Ataluren 125mg granules for oral suspension sachets

Introduction and Objective: Rett syndrome (RTT) is a genetic neurodevelopmental disorder that predominantly affects the female. The disease develops after 6 months of age causing abnormalities in the child's development. The aim of this article is to bring together the latest information and clinical, genetic and therapeutic perspectives on RTT. Review Methods: The review was based on publicly available PubMed and Google Scholar, Web of Science and Scopus databases from 2019 to 2024 using the following phrases: rett syndrome, rett syndrome treatment, rett syndrome rehabilitation, MECP2. Publications were analyzed using a non-systematic review method to create a brief synthesis of the available information. Brief Description of the State of Knowledge: Rett syndrome is characterised by a loss-of-function mutation in the MECP2 gene, which is located on the long arm of the X chromosome. The diagnosis is confirmed by clinical criteria such as complete loss of acquired targeted hand skills, spoken language, gait abnormalities and confirmation of the mutation in the MECP2 gene. Treatment focuses on multidisciplinary management of the symptoms associated with the disease and an individualised rehabilitation programme. Recent studies show positive effects of trofinetide treatment, and gene therapy, genome editing and ataluren promise to be a promising treatment for RTT. Summary: The authors highlight the need for development of early diagnosis of RTT in infants, rehabilitation focused on family-centred care (FCC) and the need for further research towards innovative treatments for Rett Syndrome.

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) for the treatment of nonsense mutation Duchenne muscular dystrophy. The marketing authorization has been recently withdrawn by the European Commission following a recommendation from the Committee for Medicinal Products for Human Use of the European Medicines Agency. This negative recommendation was based on the fact that three randomized controlled trials of ataluren in nonsense mutation Duchenne muscular dystrophy (007, 020, and 041) have failed to show statistically significant differencs in favor of the treatment in the selected primary outcomes for each individual study, i.e., 6-min walk distance, in the intent-to-treat population for 007 and 020 and in a subgroup for 041. However, observed differences always favored treatment, and several clinically meaningful secondary outcomes were positive and statistically significant across studies. Importantly, the largest and longest phase III study (041) showed a statistically significant effect in favor of ataluren in the wider intent-to-treat population. Furthermore, a long-term registry of "real-world" ataluren treatment data (Strategic Targeting of Registries and Database of Excellence, STRIDE), in addition to confirming a reassuring safety profile, suggested a prolonged maintenance of ambulatory, upper limb, and respiratory function. We deem that a withdrawal of ataluren from the European market would harm not only patients with nonsense mutation Duchenne muscular dystrophy, but the whole neuromuscular field, in which clinical trials are challenging because of the heterogenous complex slow-progressing nature of the disorders.

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Aim: To report the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) from the phase III, 72-week, placebo-controlled period of Study 041. Materials & methods: Inclusion criteria: boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen for ≥12 months, and baseline 6-minute walk distance (6MWD) ≥150 m. Randomization: 1:1, ataluren (40 mg/kg/day):placebo. Primary end point: slope of 6MWD change (average rate of change). Secondary end points: changes in 6MWD, time to 10% persistent worsening in 6MWD, North Star Ambulatory Assessment score, timed function tests and safety. Study populations: intention-to-treat; patients aged ≥7 to ≤16 years with baseline 6MWD ≥300 m and stand from supine ≥5 s; patients with baseline 6MWD 300–400 m. Results: In the intention-to-treat population (n = 359), over 72 weeks, ataluren reduced the rate of 6MWD decline by 21% (p = 0.0248), reduced the average 6MWD change (p = 0.0248), delayed time to 10% persistent worsening in 6MWD (p = 0.0078), and reduced North Star Ambulatory Assessment total score decline (p = 0.0235), change in 10 m walk/run time (p = 0.0422) and change in time to climb four stairs (p = 0.0293) versus placebo. In the 6MWD 300–400 m subgroup (n = 169), ataluren reduced the rate of 6MWD decline by 30% (p = 0.0310) versus placebo. Ataluren treatment benefits were seen in secondary end points in this subgroup, except for change in time to descend four stairs. In the 6MWD ≥300 m and time to stand from supine ≥5s subgroup (n = 185), there was a 9% slower rate of 6MWD decline for ataluren versus placebo over 72 weeks (p = 0.3626). Ataluren reduced change in time to climb four stairs (p = 0.0179) versus placebo in this subgroup; no treatment benefits were seen for other secondary end points. Ataluren was well tolerated (serious adverse events: ataluren, 7.1%; placebo, 6.8%); no deaths occurred. Conclusion: Long-term ataluren treatment has a favorable benefit–risk profile, slowing motor function decline in the largest phase III nmDMD study to date.

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Case Presentation: AGRB, male, 9 years old, 52kg, previously healthy, born and raised in Pirambu, Bebedouro village, Sergipe.Adtted on 10/09/2022 to the pediatrics sector of the Sergipe Emergency hospital, reporting headache, fever and vomiting for 7 days, with subsequent evolution with pain in the posterior region of the right thigh, in addition to low back pain.Physical examination showed normal breathing and heart rate.Decreased strength in lower limbs, being worse on the left side.No patellar reflex and left Achilles.Normal right reflexes.Strength preserved in upper limbs.Presence of Babinski's sign on the right.No signs of trunk involvement.During the medical evaluation, a magnetic resonance imaging (MRI) of the dorsal column was requested, with findings of multiple foci with heterogeneous gadolinium uptake affecting the central portion and anterior funiculi of the spinal cord from D8 to the medullary cone, with T2 hypersignal in the spinal cord parenchyma adjacent and extending to the D4 level, with mass effect, with partial erasure of the CSF column in correspondence.The vertebral bodies, joints and musculature had normal contours and structures.It was concluded, then, that the examination showed an inflammatory-type lesion with a focus on schistosomiasis with involvement of the spinal cord associated with epidemiological data and clinical suspicion.Collected CSF that showed total proteins in the amount of 128.6 mg/dL, 597 cells/ mm3 (PNM: 14% and LMN: 86%) with positive IFI for schistosomiasis.Treatment with ivermectin 6 mg was started, administering 2 pills every 24 hours for 2 days.After ivermectin, pulse therapy was started with 1g/day of methylprednisolone for 5 days.After pulse therapy, a dose of praziquantel was started and prolonged corticosteroid therapy was maintained with prednisone 1 mg/kg/day for 6 months.Discussion: Schistosomiasis is considered endemic in 19 districts, one of which is the state of Sergipe, and the S. mansoni species, in addition to being the most prevalent, is also the one most associated with myeloradiculopathy.Diagnosis is based on epidemiology, neurological symptoms, microscopic and serological techniques, and magnetic resonance imaging (MRI) evaluation.In addition, it is necessary to rule out other possible diagnoses.Symptomatology corroborates to determine the degree of involvement of the lesion.Final Comments: Schistosomiasis is an important and endemic parasitic.

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Abstract Genetic ailments such as Duchenne muscular dystrophy (DMD) and cystic fibrosis (CF) arise due to nonsense mutations. A nonsense mutation occurs when a point mutation changes a sense codon that codes for an amino acid to a stop codon, which leads to premature termination of mRNA translation. Because of this, a truncated protein product is produced; therefore, it is called a premature termination codon (PTC), and several diseases, such as CF, DMD, and congenital myopathy, arise due to the production of a truncated protein. The bioactive compound ataluren, formerly known as PTC124, is believed to modulate the translation machinery and enhance the synthesis of fully functioning, full‐length protein by permitting the readthrough of PTCs during mRNA translation. Ataluren, known by the brand name Tranlsarna, is currently authorized to treat nonsense mutations in DMD and other diseases in the European Union and other countries. In this work, an earnest effort has been made to bring about significant breakthroughs and elucidate its mechanisms of action, and an up‐to‐date synthetic review has been carried out.

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OBJECTIVE: Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). METHODS: Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. RESULTS: As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan-Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. CONCLUSION: Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.

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Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation.

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BACKGROUND: This paper details the results of an evaluation of the level of consensus amongst clinicians on the use of ataluren in both ambulatory and non-ambulatory patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). The consensus was derived using a modified Delphi methodology that involved an exploration phase and then an evaluation phase. METHODS: The exploration phase involved 90-minute virtual 1:1 interviews of 12 paediatric neurologists who cared for 30-120 DMD patients each and had patient contact every one or two weeks. The respondents managed one to ten nmDMD patients taking ataluren. The Discussion Guide for the interviews can be viewed as Appendix A. Following the exploration phase interviews, the interview transcripts were analysed by an independent party to identify common themes, views and opinions and developed 43 draft statements that the Steering Group (authors) reviewed, refined and endorsed a final list of 42 statements. Details of the recruitment of participants for the exploration and evaluation phases can be found under the Methods section. RESULTS: A consensus was agreed (> 66% of respondents agreeing) for 41 of the 42 statements using results from a consensus survey of healthcare professionals (n = 20) experienced in the treatment of nmDMD. CONCLUSIONS: The statements with a high consensus suggest that treatment with ataluren should be initiated as soon as possible to delay disease progression and allow patients to remain ambulatory for as long as possible. Ataluren is indicated for the treatment of Duchenne muscular dystrophy that results from a nonsense mutation in the dystrophin gene, in ambulatory patients aged 2 years and older (see Summary of Product Characteristics for each country).

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