Lymphopenia is Not the Primary Therapeutic Mechanism of Diroximel Fumarate in Relapsing-Remitting Multiple Sclerosis: Subgroup Analyses of the EVOLVE-MS-1 Study.
IF 3.9
3区 医学
Q1 CLINICAL NEUROLOGY
引用次数: 0
Abstract
Introduction: In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia.
Methods: EVOLVE-MS-1-an open-label, 96-week, phase 3 study-assessed DRF safety and exploratory efficacy in patients with relapsing-remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline).
Results: Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week 96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11-0.17) without lymphopenia and 0.12 (0.09-0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week 96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1-Q4), ARR at week 96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week 96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week 96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients.
Conclusion: In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action.
Trial registration: ClinicalTrials.gov identifier NCT02634307.
淋巴细胞减少症并非富马酸双羟萘酸二甲酯治疗复发性多发性硬化症的主要机制：EVOLVE-MS-1研究的分组分析。
简介在EVOLVE-MS-1（NCT02634307）研究中，服用富马酸双嘧达莫(DRF)的平均绝对淋巴细胞计数(ALC)在第1年从基线下降了约28%，随后趋于稳定，与富马酸二甲酯(DMF)观察到的ALC下降相似。之前的研究报告显示，DMF的临床疗效在有淋巴细胞减少症和无淋巴细胞减少症的患者中没有本质区别：EVOLVE-MS-1是一项为期96周的开放标签3期研究，评估了DRF在复发缓解型多发性硬化症患者中的安全性和探索性疗效。该研究分析了与疗效相关的结果，比较了（1）淋巴细胞减少症患者（≥1个ALC低于正常下限[LLN]）和无淋巴细胞减少症患者（所有ALC均≥LLN）；（2）按第96周ALC从基线下降情况分层的四分位数：Q1（降幅≥ 47%）；Q2（降幅为 30% 至 结果：无淋巴细胞减少症患者（n = 593）和有淋巴细胞减少症患者（n = 452）的基线特征相似。第96周时，无淋巴细胞减少症的调整后年化复发率（ARR；95%置信区间）为0.14（0.11-0.17），有淋巴细胞减少症的调整后年化复发率（ARR；95%置信区间）为0.12（0.09-0.15）。第96周时，12周确诊残疾进展（CDP12）的估计比例为：无淋巴细胞减少症的10.2%，有淋巴细胞减少症的9.3%。如果按四分位数（Q1-Q4）分层，第96周时的ARR分别为0.11（Q1）、0.09（Q2）、0.13（Q3）和0.17（Q4）。第96周时，CDP12的估计比例分别为9.6%（第一季度）、10.2%（第二季度）、5.7%（第三季度）和10.9%（第四季度）。第96周时，47.2%（Q1）、47.8%（Q2）、45.4%（Q3）和37.3%（Q4）的患者没有疾病活动迹象：EVOLVE-MS-1中接受DRF治疗的患者，无论淋巴细胞减少或ALC从基线下降的幅度如何，临床和放射学测量结果均显示疾病活动性降低；然而，与ALC下降幅度最小的患者相比，ALC下降幅度较大的患者的ARR似乎更低，无复发和无钆增强病变的比例更高。这支持了之前的证据，即虽然淋巴细胞减少可能有助于富马酸盐的疗效结果，但它并不是主要的作用机制：试验注册：ClinicalTrials.gov 识别码 NCT02634307。
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来源期刊
Neurology and Therapy
CLINICAL NEUROLOGY-
CiteScore
5.40
自引率
8.10%
发文量
103
审稿时长
6 weeks
期刊介绍：
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Neurology and Therapy aims to provide reliable and inclusive, rapid publication for all therapy related research for neurological indications, supporting the timely dissemination of research with a global reach, to help advance scientific discovery and support clinical practice.
Neurology and Therapy is an international, open access, peer reviewed, rapid publication journal dedicated to the publication of high-quality clinical (all phases), observational, real-world and health outcomes research around the discovery, development, and use of neurological and psychiatric therapies, (also covering surgery and devices). Studies relating to diagnosis, pharmacoeconomics, public health, quality of life, and patient care, management, and education are also welcomed.
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