Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial
Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial
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DOI：
10.1016/s1474-4422(18)30320-x
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发表时间：
2018-12-01
期刊：
影响因子：
48
通讯作者：
Fischbeck, Kenneth H.
中科院分区：
文献类型：
--
作者：
Grunseich, Christopher;Miller, Ram;Fischbeck, Kenneth H.
脊髓和球性肌萎缩症是一种由雄激素受体基因CAG重复扩增引起的x连锁神经肌肉疾病。患有此病的患者胰岛素样生长因子-1 （IGF-1）浓度低，IGF-1过表达和给药的研究在转基因模型中显示有益；因此，IGF-1通路是一个潜在的治疗靶点。我们评估了BVS857（一种IGF-1模拟物）在脊髓和球性肌萎缩患者中的安全性、耐受性和初步疗效。在这项随机、双盲、安慰剂对照试验中，我们从丹麦（哥本哈根）、德国（乌尔姆）、意大利（帕多瓦）和美国三个地点（马里兰州贝塞斯达、加利福尼亚州尔湾和俄亥俄州哥伦布）的神经肌肉中心招募了患者。符合条件的患者为18岁或以上，经遗传诊断为脊髓和球性肌萎缩，能够走动，有症状性虚弱，血清IGF-1浓度为170 ng/mL或更低。患者被随机分配（2:1）研究药物或安慰剂的数字方案。患者、研究者和研究人员对治疗分配不知情。在对8名患者进行安全性和耐受性评估后，BVS857每周1次（0.06 mg/kg静脉注射），持续12周。主要结局指标为安全性、耐受性以及BVS857对MRI测量的大腿肌肉体积（TMV）的影响。采用ANCOVA分析第85天TMV与基线的比值。使用成人肌病评估工具测量肌肉力量和功能的次要指标，通过双能x线吸收仪测量瘦体重，以及BVS857药代动力学。该试验已在ClinicalTrials.gov注册，注册号为NCT02024932。31例患者被评估为合格，其中27例被随机分配到BVS857治疗组（n=18）或安慰剂组（n=9）， 24例被纳入初步疗效分析（BVS857组，n=15；安慰剂组，n=9）。BVS857总体安全，无严重不良事件。BVS857组和安慰剂组在不良事件方面没有显著差异。BVS857组18例患者中有13例（72%）检测到免疫原性，包括5例患者中具有中和内源性IGF-1能力的交叉反应抗体。从基线到第85天，安慰剂组TMV下降（-3.4% [-110 cm(3)]），但BVS857组没有下降（0% [2 cm(3)]）。与安慰剂组相比，BVS857组TMV的变化有显著差异（几何平均比1.04 [90% CI 1.01-1.07]; p=0.02）。在肌肉力量和功能方面，两组之间没有差异。结论：脊髓和球性肌萎缩患者给予BVS857治疗12周后，TMV保持稳定。干预与高免疫原性发生率相关，并没有改善肌肉力量或功能。可能需要进一步的研究来评估激活IGF-1通路在这种疾病中的功效。爱思唯尔有限公司版权所有版权所有。
Background Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy.Methods In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). Eligible patients were 18 years or older with a confirmed genetic diagnosis of spinal and bulbar muscular atrophy, were ambulatory, had symptomatic weakness, and had serum IGF-1 concentrations of 170 ng/mL or lower. Patients were randomly assigned (2:1) to study drug or placebo by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. After a safety and tolerability assessment with eight patients, BVS857 was administered once a week (0.06 mg/kg intravenously) for 12 weeks. Primary outcome measures were safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) measured by MRI. The ratio of TMV at day 85 to baseline was analysed with ANCOVA per protocol. Secondary outcomes of muscle strength and function were measured with the Adult Myopathy Assessment Tool, lean body mass through dual energy x-ray absorptiometry, and BVS857 pharmacokinetics. This trial was registered with ClinicalTrials.gov, NCT02024932.Findings 31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. Immunogenicity was detected in 13 (72%) of 18 patients in the BVS857 group, including crossreacting antibodies with neutralising capacity to endogenous IGF-1 in five patients. TMV decreased from baseline to day 85 in the placebo group (-3.4% [-110 cm(3)]) but not in the BVS857 group (0% [2 cm(3)]). A significant difference in change in TMV was observed in the BVS857 group versus the placebo group (geometric-mean ratio 1.04 [90% CI 1.01-1.07]; p=0.02). There were no differences between groups in measures of muscle strength and function.Interpretation TMV remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. Copyright (C) 2018 Elsevier Ltd. All rights reserved.