European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene

doi:10.1016/j.nmd.2014.11.011

Neuromuscular Disorders

Volume 25, Issue 1, January 2015, Pages 5-13

https://doi.org/10.1016/j.nmd.2014.11.011 Get rights and content

Highlights

•
First in class medicine ataluren received conditional approval in Europe for treatment of Duchenne disease.
•
EMA used early approval mechanism to address unmet medical need despite limited efficacy data.
•
A study is ongoing to confirm ataluren's ability to slow disease progression.
•
The clinical benefits of ataluren and the terms of the conditional approval are subject to annual review.

Introduction

Duchenne muscular dystrophy (DMD) is a rare disease, with an overall estimated prevalence of 5/100,000 in the European Union (EU) [1]. As patients with nmDMD account for about 13% of the whole DMD patient population, it is estimated that approximately 2400 patients have nmDMD in the EU. There is no cure available and the current management of the disease is based on prevention and management of complications. Symptoms of muscle weakness are typically present from about three years of age. As the disease progresses, affected boys will typically need assisted ventilation in their late teens and die due to respiratory complications or heart failure in the 2nd–4th decade of life [2], [3], [4].

Ataluren targets the ribosomal translational machinery. It enables read-through of premature stop codons created by nonsense mutations in the mRNA of nmDMD patients, and hence expression of a full-length functional dystrophin protein (Fig. 1).

The applicant company PTC Therapeutics Ltd. submitted an initial marketing authorisation application for ataluren (Translarna©) to the European Medicines Agency for the treatment of nmDMD, in patients aged 5 years and older.

The demonstration of clinical benefit for ataluren was based on a single, phase 2b randomised, double-blind, placebo-controlled trial (PTC124-GD-007-DMD) comparing the efficacy and safety of ataluren 10, 10, 20 mg/kg TID and ataluren 20, 20, 40 mg/kg TID vs. placebo, in male patients ≥5 years of age who had a genetically confirmed nonsense mutation in the dystrophin gene. The review was conducted by the Committee for Human Medicinal Products (CHMP) of the EMA. Although the efficacy data available lacked robustness, the beneficial effects of ataluren were considered plausible and clinically relevant for this rare disease with high unmet medical need. The observed safety profile of ataluren was overall comparable to that of placebo.

A conditional marketing authorisation, subject to the completion of an ongoing confirmatory study, was granted in the EU on 5th August 2014 for the treatment of DMD resulting from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 5 years and older.

This paper summarises the scientific review of the application leading to the conditional approval in the EU, with a focus on the main issues discussed as part of this review. The detailed scientific assessment report and product information, including the summary of product characteristics (SmPC), are available on the EMA website (http://www.ema.europa.eu).

Section snippets

Non-clinical aspects

Ataluren's mechanism of action was described as promotion of the production of a functional protein by enabling read-through of the premature stop codon associated with a nonsense mutation. Ataluren functions at the level of translation; it does not interfere with transcription or mRNA stability and does not alter levels of mRNA with premature stop codons or wild type mRNA. Ataluren does not enable read-through across premature stop codons due to frameshift mutations (insertions or deletions)

Clinical pharmacology

Ataluren has an estimated oral bioavailability of ≥55%. Steady-state plasma concentrations are dose-proportional for doses between 10 and 50 mg/kg, and no accumulation was observed after repeated dosing. Ataluren plasma half-life ranges from 2 to 6 hours. No dedicated studies were performed in subjects with hepatic or renal failure. Elimination of ataluren is likely dependent on hepatic and intestinal glucuronidation followed by renal excretion. Therefore, patients with either impairment should

Clinical efficacy

The single pivotal study 007 was a phase 2b randomised, double-blind, placebo-controlled trial. Eligible patients were aged ≥5 years and had a genetically confirmed nonsense mutation in the dystrophin gene. Important inclusion criteria were the ability to walk ≥75 m unassisted and, for patients receiving corticosteroid therapy, the requirement to have such therapy stabilised prior to study entry. All patients were male, with a mean age of 8 years (range 5–20 years). The treatment arms were well

Clinical safety

More than 500 patients had received ataluren in clinical trials at the time of approval, including more than 200 in the target indication. Most of the nmDMD treated patients had been exposed to ataluren for 48 weeks or longer in completed studies.

The safety profile of ataluren observed in the pivotal trial 007 was overall comparable to that of placebo. The adverse events that were reported in ≥5% of patients in any treatment arm are summarised in Table 7. The most common adverse events included

Benefit-risk assessment

The choice of the primary endpoint, the mean change in 6MWD from baseline to week 48, was considered appropriate. Despite some limitations, the 6-minute walk test is considered to be a clinically meaningful and reliable outcome measure in boys with declining ambulation [6]. A 30 m change in the 6MWD is generally accepted as a clinically relevant effect, since it is correlated with meaningful patient reported outcome changes, and is predictive of disease progression and future loss of ambulation

Acknowledgements

The scientific assessment as summarised in this report is based on the marketing authorisation application submitted by the applicant company and on important contributions from, among others, the rapporteur and co-rapporteur assessment teams, CHMP members and additional experts.

First page preview

Click to open first page preview

View PDF

References (16)

BushbyK. et al.
Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management
Lancet Neurol
(2010)
BushbyK. et al.
Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care
Lancet Neurol
(2010)
EmeryA.E.
The muscular dystrophies
Lancet
(2002)
KeremE. et al.
Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial
Lancet Respir Med
(2014)
GoemansN. et al.
Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids
Neuromuscul Disord
(2013)
Orphanet
Prevalence of rare diseases: bibliographic data
May 2014 - n°1
(2014)
McDonaldC.M. et al.
The 6-minute walk test and other clinical endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study
Muscle Nerve
(2013)
HenricsonE.K. et al.
The 6-minute walk test and person-reported outcomes in boys with duchenne muscular dystrophy and typically developing controls: longitudinal comparisons and clinically-meaningful changes over one year
PLoS Curr
(2013)

There are more references available in the full text version of this article.

Cited by (129)

Development of a new instrument to evaluate gait characteristics of individuals with Duchenne Muscular Dystrophy: Gait Assessment Scale for Duchenne Muscular Dystrophy, and its validity and reliability
2023, Early Human Development
Patients with Duchenne Muscular Dystrophy (DMD) have gait disorders. Therefore, specific gait assessment tools are needed.
The aim of this study was to develop a gait assessment instrument for DMD patients (DMD-GAS), and investigate its validity and reliability.
The scale was developed considering the expert opinions which included 10 physiotherapists who had experience in the management of patients with DMD, and the Content Validity Index (CVI) was calculated. The final version of the DMD-GAS that was agreed upon the experts consisted of 10 items, and each item scored between 0 and 2. The intra-rater reliability was established by the video analysis of children with a 1-month interval and inter-rater reliability was determined by the scores of 3 physiotherapists.
The study included 56 patients with DMD.
The criterion validity was determined by investigating the relationship between the total score of the DMD-GAS and Motor Function Measure (MFM), 6 Minute Walk Test (6MWT), and the data obtained from GAITRite.
The CVI of the DMD-GAS was 0.90 (p < 0.05). The construct validity and internal consistency of the DMD-GAS were excellent as well as the intra- and inter-rater reliability (>0.90). Moderate-to-very strong correlations were found between the total score of the DMD-GAS and the MFM-total score (r = 0.78), 6MWT (r = 0.71), gait speed (r = 0.50), stride length (r = 0.56), and base of support (r = −0.70) (p < 0.01).
The results indicated that DMD-GAS was a reliable and valid instrument to determine gait characteristics of the patients with DMD in clinical settings.
NCT05244395.
Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial
2023, The Lancet Neurology
Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: –27·7 [41·4] m; placebo: –30·3 [60·5] m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.
Inherited myopathies in the Middle East and North Africa
2022, Gene Reports
Myopathies are genetically inherited muscle degenerative disorders that mainly cause muscle weakness and a more or less marked muscle wasting (atrophy), although rare but numerous and in different forms. They are characterized by allelic, genetic, and clinical heterogeneity. Due to the high rate of consanguinity in the Middle East North Africa region, hereditary diseases are widespread and diverse, mainly linked with recessive transmission. To date, there is no effective cure for these neuromuscular diseases probably due to the under-diagnosis which makes any related information inaccessible, such as prevalence and diagnostic resources, which leads to poor prognosis. A state-of-the-art of these myopathies is highly recommended guiding clinical diagnosis, improving patient management, and maintaining the quality of life and optimal longevity of patients. For this, definitive genetic diagnosis is essential for the optimal exploration of these genetically heterogeneous diseases. Here, we reviewed hereditary gene alterations and the principals inherited myopathies in a recessive and X-linked pattern reported in the Middle East and North Africa region.
Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities
2022, Progress in Retinal and Eye Research
Inherited retinal diseases (IRDs) are a clinically complex and heterogenous group of visual impairment phenotypes caused by pathogenic variants in at least 277 nuclear and mitochondrial genes, affecting different retinal regions, and depleting the vision of affected individuals. Genes that cause IRDs when mutated are unique by possessing differing genotype-phenotype correlations, varying inheritance patterns, hypomorphic alleles, and modifier genes thus complicating genetic interpretation. Next-generation sequencing has greatly advanced the identification of novel IRD-related genes and pathogenic variants in the last decade. For this review, we performed an in-depth literature search which allowed for compilation of the Global Retinal Inherited Disease (GRID) dataset containing 4,798 discrete variants and 17,299 alleles published in 31 papers, showing a wide range of frequencies and complexities among the 194 genes reported in GRID, with 65% of pathogenic variants being unique to a single individual. A better understanding of IRD-related gene distribution, gene complexity, and variant types allow for improved genetic testing and therapies. Current genetic therapeutic methods are also quite diverse and rely on variant identification, and range from whole gene replacement to single nucleotide editing at the DNA or RNA levels. IRDs and their suitable therapies thus require a range of effective disease modelling in human cells, granting insight into disease mechanisms and testing of possible treatments. This review summarizes genetic and therapeutic modalities of IRDs, provides new analyses of IRD-related genes (GRID and complexity scores), and provides information to match genetic-based therapies such as gene-specific and variant-specific therapies to the appropriate individuals.
Translation termination codons in protein synthesis and disease
2022, Advances in Protein Chemistry and Structural Biology
Fidelity of protein synthesis, a process shaped by several mechanisms involving specialized ribosome regions and external factors, ensures the precise reading of sense as well as stop codons (UGA, UAG, UAA), which are usually localized at the 3′ of mRNA and drive the release of the polypeptide chain.
However, either natural (NTCs) or premature (PTCs) termination codons, the latter arising from nucleotide changes, can undergo a recoding process named ribosome or translational readthrough, which insert specific amino acids (NTCs) or subset(s) depending on the stop codon type (PTCs). This process is particularly relevant for nonsense mutations, a relatively frequent cause of genetic disorders, which impair gene expression at different levels by potentially leading to mRNA degradation and/or synthesis of truncated proteins. As a matter of fact, many efforts have been made to develop efficient and safe readthrough-inducing compounds, which have been challenged in several models of human disease to provide with a therapy. In this view, the dissection of the molecular determinants shaping the outcome of readthrough, namely nucleotide and protein contexts as well as their interplay and impact on protein structure/function, is crucial to identify responsive nonsense mutations resulting in functional full-length proteins. The interpretation of experimental and mechanistic findings is also important to define a possibly clear picture of potential readthrough-favorable features useful to achieve rescue profiles compatible with therapeutic thresholds typical of each targeted disorder, which is of primary importance for the potential translatability of readthrough into a personalized and mutation-specific, and thus patient-oriented, therapeutic strategy.
Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy
2024, CPT: Pharmacometrics and Systems Pharmacology

View all citing articles on Scopus

: Disclaimer: This publication is a summary of the European Public Assessment Report and the summary of product characteristics available on the EMA website, focusing on the main issues discussed during the scientific evaluation. Healthcare professionals and interested readers are referred to the EMA website for up-to-date information on this marketing authorisation (http://www.ema.europa.eu). Serge Bakchine is the Chair of the EMA Scientific Advisory Group on Neurology and did not participate in the CHMP review of ataluren. The authors remain solely responsible for the opinions expressed in this publication.

View full text

Special reportEuropean Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene

Highlights

Introduction

Section snippets

Non-clinical aspects

Clinical pharmacology

Clinical efficacy

Clinical safety

Benefit-risk assessment

Acknowledgements

First page preview

Lancet Neurol

Lancet Neurol

Lancet

Lancet Respir Med

Neuromuscul Disord

Prevalence of rare diseases: bibliographic data

May 2014 - n°1

The 6-minute walk test and other clinical endpoints in Duchenne muscular dystrophy: reliability, concurrent validity, and minimal clinically important differences from a multicenter study

Muscle Nerve

The 6-minute walk test and person-reported outcomes in boys with duchenne muscular dystrophy and typically developing controls: longitudinal comparisons and clinically-meaningful changes over one year

PLoS Curr

Special report
European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene