George Apostol

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.

The challenges of clinical trials in fragile X syndrome.

RationaleAdvances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement.ObjectivesWe review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders.ResultsResidual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains.ConclusionAppropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders.

Divalproex Extended-Release in Adolescent Migraine Prophylaxis: Results of a Randomized, Double-Blind, Placebo-Controlled Study

Objective.— To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended‐release vs placebo in the prophylaxis of migraine headaches in adolescents.

A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study of α4β2 Agonist ABT-894 in Adults with ADHD

Dysregulation of the neuronal nicotinic acetylcholine receptor (NNR) system has been implicated in attention-deficit/hyperactivity disorder (ADHD), and nicotinic agonists improve attention across preclinical species and humans. Hence, a randomized, double-blind, placebo-controlled, crossover study was designed to determine the safety and efficacy of a novel α4β2 NNR agonist (ABT-894 (3-(5,6-dichloro-pyridin-3-yl)-1(S),5 (S)-3,6-diazabicyclo[3.2.0]heptane)) in adults with ADHD. Participants (N=243) were randomized to one of four dose regimens of ABT-894 (1, 2, and 4 mg once daily (QD)) or 4 mg twice daily (BID) or the active comparator atomoxetine (40 mg BID) vs placebo for 28 days. Following a 2-week washout period, participants crossed over to the alternative treatment condition (active or placebo) for an additional 28 days. Primary efficacy was based on an investigator-rated Conners’ Adult ADHD Rating Scale (CAARS:Inv) Total score at the end of each 4-week treatment period. Additional secondary outcome measures were assessed. A total of 238 patients were assessed for safety end points, 236 patients were included in the intent-to-treat data set, and 196 were included in the completers data set, which was the prespecified, primary data set for efficacy. Both the 4 mg BID ABT-894 and atomoxetine groups demonstrated significant improvement on the primary outcome compared with placebo. Several secondary outcome measures were also significantly improved with 4 mg BID ABT-894. Overall, ABT-894 was well tolerated at all dose levels. These results provide initial proof of concept for the use of α4β2 agonists in the treatment of adults with ADHD. Further investigation of ABT-894, including higher doses, is therefore warranted.

Safety and Efficacy of ABT-089 in Pediatric Attention-Deficit/Hyperactivity Disorder: Results from Two Randomized Placebo-Controlled Clinical Trials.

OBJECTIVE To assess the safety and efficacy of ABT-089, a novel α(4)β(2) neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHOD Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years of age were conducted. Study 1 (n = 274) assessed six treatment groups over 8 weeks: 4 once-daily (QD) ABT-089 doses (0.085-0.700 mg/kg), QD atomoxetine, and placebo. Study 2 (n = 119) assessed three treatment groups over 6 weeks: 2 QD ABT-089 doses (0.7 mg/kg, 1.4 mg/kg) and placebo. The primary efficacy variable was the investigator-administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV: Home Version (ADHD-RS-IV [HV]) Total Score. Safety was assessed by adverse event (AE) monitoring, laboratory tests, vital signs, physical examinations, and electrocardiogram measures. RESULTS There was no statistically significant difference between ABT-089 and placebo in mean change from baseline to final evaluation of ADHD-RS-IV (HV) Total Score or other outcome measures at any dose in either study. In Study 1, atomoxetine showed statistically significant improvement for the primary and most secondary endpoints. ABT-089 was generally safe and well tolerated, with no statistically significant difference between any ABT-089 dose and placebo in the overall incidence of any specific AE, and no clinically significant changes in other safety measures. CONCLUSIONS ABT-089 did not show efficacy on the primary efficacy variable, the ADHD-RS-IV (HV) Total Score, or other measures of ADHD symptomatology in children with ADHD, and had a safety profile similar to placebo. These results contrast with published reports of efficacy of nicotinic modulators in adults with ADHD.

Divalproex Sodium Extended‐Release for the Prophylaxis of Migraine Headache in Adolescents: Results of a Stand‐Alone, Long‐Term Open‐Label Safety Study

Objective.— The objective of this long‐term open‐label study in adolescents was to assess the safety and tolerability of divalproex sodium extended‐release in the prophylaxis of migraine headaches.

Development of mavoglurant and its potential for the treatment of fragile X syndrome.

Introduction: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. With no curative treatment available, current therapeutic approaches are aimed at symptom management. FXS is caused by silencing the FMR1 gene, which encodes FMRP; as loss of FMRP leads to the development of symptoms associated with FXS. Areas covered: In this evaluation, the authors examine the role of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of FXS, and its suitability as a target for rescuing the disease state. Furthermore, the authors review the evidence from preclinical studies of pharmacological interventions targeting mGluR5 in FXS. Lastly, the authors assess the findings from clinical studies in FXS, in particular the use of the Aberrant Behavior Checklist-Community Edition (ABC-C) and the recently developed ABC-C for FXS scale, as clinical endpoints to assess disease modification in this patient population. Expert opinion: There is cautious optimism for the successful treatment of the core behavioral and cognitive symptoms of FXS based on preclinical data in animal models and early studies in humans. However, the association between mGluR5-heightened responsiveness and the clinical phenotype in humans remains to be demonstrated. Many questions regarding the optimal treatment and outcome measures of FXS remain unanswered.

Safety and Tolerability of Divalproex Sodium Extended‐Release in the Prophylaxis of Migraine Headaches: Results of an Open‐Label Extension Trial in Adolescents

Objective.— To evaluate the long‐term safety and tolerability of divalproex sodium extended‐release in the prophylaxis of migraine headaches in adolescents.

Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.