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Laquinimod Therapy in Multiple Sclerosis: a Comprehensive Review

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Laquinimod Therapy in Multiple Sclerosis: a Comprehensive Review Neurol Ther DOI 10.1007/s40120-014-0017-6 REVIEW Laquinimod Therapy in Multiple Sclerosis: A Comprehensive Review Channa Kolb-Sobieraj • Sahil Gupta • Bianca Weinstock-Guttman To view enhanced content go to www.neurologytherapy-open.com Received: December 20, 2013 Ó The Author(s) 2014. This article is published with open access at Springerlink.com ABSTRACT drug recently evaluated in a third phase III clinical trial that demonstrated beneficial effects in Introduction: Multiple sclerosis (MS) is delaying disease progression and preventing brain considered an autoimmune disease with atrophy, suggesting a potential neuroprotective inflammatory and neurodegenerative underlying effect and a favorable safety profile. processes that affect the central nervous system. Areas Covered: This is a comprehensive review The available disease-modifying therapies (DMTs) covering clinical efficacy and safety data obtained approved to treat MS have only shown partial from two phase III clinical trials, as well as the benefit in controlling the disease progression, presumed beneficial mechanism of action, of primarily impeding its inflammatory component, laquinimod. This article also provides a short while the parenteral administration of most of overview of the oral DMTs recently approved for these therapies has shown to affect patient the treatment of relapsing MS, as well as compliance. Laquinimod is a promising new oral challenges that still remain to be overcome to Electronic supplementary material The online fully control the relentless course of MS. version of this article (doi:10.1007/s40120-014-0017-6) Conclusion: Laquinimod has been shown to contains supplementary material, which is available to authorized users. have a novel immunomodulatory and potential neuroprotective mechanism of action as C. Kolb-Sobieraj (&) Á S. Gupta Á B. Weinstock- suggested from animal models and in vitro Guttman (&) Department of Neurology, School of Medicine and experimental data. Phase III clinical trials Biomedical Sciences, State University of New York at ALLEGRO (Clinicaltrials.gov #NCT00509145) Buffalo, New York, USA e-mail: [email protected] and BRAVO (Clinicaltrials.gov #NCT00605215) B. Weinstock-Guttman have demonstrated clinical efficacy and e-mail: [email protected]; tolerability, while the third phase III study is [email protected] currently evaluating the safety and efficacy of C. Kolb-Sobieraj Á S. Gupta Á B. Weinstock-Guttman laquinimod at a higher dosage. Emerging oral Baird MS Center, Jacobs Neurological Institute, Buffalo General Medical Center, New York, USA treatments like laquinimod will provide new S. Gupta options for patients to consider that can lead to e-mail: [email protected] Neurol Ther better patient adherence and improved MS is considered an autoimmune disease outcomes. with inflammatory and neurodegenerative underlying processes that affect the central Keywords: Clinical trials; Disease modifying nervous system (CNS). Auto-reactive T therapies; Laquinimod; Multiple sclerosis; lymphocytes, B cells and macrophages enter Neurology; Neuroprotection the CNS causing myelin and axonal destruction and further chronic microglial activation [7]. Axonal damage and microglial activation lead INTRODUCTION to the irreversible and relentless clinical progression in patients with MS [8]. Due to the New oral disease-modifying therapies (DMTs) are heterogeneous response to therapies between currently available for the treatment of relapsing patients, often with suboptimal efficacy, and multiple sclerosis (MS). Laquinimod (quinolin-3- concern for side effects associated with current carboxamide) is one of the new once-a-day oral DMTs, new therapies are sought to address these medications being studied as a potential treatment concerns. In particular, patients with option for relapsing remitting MS [1]. Laquinimod progressive MS have a great unmet need for is structurally similar to another compound, effective interventions. Developing new roquinimex (linomide) which was also studied as therapies such as laquinimod may help a potential treatment for MS [2]. Roquinimex was address some of these deficiencies. found in early phase II and III trials to prevent This review is based on previously conducted clinical relapses and magnetic resonance imaging studies and does not involve any new studies of (MRI) activity in MS. However, the phase III trials human or animal subjects performed by any of were halted due to unexpected serious adverse the authors. events such as pericarditis, serositis and myocardial infarction that were not detected during the phase NOVEL MECHANISM OF ACTION II trials [3, 4]. Following the failed clinical trial with roquinimex, laquinimod was discovered by Laquinimod has shown to exert beneficial effects Jonsson et al. [5] in a structure activity screening on many in vitro and in vivo models of MS. A program to find compounds with efficacy against graphic synopsis of its potential mechanism of autoimmune disorders but lacking the side effects action is represented in Fig. 1. Laquinimod was of roquinimex. Chemical modifications involving found to influence the ratio of pro-inflammatory the quinolone ring and elongation of the amidic versus anti-inflammatory cytokine production in methyl group were performed on the roquinimex EAE rat models and peripheral blood structure which led to the discovery of laquinimod mononuclear cells from healthy volunteers [9]. with the chemical structure N-ethyl-N-phenyl-5- Cytokine analysis of EAE-induced rats treated chloro-1, 2-dihydro-4-hydroxy-1-methyl-2-oxo-3- with laquinimod revealed a decrease in pro- quinoline-carboxamide. These modifications led inflammatory markers, tumor necrosis factor-a to a 20-fold increase in potency of laquinimod in and interleukin (IL)-12. Concurrently, an increase treating animal models of experimental in anti-inflammatory markers transforming autoimmune encephalomyelitis (EAE) with a growth factor-b and IL-4 were noted in the same relatively favorable safety profile [6]. laquinimod-treated EAE rats [9]. It was also found Neurol Ther Fig. 1 The figure illustrates the mechanism of action of laquinimod and its presumed site of action. IFN interferon, IL interleukin, TNF tumor necrosis factor that laquinimod given preventatively blocked the to suppress clinical signs of disease in doses of entry of inflammatory T cells into the CNS. 1 mg/kg/day and higher [6]. Laquinimod, given Preventative treatment with laquinimod also at the time of symptom onset in myelin delayed clinical presentation of EAE in a dose- oligodendrocyte glycoprotein-induced EAE, dependent manner [10]. A dose-dependent effect reduced the severity of the disease at the dose of laquinimod on reducing another pro- of 25 mg/kg/day. This was considered the inflammatory cytokine, IL-17, was also seen in therapeutic dose. In another experiment, another experiment involving EAE rats treated laquinimod was given preventively at the time with laquinimod versus placebo [11]. The same of disease induction at doses of 5 mg/kg or 25 team observed a decrease in IL-17 and other pro- mg/kg/day. It was found that laquinimod had a inflammatory markers, IL-3 and granulocyte dose-dependent effect on preventing clinical colony-stimulating factor in peripheral blood disease presentation of EAE in EAE-induced mononuclear cells from healthy human controls mice [11]. [9]. Laquinimod was found to act more like an Laquinimod was also found to inhibit acute immune modulating drug, rather than an EAE clinical symptoms when administered after immunosuppressive one. Laquinimod-treated the mice developed clinical symptoms of rats were able to mount a cellular and progressive paresis. Oral laquinimod was able humoral response, including humoral Neurol Ther immunoglobulin (Ig)M and IgG against a experiment, rats were treated preventively (the presented pathogen [12]. Laquinimod did not day of EAE inoculation) with laquinimod to affect the proliferation or survival of peripheral measure the degree of axonal damage in a blood mononuclear cells in healthy human model of optic neuritis [6]. Axonal damage subjects exposed to different concentrations of and loss were measured by the accumulation of the drug [12]. The viability of cardiac allograft amyloid precursor protein antibodies at the tissue in the presence of laquinimod also sites of axonal damage and by the number of testifies to its lack of immunosuppressive effect fiber counts within the optic nerve. It was [9]. observed that the day of disease manifestation Oral laquinimod penetrates the CNS in was significantly delayed in the group which physiologic and inflammatory pathologic received laquinimod in the dosage of 5 mg/kg conditions. When oral 14C-laquinimod was subcutaneously. However, the severity of administered to track its distribution to the symptoms did not differ between the groups, brain and spinal cord in EAE and healthy mice, which leads us to believe that laquinimod healthy rats showed a 7–8% laquinimod effectively delays disease onset autoimmune distribution to the brain and spinal cord in optic neuritis [15]. Another study used relation to the peripheral blood concentration scanning electron microscopy to visualize at 2 h post dose, while EAE rats revealed a 13% axonal damage in the spinal cords of EAE mice distribution of laquinimod to the brain and treated preventively with laquinimod versus spinal cord in relation to the peripheral blood at placebo [6]. The spinal cords of the an hour post dose [9]. A parallel time to the laquinimod-treated rats showed less peak
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