Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.

INTRODUCTION: In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. METHODS: EVOLVE-MS-1-an open-label, 96-week, phase 3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). RESULTS: Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week 96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week 96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week 96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week 96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week 96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. CONCLUSION: In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02634307.

Early use of high-efficacy therapies in multiple sclerosis in the United States: benefits, barriers, and strategies for encouraging adoption.

Multiple sclerosis (MS) is characterized by progressive neuroinflammation and neurodegeneration from disease onset that, if left untreated, can result in the accumulation of irreversible neurological disability. Early intervention with high-efficacy therapies (HETs) is increasingly recognized as the best strategy to delay or mitigate disease progression from the earliest stages of the disease and to prevent long-term neurodegeneration. Although there is growing clinical and real-world evidence supporting early HET intervention, foregoing this strategy in favor of a traditional escalation approach prioritizing lower-efficacy disease-modifying therapies remains a common approach in clinical practice. This review explores potential health care professional- and patient-related barriers to the early use of HETs in patients with MS in the United States. Barriers can include regulatory and reimbursement restrictions; knowledge gaps and long-term safety concerns among health care professionals; and various individual, cultural, and societal factors affecting patients. Potential strategies for overcoming these barriers and encouraging early HET use are proposed.

Twenty Years of Subcutaneous Interferon-Beta-1a for Multiple Sclerosis: Contemporary Perspectives.

Multiple sclerosis (MS) is a chronic, progressive, inflammatory disorder of the central nervous system. Relapsing-remitting MS (RRMS), the most common form of the disease, is characterized by transient neurological dysfunction with concurrent accumulation of disability. Over the past three decades, disease-modifying therapies (DMTs) capable of reducing the frequency of relapses and slowing disability worsening have been studied and approved for use in patients with RRMS. The first DMTs were interferon-betas (IFN-ßs), which were approved in the 1990s. Among them was IFN-ß-1a for subcutaneous (sc) injection (Rebif®), which was approved for the treatment of MS in Europe and Canada in 1998 and in the USA in 2002. Twenty years of clinical data and experience have supported the efficacy and safety of IFN-ß-1a sc in the treatment of RRMS, including pivotal trials, real-world data, and extension studies lasting up to 15 years past initial treatment. Today, IFN-ß-1a sc remains an important therapeutic option in clinical use, especially around pregnancy planning and lactation, and may also be considered for aging patients, in which MS activity declines and long-term immunosuppression associated with some alternative therapies is a concern. In addition, IFN-ß-1a sc is used as a comparator in many clinical studies and provides a framework for research into the mechanisms by which MS begins and progresses.

Diroximel fumarate in patients with relapsing-remitting multiple sclerosis: Final safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF. OBJECTIVE: To report final outcomes from EVOLVE-MS-1. METHODS: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory. RESULTS: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15). CONCLUSION: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

Safety and efficacy with alemtuzumab over 13 years in relapsing-remitting multiple sclerosis: final results from the open-label TOPAZ study.

Background and objectives: Alemtuzumab demonstrated superior efficacy versus subcutaneous interferon (IFN) beta-1a in participants with relapsing-remitting multiple sclerosis in the 2-year CARE-MS I and II trials. Efficacy was maintained in the 4-year CARE-MS extension, during which alemtuzumab-treated participants ('alemtuzumab-only') could receive additional courses upon disease activity, and IFN-treated participants switched to alemtuzumab ('IFN-alemtuzumab'). Participants who completed the CARE-MS extension could enroll in the open-label TOPAZ study which assessed safety and efficacy for 5-7 years (11-13 years after alemtuzumab/IFN initiation). Methods: Participants received additional alemtuzumab courses as needed. Assessments included adverse events (AEs; primary outcome), annualized relapse rate (ARR), 6-month confirmed disability worsening [CDW; ⩾1.0-point Expanded Disability Status Scale (EDSS) score increase or ⩾1.5 if baseline EDSS = 0], and 6-month confirmed disease improvement [CDI; >1.0-point EDSS decrease (baseline score ⩾2.0)]. Results: 43.5% of alemtuzumab-only participants from CARE-MS II and 54.2% from CARE-MS I received no additional alemtuzumab courses; 30.0% and 20.9%, respectively, received one additional course (the median). Incidences of AEs, including thyroid AEs and infections, declined over time. The safety profile of alemtuzumab was similar for participants who received zero, one, or two additional courses. For CARE-MS II participants, who had inadequate response to previous treatment, ARR remained low during Years 3-13 for the alemtuzumab-only [0.17; 95% confidence interval (CI) 0.15-0.20] and IFN-alemtuzumab (0.14; 0.11-0.17) groups. At Year 11, the proportions of participants who were either free from CDW or who had CDI were higher in the alemtuzumab-only group (58% and 49%, respectively) than in the IFN-alemtuzumab group (51% and 37%). For CARE-MS I participants, who were previously treatment-naïve, clinical outcomes remained improved, and no between-group differences were apparent. Conclusion: Safety risks associated with alemtuzumab treatment declined over time. Clinical benefits were maintained up to 11-13 years, and most participants did not require more than one additional course. Clinicaltrialsgov identifiers: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Secondary Progressive Multiple Sclerosis: A Review of Clinical Characteristics, Definition, Prognostic Tools, and Disease-Modifying Therapies.

Many challenges exist in the precise diagnosis and clinical management of secondary progressive multiple sclerosis (SPMS) because of the lack of definitive clinical, imaging, immunologic, or pathologic criteria that demarcate the transition from relapsing-remitting MS to SPMS. This review provides an overview of the diagnostic criteria/definition and the heterogeneity associated with different SPMS patient populations; it also emphasizes the importance of available prospective/retrospective tools to identify patients with SPMS earlier in the disease course so that approved disease-modifying therapies and nonpharmacological strategies will translate into better outcomes. Delivery of such interventions necessitates an evolving patient-clinician dialog within the context of a multidisciplinary team.

Immune cell subset profiling in multiple sclerosis after fingolimod initiation and continued treatment: The FLUENT study.

Background: Fingolimod is a sphingosine 1-phosphate receptor modulator approved for relapsing MS. Long-term effects on the immunological profile are not fully understood. Objective: Investigate fingolimod's temporal effects on immune cell subsets, and safety outcomes. Methods: In FLUENT, a 12-month, prospective, non-randomized, open-label, phase IV study, adult participants received fingolimod 0.5 mg/day. Changes in immune cell subsets, anti-John Cunningham virus (JCV) antibody index, and serum neurofilament levels were assessed. Results: 165 fingolimod-naive and 217 participants treated for 2-12 years in routine clinical practice were enrolled. Levels of all monitored peripheral lymphocyte subsets were reduced from month 3 in fingolimod-naive participants. Greatest reductions occurred in naive and central memory CD4+ and CD8+ T cells, and in naive and memory B cells. Most lymphocyte subset levels remained stable in the continuous fingolimod group. Components of the innate immune system remained within reference ranges. No increase in JCV seropositivity was observed. No single cellular subset correlated with anti-JCV antibody index at any time point. Neurofilament levels remained within healthy adult reference limits throughout. No opportunistic infections were reported; no new or unexpected safety signals were observed. Conclusion: FLUENT provides insights into the utility of immunological profiling to evaluate therapy response and potential infection risk.

Health-Related Quality of Life with Diroximel Fumarate in Patients with Relapsing Forms of Multiple Sclerosis: Findings from Qualitative Research Using Patient Interviews.

INTRODUCTION: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS). Clinical and real-world studies of DRF have demonstrated improved gastrointestinal (GI) tolerability and low (< 1%) GI-related treatment discontinuation versus dimethyl fumarate (DMF) and high rates of treatment adherence. Our aim was to conduct a concept elicitation study to identify treatment-related concepts most meaningful to patients and to evaluate how these concepts shape the patient perspective of DRF. METHODS: In-depth qualitative interviews were conducted with patients from October to December 2020. US adults who had been prescribed DRF through routine clinical care and had taken DRF for ≥ 3 weeks in the past 6 months were eligible to participate. Semi-structured interviews explored patient perceptions on treatment selection and impact. RESULTS: Seventeen patients participated in the study. Mean (SD) age was 49.3 (12.0) years. Sixteen patients reported prior disease-modifying therapy, while 10 (58.8%) had prior DMF. DRF treatment duration ranged from ~ 6 weeks to 10 months. Four key concepts emerged: (1) overall wellness and quality of life, (2) ease of administration, (3) minimal and manageable side effects, and (4) patient optimism due to MS treatments. Mode of administration (82.4%), no/mild side effects (70.6%), convenience over injectable/infusion medications (58.8%), and effectiveness (64.7%) were cited as positive aspects of DRF treatment. Frequent dosing (52.9%) and food requirements (41.2%) were cited as negative attributes; however, 94.1% had no dietary changes since starting treatment. CONCLUSION: The patient perspective is a key aspect when considering a disease-modifying therapy for MS, given the multitude of options currently available. Overall wellness, ease of administration, and minimal and manageable side effects were DRF-related concepts most meaningful to patients on therapy. Acknowledging these patient perceptions in shared decision-making may lead to greater patient adherence and optimal treatment outcomes.

Multiple sclerosis (MS), an immune-related disease, may present with neurological symptoms that come and go. Diroximel fumarate (DRF) is a next-generation oral treatment for MS, which has been shown in clinical trials to have fewer gastrointestinal side effects compared to dimethyl fumarate (DMF), another oral treatment. Patients' perspective can shed light on what they value when choosing a treatment, so we interviewed 17 people with MS about how DRF treatment affects their daily life and work. The study participants (49.3 years old on average) received DRF for ~ 6 weeks to 10 months. Around 5 in 10 people had positive feelings about their current health following treatment with DRF. Most felt there was either improvement or no negative change in quality of life since starting DRF treatment; DRF did not affect their work or daily obligations. Treatment characteristics of DRF that were perceived as most important included ease of administration, minimal and manageable side effects, and the facilitation of overall wellness and quality of life. While the oral dosing of DRF was more convenient than injectable or infusion therapy options, about half of the respondents preferred a less frequent treatment regimen than the twice daily dosing of DRF which needs to be taken with food. However, those who switched to DRF from DMF (or other oral medications for MS) expressed that the transition was smooth. Understanding factors that are important to patients can guide treatment choices and help patients stay on treatment longer and have better MS outcomes.

Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study.

INTRODUCTION: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated. METHODS: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1. RESULTS: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%). CONCLUSION: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: The CLARITY extension study.

BACKGROUND: No evidence of disease activity (NEDA-3) is a patient-centric outcome increasingly used as the goal of multiple sclerosis treatment. OBJECTIVE: Determine treatment durability of cladribine tablets beyond 2 years considering the variable bridging interval of 0.1-116.0 weeks between CLARITY and CLARITY Extension. METHODS: Between CLARITY and CLARITY Extension, patients transitioned from cladribine tablets 3.5 mg/kg to placebo (CP3.5 group, n = 98) or continued further treatment with cladribine tablets 3.5 mg/kg (CC7.0 group, n = 186). Treatment assignment was randomized and blinded in both CLARITY and CLARITY Extension. RESULTS: The 2-year NEDA-3 in CLARITY Extension (encompassing both years of CLARITY Extension) was 29.6% in the CP3.5 group and 32.8% in the CC7.0 group. There was no evidence that treatment effect differed with varying bridging intervals. For patients in the CP3.5 group with a bridging interval of ⩽48 weeks, 1 year NEDA-3 (the first year of CLARITY Extension) was 44.4% (28/63) compared with 31.4% (11/35) in patients with a bridging interval of >48 weeks. CONCLUSION: Treatment with cladribine tablets in CLARITY, followed by either placebo or cladribine tablets in CLARITY Extension, produced sustained benefits for NEDA-3 and its constituent elements for a follow up period up to 6 years from CLARITY baseline.

A Study Comparing Patient and Clinician Perspectives of Treatments for Multiple Sclerosis via Group Concept Mapping.

BACKGROUND: Clinicians treating multiple sclerosis (MS) should consider patient preferences when making treatment decisions. An online mixed-methods approach to elicit patient-centered concepts, group concept mapping (GCM), was used to generate statements reflecting the patient experience in relapsing-remitting MS and identify the most important patient-centered outcomes from patient and clinician perspectives. PATIENTS AND METHODS: Twenty patients and 12 MS specialists in the United States provided statements describing what an ideal treatment would do to improve symptoms and daily functioning. Statements were sorted by participants into meaningful domains and rated on importance on an 11-point scale. RESULTS: Sixty-four unique statements supporting 6 domains of clustered concepts were generated. Patient and clinician ratings of importance were highly correlated (r=0.82); however, patients rated the domains of Activities of Daily Living, Prevent & Cure, and Address Symptoms as highest in importance, whereas clinicians rated Prevent & Cure, Safe & Effective, and Activities of Daily Living as highest in importance. Statements rated above the domain mean by both patients and clinicians included "Improve cognitive function" and "Improve motor function" in the Activities of Daily Living domain and "Help with memory issues" and "Help preserve cognition" in the Address Symptoms domain. The statement "Improve short term memory" was 1 of 3 statements rated above the domain mean by patients but below the domain mean by clinicians. CONCLUSION: High levels of agreement of concept importance were found between patients and MS specialists, although certain domains and statements were rated more highly by one group. Overall, concepts such as cognitive function, physical and emotional functioning, and activities of daily living were perceived as having great importance for treatment outcomes versus symptom-focused outcomes like gait or tingling sensations. This comprehensive concept model for the MS patient experience can be used for further development of patient-centered outcome measures in MS treatment.

Improved gastrointestinal profile with diroximel fumarate is associated with a positive impact on quality of life compared with dimethyl fumarate: results from the randomized, double-blind, phase III EVOLVE-MS-2 study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS). DRF demonstrated significantly improved gastrointestinal (GI) tolerability versus dimethyl fumarate (DMF) with fewer days of Individual Gastrointestinal Symptom and Impact Scale (IGISIS) scores ⩾2, GI adverse events (AEs), and treatment discontinuations due to GI AEs. Our aim was to evaluate the impact of GI tolerability events on quality of life (QoL) for patients with relapsing-remitting MS who received DRF or DMF in EVOLVE-MS-2. METHODS: A post hoc analysis was conducted in patients who were enrolled in the randomized, blinded, 5-week, EVOLVE-MS-2 [ClinicalTrials.gov identifier: NCT03093324] study of DRF versus DMF. Patients completed daily IGISIS and Global GISIS (GGISIS) eDiary questionnaires to assess GI symptom intensity and interference with daily activities and work. RESULTS: In total, 504 patients (DRF, n = 253; DMF, n = 251) received study drug and 502 (DRF, n = 253; DMF, n = 249) completed at least one post-baseline questionnaire. With DRF, GI symptoms were less likely to interfere 'quite a bit' or 'extremely' with regular daily activities [IGISIS: DRF, 9.5% (24/253) versus DMF, 28.9% (72/249)] or work productivity [GGISIS: DRF, 6.1% (10/165) versus DMF, 11.3% (18/159)]. DRF-treated patients had fewer days with ⩾1 h of missed work (DRF, 43 days, n = 20 versus DMF, 88 days, n = 26). DMF-treated patients reported highest GI symptom severity and missed work at week 2-3 shortly after completing the titration period, which coincided with the majority of GI-related treatment discontinuations [58.3% (7/12)]. GI tolerability AEs [DRF, 34.8% (88/253); DMF, 48.2% (121/251)], concomitant symptomatic medication use [DRF, 19.3% (17/88) versus DMF, 30.6% (37/121)], and GI-related discontinuations (DRF, 0.8% versus DMF, 4.8%) were lower with DRF versus DMF. CONCLUSIONS: The improved GI tolerability with DRF translated into clinically meaningful benefits to QoL, as patients experienced less impact on daily life and work and required less concomitant symptomatic medication use. TRIAL REGISTRATION: [ClinicalTrials.gov identifier: NCT03093324].

Effect of Multiple Sclerosis on Daily Activities, Emotional Well-being, and Relationships: The Global vsMS Survey.

BACKGROUND: The vsMS survey was conducted to better understand the negative effects of fatigue, cognitive impairment, emotional burden, and decreased physical functioning on the personal, professional, and social lives of individuals with multiple sclerosis (MS). METHODS: The vsMS survey was an online survey conducted in Australia, Canada, France, Italy, Spain, the United Kingdom, and the United States that assessed the impact of MS on individuals' daily activities, emotional well-being, relationships, and employment. RESULTS: The survey included 1075 participants with relapsing-remitting MS. Almost 42% of participants reported that their ability to perform and manage daily activities had worsened during the previous 2 years. More than 50% reported limitations in daily activities due to fatigue, physical weakness, problems with balance/coordination, heat/cold sensitivity, memory problems, numbness/tingling, trouble concentrating, impaired movement/muscle stiffness, and impaired sleeping. Participants also reported a negative effect on emotional and social factors, including self-esteem, general outlook, well-being, maintaining/starting relationships, ability to progress in their career/keep their job, and ability to cope with life roles. CONCLUSIONS: These data highlight the importance of addressing the impact of MS and the social and emotional disease burdens on daily activities when planning the care of patients with MS.

Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

IMPORTANCE: Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. OBJECTIVE: To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. INTERVENTIONS: Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. DESIGN, SETTING, AND PARTICIPANTS: The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. MAIN OUTCOMES AND MEASURES: The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. RESULTS: Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). CONCLUSIONS AND RELEVANCE: Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01633112.

Efficacy and Safety of Alemtuzumab Through 9 Years of Follow-up in Patients with Highly Active Disease: Post Hoc Analysis of CARE-MS I and II Patients in the TOPAZ Extension Study.

BACKGROUND: Alemtuzumab efficacy versus subcutaneous interferon-ß-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously. OBJECTIVES: In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm. METHODS: Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition. RESULTS: In the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0-2 and 0.16 in years 3-9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was - 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9. CONCLUSIONS: Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations. CLINICALTRIALS. GOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553; NCT02255656.

Quality of Life Improves with Alemtuzumab Over 6 Years in Relapsing-Remitting Multiple Sclerosis Patients with or without Autoimmune Thyroid Adverse Events: Post Hoc Analysis of the CARE-MS Studies.

INTRODUCTION: In clinical trials of alemtuzumab, autoimmune thyroid adverse events (AEs) were frequent. Here, we assess the impact of thyroid AEs on health-related quality of life (HRQL) in alemtuzumab-treated patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In phase 3 CARE-MS I (NCT00530348) and II (NCT00548405) trials, patients with RRMS were administered alemtuzumab 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Patients could participate in an extension study (NCT00930553) through year 6. HRQL was assessed at baseline and annually using the Functional Assessment of Multiple Sclerosis (FAMS), EuroQoL-5 Dimension Visual Analog Scale (EQ-5D VAS), and 36-Item Short-Form Survey (SF-36) questionnaires. Outcomes were analyzed in patients with or without thyroid AEs (nonserious or serious). A subset of patients with thyroid AEs was analyzed to assess HRQL before and during the onset of thyroid AEs. RESULTS: A total of 811 CARE-MS patients were treated with alemtuzumab. Of these, 342 (42%) patients experienced thyroid AEs over 6 years; serious thyroid AEs occurred in 44 (5%) patients. At year 6, HRQL outcomes generally remained slightly improved or similar to core study baseline in alemtuzumab-treated patients with or without thyroid AEs: FAMS (least-squares mean change from baseline without thyroid AEs, 0.7; with nonserious thyroid AEs, 5.1; with serious thyroid AEs, - 5.3), EQ-5D VAS (2.0; 3.0; - 6.8), SF-36 mental component summary (MCS [0.6; 1.6; - 2.8]), SF-36 physical component summary (PCS [0.8; 1.0; 1.1]). Over 6 years, 63-82% of patients in each group had improved/stable SF-36 MCS and PCS scores. Among patients with thyroid AE onset in year 3 (peak incidence), there were minimal differences between HRQL outcomes before onset (year 2) and after onset (year 3). CONCLUSION: Autoimmune thyroid AEs (serious and nonserious) had minimal impact on HRQL in alemtuzumab-treated patients. These data may aid therapeutic decisions in patients with relapsing MS.

This study looked at alemtuzumab, an approved treatment for multiple sclerosis (MS). People who receive alemtuzumab may develop thyroid problems. The researchers wanted to know whether people who developed thyroid problems with alemtuzumab had a worse quality of life compared with those who did not. The researchers measured quality of life using a questionnaire. The questionnaire looked at people's physical, social, and psychological well-being over 6 years. A total of 811 people with MS treated with alemtuzumab took part in this study. Of these, 469 people (58%) did not develop thyroid problems and 342 people (42%) developed thyroid problems. The thyroid problems were serious in 44 people. The researchers observed that thyroid problems during alemtuzumab treatment did not make quality of life worse in most people. Some people with serious thyroid problems had worsened quality of life; this was mostly among people who required certain treatments for their thyroid problems. Quality of life did not change much in people while the thyroid problems were ongoing. This study shows that thyroid problems after alemtuzumab treatment for MS have little negative impact on quality of life for most people. These findings may help healthcare providers make decisions about MS treatment.

Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies.

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension. RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%). CONCLUSION: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit. CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies.

BACKGROUND: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses. OBJECTIVE: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions. METHODS: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course. RESULTS: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses. CONCLUSION: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.

Clinical and MRI efficacy of sc IFN ß-1a tiw in patients with relapsing MS appearing to transition to secondary progressive MS: post hoc analyses of PRISMS and SPECTRIMS.

This study evaluated efficacy of subcutaneous (sc) interferon beta-1a (IFN ß-1a) 44 µg 3 × weekly (tiw) in patients appearing to transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS). The PRISMS study included 560 patients with RRMS (EDSS 0-5.0; ≥ 2 relapses in previous 2 years), and the SPECTRIMS study included 618 patients with SPMS (EDSS 3.0-6.5 and ≥ 1-point increase in previous 2 years [≥ 0.5 point if 6.0-6.5]) randomly assigned to sc IFN ß-1a 44 or 22 µg or placebo for 2-3 years, respectively. These post hoc analyses examined five subgroups of MS patients with EDSS 4.0-6.0: PRISMS (n = 59), PRISMS/SPECTRIMS (n = 335), PRISMS/SPECTRIMS with baseline disease activity (n = 195; patients with either ≥ 1 relapse within 2 years before baseline or ≥ 1 gadolinium-enhancing lesion at baseline), PRISMS/SPECTRIMS without baseline disease activity (n = 140), and PRISMS/SPECTRIMS with disease activity during the study (n = 202). In the PRISMS and PRISMS/SPECTRIMS subgroups, sc IFN ß-1a delayed disability progression, although no significant effect was observed in PRISMS/SPECTRIMS subgroups with activity at baseline or activity during the study (regardless of baseline activity). In the PRISMS/SPECTRIMS subgroup, over year 1 (0-1) and 2 (0-2), sc IFN ß-1a 44 µg tiw significantly reduced annualized relapse rate (p ≤ 0.001), and relapse risk (p < 0.05) versus placebo. Similar results were seen for the PRISMS/SPECTRIMS with baseline disease activity subgroup. Subcutaneous IFN ß-1a reduced T2 burden of disease and active T2 lesions in the PRISMS/SPECTRIMS subgroups overall, with and without baseline activity. In conclusion, these post hoc analyses indicate that effects of sc IFN ß-1a 44 µg tiw on clinical/MRI endpoints are preserved in a patient subgroup appearing to transition between RRMS and SPMS.

Lymphopenia and DMTs for relapsing forms of MS: Considerations for the treating neurologist.

PURPOSE OF REVIEW: To provide neurologists with an update on the proposed mechanisms of action (MOAs) of disease-modifying therapies (DMTs) for the treatment of relapsing MS, and their effect on peripheral blood leukocytes, in order to inform treatment decisions. RECENT FINDINGS: DMTs have vastly differing MOAs, including effects on peripheral blood leukocyte counts, particularly lymphocytes. The clinical implications of changes in lymphocyte counts need to be understood in the context of the underlying MOAs of each respective DMT, with treatment tailored to individual patient needs. SUMMARY: DMTs can alter lymphocyte counts, subsets, activation, and distribution, and thus can influence immune surveillance. Serial monitoring of total leukocytes and absolute lymphocyte counts (ALCs) is advisable in patients receiving DMTs. ALCs should be interpreted regarding expected immunologic changes and individual patient characteristics. Any decision to switch DMTs should consider these factors, along with drug efficacy, safety, and effect on quality of life.