Eculizumab

6岁的乐乐（化名）本来只是发了一场小感冒，家人以为休息几天就会好。没想到短短一周内，他突然脸色苍白、精神萎靡，眼睑和下肢明显浮肿，尿液也越来越少，还带有血色。父母紧急带他就诊，检查结果却让人揪心：血红蛋白急剧下降、血小板明显减少、肌酐升高，同时伴有高血压和溶血性贫血。起初医生考虑典型溶血尿毒综合征（HUS），但乐乐并没有腹泻或志贺毒素感染病史。进一步补体学检查提示：补体系统异常激活，遗传学检测发现 补体调控基因变异，最终确诊为 非典型溶血尿毒综合征（aHUS）。什么是aHUS？aHUS属于血栓性微血管病（TMA) 系列疾病中的一种，临床表现为微血管病性溶血性贫血、血小板减少和内皮细胞损伤导致的缺血性器官损伤，尤以肾脏受累最为常见。病理特征为肾脏毛细血管和小动脉中的纤维蛋白和血小板血栓，内皮细胞肿胀以及肾小球基底膜双轨征样改变。目前aHUS特指补体旁路途径调控蛋白异常所致，即补体介导溶血尿毒综合征（CM-HUS)。临床表现aHUS患儿具有TMA微血管溶血性贫血、血栓性血小板减少及缺血性多器官损伤(尤以肾脏损伤为主)三大特征。约70%的患者具有至少1种前驱触发因素，其中感染因素最为常见，约50%的患者有消化道和呼吸道前驱感染史。各年龄段患儿均可发病，肾脏表现为血尿、蛋白尿、血红蛋白尿、高血压、尿量减少甚至无尿；除急性溶血性贫血、血小板减少和肾损害症状外，亦可有神经系统症状、心力衰竭、呼吸紊乱、胰腺炎、肝损伤，小肠结肠炎等多脏器损害。aHUS病情容易复发，对具有家族遗传史的患者，需要密切关注复发倾向。诊断具有临床三联征的表现：微血管性溶血性贫血、消耗性血小板减少及血栓导致的器官受损。血红蛋白<100 g/L，外周血涂片有破碎红细胞，网织红细胞升高，乳酸脱氢酶升高；血小板<150×109/L；同时存在急性器官损伤，尤以肾损伤为主，即血肌酐升高超过同年龄同性别健康儿童水平上限，除外STEC感染、TTP、继发性TMA和继发性HUS，即考虑诊断为aHUS。治疗针对aHUS的治疗策略是纠正补体系统的失调。在补体抑制剂应用以前，血浆治疗是一线选择，但血浆疗法对补体基因异常患者效果不佳，且不能解决复发率高、肾损害进展等问题。依库珠单抗是一种重组人源化单克隆抗体，抑制C5裂解为C5a和C5b并防止末端补体复合物C5b-9的形成，保留了上游补体因子(如C3a和C3b)的功能。依库珠单抗的使用极大地改善了aHUS患儿的预后。目前依库珠单抗已成为aHUS的一线治疗药物。临床确立aHUS的诊断后，应尽快启动依库珠单抗的治疗。参考资料：1.  中国罕见病联盟儿童非典型溶血尿毒综合征专业委员会,国家儿童医学中心(首都医科大学附属北京儿童医院),《中华实用儿科临床杂志》编辑委员会.中华实用儿科临床杂志,2023,38(06)401-412.2. Palma LMP , Vaisbich-Guimaraes MH , Sridharan M ，et al. Thrombotic microangiopathy in children[J]．Pediatr Nephrol， 2022,37(9):1967-1980.来源 | 梅斯医学编辑 | wanny神经系统罕见病交流群↓点击下方“阅读原文”，下载梅斯医学APP吧！

It still remains to be seen if Rocket will have enough cash to carry the biotech through the pivotal gene therapy readout. \n The FDA has freed Rocket Pharmaceuticals from a clinical hold, giving the gene therapy developer permission to take flight with its pivotal cardiomyopathy disorder trial.The hold was implemented in late May, around the same time Rocket reported a patient death in its phase 2 study.The lift announcement, occurring at market open today, initially launched Rocket’s stock upwards, though shares have now leveled out a bit to a 10% boost from open, settling at $3.22 per share.The New Jersey-based biotech will now resume its study designed to support accelerated approval of RP-A50, an AAV9 gene therapy made to restore cardiac function by delivering the LAMP2B transgene to heart cells. To date, six patients with Danon disease—a genetic condition known to weaken the heart muscle—have received Rocket’s investigational therapy in the study.Previously, Rocket had stopped dosing and notified the FDA after a patient developed complications linked to capillary leak syndrome, which can cause extremely low blood pressure and organ damage. The patient later developed an acute systemic infection and ultimately died.The federal agency had already imposed a clinical hold before the death to assess the causes of the adverse event. At the time, Rocket identified the addition of a C3 inhibitor to the pretreatment regimen as a potential cause of the capillary leak syndrome. The biotech had incorporated the immunomodulatory agent to counter complement activation by the AAV and prevent thrombotic microangiopathy (TMA).Now, the FDA is allowing the study to continue at a lower dose without the C3 inhibitor, according to Rocket’s release. The mid-stage trial will resume with a new dose of 3.8 x 1013 GC/kg of RP-A501 in three patients, with a minimum of four weeks between dosing. This compares to the first six patients treated at a dose level of 6.7 x 1013 GC/kg.The dose change aligns with the lower range of doses associated with efficacy in Rocket’s phase 1 study, according to the biotech.The company will also use an immunomodulatory regimen similar to that seen in the phase 1 pediatric cohort, while also lowering the threshold for administering C5 inhibitor eculizumab.Rocket has already enrolled the number of patients needed to run the pivotal trial and hasn’t heard of any patients no longer interested in dosing, according to an Evercore ISI analyst note. Dosing is expected to start again in 2026, Rocket told the firm in a call this morning.  After safety data is collected from the next three patients, Rocket will reconvene with the FDA to discuss dosing for the rest of the study, according to Evercore.  However, based on a current cash runway of $271 million that is expected to stretch through the second quarter of 2027, it doesn’t seem likely that Rocket will have enough money to make it all the way through the pivotal readout. Evercore did note that selling off a priority review voucher for another asset called RP-L201 could help. The analyst still predicts a high chance of approval for the therapy in X-linked Danon disease, with the only currently available treatment being a heart transplant. The gene therapy RP-A501 has secured regenerative medicine advanced therapy, fast track, rare pediatric and orphan drug tags from the FDA.  At William Blair, analysts are viewing the lift and discontinuation of the C3 complement inhibitor as positives, though they noted in an Aug. 20 report that the protocol changes come with some separate risk. The analysts questioned whether the C5 inhibitor will be enough to prevent TMA cases and if the recalibrated dose will be capable of providing durable responses for adults.  Editor\'s note: This story was updated at 12:10 p.m. ET to classify Danon disease as a cardiomyopathy disease instead of a metabolic disorder, as it has historically been referred to.