Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy.
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ABSTRACT:
SUBMITTER: Pane M
PROVIDER: S-EPMC8935309 | biostudies-literature | 2022 Mar
REPOSITORIES: biostudies-literature
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Nusinersen efficacy data for 24-month in type 2 and 3 spinal muscular atrophy.
Pane Marika M Coratti Giorgia G Pera Maria Carmela MC Sansone Valeria A VA Messina Sonia S d'Amico Adele A Bruno Claudio C Salmin Francesca F Albamonte Emilio E De Sanctis Roberto R Sframeli Maria M Di Bella Vincenzo V Morando Simone S Palermo Concetta C Frongia Anna Lia AL Antonaci Laura L Capasso Anna A Catteruccia Michela M Longo Antonella A Ricci Martina M Cutrona Costanza C Pirola Alice A Bravetti Chiara C Pedemonte Marina M Brolatti Noemi N Bertini Enrico E Mercuri Eugenio E
Annals of clinical and translational neurology 20220215 3
The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Mo ...[more]
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Project description:IntroductionThe 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.MethodsParticipants 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.ResultsPart 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.DiscussionNusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.
| S-EPMC8248061 | biostudies-literature
Project description:ObjectiveWe report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.MethodsPatients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6-Minute Walk Test (6MWT) with a mean follow-up of 1.83 years after nusinersen treatment.ResultsOver 75% of the 144 patients had a 12-month follow-up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12-month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.InterpretationOur results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.
| S-EPMC8351459 | biostudies-literature
Project description:AimTo assess the evolution of bulbar function in nusinersen-treated spinal muscular atrophy type 1 (SMA1).MethodThis single-centre retrospective study identified 24 patients (14 females and 10 males) with SMA1, treated with nusinersen between 2017 and 2020. We adapted and validated the Paediatric Functional Oral Intake Scale (p-FOIS), which is an outcome measure to assess bulbar function. Analysis considered SMA1 subtype, nutritional support, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and p-FOIS scores at initiation of nusinersen treatment (baseline) and at 6, 12, and 24 months after initiation.ResultsThe median age at baseline was 11 months (range 1 month-7 years 6 months). Median age at initiation of tube feeding was 8 months (range 0-2 years 2 months). Fourteen patients were tube fed at baseline. The median p-FOIS score was 3 at baseline and 2 at 12 and 24 months. Four patients, all with type 1c SMA, remained orally fed at 24 months. Median CHOP INTEND scores increased from 32 at baseline to 42 at 12 and 24 months.InterpretationImpaired bulbar function persisted as a significant complication in most nusinersen-treated patients with SMA1, in contrast to the improvement in motor abilities demonstrated in the majority. p-FOIS allows for tracking of bulbar function progression and treatment response. Larger, prospective studies investigating the longer-term impacts of nusinersen on bulbar function are warranted.
| S-EPMC9306995 | biostudies-literature
Project description:BackgroundNeuroinflammation contributes to the onset and progression of neurodegenerative diseases, but has not been specifically investigated in patients affected by severe and milder forms of spinal muscular atrophy (SMA).MethodsIn this two-center retrospective study, we investigated signatures of neuroinflammation in forty-eight pediatric male and female SMA1 (n = 18), male and female SMA2 (n = 19), and female SMA3 (n = 11) patients, as well as in a limited number of male and female non-neurological control subjects (n = 4). We employed a Bio-Plex multiplex system based on xMAP technology and performed targeted quantitative analysis of a wide range of pro- and anti-inflammatory cytokines (chemokines, interferons, interleukins, lymphokines and tumor necrosis factors) and neurotrophic factors in the cerebrospinal fluid (CSF) of the study cohort before and after Nusinersen treatment at loading and maintenance stages.ResultsWe find a significant increase in the levels of several pro-inflammatory cytokines (IL-6, IFN-γ, TNF-α, IL-2, IL-8, IL-12, IL-17, MIP-1α, MCP-1, and Eotaxin) and neurotrophic factors (PDGF-BB and VEGF) in the CSF of SMA1 patients relative to SMA2 and SMA3 individuals, who display levels in the range of controls. We also find that treatment with Nusinersen significantly reduces the CSF levels of some but not all of these neuroinflammatory molecules in SMA1 patients. Conversely, Nusinersen increases the CSF levels of proinflammatory G-CSF, IL-8, MCP-1, MIP-1α, and MIP-1β in SMA2 patients and decreases those of anti-inflammatory IL-1ra in SMA3 patients.ConclusionsThese findings highlight signatures of neuroinflammation that are specifically associated with severe SMA and the neuro-immunomodulatory effects of Nusinersen therapy.
| S-EPMC9932014 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.
| S-EPMC8122268 | biostudies-literature
Project description:BackgroundSpinal muscular atrophy (SMA) is a motor neuron disease caused by mutations in the SMN1 gene. Nusinersen, an antisense oligonucleotide, has been shown to improve motor function in SMA patients. However, concerns regarding its renal safety remain as previous studies have linked similar treatments to renal toxicity.ObjectiveThe aim of this study was to evaluate the effects of the nusinersen treatment on platelet counts and renal functions, specifically urine protein excretion, in SMA patients and to estimate safe urinary protein levels before administration of each intrathecal injection.MethodsThis retrospective study examined data from 33 patients with SMA to assess the effects of nusinersen on motor functions and laboratory parameters including platelet count, serum creatinine, urine protein, and urine creatinine. Measurements were taken at baseline andprior to each maintenance dose, after the completion of four initial loading doses. The baseline values were compared between SMA Type 1 and Type 2 patients, while the changes in these values over time were analyzed within each group.ResultsNo significant adverse effects on platelet counts or renal functions were observed. Urine creatinine and protein levels were significantly higher in SMA Type 2 patients compared to SMA Type 1 at baseline; these parameters remained stable in SMA Type 2 but increased significantly after the loading doses in SMA Type 1. Motor function improvements were observed in both groups, with the most significant gains in SMA Type 1 after the loading doses. Thus, improvement in motor functions was associated with increase in urine creatinine.ConclusionNusinersen treatment did not cause significant renal toxicity or affect platelet counts. Urine creatinine levels may serve as a potential biomarker for assessing treatment response in SMA Type 1.
| S-EPMC11743982 | biostudies-literature
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.
| S-EPMC8567776 | biostudies-literature
Project description:BackgroundNusinersen was the first approved disease-modifying therapy for all 5q-spinal muscular atrophy (SMA) patients regardless of age or disease severity. Its efficacy in adults has recently been demonstrated in a large cohort by motor outcome measures, which were only partially suitable to detect changes in very mildly or severely affected patients. Patient-reported outcome measures (PROs) have been suggested as a valuable addition. Here, we aimed to assess treatment satisfaction and investigate whether it may be a useful PRO to monitor SMA patients.MethodsWe enrolled 91 mainly adult 5q-SMA patients treated with nusinersen in a national, multicenter, cross-sectional observational study. 21 patients underwent longitudinal follow up. Patients' satisfaction with treatment in four dimensions (global, effectiveness, convenience, side effects) was assessed by the Treatment Satisfaction Questionnaire for Medication German version 1.4 (TSQM-1.4©) and related to clinical parameters, motor scores, and treatment duration.ResultsMore than 90% of SMA patients were consistently satisfied over a median treatment duration of 10 months. Highest mean scores were observed in the dimensions 'side effects,' 'global satisfaction,' and 'effectiveness' (93.5 ± 14.8 versus 73.1 ± 21.0 and 64.8 ± 20.6, respectively). Patients' satisfaction with the convenience of treatment was considerably lower (43.6 ± 20.2). Interestingly, satisfaction with the effectiveness was higher in ambulatory (p = 0.014) compared with non-ambulatory patients and directly correlated to motor outcome measures. Five non-ambulatory patients withdrew from therapy. All of them presented with a deterioration of motor outcome measures and reported dissatisfaction with treatment effectiveness and convenience.ConclusionMost patients were satisfied with nusinersen treatment effectiveness. Less severely affected patients indicated higher satisfaction. The TSQM-1.4© helped to identify therapy non-responders, who mainly addressed dissatisfaction with effectiveness and convenience. We suggest introducing the TSQM-1.4© as an additional PRO in SMA into clinical practice.
| S-EPMC7940734 | biostudies-literature
Project description:The antisense oligonucleotide nusinersen was the first drug treatment available for all types of 5q-spinal muscular atrophy (SMA). The dosing regime has been derived from pivotal clinical trials in infants and children. The efficacy of nusinersen in severely affected adult SMA patients is still questionable, as no placebo-controlled trials have been conducted. In the present study, we systematically examined wearing-off phenomena during nusinersen maintenance dosing using a patient-centered approach. We found that adult SMA patients perceived wearing-off after nearly half of 51 investigated nusinersen administrations, primarily within the last month prior to the next administration. Symptoms and functions affected were mainly general strength and arm and leg muscle function next to endurance and independence in daily routine. Lack of walking ability and higher body mass index were characteristic phenotypic features in patients with consistent wearing-off effects. We assume that specific SMA phenotypes might benefit from higher dosing, shorter treatment intervals, change of treatment administration or a combination of all. Efforts towards treatment optimization may result in higher efficacy in distinct phenotypes.
| S-EPMC7998943 | biostudies-literature
Project description:Background and objectivesNusinersen was approved as the first disease-modifying therapy in spinal muscular atrophy (SMA). Our aim was to analyse therapy-related changes in cerebrospinal fluid (CSF) and serum parameters of adult type 2-3 SMA and to correlate biochemical data with motor functional status.MethodsNine adult SMA type 2-3 patients and ten control subjects without neurodegenerative diseases were included in our single-centre study. Cross-sectional analysis of CSF routine parameters, CSF neurofilament light chain, CSF Tau, CSF phospho-Tau and serum creatinine was performed between SMA patients at baseline (T0) and control subjects. The above-mentioned fluid parameters were longitudinally analysed in the SMA cohort after loading dose (T1) and after four maintenance doses (T2, T3, T4, T5). Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and the 6-minute walking test (6MWT) were used to evaluate motor outcomes.ResultsImprovements in HFMSE, RULM and 6MWT were observed only after the loading dose of nusinersen. No significant differences in routine CSF parameters and CSF markers of neurodegeneration were found between SMA patients and control subjects. Serum creatinine levels were significantly lower in SMA patients than in control subjects. CSF/serum albumin ratio (Qalb) significantly increased from T0 to each time point, without any further increase after the maintenance doses. Persistent systemic oligoclonal bands (OCBs) were found in five patients from baseline. Three more patients developed persistent systemic OCBs from T1; one patient showed intrathecal OCBSs from baseline to T5. Markers of neurodegeneration did not change during the follow-up and did not correlate with motor scores at baseline and at each timepoint. Serum creatinine levels significantly correlated with HFMSE and RULM at each time point.ConclusionsThe increase of the Qalb values and the development of systemic OCBs in some SMA patients could be due to repeated lumbar puncture and to the immunogenic effect of nusinersen. On the other hand, the presence of OCBs in serum and/or CSF at baseline should be further investigated. Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients.
| S-EPMC8390404 | biostudies-literature