review. Autoimmun Rev. 2017;16(6):658- 665. 43. Farez MF, Correale J, Armstrong MJ, et al. Practice guideline update summary: Vaccine- preventable infections and immunization in multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2019;93(13):584-594.

44. Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler. 2018;24(2):96-120. 45. National Institute for Health and Care Excellence. Disease-modifying therapies for multiple sclerosis; last updated: 25 July 2019. http://pathways.nice.org.uk/pathways/multiple-sclerosis. Accessed November 1, 2019. 46. Klotz L, Havla J, Schwab N, et al. Risks and risk management in modern multiple sclerosis immunotherapeutic treatment. Ther Adv Neurol Disord. 2019;12:1756286419836571. 47. Palte MJ, Wehr A, Tawa M, et al. Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study. Adv Ther. 2019;36(11):3154-3165. 48. Multiple Sclerosis Coalition. The Use Of Disease – Modifying Therapies In Multiple Sclerosis: Principles and Current Evidence Summary. Updated March 2017. http://www.nationalmssociety.org/getmedia/1e64b96c-9e55-400e-9a64- 0cdf5e2d60fe/summaryDMTpaper_-final. Accessed October 15, 2019. 49. La Mantia L, Di Pietrantonj C, Rovaris M, et al. Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis. The Cochrane database of systematic reviews. 2016;11(100909747):CD009333. 50. Melendez-Torres GJ, Armoiry X, Court R, et al. Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages. BMC neurology. 2018;18(1):162. 51. Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):402-415. 52. Vermersch P, Czlonkowska A, Grimaldi LM, et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014;20(6):705-716. 53. Panitch H, Goodin DS, Francis G, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology. 2002;59(10):1496-1506. 54. Schwid SR, Panitch HS. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther. 2007;29(9):2031-2048. 55. Calabrese M, Bernardi V, Atzori M, et al. Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis. Mult Scler. 2012;18(4):418-424. 56. Etemadifar M, Janghorbani M, Shaygannejad V. Comparison of Betaferon, Avonex, and Rebif in treatment of relapsing-remitting multiple sclerosis. Acta Neurol Scand. 2006;113(5):283-287. 57. Durelli L, Verdun E, Barbero P, et al. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet. 2002;359(9316):1453-1460. 58. Singer B, Bandari D, Cascione M, et al. Comparative injection-site pain and tolerability of subcutaneous serum-free formulation of interferonbeta-1a versus subcutaneous interferonbeta- 1b: results of the randomized, multicenter, Phase IIIb REFORMS study. BMC Neurol. 2012;12:154. 59. Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with IFNbeta-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology. 2009;72(23):1976- 1983.

60. O'Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol. 2009;8(10):889-897. 61. Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol. 2008;7(10):903-914. 62. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol. 2013;73(3):327-340. 63. Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359(17):1786-1801. 64. Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819-1828. 65. Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829-1839. 66. Zhang J, Shi S, Zhang Y, et al. Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis. The Cochrane database of systematic reviews. 2017;11(100909747):CD010968. 67. Arroyo Gonzalez R, Kita M, Crayton H, et al. Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis. Mult Scler. 2017;23(10):1367-1376. 68. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017;376(3):221-234. 69. Turner B, Cree BAC, Kappos L, et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. J Neurol. 2019;266(5):1182-1193. 70. Chitnis T, Arnold DL, Banwell B, et al. Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis. N Engl J Med. 2018;379(11):1017-1027. 71. Mayer L, Kappos L, Racke MK, et al. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. Mult Scler Relat Disord. 2019;30:236-243. 72. Salas PAO, Parra CO, Florez CEP, Goez LM, Velez-van-Meerbeke A, Rodriguez JH. Safety liver profile of teriflunomide versus interferon β in multiple sclerosis: Systematic review and indirect comparison meta-analysis. Multiple Sclerosis and Related Disorders. 2018;26((Rodriguez J.H.) Bogotá, Colombia):192-200. 73. Khatri B, Barkhof F, Comi G, et al. Comparison of fingolimod with interferon beta-1a in relapsing- remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurol. 2011;10(6):520-529. 74. Cohen JA, Khatri B, Barkhof F, et al. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J Neurol Neurosurg Psychiatry. 2016;87(5):468-475. 75. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779-1787.

Appendix A – Literature Search Strategies

1. Ovid Medline Search Strategy for Systematic reviews and Meta-analyses

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to September 19, 2019 Search Strategy:

# Searches Results

1 (MS or ("multiple" adj sclero*)).ti,ab,kw,kf. 351505

exp multiple sclerosis/ or multiple sclerosis, chronic progressive/ or multiple sclerosis, relapsing- 2 56320 remitting/

3 1 or 2 357447

4 Glatiramer Acetate/ 1283

5 glatiramer.ti,ab,kw,kf. 1642

6 exp Cladribine/ 1457

7 cladribine.ti,ab,kw,kf. 1237

8 exp Dimethyl Fumarate/ 589

9 'dimethyl fumarate'.ti,ab,kw,kf. 814

10 exp Fingolimod Hydrochloride/ 1994

11 fingolimod.ti,ab,kw,kf. 1722

12 siponimod.ti,ab,kw,kf. 67

13 teriflunomide.ti,ab,kw,kf. 431

14 exp Mitoxantrone/ or Topoisomerase II Inhibitors/ 7659

15 (mitoxantrone or (topoisomerase* adj2 inhibitor*)).ti,ab,kw,kf. 9478

16 (natalizumab or ocrelizumab or alemtuzumab or 'monoclonal antibod*').ti,ab,kw,kf. 187246

17 antibodies, monoclonal/ or antibodies, monoclonal, humanized/ or alemtuzumab/ or natalizumab/ 202877

18 exp Immunosuppressive Agents/ 307687

19 (immunosupressant* or immunosupressive).ti,ab,kw,kf. 366

20 "disease modifying".ti,ab,kw,kf. 15798

21 Dalfampridine.ti,ab,kw,kf. 123

22 (sphingosine adj4 (modulator* or blocker* or inhibitor* or antagonist*)).ti,ab,kw,kf. 980

23 interferons/ or exp Interferon-beta/ 30744

24 (interferon* or peginterferon* or IFN*).ti,ab,kw,kf. 209871

4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 25 793346 or 23 or 24

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic 26 adj3 review$) or (systematic adj2 search$) or cochrane$ or (overview adj4 review)).ti,ab,kw,kf. or 304185 (cochrane$ or systematic review?).jw.

27 (MEDLINE or systematic review).tw. or meta analysis.pt. 250826

28 26 or 27 335740

29 3 and 25 and 28 402

30 limit 29 to yr="2015 -Current" 181

2. Ovid Medline Search Strategy for Randomized Controlled Trials

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to October 15, 2019 Search Strategy:

# Searches Results

1 (MS or ("multiple" adj sclero*)).ti,ab,kw,kf. 353449

exp multiple sclerosis/ or multiple sclerosis, chronic progressive/ or multiple sclerosis, relapsing- 2 56553 remitting/

3 1 or 2 359402

4 Glatiramer Acetate/ 1289

5 glatiramer.ti,ab,kw,kf. 1654

6 exp Cladribine/ 1462

7 cladribine.ti,ab,kw,kf. 1245

8 exp Dimethyl Fumarate/ 601

9 'dimethyl fumarate'.ti,ab,kw,kf. 823

10 exp Fingolimod Hydrochloride/ 2009

11 fingolimod.ti,ab,kw,kf. 1734

12 siponimod.ti,ab,kw,kf. 72

13 teriflunomide.ti,ab,kw,kf. 437

14 Dalfampridine.ti,ab,kw,kf. 122

15 interferons/ or exp Interferon-beta/ 30811

16 (interferon* or peginterferon* or IFN*).ti,ab,kw,kf. 210654

17 exp Mitoxantrone/ or mitoxantrone.ti,ab,kw,kf. 6128

18 (natalizumab or ocrelizumab or alemtuzumab).ti,ab,kw,kf. 4551

19 alemtuzumab/ or natalizumab/ 3300

20 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 231450

(randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical 21 1244406 trials as topic.sh. or randomly.ab. or trial.ti.

22 exp animals/ not humans.sh. 4628394

23 3 and 20 and 21 2055

24 23 not 22 2036

25 limit 24 to yr="2017 -Current" 288

3. Embase Search Strategy for Systematic reviews and Meta-analyses

Date of search: September 24, 2019 No. Query Results 302 #36 #30 AND #33 AND #34 AND [2015-2019]/py 774 #35 #30 AND #33 AND #34 342,897 #34 (cochrane*:jt OR 'systematic review*':jt OR 'meta analysis'/exp OR 'systematic review'/exp OR ((systematic NEAR/3 review*):ti,ab,kw) OR ((systematic NEAR/2 search*):ti,ab,kw) OR 'meta analys*':ti,ab,kw OR metaanalys*:ti,ab,kw OR ((overview NEAR/4 (review OR reviews)):ti)) NOT ('conference abstract'/it OR 'conference review'/it) 509,312 #33 #31 OR #32 488,224 #32 'ms':ti,ab,kw OR 'multiple sclero*':ti,ab,kw 123,624 #31 'multiple sclerosis'/exp 2,047,575 #30 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #1 7 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 6,884 #29 'antimetabolite'/de 1,358 #28 (sphingosine NEAR/4 (modulator* OR blocker* OR inhibitor* OR antagonist*)):ti,ab,kw 6,101 #27 (topoisomerase* NEAR/2 (inhibitor* OR blocker* OR antagonist* OR modulator*)):ti,ab,kw 292,350 #26 'antineoplastic agent'/de 113

#25 'disease modifying therapy'/exp OR 'disease modifying drug'/exp OR 'disease modifying agent'/exp 28,377 #24 'disease modifying':ti,ab,kw 293,731 #23 'monoclonal antibody'/de OR 'monoclonal antibod*':ti,ab,kw 385,172 #22 immunosuppress* OR immunomodulat*:ti,ab,kw 1,009,120 #21 'immunosuppressive agent'/exp 269 #20 dalfampridine:ti,ab,kw 7,542 #19 'fampridine'/exp 7,042 #18 mitoxantrone:ti,ab,kw 22,767 #17 'mitoxantrone'/exp 23,990 #16 alemtuzumab OR natalizumab OR ocrelizumab:ti,ab,kw 23,957 #15 'alemtuzumab'/exp OR 'natalizumab'/exp OR 'ocrelizumab'/exp 415,323 #14 interferon* OR peginterferon* OR ifn* OR 'pegylated interferon':ti,ab,kw 113,329 #13 'interferon'/de OR 'beta interferon'/exp OR 'peginterferon'/exp OR 'beta1 interferon'/exp OR 'peginterferon beta1a'/exp OR 'beta1a interferon'/exp OR 'recombinant beta interferon'/exp OR 'recombinant interferon'/de 3,564 #12 glatiramer:ti,ab,kw 8,209 #11 'glatiramer'/exp 1,141 #10 teriflunomide:ti,ab,kw 2,483 #9 'teriflunomide'/exp 161 #8 siponimod:ti,ab,kw 280 #7 'siponimod'/exp 4,045 #6 fingolimod:ti,ab,kw 8,692 #5 'fingolimod'/exp

2,200 #4 dimethyl AND fumarate:ti,ab,kw 3,333 #3 'fumaric acid dimethyl ester'/exp 2,247 #2 cladribine:ti,ab,kw 6,564 #1 'cladribine'/exp

3. Embase Search Strategy for Randomized Controlled Trials

Date of search: October 16, 2019 No. Query Results 496 #30 #23 AND #24 AND #25 NOT (#26 OR #27 OR #28) AND [2017-2019]/py 5,085 #29 #23 AND #24 AND #25 3,594,093 #28 'conference abstract'/it OR 'conference review'/it 2,772,112 #27 animal*:ti OR beaver*:ti OR beef:ti OR bovine:ti OR breeding:ti OR canine:ti OR castoris:ti OR cat:ti OR cattle:ti OR cats:ti OR chicken*:ti OR cow:ti OR dog:ti OR dogs:ti OR equine:ti OR foal:ti OR foals:ti OR fish:ti OR insect*:ti OR livestock:ti OR mice:ti OR mouse:ti OR murine:ti OR plant:ti OR plants:ti OR pork:ti OR porcine:ti OR protozoa*:ti OR purebred:ti OR rabbit*:ti OR rat:ti OR rats:ti OR rodent*:ti OR sheep:ti OR thoroughbred:ti OR veterinar*:ti,ab,de 6,878,274 #26 ('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) NOT (('animal'/exp OR 'invertebrate'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'animal tissue'/exp OR 'animal cell'/exp OR 'nonhuman'/de) AND ('human'/exp OR 'human cell'/de)) 1,242,640 #25 ('clinical study'/mj OR 'clinical trial'/mj OR 'controlled clinical trial'/mj OR 'major clinical study'/mj OR 'randomized controlled trial'/exp OR 'randomized controlled trial (topic)'/exp OR 'control group'/mj OR (((clinical OR randomi* OR controlled OR 'double-blind') NEAR/3 (study OR trial)):ti,ab) OR placebo:ab,ti OR 'head to head':ti,ab) AND [english]/lim 513,235 #24 #21 OR #22 474,641 #23 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #1 7 OR #18 OR #19 OR #20 492,294 #22 'ms':ti,ab,kw OR 'multiple sclero*':ti,ab,kw 125,839 #21 'multiple sclerosis'/exp 273 #20 dalfampridine:ti,ab,kw

7,561 #19 'fampridine'/exp 7,071 #18 mitoxantrone:ti,ab,kw 22,808 #17 'mitoxantrone'/exp 24,337 #16 alemtuzumab OR natalizumab OR ocrelizumab:ti,ab,kw 24,295 #15 'alemtuzumab'/exp OR 'natalizumab'/exp OR 'ocrelizumab'/exp 416,922 #14 interferon* OR peginterferon* OR ifn* OR 'pegylatedinterferon' OR 'pegylated interferon':ti,ab,kw 113,771 #13 'interferon'/de OR 'beta interferon'/exp OR 'peginterferon'/exp OR 'beta1 interferon'/exp OR 'peginterferon beta1a'/exp OR 'beta1a interferon'/exp OR 'recombinant beta interferon'/exp OR 'recombinant interferon'/de 3,679 #12 glatiramer:ti,ab,kw 8,335 #11 'glatiramer'/exp 1,232 #10 teriflunomide:ti,ab,kw 2,574 #9 'teriflunomide'/exp 171 #8 siponimod:ti,ab,kw 291 #7 'siponimod'/exp 4,244 #6 fingolimod:ti,ab,kw 8,900 #5 'fingolimod'/exp 2,334 #4 dimethyl AND fumarate:ti,ab,kw 3,477 #3 'fumaric acid dimethyl ester'/exp 2,283 #2 cladribine:ti,ab,kw 6,610 #1 'cladribine'/exp

Appendix B – Included and Excluded References

List of included references

1. Arroyo Gonzalez R, Kita M, Crayton H, et al. Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2017;23(10):1367-1376. 2. Krupp LB, Vieira MC, Toledano H, et al. A Review of Available Treatments, Clinical Evidence, and Guidelines for Diagnosis and Treatment of Pediatric Multiple Sclerosis in the United States. Journal of child neurology. 2019;34(10):612-620. 3. La Mantia L, Di Pietrantonj C, Rovaris M, et al. Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis. The Cochrane database of systematic reviews. 2016;11(100909747):CD009333. 4. Lucchetta RC, Tonin FS, Borba HHL, et al. Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis: A Network Meta-Analysis. CNS drugs. 2018;32(9):813-826. 5. Melendez-Torres GJ, Armoiry X, Court R, et al. Comparative effectiveness of beta-interferons and glatiramer acetate for relapsing-remitting multiple sclerosis: systematic review and network meta-analysis of trials including recommended dosages. BMC neurology. 2018;18(1):162. 6. Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. European journal of neurology. 2018;25(2):215-237. 7. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):777-788. 8. Rae-Grant A, Day GS, Marrie RA, et al. Comprehensive systematic review summary: Disease-modifying therapies for adults with multiple sclerosis. Neurology. 2018;90(17):789-800. 9. Salas PAO, Parra CO, Florez CEP, Goez LM, Velez-van-Meerbeke A, Rodriguez JH. Safety liver profile of teriflunomide versus interferon β in multiple sclerosis: Systematic review and indirect comparison meta- analysis. Multiple Sclerosis and Related Disorders. 2018;26((Rodriguez J.H.) Bogotá, Colombia):192-200. 10. Turner B, Cree BAC, Kappos L, et al. Ocrelizumab efficacy in subgroups of patients with relapsing multiple sclerosis. Journal of neurology. 2019;266(5):1182-1193. 11. Zhang J, Shi S, Zhang Y, et al. Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis. The Cochrane database of systematic reviews. 2017;11(100909747):CD010968.

List of excluded references

Wrong study design 1. Claflin SB, Broadley S, Taylor BV. The effect of disease modifying therapies on disability progression in multiple sclerosis: A systematic overview of meta-analyses. Frontiers in Neurology. 2019;10(JAN). 2. Xu X, Chi S, Wang Q, et al. Efficacy and safety of monoclonal antibody therapies for relapsing remitting multiple sclerosis: A network meta-analysis. Multiple sclerosis and related disorders. 2018;25(101580247):322-328. 3. Lucchetta RC, Leonart LP, Becker J, Pontarolo R, Fernandez-Llimos F, Wiens A. Safety outcomes of disease- modifying therapies for relapsing-remitting multiple sclerosis: A network meta-analysis. Multiple sclerosis and related disorders. 2019;35(101580247):7-15. 4. Ali ZK, Baker DE. Formulary drug review: Ocrelizumab. Hospital Pharmacy. 2017;52(9):599-606. 5. Alroughani R, Inshasi JS, Deleu D, et al. An Overview of High-Efficacy Drugs for Multiple Sclerosis: Gulf Region Expert Opinion. Neurology and therapy. 2019;8(1):13-23. 6. Armoiry X, Kan A, Melendez-Torres GJ, et al. Short- and long-term clinical outcomes of use of beta-interferon or glatiramer acetate for people with clinically isolated syndrome: a systematic review of randomised controlled trials and network meta-analysis. Journal of neurology. 2018;265(5):999-1009. 7. Ayrignac X, Bilodeau PA, Prat A, et al. Assessing the risk of multiple sclerosis disease-modifying therapies. Expert Review of Neurotherapeutics. 2019;19(7):695-706. 8. Barkhof F, Kappos L, Wolinsky JS, et al. Onset of clinical and MRI efficacy of ocrelizumab in relapsing multiple sclerosis. Neurology. 2019(0401060, nz0).

9. Bazzari FH. Available pharmacological options and symptomatic treatments of multiple sclerosis. Systematic Reviews in Pharmacy. 2018;9(1):17-21. 10. Berardi A, Siddiqui MK, Treharne C, Harty G, Wong SL. Estimating the comparative efficacy of cladribine tablets versus alternative disease modifying treatments in active relapsing-remitting multiple sclerosis: adjusting for patient characteristics using meta-regression and matching-adjusted indirect treatment comparison approaches. Current medical research and opinion. 2019;35(8):1371-1378. 11. Chan A, Cutter G, Fox RJ, Xiao J, Lewin JB, Edwards MR. Comparative effectiveness of delayed-release dimethyl fumarate versus glatiramer acetate in multiple sclerosis patients: results of a matching-adjusted indirect comparison. Journal of comparative effectiveness research. 2017;6(4):313-323. 12. Claflin SB, Tan B, Taylor BV. The long-term effects of disease modifying therapies on disability in people living with multiple sclerosis: A systematic review and meta-analysis. Multiple sclerosis and related disorders. 2019;36(101580247):101374. 13. Comi G, Patti F, Rocca MA, et al. Efficacy of fingolimod and interferon beta-1b on cognitive, MRI, and clinical outcomes in relapsing-remitting multiple sclerosis: an 18-month, open-label, rater-blinded, randomised, multicentre study (the GOLDEN study). Journal of neurology. 2017;264(12):2436-2449. 14. Cree BAC, Arnold DL, Cascione M, et al. Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial. Therapeutic advances in neurological disorders. 2018;11(101480242):1756286418774338. 15. Dahdaleh D, Sharrack B. We can compare the relative efficacy of multiple sclerosis medications by examining the results of independent clinical trials: Yes. Multiple Sclerosis. 2015;21(1):35-36. 16. Filippini G. Ocrelizumab appears to reduce relapse and disability in multiple sclerosis but quality of evidence is moderate. Evidence-Based Medicine. 2017;22(6):215-216. 17. Gaber T, Shippen C. Cladribine tablets and multiple sclerosis: NICE technology appraisal. Progress in Neurology and Psychiatry. 2018;22(1):5-6. 18. Gasim M, Bernstein CN, Graff LA, et al. Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review. Multiple sclerosis and related disorders. 2018;26(101580247):124-156. 19. Hartung H-P, Aktas O, Boyko AN. Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England). 2015;21(1):22-34. 20. Mayer L, Kappos L, Racke MK, et al. Ocrelizumab infusion experience in patients with relapsing and primary progressive multiple sclerosis: Results from the phase 3 randomized OPERA I, OPERA II, and ORATORIO studies. Multiple sclerosis and related disorders. 2019;30(101580247):236-243. 21. Poveda JL, Trillo JL, Rubio-Terres C, Rubio-Rodriguez D, Polanco A, Torres C. Cost-effectiveness of Cladribine Tablets and fingolimod in the treatment of relapsing multiple sclerosis with high disease activity in Spain. Expert review of pharmacoeconomics & outcomes research. 2019(101132257):1-9. 22. Stahnke AM, Holt KM. Ocrelizumab: A New B-cell Therapy for Relapsing Remitting and Primary Progressive Multiple Sclerosis. The Annals of pharmacotherapy. 2018;52(5):473-483. 23. Wray S, Havrdova E, Snydman DR, et al. Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study. Multiple sclerosis (Houndmills, Basingstoke, England). 2019;25(12):1605-1617. 24. Xu Z, Zhang F, Sun F, Gu K, Dong S, He D. Dimethyl fumarate for multiple sclerosis. The Cochrane database of systematic reviews. 2015(4):CD011076. 25. Yoon EL, Cheong WL. Adherence to oral disease-modifying therapy in multiple sclerosis patients: A systematic review. Multiple sclerosis and related disorders. 2019;28(101580247):104-108. 26. Zagmutt FJ, Carroll CA. Meta-analysis of adverse events in recent randomized clinical trials for dimethyl fumarate, glatiramer acetate and teriflunomide for the treatment of relapsing forms of multiple sclerosis. The International journal of neuroscience. 2015;125(11):798-807. 27. Ünsal MA. Trial of fingolimod versus interferon beta-1a in pediatric multiple sclerosis. Turk Noroloji Dergisi. 2019;25(1):50-51.

A more recent or more robust systematic review is available 28. de Lemos LLP, Guerra Junior AA, Santos M, et al. The Assessment for Disinvestment of Intramuscular Interferon Beta for Relapsing-Remitting Multiple Sclerosis in Brazil. PharmacoEconomics. 2018;36(2):161-173.

29. Canadian Agency for Drugs and Technologies in Health 2017. CADTH Common Drug Review. Clinical Review Report. Ocrelizumab (Ocrevus). December 2017. https://www.cadth.ca/sites/default/files/cdr/clinical/SR0519_Ocrevus_RMS_CL_Report.pdf. Accessed October 10, 2019. 30. Deleu D, Mesraoua B, Canibano B, et al. Oral disease-modifying therapies for multiple sclerosis in the Middle Eastern and North African (MENA) region: an overview. Current medical research and opinion. 2019;35(2):249- 260. 31. Fogarty E, Schmitz S, Tubridy N, Walsh C, Barry M. Comparative efficacy of disease-modifying therapies for patients with relapsing remitting multiple sclerosis: Systematic review and network meta-analysis. Multiple sclerosis and related disorders. 2016;9(101580247):23-30. 32. Gerardi C, Bertele V, Rossi S, Garattini S, Banzi R. Preapproval and postapproval evidence on drugs for multiple sclerosis. Neurology. 2018;90(21):964-973. 33. Govindappa K, Sathish J, Park K, Kirkham J, Pirmohamed M. Development of interferon beta-neutralising antibodies in multiple sclerosis--a systematic review and meta-analysis. European journal of clinical pharmacology. 2015;71(11):1287-1298. 34. Hamidi V, Couto E, Ringerike T, Klemp M. A Multiple Treatment Comparison of Eleven Disease-Modifying Drugs Used for Multiple Sclerosis. Journal of clinical medicine research. 2018;10(2):88-105. 35. He D, Zhang C, Zhao X, et al. Teriflunomide for multiple sclerosis. The Cochrane database of systematic reviews. 2016;3(100909747):CD009882. 36. La Mantia L, Di Pietrantonj C, Rovaris M, et al. Comparative efficacy of interferon β versus glatiramer acetate for relapsing-remitting multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry. 2015;86(9):1016- 1020. 37. La Mantia L, Tramacere I, Firwana B, Pacchetti I, Palumbo R, Filippini G. Fingolimod for relapsing-remitting multiple sclerosis. The Cochrane database of systematic reviews. 2016;4(100909747):CD009371. 38. Lu Y, Zhao J, Zhan Q. Effect of interferon-beta1alpha therapy on multiple sclerosis based on gadolinium- enhancing or active T2 magnetic resonance imaging outcomes: a meta-analysis. Neurological research. 2016;38(10):909-915. 39. Ma LH, Sun MJ, Yuan BY, Wang MX. Ocrelizumab in the treatment of relapsing multiple sclerosis: a Meta- analysis. Chinese Journal of New Drugs. 2019;28(11):1397-1403. 40. McCool R, Wilson K, Arber M, et al. Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis. Multiple sclerosis and related disorders. 2019;29(101580247):55-61. 41. Melendez-Torres GJ, Auguste P, Armoiry X, et al. Clinical effectiveness and cost-effectiveness of beta-interferon and glatiramer acetate for treating multiple sclerosis: systematic review and economic evaluation. Health technology assessment (Winchester, England). 2017;21(52):1-352. 42. Mendes D, Alves C, Batel-Marques F. Benefit-Risk of Therapies for Relapsing-Remitting Multiple Sclerosis: Testing the Number Needed to Treat to Benefit (NNTB), Number Needed to Treat to Harm (NNTH) and the Likelihood to be Helped or Harmed (LHH): A Systematic Review and Meta-Analysis. CNS drugs. 2016;30(10):909- 929. 43. Riera R, Porfírio GJM, Torloni MR. Alemtuzumab for multiple sclerosis. Cochrane Database of Systematic Reviews. 2016;2016(4). 44. Safavi M, Nikfar S, Abdollahi M. A systematic review of drugs in late-stage development for the treatment of multiple sclerosis: a focus on oral synthetic drugs. Inflammation & allergy drug targets. 2015;13(6):351-366. 45. Siddiqui MK, Khurana IS, Budhia S, Hettle R, Harty G, Wong SL. Systematic literature review and network meta- analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis. Current medical research and opinion. 2018;34(8):1361-1371. 46. Tolley K, Hutchinson M, You X, et al. A Network Meta-Analysis of Efficacy and Evaluation of Safety of Subcutaneous Pegylated Interferon Beta-1a versus Other Injectable Therapies for the Treatment of Relapsing- Remitting Multiple Sclerosis. PloS one. 2015;10(6):e0127960. 47. Tramacere I, Del Giovane C, Salanti G, D'Amico R, Filippini G. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. The Cochrane database of systematic reviews. 2015(9):CD011381.

Wrong comparator 48. Canadian Agency for Drugs and Technologies in Health 2018. CADTH Common Drug Review. Clinical Review Report. Cladribine (Mavenclad). October 2018. https://www.cadth.ca/sites/default/files/cdr/clinical/SR0546_Mavenclad_CL_Report.pdf. Accessed October 10, 2019. 49. Echave M, Oyagüez I, Casado Ruiz V, Ginestal R, Casado MÁ. Systematic review of studies of quality of life and/or work productivity in patients treated with natalizumab. Pharmacoeconomics - Spanish Research Articles. 2017;14(3-4):77-90. 50. Filippini G, Del Giovane C, Clerico M, et al. Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis. Cochrane Database of Systematic Reviews. 2017;2017(4). 51. Garcia-Ruiz AJ, Izquierdo-Ayuso G, Navarro-Mascarell G, et al. Efficacy of the Treatments Used in Multiple Sclerosis: From Meta-analysis to Number Needed to Treat. Clinical neuropharmacology. 2017;40(1):37-42. 52. Giovannoni G, Gold R, Fox RJ, et al. Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-related Hospitalizations: Integrated Analysis of the Delayed-release Dimethyl Fumarate Phase III Studies. Clinical therapeutics. 2015;37(11):2543-2551. Duplicates 53. He D, Zhang C, Zhao X, et al. Teriflunomide for multiple sclerosis. Cochrane Database of Systematic Reviews. 2016;2016(3). 54. La Mantia L, Tramacere I, Firwana B, Pacchetti I, Palumbo R, Filippini G. Fingolimod for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews. 2016;2016(4). 55. Lu Y, Zhao J, Zhan Q. Effect of interferon-β1α therapy on multiple sclerosis based on gadolinium-enhancing or active T2 magnetic resonance imaging outcomes: a meta-analysis. Neurological Research. 2016;38(10):909-915. 56. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777-788. 57. La Mantia L, Di Pietrantonj C, Rovaris M, et al. Interferons-beta versus glatiramer acetate for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews. 2016;2016(11). 58. La Mantia L, Di Pietrantonj C, Rovaris M, et al. Comparative efficacy of interferon beta versus glatiramer acetate for relapsing-remitting multiple sclerosis. Journal of neurology, neurosurgery, and psychiatry. 2015;86(9):1016- 1020. 59. Salas PAO, Parra CO, Florez CEP, Goez LM, Velez-van-Meerbeke A, Rodriguez JH. Safety liver profile of teriflunomide versus interferon beta in multiple sclerosis: Systematic review and indirect comparison meta- analysis. Multiple sclerosis and related disorders. 2018;26(101580247):192-200. 60. Wray S, Havrdova E, Snydman DR, et al. Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study. Multiple Sclerosis Journal. 2018((Daizadeh N.; Margolin D.H.; Chirieac M.C.) Sanofi, Cambridge, MA, United States). 61. Zhang J, Shi S, Zhang Y, et al. Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews. 2017;2017(11). Wrong intervention 62. Butler M, Forte ML, Schwehr N, Carpenter A, Kane RL. 2015. Data not available 63. Li H, Hu F, Zhang Y, Li K. Comparative efficacy and acceptability of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis. Journal of neurology. 2019(jb7, 0423161).

Appendix C – Evidence from Systematic Reviews of Multiple Sclerosis Agents

Table 1. Systematic Reviews/Meta-Analyses of Multiple Sclerosis Agents Identified from 2016 to September 2019 Reference/ Study Design Treatment Population Efficacy and Safety Results (Literature Interventions search date) Rae-Grant CIS DMTs vs. Relapsing-remitting multiple sclerosis 201819,23 RRMS placebo or ALE vs. SQ IFN beta-1a 44 µg TIW – RRMS individuals PPMS other DMTs Reduction in relapses SR, MA, and SPMS MA result of 2 studies (1 class I study: CARE-MS I and 1 class II study: CARE-MS II; 914 participants): NMA (literature (adults) - Proportion of people with RRMS with at least 1 relapse at 2 years: RR 0.43 (95% CI, 0.29-0.61), searches up to favoring ALE (high confidence in the evidence) Nov 2016) - ARR: RMD 0.26 (95% CI, 0.22-0.29), favoring ALE (high confidence in the evidence) Reduction in MRI new disease activity as measured by new T2 lesion burden or atrophy measures One study (CARE-MS I, 563 individuals) - Decrease in T2 lesion volume from baseline to 2 years: SMD 0.18 (95% CI, 0.01–0.36), favoring ALE (moderate confidence in the evidence) - Proportion of people with MS with new or enlarging T2 lesions at 2 years: RR 0.84 (95% CI, 0.71–0.99), favoring ALE (moderate confidence in the evidence) One study (CARE-MS II) - Decrease in T2 lesion volume from baseline to 3 years: no differences between groups (very low confidence in the evidence) - Reduction in brain volume on T1 from baseline to 3 years: SMD of 0.37 (95% CI, 0.07–0.67), favoring ALE (less brain volume loss with ALE) (moderate confidence in the evidence) Disability progression MA result of 2 studies (1 class I study: CARE-MS I and 1 class II study: CARE-MS II) - Proportion of people with MS with disability progression sustained for 6 months over 2 years: RR 0.44 (95% CI, 0.28–0.70), favoring ALE One study (CARE-MS I) - Proportion of people with MS with confirmed disability improvement on the EDSS of at least 0.5 points from baseline to 24 months: RR was 1.55 (95% CI, 1.23–1.98), favoring ALE Safety MA of 3 studies (CARE-MS I, CARE-MS II and CAMMS223): - AE-related discontinuations at 24 months: RD -4.4% (95% CI, -7.0 to -1.8), favoring ALE (more discontinations in the IFN group) (low confidence in the evidence

Table 1. Systematic Reviews/Meta-Analyses of Multiple Sclerosis Agents Identified from 2016 to September 2019 Reference/ Study Design Treatment Population Efficacy and Safety Results (Literature Interventions search date) - Risk of cancer, death, liver toxicity, serious infection, or immune thrombocytopenic purpura: no differences between groups (very low confidence in the evidence) - Higher risk of “thyroid-associated” events (e.g., hyperthyroidism, hypothyroidism, thyroiditis, goiter, and thyroid cyst) with ALE: RD of 13.9% (95% CI, 9.3–18.6) (high confidence in the evidence) FIN vs. IM IFN beta-1a 30 µg QW – RRMS individuals 1 class I study (TRANSFORMS study, 860 individuals) - Proportion of people with RRMS with at least 1 relapse at 12 months: RR 0.58 (95% CI, 0.46-0.75), favoring FIN (high confidence in the evidence) - ARR: RMD 0.17 (95% CI, 0.08-0.26), favoring FIN (high confidence in the evidence) - Proportion of individuals with new or enlarged T2 lesions at 12 months: RR 0.83 (95% CI, 0.72–0.96), favoring FIN (moderate confidence in the evidence) - Disability progression sustained for 3 months over 1 year: RR 0.74 (95% CI, 0.45–1.21) (low confidence in the evidence) GA vs. SQ IFN beta-1a 44 µg TIW – RRMS individuals 1 class II study (REGARD study; 764 individuals) - Proportion of people with RRMS with at least 1 relapse at 2 years: RR 0.93 (95% CI, 0.77-1.14) (low confidence in the evidence) - Proportion of people with active T2 lesions at 2 years: RR 0.95 (95% CI, 0.82–1.11) (low confidence in the evidence) GA vs. SQ IFN beta-1b 250 µg alternate day – RRMS individuals MA of 2 class II studies (BECOME and BEYOND studies; 1,420 individuals) - Proportion of people with RRMS with at least 1 relapse at 2 years: RR 1.19 (95% CI, 0.75-1.90) (low confidence in the evidence) - Proportion of individuals with confirmed disability progression over 2 years: RR of 1.32 (95% CI, 1.08– 1.64), favoring GA (moderate confidence in the evidence) GA vs. IM IFN beta-1a 30 µg QW– RRMS individuals 1 class I study (CombixRx, 509 individuals) - Proportion of people with RRMS with at least 1 relapse over 3 years: RR 1.27 (95% CI, 0.93-1.74) (low confidence in the evidence) - Proportion of individuals with EDSS progression over 3 years: RR 0.87 (95% CI, 0.63–1.20) (low confidence in the evidence) IM IFN beta-1a 30 µg QW vs. SQ IFN beta-1a 44 µg TIW– RRMS 1 class II study (EVIDENCE trial 2002; 677 individuals)

Table 1. Systematic Reviews/Meta-Analyses of Multiple Sclerosis Agents Identified from 2016 to September 2019 Reference/ Study Design Treatment Population Efficacy and Safety Results (Literature Interventions search date) - Proportion of people with RRMS with at least 1 relapse at 1 year: RR 0.84 (95% CI, 0.72–0.99), favoring SQ IFNβ-1a (moderate confidence in the evidence) - Proportion of individuals with new or enlarging T2 lesions at 1 year: RR 0.67 (95% CI, 0.58–0.78), favoring SQ IFNβ-1a (moderate confidence in the evidence)

OCR 600 mg IV vs. SQ IFN beta-1a 44 µg TIW - RRMS 2 class I studies (OPERA I and OPERA II; 1,656 individuals) - ARR: RMD 0.130 (95% CI, 0.078–0.182), favoring OCR (high confidence in the evidence) - Proportion of individuals with new or enlarging T2 lesions at 2 years: RR 0.63 (95% CI, 0.57–0.70), favoring OCR (high confidence in the evidence) - Mean percentage brain volume change from week 24 to 96: SMD 0.148 (95% CI, 0.051–0.244), favoring OCR (high confidence in the evidence) - Proportion of individuals with disability progression sustained for 3 months over 2 years: 0.67 (95% CI, 0.51–0.88), favoring OCR (high confidence in the evidence) - Proportion of individuals with confirmed disability progression for 6 months over 2 years: RR 0.67 (95% CI, 0.50–0.89), favoring OCR (high confidence in the evidence) No head-to-head comparisons of cladribine, dimethyl fumarate, mitoxantrone, natalizumab, pegylated interferon Progressive multiple sclerosis (PPMS or SPMS) No head-to-head comparisons. Evidence is only available for cladribine, glatiramer acetate, fingolimod, IM IFNβ-1a 30 µg, SQ IFNβ-1a 44 µg TIW, SQ IFNβ-1b 250 µg alternate day, or ocrelizumab versus placebo Montalban CIS DMTs vs. Relapsing-remitting multiple sclerosis 201844 RRMS placebo or TER vs. SQ IFN beta-1a 44 µg – RRMS individuals PPMS other DMTs 1 RCT (TENERE study 2014; 324 patients for ITT population); rated as low-quality evidence SR and MA SPMS - Higher proportion of participants free from relapse in the IFN group compared to TER (RR = 0.68, 95% (literature (adults) CI: 0.57–0.82; N = 342) searches up to - Little difference between groups in the ARR at 48 weeks Dec 2015) Results from TENERE study (Vermersch 2014): Primary composite endpoint: time to failure (ie, first occurrence of confirmed relapse or permanent treatment discontinuation for any cause) - Percentage of treatment failure at week 48 using the Kaplan–Meier method: IFN beta 37% [probability of failure (95% CI): 0.37 (0.27, 0.46)] 61

Table 1. Systematic Reviews/Meta-Analyses of Multiple Sclerosis Agents Identified from 2016 to September 2019 Reference/ Study Design Treatment Population Efficacy and Safety Results (Literature Interventions search date) TER 7 mg 36% [probability of failure (95% CI): 0.36 (0.27, 0.45)] TER 14 mg 33% [probability of failure (95% CI): 0.33 (0.25, 0.42) (No significant differences between IFN and TER) Secondary endpoints: - ARR: o IFN vs. TER 14 mg (estimate, 95% CI: 0.22 vs. 0.26, p=0.6) (no differences) o IFN vs. TER 7 mg (estimate, 95% CI: 0.22 vs. 0.41, p=0.03) (TER 7 mg was worse than IFN) - Percentage of patients free of relapse: o IFN 80.8% vs. TER 7 mg 57.8% vs. TER 14 mg 73.9% (no statistical analysis for this comparison) IFN beta (all non-pegylated formulations combined) vs. GA - Number of patients relapse free at 96-104 weeks: no differences - ARR at 96-104 weeks: no differences - New T2 white matter lesion at 104 weeks: no differences - Number of new gadolinium lesions at 104 weeks: no differences - Number of new cortical lesions at 48 weeks: no differences - Discontinuations due to any reason at 48 and 96- 106 weeks: no differences - Discontinuations due to adverse events at 48 and 96-104 weeks: no differences Melendez- RRMS IFN beta vs. IFN beta-1a 30 µg IM once weekly vs. SQ IFN beta-1a 44 µg 3 times weekly Torres 201850 (adults) IFN beta - ARR endpoint: MA of 3 RCTs (Calabrese 2012, EVIDENCE 2007, and Etemadifar 2006)54-56 GA vs. IFN ARR: risk ratio, 0.90 95% CI (0.73, 1.10) SR, MA beta IFN beta−1a 30 μg IM weekly vs. IFN beta−1b 250 μg SC every other day (literature - ARR endpoint: MA of 2 RCTs (Durelli 2002 [INCOMIN study57] and Etemadifar 200656) searches up to ARR: risk ratio, 1.12 95% CI (0.71, 1.78) Jan-Feb 2016) IFN beta−1a 30 μg IM weekly vs. GA 20 mg SC daily - ARR endpoint: MA of 2 RCTs (CombiRx and Calabrese 2012) ARR: risk ratio, 1.25 95% CI (0.85, 1.84) IFN beta−1a 44 μg SC thrice weekly vs. GA 20 mg SC daily - ARR endpoint: MA of 2 RCTs (Calabrese 2012 and REGARD 2008) ARR: risk ratio, 0.95 95% CI (0.74, 1.22) IFN beta−1a 44 μg SC thrice weekly vs. IFN beta−1b 250 μg SC every other day - ARR endpoint: MA of 2 RCTs (Etemadifar 2006 and Singer 2012 [REFORMS study])

Table 1. Systematic Reviews/Meta-Analyses of Multiple Sclerosis Agents Identified from 2016 to September 2019 Reference/ Study Design Treatment Population Efficacy and Safety Results (Literature Interventions search date) ARR: risk ratio, 1.05 95% CI (0.76, 1.45) IFN beta−1b 250 μg SC every other day vs. GA 20 mg SC daily - ARR endpoint: MA of 2 RCTs (Cadavid 2009 [BECOME study]59 and O’Connor 2009 [BEYOND study]60 ARR: risk ratio, 1.06 95% CI (0.93, 1.22) Lucchetta RRMS DMTs vs. ALE 12 mg vs IFN beta-1a 44 TIW 201821 (adults) placebo or - ARR (MA of 3 RCTs): HR 0.45, 95% CI (0.40; 0.52), favors ALE other DMTs - Disability progression at 24 weeks (MA of 2 RCTs): HR 0.67, 95% CI (0.50; 0.91), favors ALE SR, MA, NMA - Discontinuation due to adverse events at 96 weeks (MA of 2 RCTs): Relative risk 0.34, 95% CI (literature (0.17; 0.69) searches up to OCR 600 Q6M vs IFN beta-1a 44 TIW May 2017) - ARR (MA of 3 RCTs): HR 0.55, 95% CI (0.47; 0.64), favors OCR - Disability progression at 12 weeks (MA of 2 RCTs): HR 0.67, 95% CI (0.51; 0.88), favors OCR - Disability progression at 24 weeks (MA of 2 RCTs): HR 0.66, 95% CI (0.48; 0.91), favors OCR - Discontinuation due to adverse events at 96 weeks (MA of 2 RCTs): Relative risk 0.57, 95 % CI (0.36; 0.90) - Disability improvement confirmed at 12 weeks (MA of 2 RCTs): no differences - Quality of life – Physical component – 96 weeks: no differences GA 20 mg QD vs IFN beta-1a 44 TIW - ARR (MA of 2 RCTs): no differences GA 20 mg QD vs. IFN beta-1a 30 QW - ARR (MA of 2 RCTs): HR 0.76, 95% CI (0.60; 0.97), favors GA La Mantia RRMS IFN betas (all IFN betas at high frequencies and dosages vs. GA 201649 together) vs. - Number of participants with relapse, risk of confirmed progression, time to first relapse, and GA number of patients treated with steroids: no differences SR, MA - Relapse frequency for 1 single study at 36 months (Lublin 2013-CombiRx): RR 1.40, 95% CI 1.13 to (literature 1.74, p=0.002); significantly higher relapse rates with IM IFN beta-1a 30 µg compared to GA 20 mg searches up to daily Aug 2016) - MRI measures: no differences - Discontinuations due to adverse events: no differences

Table 1. Systematic Reviews/Meta-Analyses of Multiple Sclerosis Agents Identified from 2016 to September 2019 Reference/ Study Design Treatment Population Efficacy and Safety Results (Literature Interventions search date) Zhang 201766 RRMS ALE vs. IFN IV ALE (12mg per day on five consecutive days during the first month and on 3 consecutive days at months beta-1a 12, 24, 36) vs. SQ IFN beta 1a (Rebif ) 44 μg 3 times per week SR, MA - Number of participants experiencing at least one relapse at 24 and 36 months (MA of 3 RCTs – (literature CARE-MS I, CARE-MS II, and CAMMS223): risk ratio 0.60, 95% CI 0.52 to 0.70 (moderate quality searches up to evidence), favors ALE Feb 2017) - Risk of worsening disability at 24 and 36 months (MA of 3 RCTs): risk ratio 0.60, 95% CI 0.45 to 0.79 (low quality evidence) - Risk of developing new T2 lesions on MRI at 24 and 36 months (MA of 2 RCTs): risk ratio 0.75, 95% CI 0.61 to 0.93 (low quality evidence) - Mean Expanded Disability Status Scale (EDSS) scores from baseline at 24 and 26 months: mean difference (MD) -0.35, 95% CI -0.73 to 0.03 (low quality evidence): no differences between groups - Risk of experiencing an adverse event or serious adverse events: no differences Krupp 201926 Pediatric FIN vs. IFN 1 phase 3 RCT (PARADIGMS study74) of FIN 0.5 mg daily (0.25 mg daily for patients with body weight ≤40 patients (10 beta-1a kg) vs. IM IFN beta-1a 30 µg once weekly SR to 17 years) - Adjusted ARR: 0.12 for FIN vs. 0.67 with IFN (absolute difference, 0.55 relapses; relative (literature with difference, 82%; P<0.001) searches from relapsing - Annualized rate of new or newly enlarged lesions on T2-weighted MRI: 4.39 for FIN vs. 9.27 for 1974 to 2016) MS IFN (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001) - Serious adverse events: 18 patients with FIN (infections, leukopenia, convulsions) vs. 7 patients with IFN (infections and supraventricular tachycardia) Abbreviations: ALE, alemtuzumab; ARR, annualized relapse rate; CI, confidence interval; CIS, clinically isolated syndromes; DMT, disease modifying therapy; EDSS; Expanded Disability Status Scale; FIN, fingolimod; GA, glatiramer acetate; HR, hazard ratio; IFNβ, interferon beta; IM, intramuscular; IV, intravenous; ITT, intention-to-treat; IV, intravenous; MA, meta-analysis; MRI, magnetic resonance imaging; NMA, network meta-analysis; OCR, ocrelizumab; PPMS, primary progressive multiple sclerosis; QD, once daily; QW, once weekly; RD, risk difference; RMD, raw mean difference; RR, risk ratio or relative risk; RRMS, relapsing-remitting multiple sclerosis; SMD, standardized mean difference; SPMS, secondary progressive multiple sclerosis; SQ, subcutaneous; SR, systematic review; TER, teriflunomide; TIW, three times per week

Appendix D. Randomized Controlled Trials Included in the Selected Systematic Reviews for Multiple Sclerosis

Table 1. Randomized Controlled Trials Included in the Selected Systematic Reviews for Multiple Sclerosis SYSTEMATIC REVIEWS Randomized Controlled Trials Krupp 2019 Rae-Grant 2018 Montalban Lucchetta Melendez La Mantia Zhang 2017 (pediatrics) (AAN Guideline) 2018 201821 -Torres 201649 66 (Cochrane First Author (Study name) - Population 26 and SR19,23 (ECTRIMS/EAN 201850 (Cochrane Review) guideline)44 Review) Glatiramer acetate vs. SQ interferon beta-1b (Betaseron) Cadavid 2009 (BECOME)59 – RRMS or CIS (14% to 23% of patients had CIS) (treatment naïve X X X X patients) O’Connor 2009 (BEYOND)60 – RRMS (treatment X X X X X naïve patients) Glatiramer acetate vs. IM interferon beta-1a (Avonex) Lublin 2013 (CombiRx)62 - RRMS X X X X Calabrese 201255 – RRMS (untreated patients) X X X X Glatiramer acetate vs. SQ interferon beta-1a (Rebif) Mikol 2008 (REGARD)61 – RRMS (DMT naïve) X X X X X Alemtuzumab vs.SQ interferon beta-1a (Rebif) Coles 2008 (CAMMS223 – phase 2 trial)63 – RRMS X X X (previously untreated patients) Cohen 2012 (CARE-MS I – phase 3 trial)64 - RRMS X X X X (previously untreated patients) Coles 2012 (CARE-MS II – phase 3 trial)65 - RRMS X X X X (patients on MS drugs) Interferon beta-1a SQ (Rebif) vs. IM interferon beta-1a (Avonex) Schwid 2007 (EVIDENCE)54 – RRMS (treatment X X naïve patients) Panitch 2002 (EVIDENCE)53 – RRMS (IFN naïve X patients) Etemadifar 200656 - RRMS X Calabrese 201255 - RRMS (untreated patients) X

Table 1. Randomized Controlled Trials Included in the Selected Systematic Reviews for Multiple Sclerosis SYSTEMATIC REVIEWS Randomized Controlled Trials Krupp 2019 Rae-Grant 2018 Montalban Lucchetta Melendez La Mantia Zhang 2017 (pediatrics) (AAN Guideline) 2018 201821 -Torres 201649 66 (Cochrane First Author (Study name) - Population 26 and SR19,23 (ECTRIMS/EAN 201850 (Cochrane Review) guideline)44 Review) Interferon beta-1b SQ (Betaseron) vs. IM interferon beta-1a (Avonex) Durelli 2002 (INCOMIN)57 – RRMS (previously X X untreated patients) Etemadifar 200656 - RRMS X Interferon beta-1b SQ (Betaseron) vs. SQ interferon beta-1a (Rebif) Etemadifar 200656- RRMS X REFORMS 2012 – RRMS (IFN naïve patients) X Teriflunomide vs. SQ interferon beta-1a (Rebif) Vermersch 2014 (TENERE)52 – Relapsing MS with or without progression (only 1-2% of patients had X X SPMS or progressive relapsing MS) (12-24% of patients were previously treated with IFN or GA) Fingolimod vs. IM interferon beta-1a (Avonex) Cohen 2010 (TRANSFORMS)51 – RRMS (more than 50% of patients were previously treated with IFN, X X X GA, or NAT) Khatri 2011 (extension of the TRASFORMS study)73 X Cohen 2016 (extension of the TRANSFORMS X study)74 Chitnis 2016-2018 (PARADIGMS study)70 – Relapsing MS (treatment naïve and previously X treated patients) Ocrelizumab vs. IM interferon beta-1a (Avonex) Hauser 2017 (OPERA I and OPERA II)68 – Relapsing MS (more than 70% of patients were treatment X X X naïve) Kappos 2011 (phase 2 study)75 – RRMS (50% to X X 70% of patients were treatment naïve) Abbreviations: CIS, clinically isolated syndrome; DMT, disease modifying therapy; GA, glatiramer acetate; IFN, interferon; MS, multiple sclerosis; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive MS; SR, systematic review