K. Rerat

Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials

In contrast to previous studies, targeting the mGluR pathway in fragile X syndrome patients did not improve behavior independent of FMR1 methylation. The mGluR theory of fragile X, put to the test People with the genetic disorder fragile X syndrome exhibit a variable constellation of debilitating physical and cognitive problems. Promising evidence from mouse models had raised hopes that an overactive glutamate signaling pathway (mGluR) was a smoking gun at the heart of the disease and that it could be successfully repaired. A pilot study in patients supported the mouse work: Down-regulation of mGluR improved behavioral problems, at least in patients carrying a certain genetic methylation marker. Here, in a larger, well-powered clinical trial, these results are put to the test and come up short. In adolescent or adult fragile X patients, whether they have the methylation marker or not, the glutamate antagonist mavoglurant had no effect on patient behavior. The authors discuss what further trials will be required, however, before permanently putting the mGluR theory of fragile X syndrome out to pasture. Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)–mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist—Community Edition using the FXS-specific algorithm (ABC-CFX) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits.

Is There a Difference between Levodopa/ Dopa-Decarboxylase Inhibitor and Entacapone and Levodopa/Dopa-Decarboxylase Inhibitor Dose Fractionation Strategies in Parkinson’s Disease Patients Experiencing Symptom Re-Emergence due to Wearing-Off?

Two strategies to manage symptom re-emergence due to wearing-off with conventional levodopa/dopa-decarboxylase inhibitor (DDCI) therapy were compared in patients with Parkinson’s disease (PD) in this randomized, open-label trial. PD patients receiving 3 daily doses of levodopa/DDCI were randomized to either levodopa/DDCI and entacapone or an increased dose frequency of levodopa/DDCI with or without an increased total daily dose (dose fractionation). After 1 month of treatment, patients were followed up for 1 year. A greater proportion of levodopa/DDCI and entacapone-treated patients had treatment success compared with dose-fractionated patients, according to investigator Clinical Global Impression of Change scores at 1 month (68 vs. 59%, respectively) and 1 year (60 vs. 51%, respectively). Mean ‘off’ time (time with symptoms) was improved in both groups at 1 month and 1 year, despite a reduction in the mean daily levodopa dose in the levodopa/DDCI and entacapone group at 1 month. The mean daily levodopa dose was increased in the dose fractionation group. At 1 month, there was a 4% reduction in patients experiencing dyskinesia with levodopa/DDCI and entacapone and a 3% increase with dose fractionation. These data suggest that levodopa/DDCI and entacapone reduces time with symptoms, the rate of motor complications and the daily levodopa dose compared with dose fractionation. However, as the observed differences were not statistically significant, further studies are required to confirm these results.

Levodopa/DDCI and entacapone is the preferred treatment for Parkinson’s disease patients with motor fluctuations in routine practice: a retrospective, observational analysis of a large French cohort

Levodopa is the gold standard drug for the symptomatic control of Parkinson’s disease (PD). However, long‐term treatment with conventional formulations [levodopa and a dopa decarboxylase inhibitor (DDCI)], is associated with re‐emergence of symptoms because of wearing‐off and dyskinesia. Treatment with levodopa/DDCI and entacapone extends the half‐life of levodopa, avoiding deep troughs in levodopa plasma levels and providing more continuous delivery of levodopa to the brain. In this open‐label, retrospective, observational study we investigated the effects of levodopa/DDCI and entacapone therapy in 800 PD patients with motor fluctuations. Levodopa/DDCI and entacapone treatment was assessed as good/very good in improving motor fluctuations (64%) and activities of daily living (ADL; 62%). The therapeutic utility was considered to be good/very good in 70% of cases. Moreover, there was a reduction in levodopa dose in 20% of patients. Neurologists preferred levodopa/DDCI and entacapone compared with increasing levodopa dosage, dose‐fractionation or addition of a dopamine agonist (63%, 29% and 23% of patients respectively). Reasons included achieving more continuous dopaminergic stimulation (40%), reducing motor fluctuations (54%) and improving ADL (41%). This analysis reveals the preference of neurologists for levodopa/DDCI and entacapone over conventional levodopa‐modification strategies for the effective treatment of PD motor fluctuations in clinical practice.

Anxiety and Coping Strategy Changes in Multiple Sclerosis Patients Initiating Fingolimod: The GRACE Prospective Study

The objective of this prospective study was to assess the changes in anxiety levels, and their relationship with coping strategies over the first four months of fingolimod treatment in patients with relapsing remitting multiple sclerosis (RRMS). Data were collected at the inclusion visit (Visit 1) and 4 months later (Visit 2). We used the Hospital Anxiety and Depression Scale (HADS) to assess the level of anxiety and the Coping Inventory for Stressful Situations scale to assess the coping strategies used when engaged with stressful situations. The HADS anxiety scores were compared between Visits 1 and 2, according to the preferred coping strategy. At Visit 1, half of the 198 patients included were considered to be anxious (doubtful or in a certain way). The same proportion preferentially used an avoidance-oriented strategy and one-third preferentially used an emotion-oriented strategy. The mean HADS anxiety score decreased significantly (p = 0.001) at Visit 2 (8.1 ± 4.0) compared to Visit 1 (8.8 ± 4.3), particularly in the group of patients who used an emotion-oriented strategy (p = 0.002). In conclusion, the initiation of fingolimod in patients with RRMS is followed by a decrease of anxiety levels which vary according to the coping strategy used.

D - 8 Étude Levostar sur la prise en charge des fluctuations dans la maladie de Parkinson

Introduction Des complications motrices ou non — parfois invalidantes — sont presentes chez 50 % des parkinsoniens dans les deux ans apres la mise sous traitement. Objectifs Evaluer les moyens du diagnostic des fluctuations et les strategies therapeutiques employees en routine pour les prendre en charge. Methodes Etude observationnelle descriptive francaise explorant : 1) les moyens du diagnostic des fluctuations de patients parkinsoniens depuis 2-5 ans et leur reponse au traitement, 2) le type de traitement choisi devant ces fluctuations et son maintien ou non a 4-6 mois, 3) la qualite de vie chez ces patients fluctuants, 4) l’evolution a long terme. Resultats Les patients (n = 262 ; 70 ans) etaient pour 86 % sous LDopa, 61 % sous agoniste dopaminergique et traites des le diagnostic dans 75 % des cas. Les fluctuations ont ete diagnostiquees par l’examen neurologique (73 %), l’autoquestionnaire (61 %) et l’UPDRS (19 %). Seuls 53 % des patients ont poursuivi le meme traitement jusqu’a la consultation suivante. Discussion Les principales strategies choisies dans le but d’une stimulation dopaminergique plus continue etaient : introduire Stalevo (67 %), augmenter (17 %) ou fractionner (14 %) la LDopa et ajouter de l’entacapone (16 %) ou un agoniste (3 %). Conclusion Le diagnostic et le traitement precoces des fluctuations sont necessaires d’ou l’interet du present questionnaire de depistage des fluctuations.