医学
不利影响
耐受性
SMN1型
中期分析
脊髓性肌萎缩
临床终点
形状记忆合金*
临床研究阶段
内科学
外科
麻醉
临床试验
数学
组合数学
疾病
作者
R. Finkel,John W. Day,Basil T. Darras,Nancy L. Kuntz,AM Connolly,Thomas O. Crawford,Russell J. Butterfield,PB Shieh,Gihan Tennekoon,Susan T. Iannaccone,Matthew N. Meriggioli,Francis G. Ogrinc,Sarah Kavanagh,Elaine Kernbauer,Jason D. Whittle,James L’Italien,Brian K. Kaspar,Douglas M. Sproule,Sidney A. Spector,Douglas E. Feltner,Jerry R. Mendell
标识
DOI:10.1016/j.jns.2019.10.322
摘要
The one-time survival motor neuron (SMN) GRT AVXS-101 treats the genetic root cause of SMA. In a phase 1/2a study (CL-101; NCT02122952), intravenous AVXS-101 administration improved outcomes in SMA type 1 patients. STRONG is a multicenter, open-label phase 1/2a study (NCT03381729) assessing intrathecal AVXS-101 in SMA2 patients. SMA2 patients (biallelic SMN1 loss, 3xSMN2) aged ≥6–<60 months who could sit but not stand/walk received an intrathecal AVXS-101 dose (dose A: 6.0x10e13; B: 1.2x10e14; C: 2.4x10e14 vg). Dose B enrollment was completed following demonstration of acceptable safety in dose A and B. Endpoints included safety/tolerability, optimal dose, unsupported standing ≥3 s, and change in baseline Hammersmith Functional Motor Scale-Expanded (HFMSE) score. By 24 March 2019, 31 patients were enrolled (11 sites). Enrollment is complete for dose A (n = 3, ≥6–<24 months) and B (n = 25; n = 13, ≥6–<24 months; n = 12, ≥24–<60 months), and ongoing for dose C (3 patients dosed [≥6–<24 months]; 12 planned each ≥6–<24 and ≥24–<60 months). As of 8 March 2019, no fatal treatment-emergent adverse events (TEAEs) have occurred; 7 serious TEAEs occurred in 4 patients, all of which resolved. Patients aged ≥24–<60 months showed rapid HFMSE responses (half had ≥3-point increase from baseline by 1 month post-treatment). Patients aged ≥6–<24 and ≥24–<60 months averaged a 4.2-point increase from baseline HFMSE score at last follow-up. Ten patients achieved 22 additional motor milestones. Interim STRONG data show intrathecal AVXS-101 delivery is feasible, well tolerated, and appears to improve motor function in SMA2 patients.
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