Ocrelizumab exposure in relapsing–remitting multiple sclerosis: 10-year analysis of the phase 2 randomized clinical trial and its extension

Disease-modifying therapies; Multiple sclerosis; OcrelizumabTerapias modificadoras de la enfermedad; Esclerosis múltiple; OcrelizumabTeràpies modificadores de la malaltia; Esclerosi múltiple; OcrelizumabOpen-label extension (OLE) studies help inform long-term safety and efficacy of disease-modifying therapies in multiple sclerosis (MS). We report exploratory analyses from a phase 2 trial on the longest follow-up to date of ocrelizumab-treated patients with relapsing–remitting MS (RRMS). The primary treatment period (PTP) comprised four 24-week treatment cycles; participants were randomized to double-blind ocrelizumab (2000 mg or 600 mg), placebo, or interferon β-1a (open label) for one cycle, then dose-blinded ocrelizumab 1000 mg or 600 mg for the remaining cycles. The PTP was followed by consecutive assessed and unassessed treatment-free periods (TFPs) and then the OLE (ocrelizumab 600 mg every 24 weeks). Safety and efficacy were prospectively assessed. Of 220 participants randomized, 183 (84%) completed the PTP. After the TFP, 103 entered OLE (median OLE ocrelizumab exposure 6.5 years). Most common adverse events across all periods were infusion-related reactions. MRI activity, annualized relapse rate, and confirmed disability progression (CDP) rates remained low throughout. During the assessed TFP, there was a trend toward less and later B-cell repletion, and later CDP, for patients randomized to ocrelizumab; MRI activity was observed in 16.3% of patients, the earliest 24 weeks after the last ocrelizumab dose. This is the longest follow-up of ocrelizumab-treated patients with RRMS, with no new safety signals emerging during an observation period from 2008 to 2020. Results reinforce the sustained efficacy of long-term ocrelizumab. Reduced disease activity was maintained following interruption of 6-month dosing cycles, with no evidence of rebound.This research was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Editorial assistance for this article was provided by Nicholas Fitch and Martha Hoque of Articulate Science, UK, and funded by F. Hoffmann-La Roche Ltd. The authors had full editorial control of the manuscript and provided their final approval of all content

Efficacy and safety of ozanimod in multiple sclerosis: Dose-blinded extension of a randomized phase II study

© The Author(s), 2018. Background: Ozanimod, an oral immunomodulator, selectively targets sphingosine 1-phosphate receptors 1 and 5. Objective: Evaluate efficacy, safety, and tolerability of ozanimod in relapsing multiple sclerosis. Methods: In the RADIANCE Part A phase II study (NCT01628393), participants with relapsing multiple sclerosis were randomized (1:1:1) to once-daily ozanimod hydrochloride (0.5 or 1 mg) or placebo. After 24 weeks, participants could enter a 2-year, dose-blinded extension. Ozanimod-treated participants continued their assigned dose; placebo participants were re-randomized (1:1) to ozanimod hydrochloride 0.5 or 1 mg (equivalent to ozanimod 0.46 and 0.92 mg). Results: A total of 223 (89.6%) of the 249 participants completed the blinded extension. At 2 years of the extension, the percentage of participants who were gadolinium-enhancing lesion-free ranged from 86.5% to 94.6%. Unadjusted annualized relapse rate during the blinded extension (week 24—end of treatment) was 0.32 for ozanimod hydrochloride 0.5 mg → ozanimod hydrochloride 0.5 mg, 0.18 for ozanimod hydrochloride 1 mg → ozanimod hydrochloride 1 mg, 0.30 for placebo → ozanimod hydrochloride 0.5 mg, and 0.18 for placebo → ozanimod hydrochloride 1 mg. No second-degree or higher atrioventricular block or serious opportunistic infection was reported. Conclusion: Ozanimod demonstrated sustained efficacy in participants continuing treatment up to 2 years and reached similar efficacy in participants who switched from placebo; no unexpected safety signals emerged

Laboratory predictors of uphill cycling performance in trained cyclists

This study aimed to assess the relationship between an uphill time-trial (TT) performance and both aerobic and anaerobic parameters obtained from laboratory tests. Fifteen cyclists performed a Wingate anaerobic test, a graded exercise test (GXT) and a field-based 20-min TT with 2.7% mean gradient. After a 5-week non-supervised training period, 10 of them performed a second TT for analysis of pacing reproducibility. Stepwise multiple regressions demonstrated that 91% of TT mean power output variation (W kg-1) could be explained by peak oxygen uptake (ml kg-1.min-1) and the respiratory compensation point (W kg-1), with standardised beta coefficients of 0.64 and 0.39, respectively. The agreement between mean power output and power at respiratory compensation point showed a bias ± random error of 16.2 ± 51.8 W or 5.7 ± 19.7%. One-way repeated-measures analysis of variance revealed a significant effect of the time interval (123.1 ± 8.7; 97.8 ± 1.2 and 94.0 ± 7.2% of mean power output, for epochs 0-2, 2-18 and 18-20 min, respectively; P < 0.001), characterising a positive pacing profile. This study indicates that an uphill, 20-min TT-type performance is correlated to aerobic physiological GXT variables and that cyclists adopt reproducible pacing strategies when they are tested 5 weeks apart (coefficients of variation of 6.3; 1 and 4%, for 0-2, 2-18 and 18-20 min, respectively)

Social context influences recognition of bodily expressions

Previous studies have shown that recognition of facial expressions is influenced by the affective information provided by the surrounding scene. The goal of this study was to investigate whether similar effects could be obtained for bodily expressions. Images of emotional body postures were briefly presented as part of social scenes showing either neutral or emotional group actions. In Experiment 1, fearful and happy bodies were presented in fearful, happy, neutral and scrambled contexts. In Experiment 2, we compared happy with angry body expressions. In Experiment 3 and 4, we blurred the facial expressions of all people in the scene. This way, we were able to ascribe possible scene effects to the presence of body expressions visible in the scene and we were able to measure the contribution of facial expressions to the body expression recognition. In all experiments, we observed an effect of social scene context. Bodily expressions were better recognized when the actions in the scenes expressed an emotion congruent with the bodily expression of the target figure. The specific influence of facial expressions in the scene was dependent on the emotional expression but did not necessarily increase the congruency effect. Taken together, the results show that the social context influences our recognition of a person’s bodily expression

Siponimod vs placebo in active secondary progressive multiple sclerosis: a post hoc analysis from the phase 3 EXPAND study.

BACKGROUND Siponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS. METHODS Post hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND. ENDPOINTS 3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits. RESULTS Data from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p < 0.01); there was no significant effect on T25FW. Siponimod increased likelihood of 6-month confirmed SDMT improvement vs placebo (by 62%; p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm3; p < 0.0001), and fewer T1 Gd + and N/E T2 lesions than placebo (85% and 80% reductions, respectively; p < 0.0001). CONCLUSIONS In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo. TRIAL REGISTRATION ClinicalTrials.gov number: NCT01665144

GBA mutations are associated with Rapid eye movement sleep behavior disorder

Rapid eye movement sleep behavior disorder and GBA mutations are both associated with Parkinson’s disease. The GBA gene was sequenced in idiopathic rapid eye movement sleep behavior disorder patients (n = 265), and compared to controls (n = 2240). Rapid eye movement sleep behavior disorder questionnaire was performed in an independent Parkinson’s disease cohort (n = 120). GBA mutations carriers had an OR of 6.24 (10.2% in patients vs. 1.8% in controls, P < 0.0001) for rapid eye movement sleep behavior disorder, and among Parkinson’s disease patients, the OR for mutation carriers to have probable rapid eye movement sleep behavior disorder was 3.13 (P = 0.039). These results demonstrate that rapid eye movement sleep behavior disorder is associated with GBA mutations, and that combining genetic and prodromal data may assist in identifying individuals susceptible to Parkinson’s disease

Genetic markers of Restless Legs Syndrome in Parkinson disease

INTRODUCTION: Several studies proposed that Restless Legs Syndrome (RLS) and Parkinson disease (PD) may be clinically and/or etiologically related. To examine this hypothesis, we aimed to determine whether the known RLS genetic markers may be associated with PD risk, as well as with PD subtype. METHODS: Two case-control cohorts from Tel-Aviv and New-York, including 1133 PD patients and 867 controls were genotyped for four RLS-related SNPs in the genes MEIS1, BTBD9, PTPRD and MAP2K5/SKOR1. The association between genotype, PD risk and phenotype was tested using multivariate regression models. RESULTS: None of the tested SNPs was significantly associated with PD risk, neither in any individual cohort nor in the combined analysis after correction for multiple comparisons. The MAP2K5/SKOR1 marker rs12593813 was associated with higher frequency of tremor in the Tel-Aviv cohort (61.0% vs. 46.5%, p = 0.001, dominant model). However, the risk allele for tremor in this gene has been associated with reduced RLS risk. Moreover, this association did not replicate in Tremor-dominant PD patients from New-York. CONCLUSION: RLS genetic risk markers are not associated with increased PD risk or subtype in the current study. Together with previous genetic, neuropathological and epidemiologic studies, our results further strengthen the notion that RLS and PD are likely to be distinct entities