Acazicolcept

系统性红斑狼疮治疗的进展（1）系统性红斑狼疮治疗的进展（2）SLE疗法靶向免疫细胞与非免疫细胞的靶点概览：1）B细胞在遭遇抗原并经历滤泡或滤泡外成熟（处于活化B细胞状态）后，最终分化为抗体分泌性浆细胞。2）上图展示了从幼稚B细胞到浆细胞的不同分化阶段，以及各发育阶段特征性的抗原或细胞内靶点。3）同时显示了现有或在研药物靶向的其他细胞类型及其相关分子靶点。部分分子靶点具有高度特异性（如浆细胞样树突细胞特异性靶点血液树突细胞抗原2（BDCA2）），而其他靶点则无特异性（如靶向线粒体/代谢的广谱作用靶点）。*箭头标示了细胞外与细胞内靶点在相应细胞类型中的表达位置。浆细胞清除：浆细胞是B细胞最终分化为抗体分泌细胞的终末阶段（上图）。部分产生自身抗体的浆母细胞可进一步分化为定植于骨髓的长寿命浆细胞。这些浆细胞是长期自身免疫的核心驱动因素，并可能导致B细胞清除治疗后症状复发。浆细胞表达多种抗原：其中部分具有浆细胞特异性（如CD138或B细胞成熟蛋白（BCMA，亦称TNFRSF17），而其他抗原则同时表达于其他免疫细胞（如CD19或CD38）。达雷妥尤单抗（Daratumumab）是一种靶向CD38的单克隆抗体，最初开发用于多发性骨髓瘤，该药可通过清除CD38阳性细胞发挥作用，并在SLE和狼疮性肾炎（LN）患者中显示出显著疗效。其他靶向CD38的单克隆抗体也处于SLE药物研发管线中，包括美扎吉单抗（mezagitamab）（已完成Ib期研究，II期试验进行中）和菲扎妥单抗（felzartamab）（I期试验进行中）。FcRn：新生儿Fc受体（FcRn）亚型能促进循环免疫球蛋白的再循环，从而显著延长其半衰期。尼泊卡利单抗（nipocalimab）是一种靶向FcRn的无糖基化（无效应功能）IgG1抗体，研究显示该药能以剂量依赖性方式同步降低总抗体和自身反应性抗体水平，并在干燥综合征患者中伴随临床症状的改善。目前一项针对系统性红斑狼疮（SLE）的II期临床试验正在进行中（NCT04882878）。浆细胞样树突状细胞（pDCs）：I型干扰素（IFN-I）在系统性红斑狼疮（SLE）中的明确作用，推动了以其主要来源——浆细胞样树突状细胞为靶点的治疗策略发展。Litifilimab是一种具有前景的细胞毒性IgG1单克隆抗体，可特异性识别pDC标志物血液树突细胞抗原II（BDCA，亦称CLEC4C）。两项II期临床试验显示，Litifilimab对皮肤型狼疮和系统性红斑狼疮患者具有临床疗效，但对关节狼疮表现效果较弱。Daxdilimab是靶向免疫球蛋白样转录物7（ILT7，亦称LILRA4）的单克隆抗体，同样能清除pDC。在一项针对非肾脏受累型SLE的II期试验中（NCT04925934），Daxdilimab未达到主要疗效终点，但另一项针对狼疮性肾炎（LN）的研究目前正在进行中（NCT05540665）。3）靶向共刺激信号的抗体抗原呈递后的T细胞活化需要共刺激信号，该信号通过T细胞和抗原呈递细胞表面的同源受体与细胞表面配体结合来提供。CD40/CD40L轴是研发中最具前景且进展最快的通路，但还有其他若干通路也在开发中。CD40/CD40L轴：CD40及其配体CD40L参与自身抗原识别B细胞向浆母细胞和浆细胞的滤泡及滤泡外分化，并促进pDC产生IFN-I。首款CD40L单抗的试验因干预组患者发生动脉血栓而中止，这是由于该抗体与表达CD40L的活化血小板结合所致。然而从这些事件中获得的认知推动了新一代抗CD40L药物的开发，这些药物采用Fab片段或不含FcγRIIA激活功能的融合蛋白。包括达利珠单抗（dapirolizumab）聚乙二醇化物（一种聚乙二醇化抗CD40L   Fab片段）和达佐达利泊（dazodalibep）（一种结合CD40但缺乏Fc区的非抗体融合蛋白）。达利珠单抗近期已在SLE中进行测试，尽管II期试验未达到主要剂量反应疗效终点，但据报道III期研究取得阳性结果。相比之下，使用BI655064等单抗阻断CD40的策略在狼疮性肾炎（LN）试验中结果未达预期，其开发已被终止。另一款抗CD40单抗伊卡利单抗（iscalimab）目前正在SLE和LN患者中进行试验（NCT03656562和NCT03610516）。其他共刺激分子：主要的共刺激通路涉及受体CD28（表达于T细胞）及其配体CD80和CD86（表达于抗原呈递细胞）。可通过两种方式抑制共刺激：直接使用竞争性分子CTLA4-Ig（即阿巴西普）阻断CD28与其配体结合，或间接通过结合共抑制分子如PD1或B/T淋巴细胞衰减子（BTLA）。然而该策略的潜力尚未得到证实，因阿巴西普在II期试验中未显示临床疗效。尽管如此，首创的BTLA激动剂（单抗LY3361237）目前正处于SLE的II期研究阶段，预计很快公布结果（NCT05123586）。Acazicolcept是一种Fc结构域与工程化ICOSL变体的融合蛋白，能同时抑制CD28和可诱导T细胞共刺激因子（ICOS），目前正进行SLE的II期试验（NCT04835441）。Rigerimod（又名Lupuzor）——一种能与II类主要组织相容性复合体结合并抑制B细胞和T细胞活化的小核核糖核蛋白70U1——在成功完成II期试验后，未能在III期试验中达到主要终点（NCT02504645），但另一项III期试验正在筹备中。4）抗细胞因子疗法BAFF与APRIL：BAFF（亦称B淋巴细胞刺激因子，BlyS）是一种由髓系细胞、树突细胞或其他抗原呈递细胞及多种其他细胞类型分泌的细胞因子，能促进B细胞、浆母细胞和长寿命浆细胞的存活。BAFF受体（BAFF-R）在这些产生自身抗体的B细胞中表达上调，使BAFF/BAFF-R轴成为SLE病情发作和持续自身免疫的核心驱动因素。B细胞清除治疗后，循环BAFF水平会升高以重建B细胞池。这反过来又促进自身反应性B细胞在重建过程中的存活与扩增，导致总IgG和自身抗体水平升高，并可能加剧疾病。贝利尤单抗（Belimumab）（一种中和循环BAFF的IgG1λ单抗）已在两项III期研究中针对非肾脏受累型SLE进行评估，共纳入1,684例患者。研究显示其在自身抗体滴度及皮肤黏膜、关节和血管病变相关表现方面均有改善。安慰剂组SRI-4综合应答率为38.6%，而贝利尤单抗批准剂量组达50.6%（P  <  0.001）。这些成果使贝利尤单抗成为50多年来首个获批用于SLE的药物。后续研究（BLISS-LN试验）证实贝利尤单抗可改善LN患者的长期肾脏结局。该药可采用皮下给药，长期扩展研究显示其安全性良好至少达11年，能阻止器官损伤进展并减少糖皮质激素需求。鉴于B细胞清除后BAFF水平升高，一项III期研究评估了利妥昔单抗治疗后使用贝利尤单抗的临床意义。然而虽在抗dsDNA抗体下降更显著（P  = 0.0495），但临床应答（第52周疾病控制，OR 1.27，95% CI 0.6–2.71，P =  0.53）未达统计学显著改善。此外，贝利尤单抗在妊娠期使用也可获得良好结局。这些长期疗效与安全性数据支持了EULAR建议：SLE患者应考虑早期使用贝利尤单抗或阿尼鲁单抗（anifrolumab）等生物制剂。泰它西普（Telitacicept）同样靶向BAFF信号通路。该药是一种由跨膜激活剂钙调节亲环素配体相互作用因子（TACI，亦称TNFRSF13B）受体构成的融合蛋白，可同时识别BAFF和增殖诱导配体（APRIL）。IIb研究显示泰它西普对非肾脏受累型SLE患者有效，目前正在进行III期研究（NCT05306574）。靶向IFN-I疗法：50-90%的SLE患者存在I型干扰素（IFN-I）特征性基因表达，这对先天性和适应性免疫细胞产生多重失调效应。IFN-I蛋白家族包含13种IFN-α亚型，以及IFN-ß、IFN-κ、IFN-ω和IFN-ε，所有这些亚型都能结合并激活IFN-α受体（IFNAR）。多种靶向IFN-α的单抗（包括rontalizumab和sifalimumab）未能在SLE中证明疗效。这种失败可能源于无法抑制所有这些（多数具有功能冗余的）IFN-α亚型。阿尼鲁单抗（Anifrolumab）是一种靶向IFNAR受体（所有IFN-I亚型共用）的IgG1κ单抗，在两项III期试验（TULIP-1和TULIP-2）中针对SLE进行评估。尽管试验结果存在差异（TULIP-2达到主要终点，而TULIP-1未达到），但多项次要终点显示阿尼鲁单抗组更具优势，使其最终获批用于SLE治疗。总体而言，阿尼鲁单抗组30%的患者达到LLDAS（狼疮低疾病活动状态），安慰剂组仅为19.6%（P  =  0.0011）。与pDC单抗litifilimab类似，阿尼鲁单抗在皮肤黏膜型SLE患者中显示出卓越疗效。值得注意的是，在具有IFN-I特征性表达（占入组患者的80%）与无此特征的患者之间，疗效差异甚微。目前一项针对狼疮性肾炎（LN）的试验正在进行中（NCT05138133）。然而，阻断IFN-I会增加病毒感染或再激活风险（如水痘-带状疱疹病毒或流感），可通过伐昔洛韦预防或疫苗接种来规避。IL-23与IL-17：细胞因子IL-23在初始CD4+T细胞极化为Th17致病表型的过程中早期参与作用。Th17细胞通过产生IL-17参与系统性红斑狼疮（SLE）疾病进展和器官炎症，该细胞因子可招募其他免疫细胞。乌司奴单抗（ustekinumab）——一种通过中和IL-12和IL-23共有亚基p40来抑制Th17极化的单克隆抗体——已在SLE临床试验中作为IL-23靶向治疗药物进行测试。虽然乌司奴单抗的II期试验在SLE治疗中显示出良好前景，但这些结果在后续III期试验中未能复现。古塞奇尤单抗（guselkumab）是另一种抗IL-23单克隆抗体，目前正在狼疮性肾炎患者中进行试验（NCT04376827）。抗IL-17A单抗司库奇尤单抗（secukinumab）可中和Th17细胞产生的IL-17，其III期试验因无效性分析而提前终止（NCT04181762）。其他细胞因子靶点：针对SLE其他细胞因子的单抗试验，例如靶向IL-6（PF-04236921）、IL-6受体（vobarilizumab，NCT02437890）或参与T细胞依赖性B细胞成熟的IL-21（BOS161721，NCT03371251），均未显示出临床意义的改善。同样，通过单抗BT063（NCT02554019）抑制具有免疫调节特性的B细胞成熟相关细胞因子IL-10，也未能证明临床有效性。参考文献：https:///10.1038/s41573-025-01242-0

SEATTLE--(BUSINESS WIRE)-- Alpine Immune Sciences, Inc. (NASDAQ: ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for autoimmune and inflammatory diseases, today reported financial results for the first quarter ended March 31, 2024. On April 10, 2024, Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) and Alpine announced that the companies had entered into a definitive agreement under which Vertex will acquire Alpine for $65 per share in cash. The transaction was unanimously approved by both the Vertex and Alpine Boards of Directors and is anticipated to close in the second quarter of 2024. First Quarter 2024 Financial Results Cash Position and Runway: As of March 31, 2024, Alpine's cash and investments totaled $362.4 million compared to $368.2 million as of December 31, 2023. The Company anticipates its current cash and investments are sufficient to fund planned operations into 2026. Collaboration Revenue: For the three months ended March 31, 2024, collaboration revenue was $7.0 million compared to $9.4 million for the same period in 2023. The decrease in collaboration revenue relates primarily to a $1.8 million decrease in Amgen revenue, due to work progressing simultaneously during the 2023 period on our second Research Program, which was completed in 2023, as well as on our first Research Program, which as of March 31, 2024, was also nearing completion. AbbVie revenue decreased by $0.2 million primarily due to lower contributed employee hours. All services related to our Adaptimmune collaboration were completed by June 2023. Research and Development Expense: For the three months ended March 31, 2024, research and development expense, inclusive of non-cash expenses, was $22.5 million compared to $19.6 million for the same period in 2023. The increase of $2.9 million was driven by an $4.8 million increase in povetacicept costs, primarily related to higher clinical trial, process development and manufacturing costs as we continue our RUBY studies, and a $1.6 million increase in personnel costs. This increase was partially offset by a $2.7 million decrease in acazicolcept costs, which was primarily due to decreased manufacturing costs during the 2024 period, and a $1.4 million decrease in davoceticept costs, which was due to study closeout following the voluntary termination of enrollment in our NEON-1 and NEON-2 clinical studies in October 2022. General and Administrative Expense: For the three months ended March 31, 2024, general and administrative expense, inclusive of non-cash expenses, was $7.3 million compared to $5.4 million for the same period in 2023. The increase of $1.9 million was primarily attributable to increases in personnel costs and professional services. Net Loss: Net loss for the three months ended March 31, 2024, was $17.9 million compared to $13.3 million for the same period in 2023. Alpine Immune Sciences, Inc. Selected Condensed Consolidated Balance Sheet Data (In thousands) March 31, 2024 December 31, 2023 (unaudited) Cash and cash equivalents $ 33,015 $ 43,921 Short-term investments 272,646 283,491 Total current assets 308,251 330,034 Long-term investments 56,453 40,556 Total assets 373,646 379,852 Total current liabilities 32,238 41,980 Total stockholders’ equity 332,703 327,941 Total liabilities and stockholders’ equity 373,646 379,852 Condensed Consolidated Statement of Operations and Comprehensive Income (Loss) Data (In thousands, except share and per share amounts) Three Months Ended March 31, 2024 2023 (unaudited) Collaboration revenue $ 7,032 $ 9,387 Operating expenses: Research and development 22,457 19,581 General and administrative 7,271 5,398 Total operating expenses 29,728 24,979 Loss from operations (22,696 ) (15,592 ) Other income (expense): Interest income 4,781 2,418 Interest expense — (70 ) Other, net (3 ) (22 ) Net loss $ (17,918 ) $ (13,266 ) Comprehensive income (loss): Unrealized (loss) gain on investments (551 ) 745 Unrealized loss on foreign currency translation (109 ) (31 ) Comprehensive loss $ (18,578 ) $ (12,552 ) Weighted-average shares used to compute basic and diluted net loss per share 64,033,018 47,568,149 Basic and diluted net loss per share $ (0.28 ) $ (0.28 ) About Alpine Immune Sciences Alpine Immune Sciences is committed to leading a new wave of immune therapeutics. With world-class research and development capabilities, a highly productive scientific platform, and a proven management team, Alpine is seeking to create first- or best-in-class multifunctional immunotherapies via unique protein engineering technologies to improve patients’ lives. Alpine has entered into strategic collaborations with leading global biopharmaceutical companies and has a diverse pipeline of clinical and preclinical candidates in development. For more information, visit . Follow @AlpineImmuneSci on X and LinkedIn. Special Note Regarding Forward-Looking Statements This press release contains forward-looking statements related to Vertex, Alpine and the proposed acquisition of Alpine by Vertex (the “Transaction”) that are subject to risks, uncertainties and other factors. While Vertex believes the forward-looking statements contained in this communication are accurate, these forward-looking statements represent the beliefs of Alpine and Vertex only as of the date of this communication, and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements, including all statements regarding the intent, belief or current expectation of the companies’ and members of their senior management teams. Forward-looking statements are not purely historical and may be accompanied by words such as “anticipates,” “may,” “forecasts,” “expects,” “intends,” “plans,” “potentially,” “believes,” “seeks,” “estimates,” and other words and terms of similar meaning. Such statements may relate to: the ability of Vertex to advance Alpine’s platform technology and potential therapies, such as povetacicept, on a timely basis; filings and approvals relating to the Transaction; the expected timing of the completion of the Transaction; the ability to complete the Transaction considering the various closing conditions; difficulties or unanticipated expenses in connection with integrating the companies; and any assumptions underlying any of the foregoing. Forward-looking statements are subject to certain risks, uncertainties, or other factors that are difficult to predict and could cause actual events or results to differ materially from those indicated in any such statements due to a number of risks and uncertainties. Those risks and uncertainties that could cause the actual results to differ from expectations contemplated by forward-looking statements include, among other things: uncertainties as to the timing of the Transaction; uncertainties as to how many of Alpine’s stockholders will tender their stock in the offer; the possibility that various closing conditions for the Transaction may not be satisfied or waived, including that a governmental entity may prohibit, delay or refuse to grant approval for the consummation of the Transaction; the effects of the Transaction on relationships with employees, other business partners or governmental entities; the difficulty of predicting the timing or outcome of FDA approvals or actions, if any; the impact of competitive products and pricing; that Vertex may not realize the potential benefits of the Transaction; other business effects, including the effects of industry, economic or political conditions outside of the companies’ control; Transaction costs; and actual or contingent liabilities related to the Transaction. In addition, the product candidates being developed by Alpine are subject to all the risks inherent in the drug development process, and there can be no assurance that the development of these product candidates will be commercially successful. Forward-looking statements in this communication should be evaluated together with the many uncertainties that affect Vertex’s and Alpine’s businesses, particularly those risks listed under the heading “Risk Factors” and the other cautionary factors discussed in the parties’ periodic reports filed with the Securities and Exchange Commission (the “SEC”), including Vertex’s annual report on Form 10-K for the year ended December 31, 2023, and its quarterly reports on Form 10-Q and current reports on Form 8-K, and Alpine’s annual report on Form 10-K for the year ended December 31, 2023, and its quarterly reports on Form 10-Q and current reports on Form 8-K, as well as the Solicitation/Recommendation Statement filed by Alpine and the Tender Offer Materials filed by Vertex and Adams Merger Sub, Inc., a direct wholly owned subsidiary of Vertex, all of which are available for free on the SEC’s website at . You should not place undue reliance on these statements. All forward-looking statements are based on information currently available to Vertex and Alpine, and Vertex and Alpine disclaim any obligation to update the information contained in this communication as new information becomes available, except as required by law. Additional Information and Where to Find It In connection with the proposed acquisition of Alpine, Vertex caused its acquisition subsidiary to commence a tender offer for all the issued and outstanding shares of common stock of Alpine. This communication is for informational purposes only and is neither an offer to purchase nor a solicitation of an offer to sell shares of Alpine, nor is it a substitute for any tender offer materials that Vertex or Alpine filed with the SEC. Vertex has filed with the SEC a Tender Offer Statement on Schedule TO which includes an Offer to Purchase, a related Letter of Transmittal and certain other tender offer documents (together, the “Tender Offer Materials”), and Alpine has filed with the SEC a Solicitation/Recommendation Statement on Schedule 14D-9 (the “Solicitation/Recommendation Statement”) with respect to the tender offer. ALPINE’S SECURITY HOLDERS ARE URGED TO READ THE TENDER OFFER MATERIALS AND THE SOLICITATION/RECOMMENDATION STATEMENT BECAUSE THEY CONTAIN IMPORTANT INFORMATION WHICH SHOULD BE READ CAREFULLY BEFORE ANY DECISION IS MADE WITH RESPECT TO THE TENDER OFFER. The Tender Offer Materials and the Solicitation/Recommendation Statement are available for free at the SEC’s website at . Additional copies may be obtained free of charge under the “Investors” section of Vertex’s website at or by contacting Vertex by phone at (617) 341-6108 or by email at InvestorInfo@vrtx.com, or by directing requests for such materials to the information agent for the offer, which will be named in the Tender Offer Materials. In addition to the Tender Offer Materials and the Solicitation/Recommendation Statement, Alpine and Vertex reports and other information with the SEC. Vertex’s and Alpine’s filings with the SEC are also available for free to the public from commercial document-retrieval services and at the website maintained by the SEC at and their respective investor relations websites at the addresses above. View source version on businesswire.com: Contacts Investor and Media Contact: Alpine Immune Sciences, Inc. ir@alpineimmunesciences.com media@alpineimmunesciences.com Source: Alpine Immune Sciences, Inc. View this news release online at: