scholarly journals B.01 AVXS-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal phase 3 study (STR1VE) update

2019 ◽  
Vol 46 (s1) ◽  
pp. S10 ◽  
Author(s):  
JW Day ◽  
CA Chiriboga ◽  
TO Crawford ◽  
BT Darras ◽  
RS Finkel ◽  
...  
Keyword(s):  
Preliminary Data ◽  
Muscular Atrophy ◽  
Phase 1 ◽  
Ventilatory Support ◽  
Genetic Diagnosis ◽  
Gene Replacement ◽  
Survival Motor Neuron ◽  
Open Label ◽  
Phase 3 ◽  
Pivotal Phase

Background: SMA1 is a neurodegenerative disease caused by bi-allelic survival motor neuron 1 gene (SMN1) deletion/mutation. In the phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA1 patients. We report preliminary data of STR1VE, a pivotal study (NCT03306277) evaluating efficacy and safety of a one-time intravenous AVXS-101 infusion. Methods: STR1VE is a phase 3, multicenter, open-label, single-arm study in SMA1 patients aged <6 months (bi-allelic SMN1 loss, 2xSMN2). Primary outcomes: independent sitting for ≥30 seconds (18 months) and survival (14 months). Secondary outcomes: ability to thrive and ventilatory support (18 months). Exploratory outcomes: CHOP-INTEND and Bayley Scales of Infant and Toddler Development scores. Results: Enrollment is complete with 22 patients dosed. Mean age at symptom onset, genetic diagnosis, and enrollment was 1.9 (0–4.0), 2.1 (0.5–4.0), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support, and all exclusively fed by mouth. Mean baseline CHOP-INTEND score was 32.6 (17.0–52.0), which increased 6.9 (-4.0–16.0, n=20), 10.4 (2.0–18.0, n=12), and 11.6 (-3.0–23.0, n=9) points at 1, 2, and 3 months; updates provided at congress. Conclusions: Preliminary data from STR1VE show rapid motor function improvements in SMA1 patients, paralleling phase 1 findings.

scholarly journals 066 Avxs-101 gene-replacement therapy (GRT) for spinal muscular atrophy type 1 (SMA1): pivotal phase 3 study (STR1VE) update

2019 ◽  
Vol 90 (e7) ◽  
pp. A22.1-A22 ◽  
Author(s):  
John W Day ◽  
Claudia A Chiriboga ◽  
Thomas O Crawford ◽  
Basil T Darras ◽  
Richard S Finkel ◽  
...  
Keyword(s):  
Preliminary Data ◽  
Muscular Atrophy ◽  
Phase 1 ◽  
Neuromuscular Disorders ◽  
Ventilatory Support ◽  
Genetic Diagnosis ◽  
Survival Motor Neuron ◽  
Open Label ◽  
Phase 3 ◽  
Pivotal Phase

IntroductionSMA1 is a neurodegenerative disease caused by bi-allelic survival motor neuron 1 gene (SMN1) deletion/mutation. In the phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA1 patients. We report preliminary data of STR1VE, a pivotal study (NCT03306277) evaluating efficacy and safety of a one-time intravenous AVXS-101 infusion.MethodsSTR1VE is a phase 3, multicenter, open-label, single-arm study in SMA1 patients aged <6 months (bi-allelic SMN1 loss, 2xSMN2). Primary outcomes: independent sitting for ≥30 seconds (18 months) and survival (14 months). Secondary outcomes: ability to thrive and ventilatory support (18 months). Exploratory outcomes: Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and Bayley Scales of Infant and Toddler Development scores.ResultsEnrollment is complete with 22 patients dosed. Mean age at symptom onset, genetic diagnosis, and enrollment was 1.9 (0–4.0), 2.1 (0.5–4.0), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support, and all exclusively fed by mouth. Mean baseline CHOP-INTEND score was 32.6 (17.0–52.0), which increased 6.9 (-4.0–16.0, n=20), 10.4 (2.0–18.0, n=12), and 11.6 (-3.0–23.0, n=9) points at 1, 2, and 3 months. Updates will be provided at the congress.ConclusionsPreliminary data from STR1VE show rapid motor function improvements in SMA1 patients, paralleling phase 1 findings.

scholarly journals 014 AVXS-101 gene-replacement therapy (GRT) in presymptomatic spinal muscular atrophy (SMA): study update

2019 ◽  
Vol 90 (e7) ◽  
pp. A5.3-A6
Author(s):  
Michelle Farrar ◽  
Kathryn J Swoboda ◽  
Meredith Schultz ◽  
Hugh McMillan ◽  
Julie Parsons ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Muscular Atrophy ◽  
Phase 1 ◽  
Neuromuscular Disorders ◽  
Gene Replacement ◽  
Survival Motor Neuron ◽  
Open Label ◽  
Improved Outcomes ◽  
Gene Replacement Therapy ◽  
Open Label Phase

IntroductionSMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Copies of a similar gene (SMN2) modify disease severity. In a phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA patients with two SMN2 copies (2xSMN2) dosed ≤6 months. Because motor neuron loss can be insidious and disease progression is rapid, early intervention is critical. This study evaluates AVXS-101 in presymptomatic SMA newborns.MethodsSPR1NT is a multicenter, open-label, phase 3 study (NCT03505099) enrolling ≥27 SMA patients with 2–3xSMN2. Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1×1014 vg/kg). Safety and efficacy are assessed through study end (18 [2xSMN2] or 24 months [3xSMN2]). Primary outcomes: independent sitting for ≥30 seconds (18 months [2xSMN2]) or assisted standing (24 months [3xSMN2]).ResultsFrom April–September 2018, 7 infants received AVXS-101 (4 female; 6 with 2xSMN2) at ages 8–37 days. Mean baseline Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score was 41.7 (n=6), which increased by 6.8, 11.0, 18.0, and 22.5 points at day 14 (n=4), month 1 (n=3), 2 (n=3), and 3 (n=2). As of January 31, 2019, 15 asymptomatic infants have been enrolled in SPR1NT and dosed with AVXS-101. Updated data available at the time of the congress will be presented.ConclusionsPreliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.

scholarly journals Recombinant Adeno-Associated Virus Serotype 9 Gene Therapy in Spinal Muscular Atrophy

2021 ◽  
Vol 12 ◽  
Author(s):  
Katarzyna Kotulska ◽  
Aviva Fattal-Valevski ◽  
Jana Haberlova
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Phase 1 ◽  
Gene Replacement ◽  
The European Union ◽  
Real World Data ◽  
Phase 3 ◽  
Adeno Associated Virus ◽  
Virus Serotype

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11,000 live births and before the era of treatment SMA was a leading genetic cause of mortality in infants. Recently, disease modifying therapies have been introduced in clinical practice. They include intrathecal and oral antisense oligonucleotides binding to pre-mRNA of SMN2 gene and increasing the translation of fully functional SMN protein as well as SMN1 gene replacement therapy. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trials showed that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA. Currently, phase 3 trials in SMA1 and SMA2 patients, as well as presymptomatic infants diagnosed with SMA, are ongoing. The drug was approved for medical use in the US in 2019, and in Japan and the European Union in 2020. Thus, first real-world data on efficacy and safety of onasemnogene abeparvovec in SMA patients are available.

scholarly journals P.065 AVXS-101 gene-replacement therapy (GRT)) in presymptomatic spinal muscular atrophy (SMA): study update

2019 ◽  
Vol 46 (s1) ◽  
pp. S31-S32 ◽  
Author(s):  
M Schultz ◽  
K Swoboda ◽  
M Farrar ◽  
H McMillan ◽  
J Parsons ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Phase 1 ◽  
Gene Replacement ◽  
Open Label ◽  
Phase 1 Study ◽  
Improved Outcomes ◽  
Gene Replacement Therapy ◽  
Open Label Phase ◽  
Motor Neuron Loss ◽  
Similar Gene

Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of SMN1. Copies of a similar gene (SMN2) modify disease severity. In a phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA patients with two SMN2 copies (2xSMN2) dosed ≤6 months. Because motor neuron loss can be insidious and disease progression is rapid, early intervention is critical. This study evaluates AVXS-101 in presymptomatic SMA newborns. Methods: SPR1NT is a multicenter, open-label, phase 3 study enrolling ≥27 SMA patients with 2–3xSMN2. Asymptomatic infants ≤6 weeks receive a one-time intravenous AVXS-101 infusion (1.1x1014 vg/kg). Safety and efficacy are assessed through study end (18 [2xSMN2] or 24 months [3xSMN2]). Primary outcomes: independent sitting for ≥30 seconds (18 months [2xSMN2]) or assisted standing (24 months [3xSMN2]). Results: From April–September 2018, 7 infants received AVXS-101 (4 female; 6 with 2xSMN2) at ages 8–37 days. Mean baseline CHOP-INTEND score was 41.7 (n=6), which increased by 6.8, 11.0, 18.0, and 22.5 points at day 14 (n=4), month 1 (n=3), 2 (n=3), and 3 (n=2). Updated data available at the time of the congress will be presented. Conclusions: Preliminary data from SPR1NT show rapid motor function improvements in presymptomatic SMA patients.

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