Inhibin βE (INHBE) is a possible insulin resistance-associated hepatokine identified by comprehensive gene expression analysis in human liver biopsy samples

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作者: Igawa, Hirobumi ; Takamura, Toshinari ; Suzuki, Yoshiyuki ; Kushima, Youichi ; Misu, Hirofumi ; Honda, Kiyofumi ; Kaneko, Shuichi ; Sugiyama, Masakazu ; Ashihara, Motooki ; Kawabe, Yoshiki ; Kikuchi, Akihiro

The liver plays a major role in whole-body energy homeostasis by releasing secretory factors, termed hepatokines. To identify novel target genes associated with insulin resistance, we performed a comprehensive analysis of gene expression profiles using a DNA chip method in liver biopsy samples from humans with varying degrees of insulin resistance. Inhibin βE (INHBE) was identified as a novel putative hepatokine with hepatic gene expression that positively correlated with insulin resistance and body mass index in humans. Quantitative real time-PCR analysis also showed an increase in INHBE gene expression in independent liver samples from insulin-resistant human subjects. Additionally, Inhbe gene expression increased in the livers of db/db mice, a rodent model of type 2 diabetes. To preliminarily screen the role of Inhbe in vivo in whole-body energy metabolic status, hepatic mRNA was knocked down with siRNA for Inhbe (siINHBE) in db/db mice. Treatment with siINHBE suppressed body weight gain during the two-week experimental period, which was attributable to diminished fat rather than lean mass. Additionally, treatment with siINHBE decreased the respiratory quotient and increased plasma total ketone bodies compared with treatment with non-targeting siRNA, both of which suggest enhanced whole-body fat utilization. Our study suggests that INHBE functions as a possible hepatokine to alter the whole-body metabolic status under obese insulin-resistant conditions.

项与 WVE-007 相关的新闻（医药）

2024-10-30

·GlobeNewswire-Health Care

Wave Life Sciences Highlights Growing Pipeline at Research Day, including INHBE siRNA Program for Obesity and New RNA Editing Programs

WVE-007 (INHBE GalNAc-siRNA for obesity) is on track to initiate a clinical trial in 1Q 2025; new preclinical data for WVE-007 demonstrate opportunities for monotherapy, for synergistic use with GLP-1s, and for maintenance to avoid rebound weight gain following cessation of GLP-1s Recent proof-of-mechanism data for WVE-006 unlocked Wave’s best-in-class RNA editing capabilities; three new wholly owned RNA editing programs targeting PNPLA3, LDLR and APOB are first-in-class approaches to address significant unmet needs in cardiometabolic diseases Wave plans to have five GalNAc-RNA editing or GalNAc-siRNA programs in the clinic by 2026 Wave’s clinically validated platform continues to lead on the improvement of intracellular delivery using novel chemistry, including PN backbone chemistry modifications CAMBRIDGE, Mass., Oct. 30, 2024 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced updates across its growing pipeline, which were also discussed during the company’s virtual analyst and investor Research Day (link to webcast). Updates included new preclinical data for Wave’s GalNAc-small interfering RNA (siRNA) approach for obesity, WVE-007, which is on track to initiate a clinical trial in the first quarter of 2025. Wave also introduced new, wholly owned GalNAc-RNA editing programs and demonstrated its leadership in oligonucleotide chemistry innovation. “This year, we showed through multiple positive clinical datasets that our leading RNA medicines platform is opening up new possibilities for the treatment of human disease. Next to the clinic will be our WVE-007 program, which reimagines obesity treatment with a mechanism that directly impacts fat cells – particularly visceral fat – and which could be used as monotherapy, add-on to GLP-1s, or for maintenance post-GLP-1 cessation,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “Additionally, we are excited to introduce three new programs for mRNA correction and upregulation to treat cardiometabolic diseases with significant unmet needs. These programs have substantial, well-defined patient populations, strong support from human genetics, efficient paths to proof-of-concept in the clinic, and offer the opportunity to meaningfully change health outcomes for millions of people. This truly is an exciting time for Wave and for patients as we unlock new biology and build our high-value and innovative pipeline.” Key Highlights from Today’s Virtual Research Day WVE-007: INHBE GalNAc-siRNA and potential best-in-class obesity therapeutic approaching the clinic WVE-007 is Wave’s GalNAc-siRNA that targets INHBE as a novel approach to treat obesity. The approach is based on human genetics, where individuals who have a protective loss-of-function mutation in the INHBE gene have a healthier cardiometabolic profile, including less unhealthy visceral fat, lower triglycerides, and lower risk of type 2 diabetes and cardiovascular disease.Silencing of INHBE in vivo directly impacts adipocytes (fat cells) and induces lipolysis (fat burning), which is different from GLP-1s’ centrally acting mechanism that involves the digestive system and central nervous system to decrease appetite.New preclinical data in diet induced obese (DIO) mice demonstrate the potential of WVE-007 to be used across the treatment continuum, including as monotherapy, as an add-on to GLP-1s, and for maintenance to prevent weight regain and weight cycling after discontinuing GLP-1s.Wave is on track to initiate a Phase 1 clinical trial for WVE-007 in adults living with overweight or obesity in the first quarter of 2025. The trial is planned to assess safety, tolerability, pharmacokinetics, and Activin E lowering (a biomarker for target engagement), as well as body composition. New GalNAc-RNA editing programs designed to optimally address high-impact cardiometabolic diseases Building on Wave’s recent achievement of the first-ever therapeutic RNA editing with WVE-006 in alpha-1 antitrypsin deficiency, the company today announced three new, wholly owned RNA editing programs that are on track for candidate selection in 2025. Like WVE-006, these programs leverage GalNAc conjugation and have efficient clinical paths to proof-of-concept. These new programs include: PNPLA3 (mRNA correction): Homozygous PNPLA3-I148M patients are at high risk for a variety of liver diseases and there are more than 9 million impacted individuals in the US and Europe. Wave’s RNA editing approach aims to achieve at least 50% correction to restore the heterozygous phenotype with low risk of liver disease, similar to the approach with WVE-006.LDLR (mRNA upregulation) and APOB (mRNA correction): High unmet needs remain among familial hypercholesterolemia (FH) patients, with approximately half of patients not reaching goal LDL-c levels with available therapies. Wave’s AIMers to upregulate LDLR and correct APOB have potential to be first-in-class treatment approaches for best-in-class effects to reach target LDL-c levels in Heterozygous FH (HeFH) patients. Combined, LDLR and APOB AIMers would address ~1 million HeFH patients in the US and Europe. LDLR upregulation also offers significant expansion opportunities in patients with statin intolerance or prior cardiovascular events (~30 million patients in the US and Europe). Chemistry innovation enhancing intracellular delivery Today, Wave shared data demonstrating how its proprietary chemistry results in marked improvements in five key areas of intracellular delivery: 1) cellular uptake; 2) endosomal release; 3) cellular residency; 4) nuclear uptake; and 5) target engagement.Wave shared how it is using PN variants and modifications to physicochemical properties to achieve best-in-class siRNA silencing and RNA editing in a variety of extrahepatic tissues.Wave also highlighted novel chemistry used in its AIMers, including proprietary N-3-uridine chemistry (N3U), which substantially enhances RNA editing efficiency. This novel chemistry was the subject of a recent Nucleic Acids Research publication. An archived webcast of the event can be accessed by visiting “Investor Events” on the investor relations section of the Wave Life Sciences website: https://ir.wavelifesciences.com/events-publications/events. About Wave Life SciencesWave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s RNA medicines platform, PRISM®, combines multiple modalities, chemistry innovation and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. Its toolkit of RNA-targeting modalities includes editing, splicing, RNA interference and antisense silencing, providing Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s diversified pipeline includes clinical programs in Duchenne muscular dystrophy, Alpha-1 antitrypsin deficiency and Huntington’s disease, as well as a preclinical program in obesity. Driven by the calling to “Reimagine Possible”, Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit www.wavelifesciences.com and follow Wave on X (formerly Twitter) and LinkedIn. Forward-Looking StatementsThis press release contains forward-looking statements concerning our goals, beliefs, expectations, strategies, objectives and plans, and other statements that are not necessarily based on historical facts, including statements regarding the following, among others: the anticipated initiation, site activation, patient recruitment, patient enrollment, dosing, generation and reporting of data and completion of our clinical trials, including interactions with regulators and any potential registration based on these data, and the timing and announcement of such events; regulatory submissions and timing for regulatory feedback; the protocol, design and endpoints of our clinical trials; the future performance and results of our programs in clinical trials; our expectations with respect to how our clinical data successes to date may predict success for our future therapeutic candidates, future clinical data readouts and further validate of our platform; ongoing and future preclinical activities and programs; the potential of our preclinical data to predict the behavior of our compounds in humans; our identification and expected timing of future product candidates and their therapeutic potential; the anticipated benefits of our therapeutic candidates and pipeline compared to our competitors; patient population estimates related to our therapeutic candidates and the potential addressable market that our therapeutics may address; our ability to design compounds using various modalities and the anticipated benefits of that approach; the breadth and versatility of our PRISM drug discovery and development platform; the expected benefits of our stereopure oligonucleotides compared with stereorandom oligonucleotides; the potential benefits of our RNA editing capability, including our AIMers, compared to others; the benefits of RNA medicines generally; the potential for certain of our programs to be best-in-class or first-in-class; the potential benefits that our “edit-verse” may provide us, including identifying new RNA editing targets; our ability to translate genetic insights into high impact medicines; the status and progress of our programs relative to potential competitors; the progress and potential benefits of our collaborations; ;and the anticipated duration of our cash runway and our ability to fund future operations. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual results to differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in Wave’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC), as amended, and in other filings Wave makes with the SEC from time to time. Wave undertakes no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances. Investor Contact:Kate Rausch+1 617-949-4827krausch@wavelifesci.com Media Contact:Alicia Suter+1 617-949-4817asuter@wavelifesci.com

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·同写意

RNA编辑先驱打了一场翻身仗

此次医博会由同写意策划，以“发展新质生产力，共享健康新未来”为主题，用全新的视角瞄准国内外医药及大健康产业发展前沿。诚邀海内外医药及大健康各界嘉宾齐聚中国医药城，共赴时代之约。展位/报告火热征集中！ “CRISPR让个道，RNA编辑疗法要提速了”。这是今年2月，发表在《Nauter》上的一篇文章标题（《Move over, CRISPR: RNA-editing therapies pick up steam》）。正在走向前台的RNA编辑技术，因其更安全、更灵活的特性，被视为有望超越CRISPR的存在。技术方兴未艾，MNC如礼来、GSK的押注，更是一度将其热度推向高潮。不过，成立于2012年的RNA编辑先驱Wave，用了10多年的时间，才将首个RNA编辑项目WVE-006推向临床。期间，由于其他核酸药物的临床失利，Wave股价由高点的56美元/股一路跌至1美元/股左右，市场预期不再。沉寂多年后，一场由临床数据带动的反攻，正在上演。 10月16日，Wave发布WVE-006临床1b/2a期积极数据。数据显示，在两例PiZZ型AATD（α-1 抗胰蛋白酶缺乏症）患者中，单次皮下注射WVE-006使其平均血浆总AAT水平达到约11µM，患者血浆中循环野生型M-AAT蛋白在第15天达到平均6.9µM，占总AAT的60%以上。与基线相比，中性粒细胞弹性蛋白酶抑制的增加与功能性M-AAT的产生一致。平均总AAT蛋白从基线时的不可量化水平增加到第15天的10.8µM，达到了监管部门批准AAT增强疗法的基础水平。由于PiZZ型AATD患者无法自然合成M-AAT蛋白，因此，M-AAT蛋白的出现，证明了突变型Z-AAT mRNA被成功编辑。换句话说，Wave的RNA编辑平台终于实现了机制验证。Wave CEO兴奋地称之为，“人类首次治疗性RNA编辑数据”。数据发布后，Wave股价暴涨75%。在此之前的9月24日，Wave另一款反义寡核苷酸（ASO）药物WVE-N531，在中期临床中展现出成为杜氏肌肉萎缩症BIC药物的潜力，公司股价随之暴涨53%。不到一个月的时间，Wave股价涨幅超162%。看起来，Wave正在践行其Reimagine Possible（潜力重燃）的承诺。 1 超越“CRISPR”？ WVE-006临床1b/2a期的成功，意味着Wave的RNA编辑平台实现了机制验证。众所周知，CRISPR技术的诞生，让基因编辑从直板机步入智能机时代，也让我们距离成功修补人类基因缺陷的目标越来越近。去年12月，FDA更是批准了全球首款CRPISPR-Cas9基因组编辑疗法CASGEVY的上市。相比之下，RNA编辑疗法的发展要慢得多。不过，正在走向前台的RNA编辑技术，则被视为有望超越CRISPR的存在。这两种主流的基因编辑手段，在基因治疗领域扮演着重要角色，尽管它们的最终目的都是为了实现对遗传信息的精确修改，但两者仍有显著不同。 CRISPR-Cas9技术是通过直接剪切DNA链上的特定基因序列，实现对基因的编辑。这种方法虽然高效，但修改是永久性的，一旦发生错误，可能导致不可逆转的遗传变异。事实上，自诞生以来，CRISPR技术的一个主要问题就是其潜在的脱靶效应，如果CRISPR基因编辑技术对预期靶标以外的其他DNA片段进行了切割，可能会破坏非靶向基因的功能或调节，引发严重后果。此外，CRISPR技术涉及到直接修改个体的基因组，这不仅引发了伦理上的争议，也使得其应用受到了一定的限制。与CRISPR技术相比，RNA编辑技术提供了一种更安全、更灵活的治疗选择。因为，后者是通过修改信使RNA（mRNA）的方式，比如敲除、替换或抑制突变RNA片段，来实现对基因表达的调控，治疗遗传疾病。其基本原理是通过特定的酶或编辑因子，对mRNA上的碱基进行修改，从而影响蛋白质的合成。这一过程可以分为单碱基编辑和RNA外显子编辑两种主要类型。以单碱基编辑为例，通过精确地编辑特定的单个碱基，可以修正错误的遗传信息，恢复正常的蛋白质表达。比如，将mRNA上的腺嘌呤（A）编辑为肌苷（I）。这也是WVE-006的药物机制。可以看到，由于这是在mRNA水平上进行，不直接改变DNA序列，因此可以有效避免脱靶效应和伦理问题。此外，mRNA分子寿命较短，意味着通过RNA编辑介入的效果是可逆的。《Nature》上的一篇文章评价道，RNA编辑技术的发展标志着我们对生命科学的理解已经进入了一个新的层次。成立于2012年的RNA编辑先驱，Wave也被寄予厚望。只不过，大多时候，前沿技术的发展总是充满波折与挑战。在临床试验中，如何确保编辑的精确性和效率，如何评估和优化长期安全性和稳定性，还有待验证。 Wave更是用了10多年的时间，才将WVE-006推向临床，获得初步验证。 2 命途多舛尽管Wave在核酸赛道深耕多年，核酸技术平台PRISM也独具特色，是唯一提供三种RNA靶向方式（编辑、剪接和沉默，包括siRNA和反义RNA）的寡核苷酸平台。但Wave却命途多舛，上市以来多个项目失败，导致市场预期降至谷底。比如2019年3月，Wave停止了两款处于I/II期临床的反义寡核苷酸（ASO）药物，WVE-120101和WVE-120102。这是两款治疗亨廷顿病的疗法。亨廷顿是一种罕见的遗传性神经退行性疾病，该疾病从被医学提出至今已长达150余年，距确定病因至今也已有30年，但目前仍没有治愈之法。研究人员一度希望ASO疗法能够改变亨廷顿病的游戏规则。然而，现实是多款针对亨廷顿病的ASO药物相继折戟。数据显示，WVE-120102和WVE-120101两个药物所有评估剂量均未显示统计学显著的临床疗效证据。在此之前，罗氏与Ionis合作研发的ASO 药物Tominersen停止III期临床，这被外界视为亨廷顿基因疗法希望破灭。两则坏消息，导致Wave的股价暴跌46%。然而，令人意想不到的是，这只是Wave厄运的开始。 2019年底，Wave在对I期OLE研究结果进行中期分析后，决定终止外显子51跳跃突变杜氏肌营养不良症（DMD）药物suvodirsen的开发。研究结果显示，使用药物后肌营养不良蛋白表达与基线相比没有变化。消息公布后，Wave股价暴跌超50%。半个月前，市场还寄希望其能够超越Sarepta，但随着亨廷顿病和DMD的失败，希望破灭，其股价也从高点的56美元/股，跌至不足8美元/股。在接连失败的打击中，Wave决定裁员1/4，降低运营成本，并削减了其他DMD的研发工作。此后接近3年时间，Wave几乎没有任何提振市场的消息传来，股价甚至一路下跌至1美元/股左右。当然，Wave并没有放弃研发。毕竟其有技术平台，也有多款药物在研。 WVE-N531(剪接)，用于治疗DMD的外显子53分子; WVE-006(编辑)，用于治疗AATD(α-1抗胰蛋白酶缺乏症)的SERPINA1分子； WVE-003(沉默)，用于治疗亨廷顿病的mHTT SNP3分子; WVE-004(沉默)，用于治疗相关的ALS和FTD(肌萎缩侧索硬化症和额颞叶痴呆)的C9orf72分子；以及INHBE项目治疗代谢疾病。 Wave的技术平台和相关药物也得到了GSK的青睐。2022年12月13日，双方达成合作。首先是利用Wave的PRISM平台以及GSK在遗传学与基因组学的专业进行发现合作，以推进GSK最多8个以及Wave最多3个项目。除了这些项目，GSK也将获得Wave临床前项目WVE-006的全球独家权利。根据协议，Wave将从GSK获得1.7亿美元的预付款，以及关于WVE-006项目的开发与里程碑启动款项等款项，最高可达33亿美元。 3 潜力重燃在与GSK达成合作后一周，Wave公布了WVE-N531治疗DMD男孩的1b/2a期积极数据。在Wave的WVE-N531试验的A部分中，WVE-N531展示出行业领先的外显子跳跃水平，达53%。并且，相比已获批的ASO药物，WVE-N531的药代动力学参数显示药物的半衰期为25天。这可能支持其每月给药，高于现有药物的1周一次。这得益于其新型化学修饰技术PN化学。与更传统的磷酸硫酯或磷酸二酯连接相比，含有PN化学的寡核苷酸连接更稳定，因此，有实现更长的药物半衰期和长期效果的潜力。上述数据公布及与GSK的合作宣布后，Wave股价接连大涨。而今年9月24日，最新的临床数据显示，除了继续保持领先的外显子跳跃水平（57%），WVE-N531也实现了9%的平均肌肉含量调整后的抗肌萎缩蛋白，安全性与耐受性良好。这再次带动Wave股价暴涨53%。与此同时，尽管在亨廷顿病领域遭遇沉重打击，但Wave仍保留了一款ASO药物，WVE-003。可以说，WVE-003承载着已停止研究的WVE-120101和WVE-120102这两款药物的希望。其特别之处在于，高针对性。 WVE-003能够识别并针对变有害的亨廷顿蛋白（mHTT），不影响正常的亨廷顿蛋白（wtHTT）。由于wtHTT的功能对中枢神经系统的健康至关重要，且mHTT可能干扰wtHTT的功能，今年6月，Wave公布了WVE-003的I/II期SELECT-HD研究数据。结果显示，WVE-003组患者的mHTT水平相比安慰剂组显著下降（治疗第24周时，mHTT降低了46%；治疗第28周时，mHTT降低了44%）。 Wave认为WVE-003的销售峰值有望达到50亿美元。不过，武田已于10月11日决定放弃行使包括WVE-003在内的亨廷顿氏病疗法的期权。双方的合作始于2018年，武田已向Wave支付了约2.6亿美元。WVE-003是之前的合作协议产生的最后一个未宣告失败的成果，但武田决定放弃引进该药物。而相比其他核酸疗法，Wave更是高度重视开发RNA靶向药物，首个RNA编辑项目WVE-006也获得了GSK的押注。 WVE-006是针对AATD的RNA编辑寡核苷酸疗法。AATD是一种常见的遗传性基因疾病，通常由SERPINA1基因中G到A的点突变（Z等位基因）引起，会引发严重的肺和肝疾病。目前AATD肺病的唯一治疗选择是通过每周静脉输注以递送AAT蛋白，仅针对肺病（2023年全球销售额超过14亿美元）；AATD肝病目前尚无治疗方法，许多患者最终需要接受肝脏移植。因此，包括WVE-006在内的新疗法颇受市场关注。WVE-006的原理是通过设计特定的小分子RNA，针对性地引导细胞内的ADAR酶对特定mRNA上的错配碱基进行精准编辑，从而修正错误的遗传信息，恢复AAT蛋白的正常表达。同时，WVE-006作为全球首个进入临床试验的RNA编辑化合物，也在一定程度上影响着市场对于RNA编辑疗法的想象与预期。 10月16日，Wave公布Ib/IIa期RestorAATion-2研究积极数据。尽管数据仅来自两名患者，但Wave表示这些数据显示了令人信服的证据，其药物成功地编辑了细胞用来将DNA转化为蛋白质的信使分子，即其RNA编辑平台实现了机制验证。 Wave CEO兴奋地称之为，人类首次治疗性RNA编辑数据。数据发布后，Wave股价暴涨75%。完成RestorAATion-2研究后，WAVE将把WVE-006的开发和商业化权益转移给GSK，并有资格获得高达5.25亿美元的里程碑付款，以及分层版税。如果从9月算起，其股价已经上涨162%，打了一个漂亮的翻身仗。如果有什么秘诀，恐怕指向一点：尽管一度跌至谷底，但Wave并没有就此沉沦，而是有选择的坚持与改进管线研发，沉淀平台技术。目前看，其正在用积极的临床进展数据，践行其Reimagine Possible（潜力重燃）的承诺。当然，对于Wave来说，这边RNA编辑技术刚刚获得验证，那边武田退回合作，意味着其在核酸药物这条道路上，还有很多未知与挑战。同写意媒体矩阵，欢迎关注↓↓↓

基因疗法信使RNA寡核苷酸核酸药物临床申请

2024-10-17

·PipelineReview

Wave Life Sciences Announces First-Ever Therapeutic RNA Editing in Humans Achieved in RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency

Achieved proof-of-mechanism for Wave’s RNA editing platform; restoring levels of wild-type (edited) M-AAT that are consistent with the heterozygous “MZ” genotype with low risk of AATD lung and liver disease A single subcutaneous dose of WVE-006 in the first two patients with homozygous “ZZ” AATD resulted in mean plasma total AAT levels of ~11 micromolar, with mean wild-type M-AAT representing more than 60% of total AAT; durable editing with M-AAT protein observed through 57 days Wave expects to share multidose data from the RestorAATion-2 trial in 2025 Annual Research Day on October 30 th will highlight WVE-006 proof-of-mechanism data and Wave’s new wholly owned GalNAc-RNA editing programs, in addition to an obesity program update with new preclinical data for WVE-007 (INHBE GalNAc-siRNA) CAMBRIDGE, MA, USA I October 16, 2024 I Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health, today announced positive proof-of-mechanism data from the ongoing Phase 1b/2a RestorAATion-2 study of WVE-006 in alpha-1 antitrypsin deficiency (AATD). WVE-006 is a GalNAc-conjugated, subcutaneously delivered, A-to-I RNA editing oligonucleotide (AIMer) that was developed with Wave’s best-in-class oligonucleotide chemistry platform. It is uniquely designed to address AATD-related lung disease, liver disease, or both. Today’s proof-of-mechanism data are the first-ever clinical demonstration of RNA editing in humans. These data are from the first single dose cohort (200 mg) in RestorAATion-2 and include the first two patients with “ZZ” AATD (Pi*ZZ AATD) to reach day 57. Individuals with Pi*ZZ AATD do not naturally produce wild-type alpha-1 antitrypsin (M-AAT) protein; therefore, the presence of M-AAT protein is confirmation of successful editing of mutant Z-AAT mRNA. Additionally, restoring 50% M-AAT would be consistent with the heterozygous “MZ” genotype with low risk of AATD lung and liver disease. Circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT. Increases in neutrophil elastase inhibition from baseline were consistent with production of functional M-AAT. Mean total AAT protein increased from below the level of quantification at baseline to 10.8 micromolar at day 15, meeting the level that has been the basis for regulatory approval for AAT augmentation therapies. Increases in total AAT from baseline and M-AAT protein were observed as early as day 3 and through day 57. WVE-006 has been well-tolerated with a favorable safety profile to date. All adverse events in RestorAATion-2, as well as in the ongoing RestorAATion-1 trial of healthy volunteers, are mild to moderate, with no Serious Adverse Events reported. The RestorAATion-2 trial is ongoing and Wave expects to share multidose data in 2025. “Achieving the first-ever therapeutic RNA editing in humans is a significant milestone for our organization, for our GSK collaboration, and for the entire oligonucleotide field. It also unlocks and derisks Wave’s RNA editing platform, in light of the continued strong clinical translation of our proprietary best-in-class chemistry, including PN, stereochemistry and our N3U AIMer modification,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “The level of mRNA editing we are observing with a single dose exceeded our expectations and we expect M-AAT levels to continue to increase with repeat dosing, based on our preclinical data. These initial data, alongside WVE-006’s durability and convenient subcutaneous administration, are all supportive of a best-in-class profile for WVE-006 relative to other editors and in the broader AATD space. These data also increase our confidence in our wholly owned pipeline, including our HD, DMD and obesity programs, as well as our next RNA editing targets. We look forward to introducing the next RNA editing programs, as well as providing an update on our INHBE GalNAc-siRNA program in obesity, at our Research Day on October 30.” There are an estimated 200,000 individuals living with AATD in the US and Europe who are homozygous for the SERPINA1 Z mutation. Treatment options are currently limited to weekly IV augmentation therapy for lung disease only (representing over $1.4 billion in worldwide sales in 2023). There are no approved therapies to address AATD liver disease, which ultimately requires many individuals living with AATD to undergo liver transplantation. GSK has the exclusive global license for WVE-006. Development and commercialization responsibilities will transfer to GSK after Wave completes the RestorAATion-2 study. In total, Wave is eligible for up to $525 million in milestones, as well as tiered royalties on net sales, for WVE-006. About Wave Life Sciences Wave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s RNA medicines platform, PRISM®, combines multiple modalities, chemistry innovation and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. Its toolkit of RNA-targeting modalities includes editing, splicing, RNA interference and antisense silencing, providing Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s diversified pipeline includes clinical programs in Duchenne muscular dystrophy, Alpha-1 antitrypsin deficiency and Huntington’s disease, as well as a preclinical program in obesity. Driven by the calling to “Reimagine Possible”, Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information on Wave’s science, pipeline and people, please visit www.wavelifesciences.com and follow Wave on X (formerly Twitter) and LinkedIn . SOURCE: Wave Life Sciences

临床结果引进/卖出寡核苷酸

100 项与 WVE-007 相关的药物交易

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