Artios Pharma Ltd.

关注并星标CPHI制药在线 DNA双链断裂(DSB)是最严重的DNA损伤类型，主要通过同源重组（HR）及非同源末端连接 （NHEJ）两种典型途径进行修复，而这两种修复途径的选择主要取决于细胞所处的细胞周期节点。一般情况下，HR在S/ G2期活跃，NHEJ在整个细胞周期都有发生，但在G1/G2期更为活跃。当HR和NHEJ同时受损时，细胞就会进化出后备修复途径——微同源末端介导的连接（MMEJ）。MMEJ是发生在细胞中的一种较少见的机制，活跃于细胞周期的S期和G2期，部分在G0/G1期出现。 关于Polθ DNA聚合酶θ（Polθ）属于DNA聚合酶A家族，由哺乳动物细胞中的POLQ基因编码。Polθ是MMEJ途径的重要组成部分，作为效应蛋白参与DNA双链断裂修复。研究发现，DNA末端切除发生时，在存在BRCA2的情况下，BRCA2不仅将重组酶RAD51募集到DSB 促进HR，而且还抑制替代末端连接（alt-EJ）等修复途径。 当HR介导的修复受到损害时，若BRCA1或BRCA2突变，Polθ会高度表达并引导DSB修复朝向alt-EJ，开启MMEJ的DNA修复过程。此外，Polθ还具有逆转录RNA并促进以RNA为模板的DNA修复功能。但在HR 缺陷的情况下，Polθ的抑制通过毒性RAD51中间体的积累和alt-EJ修复途径的抑制，导致细胞死亡。 研究发现，Polθ在正常组织中几乎不表达，但在乳腺癌、卵巢癌、肺癌等多种肿瘤中高表达，而且这些瘤种中又普遍存在HR修复缺陷。因此，Polθ被认为是合成致死药物研发的潜力靶点。 Polθ抑制剂进展 据insight数据库，目前全球药企已研发出多款Polθ抑制剂，详见下表。在研Polθ抑制剂被开发用于治疗多种实体瘤，但进展缓慢，大多处于临床前阶段，最快处于1/2期临床。 具体品种来看，GSK101是GSK与IDEAYA Biosciences合作开发的一款Polθ抑制剂。临床前研究显示：GSK101与niraparib联用与单药相比，在BRCA突变模型中能产生更深入、更持久的抗肿瘤作用。 Artios Pharma是Polθ靶点的领头羊，开发了多款口服、选择性、强效Polθ抑制剂，如ART4215、ART6043、ART558和ART812。其中ART4215是第一个进入临床试验（2021年8月）的Polθ抑制剂，2022年其联合PARP抑制剂他拉唑帕利治疗BRCA缺陷型乳腺癌的2期临床研究启动。来自第一阶段的剂量组初步数据表明，ART4215具有良好的耐受性。ART6043进展也相对较快，也处于1/2期临床。ART558和ART812处于临床前阶段。 我国药企也积极布局Polθ靶点，如先声药业、圣域生物。其中先声药业开发了三款Polθ抑制剂，即SIM 0508、SS008871、ZM-2311。其中SIM0508是一种选择性、强效小分子Polθ抑制剂，在临床前研究中表现出良好的口服药代动力学性质和安全性，且未观察到明显的血液学毒性。今年8月，SIM0508在国内获批临床，拟用于治疗晚期实体瘤。 SS008871也是先声药业开发的一种小分子Polθ抑制剂，其能有效地抑制 Polθ活性，在低单位数纳摩尔级别下强烈抑制细胞MMEJ通路。在体内实验中，SS008871单独或联合奥拉帕利均显示出对 BRCA2-/- DLD-1 异种移植模型的肿瘤生长的抑制作用。而且，SS008871在人类造血干细胞等体外试验中没有出现明显的造血毒性风险，具有良好的安全性。 圣域生物开发了两款Polθ抑制剂，即SYN818和SYX1097。其中SYN818是圣域生物自主研发的一款新型小分子Polθ抑制剂，临床前研究显示其能高效抑制Polθ蛋白活性，阻断MMEJ修复通路，与HR缺陷存在联合致死效果，从而发挥抗肿瘤作用。同时，SYN818在体内外研究中也表现出与PARP抑制剂的显著联合增效作用。此外，SYN818在临床前研究中还表现出优异的药代动力学性质和良好的安全性。 根据临床前研究数据，圣域生物指出SYN818具有潜在“best-in-class”特性，其不仅对HR缺陷肿瘤细胞具有单独成药的潜力，还具有与PARP抑制剂、放化疗、抗体偶联药物等联合用于多种肿瘤治疗的潜质，有望降低现有治疗方案的临床毒性、克服耐药，具有广阔的临床开发前景。今年7月，该药先后在国内和美国获批临床，成为圣域生物首个迈入临床开发阶段的创新药。 总结 作为合成致死药物研发新靶点，Polθ进展缓慢。目前虽已出现多款在研药物，但布局企业相对集中，且在研药物大多处于临床前阶段。这也意味着Polθ抑制剂的开发存在很大失败的风险，后续企业在布局时要慎重。 END 【智药研习社线上研习会报名】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

关注并星标CPHI制药在线 近日，杭州圣域生物（SynRx Therapeutics）自主研发的创新药物SYN818片的新药临床试验申请（IND）获得美国FDA的许可，即将启动1期临床试验。就在几日前，SYN818片在中国的IND申请也获得国家药监局药品评审中心（CDE）的受理。 SYN818是由圣域生物自主研发的一款新型小分子抑制剂化合物。该药物通过精准靶向DNA聚合酶θ（Polθ），有效抑制肿瘤细胞的DNA损伤修复，从而有选择性的杀死肿瘤细胞。临床前研究显示，SYN818能够高效抑制Polθ蛋白活性，阻断MMEJ修复通路，与同源重组缺陷（HRD）存在联合致死效果，从而发挥抗肿瘤作用。同时，它在体内外研究中也表现出与PARPi的显著联合增效作用。SYN818在临床前研究中表现出强效抗肿瘤活性、优异的药代动力学性质，以及良好的安全性，未观察到显著的血液毒性。 根据临床前研究数据，SYN818作为一个Polθ抑制剂具有潜在“best-in-class”的特征。SYN818不仅对HRD肿瘤细胞具有单独成药的潜力，还具有与PARP抑制剂、放化疗、抗体偶联药物等联合用于多种肿瘤治疗的潜质，有望降低现有治疗方案的临床毒性、克服耐药，具有广阔的临床开发前景。 此外，圣域生物的另一款处于临床前阶段的高潜力Polθ抑制剂也在今年4月举办的美国癌症研究协会年会（AACR 2024）上亮相， 其与PARP抑制剂联用具有强大的协同作用，亦可能单独治疗HR通路缺陷的患者。在非临床研究阶段，SYX1097展现了出色的动物体内疗效，优良的药代动力学特征及理想的安全性表现，在较高剂量下亦未见明显血液毒性，从而揭示了宽广的治疗窗。 合成致死靶点之Polθ Polθ是DNA聚合酶A家族成员之一，由哺乳动物细胞中的POLQ基因编码，具有N端解旋酶样结构域和C端DNA聚合酶结构域，通过非结构中心结构域分离开。Polθ是MMEJ途径的重要组成部分，作为效应蛋白参与DNA双链断裂修复。MMEJ生化步骤中，Polθ解旋酶活性促进含有微同源性(互补DNA序列的短片段)的ssDNA退火，Polθ聚合酶活性完成DNA合成填充切除的缺口。在具有功能性HR修复途径的正常细胞中，Polθ参与的MMEJ途径是不活跃的，其对DSB修复的影响有限。HR和MMEJ途径共享相同的底物，同源重组缺陷(HRD)的肿瘤细胞存活会高度依赖MMEJ介导的DNA修复。因此，在HRD肿瘤中抑制Polθ可以诱发合成致死。 此外，PARP作为损伤感应器与Polθ作为效应蛋白均参与HR受损后的MMEJ后备修复通路，由于其不同的作用机制，PARPi和Polθ抑制剂联合治疗可能在HR缺陷肿瘤中具有协同作用；另外，尽管PARPi单药治疗在BRCA突变的癌症中观察到了显著的临床获益，但相当一部分患者产生原发性(＞40％)和继发性耐药，因此需要新的治疗策略来克服PARP的耐药性，以及利用其他的DNA修复缺陷新途径。 鉴于Polθ在正常组织中的几乎不表达，但在乳腺癌、卵巢癌、头颈肿瘤和肺癌等多种肿瘤中高表达，而这些瘤种中又普遍存在同源重组修复缺陷, Polθ被认为是合成致死药物研发的潜力靶点。 Polθ抑制剂：Artios、IDEAYA领衔，国内紧跟脚步 目前，Polθ已经被证实与肿瘤的形成、肿瘤细胞放射治疗的敏感性以及患者预后有关。全球药企针对该靶点有多款新药在研，在研Polθ抑制剂进展缓慢，最快处于1/2期临床，大多处于临床前阶段。从布局企业来看，Polθ抑制剂研发企业并不多，且相对集中。 Artios Pharma是Polθ领域的大玩家，ART4215是Artios开发的一种选择性的口服生物可利用的POLQ聚合酶结构域小分子抑制剂，也是全球首 个Polθ抑制剂，2022年已启动ART4215联合PARP抑制剂他拉唑帕利治疗BRCA缺陷型乳腺癌的2期研究。来自第一阶段的剂量组初步数据表明，ART4215具有良好的耐受性。此外，Artios还布局2款Polθ抑制剂，ART6043处于临床1/2期；ART558和ART812处于临床前。 IDEAYA Biosciences是一家致力于突破合成致死领域技术困境的创新企业。2020年6月，IDEAYA Biosciences和葛兰素史克公司（GSK）宣布在“合成致死”领域建立战略合作伙伴关系，而这一战略合作伙伴关系包含IDEAYA Biosciences的三个合成致死研发项目，分别靶向MAT2A、Polθ和Werner解旋酶。 GSK101（IDE705）是一种潜在首 创Polθ小分子抑制剂。临床前研究显示，在BRCA突变模型中，GSK101联用niraparib与单药相比，能产生更深入、更持久的抗肿瘤作用。去年8月，该药在美国获批1/2期临床，评估其联合GSK的PARP小分子抑制剂niraparib治疗携带BRCA或其他同源重组（HR）突变或同源重组缺陷（HRD）肿瘤的效果。 此外，有研究指出一种在20世纪50年代发现的抗生素新生霉素（novobiocin，NVB）也是一种人类DNA聚合酶Polθ的抑制剂，能有效地杀死携带同源重组（HR）DNA修复缺陷的肿瘤细胞，更加令振奋的是，这种杀伤能力对那些对PARP抑制剂产生耐药的肿瘤细胞也有效。2023年1月，美国食品和药物管理局（FDA）批准Novobiocin用于携带BRCA2或BRCA1基因突变的癌症患者的临床试验。 除了圣域生物，国内药企如先声药业也积极布局了该靶点，已经有2款Polθ抑制剂处于临床前阶段，分别为SIM0508和SS008871。其中，SIM0508能够抑制HR缺陷的BRCA2-/-DLD-1细胞的增殖，并显示出DLD-1亲本细胞和非恶性细胞的>125倍选择性，SIM0508片的临床试验申请在今年6月已获得CDE受理。另一款Polθ抑制剂SS008871和奥拉帕尼的组合能进一步导致肿瘤消退，且在人类造血干细胞等体外试验中没有出现明显的造血毒性风险，具有良好的安全性。 参考文献： 1.Zhou, J., et, al. (2021). A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors. Nature Cancer. Doi:10.1038/s43018-021-00203-x. 2.《实力靶点Polθ：潜力迸发，巨头入局》.医药魔方.2021-08-12 3.各企业官网 END 【智药研习社直播预告】 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

Preliminary Results for the year ended 31 December 2023 COMMERCIALISATION BUILDING, WITH REVENUE MORE THAN DOUBLED New products and services launched; and breakthrough studies completed on combined ctDNA and CTC-DNA analysis Strong start to 2024 with two global pharmaceutical customers announced GUILDFORD, SURREY / ACCESSWIRE / June 5, 2024 / ANGLE plc (AIM:AGL)(OTCQX:ANPCY), a world-leading liquid biopsy company with innovative circulating tumour cell (CTC) diagnostic solutions for use in research, drug development and clinical oncology, today announces unaudited preliminary results for the year ended 31 December 2023. Financial Highlights Revenues for the full year more than doubled to £2.2 million (2022: £ 1.0 million) Loss for the year £20.1 million, or 7.73 pence per share (2022: loss £21.7 million or 8.79 pence per share) Cash and cash equivalents at 31 December 2023 of £16.2 million (2022: £31.9 million) with R&D Tax Credits due at 31 December 2023 of £1.5 million (2022: £2.9 million) Fundraise announced today raising £8.50 million (gross) with an Open Offer to shareholders initiated raising up to £2.06 million Operational Highlights Pharma Services Contracts signed with new and repeat customers including: services agreement signed at year end and announced early 2024 with global Japanese pharma company, Eisai, for use of ANGLE's quantitative HER2 assay in a Phase II trial new contract with Crescendo Biologics to use ANGLE's Portrait Flex assay in a Phase I clinical study in prostate cancer follow-on contract with Artios Pharma for use of DNA Damage Response (DDR) assays in a Phase I clinical trial in multiple advanced cancers Launch of Portrait Flex, Portrait DDR (γH2AX and pKAP1), and Portrait PD-L1 assays from the Company's GCLP-compliant laboratory Products Expansion of global distribution network and associated infrastructure (including product management, logistics, service, and maintenance) across Europe, Africa, the Middle East and Asia-Pacific with first commercial sales in fourth quarter Launch of Portrait+ CTC Staining Kit as first sample-to-answer product providing laboratories with a fully validated, standardised protocol for CTC identification and analysis across multiple cancer types Strategic partnership with BioView to develop a quantitative breast cancer CTC HER2 assay kit. Development work generating revenue for ANGLE of £1.2 million Installed base of over 290 Parsortix® instruments with 210,000 cumulative samples processed at year end Content (applications) 16 peer-reviewed scientific papers published in 2023 bringing the total number of peer-reviewed publications as at 31 December 2023 to 92 (2022: 76) Good progress made in clinical studies: recruitment on track in INFORM study across four major cancer types building a biobank of samples for assay development and validation recruitment in ovarian and prostate cancer studies completed and Parsortix cell harvest stored for future molecular analysis Development of a dual analysis solution for comprehensive DNA molecular analysis of CTCs and ctDNA from a single blood sample: research study results found that clinically relevant DNA variants were identified in CTCs that were not present in ctDNA from the same blood draw potential to expand clinically relevant information to inform personalised therapy when the two are analysed together Corporate Highlights Board strengthened for the next phase of the Company's development with the appointment of a new Non-executive Chairman and two new Non-executive Directors Senior management team strengthened with the appointment of highly experienced, commercially focused industry professionals to the positions of Chief Commercial Officer and Chief Scientific Officer Outlook Strong start to 2024 with product and services customer relationships developing well and significant expansion of pharma services business three service agreements signed with two large pharma customers, Eisai and AstraZeneca development of HER2 assay for Eisai to detect and assess HER2 low and HER2+ cancers in a Phase II study at a value to ANGLE of US$250,000 development of a DDR assay for AstraZeneca with the initial 6-month development phase worth £150,000 to ANGLE development of an Androgen Receptor assay for AstraZeneca with the initial 12-month development phase worth £550,000 to ANGLE active discussion ongoing with multiple prospective pharma customers including six large pharma customers product sales building with expansion of direct salesforce and highly engaged network of global distributors Revenue for H1 2024 is expected to be between £1.0 million and £1.3 million with a total of c.40% of FY24 market expectations for revenue1 already contracted year to date. The Company has a strong current pipeline of opportunities that has more than doubled year to date, with significant potential growth opportunities across a variety of end customers, including large pharma. As such, the management remains confident in delivering strong growth in 2024 in line with current market expectations Completion of the fundraising, announced separately today, alongside delivery of market expectations is anticipated by the Company to secure cashflow breakeven on a monthly basis by the end of 2025 ANGLE Chief Executive, Andrew Newland, commented: "ANGLE has made considerable commercial progress in 2023 through the ongoing execution of our strategy. Major efforts have been focused on both the products and services commercialisation channels and on the development of "content" to provide applications of the Parsortix system for customers. This has resulted in the launch of four imaging assays, a strategic partnership with BioView for the development of a quantitative HER2 assay kit, repeat and new business with pharmaceutical customers for services and positive research study results for the Company's comprehensive solution for dual molecular analysis of CTC-DNA and ctDNA from a single blood sample. 2023 also saw the first product sales from our newly established global distribution network and we are optimistic about the growth in global sales of the Parsortix system, consumables, and assay kits during the current financial year. I am delighted that 2024 has started strongly with three new contracts with two large pharma customers and we look forward to continuing this commercial momentum in the year ahead." 1. Current consensus revenue is £6.45m for FY24. (Source: Bloomberg) ANGLE plc +44 (0) 1483 343434 Andrew Newland, Chief Executive Ian Griffiths, Finance Director Berenberg (NOMAD and Broker) Toby Flaux, Ciaran Walsh, Milo Bonser +44 (0) 20 3207 7800 FTI Consulting Simon Conway, Ciara Martin Matthew Ventimiglia (US) +44 (0) 203 727 1000 +1 (212) 850 5624 For Frequently Used Terms, please see the Company's website on The information contained within this announcement is deemed by the Company to constitute inside information as stipulated under the EU Market Abuse Regulation (596/2014). Upon the publication of this announcement via a regulatory information service, this information is considered to be in the public domain. These Preliminary Results may contain forward-looking statements. These statements reflect the Board's current view, are subject to a number of material risks and uncertainties and could change in the future. Factors that could cause or contribute to such changes include, but are not limited to, the general economic climate and market conditions, as well as specific factors including the success of the Group's research and development, commercialisation strategies, the uncertainties related to clinical study outcomes and regulatory clearance, obtaining reimbursement and payor coverage, acceptance into national guidelines and the acceptance of the Group's products and services by customers. The Company values communications with its shareholders and, as soon as feasible, will organise a webcast and other communications with shareholders. Click on, or paste the following link into your web browser, to view full announcement: This information is provided by RNS, the news service of the London Stock Exchange. RNS is approved by the Financial Conduct Authority to act as a Primary Information Provider in the United Kingdom. Terms and conditions relating to the use and distribution of this information may apply. For further information, please contact rns@lseg.com or visit . SOURCE: ANGLE plc View the original press release on accesswire.com