Siltuximab

28岁的林女士，近半年总觉得人有点“虚”——容易疲劳、体重莫名下降、还总是低烧、盗汗。本以为是工作压力大，拖着没当回事。直到某天，她无意中摸到左腋下有个小包块，按压不疼，但越来越大，她才决定去医院看看。B超显示：腋窝肿块约3.8×2.5cm，血常规显示贫血、CRP升高、白蛋白偏低。医生建议住院进一步评估。胸腹增强CT提示：纵隔、腹膜后多个淋巴结增大，一时间，“淋巴瘤？”“肿瘤转移？”成了家人最担心的词。最终在全麻下行腋下肿块切除手术。可病理结果却出乎所有人意料：淋巴结增生性病变，符合Castleman病（卡斯特曼病），浆细胞型。这是一种罕见的淋巴结增生性疾病，容易误诊为淋巴瘤或感染性疾病，既非良性肿瘤，也不完全是癌症。林女士的病情进一步检查后，被诊断为多中心性Castleman病（MCD），需长期随访和治疗。什么是卡斯尔曼病Castleman 病（Castleman disease，CD），卡斯尔曼病，又称巨大淋巴结病或血管滤泡性淋巴结增生症。是一种较为少见的淋巴增生性疾病。1956 年由 Benjamin Castleman 首次报道。临床上根据肿大淋巴结分布和器官受累的情况不同，可将 CD 分为单中心型（unicentric CD，UCD） 和多中心型（multicentric CD，MCD）。前者往往仅累及单个淋巴结区域，相关症状较轻，外科治疗效果良好；后者则累及多个淋巴结区域，有较为明显的全身症状，预后较差。临床表现CD是一种罕见的淋巴组织增生性疾病，临床表现多样，轻则无症状，仅表现为淋巴结肿大，重则可引发严重的全身炎症反应和多器官功能障碍。确诊需依赖淋巴结活检，并排除其他疾病。单中心型卡斯尔曼病（UCD）通常仅累及身体某一部位的单个或多个淋巴结，常见于胸部、颈部或腹部。多数UCD患者无明显症状，仅因肿大的淋巴结压迫周围结构引发不适。个别患者可出现低热、乏力、体重减轻、皮疹等轻度系统症状，这些表现通常在病灶切除后缓解。部分患者可能伴有副肿瘤性天疱疮、闭塞性细支气管炎或发育迟缓。多中心型卡斯尔曼病（MCD）表现为多个区域淋巴结肿大，并伴有明显的全身炎症症状，如发热、盗汗、乏力、贫血、水肿、肝脾肿大及肾功能异常。MCD可分为HHV-8阳性型和特发性型（iMCD）。其中iMCD又包括TAFRO亚型和NOS亚型，前者病情进展迅猛，伴血小板减少、水肿、骨髓纤维化和器官肿大，后者则表现相对温和，常伴血小板增多和免疫球蛋白升高。HHV-8相关MCD多见于免疫功能低下者，常合并HIV感染及卡波西肉瘤等。此外，iMCD可能与POEMS综合征、恶性肿瘤或其他免疫紊乱相关联。UCD患者虽然较少出现严重并发症，但应警惕副肿瘤性天疱疮的发生，其为UCD最致命的潜在并发症。诊断Castleman病的诊断较为复杂，因其临床表现多样且与多种常见疾病（如感染、淋巴瘤、自身免疫病）相似，常被误诊或漏诊。确诊通常需结合临床表现、实验室检查、影像学评估以及病理组织学特征，并在排除其他可能疾病后作出。诊断主要依赖以下三类评估：一是淋巴结活检，这是诊断的核心环节。需进行完整的切除性活检，而非细针抽吸或核心活检。镜下典型特征包括退化性或增生性生发中心、滤泡树突状细胞增生、小血管过度增生、浆细胞浸润等。根据组织学特征，Castleman病可分为三型：透明血管型、浆细胞型和混合型。二是实验室检查，用于评估系统性炎症和器官功能情况。常规项目包括全血细胞计数、C反应蛋白（CRP）、红细胞沉降率（ESR）、肝肾功能、白蛋白、免疫球蛋白，以及HIV/HHV-8检测。HHV-8阳性提示HHV-8相关的多中心型Castleman病（MCD）。三是影像学检查，如X光、CT、PET-CT等，用于评估淋巴结分布及活性，辅助判断是否为单中心型（UCD）或多中心型（MCD）。各亚型诊断要点如下：UCD：表现为单一部位淋巴结肿大，多无全身症状，诊断依赖切除淋巴结的病理特征。HHV-8阳性的MCD：具备多发淋巴结肿大、炎症症状、活检显示“Castleman样”病理特征且HHV-8阳性。iMCD（特发性MCD）：需符合两个主要标准（特征性活检病理＋多区域淋巴结肿大）及11个次要标准中至少2项（至少1项为实验室异常），并排除感染、肿瘤和自身免疫病。Castleman病的诊断本质上是排除性诊断，依赖病理证据和系统性临床评估，需多学科合作，以确保准确识别和分类。治疗Castleman病的治疗根据亚型不同而异，主要分为单中心型（UCD）、特发性多中心型（iMCD）和HHV-8相关多中心型（HHV-8 MCD）。1. 单中心型Castleman病（UCD）UCD首选治疗是手术切除受累淋巴结，通常可治愈。若无法手术或复发，依据症状选择治疗：压迫症状可用利妥昔单抗，炎症症状可用抗IL-6治疗（如Siltuximab），必要时辅以放疗。2. 特发性多中心型Castleman病（iMCD）一线治疗为抗IL-6抗体Siltuximab（无此药时用Tocilizumab）。无效时可考虑糖皮质激素、利妥昔单抗、西罗莫司或化疗。部分轻症患者可先观察，重症者或器官功能受损者可联合化疗或短期激素治疗。沙利度胺等免疫调节药也有一定疗效。3. HHV-8相关多中心型Castleman病（HHV-8 MCD）利妥昔单抗是一线治疗，有时需联合抗病毒（如更昔洛韦）或细胞毒化疗。若合并HIV感染，推荐联合抗反转录病毒治疗，但避免使用骨髓抑制较强的药物如齐多夫定。总体上，Castleman病的治疗需根据亚型、症状严重程度及是否合并感染进行个体化方案选择。参考资料：1.Van Rhee F, Voorhees P, Dispenzieri A, et al. International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 2018 Nov 15;132(20):2115-2124. doi: 10.1182/blood-2018-07-862334. Epub 2018 Sep 2. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-1657.3. Liu AY, Nabel CS, Finkelman BS, et al. Idiopathic multicentric Castleman’s disease: a systematic literature review. The Lancet Haematology. 2016;3(4):e163-e175.来源 | 梅斯医学编辑 | wanny神经系统罕见病交流群↓点击下方“阅读原文”，下载梅斯医学APP吧！

– Rapid, deep, and durable reductions in high-sensitivity C-reactive protein (hs-CRP) through Day 90 achieved across all pacibekitug arms with high statistical significance as compared to placebo (p<0.0001 for all arms) – – Pacibekitug becomes the first and only IL-6 inhibitor known to demonstrate deep hs-CRP reductions with quarterly dosing in a clinical trial, achieving >85% hs-CRP reductions from baseline in the 50 mg quarterly arm – – Overall incidence rates of adverse events and serious adverse events in the pacibekitug groups were comparable to placebo through the data extract date – – Results from TRANQUILITY support the advancement of pacibekitug into a potential Phase 3 cardiovascular outcomes trial in atherosclerotic cardiovascular disease and a planned Phase 2 proof-of-concept trial in abdominal aortic aneurysm – – Conference call and webcast to be held today, May 20 at 8:30 a.m. ET – NEW YORK, May 20, 2025 (GLOBE NEWSWIRE) -- Tourmaline Bio, Inc. (Tourmaline) (NASDAQ: TRML), a late-stage clinical biotechnology company developing transformative medicines to dramatically improve the lives of patients with life-altering immune and inflammatory diseases, today announced positive topline results from its ongoing Phase 2 TRANQUILITY trial evaluating quarterly and monthly subcutaneous dosing of pacibekitug in patients with elevated high-sensitivity C-reactive protein (hs-CRP), a biomarker associated with elevated cardiovascular risk, and chronic kidney disease (CKD). The TRANQUILITY trial is the starting point of Tourmaline’s clinical development program for pacibekitug for the potential treatment of atherosclerotic cardiovascular disease (ASCVD) and other cardiovascular diseases. “We are thrilled with the data emerging from the TRANQUILITY trial and the remarkable consistency of signal across all endpoints evaluated. All active arms achieved rapid, deep, and durable reductions in hs-CRP, and overall incidence rates of adverse events and serious adverse events were comparable between pacibekitug and placebo. Importantly, this is the first time that pacibekitug or any IL-6 inhibitor has been tested in a clinical trial with quarterly dosing. It is well-recognized that less frequent administration has the potential to enhance patient adherence and ultimate clinical benefit,” said Sandeep Kulkarni, MD, Co-Founder and Chief Executive Officer of Tourmaline. “Given the strength of the data, we look forward to accelerating development of pacibekitug within atherosclerotic cardiovascular disease and abdominal aortic aneurysm. We anticipate sharing additional data from the TRANQUILITY trial at an upcoming medical conference.” “There is strong evidence suggesting that elevated levels of high-sensitivity C-reaction protein (hs-CRP) are a predictor of increased cardiovascular risk, and quarterly subcutaneous administration of pacibekitug in the TRANQUILITY trial demonstrated large and significant reductions in hs-CRP levels through Day 90,” said Dr. Deepak L. Bhatt, Director of the Mount Sinai Fuster Heart Hospital, the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York, and Chair of Tourmaline’s Cardiovascular Scientific Advisory Board (for which he is compensated). “Based upon these results, pacibekitug merits testing in future Phase 3 trials for cardiovascular risk reduction.” TRANQUILITY Topline Results: TRANQUILITY Trial Design TRANQUILITY (NCT06362759) is a multicenter, randomized, double-blind, placebo-controlled Phase 2 trial in patients with elevated hs-CRP and CKD stage 3 or 4. Participants were stratified by CKD stage and randomly assigned to receive subcutaneously administered pacibekitug 25 mg quarterly, 50 mg quarterly, or 15 mg monthly, or placebo, for a treatment period of 6 months. Participants are then followed for a period of 6 additional months. The prespecified primary endpoint of the TRANQUILITY trial is median time-averaged percent change in hs-CRP through Day 90, adjusting for baseline hs-CRP levels. The key secondary endpoint is the percentage of participants achieving time-averaged hs-CRP below 2 mg/L through Day 90. Additional prespecified endpoints include the aforementioned hs-CRP endpoints at Day 90 (i.e., using single-timepoint analyses) as well as the percentage of participants achieving hs-CRP reductions of 50% or greater. The prespecified primary analysis population includes participants who entered the study with a baseline hs-CRP of at least 1.9 mg/L (calculated as the average of Screening and Day 1 values), had at least one post-baseline hs-CRP assessment, and received all planned study drug doses during the primary evaluation period. The data in this analysis reflect a data extract date of April 23, 2025 from the ongoing trial. TRANQUILITY Baseline CharacteristicsA total of 143 participants were enrolled in the TRANQUILITY trial. Of this total, 126 participants comprised the primary analysis population. Baseline characteristics were generally balanced between groups. Key baseline characteristics of the primary analysis population are as follows: PacibekitugPlacebon=3125 mg quarterlyn=3150 mg quarterlyn=3015 mg monthlyn=34Age, years72 (62, 77)73 (66, 76)70 (61, 78)65 (60, 73)Female21 (68%)17 (55%)19 (63%)21 (62%)ASCVD15 (48%)16 (52%)20 (67%)7 (21%)Diabetes21 (68%)16 (52%)20 (67%)19 (56%)Body-mass index, kg/m233.4 (29.7, 36.3)32.2 (28.1, 35.6)35.1 (30.7, 39.8)33.4 (30.2, 36.3)eGFR, mL/min/1.73m243.5 (33.5, 53.0)37.5 (33.0, 47.0)48.0 (36.5, 56.5)42.5 (36.0, 57.0)IL-6, pg/mL4.91 (3.32, 5.93)4.62 (2.87, 7.30)5.56 (3.58, 10.03)4.86 (2.39, 7.83)hs-CRP, mg/L3.60 (2.70, 5.10)3.90 (2.35, 5.55)5.18 (3.60, 7.35)4.73 (3.80, 7.40) Data provided are median (interquartile range) or n (%). eGFR: estimated glomerular filtration rate. TRANQUILITY Pharmacodynamic DataKey pharmacodynamic data for the primary analysis population are as follows (p<0.0001 for all comparisons to placebo): PacibekitugPlacebon=3125 mg quarterlyn=3150 mg quarterlyn=3015 mg monthlyn=34Change from baseline analyses:Median time-averaged percent reduction in hs-CRP through Day 90 (primary endpoint)15%75%86%85%Median percent reduction in hs-CRP at Day 9012%70%85%89%Responder rate analyses:Percentage of participants achieving time-averaged hs-CRP < 2 mg/L through Day 9026%81%80%88%Percentage of participants achieving hs-CRP < 2 mg/L at Day 9013%77%83%88%Percentage of participants achieving time-averaged hs-CRP reduction >= 50% through Day 9019%81%87%94%Percentage of participants achieving hs-CRP reduction >= 50% at Day 9016%81%90%91% Results of post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat (ITT) population, i.e., all randomized participants, were highly consistent with the primary analyses above. TRANQUILITY Safety DataAs of the data extract date, the cumulative incidence of any adverse event (AE) was 54% in the pooled pacibekitug group, compared with 56% in the placebo group. The most common AEs in the pooled pacibekitug group, defined as those occurring in at least 3 pacibekitug-treated participants, were urinary tract infection (4%), COVID-19 (3%), dizziness (3%), and viral upper respiratory tract infection (3%). The majority of AEs were mild or moderate in severity and were single occurrences in one participant each. The overall incidence of any serious adverse event (SAE) was 10% in the pooled pacibekitug group versus 11% in the placebo group. Incidence rates of infection (24% vs 22%) and serious infection (4% vs 3%) were similar in the pooled pacibekitug group compared with the placebo group. There was no increase in AE incidence with higher pacibekitug doses. There was one death, a fatal case of COVID-19, that occurred in the 25 mg quarterly arm. There were no Grade 2 or higher injection site reactions. There were no cases of confirmed Grade 3 or higher neutropenia and no cases of confirmed Grade 2 or higher thrombocytopenia. No clinically meaningful median percent changes in LDL cholesterol, triglycerides, or total cholesterol to HDL cholesterol ratio were observed in pacibekitug arms compared to placebo. Cumulative safety data from the TRANQUILITY trial as of the data extract date are as follows: PacibekitugPlacebon=36Pooledn=10525 mg quarterlyn=3550 mg quarterlyn=3515 mg monthlyn=35AEs 20 (56%)57 (54%)20 (57%)18 (51%)19 (54%)SAEs 4 (11%)10 (10%)6 (17%)2 (6%)2 (6%)AEs leading to discontinuation02 (2%)01 (3%)1 (3%)Infection8 (22%)25 (24%)10 (29%)9 (26%)6 (17%)Serious infection 1 (3%)4 (4%)4 (11%)00Death01 (1%)*1 (3%)*00Injection site reaction Grade 2+00000Neutropenia Grade 21 (3%)2 (2%)1 (3%)01 (3%)Neutropenia Grade 3+ 00000Thrombocytopenia Grade 2+ 00000 Safety analysis population n=141.*: Fatal case of COVID-19. Future Development Plans for Pacibekitug in Cardiovascular Inflammation:Tourmaline continues to make progress in advancing the clinical development strategy for pacibekitug in cardiovascular inflammation and assessing potential Phase 3 trial designs in patients with ASCVD. Tourmaline expects to provide further information on a potential Phase 3 cardiovascular outcomes trial in ASCVD later in 2025 following discussions with regulatory authorities. Additionally, Tourmaline plans to initiate a Phase 2 proof-of-concept trial in patients with abdominal aortic aneurysm (AAA) in the second half of 2025. AAA is a common, serious vascular condition characterized by weakening and progressive enlargement of the abdominal aorta that can result in rupture and death. There is no approved medical therapy to slow or halt the growth of AAA. IL-6-driven inflammation is considered a critical mechanism promoting aneurysm expansion. The therapeutic potential of IL-6 inhibition for the treatment of AAA is supported by human genetic studies, epidemiological evidence, and mouse models of AAA. “Both monthly and quarterly dosing of pacibekitug achieved significant, rapid, and sustained IL-6 pathway inhibition, as shown by robust reductions in hs-CRP in TRANQUILITY. We are excited to advance the development of pacibekitug to address significant unmet needs of patients with high-risk cardiovascular diseases driven by inflammation, including ASCVD and AAA,” said Emil deGoma, MD, Senior Vice President of Medical Research at Tourmaline. Conference Call and Webcast Information:Tourmaline will host a live conference call and webcast to discuss these results beginning at 8:30 a.m. ET today, May 20, 2025. Members of Tourmaline management will be joined by Dr. Deepak L. Bhatt, Director of the Mount Sinai Fuster Heart Hospital and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York. Dr. Bhatt also serves as the Chair of Tourmaline’s Cardiovascular Scientific Advisory Board (for which he is compensated). To register for this event, please click here or visit the Events and Presentations section of Tourmaline’s website. A replay of the event will be available on Tourmaline’s website following the event. It is recommended that participants register at least 15 minutes in advance of the event. About Tourmaline Bio:Tourmaline is a late-stage clinical biotechnology company driven by its mission to develop transformative medicines that dramatically improve the lives of patients with life-altering immune and inflammatory diseases. Tourmaline’s lead asset is pacibekitug. For more information about Tourmaline Bio and pacibekitug, please visit https://www.tourmalinebio.com or follow us on LinkedIn or X. About Pacibekitug:Pacibekitug is a long-acting, fully-human, anti-IL-6 monoclonal antibody with best-in-class potential and differentiated properties including a naturally long half-life, low immunogenicity, and high binding affinity to IL-6. Excluding ongoing trials, pacibekitug was previously studied in approximately 450 participants, including patients with autoimmune disorders, across six completed clinical trials. Tourmaline is currently developing pacibekitug in atherosclerotic cardiovascular disease (ASCVD) and thyroid eye disease (TED) as its first two indications, with plans to expand into abdominal aortic aneurysm (AAA) and additional diseases in the future. Cautionary Note Regarding Forward-Looking Statements:Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements may be identified by words and phrases such as “believe,” “designed to,” “expect,” “may,” “plan,” “potential,” “will” and similar expressions, and are based on Tourmaline’s current beliefs and expectations. These forward-looking statements include expectations regarding the development and potential therapeutic benefits of pacibekitug, including the potential best-in-class profile of pacibekitug and the anticipated progression of pacibekitug into future clinical trials; the timing of initiation, progress and results of Tourmaline’s current and future clinical trials for pacibekitug, including the timing of a planned Phase 2 proof-of-concept clinical trial in patients with AAA and of Phase 3 clinical trial readiness in ASCVD, as well as reporting of data therefrom and additional details regarding the planning thereof; the timing of future announcements regarding Tourmaline’s development plans and the content of such announcements; the timing and likelihood of seeking regulatory approval for Tourmaline’s product candidates, including pacibekitug; the unmet need in Tourmaline’s target indications and the potential for pacibekitug to address such unmet need; and the timing and potential to expand pacibekitug into additional indications. These statements involve risks and uncertainties that could cause actual results to differ materially from those reflected in such statements. Risks and uncertainties that may cause actual results to differ materially include additional safety events occurring after the data extract date of April 23, 2025, as participants complete their trial visits and follow-up throughout the course of the trial; a review of the full dataset (including the post-April 23, 2025 dataset), after the trial has completed, which may cause our analysis following completion of the trial to differ from the analysis as of the data extract date presented above; uncertainties inherent in the development of therapeutic product candidates, such as the risk that any one or more of Tourmaline’s current or future product candidates will not be successfully developed or commercialized; the risk of delay or cessation of any planned clinical trials of Tourmaline’s current or future product candidates; the risk that prior results, such as signals of safety, activity or durability of effect, observed from preclinical trials and clinical trials, will not be replicated or will not continue in ongoing or future studies or clinical trials involving Tourmaline’s current or future product candidates and/or current or future target indications; the risk that Tourmaline’s current or future product candidates or procedures in connection with the administration thereof will not have the safety or efficacy profile that Tourmaline anticipates; risks regarding the accuracy of Tourmaline’s estimates of expenses, capital requirements and needs for additional financing; changes in expected or existing competition; changes in the regulatory environment; the uncertainties and timing of the regulatory approval process; unexpected litigation or other disputes; the impacts of macroeconomic conditions on Tourmaline’s business, clinical trials and financial position; and other risks and uncertainties that are described in Tourmaline’s Quarterly Report on Form 10-Q filed with the U.S. Securities and Exchange Commission (“SEC”) on May 2, 2025 and other filings that Tourmaline makes with the SEC from time to time. Any forward-looking statements speak only as of the date of this press release and are based on information available to Tourmaline as of the date hereof, and Tourmaline assumes no obligation to, and does not intend to, update any forward-looking statements, whether as a result of new information, future events or otherwise. Media Contact:Scient PRSarah MishekSMishek@ScientPR.com Investor Contact:Meru AdvisorsLee M. Sternlstern@meruadvisors.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/b1cc4485-af32-46c2-9fdb-144f4e1e573f