Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, ...type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full‐length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed.
What this paper adds
Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy.
Identifies open questions in populations of patients where proof of efficacy is available.
Resumen
Tratamiento Nusinersen de la atrofia muscular espinal: conocimiento actual y ausencia de conocimiento existente
La atrofia muscular espinal (SMA sigla en inglés) es un trastorno recesivo causado por una mutación en el gen de la neurona motora de supervivencia 1 (SMN1); afecta a 1 de cada 11.000 recién nacidos. La forma más grave y más común, la AME tipo 1, se asocia con mortalidad temprana en la mayoría de los casos y discapacidad grave en los sobrevivientes. Nusinersen, un oligonucleótido anti‐sentido, promueve la producción de proteína de longitud completa a partir del pseudogén SMN2. El tratamiento con Nusinersen prolonga la sobrevida de los pacientes con SMA tipo 1 y permite la adquisición de un hito motor. Los pacientes con SMA tipo 2 también muestran progreso en diferentes escalas motoras después del tratamiento Nusinersen.
Nusinersen fue aprobado recientemente por la Agencia Europea de Medicamentos y la Administración de Alimentos y Medicamentos de los EE. UU; ahora se reembolsa en varios países europeos y en los EE. UU. En Australia, la transición del programa de acceso ampliado a la disponibilidad comercial llegará pronto. En Nueva Zelanda, se abre un programa de acceso ampliado, y en Canadá se está negociando el precio para el tratamiento. En esta revisión ejemplificamos el beneficio clínico de Nusinersen en subgrupos de pacientes con SMA. Nusinersen representa el primer fármaco aprobado marcado eficaz en AME tipo 1 y tipo 2. Diferentes vacíos de conocimiento, como los resultados en pacientes mayores, en pacientes con ventilación permanente, en pacientes con formas neonatales o en pacientes después de la fusión espinal, aún deben abordarse.
Resumo
Tratamento com Nusinersen da atrofia muscular espinhal: conhecimento atual e lacunas existentes
A atrofia muscular espinhal (AME) é uma desordem recessiva causada por uma mutação no gene do neurônio motor 1 (SMN1); afeta 1 em 11.000 recém‐nascidos. A forma mais severa e mais comum, a AME tipo 1, é associada com mortalidade precoce na maioria dos casos, e incapacidade severa nos sobreviventses. Nusinersen, um oligonucleotídeo antisense, promove produção da proteína completa do pseudogene SMN2. O tratamento com Nusinersen prolonga a sobrevida de pacientes com AME tipo 1 e permite aquisição de marcos motores. Pacientes com AME tipo 2 também mostram progresso em diferentes escalas motoras com o tratamento com Nusinersen. O Nusinersen foi recentemente aprovado pela Agência Européia de Medicamentos e a Administração de Alimentos e Medicamentos dos Estados Unidos; ele agora é reembolsado em vários países europeus e nos EUA. Na Austrália, a transição do programa de acesso expandido para a disponibilidade commercial está prestes a ocorrer. Na Nova Zelândia, um programa de acesso expandido está aberto, e no Canadá a negociação de preços para o tratamento está em andamento. Nesta revisão, exemplificamos o benefício clínico do nusinersen em subgrupos de pacientes com AME. O Nusinesen representa o primeiro medicamento eficaz aprovado para AME tipos 1 e 2. Diferentes lacunas do conhecimento, como os resultados em pacientes mais velhos, em pacientes sob ventilação permanente, em pacientes com formas neonatais, ou em pacientes após fusão espinhal, ainda precisam ser abordadas.
What this paper adds
Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy.
Identifies open questions in populations of patients where proof of efficacy is available.
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Introduction: Spinal muscular atrophy (SMA) is one of the most common inherited neuromuscular disorders. It causes progressive muscle weakness and results in significant disability. Until recently, ...there were no drugs available for the treatment of SMA. Several phase 1-3 studies, including three double-blind randomized placebo-controlled studies have demonstrated the efficacy of disease-modifying approaches including gene replacement therapy, antisense oligonucleotides, and splicing modifiers.
Areas covered: This article covers the publically available data on therapeutic strategies that address the underlying cause of SMA and clinical data available on approved treatments and drugs in the pipeline.
Expert opinion: The newer therapeutic options in SMA have a good safety profile and deliver a therapeutic benefit in most patients. It is essential that the recommended standards of care are delivered along with the drugs for the best outcomes. No biomarkers to distinguish responders from non-responders are available; it is important that biomarkers be identified. Early treatment is essential for the maximum efficacy of the newly available treatments.
Spinal muscular atrophy (SMA) is a rare and devastating condition for which new disease-modifying treatments have recently been approved. Given the increasing importance of economic considerations in ...healthcare decision-making, this review summarizes the studies assessing the cost of SMA and economic evaluations of treatments. A systematic review of the literature in PubMed and Scopus up to 15 September 2020 was conducted according to PRISMA guidelines.
Nine studies reporting the annual cost of care of patients with SMA and six evaluations of the cost-effectiveness of SMA treatments were identified. The average annual cost of SMA1, the most frequent and severe form in which symptoms appear before the age of 6 months were similar according to the different studies, ranged from $75,047 to $196,429 per year. The yearly costs for the forms of the later-onset form, called SMA2, SMA3, and SMA4, which were usually pooled in estimates of healthcare costs, were more variable, ranging from $27,157 to $82,474. The evaluations of cost-effectiveness of treatment compared nusinersen treatment against standard of care (n = 3), two treatments (nusinersen and onasemnogene abeparvovec) against each other and no drug treatment (n = 1), nusinersen versus onasemnogene abeparvovec (n = 1), and standard of care versus nusinersen with and without newborn screening (n = 1). The incremental cost-effectiveness ratio (ICER) of nusinersen compared to standard of care in SMA1 ranged from $210,095 to $1,150,455 per quality-adjusted life years (QALY) gained and that for onasemnogene abeparvovec ranged from $32,464 to $251,403. For pre-symptomatic patients, the ICER value ranged from $206,409 to $735,519. The ICERs for later-onset forms of SMA (2, 3 and 4) were more diverse ranging from $275,943 to $8,438,049.
This review confirms the substantial cost burden of standard of care for SMA patients and the high cost-effectiveness ratios of the approved drugs at the current price when delivered in post-symptomatic patients. Since few studies have been conducted so far, there is a need for further prospective and independent economic studies in pre- and post-symptomatic patients.
Developing drugs for rare diseases is challenging, and the precision and objectivity of outcome measures is critical to this process. In recent years, a number of technologies have increasingly been ...used for remote monitoring of patient health. We report a systematic literature review that aims to summarize the current state of progress with regard to the use of digital outcome measures for real-life motor function assessment of patients with rare neurological diseases. Our search of published literature identified 3826 records, of which 139 were included across 27 different diseases. This review shows that use of digital outcome measures for motor function outside a clinical setting is feasible and employed in a broad range of diseases, although we found few outcome measures that have been robustly validated and adopted as endpoints in clinical trials. Future research should focus on validation of devices, variables, and algorithms to allow for regulatory qualification and widespread adoption.
Objective
This study was undertaken to determine whether a low residual quantity of dystrophin protein is associated with delayed clinical milestones in patients with DMD mutations.
Methods
We ...performed a retrospective multicentric cohort study by using molecular and clinical data from patients with DMD mutations registered in the Universal Mutation Database–DMD France database. Patients with intronic, splice site, or nonsense DMD mutations, with available muscle biopsy Western blot data, were included irrespective of whether they presented with severe Duchenne muscular dystrophy (DMD) or milder Becker muscular dystrophy (BMD). Patients were separated into 3 groups based on dystrophin protein levels. Clinical outcomes were ages at appearance of first symptoms; loss of ambulation; fall in vital capacity and left ventricular ejection fraction; interventions such as spinal fusion, tracheostomy, and noninvasive ventilation; and death.
Results
Of 3,880 patients with DMD mutations, 90 with mutations of interest were included. Forty‐two patients expressed no dystrophin (group A), and 31 of 42 (74%) developed DMD. Thirty‐four patients had dystrophin quantities < 5% (group B), and 21 of 34 (61%) developed BMD. Fourteen patients had dystrophin quantities ≥ 5% (group C), and all but 4 who lost ambulation beyond 24 years of age were ambulant. Dystrophin quantities of <5%, as low as <0.5%, were associated with milder phenotype for most of the evaluated clinical outcomes, including age at loss of ambulation (p < 0.001).
Interpretation
Very low residual dystrophin protein quantity can cause a shift in disease phenotype from DMD toward BMD. ANN NEUROL 2021;89:280–292
Human
encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to ...mutations in
is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant
-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the
gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future.
Muscular dystrophies are characterized by weakness and wasting of skeletal muscle tissues. Several drugs targeting the myostatin pathway have been used in clinical trials to increase muscle mass and ...function but most showed limited efficacy. Here we show that the expression of components of the myostatin signaling pathway is downregulated in muscle wasting or atrophying diseases, with a decrease of myostatin and activin receptor, and an increase of the myostatin antagonist, follistatin. We also provide in vivo evidence in the congenital myotubular myopathy mouse model (knock-out for the myotubularin coding gene Mtm1) that a down-regulated myostatin pathway can be reactivated by correcting the underlying gene defect. Our data may explain the poor clinical efficacy of anti-myostatin approaches in several of the clinical studies and the apparent contradictory results in mice regarding the efficacy of anti-myostatin approaches and may inform patient selection and stratification for future trials.
In spinal muscular atrophy, clinical trial results indicated that disease-modifying treatments are highly effective when given prior to symptom onset, which has prompted newborn screening programs in ...growing number of countries. However, prognosis of those patients cannot be inferred from clinical trials conducted in presymptomatic individuals, as in some cases disease presents very early.
we conducted a systematic review of articles published up to January 2023.
Among 35 patients with three
copies treated before 42 days of age and followed-up for at least 18 months, all but one achieved autonomous ambulation. Of 41 patients with two
copies, who were non-symptomatic at treatment initiation, all achieved a sitting position independently and 31 were able to walk. Of 16 patients with two
copies followed-up for at least 18 months who presented with symptoms at treatment onset, 3 achieved the walking milestone and all but one were able to sit without support.
evaluation of data from 18 publications indicates that the results of early treatment depend on the number of
copies and the initial neurological status of the patient.
Furthermore, the magnitude and duration of effect of gene therapy, and the optimal age at which to deliver it, are uncertain. ...with a current price of about US$3 200 000, this genetic treatment is ...unlikely to be equally available worldwide. ...Henzi and colleagues5 report these negative results. The good news is that the neuromuscular field has developed several strategies that could make early-phase trials more robust: the use of matched external controls,8 an understanding of independent factors that drive disease evolution,9 the use of Bayesian design,9 and digital outcome measures through wearable technology.10 The negative result for tamoxifen in the phase 3 trial should not discourage the community from continuing the evaluation of inexpensive repositioned drugs that have the potential to treat individuals worldwide.
Duchenne muscular dystrophy (DMD) is an X-linked condition caused by a deficiency of functional dystrophin protein. Patients experience progressive muscle weakness, cardiomyopathy and have a ...decreased life expectancy. Standards of care, including treatment with steroids, and multidisciplinary approaches have extended the life expectancy and improved the quality of life of patients. In the last 30 years, several compounds have been assessed in preclinical and clinical studies for their ability to restore functional dystrophin levels or to modify pathways involved in DMD pathophysiology. However, there is still an unmet need with regards to a disease-modifying treatment for DMD and the attrition rate between early-phase and late-phase clinical development remains high. Currently, there are 40 compounds in clinical development for DMD, including gene therapy and antisense oligonucleotides for exon skipping. Only five of them have received conditional approval in one jurisdiction subject to further proof of efficacy. In this review, we present data of another 16 compounds that failed to complete clinical development, despite positive results in early phases of development in some cases. We examine the reasons for the high attrition rate and we suggest solutions to avoid similar mistakes in the future.
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