AVXS-101 Phase 1 gene therapy clinical trial in SMA Type 1: Event free survival and achievement of developmental milestones

Mendell, Jerry R.; Al-Zaidy, Samiah; Shell, Richard; Arnold, W. David; Rodino‐Klapac, Louise R.; Prior, Thomas W.; Lowes, Linda; Alfano, Lindsay; Berry, Katherine; Church, Kathleen; Kissel, John T.; Nagendran, Sukumar; L’Italien, James; Sproule, Douglas M.; Cardenas, Jessica; Burghes, Arthur; Foust, Kevin D.; Meyer, Kathrin; Likhite, Shibi; Kaspar, Brian K.

doi:10.1016/j.ejpn.2017.04.1216

Cited by 10 publications

(18 citation statements)

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“…This summary of the completed 24-month post-treatment follow-up from the AVXS-101 study demonstrated improved outcomes in AVXS-101-treated infants with SMA1. The results are a substantial departure from the comparable NN101 infants with SMA1 cohort, with differences in survival, motor function, and motor milestone achievement appearing to increase over time [11]. Along with a significant positive impact on eventfree survival (100% vs 38% event-free survival), AVXS-101 treatment also had a rapid positive impact on the expected early motor function decline in infants with SMA1, as demonstrated by increased CHOP-INTEND scores (9.8 and 15.4 points at 1 and 3 months post-dose, respectively).…”

Section: Discussionmentioning

confidence: 59%

“…Infants with SMA1 who were treated with AVXS-101 did not develop as quickly as the healthy infant cohort in terms of motor milestone achievement and motor function. However, most eventually continued to gain motor function and developed new motor milestones [11]. The AVXS-101 study results and other interventional study reports suggest that intervention with disease-modifying treatment at the youngest possible age and early in the disease course, potentially before symptoms occur, might provide the best opportunity for optimal outcomes [21,22].…”

Section: Discussionmentioning

confidence: 93%

“…AVXS-101 is also designed to provide high and continuous expression of the SMN protein through a strong continuous promoter, which is essential for durable effects. In a phase 1 trial, the AVXS-101 study, all participants receiving a 1-time intravenous dose of AVXS-101 achieved permanent ventilation-free survival up to 24 months of age and further [10,11]. Eleven (92%) of 12 infants receiving the proposed therapeutic dose achieved and maintained the ability to sit unassisted, and 2 were able to stand and walk independently [10].…”

Section: Introductionmentioning

confidence: 99%

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AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort

Al-Zaidy

Kolb

Lowes

et al. 2019

JND

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136

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Background: 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. Objective: 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. Methods: 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. Results: 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).

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Section: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort

Al-Zaidy

Kolb

Lowes

et al. 2019

JND

Self Cite

136

131

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“…To this aim, adeno-associated virus (AAV) vectors represent the platform of choice for in vivo gene transfer. 8 Data obtained in the context of clinical trials for hemophilia, 9 congenital blindness, 10 and spinal muscular atrophy 11 demonstrate the safety and therapeutic potential of the AAV vector gene transfer platform. Furthermore, the experience accumulated in large animal models of neuromuscular disorders indicates that systemic administration of AAV vectors results in efficient muscle targeting.…”

Section: Introductionmentioning

confidence: 99%

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

et al. 2018

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Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by a deficiency of glycogen-debranching enzyme (GDE), which results in profound liver metabolism impairment and muscle weakness. To date, no cure is available for GSDIII and current treatments are mostly based on diet. Here we describe the development of a mouse model of GSDIII, which faithfully recapitulates the main features of the human condition. We used this model to develop and test novel therapies based on adeno-associated virus (AAV) vector-mediated gene transfer. First, we showed that overexpression of the lysosomal enzyme alpha-acid glucosidase (GAA) with an AAV vector led to a decrease in liver glycogen content but failed to reverse the disease phenotype. Using dual overlapping AAV vectors expressing the GDE transgene in muscle, we showed functional rescue with no impact on glucose metabolism. Liver expression of GDE, conversely, had a direct impact on blood glucose levels. These results provide proof of concept of correction of GSDIII with AAV vectors, and they indicate that restoration of the enzyme deficiency in muscle and liver is necessary to address both the metabolic and neuromuscular manifestations of the disease.

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“…Nusinersen, the first FDA-approved treatment for SMA, is a modified antisense oligonucleotide that increases full-length survival motor neuron (SMN) protein, and treatment results are striking. Another approach using adenovirus to deliver SMN shows highly promising preliminary results 16. An investigation of Duchenne muscular dystrophy (DMD) using the antisense oligonucleotide eteplirsen leads to increased production of a truncated but functional dystrophin in boys with DMD and a specific mutation in the dystrophin gene 17.…”

Section: No Testosterone For Spinal and Bulbar Muscular Atrophy (Sbma)mentioning

confidence: 99%

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy

Mitsumoto

2017

J Neurol Neurosurg Psychiatry

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AVXS-101 Phase 1 gene therapy clinical trial in SMA Type 1: Event free survival and achievement of developmental milestones

Cited by 10 publications

References 0 publications

AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort

AVXS-101 (Onasemnogene Abeparvovec) for SMA1: Comparative Study with a Prospective Natural History Cohort

Rescue of GSDIII Phenotype with Gene Transfer Requires Liver- and Muscle-Targeted GDE Expression

Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy

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