Tofersen

2024年11月26日，Arrowhead Pharmaceuticals与Sarepta Therapeutics达成合作协议，合作范围覆盖5款临床阶段和2款临床前管线，以及针对罕见病、遗传性肌肉疾病、CNS、肺部疾病开发最多6个靶点的siRNA药物。 根据合作协议，Arrowhead公司将获得5亿美元的预付款和3.25亿美元的股权投资。此外，在接下来的5年里，公司还将收到2.5亿美元的额外款项。Arrowhead公司还将获得3亿美元与近期临床试验入组相关的里程碑付款，以及高达103亿美元的额外里程碑付款（每个项目可达17.2亿美元），并且将享有一定比例的销售收入分成。 小核酸药物类型主要包括反义核酸（ASO）、小干扰核酸（siRNA）、微小RNA（miRNA）、核酸适配体（Aptamer）等。 小核酸药物有许多优点，比如：它们能够针对特定的基因序列进行干预，具有高度的特异性，这使得该类药物可以精准地治疗疾病，减少副作用；作用机制相对明确，开发过程中可以利用现有的生物技术和平台，因此开发周期相对较短；可以针对多种疾病进行治疗，包括遗传性疾病、肿瘤、感染性疾病、神经系统疾病等；由于小核酸药物直接调节上游基因表达，因此相对不易产生耐药性；不受限于蛋白质的可成药性，理论上可以设计用于靶向任何感兴趣的基因，有望攻克尚无药物治疗的遗传疾病和其他难治疾病。 近年来，小核酸药物被很多研究机构或业内人士认为是继小分子药物、抗体药物之后引领现代新药研发的第三次浪潮。 据PDB数据库统计，小核酸药物2023全球制剂销售额TOP 10的产品中，美国Alnylam公司的SiRNA产品几乎占据半壁江山。其次，美国Ionis公司的ASO产品也占据两席。从销售额角度看，只有诺西那生钠注射液2023年全球销售额超过10亿美元，成为“重磅炸弹”产品。 表：小核酸药物2023全球制剂销售额TOP 10 来源：PDB数据库，全球制剂销售 此外，TOP 10产品中目前有两款在国内获批上市。 2016年12月，渤健开发的反义寡核苷酸（ASO）类药物诺西那生钠注射液（Nusinersen Sodium，商品名Spinraza）获FDA批准上市，成为全球首个脊髓性肌萎缩症（SMA）治疗药物。SMA是一种常染色体隐性遗传性神经肌肉罕见病，以脊髓前角运动神经元退化变性和丢失导致的肌无力和肌萎缩为主要临床特征。SMA是造成婴幼儿死亡最常见的常染色体隐性遗传病之一，不同人群中的致病基因携带频率在1/40~1/50，新生儿的发病率约为1/10000。 2018年，诺西那生钠进入我国《第一批临床急需境外新药名单》。2019年4月，诺西那生钠注射液在我国获批上市，成为国内首款获批上市的ASO类药物。然而，一针70万元的天价让患者望而却步。 2021年医保谈判中，诺西那生钠价格从一针70万元砍至3.3万元，降价幅度高达95%，最终进入医保药品目录，惠及更多SMA患者。据PDB数据库显示，诺西那生钠进入医保目录后迅速放量，2022年在我国销售额达到7.57亿元，2023年略有下降为5.8亿元。 图：诺西那生钠注射液国内销售额 来源：PDB数据库，国内全渠道放大 2022年10月，国家药监局发布关于《仿制药参比制剂目录（第六十一批）》的通告（2022年第52号），将诺西那生钠注射液列入了参比制剂目录，为制药企业提供了高质量仿制指引。 2024年9月5日，国家药品审评中心网站显示，重庆药友制药有限责任公司提交了诺西那生钠注射液的4类仿制上市申请，成为该产品国内首家申报企业。未来随着仿制药的获批上市，诺西那生钠注射液的价格将进一步降低。 图：诺西那生钠注射液药品注册申报信息 来源：CDE官网 实际上，越来越多的药企的研发方向逐渐从罕见病向慢性病过渡。小核酸药物通过其独特的作用机制、先进的递送系统和有效的化学修饰，实现了长效给药，提高了患者的依从性和治疗效果。 2023年8月22日，诺华/Alnylam开发的全球首款且唯一一款siRNA超长效降脂药物英克司兰Inclisiran（Leqvio）在中国获批上市。英克司兰是Alnylam基于其递送系统GalNAc研发设计的一款靶向PCSK9的siRNA基因疗法，最初于2020年12月在欧盟获批，用于治疗成人高胆固醇血症及混合性血脂异常，并于2021年12月获得FDA批准上市。该药的用法为皮下注射，首次注射后，3个月再次注射，之后每6个月一次，一年仅用两次，这种给药频率大大提高药患者的依从性。 英克司兰注射液通过N-乙酰氨基半乳糖（GalNAc）修饰的递送系统，可以实现肝脏靶向性递送。GalNAc与肝脏实质细胞表面的脱唾液酸糖蛋白受体（ASGPR）高亲和力结合，引导药物进入肝脏细胞，并在细胞内形成内涵体，缓慢释放药物，从而实现长效降脂作用。 据PDB数据库统计，2024年H1，英克司兰注射液在我国的销售额约为2840万元。目前，英克司兰每针9988元，推荐皮下注射给药，一年两针的总治疗费用不超过2万元。英克司兰已参加2024国家医保谈判，国家医保局将于11月28日（明天）上午十时在国家医保局召开2024年国家医保药品目录调整新闻发布会，谈判结果即将出炉。 图：英克司兰钠注射液国内销售额 来源：PDB数据库，国内全渠道放大 截至目前，我国共有三款小核酸药物获批上市。除去诺西那生钠注射液和英克司兰钠注射液，还有一款是来自渤健的托夫生注射液。 2024年10 月 8 日，NMPA最新公示，渤健的托夫生注射液（tofersen）获批进口，用于治疗SOD1 基因突变的成人肌萎缩侧索硬化症 (ALS，“渐冻症”)。这是全球首个 SOD1-ALS 对因治疗药物，在国内通过免临床途径获批上市。 托夫生是一种ASO类药物，通过与SOD1 mRNA结合引起SOD1 mRNA 降解，从而减少SOD1蛋白合成。该产品最初于2023年4月在美国获批上市，2024年5月获EMA批准用于ALS。 此前，托夫生每剂售价为14230美元，第一年需使用 14 剂，总计199200美元（约合人民币 140 万）。 渐冻症是一种罕见的进行性神经系统疾病，影响大脑和脊髓中的运动神经元，目前尚无法被治愈，治疗的主要目的是尽可能地延缓病情的发展和缓解患者的症状。其中，仅有约2%的患者是由于SOD1基因发生突变所导致的。托夫生注射液未来能否进入医保目录暂未可知。 END 如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

Trace Neuroscience, a freshly launched startup, is developing a type of genetic medicine it believes could help most, if not all, people with ALS.Its a bold idea, considering nearly every attempt to combat the nerve-destroying disease has ended in failure. Researchers still arent sure what causes 90% of cases. And in the U.S., the short list of drugs approved to treat ALS, or amyotrophic lateral sclerosis, got shorter still this year, as a once-promising medication hit a major setback that ultimately got it pulled from the market.Yet Trace was still able to fundraise $101 million from a group of prominent biotechnology investment firms that includes Third Rock Ventures, Atlas Venture, RA Capital Management and Alphabets venture capital arm, GV. Jeffrey Tong, a Third Rock partner whos now on Traces board of directors, says there are a few reasons why the startup earned his firm's support.One was the companys underlying science. It was built on recent discoveries from the labs of Aaron Gitler, a Stanford University professor; Pietro Fratta, a professor of cellular and molecular neuroscience at University College London; and Michael Ward, a senior investigator in the National Institutes of Healths neurological disorders division. Almost at the same time, these labs identified connections between an important RNA-processing molecule and a protein thats often impaired in people with ALS and other neurodegenerative disorders.Another selling point, according to Tong, was the precedent set by Biogens Qalsody.Like Traces medicine, Qalsody is whats known as an antisense oligonucleotide, meaning it regulates protein production by binding to RNA. Qalsody flunked the main trial designed to show it can slow the functional decline associated with ALS. The drug was still approved last year, though, due to its apparent effects on neurofilament light chain, a protein tied to nerve cell damage.Traces CEO, Eric Green, plans to incorporate those learnings into the development plans for his companys drug, which is on track to enter human testing in early 2026.Green has helped set up multiple Third Rock portfolio companies. He co-founded the precision medicine developer Maze Therapeutics and served as head of translational research at heart drug startup MyoKardia. In an interview with BioPharma Dive, Green explained why his new, big-swing endeavor resonated with investors.The following conversation has been edited and condensed for clarity.BIOPHARMA DIVE: Was there a concerted effort to go to these different parties and ask them to come together and build a single company, rather than three separate ones?ERIC GREEN: Absolutely. This, to me, was just a central part of how I thought about this. I wanted us to join forces and not dilute our efforts across three companies, because everybody here brings different expertise. It's a really nice complementary team.This is my third go around doing this with Third Rock. One of the things I have learned over the years is that the more you can bring together a group of diverse experts who understand an area of biology, the greater chance you're going to have to be successful in translating that into a medicine.We have an academic world that I think is very much oriented toward independent discoveries and independent credit. That makes perfect sense from an academic standpoint, but as we think about trying to make this into a medicine, we need to join forces.There really is that shared goal and shared mission here, recognizing that we're stronger together.Atlas, RA, GV what about those firms made you want them to be part of your investor syndicate?GREEN: The first thing I had in mind was to allow us to raise a sum of money that would allow us to get through what we see as the key clinical data points where we're going to be able to learn about how this medicine is working in people with ALS.But [another piece was] to bring together a diverse set of voices. Atlas, for example, built a number of different RNA therapy and oligonucleotide companies. That was something really important to me, thinking about how we can build companies. [We wanted] a syndicate that has different perspectives, both really early company creation in the case of Third Rock and Atlas but then also people who think about company growth and some of the longer-term horizons. This was where having a group like RA has been really helpful to us. And similarly, with Google Ventures, a group that really sees companies across the life cycle, from very early discovery all the way through to clinical development and commercialization.One of the things that, to me, is a little unusual, maybe particularly exciting, about this opportunity is that we're very early. We're not far from the original discovery. But there's a potential here to move really quickly, and to go from being a discovery company to a company that's generating really meaningful clinical data. And in this indication, meaningful clinical data can have a very direct path towards getting a drug on the market.You raised $101 million. Why stop there, or set that as the goal, in terms of fundraising?GREEN: We want to build an R&D plan that we think is the right one, and then finance that. Not, Lets test the waters and see how much money we could raise. Yes, we could have certainly gotten $1 more than [our goal] and so, by definition, we were oversubscribed. But I have a pet peeve about that myself. Our goal was to set out to raise the amount of money we needed to support the R&D plan, and that's what we did. In general, we're really happy with the round we put together. And we'll have a lot of options with this syndicate to take the next steps.Your company is at the intersection of genetic medicine and neuroscience, two research areas that could be seen as high-risk. What were the biggest concerns among these investors? Do you think youve alleviated them?GREEN: ALS, and neurodegenerative diseases more broadly, are an area where there's been a lot of disappointment.It was really important for me to be able to convey what we thought was different about this opportunity. I can summarize it with three components. Here is this focus on robust human genetics as our guide to give us confidence we're going after a mechanism relevant in people with ALS, rather than in some cell or animal model of the disease. The quality of the human genetics evidence here is exceptionally high, both because it's been reproduced across so many different cohorts, but also because of this relationship with disease progression and survival. And that's unusual, as opposed to having a relationship with just the risk of disease. It really gives us confidence there's a window to intervene on this mechanism after people are diagnosed.But genetics is not enough. You need to understand what the mechanism is by which the gene is working. And this is where that set of discoveries I described from Aaron and Pietro and Michael was so critical of saying we really understand how this gene is working. This has been, even with some of the previous genetic targets, one of the limitations. We don't exactly know what it is that's going on, and therefore we don't exactly know what we want to do therapeutically.Then the third piece was, this is a mechanism that really is amenable to a particular modality, in this case, antisense oligonucleotides.Where we are today, we have a lot more confidence we actually have a particular molecule that has all those properties we're looking for that can potently correct splicing, both in cells and animal models of disease, and that can do that in a way that is sufficiently well tolerated so we'll be able to have some flexibility in how we dose in the clinic.Trace remains a single-asset company. Is that a harder sell right now, given that biotech investors appear at least somewhat more risk averse?GREEN: This was something I spent a lot of time thinking about, because my prior experience at MyoKardia, Maze, other companies, has been in broader, platform-oriented companies. So this was a big part of the thought process I had as we went from this discovery to: What's the right company?A big part of what made the single asset make sense is it allows us to really get to those important clinical inflection points on a Series A raise, as opposed to saying we're going to explore a bunch of different things, but not be able to get any of them to the point where we get the meaningful clinical data. That was also something that really resonated with investors, because I think there is a real focus on being able to get that meaningful clinical data. That was, in some ways, a tailwind for us.There are some aspects of increased risk when you think about a single asset company. So for us, it was being able to have things far enough along by the time that we launched, that we felt like we had mitigated a lot of those risks. We felt strongly about the genetics, we felt strongly about the mechanism, and we felt strongly enough about being able to find a molecule that could meet our criteria. The risk of not getting to the point where we can test this in patients is relatively mitigated. This wouldn't have made sense when we were talking in 2020 and said, Oh, here's an interesting idea, and here's an interesting mechanism, but we don't know whether it's going to be possible to find a molecule.In some ways, it became an advantage. Now we can really focus the organization on being able to get that critical data. And then after that think about how we might broaden the company, whether it be to other indications or other ways of attacking this target.Whats the current development timeline investors envision for your asset? What data represent a go-no go decision for Trace and its investors?GREEN: We're on track with our lead molecule to be in the clinic by early 2026. We'll be able to, very quickly, do these trials in patients, so that the first studies have the opportunity to show us meaningful clinical data.This is one of the places were able to benefit from some of the work that was done with [Qalsody], even though the focus there is on a very rare population of people with ALS. A lot of the things they learned with respect to biomarkers, in particular, are very relevant for how we think about our clinical development. [In particular] they were able to take advantage of neurofilament as a biomarker of disease progression that really correlated well with the ultimate changes we all hope to see, which is improvements in how people feel, function and survive with ALS.I think that gives us a much stronger toolkit for evaluating our molecules than we had before. So we're obviously going to be looking for those clinical signs, but having some strong biomarkers will help accelerate and give us more tools to see proof-of-concept in the clinic earlier. '