McGrath Michael S, Zhang Rongzhen, Bracci Paige M, Azhir Ari, Forrest Bruce D
Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA.
Neuvivo, Inc., Palo Alto, CA 94301, USA.
Biomedicines. 2024 Oct 16;12(10):2362. doi: 10.3390/biomedicines12102362.
BACKGROUND/OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival.
Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival.
The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.
背景/目的：肌萎缩侧索硬化症（ALS）是一种将一系列异质性神经退行性过程整合为单一进行性且一致致命的疾病，这使得开发统一适用的治疗方法变得困难。近期的跨国ALS自然病史发病率研究已确定先天性免疫系统的全身性慢性激活是患ALS的主要风险因素。ALS患者持续的免疫激活会导致肌肉流失和血清肌酐降低。本研究的目的是测试在2期研究中，与对照组相比，NP001治疗的ALS患者神经和肌肉破坏的减缓是否会导致生存期延长。
NP001是一种静脉注射的先天性免疫系统调节剂次氯酸钠，其2期临床研究现报告称，在仅进行了6个月的间歇性治疗后，药物接受者与安慰剂对照组相比有长期生存益处。作为一种前体药物，NP001被巨噬细胞转化为氯胺牛磺酸，一种长效的炎症调节剂。我们对所有在两项为期6个月的NP001 2期试验中完成研究的患者进行了汇总分析。呼吸肺活量和肌肉质量产物肌酐的变化确定了与安慰剂相比生存期延长了一年的治疗患者。
在炎症相关肌肉损失最严重的ALS患者中观察到的更长生存期进一步证明，ALS是一种持续存在先天性免疫功能障碍的疾病，并且NP001是一种具有持续临床活性的疾病修饰药物。
