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Enrollment Reached Over 2,200 High-Risk Patients in Bemnifosbuvir Monotherapy Cohort Results from SUNRISE-3 Expected in 2H’24 BOSTON, March 27, 2024 (GLOBE NEWSWIRE) -- Atea Pharmaceuticals, Inc. (Nasdaq: AVIR) (Atea), a clinical-stage biopharmaceutical company engaged in the discovery and development of oral antiviral therapeutics for serious viral diseases, today announced that the company has completed enrollment of the global Phase 3 SUNRISE-3 trial evaluating bemnifosbuvir, an oral nucleotide polymerase inhibitor, or placebo for the treatment of COVID-19. Over 2,200 patients were randomized into the supportive care monotherapy cohort and less than 80 patients were randomized into the combination cohort. The primary endpoint of the trial is all-cause hospitalization or death through Day 29 post-treatment in the bemnifosbuvir supportive care monotherapy cohort of high-risk patients. Secondary endpoints include other measurements of patient outcomes through Day 60 post-treatment. “COVID-19 continues to be a threat, leaving the most vulnerable at risk for severe outcomes from infection. The rapid pace of enrollment recently experienced in the monotherapy cohort of SUNRISE-3 highlights the continuing unmet medical need for new oral COVID-19 treatment options for high-risk patients, such as the elderly, immunocompromised and those with underlying risk factors,” said Jean-Pierre Sommadossi, PhD, Chief Executive Officer and Founder of Atea Pharmaceuticals. “Since full enrollment was achieved ahead of the two planned interim analyses for safety and futility by the Data Safety Monitoring Board (DSMB), the analyses are no longer relevant, and in agreement with the DSMB, we will proceed to the full analysis of the trial. We look forward to reporting SUNRISE-3 results in the second half of 2024 with the goal of moving a step closer to providing a new oral antiviral treatment for people at high risk for COVID-19 progression.” Bemnifosbuvir was granted Fast Track designation by the U.S. Food and Drug Administration for the treatment of COVID-19. About the Phase 3 SUNRISE-3 Trial The global, multicenter, randomized, double-blind, placebo-controlled Phase 3 SUNRISE-3 trial is evaluating bemnifosbuvir or placebo administered concurrently with locally available standard of care (SOC). SUNRISE-3 enrolled high-risk outpatients with mild or moderate COVID-19. Patients were randomized 1:1 to receive bemnifosbuvir 550 mg twice daily (BID) or placebo BID for five days. The trial is comprised of two study populations based on the type of SOC received: 1) the “supportive care population” evaluating bemnifosbuvir as monotherapy (primary analysis), and 2) the “combination antiviral population” assessing combination therapy if the SOC includes other compatible antiviral drugs against COVID-19 (secondary analysis). The primary endpoint of the SUNRISE-3 study is all-cause hospitalization or death through Day 29 in the supportive care monotherapy cohort in approximately 2,200 high-risk patients. In addition, secondary endpoints will measure patient outcomes in the trial through Day 60 post-treatment. In March 2024, enrollment for SUNRISE-3 was completed prior to the two scheduled interim analyses by the DSMB to assess safety and futility. Given that the trial has fully enrolled, the DSMB and Atea mutually concluded that both interim analyses would not be performed as they were no longer relevant. The interim analyses were originally planned to be conducted after approximately 650 and 1,350 evaluable patients in the monotherapy cohort, respectively, completed Day 29 post-treatment. Factoring the time required for full data analyses of SUNRISE-3 once patients have completed Day 60 post-treatment, Atea expects to report results from the SUNRISE-3 trial in the second half of 2024. The SUNRISE-3 patient population consists of those aged ≥70 years (regardless of other risk factors), individuals aged ≥55 years with one or more risk factors, those aged ≥50 years with two or more risk factors, and individuals aged ≥18 years with specific risk factors, including immunocompromised conditions, irrespective of COVID-19 vaccination status. Additionally, patients with reduced renal function were eligible for enrollment. About Bemnifosbuvir for COVID-19 Bemnifosbuvir targets the SARS-CoV-2 RNA polymerase (nsp12), a highly conserved gene which is responsible for both replication and transcription of SARS-CoV-2. Bemnifosbuvir has a unique mechanism of action, with dual targets consisting of chain termination (RdRp) and nucleotityltransferase (NiRAN) inhibition, which has the potential to create a high barrier to resistance. In vitro data confirmed that bemnifosbuvir is active with similar efficacy against all variants of concern and variants of interest that have been tested, including Omicron subvariants BA.4, BA.5, XBB, EG.5.1 and JN.1. About Atea Pharmaceuticals Atea is a clinical stage biopharmaceutical company focused on discovering, developing and commercializing oral antiviral therapies to address the unmet medical needs of patients with serious viral infections. Leveraging the Company’s deep understanding of antiviral drug development, nucleos(t)ide chemistry, biology, biochemistry and virology, Atea has built a proprietary nucleos(t)ide prodrug platform to develop novel product candidates to treat single stranded ribonucleic acid, or ssRNA, viruses, which are a prevalent cause of serious viral diseases. Atea plans to continue to build its pipeline of antiviral product candidates by augmenting its nucleos(t)ide platform with other classes of antivirals that may be used in combination with its nucleos(t)ide product candidates. Currently, Atea is focused on the development of orally-available antiviral agents for serious viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and hepatitis C virus (HCV). For more information, please visit www.ateapharma.com. Forward-Looking Statements This press release includes “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements in this press release include but are not limited to the Company’s plans relating to and time of the anticipated release of the SUNRISE-3 results. When used herein, words including “expects,” “may,” “will,” “anticipates,” “plans”, and similar expressions are intended to identify forward-looking statements. In addition, any statements or information that refer to expectations, beliefs, plans, projections, objectives, performance or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking. All forward-looking statements are based upon the Company’s current expectations and various assumptions. The Company believes there is a reasonable basis for its expectations and beliefs, but they are inherently uncertain. The Company may not realize its expectations, and its beliefs may not prove correct. Actual results could differ materially from those described or implied by such forward-looking statements as a result of various important factors, including, without limitation, the important factors discussed and updated from time to time under the caption “Risk Factors” in the reports the Company files with the SEC, including annual reports on Form10-K, quarterly reports on Form10-Q, current reports on Form 8-K and other filings each of which are accessible on the SEC’s website at www.sec.gov. These and other important factors could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent management’s estimates as of the date of this press release. While the Company may elect to update such forward-looking statements at some point in the future, except as required by law, it disclaims any obligation to do so, even if subsequent events cause our views to change. These forward-looking statements should not be relied upon as representing the Company’s views as of any date subsequent to the date of this press release. Contacts Jonae BarnesSVP, Investor Relations and Corporate Communications617-818-2985barnes.jonae@ateapharma.com Will O’ConnorStern Investor Relations212-362-1200will.oconnor@sternir.com

//  爱科百发计划在年内完成补充试验后，重新递交齐瑞索韦的上市申请。2月22日，爱科百发备受关注的抗呼吸道合胞病毒（RSV）感染新药齐瑞索韦（ziresovir，爱司韦）出现在中国国家药监局发布的药品通知件中，这引起了投资者对该产品临床数据及上市批准的猜测与担忧。为此，我们走访了爱科百发董事长兼CEO邬征博士。邬征告诉研发客：“齐瑞索韦的科学性、临床安全性和有效性数据没有问题。该药物抗病毒作用机制明确，临床试验数据翔实全面，3期注册试验AirFLO的结果不仅在第12届国际RSV年会上报告，而且一直以来得到CDE的鼓励、支持和认可，从而成为首个被CDE纳入突破性治疗品种的非肿瘤新药，并进入优先审评通道。”来源｜中国国家药监局官网AirFLO研究入组了302人，其中接受齐瑞索韦治疗的有200例。结果显示，齐瑞索韦在治疗48小时内就快速起效，将毛细支气管炎临床体征和症状评分改善提高30%。试验结果有望近期发表。“按照CDE的呼吸道合胞病毒感染药物开发指导原则和FDA的指南，3期临床试验组一般要有一定数量的患者临床数据库。我们认为各国药监机构的标准都是非常接近的，接下来爱科百发会全力以赴完成补充试验，并计划在年内完成后重新递交上市申请。我们会和CDE进行充分沟通和交流，加速齐瑞索韦的获批上市，使其成为全球首个RSV特效抗病毒药物，惠及广大患者。”邬征说道。他进一步解释，当下全球尚无针对RSV的特异性抗病毒药物，齐瑞索韦既是first-in-class新药，又是first-in-disease新药，特别是在国外没有批准且适应症又是婴幼儿这一特殊人群的背景下，CDE采用高标准、严要求实际上是对病人、家庭乃至社会负责任的态度。十年研究长跑齐瑞索韦是爱科百发核心品种，过去10余年，其开发之路就像在跑马拉松。“开发儿童用创新药是非常难的事情。启动FIH研究前，我们做了很多幼龄多种属动物实验，从动物出生第4天开始给药直到发育成年，从而取得充分的安全性数据。由于10年前儿童用FIC新药的临床开发在国内接受度有限，我们选择先在澳洲和其他国家地区进行成人和婴幼儿群体的人体临床试验。”邬征说。此后，爱科百发在全球8个不同国家或地区开展了国际多中心2期VICTOR研究，结果进一步证实齐瑞索韦在婴幼儿患者中安全性和耐受性良好，支持其进入注册3期临床，其结果已在国际专业杂志发表。2022年1月，齐瑞索韦又在中国完成治疗0～2岁住院RSV感染婴幼儿的3期AirFLO研究。据邬征介绍，中国3期试验之所以能顺利招募300多患者，一是此前在海外积累的安全性和有效性数据足以说服患者家属，二是RSV感染严重的住院婴幼儿迫切需要能快速缓解症状的抗RSV特效药。“婴幼儿免疫系统较弱，且肺部呼吸道狭窄，RSV感染严重者会出现缺氧、喘息、呼吸困难甚至死亡。至今，全球仍然缺乏有效的RSV治疗药物，因此，很多家长愿意让住院的婴幼儿患者参加试验。”他说。拓展阅读邬征：创新儿童药AK0529的安全性要做到自己孩子敢用才行目前，齐瑞索韦还在中国开展另外3项临床试验。其中，针对2～5岁儿童患者的扩展研究有望于今年完成；由中日友好医院牵头开展的成人2期试验已入组患者；针对免疫缺陷成年患者的试验正在进行中。在海外，爱科百发正与FDA沟通齐瑞索韦的国际临床开发计划，同时寻找全球合作伙伴以推进该产品的全球临床开发和商业化工作。邬征表示：“理想的合作伙伴首先要具备较强的科学性和专业性，了解急性抗病毒药物的临床设计和开发，并能在全球完成申报上市，其次是具有经济实力和资源推进产品在全球的商业化，当然还要合作双方彼此投缘。”“组合拳”怎么打2023年是RSV预防药物元年。前有GSK、辉瑞和赛诺菲/阿斯利康3款产品率先获批，上市首年合计创下超29亿美元营收；后有Moderna、默沙东、泰诺麦博、优锐医药等众多药企紧跟步伐。拓展阅读RSV疫苗元年 : 真正的战斗才开始？灼识咨询数据显示，全球RSV药物市场到2032年预计将增长至128亿美元左右，且治疗药物的市场规模将在2026年开始反超预防产品成为抗RSV主力。对此，邬征表示乐见其成。RSV药物全球市场规模   来源|爱科百发招股书“RSV预防与治疗相辅相成。前者对于婴幼儿、免疫缺陷等高危人群意义重大，但整体接受度有限，尤其受社会经济条件、医保水平等影响较大。”他进一步表示，“相较之下，治疗药物的市场较为确定，RSV感染后呼吸道受损严重的患者临床治疗需求明显，从药物经济学的角度更容易获得国家、社会和患者的支持。”目前，爱科百发还在研发另外两款RSV产品。其中，靶向RSV L蛋白的抑制剂AK0611正在开展临床前研究。它由爱科百发自主研发，通过阻断病毒复制蛋白质使得进入人体细胞内的病毒无法实现后续增殖。“病毒最大的特征就是容易产生变异，从而导致抗药性，这也是抗病毒药物鸡尾酒疗法兴起的一个重要原因。AK0611靶向的RSV L蛋白是一种发生变异可能性较小的RNA聚合酶，因此该产品与靶向RSV F蛋白的抗病毒药物联合用药有望加强疗效并降低耐药性。”邬征说。另一款靶向RSV F蛋白的预防性抗体AK0610正在开展1期临床试验。该抗体由中科院微生物研究所协同北京儿童医院率先发现，爱科百发早期参与开发并于2021年受让全球权益。据邬征介绍，它作用于RSV F蛋白更保守的区域，不容易产生耐药性；并且它是从康复的RSV感染儿童患者样本中筛选获得的人源抗体，实验数据表明其体外活性比境外已上市同类品种有更优异的抗病毒活性。除RSV之外，儿童注意缺陷多动障碍（ADHD）是爱科百发正深度布局的另一个方向。2021年11月，爱科百发引进了Commave公司儿童ADHD治疗新药爱智达（Azstarys）。目前该产品正在中国开展3期注册桥接临床试验，预计将在一年左右申报上市。3月4日，爱科百发又与专注数字药物研发的数药智能签署战略合作协议，共同推进ADHD传统药与创新数字药的联合治疗方案，包括推广后者自主研发并已获批上市的ADHD数字疗法专数达。此外，该公司在研管线还有广谱纤维化抑制剂AK3280和AK3287、靶向纤维化关键生物信号通路的AK0707等均已进入不同临床阶段。据邬征介绍：“目前公司财务状况尚可，重点临床项目会继续往前推进。在资本市场不好的背景下，我们会综合考虑靶点、成药性、赛道竞争、市场、投入等多个因素，根据项目轻重缓急分配资源，但2024年的重中之重还是推动齐瑞索韦的开发和成功上市。”编辑 | 戴佳凌dai.jialing@PharmaDJ.com 总第2069期访问研发客网站可浏览更多文章www.PharmaDJ.com

随着生物技术的飞速发展，mRNA疗法作为一种新兴的治疗手段，因其可编程性强、响应速度快等优势备受关注。在mRNA疫苗和基因治疗等领域中，高效合成高质量的mRNA是实现疗法目标的关键步骤。而在这一过程中，T7 RNA聚合酶扮演着至关重要的角色，它能够高效地催化体外合成mRNA的过程。尽管T7 RNA聚合酶在mRNA合成中发挥着重要作用，但实际操作中经常会产生双链RNA（dsRNA）这一副产物。dsRNA的存在不仅降低了mRNA的产量和纯度，还可能激发非特异性免疫反应，影响疗效和安全性。因此，减少dsRNA的产生成为了行业的一个迫切需求。目前，降低dsRNA的方法主要包括优化反应条件和使用辅助酶等。这些方法虽然可以在一定程度上减少dsRNA的产生，但往往伴随着操作复杂、成本提高等问题。与之相比，通过直接改造T7 RNA聚合酶来降低dsRNA的产生则是一种更为根本的解决方案。酶定向改造技术可以通过精确改变酶的氨基酸序列或结构，从而改善其催化特性，提高产物的纯度和产率。对于T7 RNA聚合酶而言，针对性的改造不仅可以减少dsRNA的产生，还能提升合成mRNA的整体效率和质量。翌圣镁孚泰生物突破性成果镁孚泰生物，作为mRNA体外合成原料供应商翌圣生物（点击了解更多）的子公司，利用其ZymeEditor定向进化平台的能力，持续在进化mRNA体外合成的核心酶原料——T7 RNA聚合酶。为了尽可能消除体外转录过程产生的dsRNA等副产物，镁孚泰生物进化团队通过理性设计与定向筛选结合的方式对T7 RNA聚合酶进行改造。根据文献报导，副产物dsRNA的产生主要包括两种来源（图1）：第一种是转录早期T7 RNA聚合酶由起始构象转变为延伸构象时，转录三元复合物极易解离[1]，伴随着大量长度在20 nt左右的短RNA链（即Abortive RNA）释放至体系中，这部分RNA即扮演“引物“的角色与长RNA链互补配对，并在T7 RNA聚合酶的RNA依赖的RNA聚合活性（RDRP活性）作用下延伸产生dsRNA[2,3]；第二种则由T7 RNA聚合酶具备的末端核糖核苷转移活性而引发，当转录反应进行到线性模板末端时，T7 RNA聚合酶会在不依赖模板的情况下随机增加若干个核糖核苷酸，这些核苷酸组成的“随机引物”即有可能反向折叠与目标mRNA区域发生互补配对进而延伸产生dsRNA，通过回环产生的dsRNA称为loopback dsRNA[3,4]。因此，为了减少dsRNA副产物，T7 RNA聚合酶改造的重点在于稳定早期转录三元复合物，或减弱T7 RNA聚合酶的末端转移活性和RDRP活性。图1. 能垒示意图及dsRNA形成原理在进行T7 RNA 聚合酶改造过程中，镁孚泰生物一方面通过结构及自由能分析，发现在T7 RNA聚合酶构象变化的同时也伴随着能量的变化，且延伸构象的自由能显著高于起始构象，意味着转录过程需要越过较高的能垒才能产生完整的mRNA链。高能垒不利于构象平稳转变，为此，团队借助虚拟筛选手段锁定了20余个热点氨基酸，并构建了相应的定点饱和文库。另一方面，考虑到关于T7 RNA聚合酶的末端转移及RDRP活性相关的功能、位点及结构域的报导较少，且由于功能相近这两种活性极可能与T7 RNA聚合酶主反应的转录活性（即DNA依赖的RNA聚合活性，DDRP）共享关键位点，难以找到热点氨基酸进行定点改造。因此，镁孚泰生物同时构建了基于易错PCR的数个随机突变文库，结合ZymeEditor平台的进化通量，单个文库的多样性超过106。为了兼顾T7 RNA聚合酶的产量并监测体外转录反应中dsRNA的含量，镁孚泰生物参照优化后的转录模板，精心设计了多个分子信标（FRET RNA探针），分别靶向目标mRNA产物的不同区域，将反应物产量、完整度以及体系内dsRNA含量等信息与荧光信号关联，体系的荧光强度越强，突变体的性能越有优势。理论上，该筛选方法可按不同探针的荧光强度排序，分别获得高产或Abortive RNA减少的T7 RNA聚合酶突变体，以及完整度提升或loopback dsRNA降低的T7 RNA聚合酶突变体。将反应模板更换为RNA时还可负向筛选突变体的RDRP活性，提升T7 RNA聚合酶的模板选择能力。此外，在液滴反应体系中添加修饰核苷酸、帽类似物，以及提高反应温度还可以进一步筛选耐受非天然底物、热稳定性提升的T7 RNA聚合酶突变体。根据文库大小，镁孚泰生物分别开发了基于荧光激活液滴分选（FADS）的超高通量筛选流程（图2），以及基于传统孔板法（MTPS）的高通量筛选流程（图3）。经过多轮实验，合计筛选超过107个突变体，获得多个dsRNA显著降低的突变体，其中RP051、RP059突变体反应中由Abortive RNA引起的dsRNA降低，提示这些聚合酶突变体的延伸构象更稳定；RP057、RP078突变体反应中loopback dsRNA含量降低，提示这些突变体的末端转移活性或RDRP活性被减弱。图2. FADS筛选流程【5】图3. MTPS筛选流程鉴于上述突变体的性能优势来源于不同机制，镁孚泰生物针对它们构建了DNA shuffling文库，筛选后最终获得了性能更优的组合突变体RP080-RP082（图4）。图4. 酶进化历程及突变体性能表征经过定量分析，如图5所示，在9 kb转录模板、共转录加帽条件下，使用天然核苷酸时，野生型T7 RNA聚合酶产物中dsRNA约为2.9 ng/μg，A公司竞品约0.18 ng/μg。而镁孚泰生物改造的各T7 RNA 聚合酶突变体dsRNA产量均＜0.10 ng/μg，尤其突变体RP082的dsRNA产量仅为0.015 ng/μg，相比于野生型提升近200倍，比竞品提升12倍。经过反复测试，突变体的降低dsRNA的性能优势在不同反应条件下均能稳定复现，表明上述突变体具有较好的体系兼容性，也为后续反应体系优化以进一步降低dsRNA产量奠定了基础。此外，FADS的筛选还获得了多个产物完整度、热稳定性提升的突变体，可满足更多的体外转录应用场景。图5. T7 RNA聚合酶突变体产物dsRNA检测图客户试用满意度高 目前，已有多家合作伙伴对镁孚泰生物改造的T7 RNA聚合酶突变体进行了试用，得到客户的高度认可。他们表示，新酶的使用简化了mRNA的纯化过程，提高了工作效率，并在多个应用场景中展现出卓越的性能。目前我们还有少量试用名额，如您需要试用或者改造酶的其他性能，点击阅读原文在线填写需求表，或扫描下方二维码联系我们哦!参考文献：[1] Sousa R, Mukherjee S. T7 RNA polymerase[J]. Progress in nucleic acid research and molecular biology, 2003: 1-41.[2] Steitz T A. The structural changes of T7 RNA polymerase from transcription initiation to elongation[J]. Current opinion in structural biology, 2009, 19(6): 683-690.[3] Vallejo D, Nikoomanzar A, Paegel B M, et al. Fluorescence-activated droplet sorting for single-cell directed evolution[J]. ACS synthetic biology, 2019, 8(6): 1430-1440.[4] Gholamalipour Y, Karunanayake Mudiyanselage A, Martin C T. 3′ end additions by T7 RNA polymerase are RNA self-templated, distributive and diverse in character—RNA-Seq analyses[J]. Nucleic acids research, 2018, 46(18): 9253-9263.[5] Vallejo D, Nikoomanzar A, Paegel BM, Chaput JC. Fluorescence-Activated Droplet Sorting for Single-Cell Directed Evolution. ACS Synth Biol. 2019 Jun 21;8(6):1430-1440. ●干货 | 酶定向进化之基因型与表型的关联●干货 | 酶定向进化之突变体文库筛选技术大全●干货 | 蛋白生物传感器高通量筛选方法助力代谢酶的挖掘与进化！●干货 | 酶定向进化之突变体文库构建技术大全———    ✦   镁孚泰生物    ✦    ———镁孚泰生物科技（上海）有限公司（镁孚泰生物，Molefuture）是翌圣生物科技（上海）股份有限公司旗下的全资子公司，是一家以酶进化技术为驱动、专注于提供酶改造定制化解决方案的创新型企业。依托于翌圣生物，镁孚泰生物现有六大技术平台：ZymeEditor创新酶进化平台、多宿主高效表达平台、发酵工艺开发平台、纯化工艺开发平台、超洁净酶生产平台以及酶分析与质控平台。基于这六大技术平台，镁孚泰生物可提供酶定向改造、新酶开发、酶工艺开发以及GMP级别规模化生产的全套定制解决方案，以满足酶在体外诊断、生物医药、合成生物、医疗美容、医药中间体等领域的应用需求。