Search

The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.In two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.A total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.Among participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).

Antiphospholipid syndrome (APS) affects the brain by both hypercoagulation and immunological mechanisms. APS is characterized by several autoantibodies binding to a thrombolytic complex including beta-2-glycoprotein I (β2-GPI) and annexin A2 (ANXA2). Teriflunomide, an oral drug for the treatment of multiple sclerosis (MS), has a cytostatic effect on B cells and is therefore a potential antibody-targeting treatment for APS. In this study, we assessed the effect of teriflunomide in two APS mouse models by inducing autoantibody formation against β2-GPI and ANXA2 in female BALB/c mice. The ANXA2 model displayed a behavioral change suggesting an anti-anxiety effect in open field and forced swim tests, early in the course of the disease. This effect was normalized following teriflunomide treatment. Conversely, behavioral tests done later during the study demonstrated depression-like behavior in the ANXA2 model. No behavioral changes were seen in the β2-GPI model. Total brain IgG levels were significantly elevated in the ANXA2 model but not in the teriflunomide treated group. No such change was noted in the brains of the β2-GPI model. High levels of serum autoantibodies were induced in both models, and their levels were not lowered by teriflunomide treatment. Teriflunomide ameliorated behavioral changes in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with the effect of teriflunomide on neuroinflammation. Teriflunomide ameliorated behavioral and brain IgG levels in mice immunized with ANXA2 without a concomitant change in serum antibody levels. These findings are compatible with an effect of teriflunomide on the IgG permeability to the brain and neuroinflammation.

Background: In post hoc analyses of Teriflunomide Multiple Sclerosis Oral study (TEMSO; NCT00134563), teriflunomide 14 mg significantly reduced brain volume loss (BVL) versus placebo in patients with relapsing multiple sclerosis (MS). Objective: In this post hoc analysis of TEMSO and its long-term extension (NCT00803049), we examined the relationship between teriflunomide’s effects on BVL and cognition. Methods: We analyzed data from 709 patients who received teriflunomide 14 mg in TEMSO or its extension. The change in cognitive performance, assessed using the Paced Auditory Serial Addition Test 3 (PASAT-3), was measured in subgroups stratified by BVL over 2 years (least BVL: ⩽ 0.52%; intermediate BVL: >0.52%–2.18%; most BVL: >2.18%). BVL, MRI lesions, and relapses over 2 years were evaluated as potential mediators of the effect of teriflunomide on cognition. Results: Teriflunomide 14 mg significantly improved PASAT-3 Z-scores versus placebo through year 2. In the least- and intermediate-BVL groups, significant improvements in PASAT-3 Z-score were demonstrated versus the most-BVL group over 3 years in the extension. According to the mediation analysis, 44% of the teriflunomide effect on cognition was due to effects on BVL at year 2. Conclusion: Teriflunomide improves cognition largely through its effects on BVL. Accelerated BVL earlier in the disease course may predict cognitive outcomes. ClinicalTrials.gov identifier: NCT00134563, NCT00803049

Background Multiple sclerosis (MS) accounts for 176 cases per 100,000 inhabitants (female/male ratio = 2:1) in Italy. For most of the patients (67%), the disease course is relapsing–remitting MS (RRMS). Objective To compare the costs and quality-adjusted life years (QALYs) of teriflunomide in RRMS naïve patients vs. RRMS patients previously treated (experienced) with other disease-modifying therapies in Italy. Methods A four health states Markov model-supported cost-utility analysis (CUA) covering a 7-year timespan through annual cycles was developed, following the healthcare sector and the societal viewpoints. Part of the parameters that populated the Markov model was obtained from a questionnaire administered to four primary Italian MS centres. Costs of healthcare and non-healthcare resources, expressed in euro (€) 2019, and QALYs were discounted at 3% real social discount rate. One-way, scenario and probabilistic sensitivity analyses tested the uncertainty of the baseline findings. Results Baseline CUA shows that teriflunomide in RRMS naïve patients is strongly dominant vs. experienced patients (healthcare sector perspective: − €1042.68 and + 0.480 QALYs; societal perspective: − €6782.81 and + 0.480 QALYs). Sensitivity analyses confirmed the robustness of the baseline results. Conclusion Teriflunomide in RRMS naïve vs. experienced patients is cost-effective and possibly strongly dominant from both the healthcare sector and the society viewpoints in Italy. Our findings need further confirmation from real-world studies.

Objectives To explore efficacy, risk factors, safety, and persistence of teriflunomide in relapsing–remitting multiple sclerosis (RRMS) cohort. Methods This prospective, observational cohort study included 217 consecutive teriflunomide treated RRMS patients, 192 of which with at least 3-month persistence on teriflunomide were included in effectiveness and risk factor analyses. Multivariate Cox proportional regression analysis was performed to identify factors associated with failure of no evidence of disease activity (NEDA) 3. Results At baseline 82% patients were treatment naïve while 18.0% interferon-β1b treated patients had stopped treatments for more than 1 year. After treatment, 79.0% patients achieved NEDA 3 at 12-month, mean annualized relapse rate (ARR) reduced significantly (0.79 ± 0.80 vs 0.16 ± 0.70; P P > 0.05). Male sex (hazard ratio [HR] 1.856; 95% confidence interval [CI] 1.118–3.082, P P P Conclusions Our results support efficacy and tolerability of teriflunomide for treatment-naïve RRMS patients in real-world practice. Female patients, patients with less relapses and less disability before treatment are most likely to benefit from teriflunomide treatment.

Aim: To evaluate adherence, healthcare resource utilization (HRU) and costs for glatiramer acetate (GA; injectable), dimethyl fumarate (oral) and teriflunomide (oral) in relapsing multiple sclerosis. Patients & methods: Retrospective analyses of a claims database. Results: Teriflunomide patients were older with more co-morbidities and fewer relapses versus GA and dimethyl fumarate. GA patients were mostly disease-modifying therapies (DMTs)-treatment naive. Treatment adherence was 61–70%. All DMTs reduced HRU versus pre-index. Costs were comparable across cohorts. High adherence reduced hospitalizations and several costs versus low adherers. Conclusion: Adherence rates were high and comparable with all DMTs. Similar (and high) reductions in HRU and costs occurred with all DMTs. High adherence improved economic outcomes versus low adherence. Thus, investing in adherence improvement is beneficial to improve outcomes in relapsing multiple sclerosis.

Human dihydroorotate dehydrogenase (

A phosphine-catalyzed approach to pyrrolines has been developed that involves two mechanistically unlinked catalytic processes. The first involves the redox isomerization of amino crotonates to provide access to aliphatic tosyl imines, which then engage in a (3+2) annulation with various allenoates. The reaction shows generality, with 24 examples established, along with a low yielding and moderately enantioselective variant. Mechanistic studies indicate that the viability of the process is linked to the selection of catalysts with similar propensity to add to the two coupling partners.

Teriflunomide, a once daily, oral disease-modifying therapy, has demonstrated consistent efficacy, safety and tolerability in patients with relapsing forms of multiple sclerosis (MS) and with a first clinical episode suggestive of MS treated up to 12 years. This review is an update to a previous version that examined data from the teriflunomide core clinical development program and extension studies. Data have since become available from active comparator trials with other disease-modifying therapies, treatment-related changes in brain volume (analyzed using structural image evaluation using normalization of atrophy) and real-world evidence including patient-reported outcomes. Initial data on the potential antiviral effects of teriflunomide in patients with MS, including case reports of patients infected with the 2019 novel coronavirus (SARS-CoV-2), are also presented.Lay abstract Teriflunomide, a treatment taken orally once a day, has shown consistent effectiveness and safety in patients with relapsing forms of multiple sclerosis (MS). This review is an update to a previous version that summarized the trials from when teriflunomide was in clinical development for MS. Some of the newer studies described here compared teriflunomide with other MS treatments. Studies have shown positive effects of teriflunomide on brain volume; teriflunomide may also be effective against some viruses. People taking teriflunomide generally report stable cognition and quality of life, with no worsening of fatigue or disability. In the EU, teriflunomide has been recently approved for use in pediatric patients 10 years of age and above.

Therapeutic drug monitoring (TDM) is extremely helpful in individualizing dosage regimen of drugs with narrow therapeutic ranges. It may also be beneficial in the case of drugs characterized by serious side effects and marked interpatient pharmacokinetic variability observed with leflunomide and its biologically active metabolite, teriflunomide. One of the most popular matrices used for TDM is blood. A more readily accessible body fluid is saliva, which can be collected in a much safer way comparing to blood. This makes it especially advantageous alternative to blood during life-threatening SARS-CoV-2 pandemic. However, drug’s saliva concentration is not always a good representation of its blood concentration. The aim of this study was to verify whether saliva can be used in TDM of teriflunomide. We also developed and validated the first reliable and robust LC-MS/MS method for quantification of teriflunomide in saliva. Additionally, the effect of salivary flow and swab absorptive material from the collector device on teriflunomide concentration in saliva was evaluated. Good linear correlation was obtained between the concentration of teriflunomide in plasma and resting saliva (p < 0.000016, r = 0.88), and even better between plasma and the stimulated saliva concentrations (p < 0.000001, r = 0.95) confirming the effectiveness of this non-invasive method of teriflunomide’s TDM. The analyzed validation criteria were fulfilled. No significant influence of salivary flow (p = 0.198) or type of swab in the Salivette device on saliva’s teriflunomide concentration was detected. However, to reduce variability the use of stimulated saliva and synthetic swabs is advised.

Given its potential antiviral activity, we investigated the effect of teriflunomide on EBV in patients with relapsing-remitting MS (RRMS).Saliva samples were collected at home and analysed for EBV DNA presence in patients with RRMS treated with teriflunomide for ≥3 months.The proportion of patients with detectable EBV in the teriflunomide cohort was lower than in the reference cohorts. The proportion of samples with EBV DNA or shedding from teriflunomide-treated patients was reduced relative to each reference cohort (P0.0001;5.8 virus copies/µL cut-off).This pilot study demonstrated the feasibility of at-home saliva sample collection and revealed a possible effect of teriflunomide on EBV shedding.

Teriflunomide is a drug with immunosuppressive and selective immunomodulatory action, characterized by anti-inflammatory and antiproliferative properties. Several clinical studies have demonstrated the efficacy and safety of this drug in Multiple Sclerosis, estimating a significant improvement in cognitive performance.The aim of our study is to evaluate the effects of teriflunomide by analysing the correlation between brain atrophy and the general cognitive profile and evaluating long-term changes. The effect of teriflunomide was studied in 30 patients with multiple sclerosis and 30 control subjects. Patients underwent a full cognitive profile assessment using the Brief Repeatable Battery of Neuropsychological Tests and a neuroimaging examination with a 3.0 T working scanner.Our results suggested that treatment with teriflunomide could potentially not only slow down the accumulation of microstructural tissue damage in Grey Matter and With Matter, but also better preserve the cognitive profile, particularly by highlighting the benefits in the memory domain. Thanks to drug therapy, brain volume in our patients has remained constant, leading to improvements in memory, indicating teriflunomide as a neuroprotective potential and further strengthening the evidence of a link between loss of brain volume and cognitive impairment.

Various copolymers incorporated with β-substituted acrylates, such as alkyl crotonates (e.g., methyl crotonate (MC), ethyl crotonate (EC), isopropyl crotonate (iPC), and n-butyl crotonate (nBC)) and methyl cinnamate (MCin), were synthesized by group-transfer polymerization (GTP) using a silicon-based Lewis acid catalyst. In addition to β-substituted acrylates, α-substituted acrylates (e.g., methyl methacrylate (MMA) and n-butyl methacrylate (nBMA)) were examined as comonomers. Proton nuclear magnetic resonance (1H NMR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) characterizations of the obtained copolymers revealed that each monomer component was incorporated sufficiently. The thermal stabilities of the resulting copolymers were investigated by dynamic mechanical analysis (DMA), indicating that the glass-transition temperature (Tg) of the copolymers can be widely varied over a relatively high-temperature range by selecting the optimal comonomer. More specifically, the Tg values of poly(MC-random-EC) (MC/EC molar ratio = 50/50), poly(MC-random-nBC) (MC/nBC molar ratio = 50/50), poly(MC-random-MCin) (MC/MCin molar ratio = 54/46), and poly(nBC-random-MCin) (nBC/MCin molar ratio = 56/44) were 173, 130, 216, and 167 °C, respectively. The copolymerization of β-substituted acrylates (i.e., crotonates and a cinnamate) using an organo-catalyzed group-transfer polymerization system with N-(tert-butyldimethylsilyl)bis(trifluoromethanesulfonyl)imide (Tf2NSitBuMe2) and 1-methoxy-1-(tert-butyldimethylsiloxy)-2-methyl-1-propene (tBuMe2SKA) was investigated. The tert-butyldimethylsilyl moiety served as an effective means for suppressing the termination reactions of the GTP system. One-stage and two-stage copolymerization strategies employing different monomer feed methods were evaluated and gave random and block copolymers, respectively. The glass-transition temperatures of the prepared copolymers varied significantly depending on the comonomer used during the synthesis.

Teriflunomide 14 mg (Aubagio®) is a once-daily, oral drug approved for the treatment of relapsing forms of multiple sclerosis (MS). While the efficacy and safety of teriflunomide have been thoroughly characterised across an extensive clinical program, we were interested in studying performance of the drug with respect to quality-of-life (QoL) outcomes in persons with MS in a real-world setting.Teri-LIFE was a prospective, open label, non-interventional, observational, multi-centre study that enrolled 200 teriflunomide-treated patients from three Nordic countries. The primary outcome measure changes in patient-reported QoL over 24 months as measured by the Short Form-36 (SF-36) questionnaire. Secondary endpoints included clinical efficacy, fatigue, safety, treatment satisfaction (Treatment Satisfaction Questionnaire for Medication version 1.4 (TSQM-1.4)), treatment adherence, and health economic outcomes. Most assessments were made at baseline and then at 6-monthly intervals.Overall, changes in SF-36 scores from baseline to last visit indicated a stable QoL during treatment with teriflunomide for up to 24 months. Relapse activity decreased during the study compared to the pre-baseline period (p0.001), patient-reported disability increased marginally, and no substantial change was seen in fatigue scores. The mean scores for TSQM domains increased nominally though not significantly from Month 6 to Month 24. The convenience and side effects TSQM domains recorded the highest median scores, indicating the acceptability of oral teriflunomide in this cohort. This was reflected in a generally high treatment adherence and decreased healthcare utilization during the study period. Some differences were seen between treatment-naïve and previously treated patients, likely reflecting different patient demographics and disease status at study entry, along with different treatment expectations.Teri-LIFE offers a reliable snapshot of QoL, efficacy, safety, and health economic outcomes in persons with relapsing MS treated with teriflunomide in routine clinical practice in Nordic countries The results were consistent with previous clinical trials and real-world studies.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Because of the relatively chemotherapy-refractory nature of HCC and significant potential poor hepatic reserve, chemotherapy has not been used consistently in the treatment of HCC. Effective new drugs for HCC are urgently needed. Teriflunomide, which was approved for the treatment of relapsing forms of multiple sclerosis (MS), has been identified as a potential antineoplastic drug. Long noncoding RNAs (lncRNAs) are a novel class of RNA molecules defined as transcripts longer than 200 nucleotides that lack protein coding potential. In this study, we investigated the ability of teriflunomide to act as an antineoplastic drug by examining the effects of teriflunomide treatment on HCC cells. Teriflunomide strongly inhibited the proliferation of HCC cells, induced cell apoptosis and induced cell accumulation in S phases of the cell cycle. LncRNA and mRNA expression profiles of HCC cells treated with teriflunomide compared with controls were performed by using microarray analysis. For comparison, the differentially expressed mRNAs were annotated by using gene ontology (GO) and pathway analyses. The microarray revealed that 2085 lncRNAs and 1561 mRNAs differed in the cells treated with teriflunomide compared with controls. Several GO terms including protein folding, mitochondrial outer membrane, transmembrane receptor protein phosphatase activity, negative regulation of cellular biosynthetic process, DNA packaging complex, and receptor signaling protein activity were enriched in gene lists, suggesting a potential correlation with the action mechanism of teriflunomide. Pathway analysis then demonstrated that JAK-STAT signaling pathway may play important roles in the cell apoptosis induced by teriflunomide. Co-expression network analysis indicated that a number of lncRNAs and mRNAs were included in the co-expression network, and p34710_v4 is the lncRNA with highest degree. Then the mRNAs associated with those differentially expressed lncRNAs were also annotated by using gene ontology (GO) and pathway analyses. The pathway analyses shows that teriflunomide significantly inhibited cell proliferation and promoted cell apoptosis partly by participating in Wnt signaling pathways. These findings suggest that teriflunomide could be a potential drug for chemotherapy and molecularly targeted therapies of HCC.

Teriflunomide (TER) is an immunomodulatory agent. Although the first reports on the use of TER in dogs have already appeared, immune mechanisms underlying the immunomodulatory effect of TER do not seem to have been fully elucidated yet. There were two aspects of this study. First, further insight into the mode of action of TER was gained by investigating its effect on the expression of IL-2 receptor α-chain (CD25) and Forkhead box P3 (Foxp3) by CD4+ and CD8+ T cells and apoptosis of these cells. Second, in view in the earlier lack of data on the effect of TER on T cells in dogs, the results of this study filled in this gap. TER at a concentration which can be achieved in vivo prevented or reduced the activation-induced CD25 expression on CD4+ and CD8+ T cells, respectively. Taking into consideration the role of CD25 in T cell proliferation, this effect may constitute an additional mechanism responsible for the antiproliferative effect of the drug. Under stimulation conditions, TER induced Foxp3 expression in Foxp3-negative CD4+ and CD8+ T cells, while down-regulating it under unstimulated conditions. These results suggest that TER may generate iTreg cells, but this process requires cell activation. TER was not found to affect on the absolute count and apoptosis of CD4+ and CD8+ T cells. The results suggest that the impairment of CD25 expression during T cell activation and generation of iTreg cells may constitute additional mechanisms, besides the principal one, underlying the immunomodulatory effect of TER.

Leflunomide is contraindicated in pregnant women, yet human data from leflunomide-exposed pregnancies do not indicate an embryofetal toxicity signal. The objective of the present analysis was to report pregnancy outcomes for leflunomide-exposed pregnancies in clinical trials and in the post-marketing setting. Pregnancy outcomes are summarized from leflunomide clinical trials and the post-marketing setting. The data cut-off was 31 December 2017. Of 1167 pregnancies reported in female patients exposed to leflunomide, 587 had a known outcome. Of these, 337 (57.4%) were reported prospectively and 250 (42.6%) were reported retrospectively. Of the 587 pregnancies with a known outcome (which involved 15 sets of twins), there were 333 (56.7%) live births, with 285 (48.6%) full-term births and 48 (8.2%) pre-term births. Birth defects were reported in 44 babies/fetuses/embryos from 587 pregnancies, with 2 reporting at least 3 minor defects and 20 reporting major defects. Major defects were reported in 3 of 337 (0.9%) prospectively-reported pregnancies; 1 major birth defect occurred in a live birth, and 2 were electively terminated due to a detected fetal anomaly. Two of the babies/fetuses/embryos, a live birth and an electively aborted baby/fetus/embryo, from 206 prospectively-reported pregnancies exposed to leflunomide during the first trimester experienced major defects. Birth defects showed no specific patterns and were distributed evenly across organ systems. Outcomes were consistent with the general population. These findings do not suggest an embryofetal toxicity signal for leflunomide, which is consistent with previous findings from leflunomide-exposed pregnancies.

Antigen-specific immune responses are crucially involved in both multiple sclerosis (MS) and myasthenia gravis (MG). Teriflunomide is an immunomodulatory agent approved for treatment of MS through inhibition of lymphocyte proliferation. MG associated with muscle-specific tyrosine kinase (MuSK) antibodies often manifests with a severe disease course, prompting development of effective treatment methods. To evaluate whether teriflunomide treatment may ameliorate MuSK-autoimmunity, experimental autoimmune MG (EAMG) was induced by immunizing C57BL/6 (B6) mice three times with MuSK in complete Freund's adjuvant (CFA) (n = 17). MuSK-immunized mice were treated daily with teriflunomide (n = 8) or PBS (n = 9) starting from the third immunization (week 8) to termination (week 14). Clinical severity of EAMG was monitored. Immunological alterations were evaluated by measurement of anti-MuSK IgG, neuromuscular junction deposits, and flow cytometric analysis of lymph node cells. In MS patients under teriflunomide treatment, the peripheral blood B cell subset profile was analyzed. B6 mice treated with teriflunomide displayed relatively preserved body weight, lower EAMG prevalence, reduced average clinical grades, higher inverted screen scores, diminished anti-MuSK antibody and NMJ deposit levels. Amelioration of EAMG findings was associated with reduced memory B cell ratios in the lymph nodes. Similarly, MS patients under teriflunomide treatment showed reduced memory B cell, plasma cell, and plasmablast ratios. Teriflunomide treatment has effectively ameliorated MuSK-autoimmunity and thus may putatively be used in long-term management of MuSK-MG as an auxiliary treatment method. Teriflunomide appears to exert beneficial effects through inhibition of effector B cells.

The outbreak of a severe acute respiratory syndrome caused by a novel coronavirus (COVID-19), has raised health concerns for patients with multiple sclerosis (MS) who are commonly on long-term immunotherapies. Managing MS during the pandemic remains challenging with little published experience and no evidence-based guidelines. We present five teriflunomide-treated patients with MS who subsequently developed active COVID-19 infection. The patients continued teriflunomide therapy and had self-limiting infection, without relapse of their MS. These observations have implications for the management of MS in the setting of the COVID-19 pandemic.

A regio- and stereoselective synthesis of unsymmetrically substituted pentafulvenes is reported via the condensation of readily available ynones and amino crotonates under very mild conditions. The mechanism of this 3 + 2 annulation involved a vinylogous Michael addition followed by an intramolecular enamine aldol condensation. Substrates with o-bromo tether further cyclized to pentannulated hydroquinolines through an isomerization/SNAr in the same reaction pot at the elevated temperature.

Astrocytes utilize both glycolytic and mitochondrial pathways to power cellular processes that are vital to maintaining normal CNS functions. These cells also mount inflammatory and acute phase reactive programs in response to diverse stimuli. While the metabolic functions of astrocytes under homeostatic conditions are well-studied, the role of cellular bioenergetics in astrocyte reactivity is poorly understood. Teriflunomide exerts immunomodulatory effects in diseases such as multiple sclerosis by metabolically reprogramming lymphocytes and myeloid cells. We hypothesized that teriflunomide would constrain astrocytic inflammatory responses. Purified murine astrocytes were grown under serum-free conditions to prevent acquisition of a spontaneous reactive state. Stimulation with TNFα activated NFκB and increased secretion of Lcn2. TNFα stimulation increased basal respiration, maximal respiration, and ATP production in astrocytes, as assessed by oxygen consumption rate. TNFα also increased glycolytic reserve and glycolytic capacity of astrocytes but did not change the basal glycolytic rate, as assessed by measuring the extracellular acidification rate. TNFα specifically increased mitochondrial ATP production and secretion of Lcn2 required ATP generated by oxidative phosphorylation. Inhibition of dihydroorotate dehydrogenase via teriflunomide transiently increased both oxidative phosphorylation and glycolysis in quiescent astrocytes, but only the increased glycolytic ATP production was sustained over time, resulting in a bias away from mitochondrial ATP production even at doses down to 1 μM. Preconditioning with teriflunomide prevented the TNFα-induced skew toward oxidative phosphorylation, reduced mitochondrial ATP production, and reduced astrocytic inflammatory responses, suggesting that this drug may limit neuroinflammation by acting as a metabolomodulator.

Allergic rhinitis and asthma are main airway disease with a higher prevalence. Eosinophilic inflammation, airway hyper-responsiveness, mucus hyper-secretion, and reversible airflow obstruction are immunopathogenesis symptoms of rhinitis and asthma. Crotonic acid has bioactivity on the inflammation and Gluconic acid as chelator may protect crotonic acid activity in airway and with together may control allergic rhinitis and asthma. Allergic rhinitis and asthma mice were treated with crotonic and gluconic acid. At least, total IgE, histamine, IL-4, IL-5, and IL-13 levels were measured. In lung tissues, goblet cell hyperplasia, mucus hyper-secretion, and inflammation were evaluated.The level of IL-5, Goblet cell hyperplasia, perivascular and peribronchial inflammation were controlled by crotonic in asthma and allergic rhinitis groups. But total IgE, histamine, IL-4, IL-13 levels and Mucus hyper-secretion had no significant chenges between treated and non-treated asthma and rhinitis groups.Crotonic acid can control eosinophilic inflammation via harnessing of IL-5 and prevent goblet cell hyperplasia. When it was used with gluconic acid, had strong effect on control of allergic rhinis and asthma immunopathology.

The efficacy of ponesimod and teriflunomide for the treatment of relapsing multiple sclerosis (MS) was compared in a randomized phase III trial. This study explores the exposure-response (E-R) relationships of efficacy end points (annualized relapse rate [ARR] and combined unique active lesions [CUALs]) of ponesimod observed in this trial. The E-R relationships were described using nonlinear mixed effects models for count data. The effect of baseline covariates (demography and prognostic factors) was also explored. Ponesimod 20 mg reduced ARR (primary end point) by 30.5% (95% confidence interval [CI]: 9.8% to 46.4%) and the number of CUALs by 56% (95% CI: 46% to 64%) between baseline and week 108 compared to teriflunomide 14 mg. The E-R analyses indicated a significant relationship between ARR and CUAL. In turn, CUAL was significantly related to ponesimod systemic exposure. Based on these relationships, the predicted reduction of ARR was relatively flat in the range of ponesimod systemic exposure achieved with the 20 mg clinical dose: the expected ARR decrease ranged from 28% (95% CI: 11% to 42%) at the 5th percentile of ponesimod exposure to 34% (95% CI: 19% to 47%) at the 95th percentile. No significant baseline covariates affected the ponesimod effects and, consequently, dosage adjustments are not warranted by these analyses. Although significant relationships were found between ARR and CUAL and between ponesimod exposure and CUAL, these analyses were supportive of the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.

Background Electronic health diaries hold promise in complementing standardized surveys in prospective health studies but are fraught with numerous methodological challenges. Objective The study aimed to investigate participant characteristics and other factors associated with response to an electronic health diary campaign in persons with multiple sclerosis, identify recurrent topics in free-text diary entries, and assess the added value of structured diary entries with regard to current symptoms and medication intake when compared with survey-collected information. Methods Data were collected by the Swiss Multiple Sclerosis Registry during a nested electronic health diary campaign and during a regular semiannual Swiss Multiple Sclerosis Registry follow-up survey serving as comparator. The characteristics of campaign participants were descriptively compared with those of nonparticipants. Diary content was analyzed using the Linguistic Inquiry and Word Count 2015 software (Pennebaker Conglomerates, Inc) and descriptive keyword analyses. The similarities between structured diary data and follow-up survey data on health-related quality of life, symptoms, and medication intake were examined using the Jaccard index. Results Campaign participants (n=134; diary entries: n=815) were more often women, were not working full time, did not have a higher education degree, had a more advanced gait impairment, and were on average 5 years older (median age 52.5, IQR 43.25-59.75 years) than eligible nonparticipants (median age 47, IQR 38-55 years; n=524). Diary free-text entries (n=632; participants: n=100) most often contained references to the following standard Linguistic Inquiry and Word Count word categories: negative emotion (193/632, 30.5%), body parts or body functioning (191/632, 30.2%), health (94/632, 14.9%), or work (67/632, 10.6%). Analogously, the most frequently mentioned keywords (diary entries: n=526; participants: n=93) were “good,” “day,” and “work.” Similarities between diary data and follow-up survey data, collected 14 months apart (median), were high for health-related quality of life and stable for slow-changing symptoms such as fatigue or gait disorder. Similarities were also comparatively high for drugs requiring a regular application, including interferon beta-1a (Avonex) and glatiramer acetate (Copaxone), and for modern oral therapies such as fingolimod (Gilenya) and teriflunomide (Aubagio). Conclusions Diary campaign participation seemed dependent on time availability and symptom burden and was enhanced by reminder emails. Electronic health diaries are a meaningful complement to regular structured surveys and can provide more detailed information regarding medication use and symptoms. However, they should ideally be embedded into promotional activities or tied to concrete research study tasks to enhance regular and long-term participation.

Lysine crotonylation is a newly discovered and reversible posttranslational modification involved in various biological processes, especially metabolism regulation. A total of 5159 lysine crotonylation sites in 2272 protein groups were identified. Twenty-seven motifs were found to be the preferred amino acid sequences for crotonylation sites. Functional annotation analyses revealed that most crotonylated proteins play important roles in metabolic processes and photosynthesis. Bioinformatics analysis suggested that lysine crotonylation preferentially targets a variety of important biological processes, including ribosome, glyoxylate and dicarboxylate metabolism, carbon fixation in photosynthetic organisms, proteasome and the TCA cycle, indicating lysine crotonylation is involved in the common mechanism of metabolic regulation. A protein interaction network analysis revealed that diverse interactions are modulated by protein crotonylation. These results suggest that lysine crotonylation is involved in a variety of biological processes. HSP70 is a crucial protein involved in protecting plant cells and tissues from thermal or abiotic stress responses, and HSP70 protein was found to be crotonylated in paper mulberry. This systematic analysis provides the first comprehensive analysis of lysine crotonylation in paper mulberry and provides important resources for further study on the regulatory mechanism and function of the lysine crotonylated proteome.

Background: Teriflunomide (TERI) and dimethyl fumarate (DMF) are licensed as first-line disease-modifying treatments (DMTs) for relapsing remitting Multiple Sclerosis (RRMS) and are largely replacing injectable DMTs. Methods: All RRMS patients starting TERI or DMF between January 1, 2013, and December 31, 2017, were included in the analysis. Time to first relapse, time to confirmed disability progression (CDP), and time to DMT discontinuation have been investigated. Propensity score with inverse probability treatment weighting (IPTW-PS) was used to adjust comparisons for baseline confounders. The aim of the study was to compare the effectiveness, and rate of discontinuation of TERI and DMF as first therapeutic choice in the Italian MS register. Results: A total of 683 patients were considered for the analyses, 185 on TERI and 498 on DMF. Patients on TERI had higher number of relapses (2.3 ± 1.4 vs 1.9 ± 1.1, p=.033) and higher baseline disability level assessed by Expanded Disability Status Scale (EDSS) (2.0, interquartile range-IQR 1.0–3.0 vs 1.5, IQR 1.0–2.0, p=.013). IPTW adjusted Cox models did not reveal any difference between the investigated DMTs for the investigated outcomes. Conclusions: TERI and DMF have similar effectiveness and rate of discontinuation when employed as first therapeutic choice in RRMS patients.

In clinical trials, few investigations have been conducted to determine the mechanism involved in teriflunomide-associated kidney stone formation. We report the first case of recurrent teriflunomide-induced uric acid urolithiasis. A 55-year-old man with relapsing-remitting multiple sclerosis experienced three occurrences of urolithiasis several months after the initiation of teriflunomide. While serum uric acid remained stable at 280 mmol/L, 24-hour urine uric acid was increased to 2195 mmol/24h. For the third episode, computed tomography showed three bladder stones and one stone in the right calyceal group. Endovesical lithotripsy was used to extract four orange-colored stones of more than 20 mm. Stone analysis exhibited morphology subtype IIIb with 100% of anhydrous uric acid. Given the disease control, teriflunomide was continued. After urinary alkalinisation by potassium citrate, the patient remained asymptomatic at 18 months follow-up. An inhibitory effect of dihydroorotate and/or teriflunomide on urate tubular reabsorption could explain teriflunomide-associated uric acid urolithiasis. This case in a patient without risk factors suggests that multiple sclerosis patients may be at greater risk of forming uric acid urinary stones when taking teriflunomide. Alkalinization of the urine may reduce the risk of recurrence, allowing further treatment with teriflunomide.

Teriflunomide (TFN) limits relapses in relapsing-remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.

The chiral Ir(I)-catalyzed intermolecular reaction of N-carbamoylpyrrole and indole derivatives with α,β-unsaturated carbonyl compounds such as crotonates proceeded with high enantioselectivity. The obtained chirally functionalized pyrroles and indoles are formal C-H conjugate adducts. The reaction mechanism was studied by deuterium labeling experiments.

Teriflunomide (Aubagio®), which was developed by Sanofi, is an oral immunomodulatory agent targeting the mitochondrial enzyme dihydroorotate dehydrogenase and available to adults to treat relapsing-remitting multiple sclerosis (MS). On 18 June 2021, teriflunomide received its first approval in this indication in pediatric patients aged ≥ 10 years in the EU. This article summarizes the milestones in the development of teriflunomide leading to this first pediatric approval for relapsing-remitting MS.

Background Post-translational modifications (PTMs) are at the heart of many cellular signaling events, which changes the function of protein. Crotonylation, one of the most important and common PTMs, plays a crucial role in the regulation of various biological processes. However, no study has evaluated the role of lysine crotonylation modification in chronic renal failure (CRF) patients. Methods Here, we comparatively evaluated the crotonylation proteome of normal controls and chronic renal failure patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS) coupled with highly sensitive immune-affinity purification. Results A total of 1109 lysine modification sites were identified, of which 772 sites were up-regulated and 69 sites were down-regulated. This suggested that crotonylation modification maintains high levels in the patients with chronic renal failure. Gene ontology(GO) enrichment analysis showed that the crotonylated proteins were significantly enriched in the platelet alpha granule lumen, platelet degradulation, and cell adhesion molecule binding. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG)-based functional enrichment analysis in the Kyoto encyclopedia showed that crotonylated protein was enriched in CD36, which is closely linked to renal failure. Conclusions This is the first report of the global crotonylation proteome in chronic renal failure patients. Crotonylation of histone and non-histone may play important roles in delaying the continuous deterioration of renal function in patients with chronic renal failure.

Dihydroorotate dehydrogenase (DHODH) catalyzes a key step in pyrimidine biosynthesis and has recently been validated as a therapeutic target for malaria through clinical studies on the triazolopyrimidine-based Plasmodium DHODH inhibitor DSM265. Selective toxicity towards Plasmodium species could be achieved because malaria parasites lack pyrimidine salvage pathways, and DSM265 selectively inhibits Plasmodium DHODH over the human enzyme. However, while DSM265 does not inhibit human DHODH, it inhibits DHODH from several preclinical species, including mice, suggesting that toxicity could result from on-target DHODH inhibition in those species. We describe here the use of dihydroorotate (DHO) as a biomarker of DHODH inhibition. Treatment of mammalian cells with DSM265 or the mammalian DHODH inhibitor teriflunomide led to increases in DHO where the extent of biomarker buildup correlated with both dose and inhibitor potency on DHODH. Treatment of mice with leflunomide (teriflunomide prodrug) caused a large dose-dependent buildup of DHO in blood (up to 16-fold) and urine (up to 5,400-fold) that was not observed for mice treated with DSM265. Unbound plasma teriflunomide levels reached 20-85-fold above the mouse DHODH ICsub50/sub, while free DSM265 levels were only 1.6-4.2-fold above, barely achieving ∼ ICsub90/subconcentrations, suggesting that unbound DSM265 plasma levels are not sufficient to block the pathway in vivo. Thus, any toxicity associated with DSM265 treatment in mice is likely caused by off-target mechanisms. The identification of a robust biomarker for mammalian DHODH inhibition represents an important advance to generally monitor for on-target effects in preclinical and clinical applications of DHODH inhibitors used to treat human disease.

Ublituximab is an anti-CD20 antibody that immunomodulates B-cells for relapsing multiple sclerosis (MS). With limited therapeutics available, this original meta-analysis seeks to determine the effect size (using RevMan 5.4.1) for annualized relapse rate (ARR), MRI outcomes and no evidence of disease activity (NEDA) by two years post-initiation of Ublituximab. Two RCTs (N = 1094) reveal Cohen's d for ARR= -0.17 (P = 0.006) favoring Ublituximab. MRI-tested, week 96 findings of T1 (Cohen's d= -0.43, P 0.00001) and T2 (Cohen's d= -0.55; P 0.00001) lesions favor Ublituximab compared to Teriflunomide. Less disease activity was reported in the Ublituximab group (OR=3.33, P 0.00001). Further trials are required to corroborate findings.

Summary Training and experiences are usually required to successfully culture and differentiate human embryonic stem cells (hESCs). Here, we describe a simple but highly efficient protocol to induce endoderm differentiation of hESCs with crotonate, a precursor of crotonyl-CoA for histone crotonylation deposition on endodermal genes. In this protocol, adding crotonate in different endoderm differentiation media significantly increases the differentiation efficiency and substantially reduces the amount of required reagents. For complete details on the use and execution of this protocol, please refer to Fang et al. (2021)., Graphical abstract, Highlights • Crotonate increases the efficiency of endoderm differentiation from different hESCs • Crotonate promotes homogeneous endoderm differentiation of hESCs • Crotonate reduces the amount of Activin A required for endoderm differentiation, Training and experiences are usually required to successfully culture and differentiate human embryonic stem cells (hESCs). Here, we describe a simple but highly efficient protocol to induce endoderm differentiation of hESCs with crotonate, a precursor of crotonyl-CoA for histone crotonylation deposition on endodermal genes. In this protocol, adding crotonate in different endoderm differentiation media significantly increases the differentiation efficiency and substantially reduces the amount of required reagents.

BackgroundSince September 2012, when teriflunomide was approved as a disease-modifying treatment for relapsing multiple sclerosis, real-world observational studies on teriflunomide in Chinese patients are limited.MethodsWe collected demographic characteristics and peripheral blood samples at different time points. Clinical symptoms, magnetic resonance imaging data, and concentrations of neurofilament light chains and multiple cytokines at different time points were compared to assess the efficacy. Moreover, the safety was assessed by blood routine, liver and kidney function, and a questionnaire to report adverse reactions.ResultsTeriflunomide significantly reduced serum levels of neurofilament light chains and several inflammatory cytokines. After accepting teriflunomide treatment, many clinical symptoms improved, scores of the expanded disability status scale decreased from 2.0 to 1.75, and annualized relapse rates decreased from 1.45 to 0.31. 29 (80.56%) and 15 (78.95%) patients achieved the no evidence of disease activity-3 status after 6 months and 12 months treatment, respectively. Teriflunomide was associated with mild or moderate discomfort, and discontinuation rates due to adverse events were low.ConclusionSerum neurofilament light chain protein is sensitive to teriflunomide treatment, suggesting that it has the potential to be used as an indicator to assess the efficacy of teriflunomide. Teriflunomide can significantly reduce the concentrations of inflammatory cytokines, indicating that teriflunomide may regulate neuroinflammation through the inhibitory effect on a variety of immune cells and their cytokines. Teriflunomide can improve clinical symptoms and disease severity in MS patients in southern China, and patients have good compliance.

BACKGROUND For small molecules such as teriflunomide, used to treat relapsing multiple sclerosis (MS), that are potentially embryotoxic, there is a theoretical risk of transmission of the medication from males on the drug to female sexual partners. However, that risk has been undefined up to now. METHODS Teriflunomide concentrations were assayed concomitantly in ten sexually active couples, not using barrier methods of contraception, in whom the male partner with MS was on treatment with teriflunomide 14 mg daily for at least two months. These results were compared by male and female age, teriflunomide concentrations and reported average number of incidences of sexual intercourse per month. The threshold level of detection of teriflunomide was 0.020 µg/ml in females. RESULTS The average age of the cohort was 46.70 for males and 47.10 for females. Four of ten females had detectible teriflunomide concentrations (mean 0.046µg/ml (range 0.22-0.077, standard deviation 0.025). Male age and both female teriflunomide positive threshold and female teriflunomide concentration were inversely correlated (r=0.67, R2=0.45, p=0.034) for the former and (r=0.62, R2=0.39, p=.05, ns) for the latter. No significant correlations were observed for female age, male teriflunomide concentrations, or reported mean monthly episodes of sexual intercourse. CONCLUSION This limited study suggests that the small risk that low levels of teriflunomide can be transmitted from male to female partners via sexual intercourse is related to male age. This supports the recommendations found in the United States Product Insert (USPI) stating that men taking teriflunomide who do not wish to father a child, and their female partners, should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure to reduce the plasma concentrations of the medication to less than 0.02 mg/L (0.02 µg/ml1.

Background: Teriflunomide and dimethyl fumarate (DMF) are first-line disease-modifying treatments for multiple sclerosis with similar labels that are used in comparable populations. Objectives: The objective of this study was to compare the effectiveness and persistence of teriflunomide and DMF in a Swedish real-world setting. Methods: All relapsing-remitting multiple sclerosis (RRMS) patients in the Swedish MS registry initiating teriflunomide or DMF were included in the analysis. The primary endpoint was treatment persistence. Propensity score matching was used to adjust comparisons for baseline confounders. Results: A total of 353 teriflunomide patients were successfully matched to 353 DMF. There was no difference in the rate of overall treatment discontinuation by treatment group across the entire observation period (hazard ratio (HR) = 1.12; 95% confidence interval (CI) = 0.91–1.39; p = 0.277; reference = teriflunomide). Annualised relapse rate (ARR) was comparable ( p = 0.237) between DMF (0.07; 95% CI = 0.05–0.10) and teriflunomide (0.09; 95% CI = 0.07–0.12). There was no difference in time to first on-treatment relapse (HR = 0.78; 95% CI = 0.50–1.21), disability progression (HR = 0.55; 95% CI = 0.27–1.12) or confirmed improvement (HR = 1.17; 95% CI = 0.57–2.36). Conclusion: This population-based real-world study reports similarities in treatment persistence, clinical effectiveness and quality of life outcomes between teriflunomide and dimethyl fumarate.

Teriflunomide is an oral monotherapy used to treat relapsing multiple sclerosis. Although teriflunomide may be associated with gastrointestinal symptoms, these events are mild and self-limiting. We present a 39-year-old female who developed severe diarrhea and lost 20 pounds within 3 weeks of starting teriflunomide. Despite discontinuing teriflunomide and undergoing cholestyramine washout, her symptoms persisted. Celiac disease on genetic testing was positive, but no anti-transglutaminase and anti-endomysial antibodies were detected. She underwent colonoscopy and biopsy was consistent with lymphocytic colitis. Remission was achieved within days of starting budenoside. Our case describes a rare, but serious, gastrointestinal adverse event of teriflunomide.

Background In the phase 3 TOPIC study, teriflunomide significantly reduced the risk of relapse determining conversion to clinically definite multiple sclerosis (CDMS) in patients with clinically isolated syndrome, versus placebo. We assessed clinical and safety outcomes associated with extended teriflunomide treatment in the TOPIC extension study. Methods Patients who completed the TOPIC core study (including those still on study at early termination) or converted to CDMS after at least 24 weeks in the core study were eligible to participate in the extension. The primary efficacy endpoint in the extension was time to conversion to CDMS. Results Risk of relapse determining conversion to CDMS was 47.1% lower in patients treated with teriflunomide 14 mg during the core and extension studies compared with patients treated with placebo during the core study and teriflunomide 14 mg during the extension. The incidence of adverse events was 75.8% and 81.9% for 7 and 14 mg teriflunomide, respectively. Conclusions Reduced risk of relapse determining conversion to CDMS in patients with early MS receiving teriflunomide 14 mg in the core study remained throughout the extension supporting the benefits of early treatment. No new safety signals were observed for teriflunomide 7 or 14 mg.

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying anti-rheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of anti-inflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.

γ-Cyclodextrin-based metal-organic framework (γCD-MOF) crystals were successfully synthesized using a vapor diffusion method. An applicability of γCD-MOF for encapsulation of immunosuppressive disease-modifying antirheumatic drug leflunomide (LEF) was examined. Loading of LEF in γCD-MOF was performed by impregnation and co-crystallization. The empty and loaded γCD-MOFs were characterized using X-ray powder diffraction, N2 adsorption/desorption, thermogravimetric analysis, 1H NMR and FTIR spectroscopy. It was shown that in the presence of γCD-MOF leflunomide is transformed into its pharmacologically active form - teriflunomide that can be also applied alone in the treatment of multiple sclerosis. It was demonstrated that teriflunomide released from γCD-MOF has improved pharmacologically relevant properties such as solubility, dissolution rate and membrane permeability. It can be proposed that γCD-MOF can be considered as novel strategy for delivery of leflunomide.

The BTBR T + Itpr3tf/J (BTBR) mouse has developmental disorders in the central nervous system and many aberrant neuroanatomical structures. However, identification of the pathological mechanisms underlying these abnormal neuroanatomical structures in the brains of BTBR mice is still lacking. Posttranslational modifications (PTMs) are known to be involved in the regulation of diverse cellular processes, and evidence shows that some types of PTMs are associated with the development of the central nervous system. In this study, we detected four novel PTMs in the cerebral cortex of BTBR mice as compared to C57BL/6 J (B6) mice using western blotting. Results revealed that lysine crotonylation and succinylation were elevated in the cerebral cortex of BTBR mice compared to levels in B6 mice. We speculate that elevated profiles of lysine crotonylation and succinylation may be involved in mechanisms related to neuroanatomical abnormalities in cerebral cortex of BTBR mice.

Background: Teriflunomide 14 mg significantly reduced brain volume loss (BVL) and confirmed disability worsening (CDW) compared with placebo in the TEMSO core study. Objective: To investigate the relationship between BVL from Baseline to Year 2 in the TEMSO core study and long-term CDW (Year 7) in the TEMSO long-term extension (NCT00803049). Methods: Structural Image Evaluation using Normalization of Atrophy determined BVL. Long-term CDW was assessed by Expanded Disability Status Scale confirmed for 12 and 24 weeks. An additional analysis evaluated the relative contribution of BVL (Year 2) and other outcomes as potential mediators of the effect of teriflunomide 14 mg on 12-week CDW. Results: Patients with the least BVL were significantly less likely to have 12- and 24-week CDW at Year 7 compared with patients with the most BVL. A mediation analysis revealed that BVL (Year 2) explained 51.3% of the treatment effect on CDW; new or enlarging T2w lesions over 2 years explained 30.8%, and relapses in the first 2 years explained 38.5%. Conclusions: These results highlight the potential predictive value of BVL earlier in the disease course on long-term disability outcomes. The mediation analysis suggests that teriflunomide may prevent disability worsening largely through its effects on BVL.

The demographics and management of patients with multiple sclerosis (MS) differ across geographical regions, but it is unclear whether/how these differences affect treatment outcomes. The aim of this post-hoc analysis was to assess teriflunomide use and patient-reported outcomes in the United States (US) and the rest of the world (ROW) in the phase 4 Teri-PRO study (NCT01895335).In the phase 4, real-world, Teri-PRO study, patients with relapsing forms of MS received teriflunomide for 48 weeks according to local labeling. The primary endpoint was treatment satisfaction measured using the Treatment Satisfaction Questionnaire for Medication Version 1.4 (TSQM 1.4). Secondary endpoints included scores on the Expanded Disability Status Scale (EDSS), Multiple Sclerosis Performance Scale (MSPS), and Patient-Determined Disease Steps (PDDS), and occurrence of adverse events. Primary and secondary endpoints were assessed at baseline and Week 48. An exploratory subgroup analysis assessed PROs in the black patient population.The US and ROW groups included 545 and 455 patients, respectively. The mean age of patients in the ROW group was lower, they had a shorter mean time since first symptoms of MS, and had lower mean EDSS scores at baseline, compared with the US group (all p 0.0001). Black patients made up 9% of US patients vs 0.2% of ROW patients. TSQM global satisfaction scores and effectiveness, side effects, and convenience subscale scores were significantly improved from baseline to Week 48 (all p 0.0001). Disability measures were stable from baseline to Week 48 for both groups, despite different baseline level scores between the two groups. The overall proportion of patients who experienced an AE was similar across both groups. Fewer patients in the US group vs the ROW group reported hair thinning (16.1% vs 31.2%). Black patients showed comparable baseline demographics and disease characteristics and similar change over time in PROs compared with the overall US group.Patient differences observed at baseline between the US and ROW groups suggest variation in teriflunomide prescribing practices in the real-world Teri-PRO study. Improvement in treatment satisfaction and stability of disability measures were comparable between patients in the US and ROW. This suggests that teriflunomide was effective despite differences in baseline demographics and possible cultural and management differences between these geographical regions.

Various poly(alkyl crotonate)s (PRCrs) were synthesized by group-transfer polymerization (GTP) using organic superacid catalysts such as 1-[bis(trifluoromethanesulfonyl)methyl]-2,3,4,5,6-pentafluorobenzene (C6H5CHTf2) and 1-trimethylsiloxyl-1-methoxy-2-methyl-1-propene (MTS) as an initiator. Under the optimized reaction conditions, the corresponding poly(ethyl crotonate) (PEtCr) was obtained with a narrow molecular weight distribution (MWD = 1.14) in quantitative yield (>99%). The thermal stabilities of the PRCrs obtained by organic acid-catalyzed GTP were generally superior to those of poly(alkyl methacrylate)s. The glass-transition temperature (Tg) of poly(methyl crotonate) (PMeCr) (122 °C) was higher than that of poly(methyl methacrylate) (PMMA) prepared by GTP (104 °C). The 5% weight loss temperature (Td5) of PMeCr (359 °C) was also higher than that of PMMA (304 °C). The values of the total light transmittance (Tt) (reaching 91.9%) and haze (

Teriflunomide (Aubagio®) is a disease-modifying immunomodulatory drug with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, with consequent inhibition of de novo pyrimidine synthesis and reduced lymphocyte proliferation. Based on extensive evidence from randomized controlled trials (RCTs) and the real-world setting, oral teriflunomide is an effective and generally well tolerated treatment in patients with relapsing multiple sclerosis (MS), with these benefits maintained during long-term treatment (≥ 10 years) and no new safety signals identified. In pivotal RCTs in this patient population, teriflunomide provided significantly better efficacy than placebo (TEMSO and TOWER) and was as effective as interferon β-1a (TENERE) in terms of improvements in clinical outcomes (such as reduced annualized relapse rates, prevention of disability progression) and/or MRI-assessed disease activity measures. Albeit head-to-head trials would definitively establish the relative efficacy of oral disease-modifying therapies, given its convenient oral regimen and beneficial effects in reducing relapses and disease activity, teriflunomide remains an effective option for the management of relapsing–remitting MS (RRMS).

Background: Teriflunomide is contraindicated in pregnancy. Some pregnancies have occurred despite guidance to use effective contraception. Objectives: To report outcomes of pregnancies occurring in teriflunomide clinical trials and the post-marketing setting. Methods: Outcomes are summarized for pregnancies in teriflunomide monotherapy clinical trials and the post-marketing setting (data cutoff: December 2017). Results: Of 437 confirmed teriflunomide-exposed pregnancies, 222 had known outcomes (70 from clinical trials; 152 from the post-marketing setting); 161 were reported prospectively and 61 retrospectively. There were 107 (48.2%) live births, 63 (28.4%) elective abortions, 47 (21.2%) spontaneous abortions, 3 (1.4%) ectopic pregnancies, 1 (0.5%) stillbirth, and 1 (0.5%) maternal death leading to fetal death. Four birth defects were reported among cases with known pregnancy outcome: ureteropyeloectasia (only defect considered major); congenital hydrocephalus; ventricular septal defect; and malformation of right foot valgus. A case of cystic hygroma was identified on antenatal ultrasound (pregnancy outcome unknown). One elective abortion followed prenatal diagnosis of fetal anomaly (blighted ovum). The risk of major birth defects in prospectively reported live birth/stillbirth outcomes was 3.6% (1/28) in clinical trials and 0.0% (0/51) in post-marketing reports. Conclusions: Outcomes were consistent with the general population. Current human data do not indicate a teratogenic signal in teriflunomide-exposed pregnancies.

Aim: Head-to-head clinical trials of teriflunomide (TFM) versus dimethyl fumarate (DMF) have not been conducted. Objectives: To compare the real-world effectiveness of TFM versus DMF. Methods: Anonymized data were collected from patients with relapsing multiple sclerosis (MS) initiating treatment with teriflunomide (N = 50) or DMF (N = 50). Results: On follow-up magnetic resonance imaging (MRI) compared with baseline, with TFM versus DMF treatment, the proportion of patients with new/enlarging T2 or gadolinium-enhancing lesions was 30.0 versus 40.0% (p = 0.2752). However, median annualized percent whole brain volume change was -0.1 versus -0.5 (p = 0.0212). There were no significant treatment differences on additional MRI and clinical end points and no unexpected safety signals. Conclusion: The effectiveness of teriflunomide was superior to DMF on whole brain atrophy and similar to DMF on other MRI/clinical end points.