Explore the vast range of titles available.

BackgroundBiosimilar natalizumab (biosim-NTZ) is the first biosimilar monoclonal antibody of reference natalizumab (ref-NTZ) for treatment of relapsing forms of multiple sclerosis (MS). Within the totality of evidence for demonstration of biosimilarity, immunogenicity assessments were performed in healthy subjects and patients with relapsing-remitting MS (RRMS) to confirm a matching immunogenicity profile between biosim-NTZ and ref-NTZ.MethodsImmunogenicity of biosim-NTZ versus ref-NTZ was evaluated in two pivotal clinical studies. In a comparative efficacy and safety study, patients with RRMS (n=264) received monthly infusions of biosim-NTZ/EU-ref-NTZ over 48 weeks. The primary endpoint period was Week 0 to Week 24. In a separate, comparative pharmacokinetic/pharmacodynamic (PK/PD) study, healthy subjects (n=450) received a single dose of biosim-NTZ, US-ref-NTZ or EU-ref-NTZ prior to an 85-day follow-up. In both studies, state-of-the-art, highly sensitive and drug tolerant bioanalytical assays were used to identify the proportion of participants with anti-drug antibodies (ADA) and neutralizing antibodies (NAb) against natalizumab over time.ResultsIn the comparative efficacy and safety study, biosim-NTZ and EU-ref-NTZ demonstrated similar incidences of overall ADA (79.4% vs 73.7%, respectively) and NAb (68.7% vs 66.2%, respectively) at Week 24. ADA titers over time were also concordant throughout the study period. Switching treatment from EU-ref-NTZ to biosim-NTZ had no impact on treatment-related ADA/NAb or clinical responses. Likewise, the single-dose PK/PD study reported matching overall incidence of ADA between treatment groups and matching ADA titer profiles over time.ConclusionThe immunogenicity profile of biosim-NTZ was confirmed to match that of ref-NTZ in healthy subjects and patients with RRMS by applying highly sensitive methods.

Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFNβ)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFNβ-1a subcutaneous and IFNβ-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFNβ-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFNβ therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFNβ in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFNβ. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFNβ) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFNβ preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFNβ-1a subcutaneous (s.c.) and IFNβ-1b s.c. in favor of the least immunogenic preparation IFNβ-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years) and IFNβ-1a s.c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFNβ ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.

Progressive multifocal leukoencephalopathy (PML) is a viral disease of the brain associated with immunodeficiency, immune suppressing medications, and malignancy. In the absence of effective anti-viral therapy for the causative JC virus, immune restoration has emerged as the critical therapeutic alternative. The evolving treatment of PML (and other rare JC virus–associated neurologic syndromes) requires consideration of baseline immune functioning and comorbid diseases while selecting from a number of therapeutic options to restore an effective immune response. This review focuses on the current options for management of PML in typical situations where this disease presents, including several where immune restoration is a standard therapeutic approach such as in PML associated with HIV/AIDS and in multiple sclerosis associated with natalizumab. Other circumstances in which PML occurs including associated with primary immunodeficiencies, malignancies, and transplants present greater challenges to immune reconstitution, but emerging concepts may enhance therapeutic options for these situations. Particular attention is focused on recent experience with checkpoint inhibitors, guidance for MS drug discontinuation, and strategies to monitor and facilitate immune restoration.

Background: Smoking may contribute to the induction of neutralizing antibodies to interferon β-1a. Objective: In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis. Methods: This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals. Results: Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2–4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5–5.1). Interpretations: The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.

Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 + T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 + T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities. Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

BackgroundNatalizumab is a highly effective drug for patients with relapsing-remitting multiple sclerosis (MS). A disadvantage of this treatment is the risk of progressive multifocal leukoencephalopathy in patients who are seropositive for the John Cunningham virus (JCV). JCV seroconversion rates increase under natalizumab treatment compared with non-natalizumab using controls. The aim of this study was to assess whether lower natalizumab trough concentrations are associated with reduced JCV seroconversion compared with higher natalizumab trough concentrations.MethodsTwo overlapping cohorts of patients treated with intravenous natalizumab in the Netherlands were combined for this study. JCV seroconversion was assessed during periods of high (≥15 µg/mL) and low (<15 µg/mL) natalizumab trough concentrations. Low trough concentrations were mainly the result of trough concentration guided personalised extended interval dosing (EID). The seroconversion rates during high and low trough concentrations were compared using a generalised linear mixed model with a Poisson link function.ResultsA total of 357 patients from 21 hospitals in the Netherlands were included. The annual seroconversion rate of 8.4% observed in patients during periods of high trough concentrations (n=226) was 2.32 times higher than the seroconversion rate of 4.8% in patients during periods of low trough concentrations (n=252) (95% CI=1.32 to 4.08, p=0.0035).ConclusionsThe seroconversion rate observed in patients with MS with low trough concentrations was substantially lower compared with those with high trough concentrations during natalizumab treatment. This emphasises the importance of personalised EID, where intervals between infusions are prolonged to achieve lower natalizumab trough concentrations, to increase drug safety.

Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit–risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.

B cells are considered major contributors to multiple sclerosis (MS) pathophysiology. While lately approved disease-modifying drugs like ocrelizumab deplete B cells directly, most MS medications were not primarily designed to target B cells. Here, we review the current understanding how approved MS medications affect peripheral B lymphocytes in humans. These highly contrasting effects are of substantial importance when considering these drugs as therapy for neuromyelitis optica spectrum disorders (NMOSD), a frequent differential diagnosis to MS, which is considered being a primarily B cell- and antibody-driven diseases. Data indicates that MS medications, which deplete B cells or induce an anti-inflammatory phenotype of the remaining ones, were effective and safe in aquaporin-4 antibody positive NMOSD. In contrast, drugs such as natalizumab and interferon-β, which lead to activation and accumulation of B cells in the peripheral blood, lack efficacy or even induce catastrophic disease activity in NMOSD. Hence, we conclude that the differential effect of MS drugs on B cells is one potential parameter determining the therapeutic efficacy or failure in antibody-dependent diseases like seropositive NMOSD.