口服ALS治疗降低有毒蛋白水平，延长生存期

PrimeC meets goal of lowering TDP-43 in Phase 2b study

PrimeC在2b期研究中达到降低TDP-43的目标

Oral amyotrophic lateral sclerosis (ALS) treatment PrimeC significantly reduced levels of TDP-43, a protein that abnormally accumulates in nearly all ALS cases, in a Phase 2b clinical trial.

口服肌萎缩侧索硬化症（ALS）治疗药物PrimeC在2b期临床试验中显著降低了TDP-43的水平；TDP-43是一种在几乎所有ALS病例中异常蓄积的蛋白质。

The PARADIGM study met its main efficacy goal of lowering TDP-43 levels in nerve cells relative to a placebo after six months. The reduction was sustained and became more pronounced over the full 18 months of the study, according to developer Neurosense Therapeutics .

PARADIGM研究达到了其主要疗效目标：与安慰剂相比，在6个月后降低神经细胞中的TDP-43水平。据开发商Neurosense Therapeutics称，这种降低在整个18个月研究期间持续存在，并且更加明显。

The results add to previously reported PARADIGM data showing that PrimeC slowed declines in daily functioning and extended survival among people with ALS, while having a favorable safety profile.

这些结果补充了此前报告的PARADIGM数据，数据显示，PrimeC减缓了ALS患者日常功能的下降，并延长了生存期，同时具有良好的安全性特征。

“Achieving the primary endpoint of PARADIGM with a statistically significant reduction in TDP-43 marks a defining moment for NeuroSense and for ALS research,” Alon Ben-Noon, Neurosense’s CEO, said in a company press release . “We believe this growing dataset further validates our scientific approach and positions PrimeC as one of the most comprehensively supported therapeutic candidates in ALS today.”

“PARADIGM达到了主要终点，并实现了TDP-43具有统计学显著性的降低，这标志着NeuroSense和ALS研究的一个决定性时刻，”Neurosense首席执行官Alon Ben-Noon在公司新闻稿中表示。“我们认为，这批不断增长的数据进一步验证了我们的科学方法，并使PrimeC成为目前ALS领域获得最全面支持的治疗候选药物之一。”

In ALS, motor neurons (the nerve cells responsible for controlling voluntary movement) gradually become damaged and die. This leads to progressive muscle weakness and increasing difficulties with movement, speaking, swallowing, and breathing.

在ALS中，运动神经元（负责控制自主运动的神经细胞）会逐渐受损并死亡。这会导致肌肉无力逐步加重，并使运动、说话、吞咽和呼吸越来越困难。

TDP-43 is a protein involved in regulating RNA, the molecule that carries genetic instructions needed to make proteins. In most ALS cases, TDP-43 becomes misplaced and forms abnormal clumps inside nerve cells. This is believed to disrupt several essential cellular processes and contribute to nerve cell death.

TDP-43是一种参与调控RNA的蛋白质；RNA是携带制造蛋白质所需遗传指令的分子。在大多数ALS病例中，TDP-43会错位，并在神经细胞内形成异常团块。这被认为会扰乱多个基本细胞过程，并促成神经细胞死亡。

PrimeC is an extended-release oral combination of two approved medications: the antibiotic ciprofloxacin and the anti-inflammatory medicine celecoxib. The therapy is designed to simultaneously target several mechanisms thought to contribute to ALS progression, including inflammation, abnormal iron accumulation, and disrupted RNA regulation.

PrimeC是一种口服缓释复方制剂，由两种已获批准的药物组成：抗生素ciprofloxacin和抗炎药celecoxib。该疗法旨在同时靶向被认为会促成ALS进展的多种机制，包括炎症、铁异常蓄积以及RNA调控紊乱。

The Phase 2b PARADIGM trial (NCT05357950) involved 68 adults with ALS who were randomly assigned to receive a placebo or PrimeC for six months, in addition to standard ALS treatments . Participants could then enter an open-label extension in which all received PrimeC for up to an additional year.

2b期PARADIGM试验（NCT05357950）纳入68名ALS成人患者，他们被随机分配接受安慰剂或PrimeC，为期6个月，且均在标准ALS治疗基础上进行。随后，参与者可以进入开放标签延长期，所有人接受PrimeC，最长再持续一年。

To assess whether PrimeC reduced TDP-43 accumulation, researchers measured TDP-43 in neuron-derived extracellular vesicles, small sacs released by nerve cells into the bloodstream. This allowed the researchers to distinguish nerve-derived TDP-43 from TDP-43 released by other cell types and tissues.

为评估PrimeC是否减少TDP-43蓄积，研究人员测量了神经元来源的细胞外囊泡中的TDP-43；细胞外囊泡是神经细胞释放到血液中的小囊泡。这使研究人员能够将神经来源的TDP-43与其他细胞类型和组织释放的TDP-43区分开来。

After 180 days, or about six months, TDP-43 levels were significantly lower among participants given PrimeC than in those receiving a placebo. Consistent with previous studies, TDP-43 levels increased in the placebo group.

180天后，即约6个月后，接受PrimeC的参与者中TDP-43水平显著低于接受安慰剂者。与既往研究一致，安慰剂组的TDP-43水平有所升高。

These reductions were sustained and deepened over the full 18 months of PARADIGM. Participants who continuously received PrimeC throughout the study maintained lower TDP-43 levels than those who received a placebo for the first six months and then transitioned to PrimeC.

这些降低在PARADIGM的整个18个月期间持续存在并进一步加深。在整个研究期间持续接受PrimeC的参与者，其TDP-43水平低于前6个月接受安慰剂、随后转用PrimeC的参与者。

“One of the central questions in ALS drug development is whether a therapy is truly affecting the underlying biology of the disease,” said Merit Cudkowicz, MD, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital and professor of neurology at Harvard Medical School.

“ALS药物研发中的一个核心问题是，一种疗法是否确实影响了这种疾病的基础生物学机制，”马萨诸塞州总医院Sean M. Healey & AMG Center for ALS主任、哈佛医学院神经病学教授Merit Cudkowicz, MD表示。

The results are consistent with earlier findings from PARADIGM. PrimeC slowed declines on the ALS Functional Rating Scale-Revised , which assesses one’s ability to perform everyday activities, by 36.5% after one year and by 32.8% after 18 months.

这些结果与PARADIGM此前的发现一致。PrimeC减缓了ALS Functional Rating Scale-Revised评分的下降；该量表评估一个人进行日常活动的能力；1年后减缓幅度为36.5%，18个月后为32.8%。

Long-term data showed an approximately 15-month extension in median survival and a 65% reduction in the risk of death among participants who started PrimeC at the beginning of the study compared with those whose treatment was delayed by six months.

长期数据显示，与治疗延迟6个月的参与者相比，在研究开始时即开始接受PrimeC的参与者，中位生存期延长约15个月，死亡风险降低65%。

“For decades, TDP-43 has been recognized as the pathological signature of ALS, yet demonstrating a treatment-associated reduction in people with ALS has remained elusive,” Ben-Noon said. “Combined with the clinically meaningful slowing of disease progression, significant survival benefit, and consistent biomarker findings previously reported from PARADIGM, these results provide a compelling and highly differentiated body of evidence supporting PrimeC’s potential as a disease-modifying therapy.”

“几十年来，TDP-43一直被视为ALS的病理学标志，但要证明治疗相关的降低确实发生在ALS患者身上始终难以实现，”Ben-Noon表示。“结合此前报告的PARADIGM数据所显示的具有临床意义的疾病进展减缓、显著生存获益以及一致的生物标志物结果，这些结果提供了一套有说服力且高度差异化的证据，支持PrimeC作为疾病修饰疗法的潜力。”

PrimeC was generally well tolerated, with no new safety concerns identified over up to 18 months of treatment.

PrimeC总体耐受性良好，在最长18个月的治疗期间未发现新的安全性问题。

“These results provide compelling data supporting advancement into a confirmatory Phase 3 clinical trial,” Cudkowicz said.

“这些结果提供了有说服力的数据，支持推进至确证性3期临床试验，”Cudkowicz表示。

To confirm PARADIGM’s findings, Neurosense is planning a global, pivotal Phase 3 clinical trial, called PARAGON, enrolling approximately 300 people with ALS across the U.S. and Europe. The trial has received U.S. Food and Drug Administration (FDA) clearance .

为确认PARADIGM的发现，Neurosense正计划开展一项全球性关键性3期临床试验，名为PARAGON，计划在美国和欧洲招募约300名ALS患者。该试验已获得美国食品药品监督管理局（FDA）的许可。

In the meantime, the company is in talks with regulators in several countries, including Canada, where it plans to request expedited conditional approval .

与此同时，公司正与包括加拿大在内的多个国家的监管机构进行讨论，并计划申请加速有条件批准。