In a phase 1–2 dose-escalation trial involving adults with ALS due to
SOD1
mutations who received intrathecal tofersen (an antisense oligonucleotide) or placebo, the levels of mutant SOD1 in the CSF ...were 33 percentage points lower in the highest-dose tofersen group than in the placebo group.
Background
Disease-modifying therapies (DMTs) for multiple sclerosis (MS) target immunity and have the potential to increase the risk of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) ...infection and alter its clinical course. We assessed these risks in patients with MS (PwMS).
Objective
The objective of this study was to describe the overall risk of coronavirus disease 2019 (COVID-19) infection, severe disease course, and potential population-level predictors of COVID-19 infection in PwMS, and to provide a context using a cohort of patients with systemic lupus erythematosus (SLE). In addition, the association of different MS DMTs with the incidence and clinical course of COVID-19 was evaluated. Safety data from the Biogen Global Safety Database are also presented on reported cases of COVID-19 in patients treated with Biogen MS therapies.
Methods
The IBM
®
Explorys electronic health record database of > 72,000,000 patients from US healthcare networks identified patients with MS or SLE, with and without polymerase chain reaction-confirmed COVID-19. COVID-19 cumulative incidence, hospitalization, and deaths among DMT classes were compared using logistic regression (adjusted for age, sex, body mass index, comorbidities, and race/ethnicity). As a secondary data source to assess safety data, COVID-19 reports for Biogen MS therapies were extracted and described from Biogen’s Global Safety Database.
Results
30,478 PwMS with an open DMT prescription were identified within Explorys; 344 were COVID-19 positive. The most significant risk factors for acquiring COVID-19 were comorbidity score ≥ 1, body mass index ≥ 30, and Black/African ancestry. Similar risk factors were also identified for patients with SLE. Patients with MS were less likely to develop COVID-19 when treated with interferons (0.61%) and glatiramer acetate (0.51%), vs all other MS DMTs (both
p
< 0.001); anti-CD20 therapy was associated with the highest risk (3.45%;
p
< 0.0001). In the Biogen Global Safety Database, we identified 1217 patients who were COVID-19 positive treated with intramuscular interferon beta-1a, peginterferon beta-1a, natalizumab, dimethyl fumarate, diroximel fumarate, or fampridine.
Conclusions
Comorbidities, obesity, and Black/African ancestry, but not age, were associated with a higher risk of SARS-CoV-2 infection in PwMS. Interferons and glatiramer acetate were associated with a reduced COVID-19 risk, whereas anti-CD20 therapies were associated with an increased risk, within the treated MS cohort. COVID-19 safety reports for patients receiving Biogen MS therapies were consistent with the Explorys database and MS literature, illustrating the replicability and power of this approach.
In patients treated with natalizumab, PML incidence was about 11 cases per 1000 patients with 25 to 48 months of treatment, prior immunosuppressant use, and anti–JC virus antibody–positive status. ...The incidence was estimated to be 0.09 cases or fewer per 1000 antibody-negative patients.
Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is approved for the treatment of relapsing–remitting multiple sclerosis in more than 50 countries and also for the treatment of moderate-to-severe Crohn's disease in the United States. As of February 2012, approximately 100,000 patients have been treated with natalizumab worldwide (unpublished data). In the pivotal Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis trial (AFFIRM; ClinicalTrials.gov number, NCT00027300), natalizumab monotherapy decreased the risk of progression of disability by 42 to 54% and reduced the annualized rate of relapse by 68%.
1
Natalizumab treatment is associated with the risk of progressive multifocal leukoencephalopathy (PML), . . .
This placebo-controlled, randomized trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab (an α
4
integrin antagonist) in all the primary and secondary outcome ...measures. After two years, the probability of sustained progression of disability was 17 percent with natalizumab and 29 percent with placebo. Fatigue and allergic reaction were more common among patients receiving natalizumab.
This trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab in all the primary and secondary outcome measures. In this trial, natalizumab in combination with interferon was more effective than interferon alone. Progressive multifocal leukoencephalopathy developed in two patients. In this systematic evaluation for PML in patients who received natalizumab in clinical trials, no additional cases were identified.
Relapsing multiple sclerosis is characterized by the intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. Lymphocyte migration across the blood–brain barrier is thought to be an important early step in the formation of lesions.
1
The interaction of α
4
β
1
integrin, a protein on the surface of lymphocytes, with vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels, mediates the adhesion and migration of lymphocytes in areas of inflammation.
2
–
6
Furthermore, the interaction of α . . .
Summary Background Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting ...multiple sclerosis. Methods 257 patients, aged 18–55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4–24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov , number NCT00168701. Findings Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1·4 vs 4·5, p<0·0001). It also reduced number of new or enlarging T2-hyperintense (p=0·0006) and new T1-hypointense (p=0·014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0·44 vs 0·65 for placebo; p=0·272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. Interpretation The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups. Funding Biogen Idec, Inc.
Objective
A study was undertaken to establish an enzyme‐linked immunosorbent assay (ELISA) to detect JC virus (JCV)‐specific antibodies in multiple sclerosis (MS) patients, and to evaluate its ...potential utility for identifying patients at higher or lower risk (ie, risk stratification) of developing progressive multifocal leukoencephalopathy (PML).
Methods
A 2‐step assay for detecting and confirming the presence of anti‐JCV antibodies in human serum and plasma was developed and demonstrated to be both sensitive and specific. ELISA cutpoints were statistically established using sera from >800 MS patients from natalizumab clinical studies. Subsequently, this assay was used to determine the presence of anti‐JCV antibodies in natalizumab‐treated PML patients where serum samples were collected 16‐180 months prior to the diagnosis of PML.
Results
In our evaluation of natalizumab‐treated MS patients, 53.6% tested positive for anti‐JCV antibodies, with a 95% confidence interval of 49.9 to 57.3%. The false‐negative rate of the ELISA was calculated to be approximately 2.5%, with an upper 1‐sided confidence limit of 4.4%. Notably, we observed anti‐JCV antibodies in all 17 available pre‐PML sera samples, which was significantly different from the 53.6% seropositivity observed in the overall MS study population (p < 0.0001).
Interpretation
This 2‐step assay provides a means to classify MS patients as having detectable or not detectable levels of anti‐JCV antibodies. The finding that all 17 of the pre‐PML samples that were available tested seropositive, and none tested seronegative, warrants further research on the clinical utility of the anti‐JCV antibody assay as a potential tool for stratifying MS patients for higher or lower risk of developing PML. Ann Neurol 2010
Objective:
A study was undertaken to define the prevalence of anti‐JC virus (JCV) antibodies in multiple sclerosis (MS) patients and to evaluate the analytical false‐negative rate of a 2‐step anti‐JC ...virus antibody assay.
Methods:
STRATIFY‐1 is an ongoing, longitudinal, observational study of relapsing MS patients in the United States who are being treated or considering treatment with natalizumab. Baseline serum and plasma samples were collected for anti‐JC virus antibody detection using an analytically validated, 2‐step, virus‐like particle‐based enzyme‐linked immunosorbent assay. Urine was collected for JC virus DNA detection.
Results:
At baseline (n = 1,096), overall anti‐JC virus antibody prevalence was 56.0% (95% confidence interval CI, 53.0‐59.0) in STRATIFY‐1 patients, with an assay false‐negative rate of 2.7% (95% CI, 0.9–6.2). Prevalence was significantly lower in females (53.4%; 95% CI, 49.9–56.8) than males (64.3%; 95% CI, 58.2–70.0) and increased with age, p = 0.0019 and p = 0.0001, respectively. Prevalence was similar in patients regardless of natalizumab exposure or prior immunosuppressant use, p = 0.9709 and p = 0.6632, respectively. STRATIFY‐1 results were generally consistent with those observed in another large North American cohort, TYGRIS‐US (n = 1,480).
Interpretation:
Baseline results from STRATIFY‐1 are consistent with other studies utilizing this assay that demonstrate a 50 to 60% prevalence of anti‐JC virus antibodies, a low false‐negative rate, and an association of increasing age and male gender with increasing anti‐JC virus antibody prevalence. Neither natalizumab exposure nor prior immunosuppressant use appear to affect prevalence. Longitudinal data from STRATIFY‐1 will confirm the stability of anti‐JC virus antibody prevalence over time. ANN NEUROL 2011
Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system that most commonly affects women, with an onset typically between 20 and 40 years of age. A ...diagnosis of clinically definite multiple sclerosis requires the occurrence of at least two neurologic events consistent with demyelination that are separated both anatomically in the central nervous system and temporally.
1
Magnetic resonance imaging (MRI) of the brain, by identifying lesions consistent with the occurrence of demyelination, can add certainty to the diagnosis.
2
,
3
The presence of such MRI-identified lesions in a patient with an isolated syndrome of the optic nerve . . .
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