Volanesorsen

1998年，第一个被批准用于疾病治疗的反义寡核苷酸（ASO）药物Fomivirsen上市，成功实现技术破冰。经过二十多年的发展，全球已有12款ASO药物成功获批上市，其中不乏年销售额超20亿美元/年的重磅炸弹药物Nusinersen。值得注意的是，目前国内药企尚无自研的ASO药物获批上市。小核酸药物赛道蓄势待发，谁将拿下国产首款ASO药物？01ASO药物特点及市场表现反义寡核苷酸（ASO），是化学合成的单链核苷酸分子，通常为13-30个核酸序列的短片段（故称为“寡核苷酸”），这一核酸序列被设计成为与靶向基因序列互补（故称为“反义”），通过沃森-克里克（Watson-Crick）碱基配对的方式与特异的RNA序列结合，并在生物信息学指导下通过精心设计，使该核苷酸片段对目标RNA具有高度的特异性作用，从而达到基因靶向治疗的目的。1998年获批上市的Fomivirsen，是第一个被批准用于疾病治疗的反义寡核苷酸药物，但由于同时期其他抗艾滋病药物竞品的强竞争，2002年、2006年分别退出欧洲及美国市场。总的来说，首个上市的ASO药物，在技术上实现了破冰，但市场遭遇滑铁卢。后，如2013年上市的Defibrotide，展现了一定的市场表现，且至今仍是近2亿美元的抗栓品种。令人备受关注的ASO药物，当属Nusinersen。2016年上市的Nusinersen（诺西那生（钠））无疑是ASO类药物绝对的明星品种和热议品种，2019-2020年的全球销售额已超过了20亿美元/年，2021-2022年略下降，但也是＞17亿美元的重磅品种。值得一提的是，该品种曾因我国“国谈”，由天价78万直降至3.3万，在解决国内临床用药可及的同时扩大了ASO药物的应用场景和影响力。另，ASO类药物除了市场份额外，同步关注较高的一个属性就是药品价格。除了上述的78万元天价药，其他获批上市的ASO药物，也是伴随着高附加值。如2018年上市的Inotersen，以法国地区为例，单价≈2万欧元/284mg，2019年上市的Volanesorsen，单价为＞1万欧元/285mg。总的来说，小核酸ASO药物的药价附加值极高。图1 Nusinersen全球销售额（单位：万元人民币）图片来源：药智数据021998-2023，ASO获批上市12款使用化学合成寡核苷酸来互补阻断基因表达的概念始于20世纪70年代，由Paul Zamecnik进行的研究。此后，在寡核苷酸中引入了各种化学修饰，使其对核酸酶具有抗性，从而诞生了第一代ASOs的发展。自动化寡核苷酸合成器的引入进一步推进了寡核苷酸的合成。此外，第一代ASOs的局限性促进了第二代和第三代ASOs的发现与开发，这些ASOs具有对核酸酶更强的抗性、更好的稳定性和更优的药代动力学。图2 ASO治疗领域取得重要进展的时间轴图片来源：Medicine in Drug Discovery 20(2023)100166如上所述，首个上市的小核酸ASO药物是Fomivirsen，并以此在1998-2023年期间共计约12款ASO获批上市。时间节点来看，1999-2012的14年期间，无ASO后继产品获批，而2013年后ASO产品获批上市状态骤升，11年间共计上市11款ASO药物。适应症来看，小核酸ASO药物主要集中于遗传性疾病，如杜氏肌营养不良症就有4款ASO药物获批，以及其他遗传性疾病如脂蛋白脂肪酶缺乏症、脊髓型肌萎缩症，等等。开发公司，技术集中于几家龙头企业，如Ionis、Sarepta Therapeutics、Akcea Therapeutics、Nippon Shinyaku等，尤其是Ionis共计开发上市了6款ASO药物，是ASO领域乃至小核酸药物领域的绝对先行者，另，Sarepta Therapeutics同样贡献了3款ASO药物，同为第一梯队。表1 全球上市的小核酸ASO药物数据来源：公开信息统计03国内ASO药物开发企业举例目前，国内药企尚无自研的ASO药物获批上市，但已有多家申办方选择引进或自研的方式来开发ASO药物，且中美双报的申报方式也是使用的较多。下面对部分企业的品种进行举例介绍。➣CT102据公开信息显示，CT-102是杭州天龙药业有限公司与军事医学科学院联合开发的抗肝癌1.1类新药，该产品实现了我国首个反义寡核酸药物走入临床。其结构是长度为20个核苷酸的硫代脱氧寡核苷酸钠盐，机制是以人胰岛素样生长因子1型受体（IGF1R）信使核糖核酸（mRNA）为靶点，通过反义作用抑制IGF1R的活性，从而导致肿瘤细胞凋亡或诱导其分化，达到治疗疾病的目的。PS：II期临床题目为《评价注射用CT102治疗原发性肝癌的安全性、有效性和药物代谢动力学的非随机、开放性Ⅱa期临床试验》。➣HC0301据公司官网介绍，HC0301是以海昶生物QTsomeTM核酸递送技术包裹的Archexin形成的一种全新的AKT-1反义寡核苷酸的脂质纳米颗粒混悬液。目前正在美国进行Ⅰ期晚期实体瘤的剂量爬坡临床研究（NCT05267899），已经接近尾声，并且显示出非常好的安全性和疗效。根据一系列临床前研究和初步的临床研究数据可知HC0301有望成为一种新的晚期HCC的治疗策略，值得进一步研究。➣AHB-137AHB-137，是浩博医药（Ausper Bio）开发的一种用于治疗慢性乙型肝炎、有潜力成为Best-in-class的裸露ASO，是首个用于临床试验的寡核苷酸技术平台Med-Oligo™产品，有望成为功能性治愈乙型肝炎的基石。PS：国内I期临床试验题目为《评价AHB-137在健康受试者、慢性乙型肝炎患者中随机、双盲、安慰剂对照的多剂量、单次给药、多次给药的耐受性、药代动力学及药效学I期临床试验》。04ASO药物机制&修饰&待解决的问题首先，从机制来说，与目标基因结合后的反义寡核苷酸通过几种不同的作用机制来调节目标mRNA的功能，其中最常见的作用机制包括：1）通过激活内源性RNA酶促反应而促进对目标mRNA的消化降解；2）通过调节目标pre-mRNA的剪接模式从而改变目标RNA终极蛋白产物表达，这包括外显子跳跃和外显子保留。如，Fomivirsen、Mipomersen和Inotersen都是通过对目标mRNA的切割降解而达到降低与疾病相关的mRNA及其蛋白质产物的表达。图3 反义寡核苷酸的作用机制图片来源：Medicine in Drug Discovery 20(2023)100166其次，结构修饰，尤其是化学修饰。ASO药物经历了多代次的结构修饰，第一代RNA改造策略聚焦于磷酸骨架改造，硫代磷酸（PS）改造是目前最基础的化学修饰；第二代结构修饰策略主要围绕核糖2'-羟基位点进行修饰。常见方案包括将2ʹ-羟基（2ʹ-OH）替换成2ʹ-甲氧乙氧基（2ʹ-MOE）、2ʹ-甲氧基（2ʹ-O-Me）、2ʹ-氟（2ʹ-F）等结构；第三代RNA改造策略是通过改造核糖结构合成核酸类似物，常见修饰方案包括锁核酸（LNA）、肽核酸（PNA）和PMO等。虽然RNA改造已历经多次迭代，其体内耐受仍不理想，还需进一步开发新策略。图4 反义寡核苷酸中常用的化学修饰类型举例图片来源：Medicine in Drug Discovery 20(2023)100166再次，就是在上述机制、修饰的基础上，以及在部分已解决的递送难题的基础上，仍须进一步考虑适应症、安全性、有效性、成药性等问题，以扩大药物应用场景和使用方式。如适应症主要集中于遗传性疾病、罕见病等领域，范围略窄；安全性方面如这类药物容易存在的免疫药性反应、肝肾毒性、血液毒等共性问题；有效性方面如何形成独特且高效的BIC；成药性方面如何形成更多手段的给药方式以及更优的药代动力学等等。同时，从竞争角度来看，ASO药物虽然在小核酸领域的发展总体靠前，但更加丰富的小核酸药物类别正在快速研发中，要关注其他类别小核酸药物的兴起导致对ASO的颠覆性冲击。参考来源：1.药智数据Medicine in Drug Discovery 20(2023)1001663.http://www.hztljt.com/about.html4.http://www.zhejianghaichang.com/news_detail_zh/id/53.html5.http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml声明：本内容仅用作医药行业信息传播，为作者独立观点，不代表药智网立场。如需转载，请务必注明文章作者和来源。对本文有异议或投诉，请联系maxuelian@yaozh.com。责任编辑 | 橙色转载开白 | 马老师 18996384680（同微信）商务合作 | 王存星 19922864877（同微信） 阅读原文，是受欢迎的文章哦

WAINUA™ approved with launch underway; on track for EU and Canada approval decisions this year Positive Phase 3 olezarsen and donidalorsen data, preparing regulatory submissions for FCS and HAE, respectively Olezarsen granted Breakthough Therapy designation by the FDA for FCS Ionis provides full year 2024 financial guidance CARLSBAD, Calif., Feb. 21, 2024 /PRNewswire/ --Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the "Company"), today reported financial results for the fourth quarter and full year ended December 31, 2023. "This past year included many remarkable achievements as we continued to advance our vision to bring better futures to people with serious diseases. Ionis achieved two FDA approvals, delivered three positive Phase 3 data readouts, expanded our rich Phase 3 pipeline to nine medicines and advanced our next wave of wholly owned medicines as well as our technology," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "In 2024, we anticipate building on our success with important catalysts and continued value creation. The WAINUA U.S. launch is underway for patients with hereditary ATTR polyneuropathy, and we expect additional approvals in other countries this year. We plan to present positive Phase 3 data for olezarsen in familial chylomicronemia syndrome and donidalorsen in hereditary angioedema, positioning Ionis to independently launch these two medicines. We also anticipate additional readouts from multiple mid-stage programs that, if positive, would advance into Phase 3 development, further strengthening our ability to deliver a steady cadence of potentially transformational medicines for years to come." Fourth Quarter and Full Year 2023 Summary Financial Results(1): Financial Highlights Revenue more than doubled for the fourth quarter of 2023 compared to the same period in the prior year and increased 34% for the full year, driven by the successful progression of Ionis' pipeline and technology platform Operating expenses increased compared to the prior year, primarily due to strategic investments to bring eplontersen, olezarsen and donidalorsen to patients 2023 operating loss significantly improved over prior year due to substantial revenue earned during the year Cash and short-term investments of $2.3 billion as of December 31, 2023 enables continued investments to drive increasing value, including supporting our potential upcoming launches Recent Marketed Medicines Highlights WAINUA approved in the U.S., resulting in a $50 million milestone payment from AstraZeneca; launch underway for treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) SPINRAZA continued to be the global market leader for the treatment of spinal muscular atrophy (SMA) with global sales of $1.7 billion in 2023 Recent Late-Stage Pipeline Highlights Eplontersen granted Fast Track designation by the FDA for the treatment of patients with ATTR cardiomyopathy (ATTR-CM) Olezarsen granted Breakthrough Therapy designation by the FDA for the treatment of patients with familial chylomicronemia syndrome (FCS) Olezarsen granted orphan drug designation by the FDA for the treatment of patients with FCS Achieved multiple milestones with donidalorsen for the treatment of patients with hereditary angioedema (HAE): Reported positive topline data from the Phase 3 OASIS-HAE study in patients treated every four weeks or every eight weeks; preparing to submit NDA Licensed European donidalorsen commercialization rights to Otsuka; Otsuka preparing to submit MAA Donidalorsen granted orphan drug designation by EMA Reported positive Phase 2 data from the open label extension study in patients with HAE treated for two years Bepirovirsen granted fast track designation by the FDA for the treatment of patients with chronic hepatitis B (CHB) Recent Other Pipeline Highlights Achieved multiple milestones with ION582 (BIIB121) for the treatment of patients with Angelman syndrome: Completed enrollment in the Phase 1/2 HALOS study in patients with Angelman syndrome; on track for data readout in mid-2024 Presented positive clinical update from ongoing HALOS study at the FAST (Foundation for Angelman Syndrome Therapeutics) Summit Extended the long-term extension portion of HALOS study Sapablursen and ION356 granted fast track designation by the FDA for the treatment of patients with polycythemia vera (PV) and Pelizaeus-Merzbacher disease (PMD), respectively Initiated the Phase 1/2 PrPro of ION717 in patients with Prion disease AstraZeneca licensed ION826 for the treatment of heart failure, resulting in a $36 million payment from AstraZeneca Recent Technology Advancement Highlights Licensed Vect-Horus' blood-brain barrier crossing technology for the development of RNA-targeted neurological disease medicines Fourth Quarter, Full Year 2023 Financial Results and 2024 Financial Guidance "In 2023, we earned substantial revenues due to continued success with our pipeline and technology. As a result, we exceeded our 2023 revenue guidance, which drove a smaller than anticipated operating loss," said Elizabeth L. Hougen, chief financial officer of Ionis. "In 2024, with WAINUA's launch for ATTRv-PN underway, we are adding a new stream of royalty revenue to our substantial and sustained revenues. We will continue to deploy our capital resources toward growth opportunities that can enable Ionis to unlock next-level value. This includes continuing to make significant investments in near-term commercial opportunities, the expansion of our wholly owned pipeline, and advancing our technology, all of which should empower future growth." Revenue Ionis' revenue was comprised of the following: Commercial revenues in 2023 were comparable to 2022. Commercial revenue for 2023 included $240 million from SPINRAZA royalties, which was comparable to 2022. Ionis' commercial revenue in 2023 also included royalties from QALSODY U.S. product sales. R&D revenue significantly increased in 2023 compared to 2022 primarily due to continued success with Ionis' pipeline and technology. As a result, Ionis earned significant partner payments, including $50 million from AstraZeneca for the FDA approval of WAINUA for ATTRv-PN in the U.S., $36 million from AstraZeneca for licensing ION826 and payments from Ionis' new collaborations with Otsuka, Roche and Novartis. Operating Expenses Ionis' operating expenses increased for the year ended December 31, 2023 compared to 2022 primarily due to certain one-time costs, including a non-cash charge associated with a lease exit and the license fee Ionis paid to Vect-Horus. As Ionis advanced its robust pipeline, study costs increased compared to the same periods in 2022 as many of the Company's Phase 3 studies are either fully enrolled or approaching full enrollment, resulting in higher R&D expenses year over year. R&D expenses for the fourth quarter of 2023 were lower compared to the fourth quarter of 2022, primarily due to the $80 million upfront payment Ionis paid to Metagenomi in 2022. Ionis' SG&A expenses increased year over year primarily due to launch preparation activities for WAINUA, olezarsen and donidalorsen. Balance Sheet As of December 31, 2023, Ionis' cash, cash equivalents and short-term investments increased to $2.3 billion compared to $2.0 billion at December 31, 2022 primarily due to the $500 million Ionis received from Royalty Pharma in January 2023 and significant partner payments throughout 2023. Ionis' working capital also increased over the same period primarily due to the Company's higher cash and short-term investments balance. In 2023, the Company recorded a long-term liability for future royalties due to Royalty Pharma. In June 2023, Ionis issued $575 million of senior convertible notes due in June 2028 with an interest rate of 1.75%. The Company used the majority of the proceeds to repurchase $504 million of its 0.125% convertible notes. 2024 Financial Guidance The Company's 2024 guidance reflects its plan to deploy its capital resources toward growth opportunities, including continued investments in its near-term commercial opportunities, expanding its wholly owned pipeline and advancing its technology platform. Additionally, the Company expects to continue earning substantial revenue from its commercial portfolio and partnered programs. Webcast Management will host a conference call and webcast to discuss Ionis' fourth quarter and full year 2023 results at 11:30 a.m. Eastern time on Wednesday, February 21, 2024. Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address. To access the Company's fourth quarter and full year 2023 earnings slides click here. For more information about SPINRAZA and QALSODY, visit and , respectively. QALSODY is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s). INDICATION for WAINUA™ (eplontersen) WAINUA injection, for subcutaneous use, 45 mg is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. IMPORTANT SAFETY INFORMATION for WAINUA™ (eplontersen) WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ADVERSE REACTIONS Most common adverse reactions (≥9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%). Please see link to U.S. Full Prescribing Information for WAINUA. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has five marketed medicines and a leading pipeline in neurology, cardiology, and other areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionispharma.com and follow us on X (Twitter) and LinkedIn. Ionis' Forward-looking Statement This press release includes forward-looking statements regarding Ionis' business, financial guidance and the therapeutic and commercial potential of our commercial medicines, additional medicines in development and technologies. Any statement describing Ionis' goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis' forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis' forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2022, and most recent Form 10-Q, which are on the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, "Ionis," "Company," "we," "our" and "us" all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics® is a registered trademark of Akcea Therapeutics, Inc. TEGSEDI® is a registered trademark of Akcea Therapeutics, Inc. WAYLIVRA® is a registered trademark of Akcea Therapeutics, Inc. QALSODYTM is a trademark of Biogen. SPINRAZA® is a registered trademark of Biogen. WAINUATM is a registered trademark of the AstraZeneca group of companies. *In October 2022, Ionis entered into a sale and leaseback transaction for several of its real estate assets. As a result, the Company recognized a $150 million gain on sale of real estate assets in the fourth quarter of 2022. The Company excluded the gain on sale of real estate assets and the related tax effect from its non-GAAP amounts for the applicable periods. Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP income (loss) from operations, and non-GAAP net income (loss) were adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. In 2022, Ionis' non-GAAP net loss excluded the gain on real estate assets related to the sale and leaseback transaction and the related tax effects. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis' non-GAAP results is consistent with how Ionis' management internally evaluates the performance of its operations. Key 2024 Value Driving Events(1) Company Codes: NASDAQ-NMS:IONS