Suvodirsen

“我们不奢求立马治愈，但至少能延缓症状，能有药能用”，这是来着一名DMD患儿母亲接受采访时谈到的最迫切的需求，听起来如此简单，却又如此令人心痛的难以实现。如果世界上有哪些疾病比癌症更可怕，那么不能坐、不能站、从扶膝走路到坐上轮椅只用十数年的DMD绝对是其中之一。DMD杜氏肌营养不良是一种罕见的儿童神经肌肉疾病，是严重的X染色体隐性单基因遗传病，大约每3500~5000名男婴中就有1例患病者（参考来源2），中国巨大的人口基数下，初步估计每年仍约有400-500例DMD新发患儿，累计之下，我国DMD患者已超过6万例，成为了全球DMD患者人数最多的国家之一（参考来源3）。在对DMD的多年研究之下，其致病原因基本清晰，即DMD基因变异直接导致的部分功能缺陷从而致病，从突变类型主要可分为大片段突变（缺失，重复）和小片段突变（缺失，插入，剪切位点，点突变等）。在方红军、杨赛等人2022年对171例（近期病例数相对多且完整的案例）临床表型与基因型分析中结果显示，DMD中最常见的变异是基因缺失，大缺失与小缺失共计占病例总数的68.4%，最常见的缺失热点区域位于外显子45~52区（68.5%），其次为外显子2~26区（18.9%）。临床治疗方面，目前全世界各地获批用于DMD的药物最主要的为肾上腺糖皮质激素，尽管过程中表现出的副作用明显，但综合评估之下仍是利大于弊，可以提高肌肉力量，延长步行能力，保持脊柱功能及心脏功能，增加肺功能，从而改善患儿健康状况，延长寿命；而其余如睾酮及生长激素等内分泌治疗，也对患者的骨骼健康以及心理社会情感的发展起到至关重要的作用；前沿治疗方面，虽目前部分医院可在特殊政策的支持下，可以利用超适应症用药等方式短暂用到部分DMD创新疗法，如海南博鳌医院罕见病临床医学中心2021年就引入了EXONDYS 51、VYONDYS 53与AMONDYS 45，但对于大多数DMD患者而言，虽然全球已有7款新药获批DMD治疗，但却仍没有任何一款新药在国内获批上市，确实是“无药可用”的局面，见图1。图1：DMD全球已上市药品数据来源：药智数据目前，疾病前沿药物研究领域，基因治疗最被关注，例如RNA通读疗法、外显子跳跃疗法，基于AAV的基因治疗等，开发中的新型疗法还包括基因编辑，小分子RNA结合剂等等。而2018年FDA正式发布DMD药物开发的技术指导原则更是重点强调了“通过基于生物标志物加速DMD药物获批”，对后续相关疗法上市提供了强大的推动作用。外显子跳跃疗法无法治愈，但可减轻症状据参考资料显示，目前外显子跳跃疗法新药，虽不能覆盖所有DMD患者，但已经可以针对23%的杜氏肌营养不良患者，距理想中治疗60-80%的DMD患者的目标，进了一大步。所谓外显子跳跃治疗，即通过人工合成反义寡核苷酸，抑制一个剪切增强子位点，以阻止特定外显子参与剪接，从而恢复肌肉功能，延缓病程和延长寿命。自2016年首个外显子51跳跃的新药（Eteplirsen）问世以后，之后该领域陆续有了不少相关疗法持续上路，但随之而来的就是其备受争议的开发之路。其主要原因在于，Eteplirsen自获批之后，虽临床上其提高平均dystrophin水平（0.16%提升至0.44%）被证明确有统计学意义，但其数值上距临床医生期盼的10% 目标仍相距较大，虽最终在其真实世界研究中，被证明其平均可延长DMD患者5—8年寿命，但关于其有效性，甚至是关于外显子跳跃的有效性质疑却也一直未曾停歇。迄今为止，全球领域已经有四个外显子跳跃新药获得正式批准（图2）。除Eteplirsen之外，还有戈洛迪森（Golodirsen）、维托拉生（villtolasen）与卡西姆生（Casimersen），进入临床III期阶段的新药则有两款（图3），分别是drisapersen（PRO051）与suvodirsen（WVE-210201）；至于国内方面，2021年海外获批的卡西姆生（Casimersen）目前已在国内进入了注册申请阶段，，见图4，其余三款已上市新药或也有望。排序药品靶点研发企业适应症最高阶段1戈罗迪生 golodirsenDMDSarepta Therapeutics Inc;University of Western Australia全球：批准上市2维托拉生 viltolarsenDMD日本新药株式会社全球：批准上市中国：注册申请3卡西姆生 casimersenDMDSarepta Therapeutics Inc;University of Western Australia全球：批准上市4依普勒森 eteplirsenDMDSarepta Therapeutics Inc;University of Western Australia全球：批准上市图2：全球部分外显子跳跃疗法已获批上市数据来源：药智数据排序药品靶点研发企业适应症最高阶段1曲萨珀森 drisapersen （PRO051）DMDBiomarin Pharmeceutical Inc全球： 临床Ⅲ期2舒沃地生 suvodirsen （WVE-210201）DMDWAVE Life Sciences Ltd全球： 临床Ⅲ期图3：全球部分外显子跳跃疗法处于Ⅲ期临床数据来源：药智数据另外，更值得期待的是，Sarepta等公司也终于攻克了之前外显子疗法半衰期过短的弊端，利用多肽偶联技术正在开发下一代多肽偶联PMO（PPMO）或者抗体偶联PMO用于提高PMO的血浆半衰期和实现肌肉递送。有望将dystrophin的水平提高至原来的8倍，目前进展最快即SRP-5051。通读疗法有效针对“无义突变”终止密码子通读疗法是一种很有前途的DMD疗法，它能够通读因抗肌营养不良蛋白基因无义突变而过早出现的终止密码子。几乎适用于DMD中所有无义突变，对10%左右的DMD患者有效。而阿塔鲁伦（ataluren）作为目前唯一批准用于DMD的RNA通读疗法，其乃翻译通读诱导药物，能够读取mRNA中的提前终止密码子，从而产生有功能性的肌营养不良蛋白，目前已获得欧洲药品管理局的有条件批准，但其在美国的上市申请于2017年被拒绝。究其根本，ataluren之所以被FDA进展如此困难，其最大的问题在于临床实验中表现的bell-shaped efficacy， 有关资料显示其在注册临床中，无论是dystrophin的恢复水平，还是6分钟行走，高剂量组（80mpk）的药效反而劣于低剂量组（40mpk），并且和安慰剂没有显著差异。而尽管得不到FDA的青睐，ataluren却也得到了EMA的批准上市。并且在2023年4月发表的回顾性临床研究中，比起自然病史患者，ataluren成功将失去行走能力的时间从13岁延长至17岁。目前，最新消息显示PTC公司目前将继续向美国FDA提交药物上市申请，而受到PTC与美国食品和药物管理局(FDA)会面影响，在之前讨论重新提交Translarna新药申请(NDA)的潜在途径之后，FDA建议PTC要求召开后续会议，以协调可能支持潜在NDA备案的具体内容，此会议将于2024年第一季度举行，如果一切顺利，FDA或许批准Translarna上市或将在2024年期间完成。基因治疗最有望“根治”的治疗方式针对DMD的基因疗法的临床研究，其主要集中在抗肌营养不良蛋白基因替代疗法，但由于抗肌营养不良蛋白基因的尺寸巨大，这种方法非常具有挑战性。虽然经历多年确实取得了多项实质性突破，但在有效性、安全性与生产成本等多方面的问题仍旧存在，尤其是前者。2023年的6月，FDA加速批准SRP-9001（delandistrogene moxeparvovec-rokl）用于4-5岁的部分DMD患者，成为了首款获批用于DMD的AAV基因疗法。但除了其备受关注的高昂治疗费用，SRP-9001目前最被关注还是其“疗效性”。回想当初FDA加速批准SRP-9001之际，FDA就要求了Sarepta务必进行上市后研究。而也正是这项上市后研究，让SRP-9001陷入了新的怀疑风波，据有关资料显示，在126人的上市后研究中，其最终结果显示，接受治疗1年后，Elevidys组在NSAA上的改善虽比安慰组有所提高，但Elevidys组与安慰剂组的差异并没有达到统计学显著性，简单来讲就是主要临床终点未达成。不过，Sarepta却认为，虽主要临床终点未达成，但其疗法在“10米最高行走速度”“最快爬起速度”“最大步行速度”三项关键次要终点上显著优于安慰剂。而针对这种实现次要临床终点，但主要临床终点失败的情况，从技术角度也可能获得监管批准，关键还是在于FDA对此的态度，对于Elevidys的命运将至关重要。同时，更值得注意的还有，目前全球可并非只有SRP-9001一项针对DMD的基因疗法，紧随其后的还有辉瑞以1.5亿美金从Bamboo Therapeutics收购的DMD基因疗法PF-06939926（莫哌达基），见图5。其由人肌肉特异性启动子驱动，利用rAAV9作为载体递送微型肌营养不良蛋白基因，rAAV9具有靶向定位肌肉组织的潜力。目前正处于3期临床阶段，在8个国家开设了14个试验点。图3：全球DMD基因疗法数据来源：药智数据而对于目前的DMD基因疗法而言，首款已被SRP-9001率先斩获，但紧随其后的莫哌达基、Microdystrophin与更多临床期的项目而言，未来谁能在有效性方面能略胜一筹，或许才是真正的致胜关键。小结可以发现DMD前沿疗法虽比之前确有不小的进步，但目前从有效性方面，仍没有任何一款新药能达到临床医生的期盼值，现有DMD疗法包括基因治疗都只是以延缓病程为目的，无法治愈，这很大程度上反映了对于治愈的妥协，至于何时能如人类攻克肿瘤一般实现病因治疗，则仍未可知。对比之下，正是应了社会各界对DMD的评价，比之肿瘤或许更令人绝望，而为了应对这份绝望，满足DMD患者更实际的临床需求，社会各界人士也在积极加强对该领域的关注，以目前三个前沿领域的新药研发速度来看，未来攻克该疾病的希望极大，当然这也需要更多医学力量、更多社会关注集中在DMD患者身上，愿未来世界再无DMD。来源 | 博药（药智网获取授权转载）撰稿 | 万叶责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 |  张武龙 13368443108（同微信） 阅读原文，是昨天最受欢迎的文章哦

Announced positive update in third quarter from SELECT-HD trial in HD; single doses of WVE-003 appeared generally safe and well-tolerated and suggested allele-selective reduction of mHTT protein in CSF Multidosing underway in Phase 1b/2a trial of WVE-N531 in boys with DMD amenable to exon 53 skipping; muscle biopsy data from initial cohort on track for 4Q 2022 Selected WVE-006 (Wave’s first RNA editing candidate) as development candidate for AATD with CTA submissions expected in 2023 Preclinical data presentations at OTS and ESGCT meetings highlighted potential of PRISM platform to develop potent and durable siRNA compounds and unlock new biology with AIMers Wave to host investor conference call and webcast at 8:30 a.m. ET today CAMBRIDGE, Mass., Nov. 10, 2022 (GLOBE NEWSWIRE) -- Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases, today announced financial results for the third quarter ended September 30, 2022 and provided a business update. “In the third quarter, we continued to deliver on our key milestones for 2022, including announcing a positive update from our Huntington’s disease trial and selecting our first-in-class RNA editing candidate for alpha-1 antitrypsin deficiency,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “Clinical data emerging from our pipeline supports the translational potential of our unique PRISM platform and we look forward to sharing a third data update this quarter with the first muscle biopsy data from our Phase 1b/2a clinical trial of WVE-N531 for Duchenne muscular dystrophy. Additionally, we believe that our RNA editing capability using endogenous ADAR enzymes provides a unique opportunity for Wave and we are well-positioned to be leaders in the editing field. We are working toward bringing RNA editing to the clinic and are on track to submit clinical trial applications for our alpha-1 antitrypsin deficiency program in 2023.” Recent Pipeline and Business Highlights SELECT-HD clinical trial for WVE-003 in Huntington’s disease (HD) continues to advance; only allele-selective clinical program designed to reduce mutant HTT and spare healthy HTT WVE-003 (PN-modified allele-selective silencing oligonucleotide) for HD is being evaluated in the ongoing, adaptive, double-blind Phase 1b/2a SELECT-HD clinical trial (NCT05032196). WVE-003 is the only compound in clinical development designed to selectively lower mutant huntingtin (mHTT) protein levels, while leaving wild-type (healthy) huntingtin (wtHTT) protein levels relatively intact.In September 2022, Wave announced a positive update from the company’s ongoing SELECT-HD clinical trial driven by the observation of reductions in mHTT protein in cerebrospinal fluid (CSF) after study participants received either a single 30 or 60 mg dose of WVE-003. Additionally, wtHTT protein was preserved, which appeared consistent with allele-selectivity. Single doses of WVE-003 appeared generally safe and well-tolerated.Based on the SELECT-HD data, Wave is adapting the trial to expand the single dose cohorts, including in a 90 mg single dose cohort for which biomarker data were not available at the time of analysis. Wave expects to share additional single-dose biomarker and safety data in the first half of 2023.In November 2022, these SELECT-HD data were presented in an oral presentation at the Huntington Study Group (HSG) Annual Meeting in Tampa, Florida. Phase 1b/2a clinical trial of WVE-N531 in Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping continues to advance; multi-dosing is underway at human-equivalent levels in the range explored in preclinical double-knockout (dKO) mouse WVE-N531 (PN-modified splicing oligonucleotide) for DMD is being evaluated in an open-label, intra-patient dose escalation clinical trial (NCT04906460). Dose escalation is complete and multi-dosing is underway with three 10 mg/kg doses of WVE-N531 every other week, to be followed by planned muscle biopsies. Clinical biomarker and safety data is expected in the fourth quarter of 2022. Possible cohort expansion will be informed by an assessment of the concentration and distribution of WVE-N531 in muscle tissue, as well as biomarkers, including exon skipping and dystrophin.Plasma concentrations and half-life of WVE-N531 observed in patients receiving 10 mg/kg of WVE-N531 in Wave’s ongoing clinical trial were significantly greater than plasma concentrations achieved following the highest doses of suvodirsen, Wave’s first-generation PS/PO exon skipping compound administered in a Phase 2/3 study. This pharmacokinetic analysis suggests the potential for significantly improved pharmacologic properties of WVE-N531, including distribution and stability in muscle. FOCUS-C9 clinical trial of WVE-004 for C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS and C9-FTD) continues to advance; open-label extension trial recently initiated FOCUS-C9 (NCT04931862) is an adaptive Phase 1b/2a clinical trial that is designed to rapidly optimize dose level and frequency based on early indicators of target engagement. WVE-004 is designed to selectively target transcript variants containing a hexanucleotide repeat expansion (G4C2) associated with the C9orf72 gene for the treatment of C9-ALS and C9-FTD, thereby reducing pathological mRNA products and toxic DPR proteins, including poly(GP).Based on potency and durability of pharmacodynamic effects, the multidose portion of the FOCUS-C9 trial was expanded to evaluate quarterly dosing. Data from all cohorts in the FOCUS-C9 clinical trial are expected in the first half of 2023.In November 2022, Wave presented previously disclosed clinical data from the ongoing FOCUS-C9 clinical trial at the International Society for Frontotemporal Dementias in Lille, France.An open-label extension trial for participants in the FOCUS-C9 trial was initiated in the fourth quarter of 2022. Alpha-1 antitrypsin deficiency (AATD) development candidate (WVE-006) designed to correct mutant AATD transcript to address both liver and lung manifestations of disease highlighted at virtual event In the third quarter, Wave selected WVE-006 (PN-modified GalNAc-conjugated development candidate) as its development candidate for the treatment of AATD. In September 2022, Wave highlighted WVE-006 in a virtual event, “Towards the Clinic: Spotlight on RNA Editing for AATD.” The event replay is available here. WVE-006 is Wave’s first AIMer (A-to-I(G) RNA base editing oligonucleotide) development candidate. WVE-006 is first-in-class in AATD and is the most advanced program currently in development using an oligonucleotide to harness an endogenous enzyme for editing.In October 2022, preclinical data for WVE-006 was highlighted in an oral presentation at the 18th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS). The meeting represented the first presentation in a scientific congress of preclinical data supporting WVE-006 as a potential best-in-class therapeutic approach in AATD. The OTS presentation slides are available here. PRISM platform: RNA editing and small interfering RNA (siRNA) capabilities highlighted across six presentations and posters at recent scientific congresses Wave’s preclinical-stage siRNA designs, which incorporate PRISM chemistry, were highlighted at the OTS Meeting in October 2022. The OTS poster is available here. The data demonstrated remarkably robust and durable RNA silencing in vivo in mice, further illustrating the evolution and the potential of Wave’s chemistry.Wave’s application of ADAR-mediated RNA editing to modulate protein-protein interactions in mice was also highlighted in a poster accepted at the European Society of Gene and Cell Therapy (ESGCT) meeting in October 2022. The ESGCT poster is available here. Key Anticipated Upcoming Milestones WVE-003 for HD: Additional single-dose biomarker and safety clinical data expected in 1H 2023. WVE-N531 for DMD: Clinical data, including muscle biopsies, expected in 4Q 2022 to provide further insight into the clinical effects of PN chemistry and enable decision-making for this program. WVE-004 for C9-ALS and C9-FTD: Clinical data from all cohorts in the FOCUS-C9 trial expected in 1H 2023. WVE-006 (GalNAc-conjugated AIMer) for AATD: Wave expects to submit clinical trial applications (CTAs) in 2023. Third Quarter 2022 Financial Results and Financial Guidance Wave reported a net loss of $39.0 million in the third quarter of 2022, as compared to $6.2 million in the same period in 2021. Wave recorded revenue of $0.3 million for the third quarter of 2022, as compared to $36.4 million in the same period in 2021. The decrease in revenue year-over-year was primarily driven by the amendment to the Takeda Collaboration in the third quarter of 2021. Research and development expenses were $27.6 million in the third quarter of 2022 as compared to $31.1 million in the same period in 2021. The decrease in research and development expenses in the third quarter was primarily due to decreased external expenses related to our HD programs and decreases in other research and development expenses, partially offset by increased external expenses related to C9 and our other clinical and preclinical programs. General and administrative expenses were $11.6 million in the third quarter of 2022 as compared to $12.9 million in the same period in 2021. The decrease in general and administrative expenses in the third quarter of 2022 was primarily due to decreases in compensation-related expenses, as well as decreases in other external general and administrative expenses. As of September 30, 2022, Wave had $122.0 million in cash, cash equivalents and short-term investments. As of December 31, 2021, Wave had $150.6 million in cash and cash equivalents. The decrease is primarily due to Wave’s year to date operating cash burn, partially offset by $65.5 million in net proceeds from its financing in June 2022. Wave expects that its existing cash, cash equivalents and short-term investments will enable the company to fund its operating and capital expenditure requirements to the end of 2023. Investor Conference Call and WebcastWave management will host an investor conference call today at 8:30 a.m. ET to discuss the third quarter 2022 financial results and provide a business update. A webcast of the conference call may be accessed by visiting “Events” on the investor relations section of the Wave Life Sciences corporate website: ir.wavelifesciences.com/events-and-presentations. Analysts planning to participate during the Q&A portion of the live call can join the conference call at the following audio conferencing link: available 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 the SELECT-HD Clinical TrialThe SELECT-HD trial is a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-003 in people with a confirmed diagnosis of HD who are in the early stages of the disease and carry SNP3 in association with their cytosine-adenine-guanine (CAG) expansion. Additional objectives include assessing the plasma pharmacokinetic profile and exposure in the cerebrospinal fluid, as well as exploratory pharmacodynamic (mHTT, wtHTT and neurofilament light chain) and clinical endpoints. It is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee. In an initial data analysis, single doses of WVE-003 up to 90 mg appeared generally safe and well-tolerated. Adverse events (AEs) were balanced across treatment groups, including placebo, and all were mild to moderate in intensity. No serious adverse events (SAEs) were observed and no participants discontinued from the study. Among participants in the 30 and 60 mg WVE-003 cohorts, the mean reduction in CSF mHTT from baseline was 22% (median reduction 30%) at 85 days following a single dose. The difference in the mean reduction in CSF mHTT compared to placebo was 35% at 85 days post-single dose. For these analyses, the 30 and 60 mg single dose cohorts were pooled as there was no apparent dose response between these two cohorts. Wave will continue to evaluate dose response in the expanded single dose cohorts. In the 30 and 60 mg cohorts, wtHTT protein was preserved, which appears consistent with allele-selectivity. Increases in neurofilament light chain (NfL) from baseline were observed in some participants. Wave will continue to monitor trends in NfL as SELECT-HD advances. There were no clinically meaningful elevations in CSF white blood cell counts or protein that would indicate inflammation in the CNS. There were no meaningful changes in clinical outcome measures, although the dataset and duration were not sufficient to assess clinical effects. About the FOCUS-C9 Clinical TrialThe FOCUS-C9 trial is an ongoing, global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of single- and multiple-ascending intrathecal doses of WVE-004 for people with C9-ALS and/or C9-FTD. Additional objectives include measurement of poly(GP) DPR proteins in the cerebrospinal fluid (CSF), plasma and CSF pharmacokinetics (PK), and exploratory biomarkers and clinical outcomes. The FOCUS-C9 trial is designed to be adaptive, with dose escalation and dosing frequency being guided by an independent committee. In an initial data analysis, reductions in poly(GP) were observed across all active treatment groups (10 mg, n=2 patients; 30 mg, n=4 patients; 60 mg, n=3 patients), reaching statistical significance versus placebo (n=3 patients) after single 30 mg doses, with a 34% reduction in poly(GP) at day 85 (p=0.011). At the time of analysis, none of the patients dosed with 60 mg had reached day 85. As the poly(GP) reduction in the 30 mg single dose cohort does not appear to have plateaued, Wave will extend the observation period from approximately three months (85 days) to approximately six months to identify the maximum reduction of poly(GP) and duration of effect of low single doses. Based on the durability and potency observed in the 30 mg cohort, FOCUS-C9 has been adapted to include additional patients receiving 20 mg and 30 mg single doses of WVE-004. Adverse events (AEs) were balanced across treatment groups, including placebo, and were mostly mild to moderate in intensity. Four patients (including one on placebo) experienced severe and/or serious adverse events; three were reported by the investigators to be related to ALS or administration, and one was reported by the investigator to be related to study drug. There were no treatment-associated elevations in CSF white blood cell counts or protein and no other notable laboratory abnormalities were observed. Support for FOCUS-C9 is provided by the Alzheimer’s Drug Discovery Foundation. About PRISM™PRISM is Wave Life Sciences’ proprietary discovery and drug development platform that enables genetically defined diseases to be targeted with stereopure oligonucleotides across multiple therapeutic modalities, including silencing, splicing and editing. PRISM combines the company’s unique ability to construct stereopure oligonucleotides with a deep understanding of how the interplay among oligonucleotide sequence, chemistry and backbone stereochemistry impacts key pharmacological properties. By exploring these interactions through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, the company continues to define design principles that are deployed across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles. About Wave Life SciencesWave Life Sciences (Nasdaq: WVE) is a clinical-stage genetic medicines company committed to delivering life-changing treatments for people battling devastating diseases. Wave aspires to develop best-in-class medicines across multiple therapeutic modalities using PRISM, the company’s proprietary discovery and drug development platform that enables the precise design, optimization, and production of stereopure oligonucleotides. Driven by a resolute sense of urgency, the Wave team is targeting a broad range of genetically defined diseases so that patients and families may realize a brighter future. To find out more, please visit www.wavelifesciences.com and follow Wave on Twitter @WaveLifeSci. 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 of data and completion of our adaptive clinical trials, and the announcement of such events; the protocol, design and endpoints of our ongoing and future clinical trials; the future performance and results of our programs in clinical trials; future preclinical activities and programs; regulatory submissions; the progress and potential benefits of our collaborations with partners; 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 therapeutic benefits of our potential therapies compared to others; our ability to design compounds using multiple modalities and the anticipated benefits of that approach; the potential benefits of PRISM, including our novel PN backbone chemistry modifications, and our stereopure oligonucleotides compared with stereorandom oligonucleotides; the potential benefits of our novel ADAR-mediated RNA editing platform capabilities, including our AIMers, compared to others; the status and progress of our novel programs relative to potential competitors; anticipated benefits of our proprietary manufacturing processes and our internal manufacturing capabilities; the benefit of nucleic acid therapeutics generally; the strength of our intellectual property; our assumptions based on our balance sheet and the anticipated duration of our cash runway; our intended uses of capital; and our expectations regarding the impact of the COVID-19 pandemic on our business. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including the following: our ability to finance our drug discovery and development efforts and to raise additional capital when needed; the ability of our preclinical programs to produce data sufficient to support our clinical trial applications and the timing thereof; the clinical results of our programs and the timing thereof, which may not support further development of product candidates; actions of regulatory agencies and their receptiveness to our adaptive trial designs, which may affect the initiation, timing and progress of clinical trials; our effectiveness in managing regulatory interactions and future clinical trials; the effectiveness of PRISM, including our novel PN backbone chemistry modifications; the effectiveness of our novel ADAR-mediated RNA editing platform capability and our AIMers; our ability to demonstrate the therapeutic benefits of our candidates in clinical trials, including our ability to develop candidates across multiple therapeutic modalities; our dependence on third parties, including contract research organizations, contract manufacturing organizations, collaborators and partners; our ability to manufacture or contract with third parties to manufacture drug material to support our programs and growth; our ability to obtain, maintain and protect our intellectual property; our ability to enforce our patents against infringers and defend our patent portfolio against challenges from third parties; competition from others developing therapies for similar indications; our ability to maintain the company infrastructure and personnel needed to achieve our goals; the severity and duration of the COVID-19 pandemic and variants thereof, and its negative impact on the conduct of, and the timing of enrollment, completion and reporting with respect to our clinical trials; and any other impacts on our business as a result of or related to the COVID-19 pandemic, as well as the information under the caption “Risk Factors” contained in our most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (SEC) and in other filings we make with the SEC from time to time. We undertake no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances. WAVE LIFE SCIENCES LTD.UNAUDITED CONSOLIDATED BALANCE SHEETS (In thousands, except share amounts) September 30, 2022 December 31, 2021 Assets Current assets: Cash and cash equivalents $96,954 $150,564 Short-term investments 25,044 — Prepaid expenses 7,419 6,584 Other current assets 2,017 5,416 Total current assets 131,434 162,564 Long-term assets: Property and equipment, net 18,552 22,266 Operating lease right-of-use assets 27,827 18,378 Restricted cash 3,654 3,651 Other assets 44 148 Total long-term assets 50,077 44,443 Total assets $181,511 $207,007 Liabilities, Series A preferred shares and shareholders’ equity (deficit) Current liabilities: Accounts payable $15,934 $7,281 Accrued expenses and other current liabilities 11,056 14,861 Current portion of deferred revenue 32,341 37,098 Current portion of operating lease liability 4,928 4,961 Total current liabilities 64,259 64,201 Long-term liabilities: Deferred revenue, net of current portion 80,230 77,479 Operating lease liability, net of current portion 33,667 24,955 Total long-term liabilities 113,897 102,434 Total liabilities $178,156 $166,635 Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at September 30, 2022 and December 31, 2021 $7,874 $7,874 Shareholders’ equity (deficit): Ordinary shares, no par value; 86,841,523 and 59,841,116 shares issued and outstanding at September 30, 2022 and December 31, 2021, respectively $802,697 $749,851 Additional paid-in capital 116,535 87,980 Accumulated other comprehensive income (loss) (123) 181 Accumulated deficit (923,628) (805,514)Total shareholders’ equity (deficit) $(4,519) $32,498 Total liabilities, Series A preferred shares and shareholders’ equity (deficit) $181,511 $207,007 WAVE LIFE SCIENCES LTD.UNAUDITED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (In thousands, except share and per share amounts) Three Months Ended September 30, Nine Months Ended September 30, 2022 2021 2022 2021 Revenue $285 $36,423 $2,410 $39,199 Operating expenses: Research and development 27,575 31,086 84,778 96,114 General and administrative 11,609 12,944 36,789 33,991 Total operating expenses 39,184 44,030 121,567 130,105 Loss from operations (38,899) (7,607) (119,157) (90,906)Other income (expense), net: Dividend income and interest income, net 596 6 746 25 Other income (expense), net (701) 1,371 297 3,421 Total other income (expense), net (105) 1,377 1,043 3,446 Loss before income taxes (39,004) (6,230) (118,114) (87,460)Income tax provision — — — — Net loss $(39,004) $(6,230) $(118,114) $(87,460)Net loss per share attributable to ordinary shareholders—basic and diluted $(0.42) $(0.12) $(1.60) $(1.75)Weighted-average ordinary shares used in computing net loss per share attributable to ordinary shareholders—basic and diluted 93,900,484 50,709,877 73,754,417 50,017,521 Other comprehensive loss: Net loss $(39,004) $(6,230) $(118,114) $(87,460)Foreign currency translation (76) (11) (304) (131)Comprehensive loss $(39,080) $(6,241) $(118,418) $(87,591) Investor Contact:Kate Rausch617-949-4827krausch@wavelifesci.com Media Contact:Alicia Suter617-949-4817asuter@wavelifesci.com