Disease Activity in Pregnant and Postpartum Women With Multiple Sclerosis Receiving Ocrelizumab or Other Disease-Modifying Therapies.

BACKGROUND AND OBJECTIVES: Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy periods. METHODS: We performed a retrospective cohort study using data from the MSBase Registry including pregnancies conceived after December 31, 2010, from women aged 18 years and older, with relapsing-remitting MS or clinically isolated syndrome. Women were classified by preconception exposure to DMTs, including OCR, rituximab (RTX), natalizumab (NAT), stratified into active (NAT-A; continued ≥28 weeks of gestation, restarted ≤1 month postpartum) or conservative (NAT-C; continued ≤4 weeks of gestation, restarted >1 month postpartum) strategies, dimethyl fumarate (DMF) or low-efficacy DMTs (interferon-beta, glatiramer acetate). Annualized relapse rates (ARRs) were calculated for 12-month prepregnancy, pregnancy, and 6-month postpartum periods. RESULTS: A total of 2,009 live births from 1,744 women were analyzed, including 73 live births from 69 women treated with preconception OCR. For OCR, no within-pregnancy relapse was observed and 3 women (4.1%) experienced 1 relapse in the postpartum period (ARR 0.09 [95% CI 0.02-0.27]). For NAT-A, 3 (3.7%) of 82 women relapsed during pregnancy (0.05 [0.01-0.15]) and 4 (4.9%) relapsed during postpartum (0.10 [0.03-0.26]). However, for NAT-C, 13 (15.9%) of 82 women relapsed within pregnancy (0.32 [0.20-0.51]) and 25 (30.5%) relapsed during postpartum (0.74 [0.50-1.06]). In the low-efficacy DMT group, 101 (7.6%) of 1,329 women experienced within-pregnancy relapse (0.12 [0.10-0.14]), followed by an increase in postpartum relapse activity with 234 women (17.6%) relapsing (0.43 [0.38-0.48]). This was similarly seen in the DMF group with 13 (7.9%) of 164 women experiencing within-pregnancy relapse (0.12 [0.06-0.20]) and 25 (15.2%) of 164 relapsing postpartum (0.39 [0.26-0.57]). Our RTX cohort had 0 of 24 women experiencing within-pregnancy relapse and 3 (12.5%) of 24 experiencing postpartum relapse. DISCUSSION: Women treated with OCR or NAT-A were observed to have low relapse rates during pregnancy and postpartum. NAT-C was associated with increased risk of relapses. There was no within-pregnancy relapse in our RTX cohort, although we caution overinterpretation due to our sample size. An effective DMT strategy with a favorable safety profile for the mother and infant should be discussed and implemented well in advance of planning a family. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with relapsing-remitting MS or clinically isolated syndrome who become pregnant, ocrelizumab, rituximab, and natalizumab (continued ≥28 weeks of gestation and restarted ≤1 month postpartum) were associated with reduced risk of relapses, compared with other therapeutic strategies.

Evaluating efficacy and safety of ocrelizumab biosimilar (Xacrel) compared to the originator (Ocrevus) in relapsing multiple sclerosis: a phase III, randomized, equivalency, clinical trial.

Multiple sclerosis is an inflammatory demyelinating disease and represents a global health concern. Ocrelizumab, a humanized IgG monoclonal antibody, selectively targets CD20 on B cells and CD20-expressing T cells. This study aimed to compare the efficacy and safety of the biosimilar ocrelizumab candidate (Xacrel) to the originator product (Ocrevus) in Relapsing Multiple Sclerosis (RMS) patients. In this randomized trial, patients received either Xacrel or Ocrevus for 96 weeks. The primary endpoint was the equivalency of the medications in reducing the annualized relapse rate (ARR) at week 48. The secondary endpoints included time to the onset of disability progression confirmed at 12 and 24 weeks, the proportion of relapse-free patients, magnetic resonance imaging (MRI) evaluations, safety assessments, and immunogenicity over 96 weeks. A total of 170 patients were randomized (1:1 ratio). In the per protocol analysis, the upper and lower limits of 95% two-sided confidence intervals of difference between treatments in the 48-week ARR rate were in the predefined margin of - 0.2 to 0.2 (- 0.002; 95% CI - 0.080 to 0.075). The two products were also comparable in terms of other efficacy parameters, safety, and immunogenicity. The results confirmed that Xacrel is equivalent to Ocrevus in terms of 48-week ARR in RMS patients, with no considerable difference in other efficacy parameters and the safety profile during the 96 weeks. The trial was registered in Iranian registry of clinical trials (IRCT) on 10/06/2019 with the registration number of IRCT20150303021315N13 and in Clinicaltrials.gov on 19/07/2021 with the registration code of NCT04966338.

Pharmacokinetics and Pharmacodynamics of Natalizumab 6-Week Dosing vs Continued 4-Week Dosing for Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Exposure to natalizumab, an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS), is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Compared with every-4-week (Q4W) dosing, extended-interval dosing of natalizumab is associated with decreased risk of PML. Clinical efficacy was maintained in the majority of patients switched to every-6-week (Q6W) dosing in the phase 3b NOVA clinical trial. In this article, we report pharmacokinetics (PK) and pharmacodynamics (PD) of Q6W vs Q4W dosing in NOVA. METHODS: In NOVA study Part 1, participants with RRMS (aged 18-60 years) and Expanded Disability Status Scale score <5.5, who were stable on IV natalizumab Q4W dosing for ≥12 months, were randomized to continue IV Q4W dosing or switched to IV Q6W dosing of natalizumab and followed for 72 weeks. Exploratory outcomes were measurements of trough serum natalizumab concentration, α4-integrin saturation, and soluble vascular cell adhesion molecule-1 (sVCAM-1) concentration. A mixed model of repeated measures was used to estimate mean treatment differences between groups. Patient-level PK and PD data were examined in those with relapse or radiologic disease activity. RESULTS: In NOVA, 486 (Q6W, n = 245; Q4W, n = 241) and 487 (Q6W, n = 246; Q4W, n = 241) participants were included in the PK and PD populations, respectively. Mean trough natalizumab concentrations ranged from 10 to 21 µg/mL (Q6W) and 33-38 µg/mL (Q4W), and mean α4-integrin saturation remained above 65.5% (Q6W) and above 77.9% (Q4W). In the Q6W group, mean sVCAM-1 levels increased 23.6% by week 24 and remained elevated throughout the study, while mean sVCAM-1 levels remained generally stable in the Q4W group. Most participants with T2 lesion activity or relapse activity, in either treatment arm, maintained trough natalizumab levels >10 µg/mL and trough α4-integrin saturation >50%. DISCUSSION: Compared with Q4W dosing, Q6W dosing was associated with a 60%-70% decrease in mean trough natalizumab levels and a 9%-16% decrease in mean α4-integrin saturation. At the patient level, neither natalizumab concentration nor α4-integrin saturation was consistently predictive of lesion or relapse activity, suggesting that trough natalizumab and α4-integrin saturation measurements should be interpreted with caution in clinical practice. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT03689972; EudraCT, 2018-002145-11. Submitted 2018-09-27. First patient enrolled: 2018-12-26. https://clinicaltrials.gov/study/NCT03689972.

Cost-effectiveness of oral versus injectable disease modifying therapies in relapsing multiple sclerosis: a systematic review analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic and progressive neurological autoimmune disease that affects the central nervous system. There are two types of drugs used to treat this disease: injectable and oral drugs. The present study aimed at systematically reviewing the cost effectiveness of oral versus injectable drugs. METHODS: The researchers searched the PubMed, Scopus, and Web of Science databases to find relevant studies. After removing the duplicates, two authors independently assessed the records. The studies that had conducted full economic evaluations of oral versus injectable drugs in MS patients were included. The Quality of Health Economic Studies (QHES) tool was also used to assess the quality of the studies. RESULTS: Thirty studies that had conducted the economic analysis of oral versus injectable therapies in MS patients were included in this review. The QHES scores for all records were generally high (≥ 77) and they were of good quality. The lowest and highest levels of incremental net monetary benefit were respectively obtained through the comparison of Fingolimod and Alemtuzumab (-1,419,333) and the comparison of Teriflunomide and Interferon ß-1a (1,792,810). The amount of INMB (incremental net monetary benefit) in the comparisons between oral and injectable drugs showed that the highest and lowest amount of INMB calculated between) Fingolimod and injectable drugs, respectively, compared to (interferon ß-1a) 98,253 and (Ocrelizumab) -212,417, the highest amount in dimethyl fumarate is also against (peginterferon ß-1a) 191,470 and the lowest against (alemtuzumab) -124,333, Teriflunomide against injectable drugs is the highest against (peginterferon ß-1a) 89,956 and the lowest (Ocrelizumab) - 194,169, as well as Cladribine compared to injectable drugs, the highest was compared to (interferon ß-1a) 236,430 and the lowest (Ocrelizumab) was 23,965. CONCLUSION: A large number of health economic evaluations of disease-modifying therapies (DMTs) in MS were available at the international level, the comparison of which was difficult and sometimes contradictory. However, despite the difference in the results, Cladribine tablets were cost-effective in all studies compared with injectable drugs. In addition, the present study could be of great importance for policymakers and other beneficiaries regarding the cost-effectiveness of the aforementioned drugs.

Brain volume loss in relapsing multiple sclerosis: indirect treatment comparisons of available disease-modifying therapies.

BACKGROUND: Brain volume loss (BVL) has been identified as a predictor of disability progression in relapsing multiple sclerosis (RMS). As many available disease-modifying treatments (DMTs) have shown an effect on slowing BVL, this is becoming an emerging clinical endpoint in RMS clinical trials. METHODS: In this study, a systematic literature review was conducted to identify BVL results from randomized controlled trials of DMTs in RMS. Indirect treatment comparisons (ITCs) were conducted to estimate the relative efficacy of DMTs on BVL using two approaches: a model-based meta-analysis (MBMA) with adjustment for measurement timepoint and DMT dosage, and a network meta-analysis (NMA). RESULTS: In the MBMA, DMTs associated with significantly reduced BVL versus placebo at two years included fingolimod (mean difference [MD] = 0.25; 95% confidence interval [CI] = 0.15 - 0.36), ozanimod (MD = 0.26; 95% CI = 0.12 - 0.41), teriflunomide (MD = 0.38; 95% CI = 0.20 - 0.55), alemtuzumab (MD = 0.38; 95% CI = 0.10 - 0.67) and ponesimod (MD = 0.71; 95% CI = 0.48 - 0.95), whereas interferons and natalizumab performed the most poorly. The results of NMA analysis were generally comparable with those of the MBMA. CONCLUSIONS: Limitations of these analyses included the potential for confounding due to pseudoatrophy, and a lack of long-term clinical data for BVL. Our findings suggest that important differences in BVL may exist between DMTs. Continued investigation of BVL in studies of RMS is important to complement traditional disability endpoints, and to foster a better understanding of the mechanisms by which DMTs can slow BVL.

Real-world persistence and adherence of ofatumumab versus oral and injectable disease-modifying therapies in patients with multiple sclerosis.

BACKGROUND: Ofatumumab (OMB) was approved as a self-injectable disease-modifying therapy (DMT) for relapsing multiple sclerosis (MS) in August 2020. This study aimed to examine treatment persistence and adherence of OMB to oral and platform self-injectable DMTs in a real-world setting. METHODS: This was a retrospective cohort study using IQVIA Pharmetrics Plus® in adults diagnosed with MS and treated with OMB, oral DMTs, or platform self-injectable DMTs (index treatment) between August 2020 and November 2021. Patients had at least 12 months of continuous enrollment before the index date and 6 months of follow-up after the index date; the index date was defined as the date of the first pharmacy claim for an index treatment. Inverse probability of treatment weighting (IPTW) analysis was used to account for differences in baseline characteristics among patients initiating OMB versus oral DMTs and, separately, OMB versus platform self-injectable DMTs. Persistence was defined as the number of days from the index date until the earliest time of discontinuation (>60-day gap) or switch to a new DMT. Adherence was calculated based on proportion of days covered (PDC) with adherence defined as PDC ≥0.8. Persistence and adherence were compared between OMB versus oral DMTs and OMB versus platform self-injectable DMTs. Persistence was assessed via Kaplan-Meier analyses of the weighted sample, and log-rank tests were used to compare time to treatment discontinuation and treatment switch. The proportion of patients adherent at 6 and 12 months post index were compared using chi-square tests. RESULTS: A total of 11,167 patients were identified with an incident claim of OMB, an oral DMT, or a platform self-injectable DMT. After applying all inclusion and exclusion criteria and IPTW, two sets of study cohorts were created. For the oral DMT analysis, 577 patients treated with OMB and 2,468 patients treated with oral DMTs were identified. For the self-injectable DMT analysis, 574 patients treated with OMB and 578 patients treated with a platform self-injectable DMT were identified. At 6- and 12-month follow-up, the proportion of patients who were persistent on DMT was higher in the OMB cohort compared with the oral DMT cohort (6 months: 79.9% vs. 75.4 %, 12 months: 71.4% vs. 62.9 %; p < 0.05), as well as in the OMB cohort compared with the self-injectable DMT cohort (6 months: 79.3% vs. 60.4 %, 12 months: 71.5% vs. 48.7 %; p < 0.0001). A similar proportion of patients were adherent to OMB versus oral DMTs at 6- and 12-months post index, whereas a higher proportion of patients treated with OMB versus platform self-injectable DMTs were adherent at 6- and 12-months post index. CONCLUSIONS: OMB showed better persistence and adherence compared with platform self-injectable DMTs, as well as better persistence compared with oral DMTs. This real-world analysis provides additional insights into OMB utilization among patients with MS in clinical practice and demonstrates that OMB is a valuable treatment option for these patients.

Safety, tolerability, and efficacy of diroximel fumarate in a cohort of Black patients with multiple sclerosis from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise ∼13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population. METHODS: EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups. RESULTS: Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 × 109/L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively. CONCLUSION: This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS.

Ozanimod: A Review in Relapsing Forms of Multiple Sclerosis.

Ozanimod (Zeposia®), an orally administered sphingosine 1-phosphate (S1P) receptor modulator (S1PRM) that is selective for the S1P1 and S1P5 receptor subtypes, is approved in the USA for relapsing forms of multiple sclerosis (RMS). In pivotal phase III clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and the number of new or enlarging T2 lesions and gadolinium-enhancing lesions, and was associated with reduced brain volume loss, compared with interferon (IFN)-ß1a. However, there were no significant differences in 3- and 6-month disability progression between the groups. Ozanimod was generally well tolerated, with the most common adverse reactions including upper respiratory tract infection and hepatic transaminase elevation. Efficacy and tolerability were sustained over more than 6 years with continued treatment. S1PRM-related adverse events seen with ozanimod are generally manageable with screening and/or monitoring. Notably, ozanimod does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS.

In multiple sclerosis (MS), lymphocytes (a type of immune cell) are thought to enter the CNS and attack the myelin sheath surrounding neurons. Relapsing forms of MS (RMS) involve episodes of neurological dysfunction with complete or partial recovery. Sphingosine 1-phosphate (S1P) receptor modulators (S1PRMs) are an oral treatment for RMS that prevent the movement of lymphocytes from lymphoid tissues into peripheral blood and, therefore, into the CNS. Ozanimod (Zeposia^®) is an S1PRM that is selective for the S1P₁ and S1P₅ receptor subtypes. In clinical trials in patients with RMS, ozanimod significantly reduced annualised relapse rates and disease activity as seen on MRI compared with interferon (IFN)-ß1a; however, there were no differences in disability progression between the groups. Ozanimod was generally well tolerated; common adverse reactions included upper respiratory tract infection and hepatic transaminase elevation. Ozanimod requires screening and monitoring for certain adverse events that are associated with S1PRMs but does not require first-dose cardiac monitoring in the USA. In conclusion, ozanimod is a valuable once-daily oral disease-modifying therapy that extends the available treatment options for patients with RMS.

The recurrence of disease activity after ocrelizumab discontinuation in multiple sclerosis.

INTRODUCTION: Ocrelizumab (OCR) is a highly effective treatment of multiple sclerosis (MS), and B cell repopulation profiles suggest that it might be used as an immune reconstitution therapy. However, data on disease recurrence after stopping treatment with OCR are scarce. Our objective was to evaluate the recurrence of disease activity after OCR discontinuation. METHODS: In this multicenter retrospective cohort study, we included MS patients who discontinued OCR, without switching to another treatment, for twelve months or more, after having received at least one full dosage of 600 mg. We defined focal inflammation as the occurrence of a clinical relapse or significant MRI activity (≥3 new T2 lesions or ≥2 contrast-enhancing lesions). RESULTS: We included 53 MS patients; 41 relapsing remitting (RRMS), 5 secondary progressive (SPMS) and 7 primary progressive (PPMS) patients. Median follow-up period after OCR discontinuation was 16 months. We only observed focal inflammation after discontinuation in RRMS patients; 2.4 % (1/41) patients presented with significant MRI activity and matching clinical symptoms, and 7.3 % (3/41) patients presented with a suspected clinical relapse without radiological activity: a total of 9.8 % (4/41) at a median time of 17 months after the last infusion. DISCUSSION: We found focal inflammation after discontinuation of OCR in 4 (9.8 %) of the RRMS patients, of which 1 was radiologically confirmed. Our observations highlight that recurrence of focal inflammation seems low but discontinuation may not be appropriate for everyone. Further larger studies are important to determine the immune reconstitution therapy potential of OCR.

Effectiveness of Disease-Modifying Treatment on Spinal Cord Lesion Formation in Relapse-Onset Multiple Sclerosis: An MSBase Registry Study.

BACKGROUND: Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs. METHODS: Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses. RESULTS: Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p < 0.001) and fewer relapses (HR 0.45 [95% CI 0.28, 0.72], p = 0.004). CONCLUSION: A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions.

Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

BACKGROUND: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. METHODS: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). FINDINGS: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. INTERPRETATION: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. FUNDING: Merck.

MultiSCRIPT-Cycle 1-a pragmatic trial embedded within the Swiss Multiple Sclerosis Cohort (SMSC) on neurofilament light chain monitoring to inform personalized treatment decisions in multiple sclerosis: a study protocol for a randomized clinical trial.

BACKGROUND: Treatment decisions for persons with relapsing-remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone. METHODS: Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures. DISCUSSION: MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT06095271. Registered on October 23, 2023.

Comparative efficacy of subcutaneous versus intravenous natalizumab on annualized relapse rate: A post-hoc analysis of the REFINE study.

BACKGROUND: The non-inferiority of the efficacy of subcutaneous (SC) vs intravenous (IV) administration of natalizumab (NTZ) once every 4 weeks in relapsing-remitting multiple sclerosis (RRMS) was recently demonstrated on the primary outcome of the REFINE study, i.e. MRI "combined unique active lesions number" (CUAL). To provide further evidence on the comparative efficacy of the two NTZ formulations, the effect of NTZ-SC vs NTZ-IV on annualized relapse rate (ARR) was investigated re-analysing the REFINE dataset. METHODS: Post-hoc analysis of the REFINE study dataset aimed at exploring the non-inferiority of the efficacy of NTZ-SC vs NTZ-IV on ARR, i.e. the main secondary outcome of the REFINE study. Robustness of the non-inferiority analysis on CUAL with respect to the presence of cases from the SC arm who received a rescue treatment, including NTZ-IV, was also assessed by sensitivity analyses. Three non-inferiority margins were selected, corresponding to 25 %, 33 %, and 50 % fractions of the effect size of NTZ-IV vs placebo observed in the AFFIRM study on ARR (i.e. 0.125, 0.170, and 0.250). RESULTS: Ninety-nine RRMS patients were included. The mean difference in the effect of NTZ-SC vs NTZ-IV on ARR was close to 0. The lower bound of the 95 % confidence interval (worst case scenario) was -0.119, corresponding to 25 % (p = 0.025) of the effect of NTZ-IV vs placebo on ARR. Sensitivity analyses confirmed the results of the primary non-inferiority analysis on the outcome CUAL. CONCLUSIONS: NTZ-SC resulted not inferior to NTZ-IV on ARR for all the non-inferiority margins. The non-inferiority analysis of the efficacy of NTZ-SC vs NTZ-IV on CUAL was demonstrated to be robust with respect to rescued patients.

Effects of disease-modifying therapies on remyelination in multiple sclerosis; evaluation via visual evoked potential test.

BACKGROUND: Assessment of the visual pathway, which is frequently affected by MS, provides the opportunity to measure the remyelination of acute and chronic MS lesions in vivo and non-invasively. VEP can be used in this context. Amplitude is a parameter of axonal loss, whereas latency is an in vivo biomarker of myelin repair. This study aimed to evaluate DMT's neuroprotective and pro-remyelinating potential by evaluating VEP latency and amplitude in MS patients. MATERIALS AND METHODS: A total of 74 patients with relapsing MS who had no evidence of optic neuritis were included in the study. Patient data were retrospectively analyzed and recorded. In the VEP test, latency above 118 ms and amplitude below 5.0 µV were considered abnormal. Classified according to DMTs (injectables, teriflunomide, dimethyl fumarate, fingolimod, cladribine, and alemtuzumab). Visual evoked potential tests, clinical features, and cerebrospinal fluid examinations were evaluated by three independent neurologists (one of whom was also a clinical neurophysiologist). RESULTS: The mean age at diagnosis was 29.2 ± 9.01, and the mean age at first VEP was 34.97 ± 10.64. In women, latency was lower, and amplitude was higher. The mean differences in latency and amplitude were, respectively, latency prolonged by 0.7 ms on the right and 0.5 ms on the left, and amplitude increased by 0.6 µV on the right and 0.37 µV on the left. However, these changes were not statistically significant. Latency worsening was more prominent in those with longer disease duration (p = 0.011). Those with amplitude or latency worsening had higher EDSS (p = 0.016 and 0.013, respectively). DMTs did not affect these changes. CONCLUSION: Prolonged latency is associated with a long disease duration. Deterioration in both amplitude and latency is evident in high EDSS. These results may be an indirect consequence of axonal degeneration dominating remyelination. DMTs do not ameliorate impaired remyelination and neurodegeneration but seem to be sufficient for short-term maintenance of the current state.

The patient-reported outcomes for the new brand-generic teriflunomide in relapsing-remitting multiple sclerosis.

BACKGROUND: Patient-reported outcomes (PROs) provide valuable insights into the impact of disease-modifying therapies (DMTs) on patients' daily lives and disease progression. This study evaluates treatment satisfaction and tolerability among patients using a brand-generic Teriflunomide (Tebazio®, 14 mg tablet) manufactured by Zistdaru Danesh Biopharmaceuticals. MATERIALS AND METHODS: A Phase IV observational study was conducted on patients with Relapsing-Remitting Multiple Sclerosis (RRMS) who were either initiated on or switched to Teriflunomide 14 mg. The primary focus was on the medication's safety. Patient satisfaction was measured using the Treatment Satisfaction Questionnaire for Medication [Version 1.4] (TSQM-14). Additionally, medication adherence and discontinuation rates were monitored. RESULTS: Of the 235 RRMS patients enrolled, participated in this study, all received the Teriflunomide treatment orally on a daily basis. Over the 18-month follow-up period, 25.96 % of patients discontinued the treatment. Discontinuation was mainly due to adverse events (11 %), lack of patient willingness to continue (12.7 %), and disease progression (4.2 %). The most commonly reported adverse events included dermatologic disorders, elevated liver enzymes, and gastrointestinal issues. TSQM-14 scores demonstrated significant improvements over the 18-month period. A high medication adherence rate of 98.1 % was also recorded. CONCLUSION: Patients reported notable satisfaction with Teriflunomide, as reflected in their TSQM scores, which suggests a likelihood of improved patient adherence. The 14 mg brand-generic Teriflunomide was well-accepted by Iranian RRMS patients, with no significant concerns arising during the study. These findings also highlight the significance of patient-reported outcomes in DMTs, with potential benefits for adherence and clinical practice.

The effect of alemtuzumab on neurodegeneration in relapsing-remitting multiple sclerosis: A five-year prospective mono-center study.

BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) is an inflammatory and neurodegenerative disease. After two or more short courses of alemtuzumab (ALZ), an immune reconstitution is achieved, which long-term results in reduced disease activity. We aimed to investigate the effect of ALZ on measures of neurodegeneration (i.e., brain atrophy, and retinal layer thinning). METHODS: We designed an observational prospective mono-center study in RRMS patients initiating ALZ treatment. Patients were assessed at baseline (month 0) and thereafter annually for five years with clinical measures, synthetic magnetic resonance imaging (SyMRI) and optical coherence tomography (OCT), with a re-baseline SyMRI scan and an OCT exam 24 months after initiating ALZ. Persons with neurological symptoms but without evidence of neurological disease served as symptomatic controls (SCs, n = 27). RESULTS: Forty-nine RRMS patients were included. Baseline median expanded disability status scale [2.0 (IQR 1.5)] was unchanged during follow-up, 71 % were progression-free, 33 % achieved no evidence of disease activity-3 (NEDA-3). Between baseline and month 60, SyMRI showed a reduction of brain parenchymal fraction (BPF) and grey matter (GM) volume in patients. The BPF reduction was greater in RRMS patients than in SCs (p < 0.05), and more pronounced in patients with high pre-baseline disease activity than in those without (p < 0.01). OCT showed significant thinning of macular ganglion cell and inner plexiform layers (mGCIPL) and in peripapillary retinal nerve fiber layer (pRNFL) in patients. In contrast, absolute values of white matter (WM) volume and myelin content (MyC) quantified by SyMRI, were stable or increased after re-baseline (month 24) and up to month 60, and this increase appeared limited to patients without high pre-baseline disease activity and to patients with NEDA-3 or disability worsening during follow-up. A strong positive correlation between WM volume and GM volume at baseline was lost after ALZ intervention for their delta values, i.e., change from re-baseline (month 24) to month 60. While the positive baseline correlation between WM volume and MyC increased for their delta values, the positive baseline correlation between GM volume and MyC changed to negative for their delta values. CONCLUSION: We showed that neurodegeneration continued in RRMS patients under ALZ treatment, but it appeared to be limited to BPF and GM, and more pronounced in patients with disease activity. Our data suggest that patients who respond to ALZ treatment show signs of remyelination. OCT and SyMRI have potential to quantify measures of neurodegeneration that is affected by treatment intervention in RRMS.

Rapid depletion of CD20+ B and T cells following ofatumumab therapy onset.

BACKGROUND: The humanized monoclonal anti-CD20-antibody ofatumumab is highly effective in treating relapsing multiple sclerosis (MS). OBJECTIVE: This study aimed to investigate the immanent effect of ofatumumab on the peripheral immune system, particularly targeting B and T cells expressing CD20. METHODS: Blood samples of 53 MS patients receiving ofatumumab were collected prior to first application and after one week, two weeks and three months. Multicolor flow cytometry was used to phenotype peripheral blood mononuclear cells, and immunoglobulin (Ig) concentrations were measured by nephelometry. RESULTS: Among CD20+ lymphocytes, 13 % co-expressed CD3 (identifying them as CD3+CD20+ T lymphocytes), with a noticeable shift in the CD4/CD8-ratio towards CD8+ T cells. One week after administering ofatumumab, a significant reduction of CD20+ lymphocytes with complete depletion of CD3+CD20+ T lymphocytes was observed, persisting during the investigation period. During the treatment, IgM levels showed a slight but significant decrease, whereas IgA and IgG levels remained stable. CONCLUSION: Ofatumumab effectively depletes CD20+ lymphocytes already after the first administration. This depletion affects not only B cells, but also a small proportion of T cells (CD3+CD20+), affirming the hypothesis that the anti-inflammatory effects of CD20+ cell depletion might extend to the reduction of CD3+CD20+ T lymphocytes.

A multicenter multinational study to evaluate different aspects of the relationship between MS and pregnancy.

BACKGROUND: To investigate the pregnancy-related issues in females with multiple sclerosis (MS) from Turkiye, Egypt, Kuwait, and Iran. METHODS: 1692 pregnancies of 701 females with MS were evaluated in this retrospective multicenter, international project. Demographics, clinical features, pregnancy outcomes, relapses, effects of exposure to disease-modifying drugs on pregnancy and fetus, and worries about pregnancy decisions were investigated. RESULTS: 85.9 % of females were diagnosed with relapsing-remitting multiple sclerosis. The mean age was 39.0 ± 9.0 years (min 20, max 68). The mean EDSS score was 2.26 ± 1.8. The number of conceptions was inversely correlated with the level of education with significance (p<0.05). Among the concerns related to pregnancy, 31.7 % pertain to disability progression, 14.4 % are associated with relapses, and 7.3 % involve the cessation of treatment. Additionally, 82.3 % of females with MS experienced no relapses during both pregnancy and the postpartum period. Most of the relapses (22.9 %) occurred in the postpartum period. Higher EDSS scores were detected in patients who have higher numbers of pre-MS period pregnancies (p= 0.042; r:0.2591). A similar correlation was found between the total number of pregnancies and higher EDSS levels (p=0.003, r:0.2614). Considering the relationship between EDSS score and the number of pregnancies after MS diagnosis, no significance was found (p = 0.595). The age at first pregnancy did not affect the onset age of MS. Significant positive correlation was found between the age of onset and the total number of pregnancies and pre-MS pregnancies. As the number of pregnancies increased, the disease onset was at a later age (correlation = 0.4258). CONCLUSION: Presence of pre-MS pregnancies increased the age of onset of MS and caused more disability. The reduction in the number of pregnancies following the diagnosis of MS was related with a consistent hesitancy among patients in this regard.

Effect of alemtuzumab over sNfL and sGFAP levels in multiple sclerosis.

Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS). Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years. Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison. Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values. Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values.

The Faces of "Too Late"-A Surprisingly Progressive Cohort of "Stable" Relapsing Remitting Multiple Sclerosis Patients.

Background and Objectives: Although available therapies have changed the natural evolution of multiple sclerosis (MS), in time some patients assume a progressive course and no longer respond to treatment. There is no definitive clinical or laboratory parameter to certify MS progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS) in early phases of transition. Our study aims to evaluate the value of clinical parameters and serum neurofilament light chain levels (sNfLs) as early warning signs of conversion to SPMS. Materials and Methods: The Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), 25-foot walk test (25FWT) and Symbol Digit Modalities Test (SDMT) were evaluated at 12 months apart in a cohort of 83 RRMS treated patients. sNfLs were evaluated at the second time point. Results: sNfLs correlate with EDSS and SDMT, with EDSS change and disease duration. Clinical parameters correlate among themselves and perform well in supporting the diagnosis of SPMS in logistic regression and ROC curves analysis. Eighty percent of the RRMS patients in our study (of which 65% are treated with high-efficacy disease-modifying drugs) showed some type of progression independent of relapses (PIRA) after 12 months, with one in five patients experiencing isolated cognitive worsening and almost two-thirds some type of motor worsening. We found no differences in terms of progression between patients treated with platform drugs versus high-efficacy drugs. Conclusions: An elevated level of progression independent of relapses (PIRA) was found in our cohort, with high-efficacy drugs providing no supplementary protection. As sNfL levels were correlated with the progression of EDSS (the main clinical progression marker), they may be considered potential prognostic markers, but further studies are necessary to precisely define their role in this direction. The lack of early sensitive markers for risk of progression may contribute to therapeutic delay and failure.