WVE-N531

Achieved first-ever RNA editing in humans in RestorAATion-2 trial of WVE-006 (GalNAc-AIMer) in alpha-1 antitrypsin deficiency and announced three wholly owned GalNAc-AIMer preclinical programs that offer first-in-class approaches to address unmet needs in cardiometabolic diseases WVE-007 (INHBE GalNAc-siRNA) clinical trial on track for 1Q 2025; preclinical data demonstrates opportunities for monotherapy, for synergistic use with GLP-1s, and for maintenance to avoid rebound weight gain following cessation of GLP-1s Received supportive initial feedback from FDA on WVE-003; FDA is engaged in discussing pathways to accelerated approval and open to Wave’s plan to evaluate biomarkers, including caudate atrophy, as an endpoint to evaluate HD progression; IND submission expected in 2H 2025 Delivered positive interim data from FORWARD-53 study of WVE-N531; expect feedback on a pathway to accelerated approval from regulators, as well as the complete 48-week FORWARD-53 data, in 1Q 2025 Cash and cash equivalents of $310.9 million as of September 30, 2024, plus additional ~$28 million net proceeds received on October 1 from full exercise of greenshoe option, with runway expected into 2027 Investor conference call and webcast at 8:30 a.m. ET today CAMBRIDGE, Mass., Nov. 12, 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 financial results for the third quarter ended September 30, 2024, and provided a business update. “Since the start of the third quarter, we have delivered positive clinical updates across DMD and AATD, unlocked RNA editing for Wave, and advanced our novel, wholly owned pipeline focused on GalNAc-conjugated programs,” said Paul Bolno, MD, MBA, President and Chief Executive Officer of Wave Life Sciences. “Our achievement of proof-of-mechanism for WVE-006 marked a historic breakthrough for the oligonucleotide field with the first-ever in-human evidence of RNA editing, providing a strong foundation to expand our wholly owned editing pipeline. We are also advancing WVE-007 for obesity and WVE-N531 for DMD towards key milestones in the first quarter. In HD, we are encouraged by a potential path forward to bring the first-ever therapeutic approach that preserves healthy wild-type protein to people living with HD, a devastating disease with limited treatment options. We continue to receive substantial interest on HD, including from potential strategic partners. With the continued demonstration of our novel chemistry in the clinic and cash runway expected into 2027, we are well capitalized and well positioned to deliver multiple value inflection points across our portfolio as we continue to build a leading RNA medicines company.” Recent Business Highlights GalNAc-RNA editingAATD WVE-006 is a GalNAc-conjugated, subcutaneously delivered, A-to-I RNA editing oligonucleotide (AIMer) that is uniquely designed to address Alpha-1 antitrypsin deficiency (AATD)-related lung disease, liver disease, or both. WVE-006 does not use a lipid-nanoparticle (LNP) delivery system.There are an estimated 200,000 Pi*ZZ patients in the US and Europe. Treatment options are currently limited to weekly IV augmentation therapy for lung disease only (representing over $1 billion in worldwide sales in 2023). There are no approved therapies to address AATD liver disease, which ultimately requires many patients to undergo liver transplantation.WVE-006 is currently being evaluated in the top dose cohort of RestorAATion-1 (healthy volunteers) and in the first dose cohort of RestorAATion-2 in Pi*ZZ patients with AATD.In October, Wave announced positive proof-of-mechanism data from the first single dose cohort with the first two patients to reach day 57 in the ongoing RestorAATion-2 study, representing the first-ever clinical demonstration of RNA editing in humans. 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. 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 neutrophil elastase inhibition from baseline were consistent with production of functional M-AAT. WVE-006 was well-tolerated with a favorable safety profile across both RestorAATion-1 and RestorAATion-2.Expected upcoming milestone: Wave expects to share multidose data from RestorAATion-2 in 2025. New AIMers At Research Day in October, Wave announced three new, wholly owned RNA editing programs that build on its recent achievement of the first-ever therapeutic RNA editing with WVE-006 in AATD. As with WVE-006, these programs leverage GalNAc conjugation and have efficient clinical paths to proof-of-concept. These new programs include PNPLA3, which aims to use an mRNA correction treatment approach for those at high risk for a variety of liver diseases, and LDLR and APOB which utilize first-in-class mRNA upregulation and mRNA correction treatment approaches (respectively) to achieve target LDL-c levels in heterozygous familial hypercholesterolemia patients.Expected upcoming milestone: Wave expects to select clinical candidates for PNPLA3, LDLR and APOB in 2025. Obesity (GalNAc-siRNA) WVE-007 is a GalNAc-conjugated small interfering RNA (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.At its recent Research Day, Wave shared data supporting WVE-007’s potential to address obesity as a monotherapy, as an add-on to GLP-1s for further improvement of weight loss or to reduce the doses of GLP-1s, and for maintenance to prevent weight regain and weight cycling after discontinuing GLP-1s.Expected upcoming milestone: Wave expects to initiate a clinical trial for WVE-007 in the first quarter of 2025. HD (allele-selective silencing) WVE-003 is a first-in-class, allele-selective oligonucleotide for the treatment of Huntington’s disease (HD). Results of the SELECT-HD clinical trial demonstrated the first-ever allele-selective reductions in CSF mutant huntingtin (mHTT) protein and preservation of healthy, wild-type huntingtin (wtHTT) protein with multiple doses of WVE-003, as well as a statistically significant correlation between mHTT reductions and slowing of caudate atrophy. By sparing wtHTT protein, which is critical to the health of the central nervous system, WVE-003 is uniquely positioned to address presymptomatic HD patients, as well as symptomatic patients.There are currently no disease modifying therapies for HD, which affects over 200,000 individuals across pre-symptomatic and symptomatic disease stages in the US and Europe. WVE-003 is expected to address approximately 40% of the HD population (potential $5 billion commercial opportunity), and up to 80% of patients with HD may be addressed in the future with other SNP-targeted candidates (potential $10 billion commercial opportunity).At Wave’s recent Research Day, Jeffrey Long, PhD, Professor of Psychiatry and Biostatistics at the University of Iowa, discussed the opportunity for caudate atrophy as a biomarker to expedite clinical development in HD. Dr. Long shared data which supports that the slowing of caudate atrophy predicts significant delays in the loss of function for people living with HD. The potential for changes in caudate volume to predict clinical outcomes in HD and its sensitivity to change early in the disease course makes it an optimal biomarker to enable smaller, more efficient clinical trials.In November 2024, Wave received supportive initial feedback from FDA, who recognize the severity of HD and are receptive to and engaged with Wave regarding a potential pathway to accelerated approval. FDA is open to Wave’s plan to evaluate biomarkers, including caudate atrophy, as an endpoint to assess HD progression with the potential to predict clinical outcome. Planning is underway for a global, potentially registrational Phase 2/3 study of WVE-003, including finalization of key aspects of design.In November 2024, the FDA granted Orphan Drug Designation to WVE-003.Expected upcoming milestone: Wave expects to submit an Investigational New Drug (“IND”) application for WVE-003 in the second half of 2025. DMD (exon skipping) WVE-N531 is an exon skipping oligonucleotide designed to induce production of endogenous, functional dystrophin protein for the treatment of boys with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. In the third quarter, the FDA granted Rare Pediatric Disease Designation and Orphan Drug Designation to WVE-N531.In September, Wave announced positive interim data from the Phase 2 FORWARD-53 study of WVE-N531. The interim analysis was conducted after 24 weeks of 10 mg/kg dosing every two weeks. Dystrophin results, from a pre-specified analysis of ambulatory boys, showed mean absolute muscle content-adjusted dystrophin expression was 9.0% (range: 4.6-13.9%) as measured by Western Blot. The dystrophin expression was quantified from two isoforms consistent with those observed in Becker muscular dystrophy patients who display milder disease. 89% of ambulatory participants achieved muscle content-adjusted dystrophin levels of at least 5%. Mean exon skipping was 57% (range: 31-75%) as measured by RT-PCR.WVE-N531 could address up to 10% of the DMD population, which encompasses over 2,000 boys in the US and Europe. Wave is also advancing a broader DMD pipeline of oligonucleotides for skipping other exons, with the goal of providing new and best-in-class treatment options for up to 40% of boys with DMD. In 2023, exon skipping therapeutics for DMD achieved approximately ~$1 billion in sales, primarily in the US, across exons covering approximately ~29% of the DMD population.Expected upcoming milestone: In the first quarter of 2025, Wave expects to deliver the complete 48-week FORWARD-53 data and receive feedback from regulators on a pathway to accelerated approval. Financial Highlights Cash and cash equivalents were $310.9 million as of September 30, 2024, as compared to $200.4 million as of December 31, 2023. In the third quarter of 2024, Wave received approximately $187.5 million in net proceeds from the upsized September 2024 offering. Subsequent to the third quarter of 2024, on October 1, 2024, Wave received approximately $28.2 million in net proceeds from the September 2024 offering. Wave expects that its current cash and cash equivalents will be sufficient to fund operations into 2027. Potential future milestone and other payments to Wave under its GSK collaboration are not included in its cash runway.Revenue recognized was ($7.7) million for the third quarter of 2024, as compared to $49.2 million in the third quarter of 2023, which included one-time revenue recognition events under our Takeda Collaboration related to the termination of the C9 program and the achievement of a development milestone. The year over year decrease is primarily driven by these one-time events in the prior year period. In addition, under our GSK collaboration, we recorded a non-cash reduction to cumulative revenue in the current period due to a change in the estimate to fulfill the performance obligations in accordance with revenue recognition standards. This adjustment changes the timing of revenue reporting for this program, with no impact on the program’s progress or cash flow.Research and development expenses were $41.2 million in the third quarter of 2024, as compared to $31.6 million in the third quarter of 2023. General and administrative expenses were $15.0 million in the third quarter of 2024, as compared to $13.1 million in the third quarter of 2023.Net loss was $61.8 million for the third quarter of 2024, as compared to net income of $7.3 million for the third quarter of 2023. Investor Conference Call and WebcastWave will host an investor conference call today at 8:30 a.m. ET to review the third quarter 2024 financial results and pipeline updates. 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 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 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; 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, and their potential to transition into clinical-stage programs ; the potential of our preclinical data to predict the behavior of our compounds in humans; regulatory submissions and timing for regulatory feedback; the progress and potential benefits of our collaborations; the potential achievement of milestones under our collaborations and receipt of cash payments therefor; the potential commercial opportunities that our therapeutic candidates may address; 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; 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 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; the status and progress of our programs relative to potential competitors; anticipated benefits of our proprietary manufacturing processes and our internal manufacturing capabilities; the benefits of RNA medicines generally; the strength of our intellectual property and the data that support our IP; the anticipated duration of our cash runway and our ability to fund future operations; our intended uses of capital; and our expectations regarding the impact of any potential global macro events 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 our product candidates; actions of regulatory authorities and their receptiveness to our adaptive trial designs and accelerated approval pathways, 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; the effectiveness of our RNA editing 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 the indications we are pursuing; our ability to maintain the company infrastructure and personnel needed to achieve our goals; and 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, 2024 December 31, 2023 Assets Current assets: Cash and cash equivalents $310,948 $200,351 Accounts receivable — 21,086 Prepaid expenses 10,572 9,912 Other current assets 2,995 4,024 Total current assets 324,515 235,373 Long-term assets: Property and equipment, net of accumulated depreciation of $45,490 and $42,709 as of September 30, 2024 and December 31, 2023, respectively 10,928 13,084 Operating lease right-of-use assets 19,119 22,637 Restricted cash 3,746 3,699 Other assets 196 156 Total long-term assets 33,989 39,576 Total assets $358,504 $274,949 Liabilities, Series A preferred shares, and shareholders’ equity Current liabilities: Accounts payable $12,781 $12,839 Accrued expenses and other current liabilities 14,642 16,828 Current portion of deferred revenue 135,907 150,059 Current portion of operating lease liability 7,398 6,714 Total current liabilities 170,728 186,440 Long-term liabilities: Deferred revenue, net of current portion 18,490 15,601 Operating lease liability, net of current portion 19,772 25,404 Total long-term liabilities 38,262 41,005 Total liabilities $208,990 $227,445 Series A preferred shares, no par value; 3,901,348 shares issued and outstanding at September 30, 2024 and December 31, 2023 $7,874 $7,874 Shareholders’ equity: Ordinary shares, no par value; 148,392,939 and 119,162,234 shares issued and outstanding at September 30, 2024 and December 31, 2023, respectively $1,139,714 $935,367 Additional paid-in capital 153,196 129,237 Accumulated other comprehensive loss (159) (124)Accumulated deficit (1,151,111) (1,024,850)Total shareholders’ equity $141,640 $39,630 Total liabilities, Series A preferred shares, and shareholders’ equity $358,504 $274,949 WAVE LIFE SCIENCES LTD.UNAUDITED CONSOLIDATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE INCOME (LOSS)(In thousands, except share and per share amounts) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Revenue $(7,676) $49,214 $24,554 $84,249 Operating expenses: Research and development 41,197 31,642 115,037 95,935 General and administrative 15,042 13,128 42,887 37,628 Total operating expenses 56,239 44,770 157,924 133,563 Income (loss) from operations (63,915) 4,444 (133,370) (49,314)Other income, net: Dividend income and interest income 1,798 1,960 6,425 6,084 Other income, net 337 171 684 1,296 Total other income, net 2,135 2,131 7,109 7,380 Income (loss) before income taxes (61,780) 6,575 (126,261) (41,934)Income tax benefit (provision) — 677 — 677 Net income (loss) $(61,780) $7,252 $(126,261) $(41,257)Less: net income attributable to participating securities $— $(257) $— $— Net income (loss) attributable to ordinary shareholders, basic and diluted $(61,780) $6,995 $(126,261) $(41,257)Net income (loss) per share attributable to ordinary shareholders—basic $(0.47) $0.07 $(0.97) $(0.39)Weighted-average ordinary shares used in computing net income (loss) per share attributable to ordinary shareholders—basic 132,563,467 106,025,063 130,470,603 104,529,266 Net income (loss) per share attributable to ordinary shareholders—diluted $(0.47) $0.07 $(0.97) $(0.39)Weighted-average ordinary shares used in computing net income (loss) per share attributable to ordinary shareholders—diluted 132,563,467 106,975,231 130,470,603 104,529,266 Other comprehensive income (loss): Net income (loss) $(61,780) $7,252 $(126,261) $(41,257)Foreign currency translation 120 (32) (35) (153)Comprehensive income (loss) $(61,660) $7,220 $(126,296) $(41,410) Investor Contact:Kate Rausch+1 617-949-4827krausch@wavelifesci.com Media Contact:Alicia Suter+1 617-949-4817asuter@wavelifesci.com

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↓↓↓