BMPR2

引言BRCC3 (BRCA1/BRCA2-containing complex亚基3)在特发性肺动脉高压患者和实验性肺动脉高压动物的肺组织中表达降低。激活素受体样激酶2 (ALK2)的BRCC3去泛素化激活了肺血管平滑肌细胞中TGF-β(转化生长因子-β)信号的BMP(骨形态发生蛋白)臂。BRCC3功能获得可能降低人类肺动脉高压易感性。2024年4月2日，扬州大学龚开政、加州大学圣地亚哥分校John Y.-J. Shyy及 Jason X.-J. Yuan共同通讯在Circulation（IF 38）在线发表题为“BRCC3 Regulation of ALK2 in Vascular Smooth Muscle Cells: Implication in Pulmonary Hypertension”的研究论文，该研究发现BRCC3通过维持BMP信号(即ALK2-Smad1/5-PPARγ轴)的完整性，同时抑制PASMCs中TGF-β信号，在维持肺血管稳态中起关键作用。在PAH患者和实验性肺动脉高压动物的pasmc中，BRCC3显著下调。BRCC3通过在Lys-472和Lys-475位点去泛素化ALK2，激活受体调控的Smad1/5/9 (Smad1/5/9)，从而导致BMP调控的PPARγ、p53和Id1的转录激活。BRCC3过表达也通过下调TGF-β表达和抑制Smad3磷酸化来减弱TGF-β信号传导。体外实验表明，BRCC3或去泛素样ALK2-K472/475R的过表达可减弱PASMC的增殖和迁移，增强PASMC的凋亡。在SM22α-BRCC3-Tg小鼠中，由于PASMCs中ALK2-Smad1/5-PPARγ轴的激活，肺动脉高压得到改善。相比之下，Brcc3-/-小鼠由于抑制ALK2-Smad1/5信号通路，对实验性肺动脉高压的易感性增加。总之，这些结果表明，BRCC3通过维持BMP信号(即ALK2-Smad1/5-PPARγ轴)的完整性，同时抑制PASMCs中TGF-β信号，在维持肺血管稳态中起关键作用。这种BMP/TGF-β通路的再平衡对于PAH的缓解具有重要的临床转化意义。BMPR2(骨形态发生蛋白2型受体)的突变和功能障碍与特发性和遗传性肺动脉高压(PAH)的发展有关。BMPR2在缺乏遗传原因的PAH患者中趋于下调，可能是由于炎症或环境影响。在BMP(骨形态发生蛋白)结合后，BMPR2结合并磷酸化其同源I型受体ALK2 (激活素受体样激酶-2；也被称为激活素A受体，I型)来激活BMP-BMPR2-Smad1/5/9信号级联。磷酸化的(p) Smad1/5/9易位进入细胞核，导致典型转录因子如Id1和非典型转录因子包括PPARγ和p53的激活，这些转录因子对肺动脉平滑肌细胞(PASMCs)发挥抗增殖和促凋亡作用。TGF-β(转化生长因子-β)或激活素-A结合后，TGF-β受体通过磷酸化Smad2/3发出信号，对肺血管细胞产生促增殖作用。然而，BMP和TGF-β臂对血管细胞的增殖、肥大、分化和存活有不同的影响，这取决于谱系和生物学背景。TGF-β家族受体(包括BMPR2/ALK2和TGF-β r2 /R1)和受体调节(R) Smads (Smad1/5/9或Smad2/3)的翻译后修饰(如磷酸化和泛素化)显著影响其活性，从而调节靶细胞命运。与K48相关的蛋白质泛素化通常与其蛋白酶体降解有关，而与K63相关的泛素化则参与多种细胞事件，包括DNA修复、细胞内蛋白质运输和激酶信号传导。SMURF1 (Smad泛素化调节因子1)作为HECT (E6AP C端同源)型E3泛素连接酶的成员，泛素化R-Smads (Smad1/5)进行蛋白酶体降解，从而阻断BMP信号传导。此外，SMURF1通过I-Smads对BMPRI和Smad1/5的降解，下调BMP信号。在实验性肺动脉高压(PH)啮齿动物中，SMURF1显著升高。然而，SMURF1是否介导多环芳烃肺血管中BMP成分蛋白的泛素化以及任何再平衡机制目前尚不清楚。BRCC3在PAH减轻中的保护作用示意图（Credit: Circulation）PASMCs向高增殖状态的表型变化与肺血管重构和小动脉肌肉化的发展有关。在PAH患者和实验性PH动物的PASMCs中，抗增殖BMP信号下调，而TGF-β、激活素和GDFs(生长分化因子)诱导的促增殖信号增强。事实上，ActRIIA(一种激活素受体IIA的融合蛋白配体陷阱)能够抑制促增殖TGF-β信号，降低肺血管阻力，提高PAH患者的生存率(PulSAR和STELLAR试验)。该研究表明，BRCC3水平在人类多环芳烃疾病和啮齿动物PH模型中较低。BRCC3通过在PASMCs中去泛素化ALK2激活ALK2-Smad1/5/9-PPAR γ轴。因此，BRCC3似乎在疾病发病机制中拮抗SMURF1，上调和激活BRCC3可能是PAH/PH的一种新的治疗策略。原文链接https://doi.org/10.1161/CIRCULATIONAHA.123.066430责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文CRISPR技术进化史 | 24年Cell综述

2024年以来，MNC巨头默沙东股价已经录得21.65%涨幅，这对于数千亿美金市值“大块头”来说是难得的。默沙东有如此凶猛的股价表现，得益于一款重磅药物商业化的预期。3月26日，美国FDA批准了治疗肺动脉高压病（PAH）新药Winrevair（商品名）上市申请，隔日默沙东股价大涨4.96%。Winrevair每瓶定价1.4万美元（一般可使用三周），全年的费用约为24.2万美元。Winrevair的获批对默沙东显然是“及时雨”，公司超过40%的收入来自于K药（关键专利2028年到期），且公司超过30亿美元的单品屈指可数（HPV九价、西格列汀），Winrevair的商业化能够使其营收更加多元化，平滑大单品下滑的风险。同时，Winrevair也是全球医药行业投资者备受期待的重磅炸弹，2023年Evaluate评选出最有价值的在研新药TOP10榜单中，Winrevair位列第一。（图数据来源：Evaluate）而摩根大通分析师预计，可预见Winrevair将迅速成为肺动脉高压患者护理标准的一部分，2030年销售额有望达到50亿美元。01肺动脉高压：肺血管“癌症”肺动脉高压（PAH）是一种以肺动脉压力增高，伴有小肺动脉病变为特征的极度肺血管恶性疾病。PAH患者随着肺动脉压力升高，心脏负荷会持续加重，最终导致右心室肥大、心力衰竭，严重则导致死亡；在临床表现上，患者往往会出现气喘、脚肿、肚子胀、肝脏肿大、咯血等。PAH发病诱因较为复杂，先天性心脏病、瓣膜病、慢阻肺、风湿免疫等疾病都可能引发疾病，而特发性、遗传性肺动脉高压则属于罕见病。2019年国内数据显示，PAH患者如果不治疗，患者平均生存期仅为2.8年，又被称为“肺血管疾病中的癌症”。不过，随着靶向药物的发展，PAH患者生存期有着显著改善，1年生存期达到89%；5年生存期提升至53%。据柳叶刀杂志最新报道，2021年全球患肺动脉高压的人数占世界人口总量的1％，全球大约有4000万名肺动脉高压患者；而据国内最新数据显示，我国肺动脉高压患者约有500万至800万人。据贝哲斯咨询统计，2023年全球肺动脉高压药物市场规模到达到了449.58亿元，预估到2029年市场规模达到698.31亿元，2023-2029年复合增速约7.33%。在肺动脉高压药物市场，MNC巨头强生可谓是一马当先，早在2017年以300亿美元收购瑞士生物技术公司Actelion，获得了Opsumit、Uptravi等一系列肺动脉高压产品。2023年，强生的肺动脉高压治疗管线总营收38.15亿美元，同比增长11.6%。其中马西替坦（Opsumit）营收19.73亿美元，同比增长10.6%；赛乐西帕（UPTRAVI）销售额15.82亿美元，同比增长19.7%。尽管强生这笔押注肺动脉高压资产的交易投资回报率非常平庸，但依旧不缺乏MNC看好这个看起来“狭小”的药物赛道，除了2021年115亿美元收购Acceleron获得Winrevair外，2021年辉瑞也花了超60亿美元收购Arena，其资产组合包括用于肺动脉高压检测的Ralinepag。02Winrevair的突破性默沙东的Winrevair，为何能承载如此厚重的市场期望？目前，肺动脉高压主要通过扩张血管的药物进行治疗，如内皮素拮抗剂（ERA）、前列环素类似物及PDE5抑制剂来增加肺部血流量。其中前列腺素/前列环素类似物，以明确的临床证据获益（降低肺动脉压力和肺血管阻力、增加心排量&六分钟步行距离、延长生存时间等益处）占据肺动脉高压药物市场的主导地位，2022年占整个市场规模的45%，随后分别是内皮素拮抗剂、鸟苷酸环化酶激活剂、PDE5抑制剂等。但上述提到的治疗药物，绝大部分的治疗思路只是通过各种途径来促进肺血管扩张，目的是为了血流通过顺畅一些，只具备延缓疾病进程或改善患者症状的作用，并不能够逆转疾病进展。聚焦逆转肺血管重构的治疗策略，才能够打破原有肺血管扩张的治疗模式，破除现有“治标不治本”的窘境，Winrevair让市场看到了这种可能性。与其他药物不同的是，Winrevair是一种激活素信号抑制剂，是激活素受体IIA-Fc型（ActRIIA Fc）融合蛋白。Winrevair可选择性结合TGF-β家族配体，恢复BMPR-2信号通路的平衡（该通路失衡恰恰是肺动脉高压的驱动因素之一）。一方面从Winrevair机制的角度，其能够恢复肺动脉壁和右心室重构相关的促增殖和抗增殖信号通路之间的平衡，起到抑制细胞增殖、逆转血管重构和畅通血管的效果；另一方面，在临床前实验中它也证实了可逆转肺动脉壁和右心室的重塑。在默沙东2023年3月公布Winrevair三期临床STELLAR研究数据显示，在PAH患者中，Winrevair在治疗24周后将患者的6分钟行走距离（6MWD）与基线相比提高40.8米，达到试验主要终点。在9项次要重点分析中的8项显著和具有临床意义的改善，仅有AH-SYMPACT认知/情绪影响领域评分没有显著改善。与安慰剂相比，在中位随访时间为32.7周时，它将患者的疾病临床恶化或死亡风险降低84%，改善在持续使用该药物治疗的18至24个月期间维持。在安全性方面，接受Winrevair治疗的最常见副作用为轻微出血（鼻出血和牙龈出血）、毛细管扩张、头晕、血小板减少和血红蛋白水平升高以及升高血压，整体安全可耐受。Winrevair的上市，无疑在PAH治疗领域具备里程碑意义，不仅将该疾病治疗带入精准生物制剂时代，同时也突破了原有的治疗策略，进而明证Winrevair可能是当前最好的PAH治疗药物。03国内的机会尽管国内PAH患者群体占到全球数量10-20%，但相关创新药物的研发热度远不及肿瘤、自免等热门领域，同时目前国内获批PAH药物也普遍以国际上的老药为主。（图源：CPHI制药在线）更热闹的可能是PAH仿制药市场，以内皮素拮抗剂为例，如马昔腾坦、波生坦专利还未完全过期，已经分别有2家、8家药企正在争夺首仿。而部分前列腺素/前列环素类似物已经进入国产仿制药竞争时代，如曲前列尼尔，复星医药、兆科药业仿制药已经获批在市销售，销售增长惊人。从国内在研PAH创新药管线进展来看，几乎很少将肺动脉高压适应症作为主要的研发方向，这可能与国内市场的支付体系和相关药物研发难度有一定的关系。值得一提的是Biotech鸿运华宁，其开发了ETa特异性单抗GMA301，其汲取了ETa选择性拮抗剂的疗效优点，并对潜在可能的副作用进行结构改良；临床前研究表明，GMA301具有靶向特异性好、药效作用时间长、无肝毒性的特点。目前，GMA301正在进行全球多中心的Ib期临床。另外还值得注意的是港股上市Biotech云顶新耀（子公司云屹药业），早在2017年公司从Arena获得了Ralinepag的大中华区权益。已有的Ralinepag二期数据显示：接受其治疗后的患者不仅能够明显改善肺血管阻力（PVR），还可显著改善6分钟行走距离（6MWD）。目前云顶新耀正在国内推进Ralinepag的三期临床，其可能成为进度最接近商业化的PAH创新药物。（图源：CPHI制药在线）结语：从整体国内对肺动脉高压疾病领域的研发热情来看，我们很可能忽视了这类药物所蕴藏的巨大的机会。或许，需要Winrevair迸发出极大的商业化能量时，国内药企们才会如梦惊醒。免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

TREK-DX, the first randomized, double-blind, placebo-controlled study to be conducted in a dupilumab-experienced atopic dermatitis (AD) patient population, has started enrolling patients in the US under an updated protocol; new European sites are on track to open in the first half of 2024 In a preliminary review of blinded data from 22 patients treated to date, 45% (10/22) of patients saw at least a 90% reduction in their EASI score (EASI-90) and 50% (11/22) of patients achieved a vIGA score of 0 or 1 (clear or almost clear skin) after 16 weeks. Topline unblinded data from the full dataset is expected at the end of 2024 Translational data demonstrates differentiated effects of targeting IL-13R versus IL-4R, suggesting eblasakimab has the potential to be effective in AD patients that do not achieve an adequate response to dupilumab, a significant and underserved patient population with few safe and long-term treatment options SAN MATEO, Calif. and SINGAPORE, March 11, 2024 (GLOBE NEWSWIRE) -- ASLAN Pharmaceuticals Ltd. (Nasdaq: ASLN), a clinical-stage, immunology focused biopharmaceutical company developing innovative treatments to transform the lives of patients, today announced that it has begun to enroll patients in the US under an updated protocol in the ongoing TREK-DX trial, studying eblasakimab in dupilumab-experienced patients with moderate-to-severe atopic dermatitis (AD). TREK-DX is the first randomized, double-blind, placebo-controlled trial to be conducted in AD patients who have been previously treated with dupilumab, a market estimated to reach $10 billion by 20291. Based on findings from the TREK-AD study which highlighted the changing AD patient population in the US, the TREK-DX inclusion criteria have been tightened to enroll patients with a baseline Eczema Area and Severity Index (EASI) score of at least 18, instead of 16. In conjunction with this, independent reviewer confirmation of baseline EASI scores has also been implemented. US sites are now enrolling patients according to the updated criteria and additional sites in Europe are on track to open in the first half of 2024. TREK-DX will enroll approximately 75 patients who have discontinued dupilumab treatment for any reason, including inadequate control of AD, loss of access or an adverse event, and treat them with either 400mg eblasakimab or placebo once weekly for 16 weeks. At the time of the data cut off for this preliminary review of blinded data from 22 patients enrolled under the original inclusion criteria, who were randomized 2:1 active to placebo, 17 patients completed the 16 week treatment period and 5 patients discontinued before the completion of the 16 week treatment period. At 16 weeks or the last visit, EASI score decreased at least 90% (EASI-90) in 10 patients, or 45%, and 11 patients, or 50%, achieved a validated Investigator Global Assessment (vIGA) score of 0 or 1 (clear or almost clear skin). Of the 9 patients who previously had an inadequate response to dupilumab, 5 patients (56%) achieved EASI-90 and 5 patients (56%) a vIGA score of 0 or 1. Treatments have been well-tolerated to date and no new safety signals were identified. There have been no reports of conjunctivitis and no reports of injection site reactions. Topline unblinded data from the full dataset is expected at the end of 2024. “63% of dupilumab-treated patients fail to achieve clear or almost clear skin (IGA score of 0 or 1) after 16 weeks2, and around half of those patients that do achieve this response do not maintain it after the subsequent 36 weeks3, so there is a significant need for additional biologic therapies that could provide a safe and efficacious long-term treatment option for patients that do not achieve an adequate response to dupilumab. EASI-90 and vIGA are among the most stringent of endpoints in AD studies. Although this is based on a preliminary review of the blinded data, we are encouraged to observe a high percentage of patients in the TREK-DX study meeting these endpoints to date. Our market research found that most AD patients are only moderately satisfied with their current treatment. This, together with the translational data we have generated, supports the potential role of eblasakimab as a treatment for these patients, and the data we are generating in the TREK-DX study could demonstrate that, for many patients, eblasakimab could control their disease even where dupilumab has not,” saidDr Carl Firth, Chief Executive Officer, ASLAN Pharmaceuticals. Translational data demonstrates differentiated effects of targeting IL-13R versus IL-4R, suggesting eblasakimab has the potential to be effective even in instances where dupilumab is not Eblasakimab targets the IL-13 receptor (IL-13R) subunit of the Type 2 receptor, preventing signaling through both interleukin 4 (IL-4) and interleukin 13 (IL-13). Both are key drivers of inflammation in AD, however, recently published translational data highlighted the advantages of targeting IL-13R by eblasakimab over the IL-4 receptor (IL-4R), the target of dupilumab, in AD patient peripheral blood mononuclear cells4. IL-13R blockade resulted in more efficient reduction of cytokines implicated in Type 2-driven (allergic) inflammation compared to IL-4R blockade, as well as lower levels of Type 1 pro-inflammatory cytokines. Additional data from head-to-head studies between eblasakimab and dupilumab in skin biopsies from AD patients confirmed the differentiated effects of targeting IL-13R versus IL-4R5. In this study, eblasakimab reduced localized secretion of pro-inflammatory Type 2 cytokines by the skin tissue more efficiently than dupilumab, suggesting eblasakimab could have the potential to be effective in AD patients that do not achieve an adequate response to dupilumab. References Decision Resources Group (2023) Atopic Dermatitis Disease Landscape and Forecast Report Thaci et al (2019) J Dermatol Sci 94(2):266-275 Worm et al (2020) JAMA Derm 156(2):131-143 Cevikbas et al (2023) 1st International Society of Investigative Dermatology Meeting, May 10-14, 2023 Cevikbas et al (2023) 7th Annual Dermatology Drug Development Summit, October 31-November 2, 2023 About TREK-DX TREK-DX trial is a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the efficacy and safety of eblasakimab in patients with moderate-to-severe AD previously treated with dupilumab. The trial will enroll approximately 75 patients who have discontinued dupilumab treatment for any reason, including inadequate control of AD, loss of access or an adverse event. The trial consists of a 16-week treatment period and an 8-week safety follow-up period. The primary efficacy endpoint is percentage change in Eczema Area Severity Index (EASI) score from baseline to week 16. Key secondary efficacy endpoints include the proportion of patients achieving validated Investigator Global Assessment (vIGA) score of 0 (clear) or 1 (almost clear), proportion of patients with a 75% or greater reduction in EASI (EASI-75), proportion of patients achieving EASI-50 and EASI-90, and changes in peak pruritus. About eblasakimab Eblasakimab is a potential first-in-class monoclonal antibody targeting the IL-13 receptor subunit of the Type 2 receptor, a key pathway driving several allergic inflammatory diseases. Eblasakimab’s unique mechanism of action enables specific blockade of the Type 2 receptor and has the potential to improve upon current biologics used to treat allergic disease. By blocking the Type 2 receptor, eblasakimab prevents signaling through both interleukin 4 (IL-4) and interleukin 13 (IL-13) – the key drivers of inflammation in AD and Type 2 driven COPD. Positive results from the Phase 2b TREK-AD study in moderate-to-severe AD support eblasakimab’s potential to deliver a monthly dosing regimen from initiation in AD without compromising on efficacy and with an encouraging safety pro to date, with preparations for Phase 3 underway. ASLAN is also investigating eblasakimab in dupilumab experienced, moderate-to-severe AD patients in the Phase 2 TREK-DX study. About ASLAN Pharmaceuticals ASLAN Pharmaceuticals (Nasdaq: ASLN) is a clinical-stage, immunology-focused biopharmaceutical company developing innovative treatments to transform the lives of patients. ASLAN is developing eblasakimab, a potential first-in-class antibody targeting the IL-13 receptor in moderate-to-severe atopic dermatitis (AD) with the potential to improve upon current biologics used to treat allergic disease, and has reported positive topline data from a Phase 2b, dose-ranging study in moderate-to-severe AD patients. ASLAN is also investigating eblasakimab in dupilumab experienced, moderate-to-severe AD patients in the Phase 2 TREK-DX study with a topline data readout expected at the end of 2024. Farudodstat, a potent oral inhibitor of the enzyme dihydroorotate dehydrogenase (DHODH), is being developed by ASLAN as a potential first-in-class treatment for alopecia areata (AA) in a Phase 2a, proof-of-concept trial with an interim readout expected in mid-2024. ASLAN has teams in San Mateo, California, and in Singapore. For additional information please visit ASLAN’s website or follow ASLAN on LinkedIn. Forward-looking statements This release contains forward-looking statements. These statements are based on the current beliefs and expectations of the management of ASLAN Pharmaceuticals Limited and/or its affiliates (the "Company"). These forward-looking statements may include, but are not limited to statements regarding the Company’s business strategy and clinical development plans; the Company’s plans to develop and commercialize eblasakimab; statements related to the safety and efficacy of eblasakimab, including preliminary blinded data; the Company’s plans and expected timing with respect to manufacturing activities, clinical trials, clinical trial enrolment and clinical trial results for eblasakimab; and the potential of eblasakimab as a first-in-class treatment for atopic dermatitis. The Company’s estimates, projections and other forward-looking statements are based on management's current assumptions and expectations of future events and trends, which affect or may affect the Company’s business, strategy, operations, or financial performance, and inherently involve significant known and unknown risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of many risks and uncertainties, which include, unexpected safety or efficacy data observed during preclinical or clinical studies; risks that future clinical trial results may not be consistent with interim, initial or preliminary results or results from prior preclinical studies or clinical trials; risks that trends or characteristics based on preliminary blinded data may not be consistent with unblinded data; clinical site activation rates or clinical trial enrolment rates that are lower than expected; the impact of geopolitical conflicts and bank failures on the Company’s business and the global economy; general market conditions; changes in the competitive landscape; and the Company’s ability to obtain sufficient financing to fund its strategic and clinical development plans. Other factors that may cause actual results to differ from those expressed or implied in such forward-looking statements are described in the Company’s US Securities and Exchange Commission filings and reports (Commission File No. 001- 38475), including the Company’s Annual Report on Form 20-F filed with the US Securities and Exchange Commission on March 24, 2023. All statements other than statements of historical fact are forward-looking statements. The words “believe,” “may,” “might,” “could,” “will,” “aim,” “estimate,” “continue,” “anticipate,” “intend,” “expect,” “plan,” or the negative of those terms, and similar expressions that convey uncertainty of future events or outcomes are intended to identify estimates, projections, and other forward-looking statements. Estimates, projections, and other forward-looking statements speak only as of the date they were made, and, except to the extent required by law, the Company undertakes no obligation to update or review any estimate, projection, or forward-looking statement. ASLAN Media and IR contacts Emma Thompson Spurwing Communications Tel: +65 6206 7350 Email: ASLAN@spurwingcomms.com Ashley R. Robinson LifeSci Advisors, LLC Tel: +1 (617) 430-7577 Email: arr@lifesciadvisors.com