Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial.
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SUBMITTER: Strauss KA
PROVIDER: S-EPMC9205281 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.
| S-EPMC9205287 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is a debilitating disorder characterized by degeneration of large motor neurons. It is a heterogeneous group of disorders caused by a homozygous deletion in the survival motor neuron (SMN) gene on chromosome 5, resulting in a SMN protein deficiency. Small amounts of SMN protein are also produced by the SMN2 gene, which that differs from SMN1 by a single nucleotide. Spinal muscular atrophy types and phenotypic severity depend on the number of variations of the SMN2 gene and the amount of SMN2 protein produced. Because the SMN protein deficiency is the root cause of the disease, treatment strategies for SMA revolve around increasing SMN protein production. Nusinersen (Spinraza, Biogen, Cambridge, MA) was the only treatment option available for SMA until the FDA approved onasemnogene abeparvovec-xioi (Zolgensma, AveXis Inc, Bannockburn, IL), a one-time-administered adeno-associated viral vector-based gene therapy that delivers the SMN gene to the motor neuron cells. Data from clinical studies show significant improvement in motor milestone achievements and ventilator-free survival but are limited by approximately 5 years' worth of results. This one-time intravenous injection of this new gene therapy also bears a hefty price tag; however, it may be more cost effective in the long run versus the multiple intrathecal administrations needed with nusinersen. Drug access and use are hindered by drug cost, payer reimbursement issues, and lack of long-term data from clinical studies. Questions also remain regarding the safety and efficacy of repeated drug administration for patients with advanced disease.
| S-EPMC8244960 | biostudies-literature
Project description:BackgroundRecently gene therapy with onasemnogene abeparvovec has been approved for the treatment of spinal muscular atrophy (SMA). As the experience from clinical trials is limited, there are still uncertainties for which patient population the treatment can be considered safe and effective.MethodsWe report our experience with eight consecutive patients with SMA who were treated with the standard dose of onasemnogene abeparvovec (1.1×1014 vg/kg) at the University Hospital Bonn, Germany. All patients received prophylactic immunosuppression with 1 mg/kg/d prednisolone for four weeks starting on the day before gene therapy.ResultsWe treated eight patients (4 male, 4 female, age range 10-37 months) with a body weight between 7.1 and 11.9 kg. All patients had 2 or 3 copies of the SMN2-gene and were previously treated with nusinersen. Following treatment with onasemnogene abeparvovec all patients showed a temporary increase of the body temperature and an increase of transaminase levels. In all but one patient it was necessary to increase or prolong the standard steroid dose to control the immune response. In one severe case, liver damage was associated with impaired liver function. This patient received a steroid pulse therapy for five days. Blood counts revealed asymptomatic thrombocytopenia (<150×109/L) in 6/8 patients and a significant increase of monocytes following gene therapy. Liver values and blood counts returned to almost normal levels during the post-treatment observation period. Troponin I increased above normal limit in 4/8 patients but was not associated with any abnormalities on cardiac evaluation.ConclusionsIn a broader spectrum of patients, treatment with onasemnogene abeparvovec was associated with a higher rate of adverse events. In our cases it was possible to control the immune response by close monitoring and adaptation of the immunosuppressive regimen. Further research is needed to better understand the immune response following gene therapy and ideally to identify patients at risk for a more severe reaction.
| S-EPMC8075402 | biostudies-literature
Project description:BackgroundImprovement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care.ObjectiveA multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec.MethodsWe defined bulbar function as the ability to meet nutritional needs while maintaining airway protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion.ResultsOverall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint.ConclusionsIn these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation.
| S-EPMC10357176 | biostudies-literature
Project description:ImportanceThis ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy.ObjectiveThe primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained.Design, setting, and participantsThis study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020.ExposuresMedian time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort.Main outcomes and measuresThe primary outcome measure was the incidence of serious adverse events (SAEs).ResultsAt data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen.Conclusions and relevanceThe findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose.Trial registrationClinicalTrials.gov Identifier: NCT03421977.
| S-EPMC8129901 | biostudies-literature
Project description:As part of the National Institute for Health and Care Excellence (NICE) highly specialised technology (HST) evaluation programme, Novartis submitted evidence to support the use of onasemnogene abeparvovec as a treatment option for patients with pre-symptomatic 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the survival of motor neuron (SMN) 1 gene and up to three copies of the SMN2 gene. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the External Assessment Group (EAG). This article summarises the EAG's review of the evidence submitted by the company and provides an overview of the NICE Evaluation Committee's final decision, published in April 2023. The primary source of evidence for this evaluation was the SPR1NT trial, a single-arm trial including 29 babies. The EAG and committee considered that the SPR1NT trial results suggested that onasemnogene abeparvovec is effective in treating pre-symptomatic SMA; however, long-term efficacy data were unavailable and efficacy in babies aged over 6 weeks remained uncertain. Cost-effectiveness analyses conducted by the company and the EAG (using a discounted price for onasemnogene abeparvovec) explored various assumptions; all analyses generated incremental cost-effectiveness ratios (ICERs) that were less than £100,000 per quality-adjusted life-year (QALY) gained. The committee recommended onasemnogene abeparvovec as an option for treating pre-symptomatic 5q SMA with a bi-allelic mutation in the SMN1 gene and up to three copies of the SMN2 gene in babies aged ≤ 12 months only if the company provides it according to the commercial arrangement (i.e. simple discount patient access scheme).
| S-EPMC10721753 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is a common autosomal-recessive motor neuron disease caused by the homozygous loss of the SMN1 gene. A nearly identical gene, SMN2, has been shown to decrease the severity of SMA in a dose-dependent manner. However SMN2 is not the sole phenotypic modifier, because there are discrepant SMA cases in which the SMN2 copy number does not explain the clinical phenotype. This report describes three unrelated SMA patients who possessed SMN2 copy numbers that did not correlate with the observed mild clinical phenotypes. A single base substitution in SMN2, c.859G>C,, was identified in exon 7 in the patients' DNA. We now show that the change creates a new exonic splicing enhancer element and increases the amount of full-length transcripts, thus resulting in the less severe phenotypes. This demonstrates that the c.859G>C substitution is a positive modifier of the SMA phenotype and that not all SMN2 genes are equivalent. We have shown not only that the SMA phenotype is modified by the number of SMN2 genes but that SMN2 sequence variations can also affect the disease severity.
| S-EPMC2771537 | biostudies-literature
Project description:Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5' splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.
| S-EPMC5966403 | biostudies-literature
Project description:Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre-messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMA?7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMA?7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3' splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.
| S-EPMC4602033 | biostudies-literature
Project description:Spinal muscular atrophy 5q (SMA5q) is one of the most severe and common genetic diseases. In the natural course, the disease leads to premature death (in acute forms) or severe motor disability (in chronic forms). As the genetic basis of SMA is very homogenous, the diagnostics are based entirely on simple and sensitive genetic testing. In the last few years, innovative methods of therapy have been developed based on SMN2 gene modification, such as splicing, or replacement of the damaged SMN1 gene (gene therapy). Although these approaches have shown high efficacy, results depend on the age/disease stage at which therapy is initiated. The best results have been obtained in presymptomatic patients. Indeed, introduction of therapy in the pre- or early symptomatic stage of the disease seems to be crucial for maximizing effects. Thus, all the criteria for the implementation of neonatal screening for SMA have been met, and many countries, ie, the USA, Germany, Belgium, and Australia, have started NBS national/pilot programs for SMA. The initial results of these programs indicate a high frequency of the disease, reaching 1 per 7 thousand live births in Europe, as well as early symptomatology (first weeks of life in severe cases) and a high frequency of patients with 4 SMN2 copies. Overall, the time for therapy inclusion in patients with 4 SMN2 copies remain under discussion. More precise predictors/biomarkers of the clinical course are needed. At the same time, it seems advisable to offer other solutions, such as population carrier screening. As the long-term effects of different treatments on the natural history of SMA are unknown, the natural history of the disease needs to be re-evaluated.
| S-EPMC7751307 | biostudies-literature