Confirmed Disability Improvement Research Articles

Alemtuzumab treatment for multiple sclerosis in Austria: An observational long-term outcome study.

Observational real-world study to analyze the clinical effects of alemtuzumab (ALEM) and subsequent disease-modifying therapy (DMT) usage in multiple sclerosis (MS). Data retrieved from the Austrian MS treatment registry (AMSTR) included baseline (BL) characteristics (at ALEM start), annualized relapse rate (ARR), 6-month confirmed progression independent of relapse activity (PIRA; ≥ 0.5-point Expanded Disability Status Scale (EDSS) score increase), 6-month confirmed disability improvement (CDI; ≥ 0.5-point EDSS decrease), and safety outcomes until initiation of a subsequent DMT. The EDSS was re-baselined at 30 days from ALEM start (BL EDSS). Eighty-seven ALEM-treated patients (median age: 32 years, 72% female, 14% treatment-naïve) were followed for a median of 55 (interquartile range 31-68) months. We found significant reductions in the ARR from 1.16 before ALEM to 0.15 throughout Years 1-9 (p < 0.001). Subsequent DMTs were initiated in 19 patients (22%, 74% anti-CD20 monoclonal antibodies). At Year 5 (n = 53), more patients achieved CDI (58%, 95% confidence interval (CI) 45%-71%) than had experienced PIRA (14%, CI 7.5%-24%), and 58% remained relapse-free. Shorter MS duration (p < 0.001, hazard ratio (HR) 0.86 (CI 0.80-0.93)) and no previous high-efficacy treatment (p < 0.001, HR 5.16 (CI 2.66-10.0)) were the best predictors of CDI, while PIRA was associated with a higher number of previous DMTs (p = 0.04, HR 3.06, CI 1.05-8.89). We found no new safety signals. ALEM had long-lasting beneficial effects on the ARR and disability improvement, especially when initiated early in the course of the disease. Only a subset of patients received subsequent DMTs.

Comparative Effectiveness of Natalizumab, Fingolimod, and Injectable Therapies in Pediatric-Onset Multiple Sclerosis: A Registry-Based Study.

Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60

BackgroundOngoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher...

Long-term clinical outcomes in patients with multiple sclerosis who are initiating disease-modifying therapy with natalizumab compared with BRACETD first-line therapies.

Aggressive disease control soon after multiple sclerosis (MS) diagnosis may prevent irreversible neurological damage, and therefore early initiation of a high-efficacy disease-modifying therapy (DMT) is of clinical relevance. Evaluate long-term clinical outcomes in patients with MS who initiated treatment with either natalizumab or a BRACETD therapy (interferon beta, glatiramer acetate, teriflunomide, or dimethyl fumarate). This retrospective analysis utilized data from MSBase to create a matched population allowing comparison of first-line natalizumab to first-line BRACETD. This study included patients who initiated treatment either with natalizumab or a BRACETD DMT within 1 year of MS diagnosis and continued treatment for ⩾6 months, after which patients could switch DMTs or discontinue treatment. Patients had a minimum follow-up time of ⩾60 months from initiation. A subgroup analysis compared the natalizumab group to patients in the BRACETD group who escalated therapy after 6 months. Outcomes included unadjusted annualized relapse rates (ARRs), time-to-first relapse, time-to-first confirmed disability improvement (CDI), and time-to-first confirmed disability worsening (CDW). After 1:1 propensity score matching, 355 BRACETD patients were matched to 355 natalizumab patients. Patients initiating natalizumab were less likely to experience a relapse over the duration of follow-up, with ARRs [95% confidence interval (CI)] of 0.080 (0.070-0.092) for natalizumab patients and 0.191 (0.178-0.205) for BRACETD patients (p < 0.0001). A Cox regression model of time-to-first relapse showed a reduced risk of relapse for natalizumab patients [hazard ratio (95% CI) of 0.52 (0.42-0.65); p < 0.001] and a more favorable time-to-first CDI. The risk of CDW was similar between groups. The subgroup analysis showed an increased relapse risk as well as a significantly higher risk of CDW for BRACETD patients. Early initiation of natalizumab produced long-term benefits in relapse outcomes in comparison with BRACETD, regardless of a subsequent escalation in therapy.

A five-year observational prospective mono-center study of the efficacy of alemtuzumab in a real-world cohort of patients with multiple sclerosis.

Alemtuzumab (ALZ) is a pulsed immune reconstitution therapy for multiple sclerosis (MS). To assess basic characteristics, therapeutic effects, and prognostic biomarkers on clinical and imaging parameters of disease activity for relapsing-remitting MS (RRMS) patients selected for ALZ, in a real-world long-term setting. Fifty-one RRMS patients [female = 31; mean age 36 (standard deviation 7.1) years; median expanded disability status scale (EDSS) 2 (interquartile range (IQR) 1.5)] initiating ALZ treatment, were consecutively included. Patients were assessed at baseline and thereafter annually for 5 years with clinical measures, symbol digit modality test (SDMT), and magnetic resonance imaging (MRI). Concentrations of glial fibrillary acidic protein (GFAP), reflecting astrogliosis, and neurofilament light (NfL), reflecting axonal damage, were measured in cerebrospinal fluid (CSF) and serum samples collected at baseline and after 2 years in CSF, and annually in serum. Control subjects were symptomatic controls (SCs, n = 27), who were examined at baseline and after 5 years without evidence of neurological disease. While the mean annualized relapse rate was significantly reduced from baseline at each year of follow-up, disability was essentially maintained at a median EDSS of 1.5 and IQR between 1.13 and 2.25. New MRI activity was recorded in 26 patients (53%) over 5 years. The proportion of patients who achieved no evidence of disease activity (NEDA-3), 6-months confirmed disability worsening (CDW), and 6-months confirmed disability improvement (CDI) at 5 years were 33, 31, and 31%, respectively. The SDMT score was reduced for patients (p < 0.001), but unchanged for SCs. ALZ treatment did not change GFAP levels, whereas there was a significant decrease for RRMS patients in median CSF and serum NfL levels at follow-up [CSF month 24: 456 pg./mL (IQR 285.4) (p = 0.05); serum month 24: 6.7 pg/mL (IQR 4.7) (p < 0.01); serum month 60: 7.2 pg/mL (IQR 4.7) (p < 0.01)], compared to baseline [CSF: 1014 pg/mL (IQR 2832.5); serum 8.6 pg/mL (IQR 17.4)]. In this real-world mono-center population, we observed a progression-free survival of 69%, cumulative NEDA-3 of 33%, and reduced NfL levels, over a five-year follow-up. This confirms ALZ as an effective pulsed immune reconstitution therapy that significantly reduces neuro axonal loss, and therefore has the potential to reduce long-term neurological disability. ALZ did not appear to affect astrogliosis.

Does initial high efficacy therapy in multiple sclerosis surpass escalation treatment strategy? A comparison of patients with relapsing-remitting multiple sclerosis in the Czech and Swedish national multiple sclerosis registries.

In relapsing-remitting multiple sclerosis (RRMS) the most common treatment strategy has been to start with low-moderate efficacy disease modifying therapy (LE-DMT) and to escalate to more efficacious treatments in cases of breakthrough disease activity. However, recent evidence suggests a better outcome in patients commencing with moderate-high efficacy DMT (HE-DMT) immediately after clinical onset. The aim of this study is to compare disease activity and disability outcomes in patients treated with the two alternative strategies using the Swedish and Czech national multiple sclerosis registries, taking advantage of the fact that the relative frequency of each strategy differs markedly between these two countries. Adult RRMS patients who initiated their first-ever DMT between 2013 and 2016 and were included in the Swedish MS register were compared with a similar cohort from the MS register of the Czech Republic using propensity score overlap weighting as a balancing method. The main outcomes of interest were time to confirmed disability worsening (CDW), time to achieve an expanded disability status scale (EDSS) value of 4, time to relapse, and time to confirmed disability improvement (CDI). To support the results, a sensitivity analysis focusing solely on patients from Sweden starting with HE-DMT and patients from the Czech Republic starting with LE-DMT was performed. In the Swedish cohort, 42% of patients received HE-DMT as initial therapy compared to 3.8% of patients in the Czech cohort. The time to CDW was not significantly different between the Swedish and Czech cohorts (p-value 0.2764), with hazard ratio (HR) of 0.89 and a 95% confidence interval (CI) of 0.77-1.03. Patients from the Swedish cohort exhibited better outcomes for all remaining variables. The risk of reaching EDSS 4 was reduced by 26% (HR 0.74, 95%CI 0.6-0.91, p-value 0.0327), the risk of relapse was reduced by 66% (HR 0.34, 95%CI 0.3-0.39, p-value <0.001), and the probability of CDI was three times higher (HR 3.04, 95%CI 2.37-3.9, p-value <0.001). The analysis of the Czech and the Swedish RRMS cohorts confirmed a better prognosis for patients in Sweden, where a significant proportion of patients received HE-DMT as initial treatment.

Ublituximab Efficacy in Treatment-Naive Participants With Relapsing Multiple Sclerosis in the Phase 3 ULTIMATE I and II Studies (P6-3.015)

<h3>Objective:</h3> To evaluate efficacy with ublituximab in treatment-naive participants with relapsing multiple sclerosis enrolled in ULTIMATE I and II. <h3>Background:</h3> Ublituximab is a novel monoclonal antibody targeting a unique epitope of CD20. Ublituximab is glycoengineered for enhanced antibody-dependent cellular cytotoxicity and is administered in 1-hour infusions after the first infusion. In ULTIMATE I and II, ublituximab significantly improved annualized relapse rate (ARR) versus teriflunomide. <h3>Design/Methods:</h3> The Phase 3 ULTIMATE I (N=549) and II (N=545) studies evaluated ublituximab 450 mg intravenous infusion every 24 weeks or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc subpopulation analyses evaluated efficacy measures at Week 96 in participants who had not received approved disease-modifying therapy (DMT) within 5 years prior to study enrollment. The pooled treatment-naive population included 345 ublituximab and 377 teriflunomide participants evaluable for clinical outcomes, and 340 and 372, respectively, evaluable for radiographic outcomes. <h3>Results:</h3> In the treatment-naive population, the adjusted ARR was 0.081 versus 0.188 for ublituximab versus teriflunomide (<i>P</i>&lt;0.0001), and by Kaplan-Meier estimate, 11.2% versus 5.5% achieved 12-week confirmed disability improvement at Week 96; hazard ratio (95% CI), 2.031 (1.174–3.513; <i>P</i>=0.0095). For ublituximab versus teriflunomide, the total number (least squares means) of gadolinium-enhancing T1 lesions per scan was 0.031 versus 0.791; for new/enlarging T2 lesions, 0.390 versus 4.144 (both <i>P</i>&lt;0.0001). Change from baseline in Multiple Sclerosis Functional Composite score was 0.53 versus 0.28 for ublituximab versus teriflunomide (<i>P</i>=0.0047). No evidence of disease activity rates (Weeks 24–96, re-baselined) with ublituximab (n=324) versus teriflunomide (n=350) were 82.7% versus 23.1% (<i>P</i>&lt;0.0001). Occurrence of 12-week confirmed disease progression was low in both treatment groups. <h3>Conclusions:</h3> In pooled post hoc analyses of ULTIMATE I and II, ublituximab was associated with significant treatment benefit across multiple efficacy measures at Week 96 versus teriflunomide in participants who had not received prior DMT. <b>Disclosure:</b> Dr. Steinman has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for 180 Life Sciences. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for BioAtla. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Pasithea. Dr. Steinman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Steinman has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for National Academy of Sciences. Dr. Steinman has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Gibson Dunn. The institution of Dr. Steinman has received research support from Roche. The institution of Dr. Steinman has received research support from Novartis. Dr. Steinman has received intellectual property interests from a discovery or technology relating to health care. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW Pharmaceuticals. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Fox has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Fox has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Alexion. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Genentech. Dr. Fox has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myers Squibb. The institution of Dr. Fox has received research support from Biogen. The institution of Dr. Fox has received research support from Genentech. The institution of Dr. Fox has received research support from Celgene - BMS. The institution of Dr. Fox has received research support from Chugai. The institution of Dr. Fox has received research support from Novartis. The institution of Dr. Fox has received research support from EMD-Serono. The institution of Dr. Fox has received research support from TG Therapeutics. The institution of Dr. Fox has received research support from AbbVie. The institution of Dr. Fox has received research support from Sanofi Genzyme. The institution of Dr. Fox has received research support from AbbVie. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS Celgene. Dr. Hartung has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Geneuro. Dr. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Hartung has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Hartung has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers Neurology. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Alvarez has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Alvarez has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Alvarez has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Celgene. Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. The institution of an immediate family member of Dr. Alvarez has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Qian has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. Dr. Qian has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Qian has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Genzyme. Dr. Qian has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BMS. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squibb/Celgene. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche/Genentech. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi/Genzyme. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Wray has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for EMD Serono. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Roche/Genentech. Dr. Wray has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi/Genzyme. The institution of Dr. Wray has received research support from Biogen. The institution of Dr. Wray has received research support from Hope. The institution of Dr. Wray has received research support from Bristol Myers Squibb/Celgene. The institution of Dr. Wray has received research support from Novartis. The institution of Dr. Wray has received research support from Roche/Genentech. The institution of Dr. Wray has received research support from Sanofi/Genzyme. The institution of Dr. Wray has received research support from TG Therapeutics. Dr. Robertson has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Biogen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bristol Myers Squibb. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Genentech. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Greenwich Biosciences. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Horizon. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Janssen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi Genzyme. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for TG Therapeutics. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Robertson has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Biogen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. Dr. Robertson has received personal compensation in the range of $50,000-$99,999 for serving on a Speakers Bureau for Genentech. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Novartis. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for PRIME CME. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Janssen. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Horizon. Dr. Robertson has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for TG Therapeutics. Dr. Robertson has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for McVeigh. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Mccumber. Dr. Robertson has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Goodis. The institution of Dr. Robertson has received research support from Biogen. The institution of Dr. Robertson has received research support from EMD Serono. The institution of Dr. Robertson has received research support from Jansenn. The institution of Dr. Robertson has received research support from Genentech. The institution of Dr. Robertson has received research support from Patient-Centered Outcomes Research Institute. The institution of Dr. Robertson has received research support from Novartis. The institution of Dr. Robertson has received research support from Sanofi Genzyme. The institution of Dr. Robertson has received research support from TG Therapeutics. The institution of Dr. Robertson has received research support from Prime. The institution of Dr. Robertson has received research support from Greenwich Biosciences. The institution of Dr. Robertson has received research support from Atara Biotherapeutics. The institution of Dr. Robertson has received research support from CorEvitas. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Consortium of Multiple Sclerosis Centers. Dr. Robertson has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Multiple Sclerosis Association of America. Dr. Huang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Huang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech. Krzysztof Selmaj has nothing to disclose. Dr. Wynn has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mylan. Dr. Wynn has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Abbvie. Dr. Wynn has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. Dr. Wynn has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi. Dr. Wynn has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for TEVA. The institution of Dr. Wynn has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Banner Life. Dr. Wynn has received personal compensation in the range of $100,000-$499,999 for serving as an Expert Witness for Biogen. The institution of Dr. Wynn has received research support from Novartis. The institution of Dr. Wynn has received research support from Sanofi. The institution of Dr. Wynn has received research support from Adamas Pharmaceutics. The institution of Dr. Wynn has received research support from EMD Serono. The institution of Dr. Wynn has received research support from Roche. Dr. Wynn has a non-compensated relationship as a Director, Consultants in Neurology Comprehensive Care Center with National MS Society that is relevant to AAN interests or activities. Jenna Bosco has received personal compensation for serving as an employee of TG Therapeutics. Jenna Bosco has received stock or an ownership interest from TG Therapeutics. Dr. Mok has received personal compensation for serving as an employee of TG Therapeutics. Dr. Mok has received stock or an ownership interest from TG Therapeutics. Chris Garner has received personal compensation for serving as an employee of TG Therapeutics Inc.. Chris Garner has stock in TG Therapeutics, Inc.. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Atara. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avotres. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hexal/Sandoz. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siemens. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Therini. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic AG. The institution of Dr. Cree has received research support from Genentech. Dr. Cree has received publishing royalties from a publication relating to health care.

Switching to natalizumab or fingolimod in multiple sclerosis: Comparative effectiveness and effect of pre-switch disease activity.

Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, "BRACETD") often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch. Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59-0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60-0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03-1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod.

Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis

BackgroundTo compare the effectiveness and treatment persistence of ocrelizumab, cladribine and natalizumab in patients with relapsing–remitting multiple sclerosis switching from fingolimod.MethodsUsing data from MSBase registry, this multicentre cohort study included...

Improvements in Cognitive Processing Speed, Disability, and Patient-Reported Outcomes in Patients with Early Relapsing-Remitting Multiple Sclerosis Treated with Natalizumab: Results of a 4-year, Real-World, Open-Label Study.

STRIVE was a prospective, 4-year, multicenter, observational, open-label, single-arm study of natalizumab treatment in anti-JC virus antibody-negative patients with early relapsing-remitting multiple sclerosis (RRMS). Study objectives examined the effects of natalizumab on cognitive processing speed, confirmed disability improvement (CDI), and patient-reported outcomes (PROs). Clinical and PRO secondary endpoints were assessed annually over 4 years in STRIVE. The Symbol Digit Modalities Test (SDMT) was used as a measure of cognitive processing speed. PROs were assessed using the Multiple Sclerosis Impact Score (MSIS-29) and the Work Productivity and Activity Impairment Questionnaire (WPAI). At all four annual assessments, the proportion of patients in the intent-to-treat (ITT) population (N = 222) who exhibited clinically meaningful improvement in their SDMT score from baseline (i.e., change ≥4 points) ranged from 41.9 to 54.0%. The cumulative probability of CDI at 4 years in patients in the ITT population with a baseline Expanded Disability Status Scale score ≥2 (N = 133) was 43.9%. Statistically significant reductions in the mean change from screening in the MSIS-29 physical and psychological scores, indicating improved quality of life, were observed over all 4 years (P ≤0.0012 for all). A statistically significant decrease from screening in the impact of MS on regular activities, signifying an improvement in this WPAI measure, was also observed over all 4 years of the study. These results further extend our knowledge of the effectiveness, specifically regarding improvements in cognitive processing speed, disability and PROs, of long-term natalizumab treatment in early RRMS patients. GOV: NCT01485003 (5 December 2011).

Multiple Sclerosis Severity Score (MSSS) improves the accuracy of individualized prediction in MS

Background: The MSBase prediction model of treatment response leverages multiple demographic and clinical characteristics to estimate hazards of relapses, confirmed disability accumulation (CDA), and confirmed disability improvement (CDI). The model did not include Multiple Sclerosis Severity Score (MSSS), a disease duration-adjusted ranked score of disability. Objective: To incorporate MSSS into the MSBase prediction model and compare model accuracy with and without MSSS. Methods: The associations between MSSS and relapse, CDA, and CDI were evaluated with marginal proportional hazards models adjusted for three principal components representative of patients’ demographic and clinical characteristics. The model fit with and without MSSS was assessed with penalized r2 and Harrell C. Results: A total of 5866 MS patients were started on disease-modifying therapy during prospective follow-up (age 38.4 ± 10.6 years; 72% female; disease duration 8.5 ± 7.7 years). Including MSSS into the model improved the accuracy of individual prediction of relapses by 31%, of CDA by 23%, and of CDI by 24% (Harrell C) and increased the amount of variance explained for relapses by 49%, for CDI by 11%, and for CDA by 10% as compared with the original model. Conclusion: Addition of a single, readily available metric, MSSS, to the comprehensive MSBase prediction model considerably improved the individual accuracy of prognostics in MS.

Ublituximab: A Novel Anti-CD20 Therapy for Multiple Sclerosis

Ublituximab is a novel anti-CD20 therapy developed for the treatment of patients with multiple sclerosis. It is a glycoengineered chimeric antibody with a novel epitope on CD20, with high antibody-dependent cell-mediated cytotoxicity. Maintenance doses are administered every 6 months over an hour, providing a convenient dosing regimen. The identical phase III randomized, double-blind, active comparator to teriflunomide trials ULTIMATE I and II were completed in early 2022. ULTIMATE I and II, respectively, demonstrated that ublituximab had a strong clinical effect, with annualized relapse rates of 0.08 and 0.09 or reductions of 59% and 49% over teriflunomide. In addition, in ULTIMATE I and II, radiographic efficacy similarly reduced contrast-enhancing lesions by 97% and 96% and new/enlarging T2 lesions by 92% and 90%, respectively. Although ublituximab did not decrease confirmed disability progression in a pooled analysis of both studies, there was an increase in the confirmed disability improvement. Ublituximab was well tolerated, including infusion reactions that were predominantly mild and only seen with the first infusion. Further long-term safety data, as well as relative efficacy compared with current anti-CD20 therapies, will need to be evaluated in the real-world setting if ublituximab is to be approved as expected in December 2022.

Ocrelizumab treatment in multiple sclerosis: A Danish population-based cohort study.

Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting. A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed. A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3years. At baseline, the mean age was 41.4years in the RRMS group, 44.5years in the PPMS group and 50.3years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24weeks confirmed disability worsening. Conversely, 16.7% showed a 24weeks confirmed disability improvement. After ~1year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections. It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

Treatment Escalation vs Immediate Initiation of Highly Effective Treatment for Patients With Relapsing-Remitting Multiple Sclerosis

Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The difference in the association of these national strategies with clinical outcomes is unknown. To investigate the association of national differences in disease-modifying treatment (DMT) strategies for RRMS with disability outcomes. This cohort study used data on 4861 patients from the Danish and Swedish national multiple sclerosis (MS) registries from the date of index DMT initiation (between January 1, 2013, and December 31, 2016) until the last recorded visit at time of data extraction (October 2, 2019). All MS-specific DMTs initiated during the observation period were included in the analysis. The primary study outcome was time to 24-week confirmed disability worsening. Secondary outcomes were 24-week confirmed disability improvement, milestone Expanded Disability Status Scale scores of 3 and 4, annualized relapse rate, time to first relapse, and treatment switching. Data were analyzed using inverse probability of treatment weighting-based models using a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the 2 countries. A total of 2700 patients from the Swedish MS registry (1867 women [69.2%]; mean [SD] age, 36.1 [9.5] years) and 2161 patients from the Danish MS registry (1472 women [68.1%]; mean [SD] age, 37.3 [9.4 years]) started a first DMT between 2013 and 2016, were included in the analysis, and were observed for a mean (SD) of 4.1 (1.5) years. A total of 1994 Danish patients (92.3%) initiated a low to moderately effective DMT (teriflunomide, 907 [42.0%]) and 165 (7.6%) initiated a highly effective DMT, whereas a total of 1769 Swedish patients (65.5%) initiated a low to moderately effective DMT (teriflunomide, 64 [2.4%]) and 931 (34.5%) initiated a highly effective DMT. The Swedish treatment strategy was associated with a 29% reduction in the rate of postbaseline 24-week confirmed disability worsening relative to the Danish treatment strategy (hazard ratio, 0.71; 95% CI, 0.57-0.90; P = .004). The Swedish treatment strategy was also associated with a 24% reduction in the rate of reaching an expanded disability status scale score of 3 (hazard ratio, 0.76; 95% CI, 0.60-0.97; P = .03) and a 25% reduction in the rate of reaching an expanded disability status scale score of 4 (hazard ratio, 0.75; 95% CI, 0.61-0.96; P = .01) relative to Danish patients. The findings of this study suggest that there is an association between differences in treatment strategies for RRMS and disability outcomes at a national level. Escalation of treatment efficacy was inferior to using more efficacious DMT as initial treatment.

Comparable Efficacy and Safety of Teriflunomide versus Dimethyl Fumarate for the Treatment of Relapsing-Remitting Multiple Sclerosis.

Background The aim of this observational study is to investigate the efficacy and safety of two approved oral disease-modifying therapies (DMTs) in patients with remitting-relapsing multiple sclerosis (RRMS): dimethyl fumarate (DMF) vs. teriflunomide (TRF). Methods A total of 159 RRMS patients (82 on TRF and 77 on DMF) were included. The expanded disability status scale (EDSS), confirmed disability improvement (CDI), confirmed disability progression (CDP), and annualized relapse rate (ARR) were evaluated for the two-year period prior to enrollment in our study. The drug-associated adverse effects (AEs) were recorded. We conducted propensity matching score to compare the efficacy between TRF and DMF. Results After matching for the confounders, TRF- and DMF-treated groups were not different in terms of EDSS (P value = 0.54), CDI (P value = 0.80), CDP (P value = 0.39), and ARR (P value >0.05). TRF discontinuation occurred in 2 patients (2.43%) due to mediastinitis and liver dysfunction, while a patient (1.29%) discontinued DMF due to depression. Incidence rate of AEs in the TRF-treated group was 81.4%: hair thinning (hair loss) (62.9%), nail loss (20.9%), and elevated aminotransferase (14.8%) were the most common AEs; in DMF-treated patients, AEs were 88.2% with predominance of flushing (73.2%), pruritus (16.9%), and abdominal pain (16.9%). Conclusion Based on our findings, DMF is as efficacious and safe as TRF for the treatment of RRMS in our Iranian study population. Multicentric studies need to corroborate these findings in other populations.

Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.

IntroductionIn 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.MethodsCARE-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.ResultsOf 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.ConclusionCDI 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.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00262-3.

The Effect of Different National Treatment Strategies on Disability Outcome in Relapsing-Remitting Multiple Sclerosis: A Propensity Score Adjusted Comparison between Denmark and Sweden

Background: Treatment strategies for relapsing-remitting multiple sclerosis (RRMS) vary markedly between Denmark and Sweden. The objective was to investigate the influence of such differences on disease modifying treatment (DMT) and disability outcome. Methods: Patients with RRMS commencing their first DMT 2013-2016 were retrospectively included from the Swedish and Danish MS registries. Time to the 24-week confirmed disability worsening (CDW, primary outcome) and 24-week confirmed disability improvement (CDI, secondary outcome) and milestone expanded disability status scale (EDSS) score 3 and 4 end-points (secondary outcomes) were analyzed using Inverse Probability of Treatment Weighting (IPTW)-based Cox regression models with robust standard errors. The IPTW model used a propensity score to weight and correct the comparison for the imbalance of confounders observed at baseline between the two countries. Findings: A total of 2700 patients from the Swedish registry and 2161 patients from the Danish MS registry commencing a first DMT between 2013 and 2016 were included in the analysis and observed for an average of 4 years. The proportion of patients initiating with a low-moderate as compared to highly effective DMT was 92.4% (teriflunomide 42%) and 7.6% in Denmark and 62.4% (teriflunomide 2.4%) and 35% in Sweden, respectively. Swedish patients were associated with a 29% reduction in the rate of post-baseline 24-week CDW relative to Danish patients (IPTW HR 0.71; 95% CI 0.57-0.90; p=0.004). The Swedish cohort was associated with a 27% and 26% reduction in the rate of reaching EDSS 3 and 4 respectively, relative to Danish patients (HR 0.73; 95% CI 0.62-0.85; p<0.001; and 0.74; 95% CI 0.59-0.93; p=0.009, reference = Denmark). Interpretation: We show for the first time that differences in treatment strategies of RRMS have an impact on disability outcomes at a national level. Escalation of treatment efficacy seemed inferior to using more efficacious DMT as initial treatment. Funding Statement: This study was supported by the Swedish Research Council, the Swedish Brain foundation, the Karolinska University Hospital & the Patient-Centered Outcomes Research Institute (PCORI), the Swedish Multiple Sclerosis Research Foundation, the Swedish Federal Government (LUA/ALF Agreement ALFGBG-722081), the Swedish Association of Persons with Neurological Disabilities, the Research Foundation of the Multiple Sclerosis Society of Gothenburg, the Edit Jacobson Foundation, and NEURO Sweden. Declaration of Interests: TS has received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen Inc; speaker honoraria from Novartis. MM has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, Genzyme, has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. FP has received research grants from Biogen and Novartis. AS reports no conflicts of interest FS has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. PVR has served on scientific advisory board for Biogen, Sanofi, Roche, Novartis, Merck, and Alexion, has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, has received support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. MK reports no conflicts of interest HJ has received honoraria for participating in advisory board from Biogen. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme and Novartis and speaker’s fees from Biogen, Novartis, Merck-Serono, Bayer-Schering, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, BiogenIdec, Merck- Serono, TEVA, Sanofi-Genzyme and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain foundation JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, Roche and SanofiGenzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Roche, BSM and SanofiGenzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, and Novartis. Ethics Approval Statement: The study was approved by the The Swedish Ethical Review Authority (Dnr: 2019-00839/1199-18), and The Danish Data Protection Authority (Org. number 202100 2973).

Alemtuzumab outcomes by age: Post hoc analysis from the randomized CARE-MS studies over 8 years

BackgroundAlemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]). MethodsPost hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years). ResultsCompared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22–0.24 vs. 0.38–0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%–92% vs. 62%–88%; achievement of 6-month confirmed disability improvement [CDI]: 20%–31% vs. 13%–25%), increased proportions free of MRI disease activity (70%–86% vs. 42%–63% per year), and slowed brain volume loss (BVL; –0.45% to –0.87% vs. –0.50% to –1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%–2.2% vs. >45 years: 8.1%) and deaths (0%–1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts. ConclusionsAlemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.

Real-world disability improvement in patients with relapsing–remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program

Background: Natalizumab has been associated with disability improvement as indicated by a confirmed Expanded Disability Status Scale (EDSS) score decrease. Objective: The aim of this study was to characterize disability improvement in patients in the Tysabri Observational Program (TOP), an ongoing observational study of relapsing–remitting multiple sclerosis patients initiating natalizumab in clinical practice. Methods: TOP data as of November 2018 were included. Confirmed disability improvement (CDI) was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline EDSS score ⩾2.0. Confirmed functional system (FS) improvement was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline score ⩾1.0 in that FS. Results: Of 5384 patients, 1287 (23.9%) had CDI; 51.8% experienced CDI in the first treatment year. Among patients with CDI, 56.6% had CDI ⩾1.5 points; 34.4% had CDI ⩾2.0 points. The cumulative probability of maintaining improvement 8 years after the CDI event was 52.6%. At treatment initiation, 5363 patients (85.2%) had impairment in ⩾1 FS. At 8 years, the cumulative probability of confirmed improvement in any FS was 88.8% and ranged from 38.3% to 58.6% in individual FS. Conclusion: These results highlight disability improvement as a potential benefit of natalizumab treatment. Improvements across all FS demonstrate the range of functional improvement.

Improvements Across Functional Systems Are Maintained Regardless of Early VS Late Confirmed Disability Improvement: CARE-MS 6-Year Follow-Up

In CARE-MS studies (NCT00530348; NCT00548405), alemtuzumab showed significant improvement vs SC IFNB-1a in clinical/MRI outcomes over 2 years in patients with RRMS, including higher rates of confirmed disability improvement (CDI). Efficacy was maintained in a 4-year extension (NCT00930553). In CARE-MS II, 71% of patients with CDI achieved improvements in >1 EDSS functional system (FS) score; improvements were seen across all FS. The objective was to assess CDI occurring early/late after alemtuzumab initiation in pooled CARE-MS I and II patients over 6 years, including maintenance of effect and pattern of improvement across FS scores.