SMA Treatment Research Articles

Cost-Effectiveness Analysis of Newborn Screening for Spinal Muscular Atrophy in Italy.

A decision-analytic model assessed the cost effectiveness of newborn screening from the National Health Service perspective in 400,000 newborns. Newborn screening enabling early identification and presymptomatic treatment of SMA was compared with no newborn screening, symptomatic diagnosis, and treatment. Transition probabilities between health states were estimated from clinical trial data. Higher-functioning health states were associated with increased survival, higher utility values, and lower costs. Long-term survival and utilities were extrapolated from scientific literature. Health care costs were collected from official Italian sources. A lifetime time horizon was applied, and costs and outcomes were discounted at an annual rate of 3%. Deterministic and probabilistic sensitivity analyses were conducted. Newborn screening followed by presymptomatic treatment yielded 324 incremental life-years, 390 incremental quality-adjusted life-years, and reduced costs by €1,513,375 over a lifetime time horizon compared with no newborn screening. Thus, newborn screening was less costly and more effective than no newborn screening. Newborn screening has a 100% probability of being cost effective, assuming a willingness-to-pay threshold of >€40,000. Newborn screening followed by presymptomatic SMA treatment is cost effective from the Italian National Health Service perspective.

Administration of adipose-derived stem cells extracellular vesicles in a murine model of spinal muscular atrophy: effects of a new potential therapeutic strategy

BackgroundSpinal Muscular Atrophy (SMA) is an autosomal-recessive neuromuscular disease affecting children. It is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene resulting in lower motor neuron (MN) degeneration followed by motor impairment, progressive skeletal muscle paralysis and respiratory failure. In addition to the already existing therapies, a possible combinatorial strategy could be represented by the use of adipose-derived mesenchymal stem cells (ASCs) that can be obtained easily and in large amounts from adipose tissue. Their efficacy seems to be correlated to their paracrine activity and the production of soluble factors released through extracellular vesicles (EVs). EVs are important mediators of intercellular communication with a diameter between 30 and 100 nm. Their use in other neurodegenerative disorders showed a neuroprotective effect thanks to the release of their content, especially proteins, miRNAs and mRNAs.MethodsIn this study, we evaluated the effect of EVs isolated from ASCs (ASC-EVs) in the SMNΔ7 mice, a severe SMA model. With this purpose, we performed two administrations of ASC-EVs (0.5 µg) in SMA pups via intracerebroventricular injections at post-natal day 3 (P3) and P6. We then assessed the treatment efficacy by behavioural test from P2 to P10 and histological analyses at P10.ResultsThe results showed positive effects of ASC-EVs on the disease progression, with improved motor performance and a significant delay in spinal MN degeneration of treated animals. ASC-EVs could also reduce the apoptotic activation (cleaved Caspase-3) and modulate the neuroinflammation with an observed decreased glial activation in lumbar spinal cord, while at peripheral level ASC-EVs could only partially limit the muscular atrophy and fiber denervation.ConclusionsOur results could encourage the use of ASC-EVs as a therapeutic combinatorial treatment for SMA, bypassing the controversial use of stem cells.

Management and Therapeutic Strategies for Spinal Muscular Atrophy

Spinal muscular atrophy is an autosomal recessive neuromuscular disorder characterized by progressive muscle weakness and atrophy. It is one of the most common single-gene disorders with an incidence rate of approximately 1 in 10,000 live births. The clinical manifestations are progressive hypotonia and muscle weakness due to the degeneration of alpha neurons in the anterior horn cells of the spinal cord and motor nuclei in the lower brain stem. Depending on the severity of the symptoms, SMA has five subtypes. Supportive measures can be offered for respiratory, gastrointestinal, and musculoskeletal complications. Carrier testing for all couples is recommended and this can be done by Multiplex Ligation-dependent Probe Amplification (MLPA). Prenatal diagnosis can be offered to carrier couples. Therapies must be given within the newborn period for maximum benefit and before the loss of motor neurons. It is achieved by identifying the SMA babies through Newborn screening. Several new FDA-approved drugs can reduce the progression of symptoms in SMA. However, they cannot offer a definite cure. Clinical follow-up and Neurological assessment demonstrate that SMA children can attain developmental milestones after receiving treatment, which is never normally attained in untreated cases. In utero SMA treatment with Zolgensma would enhance the survival rate and favorable neurological outcomes in the future. Base editing and Gene editing with CRISPR-Cas technologies to target the mutations and restore functional and stable SMN protein levels are the future hopes for a permanent cure of SMA.

Global Risdiplam Compassionate Use Program for Patients with Type 1 or 2 Spinal Muscular Atrophy

PurposeSpinal muscular atrophy (SMA) is a genetic neuromuscular disease causing progressive muscle weakness and reducing life expectancy. Risdiplam (Evrysdi; Genentech/F. Hoffmann-La Roche Ltd, Basel, Switzerland) is a drug approved for use in the treatment of patients with SMA. The ongoing global risdiplam Compassionate Use Program (CUP), initiated in November 2019, is the largest CUP in SMA, currently providing access to risdiplam for >2000 patients with type 1 or 2 SMA in 59 countries. Here, the challenges and learnings from the risdiplam CUP are presented. MethodsEnrolled patients (aged ≥2 months) had type 1 or 2 SMA and no alternative treatment options (ie, they were not medically eligible for approved SMA treatments, were unable to continue their SMA treatment due to medical reasons, were at risk for lack/loss of SMA treatment efficacy, or did not qualify for/had no access to SMA treatment within a clinical trial). Requests were made by the treating physicians via an end-to-end system. FindingsThe risdiplam CUP highlighted the importance of collaborating with patient advocacy groups early to learn about patients' perspectives on unmet medical needs, understanding the sometimes-unique nature of local regulations and requirements, and adapting physician- and patient-eligibility criteria. Key learnings were obtained from enrolling patients from low- to middle-income countries and from countries without dedicated Compassionate Use regulations, and from operating the CUP during the coronavirus disease 2019 pandemic. ImplicationsThe risdiplam CUP experience was successful in many ways and may help to design and implement future CUPs in rare diseases, as well as patients living in countries or in circumstances in which access to innovative treatments is a challenge.

5qSMA: standardised retrospective natural history assessment in 268 patients with four copies of SMN2

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.

Effects of natural extract from medicinal herbs on broilers experimentally infected with Eimeria tenella

This study aimed to evaluate the effects of natural extracts from nine medicinal herbs (SMA) on the growth performance, immunity, and intestinal integrity of broilers experimentally infected with Eimeria tenella. A total of 252 one-day-old broiler chicks were divided into 7 groups with 3 replicates per group and 12 broilers per cage. The groups were uninfected–untreated blank control group (BC), infected–untreated negative control group (NC), SMA treatment groups, Chinese medicine positive control group (CM), and chemical drug positive control group (CD). The SMA groups were infected and fed a basal diet supplemented with 0.6 (SMA-L), 0.8 (SMA-M), and 1.0 (SMA-H) g/kg SMA. The CM and CD groups were infected and fed a basal diet supplemented with 15 g/kg Jiqiuchong San and 0.2 g/kg Diclazuril, respectively. Results showed that feeding SMA could significantly reduce the number of oocysts in infected chickens, especially 1.0 g/kg SMA, which exhibited moderate anticoccidial efficacy. When infected with E. tenella, the supplementation of 1.0 g/kg SMA increased the renal index; restored the hepatic, splenic, and bursal indexes to BC levels; increased the levels of immunoglobulin A (IgA), IgM, and IgY; and reduced the contents of tumor necrosis factor (TNF-α), interferon-γ (IFN-γ), interleukin-6 (IL-6), and IL-10 of the infected chickens. Moreover, treatment with 1.0 g/kg SMA alleviated the pathological changes in cecal tissue and increased the contents of zonula occludens-1 (ZO-1), occludin, claudin-1, and mucoprotein 2 (mucin-2) in cecal tissues of E. tenella-infected chickens. We found that 1.0 g/kg SMA reduced the number of oocysts, improved immunity, and alleviated intestinal barrier damage, which could improve the growth performance of infected chickens. Thus, SMA proved to be an effective natural extract against E. tenella and has the potential to be used as an efficient anticoccidial drug or additive.

Assessment of Nuclear Gem Quantity for Evaluating the Efficacy of Antisense Oligonucleotides in Spinal Muscular Atrophy Cells.

Spinal muscular atrophy is a neuromuscular disorder caused by mutations in both copies of the survival motor neuron gene 1 (SMN1), which lead to reduction in the production of the SMN protein. Currently, there are several therapies that have been approved for SMA, with many more undergoing active research. While various biomarkers have been proposed for assessing the effectiveness of SMA treatment, a universally accepted one still has not been identified. This study aimed to describe a fast and reliable method using the number of gems in cell nuclei as a potential tool for assessment of splicing correction of oligonucleotide efficacy in SMA cells. To gain insight into whether the number of gems in cell nuclei varies based on their SMN genotype and whether the increase in gem number is associated with therapeutic response, we utilized fibroblast cell cultures obtained from a patient with SMA type II and from a healthy individual. We discovered a remarkable difference in the number of gems found in the nuclei of these cells, specifically when counting gems per 100 nuclei. The SMA fibroblasts treated with antisense oligonucleotide showed beneficial effects in correcting the abnormal splicing of SMN2 exon 7. It was observed that there was a significant increase in the number of gems in the treated cells compared to the intact SMA cells. The results obtained significantly correlate with an increase of full-length SMN transcript sharing. Based on our findings, we propose using the quantity of gems as a reliable biomarker for SMA drug development.

Correlations between clinical motor scores and CMAP in patients with type 2 spinal muscular amyotrophy treated with nusinersen

BackgroundSpinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the anterior horn cells of the spinal cord. Nusinersen for the treatment of SMA has been covered by public healthcare in France since May 2017. ObjectiveOur aim was to investigate whether there is a correlation between clinical and compound motor action potential (CMAP) measurements in SMA patients treated with nusinersen after 3 years’ follow-up. MethodMotor skills were evaluated regularly between M0 and M36 using the Motor Function Measure (MFM) score. CMAP measurements were collected regularly between M0 and M22. ResultsData for 10 patients with SMA type 2 were collected and divided into two age groups (< 5 years and > 5 years). Motor function improved, but not significantly, regarding distal motor skills (D3) in both groups, and in axial and proximal motor function (D2) in the younger group. CMAP measurements improved in all patients. CMAP increased significantly for the median nerve, and this improvement correlated significantly with global MFM and with axial and proximal tone (D2). ConclusionOur study shows gain in distal motor function with nusinersen, especially in younger patients with SMA type 2. These results encourage the screening of SMA patients and treatment as early as possible. CMAP measurements of the median nerve show clear improvement in patients treated with nusinersen and could be performed as routine follow-up.

Preliminary insights into RNA in CSF of pediatric SMA patients after 6 months of nusinersen

BackgroundSpinal muscular atrophy (SMA) is a rare autosomal-recessive neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) gene, and consequent loss of function of SMN protein, which results in progressive loss of lower motor neurons, and muscular wasting. Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre–mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Given the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery.MethodsBy RNA-sequencing approach, RNA obtained from CSF of pediatric SMA type 2 and 3 patients was processed after 6 months of nusinersen treatment, at fifth intrathecal injection (T6), and compared to baseline (T0).ResultsWe observed the deregulation of cfRNAs in patients at T6 and we were able to classify these RNAs into disease specific, treatment specific and treatment dependent. Moreover, we subdivided patients into “homogeneous” and “heterogeneous” according to their gene expression pattern. The “heterogeneous” group showed peculiar activation of genes coding for ribosomal components, meaning that in these patients a different molecular effect of nusinersen is observable, even if this specific molecular response was not referable to a clinical pattern.ConclusionsThis study provides preliminary insights into modulation of gene expression dependent on nusinersen treatment and lays the foundation for biomarkers discovery.

Treatment of spinal muscular atrophy with Onasemnogene Abeparvovec in Switzerland: a prospective observational case series study

BackgroundSpinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland.MethodsProspective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed.ResultsNine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter.ConclusionsOA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

Usefulness of YouTube in Sharing Information about New Gene Therapy for Spinal Muscular Atrophy: A Content Analysis

This study aimed to objectively assess YouTube videos' quality, reliability, and information delivery capability regarding novel spinal muscular atrophy treatments. Using the keywords "nusinersen", "spinraza", "ridisplam", "evrysdi", "onasemnogene abeparvovec", and "zolgensma", we were able to retrieve and screen 360 videos before settling on a final sample of 99 on 25 September 2022. Then, two independent raters used the mDISCERN and GQS instruments to evaluate the videos' reliability and quality and the Information Delivery Capability (IDC) score to assess the videos' accuracy and patient-friendliness. The quality, reliability, and information delivery capability of the videos about the new treatment for SMA were quite heterogeneous, with an average mDISCERN, GQS, and IDC score of 3.172 ± 0.899, 2.980 ± 1.025, and 4.141 ± 1.747, respectively. In-depth analysis showed that healthcare expert videos that explained contents while showing infographic supplements had good quality, reliability, and information delivery capability. As YouTube is already a dominant media platform, the public may obtain new information about novel therapeutics for SMA through YouTube. It is necessary to consider how SMA patients and caregivers can choose trusted sources with reliable information on YouTube, and our results can provide clues. Additionally, experts should strive to provide more accurate, reliable, and patient-oriented videos.

Newborn Screening for SMA - Can a Wait-and-See Strategy be Responsibly Justified in Patients With Four SMN2 Copies?

Early treatment after genetic newborn screening (NBS) for SMA significantly improves outcomes in infantile SMA. However, there is no consensus in the SMA treatment community about early treatment initiation in patients with four copies of SMN2. Approach to a responsible treatment strategy for SMA patients with four SMN2 copies detected in newborn screening. Inclusion criteria were a history of SMA diagnosed by NBS, age > 12 months at last examination, and diagnosis of four SMN2 copies at confirmatory diagnosis. 21 patients with SMA and four SMN2 copies were identified in German screening projects over a three-year period. In three of them, the SMN2 copy number had to be corrected later, and three patients were lost to follow-up. Eight of the fifteen patients who were subject to long-term follow-up underwent presymptomatic therapy between 3 and 36 months of age and had no definite disease symptoms to date. Five of the other seven patients who underwent a strict follow-up strategy, showed clinical or electrophysiological disease onset between 1.5 and 4 years of age. In two of them, complete recovery was not achieved despite immediate initiation of treatment after the onset of the first symptoms. A remarkable proportion of patients with four copies of SMN2 develop irreversible symptoms within the first four years of life, if a wait-and-see strategy is followed. These data argue for a proactive approach, i.e., early initiation of treatment in this subgroup of SMA patients.

Investigating attitudes toward prenatal diagnosis and fetal therapy for spinal muscular atrophy.

In utero SMA treatment could improve survival and neurologic outcomes. We investigated the attitudes of patients and parents with SMA regarding prenatal diagnosis, fetal therapies, and clinical trials. A multidisciplinary team designed a questionnaire that Cure SMA electronically distributed to parents and patients (>18years old) affected by SMA. Multivariable ordinal logistic regression was used to analyze associations between respondent characteristics and attitudes. Of 114 respondents (60% of whom were patients), only 2 were prenatally diagnosed. However, 91% supported prenatal testing and 81% felt there had been a delay in their diagnosis. Overall, 55% would enroll in a phase I trial for fetal antisense oligonucleotide (ASO) while 79% would choose an established fetal ASO/small molecule therapy. Overall, 61% would enroll in fetal gene therapy trials and 87% would choose fetal gene therapies. Patients were less likely to enroll in a fetal gene therapy trial than parents enrolling a child (OR 0.31, p<0.05). Older parental age and believing there had been excessive delay in diagnosis were associated with an interest in enrolling in a fetal ASO trial (OR 1.04, 7.38, respectively, p<0.05). In utero therapies are promising for severe genetic diseases. Patients with SMA and their parents view prenatal testing and therapies positively, with gene therapy being favored.

Cost-Effectiveness of Newborn Screening for Spinal Muscular Atrophy in The Netherlands

ObjectivesSpinal muscular atrophy (SMA) is a rare genetic disorder that causes progressive muscle weakness and paralysis. In its most common and severe form, the majority of untreated infants die before 2 years of age. Early detection and treatment, ideally before symptom onset, maximize survival and achievement of age-appropriate motor milestones, with potentially substantial impact on health-related quality of life. Therefore, SMA is an ideal candidate for inclusion in newborn screening (NBS) programs. We evaluated the cost-effectiveness of including SMA in the NBS program in The Netherlands. MethodsWe developed a cost-utility model to estimate lifetime health effects and costs of NBS for SMA and subsequent treatment versus a treatment pathway without NBS (ie, diagnosis and treatment after presentation with overt symptoms). Model inputs were based on literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and validity of results. ResultsAfter detection of SMA by NBS in 17 patients, the number of quality-adjusted life-years gained per annual birth cohort was estimated at 320 with NBS followed by treatment compared with treatment after clinical SMA diagnosis. Total healthcare costs, including screening, diagnostics, treatment, and other healthcare resource use, were estimated to be €12 014 949 lower for patients identified by NBS. ConclusionsNBS for early identification and treatment of SMA versus later symptomatic treatment after clinical diagnosis improves health outcomes and is less costly and, therefore, is a cost-effective use of resources. Results were robust in sensitivity and scenario analyses.

PP391 Economic Analysis Of Treatment For Spinal Muscular Atrophy: A Scoping Review

IntroductionSpinal muscular atrophy (SMA) is a rare, life-threatening, and seriously debilitating neuromuscular disorder, which has a heavy burden on patients, caregivers and the health system. Technological advances have improved clinical effect, but have also increased the financial burden. There is limited information in the literature on the resource utilization and economic burden of SMA. Our research aims to summarize the current literature on resource use, cost and economic evaluations of treatments for SMA, to inform further research and policy decision making.MethodsDatabases, including PubMed, Embase, Cochrane Library and CRD Database, were searched from inception. Two reviewers undertook title and abstract screening followed by full-text screening, and any disagreement was resolved in consensus. Data extraction was conducted using a customized form. Included studies were summarized using narrative synthesis structured around general and economic characteristics. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were adhered to where applicable.ResultsWe reviewed 552 abstracts and included twenty-six from 2015 to 2019. Four-fifths were published in the United States and Europe. Five full economic evaluations and one budget impact analysis compared nusinersen with AVXS-101 or best supportive care, and the remaining evaluated the economic burden of SMA. The most common outcomes were healthcare resource utilization and direct medical costs, only a few studies evaluated direct non-medical costs or indirect cost.ConclusionsSMA patients have significant medical expenditures and high utilization of healthcare services, including nusinersen-treated patients. The results highlight the substantial burden of treatment for SMA, not only for patients but also for their caregivers. SMA represents a significant hidden cost that society should be made aware of, and that should be considered in the design, implementation and evaluation of support programs for people who suffer from this disease and their families, as well as in the economic evaluation of new treatments.

SMA: REGISTRIES, BIOMARKERS & OUTCOME MEASURES: P.188 ATEND: Development of a wheelchair based motor assessment

Individuals with chronic SMA have a heterogenous presentation. The only scale validated for weak individuals is the CHOPINTEND designed for SMA1 infants. For weaker individuals who have severe contractures, motor assessments are a challenge due to limitations in the ability to transfer or lie prone. With recent developments in treatment for SMA, there is a growing need for a wheelchair based scale for non-sitters. Here, we describe the initial development of a new scale, Adult Test of Neuromuscular Disorders (ATEND), a wheelchair based assessment for older and weaker individuals with SMA.

Implementation of population-based newborn screening reveals low incidence of spinal muscular atrophy

PurposeSpinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018. MethodsScreening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion. ResultsDuring the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy. ConclusionNewborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.

Influence of Surface Mechanical Attrition Treatment (SMAT) post-treatment on microstructural, mechanical and tensile behaviour of additive manufactured AISI 316L

Additive Manufacturing (AM) is a technology in constant growth, thanks to its numerous advantages compared to conventional manufacturing. In this paper, Surface Mechanical Attrition Treatment (SMAT) was performed on 316L stainless steel parts produced by the Laser Powder Bed Fusion (LPBF) technique, also commonly known as Selective Laser Melting (SLM). Experimental characterizations (cross-sectional optical micrographs, X-ray diffraction, phase analyses, surface roughness, micro-tensile testing and microhardness profiles) show that SMA treatment can reduce the surface roughness by a factor of 10 and can increase the microhardness in the layer beneath the treated surface up to 45%. SMAT can also transform the initial near-surface tensile residual stresses present in AM parts into compressive ones and enhances the mechanical properties of SLM parts. This work demonstrates the potential of SMAT as a post-treatment to improve surface quality and increase yield strength while retaining good ductility of SLM manufactured parts.

Burden of illness of spinal muscular atrophy type 1 (SMA1)

SMA1 is a rapidly progressing, genetic, neurologic disease. Cost burden data are limited and must be updated as the treatment landscape evolves. The first SMA treatment, nusinersen, was recently approved in the US (23/12/2016) and EU (30/05/2017). We undertook two retrospective claims analyses of real-world healthcare resource utilization (HCRU) and costs among SMA1 patients. SMA1 patients ≤1-year old were identified and matched (1:1) with a random sample of infants in the QuintilesIMS PharMetrics Plus Health Plan Claims Database (US; 02/2011–11/2016). SMA1 patients were identified in Symphony Health's Integrated Dataverse® (US; 09/2016–08/2018). HCRU and costs were described. Significantly more SMA1 patients in PharMetrics (n=119) had ≥1 all-cause HCRU claims vs matched patients (98.3% vs 54.6%, P<0.0001). Mean all-cause HCRU and costs were higher for SMA1 infants; extrapolated all-cause total annual costs (month 1 post-diagnosis), were $324,751 (SMA1) vs $3,294 (matched). SMA1 patients in Symphony (n=349, median follow-up of 7.9 months) had an average 59.4 days with medical visits/year (inpatient, 14.1; related to respiratory failure, 13.4). In nusinersen-treated patients (n=45), those values were 56.6, 4.6, and 11.4 days, respectively, following treatment initiation. Excluding nusinersen-related costs, mean healthcare costs per-patient-per-year were $137,627 (median: $43,167) for all patients and $92,618 (median: $29,425) for nusinersen-treated patients. Mean nusinersen-related costs were $191,909/month (median: $144,487) for the first 3 months (loading phase), $36,882/month (median: $16,132) thereafter. EU data (pooled and country-specific) available at the time of the congress will be presented. The economic burden of SMA1 is substantial, even among patients treated with nusinersen.

REGISTRIES: P.388The RESTORE registry: a resource for measuring and improving spinal muscular atrophy (SMA) outcomes

SMA is a rapidly progressing neurologic disease caused by biallelic survival motor neuron 1 (SMN1) gene deletion/mutation. Dramatic changes in SMA treatment landscape have altered the outlook of this disease. The RESTORE registry was created to assess outcomes of patients receiving SMA treatment, provide information on the effectiveness and long-term safety of new/emerging treatments, document patient survival, and collect information on healthcare resource utilization (HRU), caregiver burden, patient functional status, and quality of life. The RESTORE registry is a prospective, multicenter, multinational, observational study. Participating centers include those involved in existing and evolving SMA registries (e.g., iSMAC, TreatNMD, NeuroNEXT, Cure SMA) and SMA treatment centers recruited de novo. Data from existing patients enrolled in partnering registries are transferred to the RESTORE registry database. Data for newly diagnosed patients are added as they enroll. Follow-up is 15 years from enrollment or until death, whichever is earlier. Assessments include SMA history and treatment, pulmonary, nutritional, and motor milestones, HRU, work productivity and activity impairment, adverse events, quality of life, and survival. The RESTORE registry has been established, and as of March 7, 2019, 14 sites have been activated in the United States and 11 patients have been enrolled. Registry sites are planned in Latin America, Europe, and Japan as part of its global expansion. The RESTORE registry has begun recruiting SMA patients, allowing short- and long-term patient outcomes assessment and extended evaluation of emerging SMA treatments, including gene therapy.