Olezarsen

Arrowhead Pharmaceuticals has unveiled highly anticipated pancreatitis results from a late-phase trial of plozasiran for a rare lipid disorder, several months after reporting topline data. Arrowhead has been putting a lot of effort into its siRNA candidate to the point that it shelved another asset , zodasiran, so it could focus on getting plozasiran to market. The company is in a development race with Ionis Pharmaceuticals which has its own RNA-based therapeutic for lipid diseases. In a key secondary endpoint of the 75-participant Phase 3 PALISADE trial in familial chylomicronemia syndrome (FCS), less than 5% of patients taking plozasiran had an acute pancreatitis event at 12 months compared with 20% of the placebo cohort, according to results presented Monday at the European Society of Cardiology annual meeting in London. The numbers work out to an 83% relative risk reduction in the instance of positively adjudicated pancreatitis, PALISADE principal investigator Gerald Watts told Endpoints News in an interview ahead of the meeting. In contrast, Ionis’ antisense oligonucleotide olezarsen cut acute pancreatitis events by 100% in the Phase 3 BALANCE trial in FCS, according to data unveiled a year ago. Updated results from April showed there was one episode of acute pancreatitis in the 80 mg olezarsen group and another in the 50 mg cohort. The pancreatitis data are important because these events can be life-threatening for patients with FCS and lead to hospitalization. But Ionis and Arrowhead’s respective trials tested patients with different histories of pancreatitis at baseline, Watts said. In Arrowhead’s trial, 89% of patients taking 25 mg plozasiran and 92% of patients taking 50 mg plozasiran had a previous episode of pancreatitis. Meanwhile, Ionis’ trial was designed to enroll at least 65% of patients with a history of pancreatitis. Robert Rosenson, PALISADE investigator and the cardiometabolics unit director of Mount Sinai Hospital, said it is difficult to differentiate between Arrowhead and Ionis’ results because the reduction in acute pancreatitis was “dramatic” in both trials. Rather, the main difference between the drugs that could influence physician and patient preference is frequency of dosing, Rosenson told Endpoints in an interview. Plozasiran is administered every three months while olezarsen is given every four weeks. “In patients with chronic illness, we know that less frequent dosing results in greater long-term adherence to therapy,” Rosenson said. Elsewhere, while it is difficult to compare data across trials, plozasiran seems to be associated with a greater reduction in triglycerides than olezarsen, Watts said. Plozasiran met the PALISADE primary endpoint as announced in June, with 25 mg and 50 mg doses attaining 80% and 78% median reductions in triglycerides at 10 months, respectively, compared with 17% for placebo. The drug also met all key secondary endpoints, including a change from baseline in levels of APOC3, which plays a key role in slowing the clearance of triglycerides. At the time, Arrowhead CEO Christopher Anzalone described the plozasiran data as “best in class.” Meanwhile, In BALANCE, 80 mg olezarsen achieved a 59% placebo-adjusted reduction in triglyceride levels at 12 months (p<0.001). People with FCS lack or have very little of an enzyme called lipoprotein lipase which is responsible for clearing triglycerides from the blood. These triglycerides can then build up to more than ten times the normal amount. The only option available for patients is to follow an extremely low-fat diet. Arrowhead is working on regulatory filings for plozasiran in FCS. In April, GlobalData analysts said plozasiran could hit $707 million in sales in 2032. However, current peak sales expectations may need to be adjusted to take into account the candidate’s potential in severe hypertriglyceridemia (SHTG), which affects around 3.4 million people in the US, TD Cowen analyst Brendan Smith told Endpoints in an interview ahead of the meeting. The drug has the potential to move from an ultra-orphan indication to a much broader dyslipidemia market, he added. Plozasiran hit the primary endpoint in a Phase 2b trial of patients with SHTG back in April and is currently being tested in a pair of Phase 3 studies in the disease called SHASTA-3 and SHASTA-4. Editor’s note: This article was updated to add a doctor’s comments, more context on the registrational olezarsen data and to correct plozasiran’s mechanism of action.

当前在售的16款小核酸药物（共19款上市，3款已退市）中，目前针对的适应症主要是针对于罕见病。但是随着中国企业的异军突起，近两年来小核酸领域给RNAi赛道带来了除传统罕见病以外，在慢病领域小核酸药品更多突破的可能。 以诺华的Leqvio（Inclisiran）为例，作为靶向PCSK9的siRNA药物在2021年获批以后，由于其每年只需两次皮下给药，就能防止肝脏生成PCSK9蛋白，从而降低低密度脂蛋白胆固醇（LDL-C）水平。虽然价格昂贵（美国定价3250美元/针，中国定价9988元/针），但是相较于安进同靶点的单抗药（一针300元，每月两次），大大提升了患者的依从性从而更好的控制血脂。也因此，这款产品在今年上半年全球销售额3.33亿美元，同比增长了135%。 LDL-C降解途径及PCSK9作用机理 就治疗三高的药物而言，低密度脂蛋白胆固醇（LDL-C）被视为动脉粥样硬化性心血管疾病血脂干预的首要靶点，但越来越多的试验数据和真实世界研究表明，即使LDL-C控制在最佳范围内，心血管事件的风险仍旧存在。因此，新的研究发现加上生物技术的发展，为血脂管理提供了新的途径，新兴降脂治疗靶点不断涌现，新兴长效靶点包括APOC3、LP(a)、ANGPTL等的新疗法已进入临床开发阶段，并取得了积极的治疗效果。 针对三高疾病的跨国药企小核酸药物管线进展 数据来源于各跨国药企公开数据 GLP-1目前被视为目前减肥与降糖领域的明星产品，即便是长效GLP-1的注射频率也只能达到一周一次，然而当INHBE被正式确认为肥胖症的重要靶点，包括再生元、Alnylam、Arrowhead在内的小核酸行业龙头都在积极布局INHBE靶向小核酸药物，以期能在更长效的作用上解决减肥与降糖问题。当然，Olezarsen被视为慢病领域的下一个爆款小核酸产品，在达到三期临床的主要终点后，FDA在今年6月接受Ionis的Olezarsen治疗家族性高乳糜微粒血症综合征（FCS）的NDA申请，其靶向肝脏APOC III，有效抑制甘油三酯的合成，同时FDA授予其优先审查资格，PDUFA日期为2024年12月19日。礼来的Lepodisiran（LY3819469）靶向Lp(a)的小核酸药物也在今年三月启动了包含中国在内的国际多中心3期临床，当然，除此以外的安进、GSK、诺和诺德、武田制药等国际大厂也积极以合作开发或收购管线的形式布局小核酸赛道。 近两年，国内的企业也纷纷发力除罕见病以外的赛道，诺华以超41亿美元的代价引进舶望制药多款治疗心血管等慢病的RNAi疗法的管线的全球商业化许可，瑞博生物以20亿美元，license out NASH/MASH适应症的管线给BI，都展现了小核酸药物火热的市场前景。 2023年全球在售的16款小核酸药物销售额 数据来源于公开数据 从2023年的销售额排名来看，Biogen/Ionis旗下的Spinraza虽然销售额存在小幅下降，但依然凭借全球首个脊髓性肌萎缩症（SMA）治疗药物以及全世界最贵小核酸的头衔牢牢占据第一排名，市场的高认可度与高定价使其销售额远超第二、三、四名之和。而Leqvio高达217%的增长率，更体现了SiRNA疗法未来在慢病领域的广阔前景。 据弗若斯特沙利文数据显示，小核酸药物全球市场规模从2016年0.1亿美元已增长至2021年32.5亿美元，年复合增长率高达217.8%。目前仍在市场的有9款ASO、6款siRNA药物，一款核酸适配体药物。已上市的小核酸市场份额高度集中，Sarepta、Ionis和 Alnylam各雄踞一方，Sarepta和 Ionis基本瓜分了ASO产品市场，而Alnylam近乎垄断siRNA药品市场。诚然，与双抗、ADC等药物市场相比，小核酸药物现有市场规模不算大，但近5年来，小核酸药物市场保持双位数增长的良好势头，市场体量从2018年的20亿美元扩充至2023年的43.2亿美元，且维持至少每年两款小核酸上市频率在持续扩充产品阵容。 除了赛道拥挤的降脂与罕见病赛道，国内其他小核酸药物公司也在包括乙肝、肺部疾病、肿瘤癌症以及CNS赛道有深度布局。布局乙肝的包括博望、瑞博、施能康、浩博、腾盛博药、星曜坤泽等均已进入了临床期间。而在肿瘤赛道，圣诺、中美瑞康、海昶、悦康等已经进入了IND，除此以外CNS领域也是目前国内众多企业突破的重点。 由此，2024年8月22日(周四)14:00~16:15，Cytiva思拓凡将携手佰傲谷举办主题为”小核酸,大赛道——小核酸药物开发全链路分享“的线上研讨会,届时欢迎大家积极报名参与。 议程安排 扫码预约报名 14:00~14:45 演讲主题 小核酸药物产业发展和核心物料的策略分析 演讲大纲 -小核酸药物发展前沿和商业化分析 -小核酸药物制备中的核心原料 -小核酸药物制备中的关键技术 讲师介绍 蔡坤，中国科学技术大学生物化学与分子生物学博士，现任上海兆维科技发展有限公司总裁科技助理，技术推广总监，中国科大-上海兆维核酸药物研发联合实验室副主任。蔡博士深耕于生物化学与分子生物学领域，加入兆维以来，致力于公司在核酸领域的市场拓展和战略策划，负责公司产品和工艺项目的管理，提供专业的技术支持。蔡博士牵头并建立了中国科大-上海兆维核酸药物研发联合实验室，同时还主持了公司与复旦大学、上海交通大学等多所高校的合作，推动了项目的多方合作和产品市场化过程。蔡博士也是对外发言人，主导媒体公关，商务宣传和客户合作的工作。 14:45~15:30 演讲主题 寡核苷酸合成工艺的开发策略 演讲大纲 -寡核苷酸合成原理 -寡核苷酸合成工艺的优化策略 -如何实现快速工艺开发 讲师介绍 郑康扬，毕业于广州大学生物工程专业，拥有6年生物制药研发生产经验和10年生物医药相关仪器及工艺技术支持经验，涉及单抗、重组蛋白、疫苗、小核酸等上游工艺。2021年加入Cytiva，主要负责全国细胞及基因治疗领域细胞培养上游工艺，以及小核酸合成开发、合成工艺放大、商业化级别小核酸合成的应用支持工作。 15:30~16:15 演讲主题 寡核酸药物下游工艺开发策略 演讲大纲 -层析工艺开发逻辑 -寡核酸药物纯化策略 -不同类型层析介质在寡核酸纯化中的应用 讲师介绍 王泓翔 博士，Cytiva下游应用专家，主要负责工业领域的层析工艺开发及相关产品的应用支持，曾参与多个临床前项目的下游工艺开发工作。 有奖互动，等你来 扫码加入群聊 交流互动、问题解答、干货分享   点击阅读原文，立即报名~