WVE-006

Statistically significant and clinically meaningful improvement of 3.8 seconds in Time-to-Rise vs. natural history with largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks; additional functional benefits observed in other outcome measures including NSAA First-ever demonstration of substantial improvements in muscle health with exon skipping – statistically significant reduction in fibrosis driven by decreases in inflammation and necrosis, coupled with transition from regenerative to mature muscle; decreases in creatine kinase and circulating inflammatory biomarkers Dystrophin expression stabilized between 24 and 48 weeks and averaged 7.8%, with 88% of boys above 5% average dystrophin; WVE-N531 remains safe and well-tolerated with no Serious Adverse Events Following recent feedback from FDA, Wave intends to file a New Drug Application in 2026 for accelerated approval, with data to support monthly dosing at launch Wave expects to file CTAs in 2026 for multiple DMD candidates for other exons, with preclinical data supporting a best-in-class exon skipping franchise Wave to host investor conference call and webcast at 8:30 a.m. ET today CAMBRIDGE, Mass., March 26, 2025 (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 positive data from the Phase 2 FORWARD-53 trial of WVE-N531, which is an exon skipping oligonucleotide being investigated in boys with Duchenne muscular dystrophy (DMD) who are amenable to exon 53 skipping. The analysis was conducted after 48 weeks of treatment with 10 mg/kg WVE-N531 dosed every two weeks (Q2W). FORWARD-53 achieved all trial goals, demonstrating sustained and industry-leading exon skipping, muscle concentrations and dystrophin restoration through 48 weeks and a 61-day tissue half-life that supports monthly dosing. WVE-N531 continues to be safe and well-tolerated. Additionally, the data demonstrate substantial decreases in inflammation and necrosis, a statistically significant reversal of muscle fibrosis (28.6% reduction between week 24 to 48; p<0.01), and a transition from regeneration to maturation of muscle. A 50% decline (<0.001) in creatine kinase (CK), as well as decreases in IL-6 and MCP-1, were also observed. Time-to-Rise (TTR) data demonstrate a statistically significant and clinically meaningful 3.8-second improvement versus natural history (p<0.05), which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. Additional functional benefits were observed on the North Star Ambulatory Assessment (NSAA) versus natural history, and in hand grip strength versus baseline. “Despite progress in Duchenne, there remains a significant unmet need for therapeutics that meaningfully impact disease progression. These data demonstrate a promising continuum from dystrophin restoration, to regeneration and maturation of muscle tissue, to functional improvement,” said Pat Furlong, founder and president of Parent Project Muscular Dystrophy. “Paired with monthly administration and a continued favorable safety profile, WVE-N531 represents a significant step forward – not just for individuals amenable to exon 53 skipping, but also for the broader exon skipping field. PPMD looks forward to working with Wave as they expediently bring WVE-N531 and their broader exon skipping pipeline to the Duchenne community.” “As a clinician deeply involved in patient care and research in muscle diseases like Duchenne, I am encouraged by these data for WVE-N531 that show dystrophin restoration and several markers of improved muscle condition,” said Laurent Servais, MD, PhD, Professor of Paediatric Neuromuscular Disease at the University of Oxford and Principal Investigator in FORWARD-53. “To see a clinically meaningful and statistically significant difference on TTR versus natural history in a Phase 2 study is another encouraging finding. I am looking forward to the continued development of WVE-N531.” Wave also announced today that the company met with the U.S. Food and Drug Administration (FDA) on WVE-N531 to discuss its interim 24-week data and initial plans for the confirmatory trial, where the Agency confirmed that the accelerated approval pathway using dystrophin expression as a surrogate endpoint remains open. Based on the FDA feedback and the 48-week data, Wave intends to file a New Drug Application (NDA) in 2026 for accelerated approval of WVE-N531. The NDA filing will be based on all FORWARD-53 data, which will include additional data to support monthly dosing. Furthermore, Wave will continue to engage the Agency with the new 48-week data, including functional outcomes, and its planned global confirmatory trial of WVE-N531. “WVE-N531’s demonstrated ability to reach both myofibers and myogenic stem cells – the regenerative muscle cells – and sustain dystrophin restoration over time is impacting muscle health in ways never before seen in DMD,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “With these transformational data and feedback from FDA in hand, we are now moving toward our first NDA filing, which puts us on the path toward becoming a commercial company.” Continued Dr. Bolno, “Most importantly, we are inspired by the opportunity ahead to deliver life-changing medicines to this community. We expect WVE-N531 to become the first-line treatment of choice for boys amenable to exon 53 skipping, including the 40-50% in the US who are not being treated with approved exon skippers due in part to the burden of weekly infusions coupled with limited efficacy. Additionally, we are accelerating our near-term clinical programs for other exons, which based on preclinical data, suggest a best-in-class exon skipping franchise. We are incredibly grateful to the trial participants and their families, as well as all our collaborators across the DMD community for their contributions to this program and all our DMD research over the past decade.” WVE-N531, as well as Wave’s programs for exons 52, 51, 45 and 44, leverage best-in-class oligonucleotide chemistry, including PN backbone chemistry and stereochemical control, enabling industry-leading muscle delivery and potency without requiring antibody or peptide conjugates. Preclinical data for Wave’s PN chemistry-containing exon skipping candidates have also demonstrated significantly higher dystrophin and drug concentrations in the heart and diaphragm versus skeletal muscle. Collectively, WVE-N531 plus Wave’s exon 52, 51, 45 and 44 programs would address ~40% of the DMD population and represent a >$2.4 billion total market opportunity in the United States alone. Wave expects to submit multiple clinical trial applications (CTAs) for other exon skipping programs in 2026. Detailed Results from FORWARD-53 Eleven boys amenable to exon 53 skipping (age 5-11; 10 ambulatory and 1 non-ambulatory) are enrolled in the ongoing open-label FORWARD-53 trial. Biopsy data are from eight of the 11 boys (all ambulatory and who had biopsies at 24 and 48 weeks) while safety and functional outcome assessments were available for all participants. All 11 boys have advanced to the extension portion of the study where they are now receiving monthly doses of WVE-N531. Results after 48 weeks of 10 mg/kg dosing every two weeks include: Safety and Tolerability WVE-N531 was safe and well-tolerated through 48 weeks. All treatment-related adverse events were mild to moderate in intensity. There were no Serious Adverse Events and no discontinuations due to any causes. Results from Muscle Biopsies Dystrophin and exon skipping: Dystrophin expression stabilized between 24 and 48 weeks of dosing with a mean of 7.8% [95% CI: 5.4-10.3%; 24-week dystrophin was 9.0% (95% CI: 6.5-11.5%) and 48-week dystrophin was 6.4% (95% CI: 3.8-9.0%); muscle content-adjusted dystrophin as measured by western blot]. The difference between the 24- and 48-week mean dystrophin measurements is within the established 30-35% inter-assay variability of the western blot, and consistency between these timepoints was confirmed with an orthogonal assay. 88% of boys (7/8) achieved greater than 5% average dystrophin between 24 and 48 weeks. Mean exon skipping reached steady state at 6 weeks and was consistent through 48 weeks of dosing with a mean of 54% (95% CI: 46-63%). Reversal of muscle damage: Participants showed significant and unprecedented improvements in multiple indicators of muscle health through 48 weeks, indicating a shift from dystrophic muscle towards healthy muscle. These data include: Decreases of the median muscle necrosis and inflammation scores from 2 to 1(representing mild damage) in muscle pathology. Decreases in markers of inflammation (MCP-1 and IL-6). A statistically significant decline in the amount of muscle fibrosis between 24 and 48 weeks (mean decrease of 28.6%, p<0.01). A 50% decrease (p<0.001) in serum creatine kinase (CK), which occurred on top of a stable corticosteroid regimen. Improved organization and uniformity of myofibers in muscle tissue. Decreases in number of stem cells and internalized nuclei, indicative of myofiber maturation between week 24 and 48. 88% of boys (7/8) achieved greater than 5% average dystrophin between 24 and 48 weeks. Mean exon skipping reached steady state at 6 weeks and was consistent through 48 weeks of dosing with a mean of 54% (95% CI: 46-63%). Decreases of the median muscle necrosis and inflammation scores from 2 to 1(representing mild damage) in muscle pathology. Decreases in markers of inflammation (MCP-1 and IL-6). A statistically significant decline in the amount of muscle fibrosis between 24 and 48 weeks (mean decrease of 28.6%, p<0.01). A 50% decrease (p<0.001) in serum creatine kinase (CK), which occurred on top of a stable corticosteroid regimen. Improved organization and uniformity of myofibers in muscle tissue. Decreases in number of stem cells and internalized nuclei, indicative of myofiber maturation between week 24 and 48. Functional Assessments Benefits were seen in multiple functional assessments among WVE-N531-treated boys (n=10), including Time-to-Rise (TTR) and North Star Ambulatory Assessment (NSAA), compared with a matched exon 53 natural history control group (n=18). TTR showed a statistically significant and clinically meaningful 3.8-second difference (p<0.05) favoring WVE-N531 compared with natural history. The minimal clinically important difference (MCID) for TTR was 1.4 seconds, based on the baseline functional characteristics of boys in the study. NSAA showed positive trends favoring WVE-N531 relative to natural history (1.2-point improvement; not significant). Positive trends were also observed among WVE-N531-treated boys (n=11) on grip strength versus baseline. TTR showed a statistically significant and clinically meaningful 3.8-second difference (p<0.05) favoring WVE-N531 compared with natural history. The minimal clinically important difference (MCID) for TTR was 1.4 seconds, based on the baseline functional characteristics of boys in the study. NSAA showed positive trends favoring WVE-N531 relative to natural history (1.2-point improvement; not significant). Additional Upcoming Milestones Across Wave’s Clinical RNA Medicines Pipeline Wave expects multiple additional milestones across its clinical pipeline of RNA medicines in 2025, including: WVE-006 (GalNAc-conjugated RNA editing oligonucleotide for alpha-1 antitrypsin deficiency): Wave expects to deliver 200 mg multi-dose data and 400 mg single-dose data from the Phase 1b/2a RestorAATion-2 trial in 2025. WVE-007 (GalNAc-conjugated siRNA for obesity, designed to silence INHBE mRNA): Wave expects to deliver clinical data from the Phase 1 INLIGHT trial in the second half of 2025, including safety, tolerability and biomarkers reflective of healthy weight loss. WVE-003 (allele-selective silencing for Huntington’s disease): Wave expects to submit an Investigational New Drug application in the second half of 2025 for its potentially registrational Phase 2/3 trial of WVE-003. Investor Conference Call and Webcast Wave will host an investor conference call today at 8:30 a.m. ET to review the FORWARD-53 data. A webcast of the conference call 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. Analysts planning to participate during the Q&A portion of the live call can join the conference call at the audio-conferencing link here. Once registered, participants will receive the dial-in information. Following the live event, an archived version of the webcast will be available on the Wave Life Sciences website. About WVE-N531 WVE-N531 is an exon skipping oligonucleotide being developed as a disease modifying treatment for boys with Duchenne muscular dystrophy amenable to exon 53 skipping. WVE-N531 was designed using Wave’s best-in-class oligonucleotide chemistry modifications, including PN backbone chemistry. WVE-N531 has received Orphan Drug Designation and Rare Pediatric Disease Designation from the U.S. Food & Drug Administration. About Duchenne Muscular Dystrophy Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic neuromuscular disorder caused predominantly by out-of-frame deletions in the dystrophin gene, resulting in absent or defective dystrophin protein. Dystrophin protein is needed for normal muscle maintenance and operation. Because of the genetic mutations in DMD, the body cannot produce functional dystrophin, which results in progressive and irreversible loss of muscle function, including the heart and lungs. Worldwide, DMD affects approximately one in 5,000 newborn boys. Approximately 8%-10% of boys with DMD have mutations amenable to treatment with an exon 53 skipping therapy. Exon skipping aims to address the underlying cause of DMD by promoting the production of dystrophin protein to stabilize or slow disease progression. 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 common 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 Alpha-1 antitrypsin deficiency, Duchenne muscular dystrophy, Huntington’s disease, and obesity, as well as several preclinical programs utilizing the company’s broad RNA therapeutics toolkit. 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 Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, our understanding of the anticipated therapeutic benefit of WVE-N531 as a therapy for DMD, and the broader exon skipping field; our understanding of the safety profile of WVE-N531; our plan and estimated timing to file an NDA for accelerated approval of WVE-N531, along with our expectations for commercialization; our expectations for WVE-N531 to become the first-line treatment of choice for boys amenable to exon 53 skipping; our plan to file CTA submissions for other exon skipping treatments and the potential for a best-in-class exon skipping franchise; addressable patient population estimates related to our therapeutic candidates; the potential commercial opportunities that our therapeutic candidates may address; anticipated milestones and anticipated benefits of our therapeutic candidates and pipeline compared to our competitors; and the potential benefits of PRISM, including our novel PN backbone chemistry modifications, and our stereopure oligonucleotides compared with stereorandom oligonucleotides. 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 events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release and actual results may 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 +1 617-949-4827 krausch@wavelifesci.com Media Contact: Alicia Suter +1 617-949-4817 asuter@wavelifesci.com DMD Community Contact: Chelley Casey +1 617-949-4830 ccasey@wavelifesci.com Source: Wave Life Sciences USA, Inc.

环球视野，深度视角 各位亲爱的股东，大家早上好中午好晚上好。 最近流量扑街，感谢各位股东不弃多多转发吧（不然我就去做标题党）。 P2之前发过，部分更新。但是没有通知额度了，有的朋友估计没看到。 星球首发，加入方式见文末。 2025年3月10日，美国基因治疗公司Beam Therapeutics发布了BEAM-302候选药物的初步临床试验结果。 结果显示，BEAM-302安全性良好，疗效显著。 我们先来了解下背景知识，不感兴趣的可以直接跳到第二节。 #01 背景知识 α1-抗胰蛋白酶缺乏症(α1-antitrypsin deficiency,AATD)，是遗传性疾病,可引起肝脏疾病,也与早发型肺气肿等肺部疾病有关。 α1抗胰蛋白酶缺乏性肝病在我国较为罕见，国内缺少大规模的流行病学统计。 国外研究显示本病在全世界活产儿发病率为1∶7000。 发病风险高的基因型多见于高加索人种，而非高加索人种罕见。 25％患此病的儿童发展为肝硬化、门脉高压，12岁以前死亡，大约25％的病人死于28岁前，另25％仅有轻度肝功能异常的病人可进入成年期，剩余25％的病人无该病的进行性发展表现。 本症为常染色体隐性遗传性疾病，其主要发病病因是遗传性因素。其病理是：α1-AT的含量是由1组常染色体等位基因的不同类型所决定的，其基因座命名为Pi，在遗传过程中，由两个M型等位基因组成的纯合子PiMM为正常的表现型，PiMM是最常见的正常功能基因型，PiZZ是α1-AT严重缺失的等位基因，纯合子为ZZ，血清中α1-AT含量是正常人的15%～20%，这种人常发生阻塞性肺气肿及幼年型肝硬化，PiS等位基因的纯合子SS个体血清中α1-AT含量缺乏的占正常人的60%，这种人亦有患肺气肿的倾向;此外其他表现型如MZ，SZ等杂合子也有α1-AT缺乏，其中有人发生肺气肿和肝硬化。 在BEAM-302之前，治疗通常有以下几种： 第一，人工合成类固醇治疗，使干细胞分泌的α1-AT增加，但是有肝转氨酶升高的副作用； 第二，补充外源性α1-AT； 第三，肝移植； 除了肝移植，其他的疗法都是治标不治本，因此迫切需要一种能够彻底治愈AATD的新型药物。 那么，BEAM-302是怎么的机制是什么？ #02 “改正错误” 既然PiZ是由于基因突变造成，且为单碱基突变。 那么Beam开发的base editor就是非常好的治疗工具。 只需要通过LNP（纳米脂质体颗粒）将基因编辑工具递送到人体内，然后进行一个A-to-G的单碱基编辑，问题不就解决了吗？ 有错就改，才是好碱基。 Base-editor的优势在于，无需断开DNA双链，直接进行基因编辑，准确度高的同时减少了染色体异常的可能。 当然，从技术原理到工业化实践还有很长的路要走。 比如，payload递送的准确性和效率，碱基编辑的效率等等。 那么，BEAM-302表现如何？ #03 “曙光” Beam Therapeutics的基因疗法BEAM-302在1/2期临床试验中，对9名AATD患者进行单次静脉注射后，未报告严重不良事件。 患者接受15、30或60毫克剂量，所有不良事件均为轻至中度，未见剂量限制性毒性。 接受15毫克剂量的3名患者在第28天功能性AAT增加1.6倍；30毫克剂量组增加1.9倍；60毫克剂量组增加2.8倍。 60毫克剂量使AAT水平达到AATD治疗阈值以上，显示出剂量依赖性疗效。 根据Beam发布的公告，基于目前的数据，BEAM-302的临床研究将继续进行剂量爬升研究。 事实上，BEAM-302并不是第一个进入临床的实验性基因编辑AATD疗法。 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。 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）候选药物。 因此，我们可以预见，AATD的治愈曙光可能就在眼前了。 #04 最后 虽然，但是。 药物的开发有着很大的不确定性，即便目前已经有两家公司的产品进入临床试验阶段。 并不能一定都进入商业化阶段，甚至全军覆没都有可能。 因此，比较残忍的一点是只有药企有利可图才有可能开发疾病的相关药物。 而根据Wave Lifescience引用的数据，AATD患者在美国和欧洲总和约为20万。 希望他们能赚钱吧。 END 找小编，扫这里！ 至此，各位股东星标了么？点赞了么？转发了么？在看了么？谢谢！ 所有内容均不作为投资建议，信息均来自公开资料。 近期文章： Illumina回应被制裁！继续运营、缩减开支！裁员？ 大道至“减”？ 测序仪：哟，这不掏上了吗？ 国产测序仪风云录|亚辉龙/大道测序进展 我们已经开始厌倦A.I. Standard BioTools：感谢Illumina！ 相关资料：注1：https://www.dayi.org.cn/disease/1156706注2：https://wedic.guahao.com/wap/word/72902注3：https://investors.beamtx.com/news-releases/news-release-details/beam-therapeutics-announces-positive-initial-data-beam-302-phase