ObjectiveLaquinimod is an oral therapeutic agent under investigation for the treatment of Crohn's disease (CD), Huntington's disease, lupus nephritis and multiple sclerosis. This dose escalation study evaluated the safety and efficacy of laquinimod as induction therapy in patients with active moderate–severe CD.DesignMulticentre, double-blind, sequential-cohort, randomised controlled trial with laquinimod doses of 0.5, 1, 1.5 or 2 mg/day or placebo (n=45 per cohort randomised in a 2:1 ratio) for 8 weeks with 4-week follow-up. Stable concomittant therapies and prior use of anti-tumour necrosis factor agents were permitted. Comprehensive safety assessments were performed and efficacy analyses included the proportions of patients in clinical remission (CD Activity Index (CDAI) <150 and no treatment failure (TF)), and with a clinical response (70 or 100 point CDAI reduction from baseline or remission and no TF).Results117 patients received laquinimod and 63 patients received placebo. The overall incidence of adverse events (AEs) in the laquinimod group was similar to the pooled placebo group (86.2%–96.7% vs 82.5%) and most AEs were mild to moderate in severity. Treatment with laquinimod 0.5 mg showed consistent effects on remission (48.3% (CI 31% to 66%) vs 15.9% (CI 9% to 27%)), response 100 (55.2% (CI 37% to 71%) vs 31.7% (CI 22% to 44%)) and response 70 (62.1% (CI 44% to 77%) vs 34.9% (CI 24% to 47%)) versus placebo. Laquinimod 1.0 mg showed less benefit (26.7% remission (CI 14% to 44%) and 53.3% response 70 (CI 36% to 70%)), and no effect was noted on remission/response at higher doses.ConclusionsLaquinimod was safe and well tolerated, and the effects on remission and response of the 0.5 mg dose suggest a treatment benefit in patients with CD.Trial registration numberNCT00737932.

IMPORTANCE Tourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics, often accompanied by behavioral and psychiatric comorbidities.Deutetrabenazine is a vesicular monoamine transporter 2 inhibitor approved in the US for the treatment of chorea associated with Huntington disease and tardive dyskinesia. OBJECTIVETo report results of the ARTISTS 2 (Alternatives for Reducing Tics in Tourette Syndrome 2) study examining deutetrabenazine for treatment of Tourette syndrome. DESIGN, SETTING, AND PARTICIPANTS This phase 3, randomized, double-blind, placebocontrolled, parallel-group, fixed-dose study was conducted over 8 weeks with a 1-week follow-up (June 21, 2018, to December 9, 2019). Children and adolescents aged 6 to 16 years with a diagnosis of Tourette syndrome and active tics causing distress or impairment were enrolled in the study. Children were recruited from 52 sites in 10 countries. Data were analyzed from February 4 to April 22, 2020. INTERVENTIONS Participants were randomized (1:1:1) to low-dose deutetrabenazine (up to 36 mg/d), high-dose deutetrabenazine (up to 48 mg/d), or a matching placebo, which were titrated over 4 weeks to the target dose followed by a 4-week maintenance period. MAIN OUTCOMES AND MEASURES The primary efficacy end point was change from baseline to week 8 in the Yale Global Tic Severity Scale-Total Tic Score (YGTSS-TTS) for high-dose deutetrabenazine. Key secondary end points included changes in YGTSS-TTS for low-dose deutetrabenazine, Tourette Syndrome Clinical Global Impression score, Tourette Syndrome Patient Global Impression of Impact score, and Child and Adolescent Gilles de la Tourette Syndrome-Quality of Life Activities of Daily Living subscale score. Safety assessments included incidence of treatment-emergent adverse events, laboratory parameters, vital signs, and questionnaires. RESULTSThe study included 158 children and adolescents (mean [SD] age, 11.7 [2.6] years). A total of 119 participants (75%) were boys; 7 (4%), Asian; 1 (1%), Black; 32 (20%), Hispanic; 4 (3%), Native American; 135 (85%), White; 2 (1%), multiracial; 9 (6%), other race; and 1 (0.6%), of unknown ethnic origin. Fifty-two participants were randomized to the high-dose deutetrabenazine group, 54 to the low-dose deutetrabenazine group, and 52 to the placebo group. Baseline characteristics for participants were similar between groups. Of the total 158 participants, 64 (41%) were aged 6 to 11 years, and 94 (59%) were aged 12 to 16 years at baseline. Mean time since Tourette syndrome diagnosis was 3.3 (2.8) years, and mean baseline YGTSS-TTS was 33.8 (6.6) points. At week 8, the difference in YGTSS-TTS was not significant between the high-dose deutetrabenazine and placebo (continued) Key Points Question Are fixed doses of deutetrabenazine up to 48 mg per day safe and effective for the treatment of tics associated with Tourette syndrome in pediatric patients? Findings In this randomized clinical trial of 158 children and adolescents, differences in tic severity b...

IMPORTANCETourette syndrome is a neurodevelopmental disorder characterized by childhood onset of motor and phonic tics; treatments for tics are associated with safety concerns. Deutetrabenazine is a selective vesicular monoamine transporter 2 inhibitor approved for the treatment of chorea associated with Huntington disease and tardive dyskinesia in adults. OBJECTIVE To examine whether deutetrabenazine is effective and safe for the treatment of Tourette syndrome in children and adolescents. DESIGN, SETTING, AND PARTICIPANTS This phase 2/3, randomized, double-masked, placebocontrolled, parallel-group, dose-titration study included children and adolescents (aged 6-16 years) with Tourette syndrome with active tics causing distress or impairment (ie, Yale Global Tic Severity Scale-Total Tic Score [YGTSS-TTS] Ն20). The trial was conducted over 12 weeks, with 1 week of

Conversion of active lesions to black holes has been associated with disability progression in subjects with relapsing-remitting multiple sclerosis (RRMS) and represents a complementary approach to evaluating clinical efficacy. The objective of this study was to assess the conversion of new active magnetic resonance imaging (MRI) lesions, identified 6 months after initiating treatment with glatiramer acetate 40 mg/mL three-times weekly (GA40) or placebo, to T1-hypointense black holes in subjects with RRMS. Subjects received GA40 (n = 943) or placebo (n = 461) for 12 months. MRI was obtained at baseline and Months 6 and 12. New lesions were defined as either gadolinium-enhancing T1 or new T2 lesions at Month 6 that were not present at baseline. The adjusted mean numbers of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a negative binomial model; adjusted proportions of new active lesions at Month 6 converting to black holes at Month 12 were analyzed using a logistic regression model. Of 1,292 subjects with complete MRI data, 433 (50.3 %) GA-treated and 247 (57.2 %) placebo-treated subjects developed new lesions at Month 6. Compared with placebo, GA40 significantly reduced the mean number (0.31 versus 0.45; P = .0258) and proportion (15.8 versus 19.6 %; P = .006) of new lesions converting to black holes. GA significantly reduced conversion of new active lesions to black holes, highlighting the ability of GA40 to prevent tissue damage in RRMS.

Background Laquinimod (LAQ) is a novel oral immunomodulator in development for the treatment of Lupus Nephritis (LN). LAQ has an immune modulatory effect on antigen presenting cells directing T cells towards an anti-inflammatory phenotype characterized by down regulation of proinflammatory cytokines, including IL-6, IL-12, IL-17, IL-23, and TNFa, and increased production of IL-10. Objectives To evaluate the safety, tolerability & clinical effect of LAQ vs. placebo in patients with active LN receiving standard of care (SoC; i.e. mycophenolate mofetil (MMF) and corticosteroids). Methods Phase IIa, multicenter, double-blind, randomized study to evaluate the safety, tolerability and clinical effect (including changes in eGFR & proteinuria) of LAQ in combination with SoC. 46 patients with active LN were randomized to 24 weeks of treatment with LAQ 0.5mg/day (n=16), LAQ 1mg/day (n=15), or placebo (n=15). Results The percentage change from baseline in eGFR at week 24 was greater in both LAQ groups vs. placebo (0.5mg vs. 1mg LAQ vs. placebo: 18.0 ± 30.7 vs. 24.3 ± 28.8 vs. 12.1 ± 20.2, respectively). The percent change from baseline in spot urine protein: creatinine ratio also showed a difference between treatment arms in favor of LAQ (0.5mg vs. 1mg LAQ vs. placebo: -61.4 ± 22.8 vs. -23.0 ± 53.6 vs. -8.3 ± 81.26, respectively). Renal responses were greater at week 24 with LAQ vs. placebo (ALMS study criteria – based on spot urine instead of 24hr collection): In the LAQ 0.5mg group, 10 patients (62.5%) achieved renal response compared to 6 (40%) in the LAQ 1mg group and 5 (33.3%) in the placebo group. There was no difference among the three treatment groups in the frequency of common adverse events (AEs) including infections. Four patients in each group experienced serious AEs (SAEs). 6 SAEs were due to infection, 3 SAEs were related to lupus, 3 were thromboembolic events, and one patient with positive anticardiolipin antibodies at baseline experienced a spontaneous abortion. One death occurred in the LAQ 1mg group (pan-lobar pneumonia & sepsis). There were no elevations of AST or ALT to above 3x ULN or bilirubin elevations above 2x ULN during the treatment period. Conclusions In this exploratory study of patients with active Lupus Nephritis, LAQ 0.5 & 1mg in combination with SoC demonstrated an additive effect in improving renal function (as assessed by eGFR & proteinuria) compared to SoC alone. Although these signals are encouraging, this small phase IIa trial was not powered to definitively establish differences among the treatment groups. Both LAQ doses appeared to be well tolerated in this group of patients. A larger study of LAQ in combination with MMF and corticosteroids compared to SoC is planned in LN patients to confirm the safety and efficacy profile observed in this study. Disclosure of Interest None Declared