Objective
CHAMPION‐NMOSD (NCT04201262) is a phase 3, open‐label, externally controlled interventional study evaluating the efficacy and safety of the terminal complement inhibitor ravulizumab in ...adult patients with anti–aquaporin‐4 antibody–positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD). Ravulizumab binds the same complement component 5 epitope as the approved therapeutic eculizumab but has a longer half‐life, enabling an extended dosing interval (8 vs 2 weeks).
Methods
The availability of eculizumab precluded the use of a concurrent placebo control in CHAMPION‐NMOSD; consequently, the placebo group of the eculizumab phase 3 trial PREVENT (n = 47) was used as an external comparator. Patients received weight‐based intravenous ravulizumab on day 1 and maintenance doses on day 15, then once every 8 weeks. The primary endpoint was time to first adjudicated on‐trial relapse.
Results
The primary endpoint was met; no patients taking ravulizumab (n = 58) had an adjudicated relapse (during 84.0 patient‐years of treatment) versus 20 patients with adjudicated relapses in the placebo group of PREVENT (during 46.9 patient‐years; relapse risk reduction = 98.6%, 95% confidence interval = 89.7%–100.0%, p < 0.0001). Median (range) study period follow‐up time was 73.5 (11.0–117.7) weeks for ravulizumab. Most treatment‐emergent adverse events were mild/moderate; no deaths were reported. Two patients taking ravulizumab experienced meningococcal infections. Both recovered with no sequelae; one continued ravulizumab treatment.
Interpretation
Ravulizumab significantly reduced relapse risk in patients with AQP4+ NMOSD, with a safety profile consistent with those of eculizumab and ravulizumab across all approved indications. ANN NEUROL 2023;93:1053–1068
Background and Purpose
Multiple sclerosis (MS) is an unpredictable disease characterised by a highly variable disease onset and clinical course. Three main clinical phenotypes have been described. ...However, distinguishing between the two progressive forms of MS can be challenging for clinicians. This article examines how the diagnostic definitions of progressive MS impact clinical research, the design of clinical trials and, ultimately, treatment decisions.
Methods
We carried out an extensive review of the literature highlighting differences in the definition of progressive forms of MS, and the importance of assessing the extent of the ongoing inflammatory component in MS when making treatment decisions.
Results
Inconsistent results in phase III clinical studies of treatments for progressive MS, may be attributable to differences in patient characteristics (e.g., age, clinical and radiological activity at baseline) and endpoint definitions. In both primary and secondary progressive MS, patients who are younger and have more active disease will derive the greatest benefit from the available treatments.
Conclusions
We recommend making treatment decisions based on the individual patient's pattern of disease progression, as well as functional, clinical and imaging parameters, rather than on their clinical phenotype. Because the definition of progressive MS differs across clinical studies, careful selection of eligibility criteria and study endpoints is needed for future studies in patients with progressive MS.
Background and purpose
Using the treatment goal of “no evidence of disease activity” (NEDA) incorporating magnetic resonance imaging (MRI) re‐baselining, we aimed to assess the efficacy of ...ocrelizumab in patients with relapsing‐remitting multiple sclerosis with a prior suboptimal response, defined by MRI or relapse criteria, to one or two disease‐modifying therapies (DMTs).
Methods
CASTING was a prospective, international, multicenter, single‐arm, open‐label phase 3 trial (NCT02861014). Patients (Expanded Disability Status Scale EDSS score ≤ 4.0, with discontinued prior DMT of ≥6 months duration due to suboptimal disease control) received intravenous ocrelizumab 600 mg every 24 weeks for 96 weeks. The primary endpoint was NEDA (defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified MRI re‐baselining at Week 8) over 96 weeks.
Results
A total of 680 patients were enrolled, 167 (24.6%) based on MRI activity only. At Week 96, 74.8% (95% confidence interval CI 71.3–78.0, n/N = 492/658) of patients had NEDA. NEDA was highest among patients enrolled due to MRI activity alone (80.6% 95% CI 68.6–89.6, n/N = 50/62) versus those enrolled for relapse (75.1% 95% CI 69.0–80.6, n/N = 172/229) or for relapse with MRI (70.5% 95% CI 60.0–79.0, n/N = 74/105). NEDA across subgroups was highest in patients with a baseline EDSS score <2.5 (77.2% 95% CI 72.8–81.2, n/N = 315/408). NEDA was higher in patients receiving one prior DMT (77.6% 95% CI 73.2–81.6, n/N = 312/402) versus two prior DMTs (70.3% 95% CI 64.3–75.8, n/N = 180/256).
Conclusions
In patients switching therapy due to suboptimal disease control, treatment with ocrelizumab led to an overall high NEDA rate across a wide range of disease‐related and demographic subgroups, regardless of prior treatment background, with no new safety signals detected.
Data from the phase IIIb CASTING trial in patients with relapsing‐remitting multiple sclerosis with a suboptimal response to one or two prior DMTs shows that switching to ocrelizumab led to a high proportion of patients with no evidence of disease activity (NEDA; defined as absence of relapses, disability progression, and inflammatory MRI measures, with prespecified magnetic resonance imaging re‐baselining at Week 8) at the end of the 96‐week treatment period.
Background and purpose
With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. We aimed to develop ...a European evidence‐based consensus for the vaccination strategy of pwMS who are candidates for disease‐modifying therapies (DMTs).
Methods
This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence‐Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk–benefit balance.
Results
Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in subpopulations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus.
Conclusion
This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.
Coronavirus disease (COVID-19) appeared in December 2019 in the Chinese city of Wuhan and has quickly become a global pandemic. The disease is caused by the severe acute respiratory syndrome ...coronavirus type-2 (SARS-CoV-2), an RNA beta coronavirus phylogenetically similar to SARS coronavirus. To date, more than 132 million cases of COVID19 have been recorded in the world, of which over 2.8 million were fatal (
https://coronavirus.jhu.edu/map.html
). A huge vaccination campaign has started around the world since the end of 2020. The availability of vaccines has raised some concerns among neurologists regarding the safety and efficacy of vaccination in patients with multiple sclerosis (MS) taking immunomodulatory or immunosuppressive therapies.
During PREVENT (a phase 3, randomized, double-blind, placebo-controlled, time-to-event study) and its open-label extension (interim analysis), 33 adults with aquaporin-4 immunoglobulin G-positive ...neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD) received eculizumab monotherapy for a median of 2.8 years (range, 14 weeks–5.2 years). At 192 weeks (~4 years), 96% of these patients were free from adjudicated relapses (Kaplan–Meier analysis; 95% confidence interval, 75.7–99.4). During PREVENT, 95% (20/21) of patients receiving eculizumab monotherapy had no disability worsening. Eculizumab monotherapy provides effective long-term relapse prevention, relieving the chronic immunosuppression burden in patients with AQP4-IgG + NMOSD. ClinicalTrials.gov; PREVENT: NCT01892345; open-label extension: NCT02003144.
Coronavirus disease 2019 (COVID‐19), a multi‐organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), continues to challenge health and care systems around the globe. The ...pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID‐19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID‐19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long‐term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID‐19 Task Force intends to raise awareness of the potential impact of COVID‐19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels.
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