The 74th American Academy of Neurology Annual Meeting will be held in Seattle, Washington, USA from April 2-8, 2022. The conference has released many latest research progress in various fields of neurological diseases. In the field of multiple sclerosis (MS), the latest data have been released around hot topics such as MRI and neurofilament light chain (NfL) biomarkers, early-stage high-efficiency treatment strategies, and a new B-cell therapy, the BTK inhibitor.
Disease Area Biomarkers
Slowly expanding lesions predict 9-year multiple sclerosis progression
Chronic active lesions are associated with MS severity, but their association with long-term disease progression has not been assessed sex. White matter lesions that expand linearly over time (ie, slowly expanding lesions, SEL) have been proposed as markers of chronic inflammation.
52 RRMS patients at baseline, 6 months, 12 months and 24 months Undergo a 3T brain MRI scan. Logistic regression analysis was used to assess the association of SEL burden, magnetization transfer rate (MTR), and T1 hyperintensity in the first 2 years with worsening of EDSS or progression to SPMS at long-term follow-up. After a median follow-up of 9.1 years (IQR=7.6; 9.4), EDSS worsened in 20/52 (38%) patients with RRM, and 13/52 (25%) patients progressed to SPMS. The study found baseline EDSS (OR=3.153, [95%CI: 1.612-8.375], p=0.003), proportion of SEL in baseline lesions (OR=1.221 [1.044; 1.575], p=0.04) and MTR value of baseline SEL (OR=0.659 [0.405; 0.920], p=0.033) was a significant independent predictor of EDSS worsening at follow-up (c-index=0.892). Baseline EDSS (OR=6.371 [1.978; 20.526], p=0.002) and MTR values for baseline SEL (OR=0.476 [0.254; 0.893], p=0.02) were independent predictors of conversion to SPMS (c-index=0.947 ).
this study shows that The proportions correlated with MS progression after 9 years. Severe SEL microstructural abnormalities independently predicted the risk of EDSS worsening and progression to SPMS.
sNFL as a test for monitoring MS treatment and Impact on NEDA-3 Assessment
Despite the increasing availability of effective treatment options, Effective biological tools remain a necessity for individualized clinical management of MS. Neurofilament light chain (NfL) is the most promising biomarker in terms of disease activity and efficacy, but its application in clinical practice remains to be resolved.
The study assessed sNFL in 961 MS patients (830 with RRMS, 53 with PPMS and 78 with SPMS). A cross-sectional analysis was performed of these patients at various disease stages, including at the time of diagnosis, before treatment, and while receiving primary DMT therapy. In addition, an analysis was performed in a subgroup of 521 treated patients with RRMS with no evidence of disease activity (NEDA)-3 status to evaluate the use of sNFL as a measure of disease activity and efficacy in MS clinical practice, particularly is under NEDA assessment. RESULTS: Pathological levels of sNFL were more common in patients with progressive MS compared with RRMS (16%) (32% in PPMS and 26% in SPMS); treatment with all DMTs was significantly lower than in untreated patients sNFL levels; pathological levels sNFL are present in 72-75% of clinically and radiologically active patients and also in 10% of NEDA-3 patients: this proportion decreases with increasing duration of NEDA-3 status.
This study shows that sNFL can provide a basis for individual monitoring and NEDA assessment of MS patients. Notably, pathological sNFL levels were observed in a subgroup of NEDA-3 patients, suggesting the need to monitor subclinical disease activity and/or progression.
Early and efficient treatment strategies
Highly effective drugs as first-line treatment for relapsing MS strong>
The actual efficacy of high-efficiency DMT in relapsing MS is not fully understood, especially as first-line therapy. Maria-ChiaraBellomo et al retrospectively recorded data from patients at the BrownNeurology Multiple Sclerosis Center between 2007 and 2021 (the study was approved by the IRB). A total of 162 patients (N=75, B=87) were included, with a mean age of 38.5 years and a mean follow-up of 2.4 years (range: 0.1-9.5). 14 patients (8.6%) were diagnosed with recurrence (N=10, B=4), and the annual recurrence rate was 0.03. Compared with baseline MRI, 17 patients (10.5%) had MRI changes (N = 14, B = 3), of which 6 patients had symptoms corresponding to MRI changes, while 11 patients were asymptomatic. The mean EDSS score at baseline was 2.47 (0-7), which decreased to 1.97 (0-6.5) after treatment. 144 patients (88.8%) had stable or improved EDSS scores. in NEThe proportion of patients with DA status was 45.1% (73 patients, N=30, B=43). Nineteen patients (25.3%) who received natalizumab discontinued the drug, while none of the patients who received ocrelizumab did. Eleven (14.7%) natalizumab-treated patients seroconverted to JCV antibody positivity, of which 9 were switched to other therapies. Anti-natalizumab antibodies developed in 4 patients receiving natalizumab. There were no serious adverse events.
<600"> span>The above findings demonstrate that both natalizumab and B-cell depletion therapy are highly effective as first-line therapy in preventing relapse, MRI lesions and delaying disability progression without significant or serious adverse events. Patients treated with B-cell depletion therapy were more likely to remain on treatment than those treated with natalizumab.
reasons for switching between highly effective and non-effective DMT span>
DMTs approved for the treatment of MS include various high-potency therapies (HETs) and non-high-potency therapies (non-HETs) ) and have different benefit-risk profiles to suit each patient’s disease severity and individual preference. The decision to initiate DMT may be strongly influenced by individual risk perceptions. Risk perception is dynamic, influenced by patient and neurologist personal, emotional, social, and experiential factors, and may vary by region. Physicians may consider HET to have greater safety concerns than non-HET, and it is usually reserved for patients with high disease activity or poor response. To investigate the effect of risk perception on switching decisions when physicians prescribe high-efficiency or non-high-efficiency DMT, GustavoSeifer et al. analyzed data from 4361 MS patients who were/are receiving DMT in the Adelphi MS Real-World Study. The results showed that, overall, switching therapy due to infection/malignancy risk was uncommon in patients switching from either HET or non-HET. Fewer patients switched due to malignancy/infection risk compared with patients without malignancy/infection risk (99.1% vs 0.9%). Compared with patients who had previously received non-HET therapy, patients who had received prior HET therapy had a lower perception of the risk of infection. In the general population, the most important reasons for doctors to switch to drug therapy were poor efficacy (50.8%), increased recurrence rate (25.1%), and increased number of lesions (19.1%), while malignancy and infection accounted for only 0.9%. At the same time, the proportion of patients who switched to drug therapy due to poor efficacy, increased recurrence rate and increased number of lesions in the non-high-efficiency DMT group was significantly higher than that in the high-efficiency DMT group (p < 0.0001).
Remibrutinib in patients with relapsing forms of multiple sclerosis Efficacy, Safety, and Tolerability of
Bruton’s tyrosine kinase (BTK) is an intracytoplasmic tyrosine kinase, a member of the TEC kinase family, that inhibits the activation of B cells and innate immune cells. Remibrutinib is a potent, highly selective, covalent BTK inhibitor with short plasma half-life and favorable pharmacology and safety profile. This conference presents the design approach of the Phase 3 REMODELI and II studies of remibrutinib. REMODELI and II are identical randomized, double-blind, double-dummy, active-controlled, parallel-group, event-driven, multicenter studies in RMS patients, including an initial double-blind core component of up to 30 months, followed by up to 5 year open label expansion phase. The primary endpoint was annual recurrence rate. Primary secondary endpoints included confirmed disability progression at 3/6 months, number of new/enlarging T2 and Gd+T1 lesions, reduction in NfL levels, and NEDA. To evaluate the efficacy, safety, and tolerability of remibrutinib versus teriflunomide in patients with relapsing forms of multiple sclerosis (RMS). Both studies are currently recruiting and plan to enroll 800 participants.
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Expert Comments
In this AAN, about multiple sclerosis (MS) research shows the latest research progress on hot topics such as imaging, biomarkers and early and efficient treatment strategies.
< p>Chronic active lesions (also known as smoldering lesions) have been attracting attention because of their association with disease progression. In recent years, it has gradually been recognized that “true MS” may be driven by smoldering pathological processes. The disease entity is not a focal inflammation, but a diffuse smoldering process affecting the entire CNS. This AAN study on smoldering lesions enlightens us to use smoldering lesions to early identify RRMS with a high risk of long-term disability progression and transformation to SPMS Patients, the development of imaging technology can provide more possibilities for lesion exploration. Neurofilament light chain (NfL), as the most potential biomarker for disease activity and efficacy assessment, is also increasingly used in our treatment of MS In the follow-up evaluation of patients, the Nfl study data disclosed by AAN this time once again provided a strong basis for our practice of individual monitoring of MS patients and evaluation of treatment goals-NEDA. Although there are still some problems in the application of Nfl in China, such as the Chinese population Definition of normal and pathological cut-off values, correlation and predictive value of different Nfl levels with clinical disease background, MRI active lesions, etc.
Early and high-efficiency treatment strategies are gradually being adopted by more European and American and domestic MS experts, precisely because there is more and more evidence that high-efficiency drugs are used as the first-line treatment for relapsing MS. The benefit was assessed both in terms of treatment target-NEDA status and treatment adherence. In addition, the study showed that patients rarely switched to treatment due to the risk of malignancy/infection (99.1% vs 0.9%). Under the favorable environment of more and more disease-modifying drugs (DMT) in my country, the choice of treatment should be based on the benefit-risk ratio of individual treatment, and the corresponding DMT treatment should be started as soon as possible.
BTK inhibitors are a new generation of DMT targeting B cells, and their efficacy and safety are gaining traction worldwide. Validated in a central clinical trial, this time AAN disclosed for the first time the research design of REMODELI and II, a global phase III clinical study of Remibrutinib, a potent, highly selective, covalent BTK inhibitor in RMS patients, expecting BTK inhibition As the latest DMT, the drug will show better efficacy and safety in the future, and provide a more powerful weapon for the treatment of MS!
Expert Profile
Guan YangtaiProfessor
Chief physician/professor, doctoral supervisor
Shanghai Jiaotong University Director of Department of Neurology, Renji Hospital Affiliated to Medical College
Chairman of the Neurological Repair and Regeneration Branch of China Medical Biotechnology Association
China Member of the Standing Committee of the Neurology Branch of the Medical Association
Standing Member of the Neurology Branch of the Chinese Medical Doctor Association
Neuroprosthetics of the Chinese Medical Doctor Association Member of the Standing Committee of the Professional Committee
Head of the Neuroimmunology Group of the Neurology Branch of the Chinese Medical Doctor Association
Neurology of the Chinese Medical Association Deputy Head of the Neuroimmunology Group of the Branch
Deputy Director of the Neuroimmunology Branch of the Chinese Society of Neuroscience
Leading Talents in Shanghai , Outstanding Academic Leader, Medical Leading Talent
National Key R&D Program “Stem Cell and Translational Research” Key Special Project-Chief Scientist
References:1.PaoloPreziosa,etal.Slowly-ExpandingLesionsPredict9-YearMultipleSclerosisDiseaseProgression.AAN2022.S26.007.2.SimonaMalucchi,etal.ApplicabilityofsNFLinMultipleSclerosisasAdditionalMeasuretoMonitorTreatmentsinClinicalPracticeandImplicationsinNEDA-3Evaluation.AAN202 span>3.MariaChiaraBellomo,etal.HighEfficacyAgentsasFirstLineTreatmentofRelapsingFormsofMS.AAN2022.P16.009.4.GustavoSeifer,etal.RiskPerceptioninMultipleSclerosis:ReasonsforSwitchingTreatmentBetweenHighEfficacyandNon-highEfficacyDisease-modifyingTherapies.AAN2022.P3.004.5.HeinzWiendl,eta.Phase3REMODELI/IITrials:Effectiveness,Safety,andTolerabilityofRemibrutinibinPatientswithRelapsingMultipleSclerosis.AAN2022.P7.003.