ABCA1

Seven years into its existence, Character Biosciences is ready to enter the clinic with a pair of experimental medicines targeting a bustling area of ophthalmology. The New Jersey biotech aims to treat age-related macular degeneration, a key driver of blindness in older adults, based on insights from genetic and imaging data that it collected from more than 6,500 people in an observational study. To get its first candidates into Phase 1 this year, Character announced Tuesday that it raised a $93 million Series B. The biotech previously raised $28 million in funding, including an $18 million Series A in 2022. The financing should take the 30-employee startup through Phase 2 testing for both intravitreal drug candidates, CEO and co-founder Cheng Zhang told Endpoints News . Investors are aMoon, Luma Group, Bausch + Lomb, Jefferson Life Sciences (an affiliate of Jefferson River Capital), Innovation Endeavors, Catalio Capital Management, S32 and KdT Ventures. Character is the second private biotech to announce a funding round on Tuesday after Hillstar Bio revealed its $67 million debut . It’s rare right now to see more than one venture funding round announcement per day, according to a Stifel report on Sunday. The average number of biotech venture rounds per month has slid 10% from two years ago and cratered 40% from the vibrant market of four years ago, according to the Stifel bankers. Character chose its drug targets based on the patient data from the observational study, and the startup believes that wealth of data can also give it a better shot at clinical success because it can hone in on the patients most likely to respond to treatment. Plus, the company worked with more than 150 ophthalmology centers for the observational study, and it plans to use some of those sites for upcoming clinical trials. “It’s been a long journey. It’s taken seven years, in fact, but we didn’t want to make any shortcuts,” Zhang said. “We wanted to build a rigorous company that is rooted in the fundamental science of patient data.” The company is exploring CTX114 as a treatment to slow the progression of geographic atrophy in advanced dry AMD, an increasingly popular category for drugmakers. Astellas and Apellis Pharmaceuticals both received FDA approval for geographic atrophy therapies in 2023 but have since faced regulatory setbacks. Last year, Astellas withdrew its application in Europe, and Apellis’ treatment was rebuffed by the bloc’s regulators, who raised questions about clinical benefit and safety. Like Astellas’ Izervay and Apellis’ Syfovre, Character is also pursuing the complement pathway with CTX114 but is tackling a “different genetically supported” part, according to Zhang. CTX114 is an engineered version of FHL-1, or factor H-like protein 1, a negative regulator of complement activation. Izervay is a complement 5 inhibitor and Syfovre is a C3 inhibitor. The company hopes CTX114 can also offer a less-frequent dosing schedule than Izervay and Syfovre, which are dosed monthy and every 25 to 60 days, respectively. As part of its due diligence on Character, aMoon investors talked with practicing ophthalmologists about the GA landscape, including Izervay and Syfovre. “They said, ‘Look, the risk-benefit for both of these drugs is just not amazing,'” aMoon partner Reut Shema said in an interview. “They said, ‘But we have nothing else. So if you give me something that’s similar efficacy, but just a little bit safer, it’s a multibillion-dollar drug.'” Meanwhile, with CTX203, Character hopes to thwart a patient’s progression to advanced AMD. CTX203 is an apolipoprotein A1 mimetic peptide that aims to stabilize ABCA1 expression. Character is also working with Bausch + Lomb to create new medicines for AMD. The duo began collaborating early last year and announced that work in January. Financial terms have’t been disclosed. “We would love, at a certain time, to move from incidence-driven drug development into a population-specific drug development,” Bausch + Lomb chief medical officer Yehia Hashad said in an interview. Character wants its platform to decipher which patients will be responders from the outset — before even going into clinical studies. “The more we are able to predict patients and treat them prior to getting to the late-stage part of the disease, the better,” Hashad said. The Bausch + Lomb tie-up does not involve Character’s CTX114 or CTX203. “Those could be highly competitive assets,” aMoon’s Shema said, “and because there’s so much interest from pharma companies, we wanted to make sure that this was open territory for different pharmas to bid for those because we think both of them have potential to be multibillion-dollar drugs.” Shema pointed out that Character also has datasets in glaucoma, which could form the basis for additional partnerships.

Character Biosciences, a biotechnology startup developing treatments for vision loss, said Tuesday it raised $93 million in a Series B round.The financing will help Character bring its two most advanced programs into clinical testing. One, dubbed CTX114, is being tested in geographic atrophy, a common eye condition and an advanced stage of age-related macular degeneration, or AMD. The other, CTX203, is designed to halt progression in people with intermediate AMD, so they dont develop geographic atrophy or other forms of advanced disease. Both drug prospects should begin Phase 1 trials this year.In geographic atrophy, Character aims to challenge two marketed drugs Apellis Pharmaceuticals Syfovre and Astellas Pharmas Izervay. Both can slow the growth of the patchy, map-like eye lesions that create blind spots in people with geographic atrophy. However, testing hasnt clearly shown that doing so preserves vision. And in rare cases, Syfovre has been associated with severe side effects.Like Syfovre and Izervay, CTX114 works on the complement system, an arm of the bodys immune system. According to Character co-founder and CEO Cheng Zhang, CTX114 does so differently, mimicking the function of a protein that stops the complement system from overactivating, but that malfunctions in AMD. Preclinical testing has suggested the approach may be more effective, though that hasnt been proven in humans.Characters second drug is being developed for people who dont yet have advanced AMD and arent typically treated. CTX203 is designed to stabilize expression of a protein called ABCA1 thats involved in lipid transport by retinal cells. Lower ABCA1 levels are associated with an abnormal buildup of lipids that can lead to AMD progression.While there are many medications for wet AMD, drugmakers have had less success with the dry form that accounts for the bulk of the estimated 200 million people worldwide with the disease. Zhang says a big reason why is the diseases heterogeneity and varied progression, which makes it difficult to design clinical trials. Character has collected a trove of AMD patient data to help design its drugs and identify the specific groups of people it intends to enroll in studies.What gives us comfort is that we have mapped out those challenges, we have a deeper understanding of how we might mitigate those risks, Zhang said. We can subtype patients, understand those patients who are more likely to respond to our therapy, and have a drug that has more applications in the first place.Characters Series B round was led by aMoon and Luma Group, and involved Bausch + Lomb, Jefferson Life Sciences and four other investors. Bausch + Lomb also announced a collaboration with the biotech in January.Characters patient-first approach is unique in its ability to identify those who are most likely to benefit from therapy, and we look forward to seeing the clinical impact of this approach with the use of proceeds from this financing, Jamie Kasuboski, a partner and head of research at Luma Group, said in a statement.Character was formerly known as Clover Therapeutics, which was launched in 2019 by the health insurance firm Clover Health. The company previously raised an $28 million in funding, Zhang said. '

*仅供医学专业人士阅读参考 过犹不及，属实是放之四海而皆准的道理，就拿细胞癌变来说，许多时候癌变的发生，就是因为要应对时时刻刻都在发生的组织损伤，人体内相应不断重复的组织修复过程“过了”，其中的差错乃至失控就会为随后的癌变埋下伏笔[1]。而这种小概率的不幸，就最常发生在各种与外界接触的屏障组织，毕竟接触多损伤就多嘛。 但正如奇点糕所说，这种不幸毕竟是小概率事件，不然各种癌症就满天飞了，换句话说，人体内存在着能将正常组织修复和癌变区隔开来的调控机制。而近日，瑞典卡罗林斯卡学院研究者们在《自然》上发表的最新研究成果就证明了这一点：肠道中的肝脏X受体（LXR）通路，就是既能促进肠道上皮细胞在损伤后再生，又能抑制肠癌发生的一种调控机制[2]！ 研究发现，在组织损伤需要修复时，LXR通路激活可使肠上皮细胞产生促修复的关键调控因子双调蛋白（amphiregulin, AREG）；但换到癌症场景中，LXR通路的激活则会调动适应性免疫应答抗癌，因此激活LXR通路就成为了一种既能促进组织再生，又不增加癌变风险的干预策略，这既可以帮助癌症患者，也可以用于炎症性肠病（IBD）等疾病的治疗。 一图总结论文主要发现 通过分析既往研究中，以放射线和葡聚糖硫酸钠诱导（后者常用于肠炎建模）小鼠小肠损伤后，小肠组织基因表达的改变，研究者们找到了4个受LXR调控的靶基因（Abca1, Apoc3, Apoa1和Apoa4），并在小鼠实验中用LXR激动剂证实，LXR通路激活可加快小鼠肠道损伤后的修复（如增加隐窝面积），且Abca1和Abcg1两个靶基因表达被明显诱导上调。 当然了，修复损伤后的组织和保护肠道不受损伤，是完全不同的两个概念，研究者们也专门分析证实，LXR通路激活的作用出现在损伤发生后，且促修复作用还不会使肠道内发生炎症反应或免疫细胞聚集，这也是一种降低风险的保护效应了。而在组织修复过程中必不可少的，则是被LXR通路激活促表达的双调蛋白。 激活LXR通路可在肠道损伤发生后起到促修复作用 而在LXR的上游，能够在肠道损伤发生后进行感知并将LXR激活的，则是CYP450单加氧酶家族成员CYP27A1，它会在放射线或DSS诱导肠道损伤后表达率先上调（最先发生在隐窝，此后是肠上皮固有层），而CYP27A1的作用就是产生LXR的配体27-羟基胆固醇（27-HC），配体多了，LXR通路当然就能活跃起来。 CYP27A1的表达上调是LXR通路激活的上游事件 加速损伤修复当然是好事，但奇点糕一开始也说过，癌细胞特别是癌症干细胞，有时候真会明晃晃地劫持正常的组织修复机制，用来帮自己无休止地增殖和进展，正如两百年前西方学者所说，“癌症是一种永不愈合的伤口”。如果要以激活LXR通路作为一种治疗手段，它是否会增加正常组织的癌变风险，也是必须要弄清楚的。 LXR，能Hold住吗？ 本次研究的最后一部分，就在这个问题上收获了惊喜：研究者们发现，向自发性肠癌模型小鼠喂食LXR激动剂，就可显著减少小鼠肠道内的腺瘤数量和体积，而敲除Cyp27a1则作用恰好相反，这意味着CYP27A1-LXR通路确实能限制肠癌发生。空间转录组学分析显示，激活LXR通路可有效促进三级淋巴结构（TLS）形成，由此利好适应性抗肿瘤免疫应答，且这种免疫应答可能是由B细胞主导、T细胞辅助的。 CYP27A1-LXR通路能够限制肠癌发生 总而言之，激活LXR通路能加速肠道屏障修复、且不增加癌变风险，这对于炎症性肠病等疾病患者来说前景也太美好了，而卡罗林斯卡学院的研究者们还表示，对于放化疗等原因导致的肠道屏障受损，激活LXR通路或许也能加速修复，减少相关的治疗并发症，那，期待+1~ 参考文献： [1]Ge Y, Gomez N C, Adam R C, et al. Stem cell lineage infidelity drives wound repair and cancer[J]. Cell, 2017, 169(4): 636-650. e14. [2]Das S, Parigi S M, Luo X, et al. Liver X receptor unlinks intestinal regeneration and tumorigenesis[J]. Nature, 2024. 本文作者丨谭硕