Ross Colin J, Towfic Fadi, Shankar Jyoti, Laifenfeld Daphna, Thoma Mathis, Davis Matthew, Weiner Brian, Kusko Rebecca, Zeskind Ben, Knappertz Volker, Grossman Iris, Hayden Michael R
Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
BC Children's Hospital, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Genome Med. 2017 May 31;9(1):50. doi: 10.1186/s13073-017-0436-y.
Copaxone is an efficacious and safe therapy that has demonstrated clinical benefit for over two decades in patients with relapsing forms of multiple sclerosis (MS). On an individual level, patients show variability in their response to Copaxone, with some achieving significantly higher response levels. The involvement of genes (e.g., HLA-DRB1*1501) with high inter-individual variability in Copaxone's mechanism of action (MoA) suggests the potential contribution of genetics to treatment response. This study aimed to identify genetic variants associated with Copaxone response in patient cohorts from late-phase clinical trials.
Single nucleotide polymorphisms (SNPs) associated with high and low levels of response to Copaxone were identified using genome-wide SNP data in a discovery cohort of 580 patients from two phase III clinical trials of Copaxone. Multivariable Bayesian modeling on the resulting SNPs in an expanded discovery cohort with 1171 patients identified a multi-SNP signature of Copaxone response. This signature was examined in 941 Copaxone-treated MS patients from seven independent late-phase trials of Copaxone and assessed for specificity to Copaxone in 310 Avonex-treated and 311 placebo-treated patients, also from late-phase trials.
A four-SNP signature consisting of rs80191572 (in UVRAG), rs28724893 (in HLA-DQB2), rs1789084 (in MBP), and rs139890339 (in ZAK(CDCA7)) was identified as significantly associated with Copaxone response. Copaxone-treated signature-positive patients had a greater reduction in annualized relapse rate (ARR) compared to signature-negative patients in both discovery and independent cohorts, an effect not observed in Avonex-treated patients. Additionally, signature-positive placebo-treated cohorts did not show a reduction in ARR, demonstrating the predictive as opposed to prognostic nature of the signature. A 10% subset of patients, delineated by the signature, showed marked improvements across multiple clinical parameters, including ARR, MRI measures, and higher proportion with no evidence of disease activity (NEDA).
This study is the largest pharmacogenetic study in MS reported to date. Gene regions underlying the four-SNP signature have been linked with pathways associated with either Copaxone's MoA or the pathophysiology of MS. The pronounced association of the four-SNP signature with clinical improvements in a ~10% subset of the MS patient population demonstrates the complex interplay of immune mechanisms and the individualized nature of response to Copaxone.
考帕松是一种有效且安全的疗法，在复发型多发性硬化症（MS）患者中已显示出超过二十年的临床益处。在个体层面，患者对考帕松的反应存在差异，一些患者的反应水平明显更高。基因（如HLA - DRB1*1501）在考帕松作用机制（MoA）中具有较高的个体间变异性，这表明遗传学对治疗反应可能有贡献。本研究旨在确定来自晚期临床试验患者队列中与考帕松反应相关的基因变异。
使用来自考帕松两项III期临床试验的580名患者的发现队列中的全基因组SNP数据，确定与考帕松高反应水平和低反应水平相关的单核苷酸多态性（SNP）。对1171名患者的扩大发现队列中产生的SNP进行多变量贝叶斯建模，确定了考帕松反应的多SNP特征。在来自考帕松七项独立晚期试验的941名接受考帕松治疗的MS患者中检查了该特征，并在同样来自晚期试验的310名接受阿沃尼克治疗的患者和311名接受安慰剂治疗的患者中评估了其对考帕松的特异性。
由rs80191572（位于UVRAG中）、rs28724893（位于HLA - DQB2中）、rs1789084（位于MBP中）和rs139890339（位于ZAK(CDCA7)中）组成的四SNP特征被确定与考帕松反应显著相关。在发现队列和独立队列中，考帕松治疗的特征阳性患者与特征阴性患者相比，年化复发率（ARR）降低幅度更大，而在接受阿沃尼克治疗的患者中未观察到这种效果。此外，特征阳性的安慰剂治疗队列的ARR没有降低，这表明该特征具有预测性而非预后性。由该特征划定的10%的患者子集在多个临床参数上有显著改善，包括ARR、MRI测量以及更高比例的无疾病活动证据（NEDA）。
本研究是迄今为止报道的MS领域最大的药物遗传学研究。四SNP特征背后的基因区域已与与考帕松MoA或MS病理生理学相关的途径联系起来。四SNP特征与MS患者群体中约10%的子集的临床改善之间的显著关联表明了免疫机制的复杂相互作用以及对考帕松反应的个体化性质。
