RP-A501

iStock, Alex Sholom While an adverse event reported in Intellia’s gene therapy trial was a “non-concern” for analysts, it follows a handful of patient deaths in other trials for the modality and sent the company’s stock tumbling in pre-market trading. Intellia’s shares declined by 26% as the markets opened Thursday after disclosing a case of elevated liver enzymes in a late-stage study for its transthyretin amyloidosis gene editing therapy. Analysts brushed off the adverse event—the second disclosed for the candidate—considering both cases were asymptomatic and resolved without medication. The treatment, known as nexiguran ziclumeran (nex-z), is under development in partnership with Regeneron. The Phase III trial has enrolled 765 patients with ATTR, 200 of whom have been dosed so far, Intellia said in a regulatory filing posted after-market Wednesday. “The second grade 4 [liver function test] serious adverse event with nex-z is obviously disappointing and with the stock down 18% in aftermarket trading, there will be outstanding questions about safety moving forward,” William Blair analysts wrote to investors Wednesday evening. But Truist Securities analysts brushed off the adverse event, saying it “does not cross the threshold for us to be concerned about the safety pro one-and-done nex-z just yet.” BMO Capital Markets similarly called it a “non-concern.” The stock reaction was likely more due to recent patient deaths in the gene therapy space than the severity of this particular incident with Intellia, BMO said. “We believe [Intellia] post-market stock reaction to Phase III safety update reflects recent safety concerns raised in the broader gene therapy space from unfortunate patients deaths,” the group wrote. Earlier this week, Rocket reported the death of a patient in a Phase II trial of Danon disease gene therapy RP-A501. The study has been placed on hold by the FDA after the biotech voluntarily suspended it. Other deaths have occurred in studies conducted by Sarepta and Neurogene , BMO noted. But these were with different delivery vehicles and the analysts cautioned against comparisons. Treatment or Delivery? William Blair said Intellia’s adverse event raises a debate about whether the treatment, or the lipid nanoparticle (LNP) delivery mechanism, is to blame. Investigators have deemed the situation as likely related to nex-z. “[W]e believe that a single-time LNP administration is likely more safe/predictable/understood than a single-time AAV-based gene therapy,” BMO wrote. Rocket’s, Sarepta’s and Neurogene’s gene therapies all use AAV. William Blair noted that Verve Therapeutics’ recently released data for a next-gen candidate for cholesterol that uses LNP did not show signs of toxicity after a previous asset did. In the case of Intellia, reported adverse events, including asymptomatic liver transaminase elevations, have been in line with expectations based on earlier studies, the company said. A single patient exhibited grade 4 elevations based on lab tests, which Intellia said were resolving without hospitalization or medical intervention. The patient has since fallen to grade 3 alanine aminotransferase (ALT) and grade 2 aspartate transferase (AST) elevations. The new patient had normal ALT and AST at baseline, but they began to elevate a week post-infusion of nex-z. Intellia executives told analysts that the timing suggests it was not due to LNP toxicity. The ALT/AST elevations progressed to a grade 4 event at day 24, peaking at day 28. By day 36, the situation had fallen back down to a grade 3 for ALT and grade 2 for AST. The patient was never determined to be at risk of drug-induced liver injury. In the previous case that emerged in the Phase I trial of nex-z, the patient returned to normal levels about six to eight weeks after infusion. While Truist analysts were not overly concerned, they said “it’s certainly a reason to stay vigilant, especially as it appears to be a recurring theme from Phase I and Phase III MAGNITUDE.” William Blair noted that the rate of this particular adverse event, given about 305 patients treated across the clinical program so far, is about 0.66%. “We will be keeping an eye on this but it is an objectively low rate, and we do not believe at this time it should have broader read-through to other LNP-delivered genetic medicines.” Given the low incidence, William Blair is still confident in nex-z’s risk/benefit pro ATTR. With that said, the indication has seen a surge of interest of late with several new mechanisms of action entering the market, “so safety will be a consideration moving forward.” Truist noted that Intellia’s Phase III trial is proceeding without any changes to protocol with enrollment on track to wrap up by early 2027. The next data from the nex-z program will be a two-year update from the Phase I trial, which BMO noted is due in the second half of this year.

日前，Rocket Pharmaceuticals披露，在其实验性基因治疗RP-A501的2期关键临床试验中，1例患者在接受治疗后死亡。受此消息影响，Rocket公司的股价在周二暴跌超过60%，市值蒸发了数亿美元。实际上，在RP-A501的1期试验中显示出良好的耐受性，怎么才进2期就发生了严重的死亡事件？患者死亡事件根据Rocket公司报告，RP-A501的关键2期临床试验中，1例患者经历了意外的严重不良事件（SAE），涉及与毛细血管渗漏综合征相关的临床并发症，该名患者后因急性全身感染而死亡。RP-A501是一款在研的AAV基因治疗，由AAV9携带一个功能性人源LAMP2B转基因（AAV9.LAMP2B）组成，用于治疗罕见心脏病Danon病。基于Rocket公司于2024年11月发布在《新英格兰医学杂志》（NEJM）上的RP-A501的1期研究结果，RP-A501具有可控的安全性和良好的耐受性。——随访4.5年，所有患者均存活，病情稳定。常见不良反应为呕吐、头痛、肌病和丙氨酸氨基转移酶水平升高，多为1~2级。RP-A501的2期关键研究于2024年9月才完成全部患者入组。根据试验设计，在儿童安全性磨合期后入组的患者还需要进行为期3个月的观察性治疗前磨合。因此，2期试验的受试者接受RP-A501给药时间应该并不长。总之，Rocket公司报告的2期患者死亡事件，违背了此前表现出的安全性结果。可能原因目前，该临床试验已经被美国FDA暂停。Rocket公司表示正在进行全面的根本原因分析，并与FDA和其他主要利益相关者保持积极对话。着重的可能原因是，Rocket公司主动修改的RP-A501治疗前预处理方案。——最近Rocket公司在治疗前方案中加入了一种新的药物（C3免疫抑制剂），这种抑制剂可能会对RP-A501产生某种特异性影响。根据Rocket公司于周二举行的电话会议内容。是因为在原始预处理方案中的患者中观察到补体激活和血栓性微血管病（TMA），这是一种有可能危及生命的风险。为了对抗补体激活以及预防TMA，Rocket公司在预处理方案中，引入了C3抑制剂。一共有2名患者接受了C3抑制剂进行预处理，这2名患者均未发现TMA，但是均经历毛细血管渗漏综合征。因为仅在接受C3抑制剂的患者中观察到毛细血管渗漏，Rocket公司认为C3抑制剂很可能是导致该综合征的原因。其中第1名患者在输注后1周左右观察到毛细血管渗漏的迹象。Rocket公司表示当时患者的情况稳定，毛细血管渗漏正在改善，对恢复保持谨慎乐观的态度，但是该患者于周末患上急性全身性感染，导致患者死亡。在第1名接受C3抑制剂的患者观察到毛细血管渗漏综合征的早期迹象后，Rocket公司就对第2名接受C3抑制剂的患者进行了干预缩短疗程。另外，在Rocket在得知毛细血管渗漏综合征初始事件后，就自愿暂停了该研究的进一步给药，并通知了FDA。2025年5月23日，FDA搁置了该临床试验。基于临床搁置，且无法预测何时能够恢复2期研究，因此RP-A501原先的时间表不再准确。小结不过，Rocket报告，C3抑制剂的引入仅限于Danon计划，不用于其它管线开发。因此，plakophilin-2相关致心律失常性心肌病（PKP2-ACM）项目RP-A601和BAG3相关的扩张型心肌病（DCM）计划不受临床搁置的影响，正在按照计划进行。实际上，本次临床事故对Rocket公司并未造成太大的打击。因为该公司已经决定优先考虑对AAV平台的投资，同时评估如何优化其余管线价值，从而转化为现金减少支出。Rocket公司预计现有资源将为支持至2027年的运营提供资金。截止2025年3月31日，该公司拥有现金、现金等价物和投资为3.182亿美元。参考资料：1.https://ir.rocketpharma.com/news-releases/news-release-details/rocket-pharmaceuticals-provides-update-phase-2-clinical-trial-rp?utm_campaign=the_readout&utm_medium=email&_hsenc=p2ANqtz-_gIeZv9wKR7IIPr0-Pq23ObTZeeAZr6Swel6Q6D-StTkBf-yZ9hATRDD9kF9eGShvWoer7kgvg0ZwGn-7HoIwPsQrQRiI7igXbaQaJMdJvRwFiWFo&_hsmi=363425192&utm_content=363425192&utm_source=hs_email2.https://www.fiercebiotech.com/biotech/rocket-crashes-gene-therapy-patient-dies-fda-imposes-hold3.https://www.biopharmadive.com/news/rocket-danon-gene-therapy-patient-death/748955/·······················