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Liat Hayardeny - One of the best experts on this subject based on the ideXlab platform.
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Laquinimod treatment in the r6 2 mouse model
Scientific Reports, 2017Co-Authors: Gisa Ellrichmann, Liat Hayardeny, Michael R Hayden, Alina Blusch, Oluwaseun Fatoba, Janine Brunner, Christiane Reick, Dominik Sehr, Konstanze F. Winklhofer, Carsten SaftAbstract:The transgenic mouse model R6/2 exhibits Huntington’s disease (HD)-like deficits and basic pathophysiological similarities. We also used the pheochromocytoma-12 (PC12)-cell-line-model to investigate the effect of Laquinimod on metabolic activity. Laquinimod is an orally administered immunomodulatory substance currently under development for the treatment of multiple sclerosis (MS) and HD. As an essential effect, increased levels of BDNF were observed. Therefore, we investigated the therapeutic efficacy of Laquinimod in the R6/2 model, focusing on its neuroprotective capacity. Weight course and survival were not influenced by Laquinimod. Neither were any metabolic effects seen in an inducible PC12-cell-line model of HD. As a positive effect, motor functions of R6/2 mice at the age of 12 weeks significantly improved. Preservation of morphologically intact neurons was found after treatment in the striatum, as revealed by NeuN, DARPP-32, and ubiquitin. Biochemical analysis showed a significant increase in the brain-derived neurotrophic factor (BDNF) level in striatal but not in cortical neurons. The number of mutant huntingtin (mhtt) and inducible nitric oxide synthase (iNOS) positive cells was reduced in both the striatum and motor cortex following treatment. These findings suggest that Laquinimod could provide a mild effect on motor function and striatal histopathology, but not on survival. Besides influences on the immune system, influence on BDNF-dependent pathways in HD are discussed.
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Laquinimod treatment in the R6/2 mouse model
Scientific Reports, 2017Co-Authors: Gisa Ellrichmann, Liat Hayardeny, Alina Blusch, Oluwaseun Fatoba, Janine Brunner, Christiane Reick, Michael Hayden, Dominik Sehr, Konstanze F. Winklhofer, Carsten SaftAbstract:The transgenic mouse model R6/2 exhibits Huntington’s disease (HD)-like deficits and basic pathophysiological similarities. We also used the pheochromocytoma-12 (PC12)-cell-line-model to investigate the effect of Laquinimod on metabolic activity. Laquinimod is an orally administered immunomodulatory substance currently under development for the treatment of multiple sclerosis (MS) and HD. As an essential effect, increased levels of BDNF were observed. Therefore, we investigated the therapeutic efficacy of Laquinimod in the R6/2 model, focusing on its neuroprotective capacity. Weight course and survival were not influenced by Laquinimod. Neither were any metabolic effects seen in an inducible PC12-cell-line model of HD. As a positive effect, motor functions of R6/2 mice at the age of 12 weeks significantly improved. Preservation of morphologically intact neurons was found after treatment in the striatum, as revealed by NeuN, DARPP-32, and ubiquitin. Biochemical analysis showed a significant increase in the brain-derived neurotrophic factor (BDNF) level in striatal but not in cortical neurons. The number of mutant huntingtin (mhtt) and inducible nitric oxide synthase (iNOS) positive cells was reduced in both the striatum and motor cortex following treatment. These findings suggest that Laquinimod could provide a mild effect on motor function and striatal histopathology, but not on survival. Besides influences on the immune system, influence on BDNF-dependent pathways in HD are discussed.
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Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease.
Journal of neuroimmunology, 2017Co-Authors: Rehana Z. Hussain, Liat Hayardeny, Gary Cutter, William A. Miller-little, Doris Lambracht-washington, Thomas C. Jaramillo, Masaya Takahashi, Shanrong Zhang, Craig M. PowellAbstract:Abstract Background Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that Laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore Laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aβ) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Methods Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10 months between ages 4 and 14 months with Laquinimod (5, 10, or 25 mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14 months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aβ deposition and tau phosphorylation were determined by immunohistochemistry. Results In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10 months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by Laquinimod. Conclusion This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, Laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of Laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.
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Laquinimod enhances central nervous system barrier functions
Neurobiology of disease, 2017Co-Authors: Fred Lühder, Liat Hayardeny, Jan Winchenbach, Hania Kebir, Francesca Odoardi, Tanja Litke, Maike Sonneck, Jorge Ivan Alvarez, Nadine Eckert, Ella SoraniAbstract:Laquinimod is currently being tested as a therapeutic drug in multiple sclerosis. However, its exact mechanism of action is still under investigation. Tracking of fluorescently-tagged encephalitogenic T cells during experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, revealed that Laquinimod significantly reduces the invasion of pathogenic effector T cells into the CNS tissue. T-cell activation, differentiation and amplification within secondary lymphoid organs after immunization with myelin antigen, their migratory capacity and re-activation within the nervous tissue were either only mildly affected or remained unchanged. Instead, Laquinimod directly impacted the functionality of the CNS vasculature. The expression of tight junction proteins p120 and ZO-1 in human brain endothelial cells was up-regulated upon Laquinimod treatment, resulting in a significant increase in the transendothelial electrical resistance of confluent monolayers of brain endothelial cells. Similarly, expression of the adhesion molecule activated leukocyte cell adhesion molecule (ALCAM) and inflammatory chemokines CCL2 and IP-10 was suppressed, leading to a significant reduction in the migration of memory TH1 and TH17 lymphocytes across the blood brain barrier (BBB). Our data indicate that Laquinimod exerts its therapeutic effects by tightening the BBB and limiting parenchymal invasion of effector T cells, thereby reducing CNS damage.
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L7 Laquinimod in the R6/2 mouse model of huntington’s disease
Journal of Neurology Neurosurgery & Psychiatry, 2016Co-Authors: Gisa Ellrichmann, Kalliopi Pitarokoili, Liat Hayardeny, Alina Blusch, Oluwaseun Fatoba, Janine Brunner, Carsten Saft, Ralf GoldAbstract:Introduction The transgenic mouse model R6/2 (141–157 CAG repeats) of Huntington’s disease (HD) recapitulates basic pathophysiological similarities of HD and some of its clinical symptoms. Laquinimod as an immunomodulatory orally substance has shown to downregulate astrocytic and microglial activation which are common pathways in neurodegenerative diseases. Methods We investigated the therapeutic efficacy of Laquinimod in the R6/2 mouse model treating the animals with different concentrations of Laquinimod (0.5/1.5/5/25 mg/kg body weight (bw)) by oral gavage. We explore the neuroprotective potential of Laquinimod analysing behaviour (rotarod), weight, survival and histopathological changes after treatment. Results Oral treatment with Laquinimod (especially 0.5 mg/kg bw) not only improved motor impairment but also weight course and extended survival in R6/2 mice. R6/2 mice that were treated with 0.5 mg Laquinimod showed longer life spans, as determined by Kaplan Meier analysis (p-value = 0.1). Upon analysis of motor performance, latency-to-fall values during rotarod testing in R6/2 mice were significantly different at the age of 12 weeks in the 0.5 and 25 mg/kg bw treated group (p* In the histological analysis, Laquinimod treatment resulted in preservation of morphologically intact neurons in the motor cortex and striatum as revealed by neuronal marker NeuN and medium spiny neuron’s (MSN’s) marker DARPP-32. Biochemical analysis also showed significant increase in brain derived neurotrophic factor (BDNF) level in the cortical (*p Conclusion Together, these findings suggest that treatment with Laquinimod could provide a potential therapy for the up-regulation or modulation of neuroprotective pathways in HD.
Ofer Spiegelstein - One of the best experts on this subject based on the ideXlab platform.
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The Effect of CYP3A Induction and Inhibition on the Pharmacokinetics of Laquinimod, a Novel Neuroimmunomodulator
Clinical pharmacology in drug development, 2020Co-Authors: Anna Elgart, David J. Greenblatt, Pippa S. Loupe, Arik A. Zur, Sivan Weiss, Dorit Mimrod, Ofer SpiegelsteinAbstract:Laquinimod, a neuroimmunomodulator, is extensively metabolized by cytochrome P450 (CYP) 3A4, and modulations of CYP3A4 activity may lead to alterations in the pharmacokinetics and/or clinical effects of Laquinimod. To determine the drug-drug interaction potential of Laquinimod with CYP3A inhibitors and inducers, interaction assessments were conducted in healthy volunteers using single-dose administration of Laquinimod before and after multiple dosing of CYP3A inhibitors (ketoconazole, fluconazole, and cimetidine) or a CYP3A4 inducer (rifampin). For ketoconazole, subjects (n = 14) received Laquinimod 0.6 mg following 1 day of ketoconazole (400 mg daily) pretreatment, a single concomitant dose, and 28 additional days. For fluconazole, subjects (n = 14) received Laquinimod 0.6 mg after a single fluconazole dose of 400 mg followed by 200-mg daily fluconazole administration for 20 additional days. For cimetidine, subjects (n = 14) received Laquinimod 0.6 mg following 1 day of cimetidine (800 mg twice daily) pretreatment, a single concomitant dose, and 21 additional days. For rifampin, subjects (n = 14) received Laquinimod 0.6 mg following 9 days of rifampin (600 mg daily) pretreatment, a single concomitant dose, and 12 additional days. Coadministration of Laquinimod with CYP3A inhibitors, ketoconazole, fluconazole, and cimetidine increased Laquinimod area under the plasma concentration-time curve from time zero to infinity by approximately 3.1-, 2.5-, and 1.1-fold, respectively. Coadministration of Laquinimod with rifampin decreased Laquinimod area under the plasma concentration-time curve from time zero to infinity by 5-fold. These results indicate that coadministration of Laquinimod with moderate to strong inhibitors of CYP3A or strong inducers of CYP3A may give rise to significant pharmacokinetic drug interactions.
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The effect of Laquinimod, a novel immuno-modulator in development to treat Huntington disease, on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy young women
European Journal of Clinical Pharmacology, 2019Co-Authors: Anna Elgart, Oren Bar-ilan, Arik A. Zur, Dorit Mimrod, Vered Dror, Tjeerd Korver, Ofer SpiegelsteinAbstract:Purpose Laquinimod is an orally dosed immuno-modulator currently under development for Huntington’s disease (HD). Preclinical findings suggest potential teratogenicity of Laquinimod, thus the reproductive ability of females with HD treated with Laquinimod needs to be closely managed. Because combined oral contraceptives (COC) are often used in this context, the pharmacokinetics of COC containing ethinylestradiol (EE) and levonorgestrel (LNG) in combination with Laquinimod (0.6 mg/day) was evaluated. Methods In this randomized, phase-1 single-center, double-blind, placebo-controlled, 2-way crossover drug-drug interaction (DDI) study in 48 healthy premenopausal women, COC were administered in a 28-day regimen of 21 days followed by 7 pill-free days for 4 cycles and Laquinimod or placebo was administered for 28 days in cycle 1 and cycle 3 starting 7 days prior to COC administration. Blood samples for pharmacokinetic profiling of Laquinimod, EE and LNG were collected on day 21 and day 22 of Cycles 1 and 3 pre-dose and multiple times post-dose. Results The ratio of geometric means and 90% confidence intervals for AUC_0-24 and C_max of EE and LNG with and without Laquinimod were all within the bioequivalence range (80 to 125%). Laquinimod pharmacokinetics was consistent with those observed in previous studies. The adverse event profile was in line with the current knowledge on the safety profile of both drugs, with headache as the most frequently reported treatment-related adverse event. Conclusion The combination of COC and Laquinimod treatment was found to be safe, tolerable, and devoid of any noticeable pharmacokinetic interaction.
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A Thorough QT/QTc Study With Laquinimod, a Novel Immunomodulator in Development for Multiple Sclerosis and Huntington Disease.
Clinical pharmacology in drug development, 2018Co-Authors: Ofer Spiegelstein, Emil Samara, Anna Elgart, Dorit Mimrod, Laura Rabinovich, Eli Eyal, Craig R Sprenger, Joel MorganrothAbstract:In this randomized double-blind study, 4 groups of healthy subjects (50 per arm) participated to evaluate the effect of Laquinimod, an oral treatment in development for multiple sclerosis and Huntington disease, on the QTc interval. Subjects received a dose of either 0.6 or 1.2 mg/day Laquinimod for 14 days, placebo for 14 days, or 13 days of placebo followed by a dose of 400 mg moxifloxacin on day 14. Continuous 12-lead electrocardiograms were recorded on day -1 (baseline) and days 14 to 17, and quadruplicate electrocardiograms were extracted at predefined time points. The primary measure was time-matched change from baseline in individual QTc (QTcI), and an analysis of variance was conducted on the placebo-corrected change from baseline data (ddQTcI). Pharmacokinetic-pharmacodynamic and safety assessments were included. Results showed that the upper limits of the 2-sided 90%CI for ddQTcI for both Laquinimod doses were below 10 millisconds at all time points, whereas lower limits for moxifloxacin were above 5 milliseconds. No notable changes in ECG parameters were observed. Pharmacokinetic/pharmacodynamic analysis showed no positive correlation between Laquinimod plasma levels and QTcI. In conclusion, Laquinimod was not found to affect cardiac repolarization or to cause prolongation of QTcI at doses of 0.6 and 1.2 mg/day.
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Safety and in vivo immune assessment of escalating doses of oral Laquinimod in patients with RRMS
Journal of Neuroinflammation, 2017Co-Authors: Tjalf Ziemssen, Tony Sehr, Katja Thomas, Nils Richter, Ella Sorani, Emil Samara, Hayrettin Tumani, Ofer Spiegelstein, Friedemann Paul, Oren Bar-ilanAbstract:BackgroundLaquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of Laquinimod in patients with RRMS.MethodsOne hundred twelve patients were randomly assigned to Laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments.ResultsTwenty-eight patients received placebo and 84 received Laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to Laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of Laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following Laquinimod compared to placebo.ConclusionLaquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of Laquinimod on the innate immune system was demonstrated.Trial registrationEudraCT Number: 2009-011234-99. Registered 23 June 2009.
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Safety and in vivo immune assessment of escalating doses of oral Laquinimod in patients with RRMS.
Journal of neuroinflammation, 2017Co-Authors: Tjalf Ziemssen, Tony Sehr, Katja Thomas, Nils Richter, Ella Sorani, Emil Samara, Hayrettin Tumani, Ofer Spiegelstein, Friedemann Paul, Oren Bar-ilanAbstract:Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of Laquinimod in patients with RRMS. One hundred twelve patients were randomly assigned to Laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. Twenty-eight patients received placebo and 84 received Laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to Laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of Laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following Laquinimod compared to placebo. Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of Laquinimod on the innate immune system was demonstrated. EudraCT Number: 2009-011234-99 . Registered 23 June 2009.
Hans Link - One of the best experts on this subject based on the ideXlab platform.
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Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-β in Lewis rats
Journal of Neuroimmunology, 2004Co-Authors: Jian-she Yang, Ling-yun Xu, Bao-guo Xiao, Gunnar Hedlund, Hans LinkAbstract:Abstract The new orally active drug Laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day Laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, Laquinimod inhibited the inflammation of both CD4 + T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of T H 2/T H 3 cytokines IL-4, IL-10 and TGF-β. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.
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Laquinimod abr 215062 suppresses the development of experimental autoimmune encephalomyelitis modulates the th1 th2 balance and induces the th3 cytokine tgf β in lewis rats
Journal of Neuroimmunology, 2004Co-Authors: Jian-she Yang, Bao-guo Xiao, Gunnar Hedlund, Hans LinkAbstract:Abstract The new orally active drug Laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day Laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, Laquinimod inhibited the inflammation of both CD4 + T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of T H 2/T H 3 cytokines IL-4, IL-10 and TGF-β. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.
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Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats.
Journal of neuroimmunology, 2004Co-Authors: Jian-she Yang, Bao-guo Xiao, Gunnar Hedlund, Hans LinkAbstract:The new orally active drug Laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day Laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, Laquinimod inhibited the inflammation of both CD4+ T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of TH2/TH3 cytokines IL-4, IL-10 and TGF-beta. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.
Oren Bar-ilan - One of the best experts on this subject based on the ideXlab platform.
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The effect of Laquinimod, a novel immuno-modulator in development to treat Huntington disease, on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy young women
European Journal of Clinical Pharmacology, 2019Co-Authors: Anna Elgart, Oren Bar-ilan, Arik A. Zur, Dorit Mimrod, Vered Dror, Tjeerd Korver, Ofer SpiegelsteinAbstract:Purpose Laquinimod is an orally dosed immuno-modulator currently under development for Huntington’s disease (HD). Preclinical findings suggest potential teratogenicity of Laquinimod, thus the reproductive ability of females with HD treated with Laquinimod needs to be closely managed. Because combined oral contraceptives (COC) are often used in this context, the pharmacokinetics of COC containing ethinylestradiol (EE) and levonorgestrel (LNG) in combination with Laquinimod (0.6 mg/day) was evaluated. Methods In this randomized, phase-1 single-center, double-blind, placebo-controlled, 2-way crossover drug-drug interaction (DDI) study in 48 healthy premenopausal women, COC were administered in a 28-day regimen of 21 days followed by 7 pill-free days for 4 cycles and Laquinimod or placebo was administered for 28 days in cycle 1 and cycle 3 starting 7 days prior to COC administration. Blood samples for pharmacokinetic profiling of Laquinimod, EE and LNG were collected on day 21 and day 22 of Cycles 1 and 3 pre-dose and multiple times post-dose. Results The ratio of geometric means and 90% confidence intervals for AUC_0-24 and C_max of EE and LNG with and without Laquinimod were all within the bioequivalence range (80 to 125%). Laquinimod pharmacokinetics was consistent with those observed in previous studies. The adverse event profile was in line with the current knowledge on the safety profile of both drugs, with headache as the most frequently reported treatment-related adverse event. Conclusion The combination of COC and Laquinimod treatment was found to be safe, tolerable, and devoid of any noticeable pharmacokinetic interaction.
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Safety and in vivo immune assessment of escalating doses of oral Laquinimod in patients with RRMS
Journal of Neuroinflammation, 2017Co-Authors: Tjalf Ziemssen, Tony Sehr, Katja Thomas, Nils Richter, Ella Sorani, Emil Samara, Hayrettin Tumani, Ofer Spiegelstein, Friedemann Paul, Oren Bar-ilanAbstract:BackgroundLaquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of Laquinimod in patients with RRMS.MethodsOne hundred twelve patients were randomly assigned to Laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments.ResultsTwenty-eight patients received placebo and 84 received Laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to Laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of Laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following Laquinimod compared to placebo.ConclusionLaquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of Laquinimod on the innate immune system was demonstrated.Trial registrationEudraCT Number: 2009-011234-99. Registered 23 June 2009.
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Safety and in vivo immune assessment of escalating doses of oral Laquinimod in patients with RRMS.
Journal of neuroinflammation, 2017Co-Authors: Tjalf Ziemssen, Tony Sehr, Katja Thomas, Nils Richter, Ella Sorani, Emil Samara, Hayrettin Tumani, Ofer Spiegelstein, Friedemann Paul, Oren Bar-ilanAbstract:Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of Laquinimod in patients with RRMS. One hundred twelve patients were randomly assigned to Laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9 mg/1.2 mg escalating to 2.7 mg, in 0.3 mg increments. Twenty-eight patients received placebo and 84 received Laquinimod ranging from 0.9 to 2.7 mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to Laquinimod (0.9 mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of Laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following Laquinimod compared to placebo. Laquinimod doses up to 2.7 mg were safely administered to patients with RRMS. An in vivo effect of Laquinimod on the innate immune system was demonstrated. EudraCT Number: 2009-011234-99 . Registered 23 June 2009.
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Additional file 1: Figure S1. of Safety and in vivo immune assessment of escalating doses of oral Laquinimod in patients with RRMS
2017Co-Authors: Tjalf Ziemssen, Tony Sehr, Katja Thomas, Nils Richter, Ella Sorani, Emil Samara, Hayrettin Tumani, Ofer Spiegelstein, Friedemann Paul, Oren Bar-ilanAbstract:Study MS-LAQ-101 flow chart. Figure S2. Average plasma concentrations of Laquinimod on Day 21 after repeated daily administration. Figure S3. Exposure-dose plots of Laquinimod after multiple dose administration. Table S1. Distribution of study drug termination reasons. Table S2. Biochemistry shift analysis to abnormal levels. Table S3. Hematology shift analysis. (DOCX 276 kb
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Assessment of changes in immune measures of multiple sclerosis patients treated with Laquinimod.
Journal of Neuroimmunology, 2013Co-Authors: Brett T. Lund, Oren Bar-ilan, Liat Hayardeny, Eve E. Kelland, Wendy Gilmore, Leslie P. WeinerAbstract:Abstract Laquinimod is a novel orally active agent with immunomodulatory properties that was shown to be effective in suppressing disease activity in relapsing–remitting multiple sclerosis patients. Though many mechanisms of action of Laquinimod have been described, little is known about the in vivo effects of Laquinimod on the functionality of circulating human peripheral blood mononuclear cell populations. We assessed both phenotypical and functional measures of PBMC in a prospective longitudinal analysis comparing Laquinimod and placebo treated cohorts. We determined that there were no significant changes in the relative proportion of T-cells, B-cells, monocytes & macrophages, NK-cells, dendritic cells or FoxP3 + CD25 hi T-regs in Laquinimod treated patients. There were also no significant differences in the proliferative response to PHA or tetanus antigen, or in the inflammatory cytokine bias of these responses. These data demonstrated that there were no significant changes in immune function of PBMC in patients receiving two years of continuous Laquinimod therapy who retained a full complement of the major populations of circulating PBMC and retained their capacity to respond to immunologic stimuli.
Scott S Zamvil - One of the best experts on this subject based on the ideXlab platform.
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treatment of spontaneous eae by Laquinimod reduces tfh b cell aggregates and disease progression
Neuroimmunology and Neuroinflammation, 2016Co-Authors: Michel Varrindoyer, Kara Pekarek, Collin M Spencer, Claude C A Bernard, Raymond A Sobel, Bruce A C Cree, Ulf Schulzetopphoff, Scott S ZamvilAbstract:To evaluate the influence of oral Laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell-dependent MS model.Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55-specific T cell receptor transgenic (2D2) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgHMOG-ki [Th]) mice. Laquinimod was administered orally. T cell and B cell populations were examined by flow cytometry and immunohistochemistry.Oral Laquinimod treatment (1) reduced CD11c+CD4+ dendritic cells, (2) inhibited expansion of PD-1+CXCR5+BCL6+ T follicular helper and interleukin (IL)-21-producing activated CD4+CD44+ T cells, (3) suppressed B cell CD40 expression, (4) diminished formation of Fas+GL7+ germinal center B cells, and (5) inhibited development of MOG-specific IgG. Laquinimod treatment not only prevented rMOG-induced EAE, but also inhibited development of spontaneous EAE and the formation of meningeal B cell aggregates. Disability progression was prevented when Laquinimod treatment was initiated after mice developed paralysis. Treatment of spontaneous EAE with Laquinimod was also associated with increases in CD4+CD25hiFoxp3+ and CD4+CD25+IL-10+ regulatory T cells.Our observations that Laquinimod modulates myelin antigen-specific B cell immune responses and suppresses both development of meningeal B cell aggregates and disability progression in spontaneous EAE should provide insight regarding the potential application of Laquinimod to MS treatment. Results of this investigation demonstrate how the 2D2 × Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.
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Laquinimod, an up-and-coming immunomodulatory agent for treatment of multiple sclerosis.
Experimental neurology, 2014Co-Authors: Michel Varrin-doyer, Scott S Zamvil, Ulf Schulze-topphoffAbstract:Laquinimod is a novel oral drug that is currently being evaluated for the treatment of relapsing-remitting multiple sclerosis (RRMS). Although the mode of action of Laquinimod remains to be fully elucidated, current knowledge indicates that Laquinimod exerts beneficial activities both on the peripheral immune system and within the central nervous system (CNS). The immunomodulatory properties have been deciphered primarily from studies of Laquinimod in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Data indicate that Laquinimod has a primary effect on innate immunity. Laquinimod modulates the function of various myeloid antigen presenting cell populations, which then downregulate proinflammatory T cell responses. Further, data also indicate that Laquinimod acts directly on resident cells within the CNS to reduce demyelination and axonal damage. Results from clinical trials that tested Laquinimod in RRMS demonstrated that it reduced relapse rate and the mean cumulative number of active lesions, and had a more marked reduction in disability progression than relapse rate. Laquinimod treatment was associated with an excellent safety and tolerability profile. These data indicate that Laquinimod will offer a valuable new treatment option for RRMS patients.
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Laquinimod Interferes With The Development Of Follicular Helper T Cells And Germinal Center B Cells In CNS Autoimmunity (P1.195)
Neurology, 2014Co-Authors: Michel Varrin-doyer, Kara Pekarek, Ulf Schulze-topphoff, Scott S ZamvilAbstract:Objective: In this study, we investigated the effect of Laquinimod on the generation of Tfh cells and the associated B cell differentiation in active EAE and in spontaneous opticospinal EAE (OSE). Background: Laquinimod is a novel oral agent with immunomodulatory properties for the treatment of relapsing-remitting multiple sclerosis and other autoimmune diseases. Previously, we demonstrated that Laquinimod modulates adaptive T cell immune responses via its effects on antigen presenting cells (APC), including CD11c+CD4+ dendritic cells (DC) that are known to participate in the generation of T follicular helper (Tfh) cells. Tfh cells are critical in B cell differentiation, germinal center formation and IgG class switching. Here, we evaluated the influence of Laquinimod on the T-B cooperation. Methods: C57BL/6 mice immunized with recombinant murine MOG or spontaneous EAE mice (MOG-specific T cell receptor transgenic mice (2D2) crossed to MOG-specific B cell receptor knock-in mice) were treated with either Laquinimod or vehicle. Results: Laquinimod treatment was associated with decreased frequency of Tfh and reduced expression of BCL6, a transcriptional repressor that directs Tfh differentiation. Treatment also resulted in a decreased frequency of germinal center B cells that paralleled a reduction in anti-MOG IgG antibodies and clinical EAE. Next, we observed that inhibition of Tfh differentiation was observed only when APC from Laquinimod-treated mice were used, regardless of whether naive myelin-specific T cells were obtained from Laquinimod-treated or untreated mice. In the OSE model, MOG-specific B cells efficiently present MOG to 2D2 T cells, which in turn promote B cell IgG1 class switching. Laquinimod treatment resulted in significant decreases in Tfh cells and anti-MOG IgG levels, which were associated with reduced incidence and severity of the spontaneous disease. Conclusions: Laquinimod treatment of active EAE or spontaneous OSE interfered with the generation of Tfh cells, maturation of germinal center B cells and production of anti-MOG IgG. These findings indicate that Laquinimod can modulate T-B cooperation, and suggest it may be beneficial in humoral autoimmunity. Disclosure: Dr. Varrin-Doyer has nothing to disclose. Dr. Schulze-Topphoff has nothing to disclose. Dr. Pekarek has nothing to disclose. Dr. Zamvil has received personal compensation for activities with Biogen Idec, Teva Neuroscience, EMD Serono-Pfizer, Novartis, and Genzyme. 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.
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Laquinimod, a Quinoline-3-Carboxamide, Induces Type II Myeloid Cells That Modulate Central Nervous System
2013Co-Authors: Aparna Shetty, Raymond A Sobel, Michel Varrin-doyer, Nicolas Molnarfi, Sharon A. Sagan, Patricia A. Nelson, Scott S ZamvilAbstract:Laquinimod is a novel oral drug that is currently being evaluated for the treatment of relapsing-remitting (RR) multiple sclerosis (MS). Using the animal model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), we examined how Laquinimod promotes immune modulation. Oral Laquinimod treatment reversed established RR-EAE and was associated with reduced central nervous system (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 include
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Laquinimod a once daily oral drug in development for the treatment of relapsing remitting multiple sclerosis
Expert Review of Clinical Pharmacology, 2012Co-Authors: Wolfgang Brück, Scott S ZamvilAbstract:Laquinimod is a novel, small, orally administered medication that has demonstrated efficacy in the treatment of multiple sclerosis, a chronic inflammatory demyelinating disease of the CNS. In preclinical testing, Laquinimod inhibited the development of both acute and chronic paralysis in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Furthermore, Laquinimod reduced inflammation, demyelination and axonal damage in experimental autoimmune encephalomyelitis in mice treated at disease induction or at clinical disease onset. Recent findings from the 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. In conclusion, preclinical studies show that Laquinimod’s unique mechanisms of action, including its immunomodulatory and CNS-protective effects, translate into clinical benefits in relapsing–remitting multiple sclerosis p...
