Zerlasiran

关注并星标CPHI制药在线在全球人口老龄化推动下，心血管疾病一直是全球面临的严重疾病挑战。据公开资料，到2050年全球死于心血管疾病的人数将达3560万，对应市场规模达千亿美元。       以降脂明星靶点PCSK9为例，该赛道无论是传统药物还是新药销售额都亮眼。其中目前全球首个且唯一的siRNA药物Leqvio（英克司兰），由于利用siRNA技术实现了更显著的降脂疗效和更长的给药间隔（半年1次 ），极大地提升了患者依从性。基于此，Leqvio自2021年上市后，销售额连续三年高速增长，2024年达到7.54亿美元，同比增长114%。在心血管疾病高发的背景下，该赛道很多创新药物尚未达到商业化天花板，具有容纳更多药物的空间。因此，心血管疾病领域吸引了全球大小药企布局，为了实现差异化，药企们也在探索新型靶点研发。相比肿瘤、自免等其他热门疾病赛道，心血管疾病药物在市场端的优势十分明显。比如单药的使用人群广泛，立普妥的适应症就覆盖了从血脂异常到心血管事件全程管理。即便专利到期后，有多款仿制药上市，立普妥仍然占据重要的市场份额。再如，心血管疾病用药往往市场持续性长，降压药、降脂药都往往需要终身服用，全球处方量最大降压药之一的络活喜，在专利过期多年后，销售也依然强劲。拿下一款心血管疾病重磅药物，对于MNC而言，就是获得了专利独占期内业绩增长的压舱石。Lp(a)在降脂领域， 除了PCSK9外，Lp(a)（脂蛋白(a)）无疑是最热靶点。3月25日，恒瑞医药与默沙东就其Lp(a)口服小分子项目HRS-5346达成独家许可协议。根据条款，恒瑞将收取2亿美元的首付款，并有资格获得不超过17.7亿美元的特定开发、监管、商业化里程碑付款等。默沙东将获得HRS-5346在大中华区以外的全球范围内开发、生产和商业化的独家权利。这笔高额交易，将业界对Lp(a)的热情再次点燃。Lp(a)是一种由肝脏产生的脂蛋白，其水平升高被认为是冠状动脉疾病、心脏病发作和中风等心血管事件的独立危险因素，全球约20%人群Lp（a）水平偏高（50mg/dL）。但目前尚无针对Lp（a）升高的特效药。在研产品方面，目前进展最快的是诺华的Pelacarsen，这是一款反义寡核苷酸（ASO）药物，通过靶向并切割Apo（a） mRNA，来抑制Apo（a）蛋白的表达，阻断Lp（a）生成。Ⅱ期临床数据显示，Pelacarsen能将患者的Lp（a）水平降低约80%，80mg/月的给药剂量可使98%的患者Lp（a）水平降至50 mg/dL以下。目前Pelacarsen正在进行III期研究。与Pelacarsen不同，礼来的Lepodisiran是一种小干扰RNA（siRNA）疗法，旨在从基因翻译水平阻断Lp(a)的合成。在II期ALPACA研究中，在最高测试剂量（400mg）治疗后的第60天至第180天期间内，Lepodisiran使Lp(a)水平平均降低93.9%，达到了研究主要终点。接受Lepodisiran 16mg和96mg剂量的参与者在同一时间内，其Lp(a)水平分别降低了40.8%和75.2%。Lepodisiran在这项研究中显示的显著且持续的Lp(a)水平降低，表明siRNA疗法有望通过长期治疗而提供持久获益。同为siRNA疗法的Zerlasiran，由Silence Therapeutics开发，目前已经完成了IIa期临床试验，数据显示，300 mg剂量组患者在加收每16周一次的Zerlasiran治疗后，Lp（a）中位数降低89%，并维持48周。目前正进入IIb期临床试验阶段。国内方面，瑞博生物、舶望生物、赫吉亚生物、靖因药业的Lp（a）小核酸管线已取得临床进展。CETPCETP（胆固醇酯转移蛋白）是一种将胆固醇从HDL-C（好胆固醇）中转移到LDL-C（坏胆固醇）中的转运蛋白。它通过将胆固醇酯从HDL（高密度脂蛋白）转运至LDL（低密度脂蛋白）和VLDL（极低密度脂蛋白），并将甘油三酯从VLDL转运至LDL和HDL。因此，抑制CETP活性有助于升高HDL水平，并降低LDL和VLDL水平。当前在研CETP抑制剂包括Obicetrapib、CKD-508、MK-8262等。其中Obicetrapib由NewAmsterdam Pharma研发，是一种口服、选择性CETP抑制剂，在II期临床试验中，Obicetrapib单药或与Ezetimibe（依折麦布）联合均显著（所有指标P<0.05）降低患者的LDL-C（43.5%和63.4%）、非高密度脂蛋白胆固醇（non-HDL-C，37.5%和55.6%）、ApoB（24.2%和34.4%）、总低密度脂蛋白颗粒（LDL-P，54.8%和72.1%），并提高了高密度脂蛋白胆固醇水平（HDL-C，142%和136%）。目前，Obicetrapib已进入临床III期试验。ANGPTL3ANGPTL3（血管紧张素样蛋白3 ）是一种主要在肝脏中产生的蛋白，它的作用是抑制脂蛋白脂肪酶 ( LPL) 和内皮脂肪酶 (EL)。这两种酶负责分解富含甘油三酯的脂蛋白颗粒。当ANGPTL3水平升高时，它会抑制这些酶的活性，导致甘油三酯和胆固醇（包括LDL-C）在血液中堆积。反之，如果能降低ANGPTL3的水平，就能加速血脂的清除。针对ANGPTL3靶点，再生元公司的Evinacumab（依维苏单抗）于2021年获FDA批准上市，它是一种靶向ANGPTL3的全人源单克隆抗体，被批准用于治疗纯合子家族性高胆固醇血症（HoFH）患者。在研药物中，Arrowhead的Zodasiran是一种靶向ANGPTL3的RNA干扰(RNAi)药物，通过特异性降解ANGPTL3的mRNA，抑制肝脏中ANGPTL3的合成和分泌，从而降低血液中ANGPTL3的水平，改善脂质代谢。在一项II期ARCHES-2研究中，纳入204例混合型高脂血症成人患者，3:1随机分为Zodasiran组(50、100或200mg)或安慰剂组治疗，结果在第24周时，与安慰剂组相比，Zodasiran组的TG水平呈显著的剂量依赖性降低，Zodasiran50、100和200mg组的平均TG降幅分别达51%、57%和63%(P均<0.001)。与安慰剂组相比，Zodasiran组的ANGPTL3水平呈剂量依赖性降低，且与TG水平密切相关，Zodasiran50、100和200mg组的平均ANGPTL3降幅分别达54%、70%和74%。Zodasiran有望成为治疗混合型高脂血症的新选择，特别是对于那些对现有治疗反应不佳的患者。ApoC3ApoC3（载脂蛋白C3）主要在肝细胞中表达，可通过抑制脂蛋白脂肪酶（LPL）活性来增加血浆中甘油三酯水平；同时，通过干扰低密度脂蛋白受体对富含甘油三酯的脂蛋白（TRLs）及其残余物的清除来增加甘油三酯和胆固醇水平。因此，ApoC3可作为降血脂和心血管疾病的新兴靶点。针对ApoC3靶点，目前已获批上市药物有Akcea/Ionis的Waylivra（Volanesorsen）和Tryngolza（Olezarsen）。Volanesorsen是一种反义寡核苷酸（ASO）药物，于2019年5月获EMA批准上市，用于家族性乳糜微粒血症综合征（FCS）成年患者控制饮食之外的辅助疗法，FCS由LPL功能受损引起，患有FCS的患者可能出现严重的高甘油三酯血症和甘油三酯诱发的胰腺炎风险升高。Olezarsen也是由Ionis公司研发，同样是一款ASO疗法，旨在抑制机体产生ApoC3蛋白。FDA于2024年2月授予该疗法孤儿药资格和突破性疗法认定（BTD），并在12月批准其用于作为饮食控制的辅助治疗，以降低FCS成人患者的甘油三酯。在研产品方面，国内维亚臻生物的同类首创ApoC3 siRNA?疗法VSA001，于今年3月在中国FCS患者中的 III 期临床试验获得积极顶线数据，成功达到主要疗效终点和所有关键次要终点。已在国内报上市。瑞博生物的RBD5044，是全球第二个进入临床研究的靶向ApoC3 的siRNA管线，主要用于降血脂。其基于公司独有的RIBO-GalSTARTM肝靶向技术平台开发，通过siRNA介导ApoC3 基因沉默，能够高效、精准且持久地降低血浆中ApoC3 蛋白水平。与肿瘤、自免等热门疾病赛道相比，心血管疾病药物在市场端的优势十分明显，该领域盛产重磅炸弹药物。比如早期的立普妥，在2011年专利到期前，就累计为辉瑞创收超1400亿美元。即便专利到期后，立普妥仍然占据重要市场份额。还有小核酸药物乐可为，上市三年即步入重磅炸弹药物行列。因此，拿下一款心血管疾病重磅药物，意味着药企业绩基本有了保障。因此该赛道的竞争，激烈无比。以上是几个比较成熟的新兴靶点，有些尚无对应药物获批上市，谁能在这些新靶点中抢占先发优势，对业绩的增长将不可估量。参考来源：       1.Global burden of cardiovascular diseases: projections from 2025 to 2050. Eur J Prev Cardiol. doi: 10.1093/eurjpc/zwae281.?       2.https://doi-org.libproxy1.nus.edu.sg/10.1056/NEJMoa2415818。       3.Kaasenbrood L, Boekholdt SM, van der Graaf Y, et? al. Distribution of estimated 10-year risk of recurrent vascular.       4.Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3):?a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet.       5.https://ir.ionis.com/news-releases/news-release-details/ionis-announces-positive-topline-results-essence-study-olezarsen.END【企业推荐】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~

Company further extends cash guidance into 2028 LONDON--(BUSINESS WIRE)-- Silence Therapeutics plc, Nasdaq: SLN (“Silence” or “the Company”), a global clinical-stage company developing novel siRNA (short interfering RNA) therapies, today reported its financial results for the first quarter ended March 31, 2025, and reviewed recent business highlights. “Silence delivered another strong quarter focused on clinical and operational execution,” said Craig Tooman, President and Chief Executive Officer at Silence. “We remain focused on advancing enrollment into the SANRECO Phase 2 study of divesiran, a first-in-class siRNA program in PV, and continue to be on-track to complete enrollment by the end of this year. We are also looking forward to sharing additional results from the Phase 1 portion of the SANRECO study during an oral presentation at EHA next month.” Rhonda Hellums, Chief Financial Officer at Silence, added, “We ended the first quarter with over $136 million in cash, cash equivalents, and short-term investments. To maintain a healthy financial position while prioritizing the advancement of our core PV program, we are implementing cost savings initiatives and further extending our cash guidance into 2028. We remain committed to realizing the vast potential of our proprietary mRNAi GOLD™ platform and will continue to invest prudently in areas where we see the greatest opportunity to enhance value to Silence stakeholders.” First Quarter 2025 & Recent Business Highlights Divesiran for Polycythemia Vera (PV) Additional Phase 1 results from the SANRECO study of divesiran in PV patients have been accepted for oral presentation during the European Hematology Association (EHA) 2025 Annual Congress being held in Milan, Italy from June 12 – 15, 2025. Advanced patient enrollment into the Phase 2 portion of the SANRECO study of divesiran in PV patients and remain on-track to complete enrollment by year-end 2025. Zerlasiran for Cardiovascular Disease Advanced core Phase 3 readiness activities, including manufacturing and supply scale up, which remain on-track to complete by mid-2025. Partnering discussions for potential Phase 3 development are ongoing. Collaborations A Phase 1 study of SLN312 (licensed to AstraZeneca) is ongoing. Corporate Updates Appointed Tim McInerney to the Company’s Board of Directors, effective May 5, 2025. Mr. McInerney is a seasoned executive and board member with over 30 years of experience in both the investment and pharmaceutical industries. First Quarter 2025 Financial Highlights Cash Position: Cash and cash equivalents, and short-term investments of $136.5 million as of March 31, 2025, compared with $147.3 million as of December 31, 2024. R&D Expenses: Research and development (R&D) expenses were $20.8 million, an increase of $9.0 million compared to the first quarter of 2024. The increase was primarily due to the advancement of our clinical trials and an increase in manufacturing activities for our proprietary programs. G&A Expenses: General and administrative (G&A) expenses were $7.7 million, an increase of $1.0 million compared to the first quarter of 2024. The increase is primarily due to the cost of additional reporting and compliance requirements in connection with our transition to becoming a domestic issuer and large accelerated filer. Net Loss: Net loss was $28.5 million, or $0.20 basic and diluted net loss per share, compared to a net loss of $2.3 million, or $0.02 basic and diluted net loss per share for the first quarter of 2024. Total ADSs outstanding were approximately 47,230,283 as of March 31, 2025. Updates to 2025 Financial Guidance Silence has implemented cost savings initiatives to strengthen its financial position and further extend its cash runway into 2028. These measures include general and administrative reductions, as well as further prioritizing early-stage research projects and resources. The Company remains committed to realizing the vast potential of its proprietary mRNAi GOLD™ platform and will continue to invest prudently in key areas focused on enhancing value to Silence stakeholders. About Silence Therapeutics Silence Therapeutics is a global clinical-stage biotechnology company committed to transforming people’s lives by silencing diseases through precision engineered medicines created with proprietary siRNA (short interfering RNA) technology. Silence leverages its mRNAi GOLD™ platform to create innovative siRNAs designed to precisely target and silence disease-associated genes in the liver, which represents a substantial opportunity. Silence focuses on areas of high unmet medical need with programs advancing in cardiovascular disease, hematology and rare diseases. For more information, please visit https://www.silence-therapeutics.com/. Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. In some cases, you can identify forward-looking statements by terminology such as “aim,” “anticipate,” “assume,” “believe,” “contemplate,” “continue,” “could,” “design,” “due,” “estimate,” “expect,” “goal,” “intend,” “may,” “objective,” “plan,” “positioned,” “potential,” “predict,” “seek,” “should,” “target,” “will,” “would” and other similar expressions that are predictions of or indicate future events and future trends, or the negative of these terms or other comparable terminology. All statements other than statements of historical facts contained in this press release are forward-looking statements. These forward-looking statements include, but are not limited to, statements about: the Company’s business strategy and plans, including the Company’s clinical development activities and timelines; the progression and advancement of collaborations; the expected benefits of the Company’s cost saving initiatives; the Company’s ability to enhance stakeholder value; and the Company’s anticipated extended cash runway. Forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that could cause actual results and events to differ materially from those anticipated, including, but not limited to, risks and uncertainties related to: the company’s history of net operating losses; the company’s ability to obtain necessary capital to fund its clinical programs; the early stages of clinical development of the company’s product candidates; the company’s ability to obtain regulatory approval of and successfully commercialize its product candidates; any undesirable side effects or other properties of the company’s product candidates; the company’s reliance on third-party suppliers and manufacturers; the outcomes of any future collaboration agreements; and the company’s ability to adequately maintain intellectual property rights for its product candidates. These and other risks are described in greater detail under the section titled “Risk Factors” contained in the company’s Annual Report on Form 10-K and Quarterly Reports on Form 10-Q and the company’s other filings with the SEC. Any forward-looking statements that the Company makes in this press release are made pursuant to the Private Securities Litigation Reform Act of 1995, as amended, and speak only as of the date of this press release. Except as required by law, the company undertakes no obligation to publicly update any forward-looking statements, whether as a result of new information, future events or otherwise. Silence Therapeutics plc Condensed Consolidated Balance Sheets (Unaudited, in thousands, except share and per share data) Period ended March 31, 2025 December 31, 2024 Current assets Cash and cash equivalents $ 64,886 $ 121,330 Short-term investments 71,648 26,004 R&D benefit receivable 16,796 24,396 Other current assets 16,419 14,664 Trade receivables 41 972 Total current assets 169,790 187,366 Property, plant and equipment 1,693 1,818 Operating lease right-of-use assets 107 157 Goodwill 9,784 9,392 Other intangible assets 310 312 Other long-term assets 3,614 3,590 Total assets $ 185,298 $ 202,635 Current liabilities Contract liabilities $ (392 ) $ (306 ) Trade and other payables (18,812 ) (16,399 ) Operating lease liabilities, current (60 ) (117 ) Total current liabilities (19,264 ) (16,822 ) Contract liabilities (53,291 ) (51,790 ) Total liabilities $ (72,555 ) $ (68,612 ) Commitments and contingencies (Note 20) Shareholders’ equity Ordinary shares - par value £0.05 per share; 141,690,850 shares issued at March 31, 2025 (December 31, 2024: 141,674,074) (10,289 ) (10,288 ) Additional paid-in capital (613,074 ) (609,560 ) Accumulated deficit 502,536 474,044 Accumulated other comprehensive loss 8,084 11,781 Total shareholders' equity (112,743 ) (134,023 ) Total liabilities and shareholders' equity $ (185,298 ) $ (202,635 ) Silence Therapeutics plc Condensed Consolidated Statements of Operations and Comprehensive Loss (Unaudited, in thousands, except share and per share data) Three months ended March 31, 2025 2024 Revenue $ 142 $ 15,699 Cost of sales (54 ) (2,800 ) Gross profit 88 12,899 Research and development costs (20,813 ) (11,845 ) General and administrative expenses (7,684 ) (6,635 ) Operating loss (28,409 ) (5,581 ) Foreign currency (loss)/gain, net (3,769 ) 351 Other income, net 969 667 Benefit from R&D credit 2,679 2,495 Loss before income tax expense (28,530 ) (2,068 ) Income tax expense — (244 ) Net Loss $ (28,530 ) $ (2,312 ) Loss per share (basic and diluted) $ (0.20 ) $ (0.02 ) View source version on businesswire.com: https://www.businesswire.com/news/home/20250508742900/en/ Inquiries: Silence Therapeutics plc Gem Hopkins, VP, IR and Corporate Communications ir@silence-therapeutics.com Tel: +1 (646) 637-3208 Source: Silence Therapeutics plc