Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.
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ABSTRACT: Introduction
The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies.Methods
Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study.Results
Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level.Discussion
Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.
SUBMITTER: Acsadi G
PROVIDER: S-EPMC8248061 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNusinersen is an intrathecally administered antisense oligonucleotide (ASO) that improves motor function in patients with spinal muscular atrophy (SMA). In addition to efficacy, the safety of a therapy is the decisive factor for the success of the treatment. For some ASOs, various organ toxicities have been described, such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities. However, systematic data on laboratory parameters under treatment with nusinersen are mainly available from studies in infants and children. Therefore, our aim was to assess the safety of nusinersen therapy in adult SMA patients.MethodsLaboratory data from 404 nusinersen injections performed in 50 adult patients with SMA type 2 and type 3 were retrospectively analyzed.ResultsThe total observation period was 76.9 patient-years, and patients received up to 12 injections. Our data provides no new safety concerns. In cerebrospinal fluid (CSF), the mean white blood cell count and lactate remained stable over time. Total CSF protein increased by 2.9 mg/dL. No change in mean platelet count was observed under therapy. Only one patient showed sporadic mild thrombocytopenia. Coagulation parameters and inflammatory markers were stable. The mean creatinine level decreased by 0.09 mg/dL. Analysis of mean liver enzyme levels revealed no relevant changes during treatment.ConclusionOur data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term "real-world" conditions. In particular, we found no evidence of clinically relevant platelet declines, coagulopathies, or renal or hepatic organ toxicities, which are common concerns with the use of ASOs.
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Project description:Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular degenerative disease characterized by loss of spinal cord motor neurons leading to progressive muscle wasting. The most common pathology results from a homozygous disruption in the survival motor neuron 1 (SMN1) gene on chromosome 5q13 via deletion, conversion, or mutation. SMN2 is a near duplicate of SMN1 that can produce full-length SMN mRNA transcripts, but its overall production capability of these mRNA transcripts is lower than that seen in SMN1. This leads to lower levels of functional SMN protein within motor neurons. The FDA approved nusinersen in December 2016 to treat SMA associated with SMN1 gene mutation. It is administered directly to the central nervous system by intrathecal injection. An antisense oligonucleotide (ASO) drug, nusinersen, provides an upcoming and promising treatment option for SMA and represents a novel pharmacological approach with a mechanism of action relevant for other neurodegenerative disorders. Nusinersen begins with four initial loading doses that are followed by three maintenance doses per year. Three major studies (CHERISH, ENDEAR, and NURTURE) have shown to improve motor function in early and late-onset individuals and reduce the chances of ventilator requirements in pre-symptomatic infants. Studies investigating the timing of drug delivery in mouse models of SMA report the best outcomes when drugs are delivered early before any significant motor function is lost. Nusinersen is a novel therapeutic approach with consistent results in all three studies and is proof of the novel concept for treating SMA and other neurodegenerative disorders in the future.
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Project description:ObjectiveWe performed a systematic review and meta-analysis of the efficacy and safety of nusinersen and risdiplam in the treatment of spinal muscular disease (SMA).MethodsWe screened the literature published in Pubmed, Web of Science, Embase, and Cochrane before July 2023 to conduct randomized controlled trials to test the treatment of SMA patients with nusinersen and risdiplam. The data were analyzed using Review Manager 5.4 software and Stata version 15.0 software.ResultsA total of six randomized controlled trials were included, involving 728 SMA patients, to synthesize evidence. It is reported that nusinersen treatment was beneficial for increasing the score of the Hammersmith Functional Motor Scale-Expanded (HFMSE) (WMD: 4.90; 95% CI: 3.17, 6.63; p < 0.00001), Revised Upper Limb Module (RULM) (WMD: 3.70; 95% CI: 3.30, 4.10; p < 0.00001), and Hammersmith Infant Neurological Evaluation Section 2 (HINE-2) (WMD: 5.21; 95% CI: 4.83, 5.60; p < 0.00001). In addition, the risdiplam treatment group also showed statistically significant improvements in the HFMSE score (WMD:0.87; 95% CI: 0.05, 1.68; p = 0.04), the 32-item Motor Function Measure (MFM32) (WMD:1.48; 95% CI: 0.58, 2.38; p = 0.001), and (WMD: 1.29; 95% CI: 0.57, 2.01; p = 0.0005). Nusinersen and risdiplam did not cause a statistically significant increase in the RULM score for adverse events (OR: 0.93; 95% CI: 0.51, 1.7; p = 0.82) and for severe adverse events (OR: 0.77; 95% CI: 0.47, 1.27; p = 0.31).ConclusionOur analysis found that nusinersen and risdiplam treatment showed clinically meaningful improvement in motor function and a similar incidence rate of adverse events compared with the placebo. Further research should be carried out to provide a direct comparison between the two drugs in terms of safety and efficacy.
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| S-EPMC8248060 | biostudies-literature
Project description:BackgroundStudies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen.MethodsIn this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed.ResultsCHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy.ConclusionsCHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.
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