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Multiple sclerosis is a chronic autoimmune disease of the central nervous system for which a number of disease-modifying therapies are available, including interferon beta (Avonex®, Rebif®, and Betaseron/Betaferon®), glatiramer acetate (Copaxone®), and an anti-VLA4 monoclonal antibody (Tysabri®). Despite the availability and efficacy of these protein and peptide drugs, there remains a significant number of patients who are untreated, including those with relatively mild disease who choose not to initiate therapy, those wary of injections or potential adverse events associated with therapy, and those who have stopped therapy due to perceived lack of efficacy. Since these drugs have side effects that may affect a patient's decision to initiate and to remain on treatment, there is a need to provide a therapy that is safe and efficacious but that requires a reduced dosing frequency and hence a concomitant reduction in the frequency of side effects. Here we describe the development of a PEGylated form of interferon beta-1a that is currently being tested in a multicenter, randomized, double-blind, parallel-group, placebo-controlled study in relapsing multiple sclerosis patients, with the aim of determining the safety and efficacy of 125 microg administered via the subcutaneous route every 2 or 4 weeks.

IFN-β is widely used in the treatment of multiple sclerosis, yet the mechanism facilitating its efficacy remains unclear. IL-2 production by activated T cells, including those mediating autoimmunity, and subsequent autocrine stimulation is vital for T cell expansion and function. In this study, we demonstrate that in mouse and human T cells, IFN-β specifically inhibits the production of IL-2 upon TCR engagement without affecting other cytokines or activation markers. Rather than disrupting TCR signaling, IFN-β alters histone modifications in the IL-2 promoter to retain the locus in an inaccessible configuration. This in turn is mediated through the upregulation of the transcriptional suppressor CREM by IFN-β and consequent recruitment of histone deacetylases to the IL-2 promoter. In accordance, ablation of CREM expression or inhibition of histone deacetylases activity eliminates the suppressive effects of IFN-β on IL-2 production. Collectively, these findings provide a molecular basis by which IFN-β limits T cell responses.

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients. ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553) [ABSTRACT FROM AUTHOR]

Introduction: In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing–remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. Methods: CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. Results: Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a −0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a −0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. Conclusion: CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9. [ABSTRACT FROM AUTHOR]

Background: Evidence suggests that efficacy and safety of disease-modifying treatments for multiple sclerosis may differ with age. We evaluate efficacy and safety of teriflunomide across age subgroups of patients from pooled clinical trials and real-world studies. Methods: Post hoc analyses of patients who received teriflunomide 14 mg in the pooled phase II and III TEMSO, TOWER, TENERE, and TOPIC core and extension studies (n = 1978), and the real-world Teri-PRO (n = 928) and TAURUS-MS I (n = 1126) studies were conducted. Data were stratified by age at study entry: ⩽25, >25 to ⩽35, >35 to ⩽45, and >45 years. In Teri-PRO and TAURUS-MS I, an additional group, >55 years, was assessed. Results: In the pooled core studies, teriflunomide reduced annualized relapse rate (ARR) versus placebo across all ages. Unadjusted ARRs remained low across age groups in pooled extensions (0.18-0.30), Teri-PRO (0.10-0.35), and TAURUS-MS I (0.14-0.35). Baseline Expanded Disability Status Scale scores were higher with age, but stable through core and extension studies (mean increases over 7 years: ⩽25 years, +0.59; >25 to ⩽35 years, +0.46; >35 to ⩽45 years, +0.35; >45 years, +0.81). Across age groups, adverse event (AE) incidences were 78.4% to 90.7% in pooled core and extension studies and Teri-PRO, and 29.2% to 37.7% in TAURUS-MS I; serious AE incidences were ⩽21.3% in all studies. In pooled phase III and Teri-PRO studies, lymphocyte count decreases over 1 year after initiating teriflunomide, and proportions of patients developing lymphopenia, were small across age groups. Conclusions: Teriflunomide efficacy was demonstrated regardless of age. Safety was generally consistent across age groups. [ABSTRACT FROM AUTHOR]

Background: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods: Patients (N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. Conclusions: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression. ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. Objective: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. Methods: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. Results: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. Conclusion: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes. [ABSTRACT FROM AUTHOR]

Background: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. Objective: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. Methods: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. Results: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. Conclusion: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely. [ABSTRACT FROM AUTHOR]

This study clinically evaluated a novel PEGylated form of interferon beta-1a (PEG-IFN beta-1a), a potential first-line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single-dose study (n = 60) comparing subcutaneous or intramuscular PEG-IFN beta-1a (63, 125, or 188 µg) with intramuscular unmodified IFN beta-1a 30 µg and a multiple-dose study (n = 69) comparing subcutaneous PEG-IFN beta-1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2′,5′-OAS) measures, exploratory immune assessments, safety, and tolerability. A dose-proportional increase in PEG-IFN beta-1a exposure was observed, with a 4-fold greater exposure at 63 µg (6 million international units [MIU]) of PEG-IFN beta-1a than with 30 µg (6 MIU) intramuscular unmodified IFN beta-1a. Increases in neopterin and 2′,5′-OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG-IFN beta-1a than with unmodified IFN beta-1a. PEG-IFN beta-1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu-like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG-IFN beta-1a as a potentially effective treatment for patients with relapsing multiple sclerosis. [ABSTRACT FROM PUBLISHER]

Background: Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing forms of multiple sclerosis (MS) or relapsing-remitting MS (RRMS), depending on the local label. Objectives: To assess the long-term efficacy and safety of teriflunomide in patients with RRMS stratified by disease duration. Methods: This was a pooled efficacy and safety analysis using data from the phase 2 study (trial registration: NCT01487096) and the phase 3 TEMSO (NCT00134563, NCT00803049), TOWER (NCT00751881), and TENERE (NCT00883337) core and extension studies. Patients receiving placebo or teriflunomide 14 mg were stratified by disease duration at baseline (≤1 year, >1 to 5 years, >5 to 10 years, and >10 years). Study end points included annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) score, 6-month confirmed disability worsening (CDW), and safety. Results: In the core period, ARR was lower in patients treated with teriflunomide 14 mg compared with placebo across disease duration subgroups: ≤1 year (0.33 [n = 272] vs 0.56 [n = 251], P = .0013), >1 to 5 years (0.46 [n = 278] vs 0.70 [n = 268], P = .0011), >5 to 10 years (0.39 [n = 191] vs 0.52 [n = 164], P = .0571), and >10 years (0.33 [n = 154] vs 0.58 [n = 129], P = .0005). In the core+extension period (up to year 13), ARRs in teriflunomide-treated patients were similar regardless of disease duration: ≤1 year (0.19; n = 276), >1 to 5 years (0.22; n = 699), >5 to 10 years (0.26; n = 393), and >10 years (0.25; n = 325). At year 13, 6-month CDW rates for each group were 48.3% (≤1 year), 37.1% (>1 to 5 years), 52.6% (>5 to 10 years), and 36.8% (>10 years). From core study baseline to year 10 (the last time point at which all groups had at least 10 patients), EDSS scores were stable across teriflunomide-treated patients of different disease durations: ≤1 year, +0.27; >1 to 5 years, +1.11; >5 to 10 years, +0.05; and >10 years, +0.7. Overall incidences of adverse events through year 13 were 93.1% (≤1 year), 87.2% (>1 to 5 years), 88.0% (>5 to 10 years), and 88.7% (>10 years); incidences of serious adverse events during this period were 21.2% (≤1 year), 19.1% (>1 to 5 years), 15.5% (>5 to 10 years), and 18.0% (>10 years). Conclusions: Teriflunomide 14 mg reduced relapses across all patients regardless of disease duration vs placebo in the core studies. Over 13 years, ARR remained low and EDSS score increased minimally. Safety outcomes from baseline to year 13 were consistent across disease duration subgroups. [ABSTRACT FROM AUTHOR]

Background: In the 2-year CARE-MS trials (trial registration: NCT00530348; NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/magnetic resonance imaging outcomes vs subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). Efficacy in alemtuzumab-treated patients was maintained through year 9 in 2 consecutive extension studies (NCT00930553; NCT02255656 [TOPAZ]). Objectives: To evaluate the status of disability over 9 years in pooled CARE-MS patients who had either 6-month confirmed disability improvement (CDI) or 6-month confirmed disability worsening (CDW) by years 2 or 9. Methods: Alemtuzumab-treated CARE-MS patients with baseline Expanded Disability Status Scale (EDSS) score ≥2 were stratified into 3 subgroups: with CDI, with CDW, or with stable disability. CDI and CDW were defined as ≥1-point decrease and increase, respectively, in EDSS score from core study baseline confirmed over 6 months. Improved and stable EDSS scores each year were defined as ≥1-point decrease and ≤0.5-point change in either direction, respectively, from core study baseline in available patients. Results: 511/811 (63%) alemtuzumab-treated patients had baseline EDSS score ≥2. Of these, 222 (43%) patients had 365 unique CDI events and 172 (34%) patients had 217 CDW events at any time during the 9-year study; 31 (6%) had both CDI and CDW. Few patients (n = 12) had a CDW event after CDI. Of patients with CDI at any time over 9 years, mean EDSS score change was --0.58 at year 9 vs core study baseline, and 51% had lower EDSS scores at year 9. Similar EDSS outcomes were observed at year 9 in the subset of patients who achieved CDI within the first 2 years of the study. However, patients with CDW any time over 9 years had worsened disability at year 9, with a +1.71 mean change in EDSS score from core study baseline; patients with CDW in the first 2 years of the study had a +2.27 EDSS score change by year 9. EDSS scores remained stable at 9 years (mean change, --0.10) in the 148 (29%) patients who had neither CDI nor CDW. Compared with previous years, no new safety signals were identified in year 9 in CARE-MS extension study patients. Conclusions: Achievement of CDI at any point in the CARE-MS studies was associated with improved disability at year 9 vs baseline. However, those with CDW had increased disability over 9 years regardless of when worsening occurred. These findings suggest that both CDI and CDW are meaningful end points for predicting long-term disability outcomes in patients with RRMS. [ABSTRACT FROM AUTHOR]