Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma®) gene replacement therapy, are ...emerging.
This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants.
Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n = 16) and healthy infants (n = 27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events.
Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101-treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101-treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101-treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively).
In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants.
Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results.
...Objective: To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions.
Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model.
Setting/Perspective: USA/Commercial payer
Participants: Children aged <2 years with SMA1.
Interventions: Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC.
Main outcome measure: Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US.
Results: Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar.
Conclusion: This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY).
To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning.
We conducted ...a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data.
In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fat-free mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up.
The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.
ABSTRACT
Giant axonal neuropathy (GAN) is a rare pediatric neurodegenerative disease. It is best known for the “giant” axons caused by accumulations of intermediate filaments. The disease is ...progressive, with onset around age 3 years and death by the third decade of life. GAN results from recessive mutations in the GAN gene encoding gigaxonin, and our analysis of all reported mutations shows that they are distributed throughout the protein structure. Precisely how these mutations cause the disease remains to be determined. In addition to changes in peripheral nerves that are similar to those seen in neuropathies such as Charcot–Marie–Tooth type 2, GAN patients exhibit a wide range of central nervous system signs. These features, corroborated by degeneration of central tracts apparent from postmortem pathology, indicate that GAN is also a progressive neurodegenerative disease. To reflect this phenotype more precisely, we therefore propose that the disease should be more appropriately referred to as “giant axonal neurodegeneration.” Muscle Nerve 50: 467–476, 2014
Background
Patients with spinal muscular atrophy (SMA) have high healthcare resource use (HRU) due to respiratory and nutritional complications resulting from progressive muscle atrophy. While ...previous studies estimate the direct costs to be US$113,000 to US$121,682 per year in the US, they potentially understate costs for type 1 SMA (SMA1). This study analyzed HRU in hospitalizations with a diagnosis of SMA1 and compared it with hospitalizations with complex chronic conditions (CCC) other than SMA1 or those with no CCC.
Methods
This retrospective analysis of a defined subset of the 2012 Kids’ Inpatient Database (KID) compared a nationally estimated number of hospitalizations of children (aged < 3 years) categorized into three groups: (1) SMA1 (
n
= 237 admissions), (2) no CCC (
n
= 632,467 admissions), and (3) other CCC (
n
= 224,953 admissions).
Results
Mean total charges were higher for SMA1 admissions compared with admissions with no CCC (US$150,921 vs US$19,261 per admission, respectively; costs: US$50,190 vs $5862 per admission, respectively; both
p
< 0.0001). A larger proportion of SMA1 admissions were billed for one or more procedure codes (81.9%) than in the no CCC group (39.4%) or other CCC group (70.1%; both
p
≤ 0.0003). SMA1 admissions had a longer length of stay compared with admissions with no CCC (15.1 vs 3.4, respectively;
p
< 0.0001).
Conclusions
The average total charges for a single SMA1 admission were higher than those of the no CCC group. Because most infants with SMA1 require multiple hospitalizations per year, previous estimates may dramatically underestimate the direct costs associated with HRU. Further studies are required to determine the indirect costs and societal impacts of SMA1.
Dans l’étude ENDEAR, 39 % des patients atteints d’ASI-1 sont décédés/ont eu besoin de ventilation permanente dans les 6 mois suivant le début du nusinersen.
Étudier la rapidité de l’effet de la ...thérapie génique à base d’onasemnogène abeparvovec (AVXS-101) (étude de phase 1 CL-101) sur la fonction motrice par rapport au nusinersen (ENDEAR).
Les nourrissons atteints d’ASI-1 ont été traités par une dose d’AVXS-101 par voie IV ; cohorte 2, n=12, suivi de 24 mois. Les résultats étaient la survie sans événement (SSE ; CL-101 : décès ou ventilation≥16heures/jour pendant>2 sem. ; ENDEAR : décès, trachéotomie ou ventilation≥16h/jour pendant>21jours) et les améliorations de la fonction motrice par rapport à la visite de référence du test CHOP-INTEND.
Les 12 AVXS-101 patients ont montré une SSE à 24 mois contre 49/80 (61 %) nusinersen patients. À 1, 3 et ∼10 mois post-AVXS-101, CHOP-INTEND a augmenté 9,8, 15,4 et 27 points. Deux et ∼10 mois post-nusinersen, CHOP-INTEND a augmenté≤5 et de ∼10 points. À 6 mois, 11/12 (92 %) AVXS-101 patients ont conservé CHOP-INTEND≥40 contre 30/78 (38,5 %) nusinersen patients à la dernière délimitation des données intermédiaire (Jour 183–394).
L’AVXS-101 semble améliorer la survie et induire une amélioration rapide de la fonction motrice par rapport au nusinersen, ce qui est cohérent avec une restauration rapide du SMN avec une dose unique.
Le progrès dans la connaissance de l’ASI-1 souligne la nécessité d’un diagnostic précoce et de traitement avec effet rapide afin d’améliorer l’état clinique.
Weakness resulting from spinal muscular atrophy causes severe limitations in functional mobility. The early introduction of power mobility has potential to enhance development and mitigate ...disability. These outcomes are achieved by simulating normal skill acquisition and by promoting motor learning, visuospatial system development, self-exploration, cognition, and social development. There are few reports on early power mobility in spinal muscular atrophy, and it is typically not prescribed until school age. The authors evaluated 6 children under age 2 years with neuromuscular disease (5 spinal muscular atrophy, 1 congenital muscular dystrophy) for power mobility. Parents recorded the practice hours necessary to achieve independence using the Power Mobility Skills Checklist. Four children achieved independence in all items on the checklist by 7.9 months (range: 73-458 days). Introduction of early power mobility is feasible in spinal muscular atrophy patients under age 2 years and should be introduced in late infancy when children typically acquire locomotor skills.
Spinal Muscular Atrophy (SMA) presents challenges in (i) monitoring disease activity and predicting progression, (ii) designing trials that allow rapid assessment of candidate therapies, and (iii) ...understanding molecular causes and consequences of the disease. Validated biomarkers of SMA motor and non-motor function would offer utility in addressing these challenges. Our objectives were (i) to discover additional markers from the Biomarkers for SMA (BforSMA) study using an immunoassay platform, and (ii) to validate the putative biomarkers in an independent cohort of SMA patients collected from a multi-site natural history study (NHS).
BforSMA study plasma samples (N = 129) were analyzed by immunoassay to identify new analytes correlating to SMA motor function. These immunoassays included the strongest candidate biomarkers identified previously by chromatography. We selected 35 biomarkers to validate in an independent cohort SMA type 1, 2, and 3 samples (N = 158) from an SMA NHS. The putative biomarkers were tested for association to multiple motor scales and to pulmonary function, neurophysiology, strength, and quality of life measures. We implemented a Tobit model to predict SMA motor function scores.
12 of the 35 putative SMA biomarkers were significantly associated (p<0.05) with motor function, with a 13(th) analyte being nearly significant. Several other analytes associated with non-motor SMA outcome measures. From these 35 biomarkers, 27 analytes were selected for inclusion in a commercial panel (SMA-MAP) for association with motor and other functional measures.
Discovery and validation using independent cohorts yielded a set of SMA biomarkers significantly associated with motor function and other measures of SMA disease activity. A commercial SMA-MAP biomarker panel was generated for further testing in other SMA collections and interventional trials. Future work includes evaluating the panel in other neuromuscular diseases, for pharmacodynamic responsiveness to experimental SMA therapies, and for predicting functional changes over time in SMA patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m2 ), fat-free (FFMI, lean mass/height in m2 ) and fat (FMI, fat mass/height in m2 ) mass ...indexes were estimated in 25 children (aged 5–18) with SMA (2 type I, 13 type II, 10 type III) using dual-energy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was ⩾50th percentile in 11 (44%) and ⩾85th in 5 (20%). FFMI was reduced ( p < 0.005) and FMI was increased ( p < 0.005) in the overall study cohort. FMI was ⩾50th, ⩾85th and 95th percentiles in 19 (76%), 10 (40%) and 5 (20%) subjects, respectively. Using a receiver operator characteristic curve, BMI above 75th, 50th and 3rd percentiles maximized sensitivity and specificity for FMI ⩾95th, ⩾85th and ⩾50th percentiles, respectively. Children with SMA have reduced lean and increased fat mass compared to healthy children. Obesity is a potentially important modifiable source of morbidity in SMA.
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