Kindy Mark, Lupinacci Paul, Chau Raymond, Shum Tony, Ko Dorothy
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Department of Mathematics and Statistics, Villanova University, Villanova, PA, USA.
F1000Res. 2017 Mar 7;6:230. doi: 10.12688/f1000research.10519.1. eCollection 2017.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that lacks effective treatment options. Genervon has discovered and developed GM604 (GM6) as a potential ALS therapy. GM6 has been modeled upon an insulin receptor tyrosine kinase binding motoneuronotrophic factor within the developing central nervous system. This was a 2-center phase 2A, randomized, double-blind, placebo-controlled pilot trial with 12 definite ALS patients diagnosed within 2 years of disease onset. Patients received 6 doses of GM604 or placebo, administered as slow IV bolus injections (3x/week, 2 consecutive weeks). Objectives were to assess the safety and efficacy of GM604 based on ALSFRS-R, FVC and selected biomarkers (TDP-43, Tau and SOD1, pNFH). This report also includes results of compassionate treatment protocol GALS-C for an advanced ALS patient. Definite ALS patients were randomized to one of two treatment groups (GM604, n = 8; placebo, n = 4). 2 of 8 GM604-treated patients exhibited mild rash, but otherwise adverse event frequency was similar in treated and placebo groups. GM604 slowed functional decline (ALSFRS-R) when compared to a historical control (P = 0.005). At one study site, a statistically significant difference between treatment and control groups was found when comparing changes in respiratory function (FVC) between baseline and week 12 (P = 0.027). GM604 decreased plasma levels of key ALS biomarkers relative to the placebo group (TDP-43, P = 0.008; Tau, P = 0.037; SOD1, P = 0.009). The advanced ALS patient in compassionate treatment demonstrated improved speech, oral fluid consumption, mouth suction with GM604 treatment and biomarker improvements. We observed favorable shifts in ALS biomarkers and improved functional measures during the Phase 2A study as well as in an advanced ALS patient. Although a larger trial is needed to confirm these findings, the present data are encouraging and support GM604 as an ALS drug candidate.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，目前缺乏有效的治疗方案。Genervon公司已发现并研发出GM604（GM6）作为一种潜在的ALS治疗药物。GM6是根据发育中的中枢神经系统内胰岛素受体酪氨酸激酶结合运动神经营养因子构建的。这是一项2中心2A期随机双盲安慰剂对照试验，纳入了12例在疾病发作2年内确诊的明确ALS患者。患者接受6剂GM604或安慰剂，通过静脉缓慢推注给药（每周3次，连续2周）。目的是基于ALS功能评定量表修订版（ALSFRS-R）、用力肺活量（FVC）和选定的生物标志物（TDP-43、Tau和SOD1、磷酸化神经丝蛋白重链（pNFH））评估GM604的安全性和疗效。本报告还包括对一名晚期ALS患者的同情用药方案GALS-C的结果。明确的ALS患者被随机分为两个治疗组之一（GM604组，n = 8；安慰剂组，n = 4）。8例接受GM604治疗的患者中有2例出现轻度皮疹，但治疗组和安慰剂组的不良事件发生率相似。与历史对照相比，GM604减缓了功能衰退（ALSFRS-R）（P = 0.005）。在一个研究地点，比较基线和第12周之间的呼吸功能变化（FVC）时，治疗组和对照组之间存在统计学显著差异（P = 0.027）。相对于安慰剂组，GM604降低了关键ALS生物标志物的血浆水平（TDP-43，P = 0.008；Tau，P = 0.037；SOD1，P = 0.009）。同情用药治疗的晚期ALS患者在接受GM604治疗后，言语、口腔液体摄入、口腔吸力均有所改善，生物标志物也有所改善。在2A期研究以及一名晚期ALS患者中，我们观察到ALS生物标志物出现有利变化，功能指标得到改善。尽管需要更大规模的试验来证实这些发现，但目前的数据令人鼓舞，并支持GM604作为一种ALS候选药物。
