反义寡核苷酸tofersen治疗SOD1突变所致肌萎缩侧索硬化的1-2期试验

1

反义寡核苷酸tofersen治疗SOD1突变所致肌萎缩侧索硬化的1-2期试验

Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

摘 要

背景

tofersen是一种反义寡核苷酸，介导超氧化物歧化酶1（SOD1）信使RNA的降解，从而减少SOD1蛋白的合成。目前正在研究tofersen鞘内给药治疗SOD1突变所致的肌萎缩侧索硬化（ALS）。

Background

Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations.

方法

我们开展了一项1-2期剂量递增试验，目的是评估tofersen在SOD1突变所致ALS成人患者中的作用。在各剂量组（20、40、60或100 mg）中，我们以3:1的比例将参与者随机分组，分别接受为期12周的5剂tofersen或安慰剂鞘内给药。主要结局是安全性和药代动力学。次要结局是第85日的脑脊液（CSF）SOD1浓度相对于基线的变化。我们还测定了临床功能和肺活量。

Methods

We conducted a phase 1–2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured.

结果

共计50例参与者被随机分组，并被纳入分析；48例参与者接受了计划的全部5剂治疗。大多数参与者发生了与腰椎穿刺相关的不良事件。在接受tofersen治疗的参与者中，分别有4例和5例报告了不良事件CSF白细胞计数增加和蛋白升高。在接受tofersen治疗的参与者中，1例于第137日死于肺栓塞，1例于第152日死于呼吸衰竭；安慰剂组1例参与者于第52日死于呼吸衰竭。对于20 mg剂量、40 mg剂量、60 mg剂量和100 mg剂量，在tofersen组和安慰剂组之间，第85日的CSF SOD1浓度相对于基线的变化的差异分别为2个百分点（95%置信区间[CI]，-18~27）、-25个百分点（95% CI，-40~-5）、-19个百分点（95%CI，-35~2）和-33个百分点（95% CI，-47~-16）。

Result

A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture–related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose.

结论

在SOD1突变所致的ALS成人患者中，在12周期间，最高浓度tofersen鞘内给药后，CSF SOD1浓度降低。一些接受tofersen治疗的参与者出现了CSF脑脊液细胞增多。大多数参与者发生了与腰椎穿刺相关的不良事件。（由渤健公司资助；在ClinicalTrials.gov注册号为NCT02623699；在EudraCT注册号为2015-004098-33。）

Conclusions

In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture–related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699; EudraCT number, 2015-004098-33.)

Timothy Miller, Merit Cudkowicz, Pamela J. Shaw, et al. Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS. DOI:10.1056/NEJMoa2003715

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2

COVID-19患者的肺血管内皮炎、血栓形成和血管生成

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19

摘 要

背景

进行性呼吸衰竭是2019冠状病毒病（COVID-19）大流行中患者的主要死亡原因。虽然人们广泛关注该病的病理生理学，但对死于COVID-19的患者外周肺的相关形态和分子变化却知之甚少。

Background

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.

方法

我们检查了死于COVID-19的患者尸检时获得的7个肺，并与死于甲型H1N1流感继发性急性呼吸窘迫综合征（ARDS）的患者尸检时获得的7个肺和10个年龄匹配的未感染对照肺进行了比较。我们利用七色免疫组化分析、显微计算机断层成像、扫描电子显微镜、腐蚀铸型和直接多重（multiplexed）基因表达测定对肺部进行了检查。

Methods

We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro–computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.

结果

在死于COVID-19相关呼吸衰竭或流感相关呼吸衰竭的患者中，外周肺的组织学形态均为弥漫性肺泡损伤伴血管周围T细胞浸润。COVID-19患者的肺部还表现出独特的血管特征，包括与细胞内病毒相关的重度内皮损伤和细胞膜破裂。COVID-19患者肺血管的组织学分析结果显示广泛血栓形成和微血管病变。肺泡毛细血管微血栓在COVID-19患者中的发生率是流感患者的9倍（P<0.001）。COVID-19患者肺部的新血管生长量（主要通过套叠式血管生成机制）是流感患者肺部的2.7倍（P<0.001）。

Result

In patients who died from Covid-19–associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth — predominantly through a mechanism of intussusceptive angiogenesis — was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).

结论

在这一小型病例系列中，血管生成使COVID-19患者的肺部病理学有别于同样严重的流感病毒感染患者。本研究中观察结果的普遍性和临床意义有待进一步研究来确定。（由美国国立卫生研究院等资助。）

Conclusions

In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.)

Maximilian Ackermann, Stijn E. Verleden, Mark Kuehnel, et al. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. DOI:10.1056/NEJMoa2015432

3

用于预防严重跌伤的多方面策略的随机试验

A Randomized Trial of a Multifactorial Strategy to Prevent Serious Fall Injuries

摘 要

背景

跌倒所致损伤是老年人出现并发症和死亡的主要原因。虽然来自效果试验的证据表明许多跌倒是可以避免的，但导致损伤的跌倒发生率却并未下降。

Background

Injuries from falls are major contributors to complications and death in older adults. Despite evidence from efficacy trials that many falls can be prevented, rates of falls resulting in injury have not declined.

方法

我们开展了一项实效性、整群随机试验，目的是评价由接受过专门培训的护士实施，包括风险评估和个体化计划的多方面干预方案在预防跌伤方面的效果。我们将10个医疗系统的总共86个初级诊疗机构随机分组，分别采用干预措施或加强常规护理（对照）（每组43个初级诊疗机构）。参与者是居住在社区，跌伤风险较高的≥70岁成人。在至事件发生的时间分析中进行评估的主要结局是第一次严重跌伤（根据参与者报告、电子病历和保险理赔数据做出裁定）。我们假设干预组的事件发生率比对照组低20%。

Methods

We conducted a pragmatic, cluster-randomized trial to evaluate the effectiveness of a multifactorial intervention that included risk assessment and individualized plans, administered by specially trained nurses, to prevent fall injuries. A total of 86 primary care practices across 10 health care systems were randomly assigned to the intervention or to enhanced usual care (the control) (43 practices each). The participants were community-dwelling adults, 70 years of age or older, who were at increased risk for fall injuries. The primary outcome, assessed in a time-to-event analysis, was the first serious fall injury, adjudicated with the use of participant report, electronic health records, and claims data. We hypothesized that the event rate would be lower by 20% in the intervention group than in the control group.

结果

干预组（2802例参与者）和对照组（2649例参与者）参与者的人口统计学和基线特征相似；平均年龄为80岁，62.0%的参与者为女性。在至第一起事件发生的时间分析中，两组中经过裁定的第一起严重跌伤的发生率无显著差异（每100人-年随访的事件数量，干预组4.9起和对照组5.3起；风险比，0.92；95%置信区间[CI]，0.80~1.06；P=0.25）。在干预组和对照组中，第一起参与者报告的跌伤发生率分别为25.6起事件/100人-年随访和28.6起事件/100人-年随访（风险比，0.90；95% CI，0.83~0.99；P=0.004）。两组的住院或死亡发生率相似。

Result

The demographic and baseline characteristics of the participants were similar in the intervention group (2802 participants) and the control group (2649 participants); the mean age was 80 years, and 62.0% of the participants were women. The rate of a first adjudicated serious fall injury did not differ significantly between the groups, as assessed in a time-to-first-event analysis (events per 100 person-years of follow-up, 4.9 in the intervention group and 5.3 in the control group; hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.25). The rate of a first participant-reported fall injury was 25.6 events per 100 person-years of follow-up in the intervention group and 28.6 events per 100 person-years of follow-up in the control group (hazard ratio, 0.90; 95% CI, 0.83 to 0.99; P=0.004). The rates of hospitalization or death were similar in the two groups.

结论

与加强常规护理相比，由护士实施的多方面干预措施未能降低经过裁定的第一起严重跌伤的发生率。（由以患者为中心的结局研究所[Patient-Centered Outcomes Research Institute]等资助；STRIDE在ClinicalTrials.gov注册号为NCT02475850。）

Conclusions

A multifactorial intervention, administered by nurses, did not result in a significantly lower rate of a first adjudicated serious fall injury than enhanced usual care. (Funded by the Patient-Centered Outcomes Research Institute and others; STRIDE ClinicalTrials.gov number, NCT02475850.)

Klaus F. Rabe, Fernando J. Martinez, Gary T. Ferguson, et al. Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD. DOI:10.1056/NEJMoa1916046

4

nemolizumab并用外用药治疗特应性皮炎伴瘙痒的试验

Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus

摘 要

背景

nemolizumab是皮下注射的抗白介素-31受体A的人源化单克隆抗体，而白介素-31受体A与特应性皮炎的瘙痒和炎症相关。在2期研究中，nemolizumab减轻了特应性皮炎的严重程度。

Background

Nemolizumab is a subcutaneously administered humanized monoclonal antibody against interleukin-31 receptor A, which is involved in pruritus and inflammation in atopic dermatitis. In phase 2 studies, nemolizumab lessened the severity of atopic dermatitis.

方法

在一项为期16周的双盲3期试验中，我们将有中度至重度瘙痒且对外用药应答不足的日本特应性皮炎患者以2:1的比例随机分组，两组分别每4周接受一次nemolizumab（60 mg）或安慰剂皮下注射，直到第16周，而且并用外用药。主要终点是瘙痒的视觉模拟量表（VAS）评分（范围，0~100，评分较高表示瘙痒较严重）从基线至第16周的平均变化百分比。次要终点包括截至第4周时瘙痒VAS评分变化情况的时间过程，湿疹面积和严重程度指数（Eczema Area and Severity Index，EASI）评分（范围，0~72，评分较高表示较严重）的变化，皮肤病学生活质量指数（Dermatology Life Quality Index，DLQI）评分（范围，0~30，评分较高表示对日常生活的影响较大）≤4分，失眠严重程度指数（Insomnia Severity Index，ISI）评分（范围，0~28，评分较高表示较严重）≤7分和安全性。

Methods

In a 16-week, double-blind, phase 3 trial, we randomly assigned Japanese patients with atopic dermatitis and moderate-to-severe pruritus and an inadequate response to topical agents in a 2:1 ratio to receive subcutaneous nemolizumab (60 mg) or placebo every 4 weeks until week 16, with concomitant topical agents. The primary end point was the mean percent change in the visual-analogue scale (VAS) score for pruritus (range, 0 to 100, with higher scores indicating worse pruritus) from baseline to week 16. Secondary end points included the time course of change in the VAS score for pruritus up to week 4, the change in the Eczema Area and Severity Index (EASI) score (range, 0 to 72, with higher scores indicating greater severity), a score of 4 or less on the Dermatology Life Quality Index (DLQI; range, 0 to 30, with higher scores indicating a greater effect on daily life), a score of 7 or less on the Insomnia Severity Index (ISI; range, 0 to 28, with higher scores indicating greater severity), and safety.

结果

共计143例患者被随机分配接受nemolizumab治疗，72例患者被随机分配接受安慰剂治疗。基线时瘙痒的中位VAS评分为75分。第16周时，nemolizumab组和安慰剂组VAS评分的平均变化百分比分别为-42.8%和-21.4%（差异，-21.5个百分点；95%置信区间，-30.2~-12.7；P<0.001）。nemolizumab组和安慰剂组EASI评分的平均变化百分比分别为-45.9%和-33.2%。nemolizumab组和安慰剂组DLQI评分≤4分的患者百分比分别为40%和22%；ISI评分≤7分的患者百分比分别为55%和21%。nemolizumab组和安慰剂组的注射相关反应发生率分别为8%和3%。

Result

A total of 143 patients were randomly assigned to receive nemolizumab and 72 to receive placebo. The median VAS score for pruritus at baseline was 75. At week 16, the mean percent change in the VAS score was −42.8% in the nemolizumab group and −21.4% in the placebo group (difference, −21.5 percentage points; 95% confidence interval, −30.2 to −12.7; P<0.001). The mean percent change in the EASI score was −45.9% with nemolizumab and −33.2% with placebo. The percentage of patients with a DLQI score of 4 or less was 40% in the nemolizumab group and 22% in the placebo group; the percentage of patients with an ISI score of 7 or less was 55% and 21%, respectively. The incidence of injection-related reactions was 8% with nemolizumab and 3% with placebo.

结论

在这项为期16周的试验中，与特应性皮炎外用药并用安慰剂相比，外用药并用nemolizumab皮下注射更大幅减轻了患者瘙痒。nemolizumab的注射部位反应发生率高于安慰剂。我们有必要通过更长时间、更大规模的试验来确定nemolizumab对特应性皮炎是否具有持久疗效以及是否安全。（由Maruho资助；在JapicCTI注册号为173740。）

Conclusions

In this 16-week trial, the use of subcutaneous nemolizumab in addition to topical agents for atopic dermatitis resulted in a greater reduction in pruritus than placebo plus topical agents. The incidence of injection-site reactions was greater with nemolizumab than with placebo. Longer and larger trials are necessary to determine whether nemolizumab has a durable effect and is safe for atopic dermatitis. (Funded by Maruho; JapicCTI number, 173740.)

Kenji Kabashima, Takayo Matsumura, Hiroshi Komazaki, et al. Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus. DOI:10.1056/NEJMoa1917006

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5

利用腺相关病毒和微RNA抑制SOD1治疗家族性肌萎缩侧索硬化

SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS

摘 要

有超氧化物歧化酶1编码基因（SOD1）突变的两例家族性肌萎缩侧索硬化（ALS）患者接受了腺相关病毒单次鞘内输入治疗，该腺相关病毒编码靶向SOD1的微RNA。患者1在尸检时测定的脊髓组织SOD1水平低于未接受治疗的SOD1 ALS患者和健康对照的相应水平。患者1的脑脊液SOD1水平只是一过性地略微降低，而患者2的脑脊液SOD1水平未受影响。患者1接受输入给药后发生了脑膜神经根炎；患者2预先接受了免疫抑制药物治疗，该患者未出现这一并发症。患者1的右腿力量有一过性改善（这一指标在该患者的病程中保持相对稳定），但肺活量无变化。患者2的ALS功能综合指标评分和肺活量在12个月期间保持稳定。本研究表明，微RNA鞘内给药有可能成为SOD1介导的ALS的治疗方案。

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.

Christian Mueller, James D. Berry, Diane M. McKenna-Yasek, et al. SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS. DOI:10.1056/NEJMoa2005056