获批 ALS 药物显现预期安全性信号及潜在新信号

Key signals involved spinal procedures; possible new risks need study

关键信号涉及脊柱相关操作；潜在新风险仍需研究

A post-marketing analysis of safety reports found that many of the strongest signals involving Qalsody (tofersen) in people with amyotrophic lateral sclerosis (ALS) were related to the spinal procedures used to administer it. Other reporting signals involved neurological and inflammatory events.

一项上市后安全性报告分析发现，在肌萎缩侧索硬化症（ALS）患者中，与 Qalsody（tofersen）相关的许多最强信号均涉及用于给药的脊柱相关操作。其他报告信号则涉及神经系统事件和炎症事件。

The study, based on 409 reports submitted to an FDA safety database, also detected possible new signals involving respiratory disorders, including seven reports of pulmonary embolism, a serious blockage of an artery in the lungs. The researchers said these findings require further study and highlight the importance of long-term safety monitoring.

该研究基于提交至 FDA 安全性数据库的 409 份报告，还发现了涉及呼吸系统疾病的潜在新信号，其中包括七份肺栓塞报告。肺栓塞是一种严重的肺动脉阻塞。研究人员表示，这些发现需要进一步研究，并凸显了长期安全性监测的重要性。

“This study is the first to systematically conduct a post-marketing [safety] analysis of [Qalsody]. It not only validated the common [adverse events] recorded in the drug labeling but also identified novel risk signals with potential clinical significance,” the researchers wrote.

研究人员写道：“本研究首次系统开展了[Qalsody]上市后[安全性]分析。研究不仅验证了药品说明书中记录的常见[不良事件]，还发现了具有潜在临床意义的新型风险信号。”

The study, “ Safety evaluation of Tofersen in amyotrophic lateral sclerosis based on the FAERS database ,” was published in Frontiers in Neurology .

该研究题为《基于 FAERS 数据库评估 Tofersen 治疗肌萎缩侧索硬化症的安全性》，发表于《Frontiers in Neurology》。

ALS is a progressive neurological disease that damages motor neurons, the nerve cells responsible for controlling muscle movement. As these neurons gradually deteriorate and die, muscle weakness and disability worsen over time. Although the exact cause remains unclear, genetic and nongenetic factors, including environmental and lifestyle influences, are believed to contribute to ALS.

ALS 是一种进行性神经系统疾病，会损害负责控制肌肉运动的神经细胞——运动神经元。随着这些神经元逐渐退化并死亡，肌无力和残疾会随时间推移而加重。尽管确切病因仍不清楚，但人们认为遗传和非遗传因素，包括环境及生活方式影响，均可能促成 ALS。

Mutations in the SOD1 gene are present in up to 20% of familial ALS and in up to 2% of sporadic ALS cases. Such mutations can lead to abnormal forms of the SOD1 protein that may accumulate, form toxic clumps, and damage nerve cells.

高达 20% 的家族性 ALS 和高达 2% 的散发性 ALS 病例存在 SOD1 基因突变。此类突变可导致异常形式的 SOD1 蛋白，这些蛋白可能积聚、形成有毒团块并损伤神经细胞。

Qalsody is designed to reduce SOD1 levels by targeting SOD1 messenger RNA (mRNA), an intermediate molecule that carries the instructions for making the protein, for breakdown. By reducing SOD1 production, the therapy may slow disease progression and extend survival. It is administered directly into the spinal canal, or intrathecally, every 28 days after three loading doses given two weeks apart.

Qalsody 旨在通过靶向 SOD1 信使 RNA（mRNA）并促使其降解来降低 SOD1 水平；mRNA 是携带蛋白质合成指令的中间分子。通过减少 SOD1 的产生，该疗法可能减缓疾病进展并延长生存期。患者先接受三次间隔两周的负荷剂量，此后每 28 天通过鞘内注射直接给药至椎管。

The treatment was granted accelerated approval in the U.S. based on a reduction in neurofilament light chain, a biomarker of nerve degeneration, that is reasonably likely to predict clinical benefit, with continued approval depending on confirmation of its clinical benefit.

该疗法因可降低神经丝轻链水平而在美国获得加速批准。神经丝轻链是神经退行性变的生物标志物，被认为很可能预测临床获益；该疗法能否继续获批取决于其临床获益能否得到确认。

Here, researchers in China, where the treatment received breakthrough approval in 2024, analyzed data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), a database that collects voluntary reports of side effects and other safety problems involving approved medicines.

在这项研究中，中国的研究人员分析了美国食品药品监督管理局不良事件报告系统（FAERS）的数据；该系统是一个收集获批药物副作用及其他安全性问题自愿报告的数据库。该疗法于 2024 年在中国获得突破性批准。

A total of 409 reports naming Qalsody as the primary suspect drug were identified. Men accounted for more reports than women (47.4% vs. 43%). People ages 18 to 64 accounted for 43% of reports, compared with 16.6% for those ages 65 to 85 and 0.2% for those older than 85. Age information was unavailable for 40.1% of reports. Most reports came from the U.S. (72.9%).

研究共发现 409 份将 Qalsody 列为首要怀疑药物的报告。男性所占报告比例高于女性（47.4% vs. 43%）。18 至 64 岁人群占报告的 43%，相比之下，65 至 85 岁人群占 16.6%，85 岁以上人群占 0.2%。40.1% 的报告未提供年龄信息。大多数报告来自美国（72.9%）。

Consumers submitted the largest share of reports (47.4%), followed by physicians (29.3%), other health professionals (11.7%), and pharmacists (4.6%). Among 110 reports with available timing data, the median time to onset of adverse events was 97.5 days, or about three months. Of those reports, 28.2% described events occurring within the first month and 21.8% described events occurring more than one year after treatment began. According to the researchers, this indicates “the need for attention to long-term drug safety.”

消费者提交的报告占比最大（47.4%），其次是医生（29.3%）、其他医疗卫生专业人员（11.7%）和药剂师（4.6%）。在提供了时间数据的 110 份报告中，不良事件发生时间的中位数为 97.5 天，即约三个月。在这些报告中，28.2% 描述了治疗开始后第一个月内发生的事件，21.8% 描述了治疗开始一年多后发生的事件。研究人员称，这表明“需要关注药物的长期安全性”。

The reports included adverse events across 22 medical categories. The categories represented most often involved the nervous system (51.1%); injury, poisoning, and procedural complications (42.5%); general and administration-site conditions (31.5%); and musculoskeletal and connective tissue disorders (27.6%). Because one report could include events in more than one category, the percentages overlap.

这些报告涉及 22 个医学类别的不良事件。最常见的类别涉及神经系统（51.1%）；损伤、中毒和操作并发症（42.5%）；全身性疾病及给药部位反应（31.5%）；以及肌肉骨骼和结缔组织疾病（27.6%）。由于一份报告可能包含一个以上类别的事件，因此这些百分比存在重叠。

More detailed analysis found that many of the strongest reporting signals involved spinal tap–related events and abnormalities in cerebrospinal fluid (CSF), consistent with Qalsody’s intrathecal administration. The most prominent signals included a reporting category called neurological procedural complications, red blood cells in CSF, increased white blood cell counts in CSF, and increased overall CSF cell counts. CSF is the fluid that surrounds the brain and spinal cord.

更详细的分析发现，许多最强的报告信号涉及腰椎穿刺相关事件和脑脊液（CSF）异常，这与 Qalsody 的鞘内给药方式一致。最突出的信号包括一个称为神经系统操作并发症的报告类别、CSF 中出现红细胞、CSF 中白细胞计数升高，以及 CSF 总细胞计数升高。CSF 是环绕脑和脊髓的液体。

The database also flagged rare but serious side effects already documented in Qalsody’s prescribing information. These include increased intracranial pressure (elevated pressure around the brain), papilledema, myelitis and radiculitis, and aseptic meningitis, or inflammation of the protective membranes surrounding the brain and spinal cord.

该数据库还标记出了 Qalsody 处方信息中已有记录的罕见但严重的副作用，包括颅内压升高（脑周围压力升高）、视乳头水肿、脊髓炎和神经根炎，以及无菌性脑膜炎，即脑和脊髓周围保护膜发生炎症。

Researchers also identified signals in two broad medical categories not currently listed on the product label . Events involving the airways, lungs, and surrounding tissues appeared in 63 reports (15.4%), while events involving hearing and balance appeared in 10 reports (2.4%). According to the researchers, “their potential causal relationships need to be further verified through large-scale clinical studies.”

研究人员还在目前产品标签未列出的两个广泛医学类别中发现了信号。涉及呼吸道、肺和周围组织的事件出现在 63 份报告中（15.4%），涉及听力和平衡的事件出现在 10 份报告中（2.4%）。研究人员表示，“它们潜在的因果关系仍需通过大规模临床研究进一步验证。”

The study also detected a new reporting signal for pulmonary embolism based on seven reports. Pulmonary embolism is a blockage of an artery in the lungs, usually caused by a blood clot, and is not listed on the current label. The researchers emphasized that this “newly identified signal of pulmonary embolism suggests a potential thromboembolic risk in specific patient populations” that warrants close clinical monitoring and further investigation. They noted, however, that the relationship between Qalsody and blood-clotting events remains uncertain and requires further study.

该研究还根据七份报告发现了一个新的肺栓塞报告信号。肺栓塞是肺动脉阻塞，通常由血凝块引起，目前的产品标签中未列出这一事件。研究人员强调，这一“新发现的肺栓塞信号提示特定患者群体可能存在血栓栓塞风险”，有必要进行密切的临床监测和进一步研究。不过，他们指出，Qalsody 与凝血事件之间的关系仍不确定，需要进一步研究。

“These findings provide real-world evidence to inform the balance between the therapeutic potential and safety profile of [Qalsody],” they added. “Future clinical strategies should focus on mitigating central nervous system-related and procedure-related adverse events.”

他们补充道：“这些发现提供了真实世界证据，有助于权衡[Qalsody]的治疗潜力与安全性特征。”“未来的临床策略应重点减轻中枢神经系统相关和操作相关的不良事件。”