Gantenerumab

摘要：罗氏在 2025 年阿尔茨海默病协会国际会议上公布的 Ib/IIa 期数据显示，其新一代抗淀粉样蛋白抗体 trontinemab 展现出突破性潜力 —— 高剂量组 91% 的患者在 7 个月内实现脑内淀粉样蛋白阴性，清除速度与效率远超现有疗法。更关键的是，其淀粉样蛋白相关成像异常（ARIA）发生率显著降低，为阿尔茨海默病（AD）治疗带来 “范式转变” 的希望。尽管仍需 III 期验证，这一进展已重新点燃行业对淀粉样蛋白假说的信心。一、数据亮眼：清除速度与效率双突破Trontinemab 的 Ib/IIa 期 Brainshuttle AD 试验结果堪称惊艳。在剂量扩展队列中，54 名接受 3.6mg/kg 剂量的患者中，49 人（91%）在 7 个月后的 PET 扫描中达到 “淀粉样蛋白阴性” 标准，其中 39 人（72%）实现 “深度清除”—— 即淀粉样蛋白沉积量降至几乎不可检测水平。这一数据远超现有疗法：百健 / 卫材的 Leqembi 和礼来的 Kisunla 通常需要 18 个月以上治疗才能达到类似清除效果，且完全清除率不足 50%。B. Riley 证券分析师指出：“Trontinemab 的清除速度和一致性是革命性的，可能改变 AD 治疗的时间窗口 —— 早期干预的价值将被放大。”其核心优势源于独特机制：抗体部分靶向淀粉样蛋白，同时通过转铁蛋白受体穿梭模块增强血脑屏障穿透性，使药物在脑内浓度提升数倍。这种 “双功能设计” 解释了为何低剂量即可起效，且作用更精准。二、安全性改善：ARIA 风险显著降低淀粉样蛋白抗体的 “阿喀琉斯之踵”——ARIA（脑肿胀或出血）在 trontinemab 中得到有效控制。149 名受试者中仅 4 人出现 ARIA，发生率约 2.7%，远低于 Leqembi 的 15%-20%。不过，试验中一名 78 岁女性患者因脑出血死亡引发关注。该患者存在浅表铁沉积（ARIA 风险因素），用药 6 周后死亡。罗氏表示，将在 III 期试验中强化患者筛查，排除高风险人群。尽管如此，业内仍认为其安全性 “显著优于一代产品”，为长期用药奠定基础。三、从失败中重生：罗氏的 AD 研发逆袭Trontinemab 的进展标志着罗氏在 AD 领域的强势回归。2020 年，其首款抗淀粉样蛋白抗体 gantenerumab 因 III 期试验失败终止开发，成为淀粉样蛋白假说受挫的标志性事件。此次卷土重来，罗氏不仅更换了分子设计，更引入 “Brainshuttle” 技术平台，解决了前代药物血脑屏障穿透不足的问题。“这不是简单的迭代，而是技术平台的革新。” 一位神经学专家评价道。gantenerumab 的失败促使罗氏重新审视药物递送效率，最终选择与转运蛋白受体结合的策略，使抗体更精准地抵达病灶。这种转变也为其他难成药靶点提供了借鉴 ——Denali、Cognition 等公司的脑递送技术股价应声上涨，印证了行业对这一方向的认可。四、III 期挑战：从 “清除斑块” 到 “改善认知”尽管早期数据亮眼，trontinemab 仍需跨越最关键的关卡：证明淀粉样蛋白清除能切实延缓认知衰退。罗氏计划 2025 年启动两项 III 期试验（TRONIER 1 和 2），招募存在认知下降风险的早期患者，主要终点为临床进展速度。这一阶段的挑战不容小觑。历史上，多款 AD 药物在早期试验中显示出斑块清除能力，却在 III 期未能改善认知功能。Leqembi 和 Kisunla 虽获批，但认知改善幅度温和（延缓衰退约 25%），市场期待 trontinemab 能凭借更高清除效率实现更显著的临床获益。此外，给药频率也是商业化关键。Trontinemab 目前为每 4 周一次静脉输注，罗氏正开发皮下制剂，若能实现每 8-12 周给药一次，将大幅提升患者依从性，与 Leqembi 的皮下制剂形成直接竞争。五、行业影响：淀粉样蛋白假说再受关注Trontinemab 的突破为淀粉样蛋白靶向疗法注入新活力。近年来，随着非淀粉样蛋白机制（如 GLP-1、tau 蛋白）的兴起，业界对 “淀粉样蛋白假说” 的质疑渐起。而此次数据表明，只要解决递送效率和安全性问题，淀粉样蛋白仍是可行的治疗靶点。对患者而言，这意味着更多治疗选择。若 III 期成功，trontinemab 可能在 2030 年前上市，与 Leqembi、Kisunla 形成 “三代同堂” 的竞争格局，推动治疗费用下降。更重要的是，其 “快速清除” 特性可能使 AD 干预窗口前移 —— 在症状出现前清除斑块，实现真正的预防。罗氏的逆袭故事尚未结束，但 trontinemab 已证明：在 AD 这个 “研发坟墓” 中，失败并非终点，而是技术迭代的起点。这场关于淀粉样蛋白的持久战，或许正迎来新的转折点。参考来源：https://www.biospace.com/drug-development/roches-next-gen-alzheimers-antibody-clears-or-reduces-amyloid-plaques-in-seven-months识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

TORONTO — Three years after a disappointing clinical failure cast doubts on Roche’s future in Alzheimer’s disease, the company is going all in on a sequel program. And early data suggest it might be the most potent amyloid-clearing drug yet. In a packed room at the Alzheimer’s Association International Conference in Toronto on Sunday, Roche revealed the latest cut of data from its closely-watched Phase 1/2 study of trontinemab, an amyloid-targeting antibody designed to latch onto receptors that yank it across the protective blood-brain barrier. Unlike its failed predecessor gantenerumab, which only slowly and modestly reduced amyloid plaques over two years, trontinemab practically eliminated amyloid in just seven months. One patient died from a brain hemorrhage early in their treatment, causing Roche to tighten its criteria last year to exclude participants who are susceptible to the fatal side effect. Aside from that fatality, trontinemab actually appeared to cause far less frequent and less severe cases of brain bleeding and swelling than Leqembi and Kisunla, the amyloid antibodies sold by Eisai/Biogen and Eli Lilly, respectively. (The study did not compare trontinemab against those therapies.) At the meeting, scientists say they are eager to see if the finding holds up in bigger studies. “I could barely contain myself from jumping up and whooping,” Reisa Sperling, director of the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, said during a panel following Roche’s presentation. Roche’s new study doesn’t prove that removing amyloid helps patients, and the company cautioned that it was not big enough or long enough to do so. But a pair of 800-person studies that it plans to begin later this year may help answer that question. Those Phase 3 studies, the design of which was outlined for the first time on Sunday, will test the drug in people with early Alzheimer’s for 18 months. Roche also announced its intention to test trontinemab in people with so-called “preclinical Alzheimer’s” who have amyloid buildup in the brain but are not yet showing signs of memory loss. The approach could more dramatically stall, and possibly prevent, the disease. Eisai and Lilly are conducting similar prevention studies with their drugs. “We are excited about this program and the potential benefit that it might bring to patients with Alzheimer’s disease. That is very clear,” Luka Kulic, Roche’s global head of early development for neuroscience and rare diseases, told Endpoints News in an interview. “This commitment has never stopped, even after the setback.” Trontinemab is a bispecific antibody that combines gantenerumab with a new molecule dubbed a Brainshuttle that binds to transferrin receptors along the border of the protective blood-brain barrier. Roche believes that getting more of the drug into the brain more quickly could help overcome gantenerumab’s prior failure. “What we learned over the past couple of years is that it’s not just about targeting amyloid; it’s really about getting it substantially low,” Kulic said. In new data from 54 patients who got the 3.6 mg/kg dose of trontinemab — the highest dose in the current study and the one Roche plans to use in its upcoming Phase 3 studies — 91% of patients became “amyloid negative” on brain scans within 28 weeks based on a common threshold of 24 centiloids, a PET measurement that represents minimal plaques in the brain. In the upcoming Phase 3 studies, patients will get an infusion of trontinemab every four weeks for 24 weeks before switching to a “maintenance regimen,” during which they get the infusion every 12 weeks. Eisai’s drug, in contrast, is administered once or twice a month indefinitely. Lilly recommends that patients stop receiving its monthly drug after becoming amyloid negative on a PET scan. Roche hopes to avoid that requirement for additional PET scans. Jessica Langbaum, senior director of research strategy at the Banner Alzheimer’s Institute, was encouraged by trontinemab’s dramatic and rapid amyloid reduction as well as the low rates of side effects like brain bleeding and swelling, which she said “could be tremendously helpful” for use as a preventative therapy. “What’s most exciting was the energy in the room,” Langbaum told Endpoints. “The field was in despair. We have this hope now.” It’s unclear if more powerful amyloid removal is safer or more dangerous. Lilly recently found that ramping up the dose of its drug more slowly lowered the risk of brain swelling, known as amyloid-related imaging abnormality with edema or effusion, or ARIA-E. Some scientists wondered if trontinemab’s rapid amyloid reduction would backfire. “I was a little bit worried. I was thinking that if you do this very intensely, then perhaps you will get neurotoxicity,” Henrik Zetterberg, professor of neuroscience at Sweden’s University of Gothenburg who is involved in the trontinemab studies, told Endpoints. “And that didn’t happen. So I feel like this is looking good.” ARIA-E occurred in 3.9% of patients who got the 1.8 mg/kg dose and 1.4% of patients who got the 3.6 mg/kg dose, compared to 13% of patients in Eisai’s registrational study and 14% of patients in Lilly’s recent study that adjusted dosing to lower ARIA-E. Signs of brain bleeding, known as ARIA with hemosiderin or hemorrhage, or ARIA-H, occurred in 6.6% and 2.7% of patients on the lower and higher doses of trontinemab, respectively, compared with 17% of patients in Eisai’s registrational study and 20% of patients in Lilly’s recently updated dosing study. It is unclear why both forms of ARIA were more prevalent in patients receiving the smaller of two doses of trontinemab. Kulic said the difference could be due to chance, given the relatively small size of the study. But he added that “it’s reassuring” that ARIA wasn’t more common in patients who received the higher dose. The otherwise promising results were marred by the death of a 78-year-old woman who suffered a brain hemorrhage — a known risk of the drug class — six weeks into the study. An MRI scan during screening revealed that the woman had a spot of abnormal iron accumulation known as superficial siderosis that is indicative of prior bleeding and is a risk factor for ARIA. Roche previously reported the death at an Alzheimer’s conference in 2024. Kulic said the death caused Roche to tighten its “relatively relaxed” criteria for the study and prevent people with superficial siderosis from getting the drug.