A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis

Vollmer, Timothy; Sørensen, Per Soelberg; Selmaj, Krzysztof; Zipp, Frauke; Havrdová, Eva; Cohen, Jeffrey A.; Sasson, Nissim; Gilgun-Sherki, Yossi; Arnold, Douglas L.

doi:10.1007/s00415-014-7264-4

Cited by 181 publications

(206 citation statements)

References 30 publications

Supporting

Mentioning

200

Contrasting

Unclassified

Order By: Relevance

“…Participants, personnel and outcome assessors were blind in most of the trials, with few exceptions that posed a high risk of bias. 50,58,73,76,78,[83][84][85]90 When considering incomplete outcome data, a few trials had a high risk of bias due to missing data for more than 20% of the study sample or due to unequal drop-out between intervention groups. 42,62,65,67,68,75,77,78,82,[87][88][89][90]92,94,96,99 Outcome assessor bias and selective outcome reporting were also a problem in some trials, either due to not meeting requirements with a high risk of bias 71,76,77,79 or because there was not enough information to make a judgement as no study protocols were available.…”

mentioning

confidence: 99%

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

et al. 2018

View full text Add to dashboard Cite

Background and scopeMultiple sclerosis (MS) is an inflammatory-demyelinating disease of the central nervous system (CNS) that is characterized by inflammation, demyelination and degenerative changes. MS usually begins around the age between 20 and 40 years and affects two to three times as many women as men; it also constitutes the most frequent cause of non-traumatic disability in the young adult population. 1 The incidence of MS varies across regions, with rates as high as 8 to 10 new cases per 100,000 in high latitudinal regions. 2,3 Current estimates suggest that over 700,000 people are affected in Europe, with over 2.5 million cases worldwide, 4 which represent a significant burden in terms of impact on quality of life, societal costs and personal expenses. 5,6 Most patients (85%-90%) have a relapsing course from onset that is characterized by relapses and remissions of neurological symptoms Methods: This guideline has been developed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology and following the updated EAN recommendations. Clinical questions were formulated in Patients-Intervention-Comparator-Outcome (PICO) format and outcomes were prioritized. The quality of evidence was rated into four categories according to the risk of bias. The recommendations with assigned strength (strong and weak) were formulated based on the quality of evidence and the risk-benefit balance. Consensus between the panelists was reached by use of the modified nominal group technique. Results: A total of 10 questions were agreed, encompassing treatment efficacy, response criteria, strategies to address suboptimal response and safety concerns and treatment strategies in MS and pregnancy. The guideline takes into account all disease-modifying drugs approved by the European Medicine Agency (EMA) at the time of publication. A total of 21 recommendations were agreed by the guideline working group after three rounds of consensus. Conclusion:The present guideline will enable homogeneity of treatment decisions across Europe. associated with areas of CNS inflammation, and over the course of two decades, more than half of untreated patients transition to a phase of gradual worsening independent of acute attacks. 7,8 Progressive forms of MS can be present as the initial disease course (primary-progressive MS) in approximately 10%-15% of patients. 9,10 There is no curative treatment available for MS, and the current therapeutic strategy is aimed at reducing the risk of relapses and potentially disability progression. The treatment era for MS began in 1993, when the first interferon became available, and recent years have seen a large expansion in the therapeutic options for MS, with 11 disease-modifying therapies (DMTs) approved by the European Medicine Agency (EMA) in both injectable and oral formulations by the beginning of 2017. 11 The growing armamentarium of therapies brings new opportunities for individualized therapy where patients and providers must balance considerations around efficacy,...

show abstract

mentioning

confidence: 99%

ECTRIMS/EAN Guideline on the pharmacological treatment of people with multiple sclerosis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Indeed, laquinimod, a drug being developed to treat MS (86 -88), crosses the blood-brain barrier and ameliorates EAE (and potentially MS) in an AhRdependent manner (89,90). In a phase III clinical trial, laquinimod reduced brain atrophy in MS, a process thought to reflect neurodegeneration driven at least partially by astrocytes (91). Second, it suggests that deficits in AhR ligand availability may contribute to MS pathogenesis.…”

Section: Role Of Ahr In Astrocyte-mediated Inflammatory Processesmentioning

confidence: 99%

Control of immune-mediated pathology via the aryl hydrocarbon receptor

Wheeler

Rothhammer

Quintana

2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by George M. Carman Genetic and environmental factors contribute to the development of immune-mediated diseases. Although numerous genetic factors contributing to autoimmunity have been identified in recent years, our knowledge on environmental factors contributing to the pathogenesis of autoimmune diseases and the mechanisms involved is still limited. In this context, the diet, microbiome, geographical location, as well as environmental pollutants have been shown to modulate autoimmune disease development. These environmental factors interact with cellular components of the immune system in distinct and defined ways and can influence immune responses at the transcriptional and protein level. Moreover, endogenous metabolites generated from basic cellular processes such as glycolysis and oxidative phosphorylation also contribute to the shaping of the immune response. In this minireview, we highlight recent progress in our understanding of the modulation of the immune response by the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor whose activity is regulated by small molecules provided by diet, commensal flora, environmental pollutants, and metabolism. We focus on the role of AhR in integrating signals from the diet and the intestinal flora to modulate ongoing inflammation in the central nervous system, and we also discuss the potential therapeutic value of AhR agonists for multiple sclerosis and other autoimmune diseases. Multiple sclerosis (MS)4 is an autoimmune disease of the central nervous system (CNS). In 85% of the affected individuals, MS initially presents with a relapsing-remitting course characterized by temporally defined relapses, which are followed by a varying degree of remission. Most patients eventually enter the secondary progressive phase of MS, which is characterized by the progressive and irreversible accumulation of neurological deficits (1). Several biological pathways are involved in the regulation of the immune response in MS both in the peripheral and central immune compartment and are thought to play dominant roles in the different stages of the disease. Although the role of several molecules such as cytokines and toll-like receptor agonists in MS pathology has been studied at length, particularly in relation to the relapsing-remitting phase of the disease, only recently has the role of metabolites generated in basic biological processes such as glycolysis and oxidative phosphorylation become appreciated with regard to their relevance for the development, propagation, and resolution of autoimmune inflammation. Prominent examples of endogenous metabolites with central roles in MS pathology include bioactive lipids, reactive oxygen species, and adenosine triphosphate (ATP) (2-13). The effects of these endogenous metabolites are modulated by a multitude of exogenous factors such as pollutants, dietary factors, and products from the commensal flora to trigger transcriptional programs that control the immune response during MS. Ultimately, the understanding of ...

show abstract

“…Laquinimod efficacy in RRMS patients has been assessed in two Phase III trials, ALLEGRO (Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis) [99] and BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) [100]. In ALLEGRO laquinimod was compared to placebo and showed a modest, but significant reduction of the annual relapse rate, and also a reduced rate of progression [99].…”

Section: Laquinimodmentioning

confidence: 99%

“…In ALLEGRO laquinimod was compared to placebo and showed a modest, but significant reduction of the annual relapse rate, and also a reduced rate of progression [99]. Initially the primary outcome measure of reducing annual relapse rate in BRAVO was not reached [100], but following an adjustment for an imbalance between the groups in the number of patients with enhancing lesions and of mean T2 lesion volume, both predictors of relapses, a reduction in relapse rate in the laquinimod arm (21% reduction vs placebo, p=0.026) was obtained. Overall laquinimod had more pronounced effects on disability progression and brain atrophy than on relapses and new MRI lesion formation [101].…”

Section: Laquinimodmentioning

confidence: 99%