背景:成人肾上腺脑白质营养不良患者由于肾上腺神经病变的发展而预后不良。此外,大部分肾上腺神经神经病变患者发展为危及生命的进行性脑肾上腺脑白质营养不良.利格列酮是一种新型的选择性过氧化物酶体增殖物激活受体γ激动剂,可调节与肾上腺脑白质营养不良疾病进展有关的神经炎症和神经退行性过程的关键基因的表达。我们的目的是评估利格列酮对临床的影响,成像,和成人肾上腺神经病变疾病进展的生化标志物。
方法:提前96周,随机化,双盲,安慰剂对照,在法国10家医院进行的2-3期试验,德国,匈牙利,意大利,荷兰,西班牙,英国,和美国。随机分配(2:1,无分层),年龄在18-65岁之间,患有肾上腺脊髓神经病,无钆增强性病变提示进行性脑肾上腺皮质白质营养不良的门诊男性,接受每日口服利格列酮悬浮液(150mg起始剂量;在基线和第12周之间,剂量增加或减少,以达到200μg·h/mL[20%]的血浆浓度,通过计算机产生的交互式反应系统和安慰剂。研究者和患者被掩盖成组分配。主要疗效终点是在第96周的六分钟步行测试距离中相对于基线的变化,通过混合模型在全分析集中进行分析,以限制最大似然和基线值作为协变量的重复测量。不良事件也在完整分析集中进行评估。这项研究在ClinicalTrials.gov注册,NCT03231878;主要研究已完成;患者可以选择在开放标签扩展中继续治疗,正在进行中。
结果:在2017年12月8日至2018年10月16日之间,筛查了136名患者,116例被随机分配;77例接受格列酮治疗的患者中有62例[81%],39例接受安慰剂治疗的患者中有34例[87%]完成治疗。主要终点无组间差异(平均[SD]相对于基线的变化:-27·7[41·4]m;安慰剂:-30·3[60·5]m;最小二乘平均差-1·2m;95%CI-22·6至20·2;p=0·91)。在利格列酮和安慰剂组中最常见的治疗紧急不良事件是体重增加(77例患者中有54[70%],39例患者中有9例[23%],分别)和外周水肿(77中的49[64%]和39中的7[18%])。没有死亡。77名接受格列酮的患者中有14名(18%)发生了严重的因治疗引起的不良事件,39名接受安慰剂的患者中有10名(26%)发生了。最常见的严重治疗紧急不良事件,临床进行性脑肾上腺脑白质营养不良,发生在116例患者中的6例[5%],所有这些人都在安慰剂组。
结论:未达到主要终点,但瑞格列酮的耐受性普遍良好,不良事件发生率与该类药物的预期安全性一致.大脑肾上腺脑白质营养不良的发现,肾上腺神经病变患者的危及生命的事件,仅在安慰剂组患者中发生,支持进一步研究利格列酮是否可能减缓脑肾上腺脑白质营养不良的进展.
背景:Minoryx治疗学。
Adult patients with
adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral
adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2-3
trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18-65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This
study was registered with ClinicalTrials.gov, NCT03231878; the primary
study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: -27·7 [41·4] m; placebo: -30·3 [60·5] m; least-squares mean difference -1·2 m; 95% CI -22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral
adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.