Combination therapy with nusinersen and AVXS-101 in SMA type 1

Lee, Bo Hoon; Collins, Érin; Lewis, Leann; Guntrum, Debra; Eichinger, Katy; Voter, Karen Z.; Abdel-Hamid, Hoda; Ciafaloni, Emma

doi:10.1212/wnl.0000000000008207

Cited by 37 publications

(28 citation statements)

References 7 publications

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“…Clinical trials data on combination therapy are lacking. Lee et al 14 first reported 2 type 1 SMA patients who were treated with nusinersen followed by onasemnogene. In this report, we describe our experience in using combination molecular therapies to treat patients with type 1 SMA in the “real‐world” clinical setting.…”

Section: Discussionmentioning

confidence: 99%

Combination molecular therapies for type 1 spinal muscular atrophy

et al. 2020

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Background: Data on combining molecular therapies that increase survival motor neuron protein for spinal muscular atrophy type 1 (SMA1) is lacking. Methods: This was a retrospective study describing our centers' experiences in treating SMA1 patients with combination therapy. Results: Five children received nusinersen and onasemnogene abeparvovec-xioi (onasemnogene). Four were receiving nusinersen prior to onasemnogene. Nusinersen was continued in three. Marked liver enzyme elevations resulted in prolonged corticosteroid treatment in two patients with hospitalization and liver biopsy in one; milder liver enzyme elevations were noted in the other two. One patient received onasemnogene first, and then nusinersen. No adverse effects were noted. All patients improved. Conclusions: Combination molecular therapy is tolerated in SMA1 patients. Further studies are needed to determine whether there are circumstances in which combination therapy would be more efficacious than either monotherapy. Prolonged corticosteroid use and liver toxicity monitoring may be necessary with onasemnogene therapy.

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Section: Discussionmentioning

confidence: 99%

Combination molecular therapies for type 1 spinal muscular atrophy

et al. 2020

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“…Excitingly, a combined approach using SMN-dependent ASO-inducing SMN2 exon inclusion and SMN-independent myostatin inhibition have shown a favorable result in an SMA animal model [120]. Combined treatment with Zolgensma and nusinersen has recently been investigated in a small group of patients, although the long-term benefit is still unclear [121]. Zolgensma and nusinersen have different mechanisms of action, so the drug-to-drug interaction is less likely.…”

Section: Combination Therapy For Smamentioning

confidence: 99%

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

Chen

2020

IJMS

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Spinal muscular atrophy (SMA) is a congenital neuromuscular disorder characterized by motor neuron loss, resulting in progressive weakness. SMA is notable in the health care community because it accounts for the most common cause of infant death resulting from a genetic defect. SMA is caused by low levels of the survival motor neuron protein (SMN) resulting from SMN1 gene mutations or deletions. However, patients always harbor various copies of SMN2, an almost identical but functionally deficient copy of the gene. A genotype–phenotype correlation suggests that SMN2 is a potent disease modifier for SMA, which also represents the primary target for potential therapies. Increasing comprehension of SMA pathophysiology, including the characterization of SMN1 and SMN2 genes and SMN protein functions, has led to the development of multiple therapeutic approaches. Until the end of 2016, no cure was available for SMA, and management consisted of supportive measures. Two breakthrough SMN-targeted treatments, either using antisense oligonucleotides (ASOs) or virus-mediated gene therapy, have recently been approved. These two novel therapeutics have a common objective: to increase the production of SMN protein in MNs and thereby improve motor function and survival. However, neither therapy currently provides a complete cure. Treating patients with SMA brings new responsibilities and unique dilemmas. As SMA is such a devastating disease, it is reasonable to assume that a unique therapeutic solution may not be sufficient. Current approaches under clinical investigation differ in administration routes, frequency of dosing, intrathecal versus systemic delivery, and mechanisms of action. Besides, emerging clinical trials evaluating the efficacy of either SMN-dependent or SMN-independent approaches are ongoing. This review aims to address the different knowledge gaps between genotype, phenotypes, and potential therapeutics.

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“…Head to head studies comparing the amount of SMN protein expression or clinical effect size are not available. The combination of both approaches has also not been studied systematically and warrants further investigation [24]. However, from a theoretical point of view one would not expect the combinational effect to be equal to the sum of their single effects due to the common downstream pathway and mode of action, unless the biodistribution of the different therapeutic compounds was substantially different.…”

Section: Strength Of Consensus: Strong Consensus (100%)mentioning

confidence: 99%

European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy

Kirschner

Butoianu

Goemans³

et al. 2020

European Journal of Paediatric Neurology

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Spinal muscular atrophy (SMA) used to be one of the most common genetic causes of infant mortality. New disease modifying treatments have changed the disease trajectories and most impressive results are seen if treatment is initiated in the presymptomatic phase of the disease. Very recently, the European Medicine Agency approved Onasemnogene abeparvovec (Zolgensma®) for the treatment of patients with SMA with up to three copies of the SMN2 gene or the clinical presentation of SMA type 1. While this broad indication provides new opportunities, it also triggers discussions on the appropriate selection of patients in the context of limited available evidence. To aid the rational use of Onasemnogene abeparvovec for the treatment of SMA, a group of European neuromuscular experts presents in this paper eleven consensus statements covering qualification, patient selection, safety considerations and longterm monitoring.

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Combination therapy with nusinersen and AVXS-101 in SMA type 1

Cited by 37 publications

References 7 publications

Combination molecular therapies for type 1 spinal muscular atrophy

Combination molecular therapies for type 1 spinal muscular atrophy

New and Developing Therapies in Spinal Muscular Atrophy: From Genotype to Phenotype to Treatment and Where Do We Stand?

European ad-hoc consensus statement on gene replacement therapy for spinal muscular atrophy

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