CAMBRIDGE, Mass., June 25, 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 positive results from its Phase 1b/2a SELECT-HD clinical trial of WVE-003, which is being developed as a potential disease modifying therapeutic for Huntington’s disease (HD).

马萨诸塞州剑桥，2024年6月25日（环球通讯社）——WAVE生命科学有限公司。（纳斯达克：WVE）是一家临床阶段生物技术公司，专注于释放RNA药物改变人类健康的广泛潜力，今天宣布了其WVE-003 1b/2a期SELECT-HD临床试验的积极结果，该试验正在开发中作为亨廷顿舞蹈病（HD）的潜在疾病改善治疗药物。

WVE-003 is a first-in-class, allele-selective antisense oligonucleotide (ASO) designed to lower mutant huntingtin (mHTT) protein and preserve healthy, wild-type huntingtin (wtHTT) protein..

WVE-003 是一种首创的等位基因选择性反义寡核苷酸 (ASO)，旨在降低突变型狩猎蛋白 (mHTT) 蛋白，并保留健康的野生型狩猎蛋白 (wtHTT) 蛋白。

In the multidose portion of the SELECT-HD study (n=23), participants received either every-eight-week (Q8W) intrathecal doses of 30 mg WVE-003 (n=16) or placebo (n=7), with 12 weeks of follow up (total study period of 28 weeks). Key results are as follows:

在SELECT-HD研究的多剂量部分（n=23），参与者每八周（Q8W）鞘内注射30 mg WVE-003（n=16）或安慰剂（n=7），随访12周（总研究期28周）。主要结果如下：

WVE-003 was generally safe and well-tolerated, with no Serious Adverse Events (SAEs) reported; ventricular volume was in line with natural history.

WVE-003通常安全且耐受性良好，未报告严重不良事件（SAE）；心室容积符合自然史。

Significant mHTT protein lowering was observed throughout the 28-week assessment period.

在整个28周的评估期间，观察到mHTT蛋白显着降低。

At 24 weeks (8 weeks after last dose), mean mHTT lowering in cerebrospinal fluid (CSF) was 46% versus placebo (p=0.0007).

在24周（最后一次给药后8周），与安慰剂相比，脑脊液（CSF）的平均mHTT降低46%（p=0.0007）。

At 28 weeks (12 weeks after last dose), mean mHTT lowering in CSF was 44% versus placebo (p=0.0002), which supports quarterly or less frequent dosing.

在第28周（最后一次给药后12周），与安慰剂相比，脑脊液中mHTT的平均降低率为44%（p=0.0002），这支持每季度或不太频繁的给药。

wtHTT protein was preserved throughout the 28-week assessment period, validating allele-selective silencing. Additionally, statistically significant increases were observed in wtHTT protein versus placebo.

。此外，与安慰剂相比，wtHTT蛋白观察到统计学上显着的增加。

wtHTT protein supports the health and function of neurons and is crucial for CSF flow in the ventricles. mHTT also has a detrimental effect on wtHTT at the protein level, which further decreases wtHTT’s function. Only selective lowering of mHTT has potential to relieve its negative impact on wtHTT protein function..

wtHTT蛋白支持神经元的健康和功能，对脑室中的脑脊液流动至关重要。mHTT在蛋白质水平上对wtHTT也有不利影响，这进一步降低了wtHTT的功能。只有选择性降低mHTT才能缓解其对wtHTT蛋白功能的负面影响。。

Most WVE-003-treated participants had neurofilament light protein (NfL) levels that were in the range of placebo or had NfL levels that increased and returned to the range of placebo.

大多数接受WVE-003治疗的参与者的神经丝轻蛋白（NfL）水平在安慰剂范围内，或者NfL水平升高并恢复到安慰剂范围。

At 24 weeks (the last MRI assessment), mHTT reduction was correlated with slowing of caudate atrophy (R=-0.50; p=0.047). Caudate atrophy is an imaging biomarker that is predictive of clinical outcomes, including clinically meaningful worsening of Total Motor Score (TMS).

在第24周（最后一次MRI评估），mHTT减少与尾状萎缩减慢相关（R=-0.50；p=0.047）。尾状萎缩是一种成像生物标志物，可预测临床结果，包括总运动评分（TMS）的临床意义恶化。

While not powered for clinical outcomes, a slowing of decline was observed for TMS for WVE-003 versus placebo (4.25 mean difference at 24 weeks, p=not significant).

虽然没有为临床结果提供动力，但与安慰剂相比，WVE-003的TMS下降速度减慢（24周时平均差异为4.25，p=不显着）。

“We are very proud to have demonstrated mHTT lowering of 46%, with preservation of wtHTT, and are encouraged to see these reductions in mHTT significantly correlating with a slowing in caudate atrophy after just 28 weeks. These results represent a significant achievement for Wave, for the oligonucleotide field, and most importantly, for the HD community,” said Anne-Marie Li-Kwai-Cheung, MChem, MTOPRA, RAPS, Chief Development Officer at Wave Life Sciences.

Wave生命科学首席开发官Anne Marie Li Kwai Cheung说：“我们非常自豪地证明了mHTT降低了46%，保留了wtHTT，并且很高兴看到mHTT的降低与仅28周后尾状萎缩的减缓显着相关。这些结果代表了Wave，寡核苷酸领域，最重要的是HD社区的重大成就。”。

“Alongside the HD community, we have been working diligently to establish caudate volume as a biomarker for clinical development due to its association with clinical outcomes. We believe these strong data compel a case for accelerated approval for WVE-003, which we plan to discuss with regulators. We would like to express our immense gratitude to the HD community, the study participants, their families, and study site staff for their trust, support, and engagement that have helped us reach this important milestone.”.

“与HD社区一起，我们一直在努力建立尾状核体积作为临床开发的生物标志物，因为它与临床结果有关。我们相信这些强大的数据迫使我们加速批准WVE-003，我们计划与监管机构讨论。我们要对HD社区，研究参与者，他们的家人和研究现场工作人员的信任，支持和参与表示衷心的感谢，他们的信任，支持和参与帮助我们实现了这一重要里程碑。”。

“Wild-type huntingtin plays such a critical role in the central nervous system, and it’s very exciting to finally have an opportunity to evaluate mHTT lowering in the context of allele-selectivity and to see positive signals emerging,” said Ralf Reilmann, MD, founder of the George-Huntington Institute, Muenster, Germany, as well as the Primary Investigator and member of the Advisory Committee for SELECT-HD.

“野生型亨廷顿蛋白在中枢神经系统中起着至关重要的作用，最终有机会在等位基因选择性的背景下评估mHTT的降低并看到积极的信号出现，这是非常令人兴奋的，”德国明斯特乔治亨廷顿研究所（GeorgeHuntington Institute）创始人，医学博士拉尔夫·雷尔曼（RalfReilmann）以及SELECT-HD咨询委员会的主要研究者和成员说。

“Additionally, these data have arrived at an opportune time when the HD community is coalescing around rapid, efficient registrational trial design utilizing sensitive clinical endpoints to detect early treatment effects, and Wave is well positioned to take advantage of this momentum with WVE-003. These data provide hope and a compelling path forward as the community continues to drive toward a long-awaited therapy to treat this devastating disease.”.

“此外，这些数据已经到达了一个合适的时机，HD社区正在围绕快速，有效的注册试验设计进行整合，利用敏感的临床终点来检测早期治疗效果，Wave很好地利用了WVE-003的这一势头。随着社区继续推动人们期待已久的治疗方法来治疗这种毁灭性疾病，这些数据提供了希望和令人信服的前进道路。”。

HD is a debilitating and ultimately fatal autosomal dominant neurological disorder. The HD population is significant – in the United States alone, approximately 30,000 people have clinical symptoms of HD and more than 200,000 are at risk of inheriting HD. WVE-003 is expected to address approximately 40% of individuals with HD, and up to 80% of HD may be addressed in the future with other SNP-targeted candidates..

HD是一种使人衰弱并最终致命的常染色体显性神经系统疾病。HD人口非常多-仅在美国，就有大约30000人有HD的临床症状，超过200000人有遗传HD的风险。WVE-003有望解决大约40%的HD患者，未来可能会与其他针对SNP的候选人一起解决多达80%的HD患者。。

“With these results, we have delivered the first-ever clinical demonstration of allele-selective silencing in any disease target. This was only possible due to the specificity, potency and durability enabled through our PRISM platform and it is validating of more than 10 years of chemistry innovation pioneered at Wave, including PN chemistry and stereochemistry,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences.

Wave Life Sciences总裁兼首席执行官、MBA医学博士保罗·博尔诺（Paul Bolno）表示：“有了这些结果，我们首次在任何疾病靶标中进行了等位基因选择性沉默的临床证明。这只有通过我们的PRISM平台才能实现特异性、效力和耐久性，并且它验证了Wave十多年来率先进行的化学创新，包括PN化学和立体化学。”。

“The translation of genetic insights and preclinical data in the clinic is also highly encouraging and reinforces the broader value of our pipeline. We are looking forward to our Duchenne muscular dystrophy and Alpha-1 antitrypsin deficiency data this year, the continued advancement of our INHBE program for obesity, and new targets to be shared at R&D Day this Fall, which together will open up a substantial total addressable market for Wave.

“临床上遗传见解和临床前数据的翻译也非常令人鼓舞，并增强了我们管道的更广泛价值。我们期待着今年我们的杜兴氏肌营养不良症和α-1抗胰蛋白酶缺乏症数据，我们针对肥胖的INHBE计划的持续推进，以及今年秋季研发日将共享的新目标，这将共同为Wave开辟一个可观的总目标市场。

We are at a very exciting point in Wave’s history as we advance our mission to unlock the broad potential of RNA medicines.”.

随着我们推进我们的使命，以释放RNA药物的广泛潜力，我们正处于Wave历史上一个非常激动人心的时刻。”。

Cash Runway

现金跑道

Wave continues to expect that its current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025.

Wave继续预计其目前的现金和现金等价物将足以为2025年第四季度的运营提供资金。

Investor Conference Call and Webcast

投资者电话会议和网络广播

Wave will host an investor conference call today at 8:30 a.m. ET to review the SELECT-HD clinical trial results. 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.

Wave将于美国东部时间今天上午8:30召开投资者电话会议，审查SELECT-HD临床试验结果。通过访问Wave Life Sciences网站投资者关系部分的“投资者活动”，可以访问电话会议的网络广播：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 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..

计划参加现场电话问答部分的分析师可以通过此处提供的音频会议链接参加电话会议。注册后，参与者将收到拨入信息。现场活动结束后，Wave生命科学网站将提供网络广播的存档版本。。

About SELECT-HD

关于SELECT-HD

The SELECT-HD trial (NCT05032196) was 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.

SELECT-HD试验（NCT05032196）是一项全球性，多中心，随机，双盲，安慰剂对照的1b/2a期临床试验，用于评估单次和多次鞘内注射WVE-003的安全性和耐受性。确诊为HD的患者处于疾病的早期阶段，并携带SNP3与胞嘧啶腺嘌呤鸟嘌呤（CAG）扩增相关。

Additional objectives include assessing pharmacokinetics and exploratory pharmacodynamic and clinical endpoints..

其他目标包括评估药代动力学和探索性药效学和临床终点。。

About WVE-003

关于WVE-003

WVE-003 is a first-in-class, allele-selective antisense oligonucleotide that selectively lowers mutant huntingtin (mHTT) protein by targeting a single nucleotide polymorphism (SNP3) located on the mHTT messenger RNA that is not present on the wild-type huntingtin (wtHTT) mRNA. Wave’s approach to Huntington’s disease (HD) is guided by the recognition that, in addition to a gain of function of the mHTT protein, people with HD have lost one copy of the healthy wtHTT allele, leaving them with a smaller protective reservoir of wtHTT protein than unaffected individuals.

WVE-003是一种一流的等位基因选择性反义寡核苷酸，它通过靶向位于野生型亨廷顿蛋白（wtHTT）mRNA上不存在的mHTT信使RNA上的单核苷酸多态性（SNP3）来选择性降低突变亨廷顿蛋白（mHTT）蛋白。Wave对亨廷顿病（HD）的方法是通过认识到，除了获得mHTT蛋白的功能外，HD患者还失去了一个健康的wtHTT等位基因拷贝，使他们比未受影响的个体拥有更小的wtHTT蛋白保护库。

wtHTT protein is critical for neuronal function, and suppression may have detrimental long-term consequences. For more information, please refer to Wave’s published manuscript of WVE-003 preclinical data here..

wtHTT蛋白对神经元功能至关重要，抑制可能会产生有害的长期后果。有关更多信息，请参阅Wave发布的WVE-003临床前数据手稿。。

About Huntington’s Disease

关于亨廷顿氏症

Huntington’s disease (HD) is a debilitating and ultimately fatal autosomal dominant neurological disorder, which is passed down from generation to generation within affected families. The symptoms of HD have been compared to having Alzheimer’s disease, Amyotrophic lateral sclerosis, and Parkinson’s disease all at once.

亨廷顿舞蹈病（HD）是一种使人衰弱并最终致命的常染色体显性神经系统疾病，在受影响的家庭中代代相传。HD的症状被比作同时患有阿尔茨海默氏病、肌萎缩侧索硬化症和帕金森氏病。

HD is caused by an expanded cytosine-adenine-guanine (CAG) triplet repeat in the huntingtin (HTT) gene that results in production of mutant HTT (mHTT) protein. Accumulation of mHTT causes progressive loss of neurons in the brain, affecting thinking ability, emotions, and movement. Clinical symptom onset typically occurs during adulthood, between the ages of 30 and 50.

。mHTT的积累会导致大脑中神经元的逐渐丧失，从而影响思维能力，情绪和运动。临床症状发作通常发生在成年期，年龄在30至50岁之间。

It is characterized by cognitive decline, psychiatric illness, and chorea, and patients ultimately succumb to pneumonia, heart failure or other complications. There are no disease modifying treatments for HD..

。HD没有改善疾病的治疗方法。。

About Wave Life Sciences

关于波浪生命科学

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.

Wave Life Sciences（纳斯达克：WVE）是一家生物技术公司，专注于挖掘RNA药物在改变人类健康方面的广泛潜力。Wave的RNA药物平台PRISM®结合了多种模式、化学创新和对人类遗传学的深刻见解，实现了治疗罕见和流行疾病的科学突破。

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.

其RNA靶向模式工具包包括编辑，剪接，RNA干扰和反义沉默，为Wave提供了无与伦比的能力，用于设计和可持续地提供最佳解决疾病生物学问题的候选药物。Wave的多元化渠道包括杜兴氏肌营养不良症，α-1抗胰蛋白酶缺乏症和亨廷顿舞蹈病的临床计划，以及肥胖症的临床前计划。

英文链接：https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-results-phase-1b2a-select