Interim Efficacy and Safety Results from the Phase 3 ENDEAR Study of Nusinersen in Infants Diagnosed with Spinal Muscular Atrophy (SMA)

Finkel, R.; Kuntz, N.; Muntoni, Francesco; Chiriboga, Claudia A.; Darras, B.; Topaloǧlu, Haluk; Montes, Jacqueline; Su, John Q.; Zhong, Zhenshao; Gheuens, Sarah; Bennett, C. Frank; Schneider, Eugene; Farwell, Wildon

doi:10.1055/s-0037-1602912

Cited by 3 publications

(5 citation statements)

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“…In evaluating the results of this study, consideration should be given to the fact that the B-R study was completed in the context of regulatory approval of the first therapy ever for all SMA types that is both effective and safe. 11,12,28,60 It is reasonable that this milestone in the history of such a devastating disease would serve as a benchmark and thus influence the views of the SMA community about risks and benefits associated with future therapies. Patients and caregivers are likely considering nusinersen as the new baseline for treatment risks and benefits, expecting any new therapeutic options to be at least as safe and effective and offering some other drug benefit (eg, making utilization of the drug more convenient).…”

Section: Discussionmentioning

confidence: 99%

“…10 The landmark approval of nusinersen ushered in an era of new hope for the SMA community with the availability of an effective treatment approved for all types of SMA. 11,12,28,60 The approval showed proof of principle that it is possible to deliver clinically meaningful benefits, affecting motor function outcomes and rates of survival for patients with SMA, particularly when treatment is introduced soon after symptom's onset, and most significantly, presymptomatically. 11,12,28,60,61 However, for many patients with SMA and their caregivers, the disease burden and related unmet needs remain significant, particularly when the drug is provided after significant symptom onset.…”

Section: Introductionmentioning

confidence: 99%

“…11,12,28,60 The approval showed proof of principle that it is possible to deliver clinically meaningful benefits, affecting motor function outcomes and rates of survival for patients with SMA, particularly when treatment is introduced soon after symptom's onset, and most significantly, presymptomatically. 11,12,28,60,61 However, for many patients with SMA and their caregivers, the disease burden and related unmet needs remain significant, particularly when the drug is provided after significant symptom onset. 1,11e13 With a first approved therapy now in commercial use, an evolving standard of care, 42,43 and additional therapeutic options in development, 20 there is a need to supplement the existing clinical outcome measures for SMA by further understanding, measuring, and incorporating the perspectives and priorities of patients with SMA and their caregivers within therapy development and the regulatory review processes.…”

Section: Introductionmentioning

confidence: 99%

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Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community

Cruz

Belter

Wasnock

et al. 2019

Clinical Therapeutics

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Purpose: Patients' perceptions of benefiterisk are essential to informing the regulatory process and the context in which potential therapies are evaluated. To bring this critical information to regulators, Cure SMA launched a first-ever Benefit-Risk Survey for spinal muscular atrophy (SMA) to characterize decision-making and benefiterisk trade-offs in SMA associated with a potential therapy. We hypothesized that risk tolerance would be correlated with SMA type/severity and disease progression. This article presents the results of a benefiterisk survey to enhance understanding of how patients with SMA and caregivers evaluate specific benefits and risks associated with potential therapies.Methods: Affected adults, representing all SMA types (IeIV) within the Cure SMA database, and caregivers of affected individuals of all ages/types were invited via e-mail to participate. Besteworst scaling (BWS) was used to assess participants' priorities on benefiterisk trade-offs, as it provides higher discrimination and importance scaling among tested attributes. Twelve potentially clinically meaningful treatment benefits and 11 potential risks (ranging in severity and immediacy) were tested. Multiple factors were correlated with individual responses, including: SMA type/disease severity, stage of disease, respondent type, sex, and quality of life/ level of independence (current and expected). Survey respondents were also evaluated for "risk-taking attitudes."Findings: A total of 298 responses were evaluated (28% affected adults and 72% caregivers, mostly parents). Most respondents were diagnosed >5 years ago (67.3%), with 22.1% SMA type I, 45.6% SMA type II, and 27.9% SMA type III. No strong correlation was found between risk tolerance and SMA type, stage of disease progression, respondent type, sex, quality of life assessment, or rated levels of independence. Irrespective of SMA type, respondents consistently rated the following risks, associated with a potential treatment, as "least tolerable": lifethreatening allergic reactions; 1 in 1000 risk of lifethreatening side effects leading to possible organ failure; or worsening quality of life. Furthermore, all SMA type respondents rated these risks as "most tolerable": invasive mode of treatment administration (including need for general anesthesia); side effect of dizziness; and other common side effects such as nausea, vomiting, loss of appetite, headaches, back pain, or fatigue.Implications: With the approval of the first SMA treatment, these findings offer a unique opportunity to assess and characterize baseline risk-tolerance in SMA against which to evaluate future SMA treatment options. Although differences had been expected in risk tolerance among respondents based on disease baseline and certain patient attributes, this was not observed. Survey results should inform future SMA drug development and benefiterisk assessments.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community

Cruz

Belter

Wasnock

et al. 2019

Clinical Therapeutics

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“…En cuanto a la supervivencia libre de ventilación, en el grupo tratado fue del 61%, y en el simulado, del 32% (p = 0,0046). Los resultados de los tratados con nusinersen fueron similares a los conseguidos en el ensayo en fase 2, con tendencia a la mejora progresiva del desarrollo motor conforme pasa el tiempo [47]. Con estos datos se decidió que todos los pacientes pasaran a ser tratados durante el resto del ensayo (fase abierta).…”

Section: Oligonucleótidos Antisentidounclassified

Posibilidades de tratamiento en la atrofia espinal infantil

Pascual¹,

García-Romero²

2017

RevNeurol

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“…Several PMO ASOs (eteplirsen, golodirsen, viltolarsen, and casimersen) have been approved to treat different causal mutations in Duchenne muscular dystrophy; they induce skipping of target exons in the mutant DMD pre-mRNA and promote the production of partially functional dystrophin protein (22). The FDA approval of nusinersen (Spinraza) in 2016 to treat spinal muscular atrophy and the rapid development of milasen, a personalized therapy for a single patient with neuronal ceroid lipofuscinosis 7 (CLN7, a form of Batten's disease), further highlight the clinical potential of splice-switching ASOs (23,24). Although there is no FDA-approved ASO therapy for CF at present, splice-switching ASOs designed to correct CFTR defective splicing have shown efficacy in patient-derived airway cells and nasal epithelial cells (25,26).…”

Section: Introductionmentioning

confidence: 99%

Exon-Skipping Antisense Oligonucleotides for Cystic Fibrosis Therapy

Kim

Sivetz

Layne

et al. 2021

Preprint

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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), and the CFTR-W1282X nonsense mutation causes a severe form of CF. Although Trikafta and other CFTR-modulation therapies benefit most CF patients, targeted therapy for patients with the W1282X mutation is lacking. The CFTR-W1282X protein has residual activity, but is expressed at a very low level due to nonsense-mediated mRNA decay (NMD). NMD-suppression therapy and read-through therapy are actively being researched for CFTR nonsense mutants. NMD suppression could increase the mutant CFTR mRNA, and read-through therapies may increase the levels of full-length CFTR protein. However, these approaches have limitations and potential side effects: because the NMD machinery also regulates the expression of many normal mRNAs, broad inhibition of the pathway is not desirable; and read-through drugs are inefficient, partly because the mutant mRNA template is subject to NMD. To bypass these issues, we pursued an exon-skipping antisense oligonucleotide (ASO) strategy to achieve gene-specific NMD evasion. A cocktail of two splice-site-targeting ASOs induced the expression of CFTR mRNA without the PTC-containing exon 23 (CFTR-Δex23), which is an in-frame exon. Treatment of human bronchial epithelial cells with this cocktail of ASOs that target the splice sites flanking exon 23 results in efficient skipping of exon 23 and an increase in CFTR-Δex23 protein. The splice-switching ASO cocktail increases the CFTR-mediated chloride current in human bronchial epithelial cells. Our results set the stage for developing an allele-specific therapy for CF caused by the W1282X mutation.

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Interim Efficacy and Safety Results from the Phase 3 ENDEAR Study of Nusinersen in Infants Diagnosed with Spinal Muscular Atrophy (SMA)

Cited by 3 publications

References 0 publications

Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community

Evaluating Benefit-risk Decision-making in Spinal Muscular Atrophy: A First-ever Study to Assess Risk Tolerance in the SMA Patient Community

Posibilidades de tratamiento en la atrofia espinal infantil

Exon-Skipping Antisense Oligonucleotides for Cystic Fibrosis Therapy

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