Search

Currently, patients suffering from multiple sclerosis (MS), a chronic demyelinating disorder of the CNS, must be injected with medication to provide modest relief for their symptoms. Five orally available therapies are being evaluated in phase II/III clinical trials. If these therapies prove safe and tolerable, oral compounds may improve patient endorsement and compliance. Fingolimod, a novel immunosuppressant, significantly lowered annual relapse rates in phase II/III trials. Laquinimod, an immunomodulator, reduced the cumulative number of active lesions at the highest dose tested (0.6 mg/d) in a phase II trial. Cladribine, another immunomodulator, reduced annual relapse rates by >50% and gadolinium-positive lesions by >70% at both doses tested in a phase III trial. Oral fumarate, with immunomodulatory and antioxidant properties, also lowered the number of lesions in a phase II trial. Finally, teriflunomide, an immunomodulator, significantly reduced MRI lesion activity and reduced annual relapse rates in a phase II trial. In this report, we weigh the beneficial outcomes of these compounds against their risks of adverse effects.

Background: Laquinimod is a novel immunomodulatory substance developed as an orally available disease modifying treatment in multiple sclerosis (MS). The purpose of this study was to evaluate safety, tolerability, and efficacy on MRI lesions of two different doses of laquinimod compared with placebo in patients with relapsing MS. Methods: In this multicenter, double-blind, randomized trial, patients with relapsing MS received 0.1 mg or 0.3 mg laquinimod or placebo as three daily tablets for 24 weeks. Gadolinium-enhanced brain MRI scans were performed at screening, every eighth week during treatment, and 8 weeks after end of treatment. The primary efficacy variable was the cumulative number of active lesions over 24 weeks. Safety measures included adverse events, physical examination, and laboratory variables. Results: Of 256 screened patients, 209 were randomized (67 to 74 patients per group) in 20 centers. There was a significant difference between laquinimod 0.3 mg and placebo for the primary outcome measure (mean cumulative number of active lesions reduced by 44%). In the subgroup of patients with at least one active lesion at baseline the reduction was slightly more pronounced (52%). No differences with respect to clinical variables (relapses, disability) were found. The safety profile was favorable; there were no clinical signs of undesired inflammatory manifestations. Conclusion: Oral laquinimod in a dosage of 0.3 mg daily was well tolerated and effective in suppressing development of active lesions in relapsing multiple sclerosis.

Objective: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing–remitting (RR) and secondary progressive (SP) MS. Methods: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of “confirmed” clinical worsening (increase of ≥ 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score ≤ 5.0, or ≥ 0.5 point for an enrollment EDSS score of ≥ 5.5) not associated with an acute relapse. Results: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). Conclusion: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

Care of the patient with multiple sclerosis (MS) is becoming increasingly complex, with new symptomatic therapies (e.g., dalfampridine), enhanced use of disease-modifying therapies that are potentially both more efficacious and more risky (e.g., natalizumab, rituximab) than “standard” immunomodulators, the advent of oral disease-modifying therapies (DMTs) (e.g., fingolimod, cladribine, teriflunomide, laquinimod), and the possibility of regenerative or reparative therapies (e.g., stem cells, neuroprogenitor cells, antibodies to leucine-rich repeat and immunoglobulin (Ig) domain containing NOGO receptor interacting protein-1, i.e., anti-LINGO therapies). All of this is happening in the context of a suggestion that MS may fundamentally result from aberrant venous flow, so-called chronic cerebrospinal venous insufficiency (CCSVI), and a similarly fundamental pathologic discussion of the relationship between inflammation and degeneration over time in patients with MS. Noting the difficulty of choosing among many options, we present discussions of 5 new topics relevant to patients with MS and their neurologists in 2010.

Objective: We investigated whether T cell immune modulation by laquinimod was mediated through its effects on myeloid antigen presenting cells (APC) or directly on T cells. Background Laquinimod is a novel oral drug that is being evaluated for treatment of RR multiple sclerosis (MS). In the MS model, EAE, laquinimod has been shown to reduce CNS infiltration and demyelination, as well as promote T cell immune modulation. Design/Methods: The effect on the function of myeloid APC was tested by using in vivo laquinimod-treated cells as APC for meylin-specific T cells and by transferring laquinimod treated APC into mice with established EAE. Results: Oral laquinimod treatment reversed established RR-EAE, and was associated with reduced CNS inflammation, decreased Th1 and Th17 responses, and an increase in regulatory T cells (Treg). In vivo laquinimod treatment inhibited donor myelin-specific T cells from transferring EAE to naive recipient mice. In vivo laquinimod treatment altered subpopulations of myeloid antigen presenting cells (APC) that included a decrease in CD11c+CD11b+CD4+ dendritic cells and an elevation of CD11bhiGr1hi monocytes. CD11b+ cells from these mice exhibited anti-inflammatory type II (M2) phenotype characterized by reduced STAT1 phosphorylation, decreased production of IL-6, IL-12/23 and TNF, and increased IL-10. In adoptive transfer, these donor type II monocytes suppressed clinical and histologic signs in recipients with established EAE. We examined whether T cell immune modulation occurred as a direct effect of laquinimod, or as a consequence of altered APC function. Inhibition of Th1 and Th17 differentiation was observed only when type II monocytes from laquinimod-treated mice were used as APC, regardless of whether myelin-specific T cells were obtained from laquinimod-treated or untreated mice. Conclusions: Our results show that Laquinimod does not act directly on T cells, but modulates adaptive T cell immune responses via its effect on myeloid APC. Supported by: Support was provided to S.S.Z. by NIH (RO1 AI073737 and NS063008), the NMSS (RG 4124), Teva Pharmaceuticals, and the Maisin Foundation. Disclosure: Dr. Schulze Topphoff has nothing to disclose. Dr. Shetty has received research support from Boehringer Ingelheim. Dr. Varrin-Doyer has nothing to disclose. Dr. Molnarfi has nothing to disclose. Dr. Sagan has received research support from the Guthy Jackson Charitable Foundation. Dr. Sobel has received research support from the NIH. Dr. Nelson has nothing to disclose. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience and EMD Serono-Pfizer. Dr. Zamvil has received research support from the National Institutes of Health, National Multiple Sclerosis Society, the Maisin Foundation, the Guthy Jackson Charitable Foundation, Teva Neuroscience, and Boehringer Ingelheim Pharmaceuticals, Inc.

Objective: In this study we aimed to investigate whether, and how, laquinimod can prevent the occurrence of relapses in a relapsing-remitting model of MS. Background Laquinimod is an orally administered CNS-active immunomodulator. Phase III data in RRMS patients showed beneficial effects of laquinimod 0.6mg on clinical disease activity as evidenced by slowing the progression of disability, reducing the rate of MRI-measured brain volume loss and reducing relapse rates, all coupled with a favorable safety and tolerability profile. Design/Methods: We used C5BL/6 as well as SJL/J mice to induce EAE with the MOG peptide p35-55 or the PLP peptide p39-151, respectively. Dendritic cells (DCs) were analyzed from either spleen or lymph nodes. T cells were analyzed from spleen, lymph nodes or from the CNS. Results: C57BL/6 mice treated with laquinimod by daily oral gavage, were completely resistant to disease induction. To test whether the disease could also be modulated at a later stage, we induced disease in SJL/J mice, in a protocol that leads to a relapsing-remitting disease. We found that the mice treated with laquinimod were prevented from developing further relapse, in contrast to mice treated with vehicle only. Interestingly, we found that CD4+CD11c+ were almost completely absent in the Laquinimod treated mice, C57BL/6 as well as of the SJL/J mice. In addition, we detected an elevation in the total number of FoxP3+CD4+ regulatory T cells in the laquinimod treated animals. CD11c+CD4+ cells were previously implicated as immunogenic DCs, in contrast to CD11c+CD8+ cells shown to have immunomodulatory properties. Conclusions: We report that treatment of mice with laquinimod has distinct implications for cytokine production and T cell response. We suggest therefore that laquinimod appears to exert its disease-suppressive activity by modulating DC and T cell responses. Supported by: An unrestricted grant from Teva Pharmaceutical Industries (Netanya, Israel). Disclosure: Dr. Waisman has received personal compensation for activities with Teva Neuroscience as a consultant. Dr. Waisman has received research support from Teva Neuroscience. Dr. Masri has nothing to disclose. Dr. Jolivel has nothing to disclose. Dr. Lussi has nothing to disclose. Dr. Siffrin has nothing to disclose. Dr. Zipp has nothing to disclose.

Objective: Studying whether laquinimod treatment added on top of either GA (glatiramer acetate) or IFNb would result in an additive effect on disease severity in MOG-induced EAE. Background Laquinimod is an orally administered CNS-active immunomodulator. Phase III data in RRMS patients indicate clear effects of laquinimod 0.6mg on disease progression and on the accumulation of brain-tissue loss, as measured by MRI, coupled with a favorable safety and tolerability profile. Laquinimod has shown a significant effect in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. In the EAE model, laquinimod has been shown to significantly abrogate disease severity. It was suggested that Laquinimod exhibits its effect via NFkB signaling inhibition. It was shown to affect CNS residential cells as astrocytes and microglia resulting in reduction of proinflammatory cytokines. Glatiramer acetate (GA), a well-known disease modifying treatment for relapsing RRMS, is an immunomodulator that significantly inhibits disease activity in EAE. GA was shown to bind to various class II major histocompatibility complex (MHC) molecules and to create GA specific Th2 cells. These cells are migrating into the CNS and secreting anti inflammatory cytokines. INFb-which is also in use for RRMS treatment is effective in reducing inflammatory activity in EAE. Laquinimod has shown efficacy, using IFNb knock out mouse model, suggesting that laquinimod efficacy is IFNb independent. Design/Methods: MOG induced EAE C57BL/6 mice were treated with Laquinimod (5 and 25mg/kg) alone or together with suboptimal dose of GA (12.5mg/kg) or IFNb (500,000 and 50,000 IU/mouse). All treatments were started 1 day after immunization. Scoring of EAE clinical signs were carried out daily. Results: Both GA/laquinimod and IFNb/laquinimod adjunct treatment resulted in improved efficacy when compared to each treatment alone. Conclusions: These results suggesting the use of both treatment regimens together as a potential treatment for RRMS patients. Supported by: Teva Pharmaceutical industries. Disclosure: Dr. Hayardeny Nisimov has nothing to disclose. Dr. Birnberg has nothing to disclose. Dr. Raymond has received research support from TEVA Pharmaceutical. Dr. Fine has received research support from Teva Pharmaceutical. Dr. Kaye has received personal compensation for activities with Teva Neuroscience as an employee. Dr. Kaye has received research support from Teva Neuroscience.

Objective: To evaluate the antioxidant potential of Laquinimod, a novel oral therapeutic for the treatment of Multiple Sclerosis (MS). Background MS is an inflammatory autoimmune disorder, where chronic disability is due to axonal and neuronal degeneration, which is not accessible to conventional therapy and linked to oxidative stress. Laquinimod is an orally administered CNS-active immunomodulator. Phase III data in RRMS patients showed beneficial effects of laquinimod on clinical disease activity as evidenced by slowing the progression of disability, reducing the rate of MRI-measured brain volume loss and reducing relapse rates, all coupled with a favorable safety and tolerability profile. Design/Methods: We investigated the role of laquinimod in oxidative stress using hippocampal HT22 cells. In these cells, extracellular glutamate blocks cystine import via the glutamate/cystine-antiporter system Χc. Lack of intracellular cystine leads to glutathione depletion and cell death due to oxidative stress. Protection in this model was previously shown to be mediated by the transcription factors ATF4, CREB, NRF2 or SRF. We measured cell survival, concentration and time dependence, total cellular glutathione content, and the induction of antioxidant proteins by quantitative real-time PCR and transcriptional activation by dual-luciferase experiments. Results: Laquinimod robustly protected against glutamate toxicity, inhibition of γ-glutamylsynthetase, and direct oxidative stress induced by hydrogen peroxide without elevating basal intracellular glutathione levels. Protection was time-dependent and took seven days to develop. We observed a relevant effect on the expression of glutamate cysteine ligase and xCT, the functional unit of system Χc. Conclusions: Laquinimod protects hippocampal HT22 cells from oxidative stress. This protection takes seven days to develop, which hints to mechanism involving changes in gene transcription not mediated by NRF2. These results suggest transcriptional activation by other transcription factors, which are currently investigated by dual luciferase experiments using promoters of glutamate cysteine ligase and xCT. Supported by: TEVA. Disclosure: Dr. Methner has nothing to disclose. Dr. Albrecht has received research support from Novartis. Dr. Bouchachia has nothing to disclose. Dr. Hartung has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, BioMS, Genzyme Corporation, Merck Serono, Novartis, Sanofi-Aventis and Teva as a speaker and/or consultant.

Objective: Laquinimod is an orally administered CNS-active immunomodulator currently in phase III clinical trials for therapy of relapsing remitting multiple sclerosis (RRMS). Data show that RRMS patients show beneficial effects of laquinimod 0.6mg on clinical disease activity as evidenced by slowing of the progression of disability, reducing the rate of MRI-measured brain volume loss, and reducing relapse rate. The current work examines the mechanisms underlying these effects. Background Laquinimod crosses the blood-brain barrier and enters the CNS, thus in addition to peripheral effects it may act directly on CNS-resident lineages including oligodendrocytes, microglia and astrocytes. Increasing evidence implicates reactive astrocytes as critical regulators of CNS inflammation and repair in MS. Design/Methods: Here, we report that laquinimod profoundly impacts proinflammatory gene expression in a human in vitro model of reactive astrogliosis. Results: Interleukin-1beta (IL-1β) is implicated in lesion pathogenesis in RRMS, and in primary human astrocyte cultures it strongly induced inflammatory factors including cytokines, chemokines and reactive nitrogen species. Importantly, at therapeutic concentrations, laquinimod abrogated IL-1β-induced induction of cytokines including tumor necrosis factor-α (TNFα) and IL-6, and inducible nitric oxide synthase. Laquinimod also differentially regulated IL-1β-induced expression of CXC and CC chemokines, suggesting that it acts as an immunomodulator rather than an immunosuppressant in astrocyte cultures. IL-1β exerts its effects via the transcription factor NF-κB, and suggesting mechanism, laquinimod pretreatment of human astrocytes downregulated NF-κB activation. Conclusions: Collectively, these data reveal laquinimod as a regulator of the proinflammatory phenotype in a human model of reactive astrogliosis, and suggest that it may act centrally on resident CNS cells to restrict pathology in MS lesions. Supported by: A research grant from Teva Pharmaceuticals. Disclosure: Dr. Pham has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Hayardeny Nisimov has nothing to disclose. Dr. John has received personal compensation for activities with EMD Serono, Teva Neuroscience, and Biogen Idec. Dr. John has received research support from Teva Neuroscience, and Vaccinex Inc.

Objective: The study aims to investigate the cellular mode of action of laquinimod in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. Background Laquinimod is an orally administered CNS-active immunomodulator. Phase III data in RRMS patients indicate a positive effects of laquinimod 0.6 mg on clinical disease activity as evidenced by slowing the progression of disability, reducing the rate of MRI-measured brain volume loss and reducing relapse rates, all coupled with a favorable safety and tolerability profile. In EAE, it has been shown that laquinimod acts on autoaggressive T cells by reducing proinflammatory Th1 cytokine production. However, the exact cellular and molecular mechanisms of laquinimod are still incompletely understood. Design/Methods: In this study we set out to test the efficacy of laquinimod in both preventive (application of laquinimod for 14 days starting at the time of immunization) and therapeutic (starting the treatment when first symptoms occurred for 7 days) regimens in the MOG 35-55 -induced murine EAE model. Using intravital two photon microscopy combined with molecular ex vivo -analyses we are currently evaluating the locomotion and function of pathogenic effector T cells during the different phases of EAE as well as their interaction with other immune cells. Results: Our preliminary results show that laquinimod is able to ameliorate EAE in a dose-dependent manner in MOG-induced C57Bl/6 EAE as well as in a more aggressive and fulminant model using transfer of transgenic MOG-specific T cells. This was observed both in the preventive and therapeutic setting. Furthermore, we observed reduced proliferation of MOG-specific T cells and a reduction in the expression of activation markers in the priming phase and later a reduced production of pro-inflammatory cytokines such as IFN-gamma and IL17. Conclusions: In our experimental model used, laquinimod was shown to act early on antigen-specific T cells in the priming/preclinical phase before symptoms start to occur. Supported by: TEVA. Disclosure: Dr. Luhder has received research support from Teva. Dr. Winchenbach has nothing to disclose. Dr. Flugel has received research support from Teva.

Objective: The current report provides detail on pooled analyses assessing the effect of laquinimod on relapse, disability, and brain atrophy measures from the recently completed phase III trials ALLEGRO and BRAVO. Background Laquinimod is an oral, CNS acting immunomodulator in development for the treatment of multiple sclerosis. Its impact on disability progression and brain atrophy, two indices of longterm outcome for patients with multiple sclerosis (MS) are being studied in its phase III trials. Design/Methods: MS patients (N=2437) were randomized to laquinimod (n=984) or placebo (n = 1006). In both trials, patients underwent neurological examinations including the Expanded Disability Status Scale (EDSS) at screening, baseline visits and every 3 months thereafter until discontinuation or study end at 24 months. MRI scans were taken at screening, baseline, month 12 and month 24 visits. Annualized relapse rate was the primary endpoint and the risk to 3 month confirmed disability progression was a secondary endpoint. Percent change in brain volume using the SIENA technique was an exploratory endpoint in the ALLEGRO trial and a secondary endpoint in the BRAVO trial. Results: Pooled analyses on annualized relapse rate found that laquinimod reduced relapse rate by 21.4% (.30 ARR for laquinimod vs .38 for placebo patients, p = 0.0005). Pooled analyses on the risk to confirmed disability progression sustained for 3 months found laquinimod significantly reduced the risk compared to placebo 34.2% (p = 0.0017). Using a more stringent criteria of sustained disability for 6 months, there was a significant reduction by laquinimod, (46%, p Conclusions: Laquinimod slows disability progression and brain atrophy with a good safety profile suggesting it may have an important role in improving longterm outcomes in MS patients. Supported by: Teva Pharmaceuticals Israel. Disclosure: Dr. Vollmer has received personal compensation for activities with Teva Neuroscience, Daiichi Pharmaceutical Corporation, Eli Lilly & Company, Sanofi-Aventis Pharmaceuticals, Inc., PRIME Education, Inc., Projects in Knowledge, Guidepoint Global, Eisai Inc., Biogen Idec, Xenoport, Novartis, Schering-Plough Biopharma, Ono Pharmaceutical, Elan Corporation, Acorda, IMPAX, GlaxoSmithKline, Inc., and EMD Serono. Dr. Vollmer has recieved research support from EMD Serono, Teva Neuroscience, Novartis, Daiichi Pharmaceutical Corporation, Genzyme Corporation, Ono Pharmaceutical, Eli Lilly & Company, Sanofi-Aventis Pharmaceuticals, Inc., IMPAX, and Biogen Idec. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Soelberg-Sorensen has received personal compensation for activities with Merck Serono, Biogen Idec, TEVA,Genmab,Elan, Bayer Schering, and Novartis as a speaker and member of the scientific advisory board. Dr. Soelberg-Sorensen has received research support from Biogen Idec, Bayer Schering, Merck Serono, TEVA, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health. Dr. Arnold has received personal compensation for activities with Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Arnold Dr. Arnold has received research support from Bayer Healthcare, Biogen Idec, Genentech, Inc., NeuroRx Research, Roche Diagnostics Corporation, Schering, Serono, Inc., and Teva Neuroscience. Dr. Filippi has received personal compensation for activities with ECTRIMS, MSIF, MS Ireland, US NMSS, Bayer-Schering, Biogen-Dompe AG, Genmab, Merck Serono, Pepgen Corporation, Teva, and Sanofi-Aventis. Dr. Filippi has received research support from Teva, Bayer-Schering and Genmab. Dr. Statinov has received research support from Teva Pharmaceuticals. Dr. Kobys has received research support from Teva Pharmaceuticals. Dr. Becker has nothing to disclose. Dr. Jeffery has received personal compensation for activities with Berlex Labortories, GlaxoSmithKline Inc., Pfizer Inc, Serono, Inc. and Teva Neuroscience as a consultant.Dr. Jeffery has received research support from Berlex Labortories, Pfizer Inc, Serono, Inc. and Teva Neuroscience. Dr. Montalban has received personal compensation for activities with Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Montalban has received research support from Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, sanofi-aventis, Teva Pharmaceuticals, Almirall and BTG. Dr. Kappos has received research support from Acorda Therapeutics, Actelion, Allozyne, BaroFold, Inc., Bayer Pharmaceuticals Corporation, Bayhill Therapeutics, Biogen Idec, Boehringer Ingelheim Pharmaceuticals, Inc, Elan Corporation, Genmab, GlaxoSmithKline, Inc., Glenmark Pharma, Merck Serono, MediciNova, Novartis, Sanofi-Aventis Pharmaceuticals, Santhera Pharmaceuticals, Shire, Roche Diagnostics, Teva Neuroscience, UCB Pharma, Pfizer Inc, Swiss MS Society, Swiss National Research Foundation, European Union, Gianni Rubatto Foundation, Novartis and Roche Research Foundations. Dr. Boyko has received personal compensation for activities with Novartis, Merck Serono, TEVA, Gensyme, Biogen Idec, Nicomed as a member of advisory boards, a speaker and a participant of clinical trials. Dr. Selmaj has received personal compensation for activities with Genzyme, Ono, and Biogen Idec. Dr. Zipp has nothing to disclose. Dr. Havrodova has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Genzyme Corporation, GlaxoSmithKline, Inc., Novartis, Merck, Sanofi-Aventis Pharmaceuticals, Serono, Inc., and Teva as consultant, speaker and/or advisory board participant. Dr. Cohen has received personal compensation for activities with Biogen Idec, Eli Lilly & Company, Novartis, and Vaccinex. Dr. Cohen has received research support for activities with Biogen Idec, BioMS, Genzyme Corporation, Novartis, Synthon, and Teva Neuroscience.

Objective: The goal of this study was to assess the immunomodulatory in vitro effects of laquinimod on B cells from patients with relapsing-remitting multiple sclerosis (RRMS). Background The benefit of B cell-depleting therapy and other lines of evidence have emphasized a role of B cells in MS. Laquinimod is a novel orally administered drug under development for the treatment of MS, whose mode of action is not fully elucidated. Clinical data so far suggest that laquinimod is safe, well-tolerated and efficacious in reducing MRI measures of disease activity, clinical relapses and slowing the progression of disability. Design/Methods: B cells from naive MS patients were cultured with or without 1uM laquinimod for 24hrs, and analyzed by FACS for known B cell markers. B cells and CD4+ T cells from naive RRMS patients were co-cultured with or without 1uM laquinimod for 72hrs, under stimulation by CD3/CD28 and PMA+ionomycin, and cytokine levels in both B and T cells, and T cell proliferation assessed by FACS. Results: Laquinimod increased the percentage of both CD86+ and IL10+ cells within the CD25+ B cell subset, all markers associated with B cell regulatory functions. The CD25+ B cells demonstrated their regulatory capacity by reducing proliferation of T cells and the percentage of IFNg+ T cells. Laquinimod-treated B cells reduced the expression of IFNg and of IL4 and increased the expression of IL10 and TGFb in T cells, in a B-cell mediated manner. Laquinimod also reduced the expression of IL4, induced IL10 and TGFb expression in B cells in the co-culture, and decreased the percentage of IFNg+ T cells in T cells alone. Conclusions: Laquinimod modulates B cell characteristics and regulatory functions, affecting B cell cytokine and B cell-mediated- T cell cytokine profile, which may be part of the beneficial mode of action of laquinimod in MS patients. Supported by: Financial support from Teva Pharmaceuticals. Disclosure: Dr. Miller has received personal compensation for activities with Teva Pharmaceutical Industries Ltd., Medison Pharma Ltd., Biogen Idec, Merck Serono, Avanir Pharmaceuticals, Novartis, and Bayer Schering Pharma. Dr. Miller has received research support from Teva Pharmaceutical Industries Ltd., Medison Pharma Ltd., Biogen Idec, Merck Serono, and Bayer Schering Pharma. Dr. Nussbaum has nothing to disclose. Dr. Staun-Ram has received research support from Teva Pharmaceuticals. Dr. Snir has nothing to disclose. Dr. Hayardeny Nisimov has nothing to disclose. Dr. Melamed has received research support from Teva Neuroscience. Dr. Toubi has received research support from Teva Pharmaceuticals.