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Interferon beta and glatiramer acetate therapy.

ABSTRACT: Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led to their widespread use. We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures. Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis.

SUBMITTER: McGraw CA

PROVIDER: S-EPMC3557359 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Interferon beta and glatiramer acetate therapy.

McGraw Corey A CA Lublin Fred D FD

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20130101 1

Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led t ...[more]

PMID: 23264098

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Treatment Response Score to Glatiramer Acetate or Interferon Beta-1a.

Project description:ObjectiveTo compare the effectiveness of glatiramer acetate (GA) vs intramuscular interferon beta-1a (IFN-β-1a), we applied a previously published statistical method aimed at identifying patients' profiles associated with efficacy of treatments.MethodsData from 2 independent multiple sclerosis datasets, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating GA vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates (ARRs) on a set of baseline predictors.ResultsThe overall ARR ratio of GA to IFN-β-1a in the CombiRx trial was 0.72. The response score (made up of a linear combination of age, sex, relapses in the previous year, disease duration, and Expanded Disability Status Scale score) detected differential response of GA vs IFN-β-1a: in the trial, patients with the largest benefit from GA vs IFN-β-1a (lower score quartile) had an ARR ratio of 0.40 (95% confidence interval [CI] 0.25-0.63), those in the 2 middle quartiles of 0.90 (95% CI 0.61-1.34), and those in the upper quartile of 1.14 (95% CI 0.59-2.18) (heterogeneity p = 0.012); this result was validated on MSBase, with the corresponding ARR ratios of 0.58 (95% CI 0.46-0.72), 0.92 (95% CI 0.77-1.09,) and 1.29 (95% CI 0.97-1.71); heterogeneity p < 0.0001).ConclusionsWe demonstrate the possibility of a criterion, based on patients' characteristics, to choose whether to treat with GA or IFN-β-1a. This result, replicated on an independent real-life cohort, may have implications for clinical decisions in everyday clinical practice.

| S-EPMC7905777 | biostudies-literature

MTR recovery in brain lesions in the BECOME study of glatiramer acetate vs interferon β-1b.

Project description:ObjectiveTo compare magnetization transfer changes in new brain MRI lesions identified during monthly imaging in patients with multiple sclerosis (MS) randomized to treatment with 250 μg subcutaneous interferon-β-1b (IFN-β-1b) every other day or daily 20 mg glatiramer acetate (GA) in a post hoc study using data from the Betaseron Versus Copaxone for Relapsing Remitting or CIS Forms of MS Using Triple Dose Gad 3 T MRI (BECOME) trial.MethodsT1-weighted images acquired with and without fat saturation pulses in the BECOME study were evaluated and found to exhibit magnetization transfer ratio (MTR) effects, and were used to compute MTR images (FSMTR). Forty-three participants who had the required imaging and new lesions, from the 75 originally randomized into the BECOME study, were included in this post hoc analysis and evaluated longitudinally during treatment to determine FSMTRDrop, an experimental measure of the completeness of FSMTR recovery in new lesions. Two sets of new brain MRI lesions were defined, one based on the appearance of gadolinium contrast enhancement (Gd lesions) and the other based on FSMTR decreases (ΔFSMTR lesions).ResultsA total of 887 Gd lesions were identified in 43 participants (19 GA, 24 IFN-β-1b) and 321 ΔFSMTR lesions in 32 participants (16 GA, 16 IFN-β-1b). Participants randomized to GA exhibited greater average postlesion FSMTR recovery than did those randomized to IFN-β-1b in both Gd (p < 0.0001) and ΔFSMTR (p < 0.0001) lesions.ConclusionsNew brain lesions that developed during treatment with GA exhibited evidence of greater FSMTR recovery than during treatment with IFN-β-1b.Classification of evidenceThis study provides Class III evidence that MTR recovery in patients with MS with new MRI brain lesions is greater with GA than with IFN-β-1b.

| S-EPMC5035157 | biostudies-literature

Randomized study combining interferon and glatiramer acetate in multiple sclerosis.

Project description:ObjectiveA double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis.MethodsA total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics.ResultsCombination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results.InterpretationCombining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences.

| S-EPMC3631288 | biostudies-literature

The effectiveness of interferon beta versus glatiramer acetate and natalizumab versus fingolimod in a Polish real-world population.

Project description:OBJECTIVE:The aim of the study was to assess the effectiveness of disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) patients treated in MS centres in Poland. METHODS:Demographic and clinical data of all Polish RRMS patients receiving DMTs were prospectively collected from 2014 to 2018 in electronic files using the Therapeutic Program Monitoring System (SMPT). RESULTS:The study included 10,764 RRMS patients treated with DMTs in first-line and 1,042 in second-line programmes. IFNβ more effectively lengthened the times to the first relapse, disability progression, and brain MRI activity than GA. After 2 and 4 years of follow-up, more patients on IFNβ showed no evidence of disease activity (NEDA-3) in comparison to GA (66.3% and 44.3% vs 55.2% and 33.2%, respectively; p<0.001). NAT more effectively reduced brain MRI activity than FTY (p = 0.001). More patients under NAT had NEDA-3 after 2 and 4 years of follow-up compared to FTY (66.2% and 42.1% vs 52.1% and 29.5%, respectively; p = 0.03). In adjusted analysis, a higher baseline Expanded Disability Status Score (EDSS) was a predictor of relapse (p<0.001) and NEDA-3 failure (p = 0.003). CONCLUSION:IFNβ compared to GA and NAT compared to FTY more effectively reduced disease activity in a Polish population of RRMS patients.

| S-EPMC6812766 | biostudies-literature

Interferon Beta-1a versus Glatiramer Acetate: Changes of Innate Immunity in a Group of Women with Multiple Sclerosis.

Project description:IntroductionMultiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations.MethodsSixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD).ResultsA statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%.ConclusionInnate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.

| S-EPMC10623392 | biostudies-literature

Interferon ?-1b and glatiramer acetate effects on permanent black hole evolution.

Project description:To compare interferon ?-1b (IFN?-1b) and glatiramer acetate (GA) on new lesion (NL) (gadolinium-enhancing, new T2) evolution into permanent black holes (PBH)--a marker of irreversible tissue damage--in patients with relapsing-remitting multiple sclerosis (RRMS).BEYOND was a large, phase III, clinical trial comparing IFN?-1b 250 ?g, IFN?-1b 500 ?g, and GA (2:2:1). Patient scans were reexamined post hoc for PBH in a rater-blinded manner. Two predefined coprimary endpoints compared IFN?-1b 250 ?g with GA: first, number of PBH per patient at year 2 evolving from year 1 NL, then proportion of year 1 NL evolving into PBH at year 2. IFN?-1b 500 ?g and GA were compared in an exploratory fashion.Approximately 90% (1,957/2,244) of patients had NL at year 1 with follow-up at year 2. Mean numbers of PBH per patient at year 2 evolving from year 1 NL were lower for IFN?-1b 250 ?g than GA (0.30 vs 0.43; p = 0.0451). The proportion of NL evolving into PBH was similar (IFN?-1b 250 ?g vs GA: 21.6% vs 23.5%; p > 0.20). For IFN?-1b 500 ?g, both the mean PBH number per patient at year 2 evolving from year 1 NL (0.26 vs 0.43; p = 0.0037) and proportion of NL evolving into PBH (16.3% vs 23.5%; p = 0.0409) were lower relative to GA.IFN?-1b affected PBH development to a similar or better extent than GA. IFN?-1b favorably influences an MRI outcome indicative of permanent tissue destruction in the brains of patients with multiple sclerosis.This study provides Class III evidence that IFN?-1b is associated with a reduction in MRI PBH formation and evolution compared with GA between years 1 and 2 of treatment.

| S-EPMC3068007 | biostudies-other

Metabolic response to glatiramer acetate therapy in multiple sclerosis patients.

Project description:Glatiramer acetate (GA; Copaxone) is a random copolymer of glutamic acid, lysine, alanine, and tyrosine used for the treatment of patients with multiple sclerosis (MS). Its mechanism of action has not been already fully elucidated, but it seems that GA has an immune-modulatory effect and neuro-protective properties. Lymphocyte mitochondrial dysfunction underlines the onset of several autoimmune disorders. In MS first diagnosis patients, CD4+, the main T cell subset involved in the pathogenesis of MS, undergo a metabolic reprogramming that consist in the up-regulation of glycolysis and in the down-regulation of oxidative phosphorylation. Currently, no works exist about CD4+ T cell metabolism in response to GA treatment. In order to provide novel insight into the potential use of GA in MS treatment, blood samples were collected from 20 healthy controls (HCs) and from 20 RR MS patients prior and every 6 months during the 12 months of GA administration. GA treated patients' CD4+ T cells were compared with those from HCs analysing their mitochondrial activity through polarographic and enzymatic methods in association with their antioxidant status, through the analysis of SOD, GPx and CAT activities. Altogether, our findings suggest that GA is able to reduce CD4+ T lymphocytes' dysfunctions by increasing mitochondrial activity and their response to oxidative stress.

| S-EPMC5079236 | biostudies-literature

Expression data of multiple sclerosis patients receiving glatiramer acetate therapy [U133 Plus 2.0]

2012-12-07 | GSE42763 | GEO

CD8(+) T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease.

Project description:The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8(+) T cell responses that can potentially suppress pathogenic CD4(+) T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8(+) T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8(+) T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-?, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4(+) regulatory T cells in an antigen-independent manner, required CD8(+) T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8(+) T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.

| S-EPMC3689655 | biostudies-literature

Expression data of multiple sclerosis patients receiving glatiramer acetate therapy [U133 Plus 2.0]

Project description:The purpose of this study was to analyze the transcriptional effects induced by glatiramer acetate treatment (GA; Copaxone, 20 mg injected subcutaneously once daily) in blood monocytes of patients with relapsing-remitting form of multiple sclerosis (MS). By using Affymetrix DNA microarrays, we obtained genome-wide expression profiles of monocytes from 8 MS patients within the first two months of GA administration. EDTA blood samples were taken from all patients immediately before first and second GA injection as well as after 1 week, 1 month and 2 months. Total RNA of CD14+ monocytes isolated by magnetic-activated cell sorting (MACS) from each sample was extracted, labeled and hybridized to Affymetrix Human Genome U133 Plus 2.0 arrays to quantify the mRNA levels. This GEO entry provides the U133 Plus 2.0 microarray data.

2012-12-07 | E-GEOD-42763 | biostudies-arrayexpress

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