Description of the condition
Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) in which immunoreactions lead to myelin sheath attack and axons injury. It is characterised by recurrent relapses and/or progression, typically striking adults during the primary productive time of their life and ultimately leading to severe neurological disability.
(1) The characteristics of MS
The overall incidence rate of MS in the world was 3.6 cases per 100,000 person-years in women and 2.0 cases in men (Alonso 2008). It is estimated to affect 2.1 million people worldwide (National MS Society 2009). There are four clinical phenotypes of MS. Initially, more than 80% of individuals with MS experience a relapsing-remitting disease course (RRMS) characterised by clinical exacerbations of neurologic symptoms followed by complete or incomplete remission (Lublin 1996). After 10 to 20 years, or median age 39.1 years, about half of these people gradually accumulate irreversible neurologic deficits with or without clinical relapses (Confavreux 2006), which is known as secondary progressive MS (SPMS). Another 10% to 20% of individuals with MS are diagnosed with primary progressive MS (PPMS), clinically defined as a disease course without any clinical attacks or remission from onset (Lublin 1996). A significantly rarer form is progressive relapsing MS (PRMS), which initially presents as PPMS; however, during the course of the disease, these individuals develop true neurologic exacerbations (Tullman 2004). Growing evidence supports an inflammatory pathology occurring during the early relapsing stage of MS, and neurodegenerative pathology dominates the later progressive stage of the disease. Gray matter (GM) damage was shown to be frequent and extensive, and more pronounced in the progressive disease phases. Its underlying pathology is different from white matter damage in MS (Hulst 2011). Diffuse meningeal inflammation through B-cell follicle-like structures is associated with cortical pathology and an accelerated clinical course in SPMS (Fernández 2012). GM damage occurs early in the disease course, and correlates with future MS-related disability (Fernández 2012).
(2) The socioeconomic burden of MS
MS causes major socioeconomic burden for the individual patient and for society. Productivity costs are a far more important economic factor, especially due to reduced employment, which are enhanced by the early age of disease onset (Jennum 2012). Mobility problems represent a considerable personal and social burden both financially and in terms of quality of life (Pike 2012). From a patient's perspective an MS relapse is associated with a significant increase in economic costs as well as a decline in health-related quality of life and functional ability (Oleen-Burkey 2012). Direct costs are mainly due to medical care in earlier stages of disease; indirect costs are mainly due to disability and productivity loss in later stages (Naci 2010). Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and may help to reduce the social burden of MS (Karampampa 2012).
(3) The key issues of current disease-modifying therapies (DMTs) for MS
DMTs for MS currently aim to specifically reduce inflammation in relapsing MS and promote neuroprotection and neurorepair in progressive MS. As the most promising endpoints, Magnetic Resonance Imaging (MRI) measures (the percentage brain volume change (PBVC)) (Barkhof 2009; van den Elskamp 2010), T1 hypointensity (black holes) and magnetisation transfer ratio (Cadavid 2009; Zivadinov 2012)), and optical coherence tomography findings (the thickness of the retinal nerve fibre layer (RNFL)) (Fernández 2012; Lidster 2012) are or will be used in neuroprotection trials. Freedom from disease, defined as freedom from relapses, the absence of disability progression, and freedom from gadolinium-enhancing T1 or new T2 lesions detected by MRI , is used as the measure of DMTs' success (Fox 2012). However, relapses, disability progression and increasing disability may still occur in patients receiving first-line DMTs with frequent parenteral administration and even second-line DMTs with the risk of severe adverse events. Furtheremore, administration of interferon beta was not associated with a reduction in progression of disability among patients with RRMS (Shirani 2012). So far there is no DMT available that can completely halt the neurodegenerative changes associated with the disease. The unmet needs highlight the reasons for developing new DMTs for MS, focusing on superior efficacy, ease of administration, good tolerability, and long-term safety. Therefore, alternative MS treatments with oral routes of administration and new modes of action are needed to expand the current treatment repertoire, increase patient satisfaction and adherence, and thereby improve efficacy.
Description of the intervention
Laquinimod, an oral quinoline-3-carboxamide, is a derivative of linomide (roquinimex) but does not have the adverse effects associated with linomide. It has dual properties in experimental autoimmune encephalomyelitis (EAE): immunomodulatory and neuroprotective capacities (Aharoni 2012). Analyses in EAE demonstrate that laquinimod reduces infiltration of leukocytes into sites of inflammation in the CNS, and induces a T-helper-1(Th1) cytokine to Th2/3 cytokines shift, without inducing much immunosuppression (Brunmark 2002; Zou 2002; Yang 2004). Laquinimod might protect myelin and axons by decreasing interleukin (IL)-17 levels and impairing the migratory capacity of lymphocyte (Wegner 2010) and modulated B cell markers, mainly by increasing the regulatory ones CD25, IL10 and CD86, and decreased IL4, while increasing IL10 and TGFβ in both B and T cells, in a B cell-mediated manner (Toubi 2012). Laquinimod reduced trafficking of proinflammatory monocytes into the CNS (Mishra 2012) and skewed monocytes toward a regulatory phenotype and also acted via modulation of brain-derived neurotrophic factor (BDNF), which may contribute to neuroprotection in MS patients (Thöne 2012). Laquinimod modulates adaptive T cell immune responses via its effects on cells of the innate immune system, and may not influence T cells directly (Schulze-Topphoff 2012). Meanwhile, it downregulates the astrocytic pro-inflammatory response, which might have protective effects on myelin, oligodendrocytes and axons (Brück 2012).
Preclinical studies have shown that laquinimod reduces inflammation in the CNS, decreases demyelination, and prevents axonal damage in EAE mice (Brück 2011). These results translate its immunomodulatory and CNS-protective effects into clinical benefits in patients withe RRMS. Recent findings from clinical trials indicate that laquinimod has significant effects in reducing relapse rate and has more pronounced effects in reducing sustained disability progression as well as brain atrophy, with a good safety profile.
How the intervention might work
A randomised, double-blind, parallel-group, placebo-controlled study showed oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing MS. A phase Ⅱ study (LAQ/5062) showed 0.6 mg per day laquinimod significantly reduced MRI-measured disease activity and was well tolerated in patients with RRMS. The extension trial of LAQ/5062 study confirmed the good efficacy and the excellent safety and tolerability profiles of laquinimod 0.6 mg/day. In a randomised, double-blind, parallel-group, placebo-controlled, phase Ⅲ study (ALLEGRO), oral laquinimod administered 0.6 mg once daily slowed the progression of disability and reduced the rate of relapse in patients with RRMS.
Why it is important to do this review
A randomised, double-blind, parallel-group, phase Ⅲ study (BRAVO) comparing the effect of oral laquinimod 0.6 mg/day with the effect of placebo as well as with the effect of Interferon β-1a (Avonex®) is expected to be published in the near future. The long-term extensions (open-label studies) of the ALLEGRO study, the BRAVO study, and the LAQ/5062 and LAQ/5063 study investigating the long-term safety, tolerability and effect of laquinimod monotherapy (0.6 mg orally once daily) are currently ongoing. A randomised, double-blind, parallel-group, placebo-controlled, phase Ⅲ study (CONCERTO) evaluating the efficacy, safety and tolerability of two oral doses of laquinimod (0.6 mg/day or 1.2 mg/day) in subjects with RRMS will start in January 2013.
No systematic review currently exists in the peer-reviewed literature that focuses on laquinimod for patients with MS. A systematic review of all randomised controlled trials is warranted to evaluate the effectiveness and safety of laquinimod for MS.