Valoctocogene roxaparvovec

The year started well for the biotechnology industry. Steady dealmaking coupled with a rebound in initial public offerings helped lift investor confidence and, with it, drugmaker stocks.While that optimism has moderated somewhat since, a series of decisions by the Food and Drug Administration over the next three months could help the sector sustain its upturn. The agency may expand approvals for two cancer cell therapies and clear a third vaccine for respiratory syncytial virus. Sanofi and Regeneron await a decision on a lucrative new use for their top-selling Dupixent, while Geron could see decades of drug research finally pay off.Here are five FDA decisions to watch in the second quarter.CAR-T therapies for early multiple myeloma treatmentThe FDA this quarter could broaden the use of two cell therapies for multiple myeloma in decisions potentially worth billions of dollars to their respective developers.By April 5, the agency will decide whether to clear Johnson & Johnson and Legend Biotechs Carvykti for use in myeloma patients as early as after one relapse. That decision could be accompanied by a similar OK for Bristol Myers Squibbs Abecma and open up use of the therapies, which are currently only available in the U.S. for people with more advanced disease.European regulators have already endorsed earlier use of Abecma and Carvykti based on trial data showing they help people live longer without their disease progressing. But the FDA has appeared less supportive. The agency delayed a decision on Abecma last year and held a March advisory meeting to more closely scrutinize the data for it and Carvykti. In briefing documents, staff scientists flagged an apparent increase in the risk of death early on in the clinical trials of both therapies.The companies attributed that finding to limitations in the bridging therapies study participants could receive while waiting for CAR-T treatment. Panelists were convinced and backed both, agreeing that those issues likely wouldnt occur as frequently in practice.Nonetheless, the regulatory scrutiny suggests that the FDA might put new safety restrictions on Carvykti and Abecma if it chooses to clear them for earlier use. Jonathan GardnerModernas vaccine for RSVCOVID-19 vaccine makers Pfizer and Moderna have been facing the downside of their pandemic success, as falling sales have brought tough questions from investors.Moderna, for its part, aims to follow its COVID shot with several other messenger RNA-based vaccines, including one for respiratory syncytial virus thats now under FDA review.Respiratory syncytial virus, or RSV, can cause severe illnessin infants, older adults and people with compromised immune systems. Two vaccines, from GSK and Pfizer, are already approved to prevent RSV-related disease in adults over the age of 60. Sales of each have been strong, although GSK has established a clear edge.Moderna argues its vaccine, dubbed mRNA-1345, can compete. The shot is a pre-filled, single-dose vaccine, potentially offering more convenient administration.In Phase 3 testing, the vaccine was 84% effective at preventing infection with two or more symptoms in older adults. That efficacy does appear to wane over time, however.At a recent meeting, Centers for Disease Control and Prevention advisers reviewed known safety risks for GSKs and Pfizers shots, both of which were associated in very rare cases with Guillain-Barr syndrome, or GBS, a neurological condition affecting the nerves. Moderna has not reported any cases of GBS in Phase 3 testing of its shot.An FDA decision on mRNA-1345 is set for May 12. Delilah AlvaradoGerons imetelstat for myelodysplastic syndromesDrug development is a time-consuming, expensive process. Geron, a biotech founded 34 years ago to pursue stem cell research, knows this well.The companys long journey may finally reach an end by June 16, when the FDA will decide whether to approve a bone marrow disease drug Geron has been developing for nearly two decades. Called imetelstat, the drug treats myelodysplastic syndromes and some analysts believe it has blockbuster potential.Over the many years of Gerons research, imetelstat failed studies in multiple cancer types, and the company lost Johnson & Johnson as a partner along the way. But the drug finally succeeded in Phase 3 testing for myelodysplastic syndromes last year. And in March, it secured the endorsement of an FDA advisory panel despite skepticism from agency reviewers.Geron aims to challenge Bristol Myers Squibbs Reblozyl, first with a clearance in people with lower-risk disease and then in more people who have the condition. Stifel analyst Stephen Wiley estimated the drug could generate $2 billion in peak yearly sales, as it could be helpful in people who dont respond well to Reblozyl.Geron could be a buyout target, too, according to Wiley, though the company has said it plans to sell the drug on its own. Ben FidlerSanofi and Regenerons Dupixent for COPDDupixent is one of the pharmaceutical industrys most widely used and lucrative products. Approved for asthma, eczema and three other inflammatory conditions, the drug earned the companies more than $11 billion in sales last year.By June 27, the FDA could add another major indication to Dupixents list of approved uses. The regulator is currently reviewing the injectable medicine as a treatment for a type of chronic obstructive pulmonary disease, or COPD.If cleared by the FDA, Dupixent would be the first biologic drug for people with moderate-to-severe COPD who also have evidence of whats called Type 2 inflammation. A pair of late-stage studies, which enrolled nearly 1,900 people, showed Dupixent could cut the rate of COPD attacks by about one-third. Analysts therefore expect the FDA to issue an approval and forecast billions of dollars in additional yearly sales. Ned PagliaruloPfizers gene therapy for hemophilia BSome time during the second quarter, the FDA will decide whether to clear a gene therapy from Pfizer for hemophilia B, the less common form of the blood clotting disorder.Reaching this point has been a long time coming for Pfizer, which licensed the therapy from Spark Therapeutics a decade ago. In subsequent testing, treatmentlowered bleeding rates and reduced the need for regular blood transfusions powerful benefits meant to last many years with a single infusion.But its unclear whether Pfizer will find a market if the FDA chooses to approve its therapy. A rival genetic medicine, from CSL Behring and UniQure, won U.S. approval for hemophilia B in November 2022. However, few patients have been treated to date, sluggish uptake that could reflect the breadth of effective options available.The story is similar with Roctavian, a gene therapy BioMarin Pharmaceutical sells for the more common A form of hemophilia. Only three patients received Roctavian last year: two in Germany and one in the U.S.Pfizers therapy, which in January won Canadian approval, could provide another data point. But the company seems to be downplaying its potential. In recent presentations for investors, a once-weekly shot called marstacimab has gotten higher billing. Ned Pagliarulo '

3月13日，勃林格殷格翰与“中国血王”上海莱士达成合作，为后者的血友病创新药物SR604注射液提供工艺转移及临床生产制造服务。3月14日，阿斯利康以10.5亿美元收购罕见病疗法公司Amolyt，将治疗甲状旁腺功能减退症的Eneboparatide（AZP-3601）收入囊中。更早前的2月27日，诺和诺德以总价14.6亿美元与Neomorph达成合作，共同开发和商业化治疗心血管疾病和罕见病的分子胶降解剂。这三项交易看似没有任何关系，但定睛一看就会发现，巨头们都押注了同一个方向——罕见病领域。01MNC巨头为何联手“中国血王”？去年10月，勃林格殷格翰（BI）在“中国研发日”上宣布，未来五年计划在华人药业务研发投入超35亿人民币。如今，BI开始用实际行动兑现承诺。但BI作为一家拥有近140年历史的MNC巨头，为何会与从事血液制品业务的“中国血王”达成合作？实际上，勃林格殷格翰在中国市场的投入早已开始。追溯到2018年，当许多MNC巨头都趋向欧美市场时，BI选择打破常规，启动了“中国纳入”（China IN）项目，率先将中国全面纳入全球早期临床开发研究。如今，BI已在中国落地多个管线，包括新型PDE4B抑制剂BI1015550、高效口服小分子MDM2-p53拮抗剂Brigimadlin（BI907828）、DLL3/CD3双抗BI764532、Iclepertin（GlyT1i）和新型抗肥胖药物Survodutide（GCGR/GLP-1R双重激动剂），涉及肿瘤、自免、精神分裂症和肥胖等多个疾病领域。此次BI与上海莱士达成的重磅合作，是针对血友病创新药物SR604注射液。SR604是一种人源化高亲和力结合人活化蛋白C，特异性抑制人活化蛋白C抗凝血功能的单克隆抗体制剂，其优势在于每4周一次的皮下注射预防治疗，相比目前国内外血友病的常规预防治疗（每周2-3次静脉注射血源或重组凝血因子），更具依从性优势。就在本月初，SR604获国家药监局批准开展临床试验，用于血友病及先天性凝血因子Ⅶ缺乏症患者出血发作的预防治疗。目前全球尚无与该药物同靶点的产品上市，市场先发优势显著。除药物自身优势显著外，上海莱士在血液制品领域的实力，也是促成此次交易的关键。作为“中国血王”，上海莱士一直专注于血液制品业务，产品覆盖了白蛋白类、免疫球蛋白类及凝血因子类三大类，是国内同行业中凝血因子类产品种类最为齐全的生产企业之一，早已在凝血领域打造了强劲优势。如今切入血友病创新药物的研发，也是水到渠成的事情。更何况，血友病药物本就有着可观的销售表现。02罗氏摘得血友病“药王”，基因疗法登上历史舞台血友病是一种罕见的遗传性疾病，分为血友病A（甲型血友病）和血友病B（乙型血友病），其中前者占比高达80%-85%。血友病的患者人数不在少数。根据弗若斯特沙利文数据，全球血友病患病人数复合增长率为1.3%，从2015年的74.2万上升到2019年的78.3万，预计到2030年患者人数将增长到89万人。在已获批的药物中，除罗氏9/10因子双抗Hemlibra（艾美赛珠单抗）外，大多数药物类型主要为重组凝血八因子，如今全球已获批20款左右，竞争相当激烈。罗氏开发的艾美赛珠单抗，是近20年来FDA批准的首个用于治疗A型血友病的新药，2023年实现销售额达41.47亿瑞士法郎，同比增长16%，在罗氏畅销产品榜单中排名第二，并摘得血友病“药王”宝座。除上述两种药物外，在罕见病领域具有功能性治愈潜力的基因疗法，也登上历史舞台。2022年8月，BioMarin研发的Roctavian（Valoctocogene roxaparvovec）获批上市，用于治疗无FVIII因子抑制剂史且AAV5抗体阴性的严重血友病A成人患者；11月，美国FDA批准UniQure开发的Hemgenix（Etranacogene dezaparvovec），用于治疗18岁及以上血友病B患者。这意味着，针对血友病A和血友病B的基因疗法均已面世。辉瑞相当看好基因疗法，一口气布局了3条管线，其中从Spark Therapeutics引进的Beqvez（Fidanacogene elaparvovec，SPK-9001），已于今年1月在加拿大获批上市，用于治疗18岁或以上中重度至重度乙型血友病成人患者。此次批准是基于一项积极的III期研究：接受Beqvez治疗三个月，出血率可减少71%。目前，Beqvez已在美国、欧洲处于上市审评阶段，预计今年二季度揭晓结果。另一条管线Marstacimab（PF-06741086），通过靶向组织因子途径抑制剂（TFPI），可用于治疗血友病A和血友病B患者，而且无需考虑患者体内是否存在对外来凝血因子产生的中和抗体。目前，Marstacimab的关键临床III期试验已达到主要终点：与在导入期内接受按需治疗因子替代静脉治疗的患者队列相比，出血率降低92%，与接受预防性治疗队列相比，年化出血率降低了35%，均显示出优越性。此前，Marstacimab已获得FDA授予快速通道资格，若顺利获批，将可能成为首款只需每周一次皮下注射的血友病B疗法，同时也是首款按固定剂量给药的血友病A或B药物。辉瑞和Sangamo共同研发的Giroctocogene fitelparvovec（SB-525），是一款肝靶向AAV（腺病毒相关载体）的基因疗法，目前正在开展针对中度或重度A型血友病成年男性的III期研究，预计今年上半年获得顶线数据，下半年向FDA提交BLA。03国内药企征战血友病赛道面对如此巨大的市场蛋糕，国产药企必然不会错过。我国血友病患者众多且呈现持续增加的趋势。根据《血友病A诊疗指南（2022年版）》，2022年国内血友病患病人数为14.6万人，其中80-85%属于甲型血友病。另外，根据弗若斯特沙利文预测，中国血友病用药市场将于2026年达到115亿元，成为百亿赛道。目前，国内获批的血友病药物主要为重组凝血八因子，且以进口产品为主，其中神州细胞凭借国产首个重组八因子安佳因（重组人凝血因子VIII）抢得了一席之地，并且在首个完整销售年度即成为销售额10亿量级的市场重磅产品。得益于安佳因销售收入的持续增长，神州细胞预计2023年交出亮眼的成绩单：实现总营收18.5亿元至19.1亿元，同比增长81.12%到86.98%，同比减少净亏损21.19%到26.98%。如今，也有一些国产药企想进场“分蛋糕”，从FVIII/vWF-XTEN融合蛋白、TFPI单抗、Ffactor X激活剂等方向研发血友病新药，进度领先的有晟斯生物、康宁杰瑞、舒泰神。其中，晟斯生物自主研发的注射用重组人凝血因子VIII-Fc融合蛋白（FRSW107），能有效延长半衰期，实现3天一次给药或一周两次给药，是首款国产长效重组凝血因子VIII产品1类新药。2023年6月，晟斯生物向国家药监局提交了FRSW107的上市申请，用于12岁以上青少年与成年人先天性八因子缺乏的血友病A患者的出血控制，有望在今年上半年获批上市。康宁杰瑞布局的KN057，是一种靶向组织因子途径抑制物（TFPI）的单克隆抗体，可维持凝血酶水平，达到预防出血的作用，具有半衰期长、皮下注射等特点，目前已启动预防治疗血友病的III期临床研究。2023年9月，康宁杰瑞将KN057在大中华区的权益授予远大生命科学全资子公司远大蜀阳，将获得最高人民币5亿元的权益付款（包括首付款和里程碑款）及分级销售提成。需要注意的是，外资巨头已在抗TFPI药物赛道领先一步。其中，诺和诺德的Concizumab（康赛珠单抗）已于2023年9月在日本获批上市，用于有凝血因子VIII或IX抑制剂的先天性血友病患者出血倾向的抑制。III期试验数据显示：康赛珠单抗可使血友病A患者的自发性和创伤性出血减少86%，使血友病B患者的出血减少79%。另外，辉瑞的Marstacimab（马塔西单抗），针对血友病A和血友病B的III期临床试验已达到主要终点，与按需静脉注射凝血因子相比，能使患者年出血率（ABR）降低92%。舒泰神研发的凝血因子X激活剂STSP-0601，已于2023年11月取得Ib/II期临床研究总结报告，治疗伴抑制物血友病A或B患者出血事件的疗效显著，有效止血率＞94%，而且安全性良好，试验过程中未发生与药物相关的SAE，无血栓栓塞事件发生，未发现与试验药物相关的抗药抗体产生。可见，国产药企的血友病新药已处于临床后期阶段，未来几年将迎来收获期。04结语总体来看，MNC巨头们之所以争相押注罕见病领域，特别是血友病这一细分赛道，既源于罕见病药物市场巨大的潜力，也因为这些疾病领域仍存在大量未被满足的临床需求。而在这股全球的热潮中，国产药企也嗅到了这一领域的机会。尽管外资巨头在某些方面已领先一步，但国产药企也在不断努力追赶，有望在未来几年取得突破性进展。参考资料1.各家公司的财报、公告、官网2.《有望成为首款！只需一周接受一次治疗，辉瑞长效血友病疗法达3期关键试验主要终点》，药明康德，2023-05-313.《跨国药企争夺血友病赛道，诺和诺德3期临床数据不敌辉瑞》，中为股权投资，2023-06-30