Korro Bio, Inc.

Adapted from iStock, Drypsiak Vertex may have pivoted away from the space, but candidates in development by Arrowhead/Takeda, Wave, Korro and others could address the damage underlying alpha-1 antitrypsin deficiency and make today’s treatments a thing of the past. Alpha-1 antitrypsin deficiency is a genetic disorder that affects the liver and/or lungs. Approximately 1 in 3,500 people have two abnormal SERPINA1 genes for the alpha-1 antitrypsin (AAT) protein and are at risk of serious organ damage due to AATD. While M-AAT is produced in healthy humans to inhibit neutrophil elastase in the lungs, AATD patients produce Z-AAT, which does not inhibit neutrophil elastase as effectively. If too much neutrophil elastase builds up in the lungs or liver, the result is inflammation which, untreated, can lead to lifelong complications. The only currently approved treatment option for AATD is augmentation therapy , which entails delivering normal alpha-1 antitrypsin collected and purified from blood donors through weekly intravenous administration. But this treatment does not reverse pulmonary damage or stop the progression of liver damage. Multiple companies are developing candidates that would prevent or reverse this damage, and despite some setbacks in the field, in the next 5 to 10 years we could see augmentation therapy become a thing of the past. In August 2024 , Vertex Pharmaceuticals announced that the company would cease research into both of its investigational small molecules for AATD. While Vertex had hoped that VX-634 and VX-668 would treat the disease by correcting the AAT protein, the efficacy was not transformative enough. Along with Vertex’s November 2023 discontinuation of the development of VX-864 for AATD due to reports of rashes and elevated liver enzymes, these setbacks highlight some of the challenges associated with researching new treatments for AATD. Meanwhile, Arrowhead Pharmaceuticals and Takeda are recruiting for three Phase III trials for fazirsiran, an investigational subcutaneous first-in-class investigational RNA interference (RNAi) therapy for AATD-associated liver disease. While Phase II AROAAT-2002 results indicated that fazirsiran led to significant reductions in Z-AAT, the evidence for pulmonary efficacy and improvement is murky because the Phase II trial did not have a placebo arm and the median FEV1 and mean DLCOhbg—markers of pulmonary function—were stable over time in all subjects receiving experimental treatment compared to baseline. While these data do not show any signs of pulmonary decline, there is no sign of overall pulmonary improvement either. In addition, Sanofi is working on SAR447537, an AATD asset acquired from Inhibrx. Formerly known as INBRX-101 , SAR447537 is a fusion protein currently in the recruitment stage for Phase II trials involving AATD emphysema. In Phase I results, safety and pharmacokinetic data supported the intravenous use of SAR447537 every three or four weeks. However, efficacy data related to the liver are not available. In the in vivo base editing space, Beam Therapeutics is investigating the use of BEAM-302 to treat AATD. BEAM-302 is a liver-targeting lipid nanoparticle formulation that is currently undergoing Phase I/II trials and is formulated to be a one-time intravenous injection of an adenine base editor. When tested in rat and mouse models , toxic liver protein levels decreased. Finally, Wave Life Sciences, AIRNA and Korro Bio are competing in the early phases of preclinical/clinical research to develop AATD-targeting subcutaneous RNA-editing oligonucleotides. On Oct. 16, Wave reported positive proof-of-mechanism data from a Phase Ib/IIa trial of WVE-006 in AATD, while Korro Bio released preclinical data this month for its AATD investigational treatment, KRRO-110 . AIRNA had yet to release its adenosine deaminase acting on RNA (ADAR) preclinical data publicly as of July 2024. With all these investigational treatments aiming to transform the way AATD is treated, augmentation therapy could soon be obsolete. If efficacy data for RNA-based oligonucleotides is significant and points to clinical success, RNA-based oligonucleotides could hit the market as soon as four to five years from now. In the meantime, at the current trajectory, fazirsiran could reach the market as early as two to four years from now if all goes well. Given these developments in the AATD space, competition could heat up within the next decade as more efficacy data are released from therapies currently at earlier stages of development.

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。 2024年10月16日，Wave Life Sciences宣布其RNA编辑疗法WVE-006在治疗α-1 抗胰蛋白酶缺乏症 (AATD) 的1b/2a期 RestorAATion-2研究中获得了积极的机制证明数据。受此消息影响，公司股价大涨74%。 WVE-006是Wave Life Sciences基于其best-in-class寡核苷酸化学平台开发的一款GalNAc偶联、皮下递送的A-to-I RNA编辑寡核苷酸（AIMer），旨在解决AATD相关的肺部疾病和肝病。WVE-006是首个进入临床开发的RNA编辑疗法，而今天的试验结果是RNA编辑疗法在人体当中完成首次机制验证。 GSK拥有WVE-006的全球独家许可。Wave完成RestorAATion-2研究后，最多有资格获得5.25亿美元的里程碑付款以及净销售额的分级特许权使用费。 此次公布的数据来自RestorAATion-2试验中的首个单剂量组（200毫克），包括前两名Pi*ZZ型AATD患者，从试验开始至第57天的结果。由于Pi*ZZ型AATD患者不会自然产生野生型α-1抗胰蛋白酶（M-AAT）蛋白，因此，若在患者体内检测到M-AAT蛋白，便可确认突变型Z-AAT的mRNA成功编辑。此外，若患者恢复至50%的M-AAT蛋白水平，将与“MZ”杂合子基因型相符，具较低的AATD相关肺病和肝病风险。 患者血浆中的野生型M-AAT蛋白在第15天达到平均6.9微摩尔，占总AAT蛋白的60%以上。与体内产生功能性M-AAT蛋白的结果一致，患者体内中性粒细胞弹性蛋白酶的抑制与基线相较增加。基线时未能检测到患者体内的AAT蛋白，而在试验第15天时，患者的平均总AAT蛋白水平达到10.8微摩尔，达到了监管机构批准AAT增强疗法的标准。此外，早在试验第3天，患者的总AAT和M-AAT蛋白水平即较基线增加，并持续到第57天。 迄今为止，WVE-006 耐受性良好，安全性良好。RestorAATion-2以及正在进行的健康志愿者RestorAATion-1试验中的所有不良事件均为轻度至中度，未报告严重不良事件。RestorAATion-2 试验正在进行中，Wave预计将在2025年分享多剂量数据。 Wave Life Sciences总裁兼首席执行官Paul Bolno博士表示：“实现人类首个治疗性 RNA编辑对于我们公司、我们与 GSK 的合作以及整个寡核苷酸领域而言都是一个重要里程碑。根据我们的临床前数据，我们在单剂量下观察到的 mRNA 编辑水平超出了我们的预期，我们预计M-AAT水平会随着重复给药而继续增加。这些初始数据还增强了我们对我们的全资产品线的信心，包括我们的HD、DMD 和肥胖症项目。” 公司管线 总结 国外致力于开发RNA编辑疗法的公司还有Ascidian Therapeutics、AIRNA、Korro Bio、ShapeTX、Tacit Therapeutics 等，国内时夕生物、锐正基因、博雅辑因和辉大基因均有布局。 参考资料：公司官网 版权声明：本文转自细胞基因治疗前沿，如不希望被转载的媒体或个人可与我们联系，我们将立即删除 -END- 药事纵横投稿须知：稿费已上调，欢迎投稿 各位朋友好，觉得本文对您有帮助，请随手点一下下方的在看，以便让你的朋友也能看到哦。

An experimental therapy designed to change a single letter of short-lived mRNA molecules has corrected a genetic mutation that prevents people from making a vital protein, Wave Life Sciences announced Wednesday morning. By mid-afternoon, its stock $WVE was up 74%. The data come from just two patients that Wave followed for two months, but the results are the first glimpse of how RNA editing therapies might work in humans. Wave is one of several biotechs hoping the approach will provide a safe and reversible alternative to technologies like CRISPR gene editing, which make permanent changes to DNA. Wave is testing its therapy, called WVE-006, in people with an inherited condition called alpha-1 antitrypsin deficiency, or AATD. A genetic typo prevents them from properly making a protein that is secreted from the liver and helps protect the lungs from immune cells constantly warding off infections. Wave’s therapy aims to fix that mutation in mRNA. Both patients began making corrected versions of the AAT protein just three days after a single injection of the therapy. By day 15, the AAT protein rose from undetectable levels to 10.8 micromolars in the blood. More than 60% of that protein —6.9 micromolars — was the corrected form of AAT. The FDA considers 11 micromolars of protein protective against the disease. Although Wave hasn’t yet hit that bar, CEO Paul Bolno told Endpoints News in an interview that he was excited by the results and thought they were “frankly surprising.” The patients were treated with the smallest of three doses that Wave plans to test in the ongoing Phase 1b/2a study , which will enroll about 24 people and is slated to wrap up in July. “We’ve got plenty of room to explore what the upper bounds of RNA editing and protein correction are,” Bolno said. The results serve as an important reminder that CRISPR isn’t the only way to alter the genetic code. Our bodies have natural enzymes that can tweak RNA, turning an adenosine base into an inosine. This A-to-I editing, as it’s known, is conducted by an enzyme called ADAR, which gives cells an extra way to fine-tune how genes are expressed. Wave and other companies are developing ways to control this process with synthetic RNA molecules that lasso ADAR and drag it to the precise sequence they want to edit. Last fall, Wave became the first company to ask regulators for permission to test an RNA editing therapy. The first study, in healthy volunteers, was approved in the UK, and the study in AATD patients is in Canada, according to a spokesperson. Back in 2022, Wave partnered with GSK on its AATD therapy and could earn up to $550 million in milestone payments. GSK has the option to license the program and continue its clinical development after the study wraps up. At least two other companies, Korro Bio and AIRNA , are also developing RNA editing therapies for AATD. It’s a good starting point for the technology since the cause of the disease is well-understood and levels of AAT protein in the blood provide a quick and easy way to see if the treatment is working at intended. Korro, which went public through a reverse merger last year, plans to file paperwork with regulators by the end of the year for its first clinical trial, with results expected in the second half of 2025. And AIRNA, which raised $60 million in July to prepare for its own clinical study, has said it could begin tests in people next year. Wave is testing its therapy in patients that inherited AAT mutations from both parents, leaving them susceptible to developing serious lung disease in their 30s and 40s. People who only inherit a mutation from one parent, which geneticists called a heterozygous condition, have a much lower risk of developing lung disease. Bolno thinks that Wave’s therapy is on track to match or surpass that state. “We’re seeing basically a shift to heterozygous phenotype after a single dose,” he said. Infusions of lab-made AAT protein can help prevent some of the lung complications of AATD, but Wave believes that its editing treatment will have the added benefit of reducing levels of mutant protein, which can aggregate in the liver and damage the organ. The existing enzyme replacement therapies are administered through weekly intravenous infusions. Wave’s therapy is a subcutaneous injection. The company said it found healthy AAT protein in the patients 57 days after a single dose, but didn’t provide further details. In its ongoing study, Wave will give the drug to some patients every two weeks, but Bolno said early data suggest it could be spaced “monthly, quarterly or less frequently.” Intellia Therapeutics is developing a CRISPR gene editing therapy to insert an entire new copy of the gene for AAT, which could be a one-and-done treatment. The company expects to dose its first patient later this year . So far, Intellia’s other liver-targeted CRISPR therapies appear to be safe and effective. It’s too soon to know if targeting RNA instead of DNA will have any tangible benefits for AATD patients. Wave said there were mild and moderate side effects of its drug, but didn’t say what they were. Bolno said that prior tests of the drug in healthy volunteers suggest that “the safety profile looks clean.”