24-week Confirmed Disability Progression Research Articles

Emerging Cerebrospinal Fluid Biomarkers of Disease Activity and Progression in Multiple Sclerosis

Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. To identify CSF biological measures associated with progressive MS pathobiology. This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

Networks of microstructural damage predict disability in multiple sclerosis

BackgroundNetwork-based measures are emerging MRI markers in multiple sclerosis (MS). We aimed to identify networks of white (WM) and grey matter (GM) damage that predict disability progression and cognitive worsening...

Long-Term Treatment With First-Line Ocrelizumab in Patients With Early RMS: 9-Year OPERA Subgroup Analysis (S46.002)

Long-Term Treatment With First-Line Ocrelizumab in Patients With Early RMS: 9-Year OPERA Subgroup Analysis (S46.002)

Delayed Signs of Early Disability Progression After 8.5 Years of Ocrelizumab Treatment in Patients With Relapsing Multiple Sclerosis (S46.003)

Delayed Signs of Early Disability Progression After 8.5 Years of Ocrelizumab Treatment in Patients With Relapsing Multiple Sclerosis (S46.003)

Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: NEDA-3 after Re-baselining in the Phase 3 EVOLVE-MS-1 Study (P8-3.001)

Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: NEDA-3 after Re-baselining in the Phase 3 EVOLVE-MS-1 Study (P8-3.001)

Association of Higher Ocrelizumab Exposure With Reduced Disability Progression in Multiple Sclerosis.

Ocrelizumab improved clinical and MRI measures of disease activity and progression in three phase 3 multiple sclerosis (MS) studies. Post hoc analyses demonstrated a correlation between the ocrelizumab serum concentration and the degree of blood B-cell depletion, and body weight was identified as the most influential covariate on ocrelizumab pharmacokinetics. The magnitude of ocrelizumab treatment benefit on disability progression was greater in lighter vs heavier patients. These observations suggest that higher ocrelizumab serum levels provide more complete B-cell depletion and a greater delay in disability progression. The current post hoc analyses assessed population exposure-efficacy/safety relationships of ocrelizumab in patients with relapsing and primary progressive MS. Patients in OPERA I/II and ORATORIO were grouped in exposure quartiles based on their observed individual serum ocrelizumab level over the treatment period. Exposure-response relationships were analyzed for clinical efficacy (24-week confirmed disability progression (CDP), annualized relapse rate [ARR], and MRI outcomes) and adverse events. Ocrelizumab reduced new MRI lesion counts to nearly undetectable levels in patients with relapsing or primary progressive MS across all exposure subgroups, and reduced ARR in patients with relapsing MS to very low levels (0.13-0.18). A consistent trend of higher ocrelizumab exposure leading to lower rates of CDP was seen (0%-25% [lowest] to 75%-100% [highest] quartile hazard ratios and 95% confidence intervals; relapsing MS: 0.70 [0.41-1.19], 0.85 [0.52-1.39], 0.47 [0.25-0.87], and 0.34 [0.17-0.70] vs interferon β-1a; primary progressive MS: 0.88 [0.59-1.30], 0.86 [0.60-1.25], 0.77 [0.52-1.14], and 0.55 [0.36-0.83] vs placebo). Infusion-related reactions, serious adverse events, and serious infections were similar across exposure subgroups. The almost complete reduction of ARR and MRI activity already evident in the lowest quartile, and across all ocrelizumab-exposure groups, suggests a ceiling effect. A consistent trend of higher ocrelizumab exposure leading to greater reduction in risk of CDP was observed, particularly in the relapsing MS trials, and was not associated with a higher rate of adverse events. Higher ocrelizumab exposure may provide improved control of disability progression by reducing disease activity below that detectable by ARR and MRI, and/or by attenuating other B-cell-related pathologies responsible for tissue damage. This analysis provides Class III evidence that higher ocrelizumab serum levels are related to greater reduction in risk of disability progression in patients with multiple sclerosis. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in the open-label extension. ClinicalTrials.gov Identifier: NCT01247324 (OPERA I), NCT01412333 (OPERA II), and NCT01194570 (ORATORIO).

020 Long-term efficacy of ocrelizumab in relapsing multiple sclerosis: 6 study years

BackgroundEfficacy/safety of ocrelizumab in relapsing multiple sclerosis were demonstrated in the OPERA I/II (NCT01247324/NCT01412333) double-blind period (DBP). We assessed the efficacy of switching to or maintaining ocrelizumab after 4 years of the open-label extension (OLE).MethodsAt OLE commencement, patients continued ocrelizumab (OCR-OCR) or switched from interferon-β-1a to OCR (IFN-OCR). Adjusted annualised relapse rate (ARR), time-to-onset of 24-week confirmed disability progression (CDP24) and risk of requiring a walking aid (Expanded Disability Status Scale score ≥6.0) from DBP baseline were analysed.ResultsAmong IFN-OCR switchers, ARR decreased year-on-year from 0.2 in the pre-switch year to 0.04 in OLE Year 4; OCR-OCR continuers maintained low ARRs (pre-switch, 0.13; OLE Year 4, 0.05). CDP24 was lower year-on-year in OCR-OCR continuers versus IFN-OCR switchers in the pre-switch year (7.7% vs 12.0%) and at OLE Year 4 (19.2% vs 23.7%); p<0.05 all comparisons. Over the DBP and OLE, risk of requiring a walking aid was 44% lower (p=0.004) in OCR-OCR continuers versus IFN-OCR switchers.ConclusionsAfter 6 years of follow-up, rates of patients with CDP24 and risk of requiring a walking aid remained lower in earlier initiators of ocrelizumab (OCR-OCR) versus those initially receiving IFN (IFN-OCR), demonstrating maintained benefits of earlier treatment with ocrelizumab.g.giovannoni@qmul.ac.uk

PND16 Socioeconomic Value of Ocrelizumab in the Treatment of Patients with Primary Progressive Multiple Sclerosis

Ocrelizumab is the first and only disease-modifying therapy (DMT) approved by Health Canada for patients with primary progressive multiple sclerosis (PPMS). In this study, we assess the socioeconomic benefits derived from using ocrelizumab in PPMS compared with best supportive care (BSC) in Canada. A Markov-state model based on one-point spaced Expanded Disability Status Scale (EDSS) states (0–9) was used to estimate costs associated with disease progression. EDSS at baseline and transition probabilities were derived from the ORATORIO trial and MSBase natural history study, respectively. Treatment effect on delaying disability progression was modeled through the hazard ratio for time to 24-week confirmed disability progression, which was derived from a counterfactual analysis of the ORATORIO double-blind and open-label extension phases. Societal benefits included savings in direct healthcare and non-healthcare costs, and indirect costs (including informal care and productivity loss, among others). Drug costs were excluded to focus on treatment benefits. Resource use and cost inputs at 2019 prices were derived from published studies in the multiple sclerosis space or from national statistics databases. Data on PPMS prevalence and proportion of patients receiving BSC in Canada were obtained by triangulating Canadian epidemiologic data, Roche PPMS market share forecast, and real world data from the Ocrevus patient support program. The socioeconomic value of ocrelizumab compared with BSC in Canada is estimated to be CAD$61.3 million over 5 years. These cost savings are driven by reduction in the utilization of healthcare resources and community services ($33.1 million), productivity loss ($13.8 million), and informal care ($10.8 million). Ocrelizumab for PPMS offers substantial socioeconomic benefits compared with BSC in Canada.

Cladribine vs other drugs in MS: Merging randomized trial with real-life data.

ObjectiveCladribine tablets were tested against placebo in randomized controlled trials (RCTs). In this study, the effectiveness of cladribine vs other approved drugs in patients with relapsing-remitting MS (RRMS) was compared by matching RCT to observational data.MethodsData from the pivotal trial assessing cladribine tablets vs placebo (CLARITY) were propensity score matched to data from the Italian multicenter database i-MuST. This database included 3,150 patients diagnosed between 2010 and 2018 at 24 Italian MS centers who started a disease-modifying drug. The annualized relapse rate (ARR) over 2 years from treatment start and the 24-week confirmed disability progression were compared between patients treated with cladribine and other approved drugs (interferon, glatiramer acetate, fingolimod, natalizumab, and dimethyl fumarate), with comparisons with placebo as a reference. Treatment effects were estimated by the inverse probability weighting negative binomial regression model for ARR and Cox model for disability progression. The treatment effect has also been evaluated according to baseline disease activity.ResultsAll weighted baseline characteristics were well balanced between groups. All drugs tested had an effect vs placebo close to that detected in the RCT. Patients treated with cladribine had a significantly lower ARR compared with interferon (relapse ratio [RR] = 0.48; p < 0.001), glatiramer acetate (RR = 0.49; p < 0.001), and dimethyl fumarate (RR = 0.6; p = 0.001); a similar ARR to that with fingolimod (RR = 0.74; p = 0.24); and a significantly higher ARR than natalizumab (RR = 2.13; p = 0.014), confirming results obtained by indirect treatment comparisons from RCTs (network meta-analyses). The relative effect of cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years) was higher in patients with high disease activity vs all treatments except fingolimod and natalizumab. Effects on disability progression were largely nonsignificant, probably due to lack of power for such analysis.ConclusionIn patients with RRMS, cladribine tablets showed lower ARR compared with matched patients who started interferon, glatiramer acetate, or dimethyl fumarate; was similar to fingolimod; and was higher than natalizumab. The beneficial effect of cladribine tablets was generally amplified in the subgroup of patients with high disease activity.Classification of evidenceThis study provides Class III evidence that for patients with RRMS, cladribine-treated patients had lower ARR compared with interferon, glatiramer acetate, or dimethyl fumarate; similar ARR compared with fingolimod; and higher ARR compared with natalizumab.

Five years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension.

ObjectiveTo assess over 3 years of follow-up the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA: I/II studies in relapsing multiple sclerosis.MethodsAfter 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN)-β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression (CDP)/improvement (CDP), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.ResultsOf patients entering the OLE phase, 88.6% completed year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier vs patients initially receiving IFN-β-1a (16.1% vs 21.3% at year 5; p = 0.014). Patients continuing OCR maintained and those switching from IFN-β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from years 3–5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN-β-1a (−1.87% vs −2.15% at year 5; p < 0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.ConclusionCompared with patients switching from IFN-β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.Classification of evidenceThis study provides Class III evidence that earlier and continuous treatment with OCR provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN-β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.Clinical trial identifiersNCT01247324/NCT01412333.

Long-term safety and efficacy of daclizumab beta in relapsing\u2013remitting multiple sclerosis: 6-year results from the SELECTED open-label extension study

ObjectiveSELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED.MethodsEligible participants who completed 1–2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED. Safety assessments were evaluated for the SELECTED treatment period; efficacy data were evaluated from first dose of daclizumab beta in SELECT/SELECTION.ResultsNinety percent (410/455) of participants who completed treatment in SELECTION enrolled in SELECTED. Within SELECTED, 69% of participants received daclizumab beta for > 3 years, 39% for > 4 years, and 9% for > 5 years; 87% of participants experienced an adverse event and 26% a serious adverse event (excluding multiple sclerosis relapse). No deaths occurred. Overall, hepatic events were reported in 25% of participants; serious hepatic events in 2%. There were no confirmed cases of immune-mediated encephalitis. Based on weeks from the first daclizumab beta dose in SELECT/SELECTION, adjusted annualized relapse rate (95% confidence interval) for weeks 0–24 was 0.21 (0.16–0.29) and remained low on continued treatment. Overall incidence of 24-week confirmed disability progression was 17.4%. Mean numbers of new/newly enlarging T2 hyperintense lesions remained low; percentage change in whole brain volume decreased over time.ConclusionsThe effects of daclizumab beta on clinical and radiologic outcomes were sustained for up to ~ 8 years of treatment. No new safety concerns were identified in SELECTED.Trial registrationClinicaltrials.gov NCT01051349; first registered on January 15, 2010.

Efficacy and Safety of Ocrelizumab in Patients with Relapsing-Remitting Multiple Sclerosis with a Suboptimal Response to Previous Disease-Modifying Therapies (1-Year Interim Results)

Patients with relapsing-remitting multiple sclerosis (RRMS) often experience disease activity despite receiving a disease-modifying therapy (DMT). The aim of the prospective, multicentre, single-arm Phase IIIb CASTING study (NCT02861014) is to evaluate the efficacy and safety of ocrelizumab (OCR) in patients with RRMS who had a suboptimal response to an adequate course of 1 or 2 DMTs. Patients in CASTING (Expanded Disability Status Scale [EDSS] ≤4.0; disease duration ≤10 years; discontinued prior DMT of ≥6 months' duration due to suboptimal disease control) received intravenous OCR 600 mg/24 weeks (first dose, 2 × 300 mg, 14 days apart) for 96 weeks. The proportion of patients with NEDA was measured by an absence of protocol-defined relapses (PDRs), 24-week confirmed disability progression (24W-CDP), T1 gadolinium-enhancing lesions and new/enlarging T2 lesions and were calculated using the modified intent-to-treat population (mITT; patients receiving any dose who discontinued early without a protocol-defined event were imputed as having an event if the treatment discontinuation reason was lack of efficacy or death; others were excluded). MRI outcomes were rebaselined at Week 8 (prespecified analyses). A total of 680 patients (female, 64%; mean [SD] baseline EDSS score, 2.1 [1.1]; disease duration, 5.0 [2.7] years; pretreated with one DMT, n=411 [60.5%]; pretreated with two DMTs, n=265 [39.5%]) were enrolled in CASTING, most commonly for reasons of relapse on prior DMT, and are included in the mITT population. At Week 48, most patients had NEDA (N=586/674 [86.9%]). Rates of 24W-CDP (N=32/673 [4.8%]), PDR (N=28/674 [4.2%]), T1 gadolinium-enhancing lesions (N=19/673 [2.8%]) and new/enlarging T2 lesions (N=42/673 [6.2%]) were generally low; MRI outcomes were rebaselined at Week 8. The adjusted annualised relapse rate (negative binomial model) was 0.048. A total of 591 patients (86.9%) experienced ≥1 adverse event, and 34 patients (5.0%) experienced ≥1 serious adverse event (includes infusion-related reactions). Most patients in CASTING had no evidence of MS disease activity. As future data become available and are reported, CASTING will describe additional data on the efficacy and safety of ocrelizumab treatment in patients who had ongoing disease activity while receiving another DMT.

Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE.

Introduction:We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported.Methods:Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0–2 /DMF for years 3–9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed.Results:Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0–2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6–0.8 and 0.9–2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was −1.32% (range −1.60% to −1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 109/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation.Conclusions:Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS.Trial registration:ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).

Long-Term Reduction of Relapse Rate and Confirmed Disability Progression After 6 Years of Ocrelizumab Treatment in Patients with Relapsing Multiple Sclerosis

The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week controlled double-blind period (DBP) of the Phase III trials OPERA I and OPERA II (NCT01247324; NCT01412333). Results for the 3-year follow-up of the pooled OPERA open-label extension (OLE) period have previously been reported (Hauser SL, et al. ECTRIMS 2018;Abstract P590). At the start of the OLE period, patients who completed the DBP either continued OCR (OCR-OCR) or were switched from interferon (IFN) β-1a to OCR (IFN-OCR). Adjusted annualised relapse rate (ARR), time to onset of 24-week confirmed disability progression (CDP24) and change in adjusted mean Expanded Disability Status Scale (EDSS) score from the DBP baseline were analysed. Overall, 82.3% of patients who entered the OLE completed OLE study Year 4. Among IFN-OCR patients, ARR decreased from 0.20 in the year pre-switch to 0.10, 0.08, 0.07 and 0.04 at Years 1, 2, 3 and 4 post-switch (Year 1 vs pre-switch, p<0.001; Year 1 vs Year 2, p=0.31; Year 2 vs Year 3, p=0.56; Year 3 vs Year 4, p=0.05). OCR-OCR continuers maintained the low ARR through the year pre-OLE and the 4 years of the OLE period (0.13, 0.10, 0.08, 0.07 and 0.05). OCR-OCR continuers vs IFN-OCR switchers had lower proportions of patients with CDP24 in the year pre-switch (7.7% vs 12.0%), and at OLE Year 1 (10.1% vs 15.6%), OLE Year 2 (13.9% vs 18.1%), OLE Year 3 (16.2% vs 21.3%), and OLE Year 4 (19.2% vs 23.7%); p<0.05, all difference comparisons. The safety profile observed in the OLE was generally consistent with that observed during the DBP. After 6 years of follow-up, the proportion of patients with CDP24 remained lower in patients who initiated ocrelizumab treatment earlier (OCR-OCR), compared with patients who received initial IFN treatment (IFN-OCR), demonstrating that the benefits of earlier initiation of ocrelizumab were maintained compared with patients switching from IFN. Switching from IFN to ocrelizumab after 2 years at the start of the OLE period was associated with a reduction in ARR. Both OCR-OCR and IFN-OCR patients maintained their reduction in ARR through the 4-year follow-up of the OLE period.

Efficacy of daclizumab beta versus intramuscular interferon beta-1a on disability progression across patient demographic and disease activity subgroups in DECIDE

Background: Demonstration of clinical benefits on disability progression measures is an important attribute of effective multiple sclerosis (MS) treatments. Objective: Examine efficacy of daclizumab beta versus intramuscular (IM) interferon beta-1a on measures of disability progression in patient subgroups from DECIDE. Methods: Twenty-four-week confirmed disability progression (CDP), 24-week sustained worsening on a modified Multiple Sclerosis Functional Composite (MSFCS) where 3-Second Paced Auditory Serial Addition Test was replaced by Symbol Digit Modalities Test, and proportion of patients with clinically meaningful worsening in 29-Item Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS) score from baseline to week 96 were examined in the overall population and subgroups defined by baseline demographic/disease characteristics. Results: Daclizumab beta significantly reduced risk of 24-week CDP (hazard ratio (HR), 0.73; 95% confidence interval (95% CI), 0.55–0.98), risk of 24-week sustained MSFCS progression (HR, 0.80; 95% CI, 0.67–0.95), and odds of clinically meaningful worsening in MSIS-29 PHYS (odds ratio, 0.76; 95% CI, 0.60–0.95) versus IM interferon beta-1a. Point estimates showed trends favoring daclizumab beta over IM interferon beta-1a across several patient subgroups for all three outcome measures. Conclusion: Daclizumab beta showed consistent benefit versus IM interferon beta-1a across measures assessing patient disability/function and across a range of clinical baseline characteristics in patients with relapsing-remitting MS.

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

BackgroundAn evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease.MethodsIn this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis.ResultsThe percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey. Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo. Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections.ConclusionsAmong patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann–La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570.)

Peginterferon beta-1a reduces disability worsening in relapsing-remitting multiple sclerosis: 2-year results from ADVANCE.

In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing-remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL). In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as ⩾1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score ⩾ 1.0, or ⩾1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset. Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by ⩾1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks. Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing-remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL [ClinicalTrials.gov identifier: NCT00906399].

Impact of daclizumab versus interferon beta-1a on patient-reported outcomes in relapsing-remitting multiple sclerosis

BackgroundPatient-reported outcomes (PROs) provide information on treatment effects from the patient's perspective that complement outcomes on clinical measures. In DECIDE, daclizumab demonstrated superior efficacy in reducing relapses, 24-week confirmed disability progression, and brain lesions (assessed by magnetic resonance imaging [MRI]) versus intramuscular interferon beta-1a in relapsing-remitting multiple sclerosis. ObjectiveTo examine the impact of daclizumab versus interferon beta-1a on PROs in DECIDE. MethodsDECIDE was a randomized, double-blind, active-controlled, phase 3 study comparing daclizumab 150mg subcutaneous every 4 weeks with interferon beta-1a 30mcg intramuscular once weekly. The 29-item Multiple Sclerosis Impact Scale (MSIS-29) and EuroQoL 5-Dimensions (EQ-5D) were assessed at baseline and every 24 weeks. Mean changes from baseline were analyzed using analysis of covariance models. Individual items for the MSIS-29 physical (PHYS) and psychological (PSYCH) subscales were analyzed post hoc. ResultsDaclizumab treatment resulted in greater mean improvements relative to baseline in MSIS-29 PHYS and PSYCH scores starting at week 24 that persisted over 96 weeks. Mean improvements from baseline in MSIS-29 PHYS and PSYCH scores were significantly greater for daclizumab versus intramuscular interferon beta-1a at week 96. Daclizumab-treated patients showed steady improvements in EQ-5D health utility index and EQ-5D visual analog scale scores over the study period, with significantly greater improvements versus intramuscular interferon beta-1a at week 96 (p=0.0048 and p=0.0006, respectively). ConclusionsImprovements in patient-reported physical and psychological functioning and general health status with daclizumab compared with intramuscular interferon beta-1a are consistent with outcomes on clinical and brain MRI lesion measures in DECIDE (NCT01064401).

The EDSS-Plus, an improved endpoint for disability progression in secondary progressive multiple sclerosis

Background: The Expanded Disability Status Scale (EDSS) has wide scientific and regulatory precedent but limited ability to detect clinically relevant disability progression in secondary progressive multiple sclerosis (SPMS) patients, partly due to a lack of meaningful measurement of short-distance ambulatory and upper-extremity function. Objective: To present a rationale for a composite endpoint adding the timed 25-foot walk (T25FW) and 9-Hole Peg Test (9HPT) to EDSS for SPMS disability progression assessment. Methods: Using the International Multiple Sclerosis Secondary Progressive Avonex Clinical Trial (IMPACT) placebo arm (n = 215) data, we analyzed disability progression using a novel progression endpoint, “EDSS-Plus,” defined as progression on ⩾1 of 3 components (EDSS, T25FW, and/or 9HPT) confirmed ⩾24 weeks apart and with a ⩾20% minimum threshold change for T25FW and 9HPT. Results: Over 2 years, subjects classified as T25FW, 9HPT (dominant hand), or 9HPT (non-dominant hand) progressors worsened on average by 103.4%, 69.0%, and 59.2%, respectively, while non-progressors’ times remained largely unchanged. Using EDSS-Plus, 59.5% of the patients had 24-week confirmed disability progression versus 24.7% (EDSS), 41.9% (T25FW), and 34.4% (9HPT (either hand)) on each component alone. Conclusion: The 24-week confirmed minimum worsening of ⩾20% for T25FW and 9HPT clearly separates SPMS progressors from non-progressors. We propose that EDSS-Plus may represent an improved endpoint to identify SPMS disability progression.

Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing-Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies.

IntroductionDelayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated clinical and neuroradiologic efficacy and safety in the Phase 3 DEFINE and CONFIRM trials, and in the extension study (ENDORSE), in patients with relapsing–remitting multiple sclerosis (RRMS). This post hoc analysis assessed DMF efficacy in newly diagnosed patients with RRMS with 6-year minimum follow-up.MethodsPatients randomized in DEFINE/CONFIRM to DMF 240 mg twice (BID) or thrice daily (TID) continued on same dosage in ENDORSE. Patients randomized to placebo (PBO) or glatiramer acetate (CONFIRM only) were re-randomized to DMF BID or TID. Results for DMF BID (approved dosage) are reported. Newly diagnosed patients were diagnosed within 1 year prior to DEFINE/CONFIRM entry and either treatment-naive or previously treated with corticosteroids alone.ResultsThe newly diagnosed population included 144 patients continuously treated with DMF BID in DEFINE/CONFIRM and ENDORSE (DMF/DMF) and 85 treated with PBO for 2 years in DEFINE/CONFIRM followed by 4 years of DMF BID in ENDORSE (PBO/DMF). At 6 years (ENDORSE Year 4), the annualized relapse rates [ARR; 95% confidence interval (CI)] were 0.137 (0.101, 0.186) and 0.168 (0.113, 0.252) for DMF/DMF and PBO/DMF, respectively; representing 19% risk reduction (P = 0.3988). PBO/DMF patients demonstrated improvements in ARR after switching to DMF in ENDORSE: 0.260 (0.182, 0.372) for Years 0–2 (DEFINE/CONFIRM) and 0.102 (0.064, 0.163) for Years 3–6 (ENDORSE), representing 61% risk reduction for Years 3–6 versus Years 1–2 (P < 0.0001). The proportion of patients with 24-week confirmed disability progression (95% CI) at 6 years was 15.7% (10.3%, 23.7%) in DMF/DMF and 24.3% (15.9%, 36.2%) in PBO/DMF, representing 49% risk reduction versus PBO/DMF (P = 0.0397).ConclusionLong-term DMF treatment demonstrated strong and sustained efficacy in newly diagnosed patients. Results suggest greater clinical benefits with earlier initiation of treatment in this patient population.FundingBiogen.Trial registrationClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).