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In this placebo-controlled, phase 3 trial involving patients with relapsing–remitting multiple sclerosis, oral laquinimod administered once daily reduced the number of clinical relapses and slowed disability progression. Laquinimod is an oral quinoline-3-carboxamide small molecule selected for its efficacy and safety from a pool of 60 quinoline-3-carboxamide derivatives of the parent compound, roquinimex, a drug previously evaluated in phase 2 trials of treatment for multiple sclerosis but withdrawn because of safety concerns. 1 Preclinical studies have shown that laquinimod reduces inflammatory cell infiltrates in the central nervous system, decreases demyelination, and prevents axonal loss. 2 It is currently in clinical development for the treatment of multiple sclerosis. 3 – 7 A 36-week, double-blind, placebo-controlled, phase 2 clinical trial showed a significant reduction in the primary end point, the cumulative number of gadolinium-enhancing . . .

In this trial, teriflunomide reduced annualized relapse rates and disability progression over 108 weeks of treatment in patients with relapsing MS, although diarrhea, nausea, hair thinning, and abnormalities in alanine aminotransferase levels were reported. Teriflunomide, the active metabolite of leflunomide, is being investigated as a new oral disease-modifying therapy for relapsing forms of multiple sclerosis. 1 Although the two drugs are related in structure, teriflunomide has a distinct profile. 2 It reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in new pyrimidine synthesis for DNA replication. Consequently, the drug reduces T- and B-cell activation, proliferation, and function in response to autoantigens. However, teriflunomide preserves the replication and function of slowly dividing cells that use exogenous supplies of pyrimidine nucleotides through the so-called salvage pathway. 3 – 5 Teriflunomide has been shown to delay the onset of disease, . . .

Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing–remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18–55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5·5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0·50 [95% CI 0·43–0·58]) than in those assigned to teriflunomide 14 mg (0·32 [0·27–0·38]; p=0·0001) or teriflunomide 7 mg (0·39 [0·33–0·46]; p=0·0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0·68 [95% CI 0·47–1·00]; log-rank p=0·0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0·95 [0·68–1·35]; log-rank p=0·7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis. Genzyme, a Sanofi company.

Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0·55, 95% CI 0·40–0·77; p=0·0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. Teva Pharmaceutical Industries, Israel.

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18–55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov, number NCT00622700. Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416–0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515–0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540–0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. Genzyme, a Sanofi company.

In amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), spinal and lower brainstem motor neurons degenerate, but some motor neuron subtypes are spared, including oculomotor neurons (OMNs). The mechanisms responsible for this selective degeneration are largely unknown, but the molecular signatures of resistant and vulnerable motor neurons are distinct and offer clues to neuronal resilience and susceptibility. Here, we demonstrate that healthy OMNs preferentially express Synaptotagmin 13 (SYT13) compared to spinal motor neurons. In end-stage ALS patients, SYT13 is enriched in both OMNs and the remaining relatively resilient spinal motor neurons compared to controls. Overexpression of SYT13 in ALS and SMA patient motor neurons in vitro improves their survival and increases axon lengths. Gene therapy with Syt13 prolongs the lifespan of ALS mice by 14% and SMA mice by 50% by preserving motor neurons and delaying muscle denervation. SYT13 decreases endoplasmic reticulum stress and apoptosis of motor neurons, both in vitro and in vivo. Thus, SYT13 is a resilience factor that can protect motor neurons and a candidate therapeutic target across motor neuron diseases.

Background Natalizumab is a promising option for pediatric multiple sclerosis (MS) patients with active evolution and a poor response to Interferon-beta or Glatiramer Acetate. However, no data are available in large cohorts of patients and after a long-term follow up. Our study was planned to shed lights on this topic. Methods A registry was established in 2007 in Italy to collect MS cases treated with Natalizumab (NA) before 18 years of age. Results 101 patients were included (69 females), mean age of MS onset 12.9 ± 2.7 years, mean age at NA initiation 14.7 ± 2.4 years. Mean treatment duration was 34.2 ± 18.3 months. During NA treatment, a total of 15 relapses were recorded in 9 patients, annualized relapse rate was 2.3 ± 1.0 in the year prior to NA and decreased to 0.1 ± 0.3 ( p  < 0.001) at last NA infusion. Mean Expanded Disability Status Scale (EDSS) decreased from 2.6 ± 1.3 at initiation of NA to 1.8 ± 1.2 at the time of last visit ( p  < 0.001). At brain MRI, new T2 or Gd enhancing lesions were observed in 10/91 patients after 6 months, 6/87 after 12 months, 2/61 after 18 months, 2/68 after 24 months, 3/62 after 30 months, and 5/43 at longer follow up. At the time of last observation, 58 % of patients were free from clinical (relapses/increased EDSS) and/or MRI activity (new T2 or gadolinium-enhancing lesions). No relevant adverse events were recorded. Discussion NA was safe, well tolerated and very efficacious in the large majority of patients. Our data support the use of this medication in subjects with pediatric MS and an aggressive course. Conclusions A relevant reduction of relapse rate and EDSS was observed during NA treatment, compared to pre-treatment period. No evidence of disease activity (NEDA) occurred in 58 % of cases.

Alzheimer’s disease (AD) is characterized by extracellular amyloid- β (A β ) deposition, which activates microglia, induces neuroinflammation and drives neurodegeneration. Recent evidence indicates that soluble pre-fibrillar A β species, rather than insoluble fibrils, are the most toxic forms of A β . Preventing soluble A β formation represents, therefore, a major goal in AD. We investigated whether microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs, likely of microglial origin, is strikingly high in AD patients and in subjects with mild cognitive impairment and that AD MVs are toxic for cultured neurons. The mechanism responsible for MV neurotoxicity was defined in vitro using MVs produced by primary microglia. We demonstrated that neurotoxicity of MVs results from (i) the capability of MV lipids to promote formation of soluble A β species from extracellular insoluble aggregates and (ii) from the presence of neurotoxic A β forms trafficked to MVs after A β internalization into microglia. MV neurotoxicity was neutralized by the A β -interacting protein PrP and anti-A β antibodies, which prevented binding to neurons of neurotoxic soluble A β species. This study identifies microglia-derived MVs as a novel mechanism by which microglia participate in AD degeneration, and suggest new therapeutic strategies for the treatment of the disease.

In this 12-month trial involving patients with relapsing–remitting multiple sclerosis, oral fingolimod was more effective than intramuscular interferon beta-1a in reducing relapse rates. Adverse events associated with fingolimod included herpesvirus infections (two fatal infections), atrioventricular block, macular edema, skin cancer, and liver-enzyme elevation. In patients with relapsing–remitting multiple sclerosis, oral fingolimod was more effective than intramuscular interferon beta-1a in reducing relapse rates. Adverse events included herpesvirus infections (two fatal infections), atrioventricular block, macular edema, skin cancer, and liver-enzyme elevation. Oral fingolimod (FTY720) is a sphingosine-1-phosphate–receptor modulator. After phosphorylation, fingolimod acts as a functional antagonist of the sphingosine-1-phosphate type 1 receptor, inducing receptor internalization and rendering T and B cells insensitive to a signal necessary for egress from secondary lymphoid tissues. 1 , 2 The resulting redistribution to lymph nodes reduces recirculation of autoaggressive lymphocytes to the central nervous system. 3 – 5 Also, fingolimod is lipophilic, readily crosses the blood–brain barrier, and is phosphorylated within the central nervous system. 6 Through interaction with sphingosine-1-phosphate receptors on neural cells, fingolimod may have neuroprotective or reparative effects. 6 – 9 Fingolimod effectively treats experimental autoimmune encephalomyelitis, an animal . . .

ObjectivesTo assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).MethodsTwelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test–retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation.ResultsAt 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS.ConclusionsPMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.