Dataset Information

Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder.

ABSTRACT:

Objective

Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD).

Methods

This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period 1), a 4-week washout, then another 12-week treatment (period 2). The primary outcome was ataluren's safety profile. The secondary outcome measures were (1) changes in convulsive and/or drop seizure frequency and (2) changes in minor seizure types during ataluren treatment compared to placebo. Exploratory objectives assessed changes in cognitive, motor, and behavioral function as well as quality of life during ataluren therapy.

Results

We enrolled seven subjects with DS and eight subjects with CDD. Three treatment-related adverse events (AE) occurred during the blinded phases. Two subjects withdrew due to AE. Ataluren was not effective in reducing seizure frequency or improving cognitive, motor, or behavioral function or quality of life in subjects with either DS or CDD due to nonsense variants. Limitations included a small sample size and 12-week treatment phase, possibly too short to identify a disease-modifying effect.

Significance

There was no difference between ataluren and placebo; ataluren is not an effective therapy for seizures or other disorders in children with DS or CDD due to nonsense variants. There were no drug-related serious AE during the double-blind period, consistent with ataluren's favorable safety profile in larger studies. (Funded by Epilepsy Foundation, Dravet Syndrome Foundation, Finding A Cure for Seizures and Epilepsy and PTC Therapeutics, Inc.; ClinicalTrials.gov number, NCT02758626).

SUBMITTER: Devinsky O

PROVIDER: S-EPMC7951093 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder.

Devinsky Orrin O King LaToya L Bluvstein Judith J Friedman Daniel D

Annals of clinical and translational neurology 20210204 3

<h4>Objective</h4>Ataluren is a compound that reads through premature stop codons and increases protein expression by increasing translation without modifying transcription or mRNA stability. We investigated the safety and efficacy of ataluren in children with nonsense variants causing Dravet Syndrome (DS) and CDKL5 Deficiency Syndrome (CDD).<h4>Methods</h4>This single-center double-blind, placebo-controlled crossover trial randomized subjects to receive ataluren or placebo for 12 weeks (period ...[more]

PMID: 33538404

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Project description:Background: Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS) and CDKL5 deficiency disorder (CDD) are rare epileptic conditions, characterised by drug-resistant seizures. Seizure management in these patients requires careful therapy selection. This targeted literature review (TLR) aimed to collate and synthesise information from country-specific and international treatment guidelines for DS, LGS and CDD. Methods: A TLR was performed between 25th January and 11th March 2021. Online rare diseases and guideline databases were manually searched in addition to websites of national health technology assessment bodies for the following countries: Australia, Canada, France, Germany, Israel, Italy, Japan, Spain, Switzerland, UK and US, as defined by pre-specified eligibility criteria. Search terms, developed for each condition, were translated into local languages where appropriate. Descriptive analyses were performed to examine the geographical distribution of included guidelines; methodologies used to develop guidelines; cross-referencing of treatment recommendations made within other guidelines; patterns of treatment recommendations. An author map was created using R version 3.5.1, to visualise the extent of collaboration between authors. Results: Forty total guidelines were included, of which 29, 34 and 0 contained recommendations for DS, LGS and CDD, respectively (some provided recommendations for ≥1 condition). Most were country-specific, with guideline authors predominantly publishing in regional groups. Five guidelines were classified as "International" and displayed connections between author groups in the US, UK, France and Italy. Reported guideline development processes were lacking [43% (17 guidelines) had unclear/absent literature review methodologies] and those reported were variable, including both systematic and targeted literature reviews. Use of expert consultation was also variable. A high degree of heterogeneity was observed in the availability of treatment recommendations across disorders, with 271 and 190 recommendations for LGS and DS, respectively, and contradictory positive and negative treatment recommendations for several drugs in each indication [35% (11/31) and 22% (6/27) in LGS and DS, respectively]. Conclusions: This review highlights the need for further high-quality international consensus-based treatment guidelines for LGS, DS, and particularly for CDD (for which no treatment guidelines were identified). Supra-national consensus guidance based on findings from a wider geographical range may improve resource allocation and establish an improved world-wide standard of care.

Project description:CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.

Dataset Information

Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder.

Objective

Methods

Results

Significance

Publications

Ataluren for drug-resistant epilepsy in nonsense variant-mediated Dravet syndrome and CDKL5 deficiency disorder.

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