Siltuximab

– First patient dosed in May 2024 in Phase 2 TRANQUILITY trial evaluating pacibekitug (TOUR006) in patients with high cardiovascular risk – – On track to initiate a pivotal Phase 3 trial evaluating pacibekitug delivered subcutaneously every 8 weeks as first-line treatment for Thyroid Eye Disease (TED) in the second half of 2024 – – Added to the Russell 2000® Index and the broad-market Russell 3000® Index in June 2024 – – Cash, cash equivalents and investments of $334.4 million as of June 30, 2024, providing cash runway into 2027 – NEW YORK, Aug. 08, 2024 (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 its financial results for the second quarter of 2024 and outlined recent business highlights. “The second quarter of 2024 was another period of strong execution by Tourmaline, including the dosing of the first patient in the Phase 2 TRANQUILITY trial. This represents an important milestone in our pacibekitug clinical development plan, where multiple converging lines of evidence from human genetic studies, epidemiological studies, and mechanistic experiments support the therapeutic potential of IL-6 inhibition for millions of patients with cardiovascular diseases,” said Sandeep Kulkarni, MD, Co-Founder and Chief Executive Officer of Tourmaline. “Along with our ongoing clinical development efforts in TED, the TRANQUILITY trial provides us with two high-conviction paths to unlock major value creation as we approach key data readouts in 2025.” Clinical Highlights and Upcoming Milestones: TED The pivotal spiriTED Phase 2b trial in TED is currently enrolling, and Tourmaline continues to expect topline data in 2025.Tourmaline is on track to initiate a pivotal Phase 3 trial evaluating pacibekitug delivered subcutaneously every 8 weeks as first-line treatment for TED in the second half of 2024, with topline data expected in 2026. Cardiovascular Inflammation In May 2024, Tourmaline initiated the clinical development of pacibekitug for cardiovascular diseases with the first patient dosed in its Phase 2 TRANQUILITY trial.At the American Society of Preventive Cardiology Annual Congress held in August 2024, Tourmaline presented a poster describing the rationale and design of the Phase 2 TRANQUILITY trial (“Evaluating TOUR006 in Participants with Chronic Kidney Disease and Elevated hs-CRP: Rationale and Design of the TRANQUILITY Phase 2 Study”).The TRANQUILITY trial is evaluating quarterly and monthly subcutaneous dosing of pacibekitug in patients with elevated high-sensitivity C-reactive protein (hs-CRP) and chronic kidney disease (CKD). Tourmaline continues to expect topline data from this trial in the first half of 2025.If successful, results from the Phase 2 TRANQUILITY trial are expected to position Tourmaline to be Phase 3-ready in 2025 for pacibekitug in cardiovascular diseases. Other Corporate Highlights: In June 2024, Tourmaline announced the promotion of Ryan Robinson, CPA, to Chief Financial Officer and Treasurer. Mr. Robinson most recently held the role of Vice President, Finance and Controller at Tourmaline, in addition to serving as Tourmaline’s Interim Chief Financial Officer and Treasurer since October 2023.Also in June 2024, Tourmaline was added to the Russell 2000® Index and the broad-market Russell 3000® Index as part of the Russell indexes annual reconstitution. Second Quarter 2024 Financial Results: Cash Position Cash, cash equivalents and investments were $334.4 million as of June 30, 2024, as compared to $203.0 million as of December 31, 2023. Tourmaline anticipates that its current cash, cash equivalents and investments will provide cash runway into 2027, funding key pacibekitug data readouts in TED and cardiovascular disease and the opportunity to expand development efforts into additional indications. Operating Expenses Research and development expenses were $15.7 million for the second quarter of 2024, as compared to $14.5 million for the second quarter of 2023. The increase in research and development expenses was primarily driven by employee compensation costs attributable to increased headcount as well as costs related to the spiriTED and TRANQUILITY trials. Research and development expenses incurred during the second quarter of 2023 included $8.8 million of non-cash expense related to the issuance of additional shares to Pfizer Inc. (Pfizer) pursuant to an anti-dilution provision within the License Agreement between Tourmaline and Pfizer.General and administrative expenses were $6.2 million for the second quarter of 2024, as compared to $1.9 million for the second quarter of 2023. The increase in general and administrative expenses was primarily driven by employee compensation costs attributable to increased headcount, increased consulting expenses, including recruiting, commercial planning and other services, and increased professional service fees. Net Loss Net loss was $17.5 million for the second quarter of 2024 and $16.1 million for the second quarter of 2023, resulting in basic and diluted net loss per share of $0.68 and $16.29, respectively.The increase in net loss was attributable to increased operating expenses and the overall growth of Tourmaline throughout 2023 and into 2024. The decrease in net loss per share was attributable to the issuance of additional shares of common stock in conjunction with Tourmaline’s reverse merger and private placement that were completed in October 2023 as well as the underwritten follow-on public offering completed by Tourmaline in January 2024. 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 (formerly known as TOUR006). About Pacibekitug: Pacibekitug (also referred to as TOUR006) 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. Pacibekitug has been previously studied in 448 participants, including patients with autoimmune disorders, across six completed clinical trials. Tourmaline is developing pacibekitug in TED and ASCVD as its first two indications, with additional diseases under consideration. 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; the timing of initiation, progress and results of Tourmaline’s current and future clinical trials for pacibekitug, including reporting of data therefrom; the timing and potential of preclinical research and development activities; market opportunities; the timing and potential to expand pacibekitug into additional indications; and Tourmaline’s anticipated cash runway. 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 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, will not be replicated or will not continue in ongoing or future studies or clinical trials involving Tourmaline’s current or future product candidates; 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 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 or about August 8, 2024 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. Tourmaline Bio, Inc.Condensed Consolidated Statements of Operations (unaudited)(amounts in thousands, except per share data) Three Months EndedJune 30, Six Months EndedJune 30, 2024 2023 2024 2023 Operating expenses: Research and development$15,734 $14,454 $27,110 $20,591 General and administrative 6,237 1,920 12,378 3,285 Total operating expenses 21,971 16,374 39,488 23,876 Loss from operations (21,971) (16,374) (39,488) (23,876)Other income, net 4,484 245 8,690 245 Net loss$(17,487) $(16,129) $(30,798) $(23,631)Net loss per share, basic and diluted$(0.68) $(16.29) $(1.24) $(24.93)Weighted-average common shares outstanding, basic and diluted 25,724 990 24,908 948 Tourmaline Bio, Inc.Selected Condensed Consolidated Balance Sheet Data (unaudited)(amounts in thousands) June 30, December 31, 2024 2023Cash, cash equivalents and investments$334,411 $202,951Working capital$291,766 $203,872Total assets$344,791 $210,295Total stockholders’ equity$338,282 $205,042 Media Contact:Scient PR Sarah Mishek SMishek@ScientPR.com Investor Contact:Meru AdvisorsLee M. Sternlstern@meruadvisors.com

▎药明康德内容团队编辑   20世纪80年代起，为了救治激增的艾滋病患者，Carl June博士在组建了自己的实验室后，开始设计一种全新的工程化T细胞，利用T细胞表面表达的嵌合抗原受体（CAR）将细胞引导至目标细胞，攻击受HIV感染的细胞。这就是最初的CAR-T细胞。 进入21世纪，June博士将CAR-T细胞疗法引入癌症治疗，利用工程化的T细胞靶向特定的肿瘤抗原。这项为艾滋病治疗而设计的疗法，成为了癌症治疗领域的里程碑突破。CAR-T疗法实现了对多种血液癌症患者的“治愈”，首款CAR-T疗法也在2017年获得FDA批准上市。 ▲Carl June博士（图片来源：药明康德内容团队制作） 不过时至今日，CAR-T疗法依然面临着多重挑战。目前获批的CAR-T疗法受限于特定类型白血病、淋巴瘤和骨髓瘤的治疗，但对于实体瘤，CAR-T细胞难以被递送至肿瘤部位以及复杂的肿瘤微环境（TME）中；此外，TME缺氧、酸性以及免疫抑制的环境也会限制CAR-T细胞的功能、诱导T细胞耗竭，这些障碍都导致针对实体瘤的CAR-T获批疗法尚未出现。 在血液癌症的治疗中，CAR-T疗法在癌症长期缓解的问题上同样面临着挑战，尤其是如何延长CAR-T细胞的寿命。CAR-T疗法往往最初可以取得很好的效果，但对于不同患者，长期的疗效却存在差异，并且可能出现癌症复发。 为了克服这些障碍，一项极具潜力的策略是将CAR-T细胞与其他现有疗法相结合，开发能增强CAR-T疗效、减轻毒性、扩大治疗范围的全新联合疗法。在一篇发表于Cancer Cell的综述文章中，被称作“CAR-T之父”的Carl June博士深度介绍了在临床试验阶段的不同CAR-T联合治疗策略，展望了各疗法在增强疗效与降低毒性方面的潜力。 增强CAR-T疗效的联合疗法 ▲增强CAR-T疗效的6项联合疗法策略（图片来源：参考资料[1]） 从这张图出发，June博士首先讲述了联合疗法在增强CAR-T细胞疗效方面的多项策略。 1. 靶向免疫检查点的抗体 这项策略的思路很直接——靶向PD-1和PD-L1的单克隆抗体可增强肿瘤浸润淋巴细胞的功能，恢复它们攻击癌细胞的能力，因此将这些免疫检查点抑制剂（ICI）与CAR-T疗法结合，理应可以提高TME内CAR-T细胞的寿命和功效。 在B细胞淋巴瘤等血液癌症中，CAR-T细胞与ICI联合的临床试验展现了高反应率和可控的毒性水平。值得注意的是，免疫疗法组合的应用时机对于治疗效果也至关重要：在CAR-T细胞输注前启动抗PD-L1抗体疗法，整体的治疗效果较差。 与血液癌症相比，这款联合疗法治疗实体瘤的临床收益相对有限，并且出现了一些分歧的结果。例如，针对恶性胸膜间皮瘤的1期临床试验取得了令人鼓舞的结果，但在两项分别针对胶质母细胞瘤和神经母细胞瘤的临床试验中，疗效改善较为有限。文章指出，这可能与后两种癌症本身也更难治疗有关。 2. 肿瘤靶向抗体及BiTE 双特异性T细胞接合剂（bi-specific T cell engagers，BiTE）是一类具有抗肿瘤效应的双特异性抗体，能够靶向性激活自身T细胞来杀伤肿瘤细胞。 这项策略的核心思路在于双靶向或多靶向。利妥昔单抗（rituximab）和奥比妥珠单抗（obinutuzumab）是两款已获批的靶向CD20的单克隆抗体，而格菲妥单抗（glofitamab）、莫妥珠单抗（mosunetuzumab）是靶向CD3/CD20双抗体的BiTE。将靶向CD20（或CD3/CD20）的抗体与靶向CD19/B细胞成熟抗原（BCMA）的获批CAR-T产品相结合，可更有效地根除肿瘤细胞并降低抗原逃逸风险。 目前，利妥昔单抗与CAR-T联合使用的多项临床实验正在开展。在治疗难治性大B细胞淋巴瘤（LBCL）以及难治性B细胞急性淋巴细胞白血病（B-ALL）的临床试验中，该联合疗法均显著改善了长期结果，展现出初步的良好结果。目前，正在进行的临床试验正在进一步评估利妥昔单抗、其他已获批准的CD20靶向抗体和BiTE与CAR-T细胞联合治疗的疗效。 3. 小分子药物 除了抗体外，还有几种小分子药物已获批用于治疗血液癌症和实体瘤，其中一些与CAR-T联合使用的临床试验正在进行中。文章重点介绍了两种小分子药物的作用机制。 第一种小分子是一款布鲁顿酪氨酸激酶（BTK）抑制剂——伊布替尼（ibrutinib）。BTK是B细胞抗原受体信号转导通路的关键激酶，这款药物已经获批用于治疗不同类型的B细胞淋巴瘤。伊布替尼可以通过一系列的路径来增强CAR-T细胞疗效，包括减少抑制性受体、增加记忆T细胞、促进向Th1极化的转变，以及增加免疫突触。 伊布替尼与CAR-T联合使用的临床试验初步结果表明，这种联合方法对TP53突变的慢性淋巴细胞白血病（CLL）患者收益明显。例如近期的一项2期临床试验对接受伊布替尼治疗后未完全起效的CLL患者添加使用CD19-CAR-T细胞，并取得良好的结果——72%的患者在一年后未检测到疾病，48月时的总生存率达到84%。此外，还有研究正在探索伊布替尼和其他BTK抑制剂（如阿卡替尼和泽布替尼）与CAR-T联合，在更广泛的血癌类型中的应用。 另一类与CAR-T疗法联用的小分子药物是靶向蛋白质降解剂——来那度胺（lenalidomide）。来那度胺已用于治疗多发性骨髓瘤（MM）等血液系统恶性肿瘤。这种药物除了促进向Th1极化的转变、增加免疫突触，还促进了干扰素γ、IL-2等细胞因子生成。 临床前研究表明来那度胺可增强CAR-T细胞的疗效，并在多次刺激下维持CAR-T细胞功能，这可能有助于防止T细胞衰竭。在最近的临床试验中，该联合疗法治疗多发性骨髓瘤的耐受性良好，总体反应率达到100%。 4. 其他疗法：癌症疫苗、溶瘤病毒、放射性疗法 此外，文章还介绍了癌症疫苗、溶瘤病毒（OV）疗法、放射性疗法分别与CAR-T疗法联合使用的治疗策略在临床试验阶段的进展。 癌症疫苗本身旨在激活免疫系统以对抗癌细胞，在与CAR-T联用时，有可能增强CAR-T细胞的活化、增殖和持久性。在一项1/2期临床试验中，利用RNA疫苗增强CAR-T细胞的策略展现出良好的初步结果——21名实体瘤患者的疾病控制率为67%，展现出使用癌症疫苗增强CAR-T细胞持久性的潜力。 溶瘤病毒能够在肿瘤细胞中选择性复制，同时保留健康细胞。将溶瘤病毒与CAR-T联合使用时，临床前研究已经显示出克服肿瘤免疫抑制的潜力。目前，临床试验正在评估这种组合方法在实体瘤中的疗效。 放射性治疗其广泛适用于不同类型的肿瘤、非侵入性以及消除肿瘤细胞的功效而受到重视。在一项针对复发性或难治性弥漫大B细胞淋巴瘤（DLBCL）的CAR-T疗法2期临床试验中，在CAR-T细胞治疗之前接受放疗的患者实现了100%的反应率。这一结果表明，放射性治疗可以作为CAR-T治疗前的减瘤和桥接方案，以及复发后挽救治疗的可行选择。 最后，文章介绍了细胞因子在增强CAR-T疗效中的潜力。CAR-T细胞经过改造可以共表达细胞因子，在提高疗效和持久性方面展现出巨大潜力。目前，分别分泌IL-12、IL-15、IL-18、IL-21等细胞因子的CAR-T细胞临床试验正在进行中，展现出提升持久性或控制肿瘤的潜力。 ▲正在临床试验阶段，旨在增强CAR-T疗效的联合疗法盘点（数据来源：参考资料[1]；数据截至2024年4月11日/制图：药明康德内容团队） 降低CAR-T毒性的联合疗法 除了增强疗效，降低CAR-T的毒性成为现阶段联合疗法研发的另一个目标。目前CAR-T治疗可能导致的严重副作用有两类。其一是细胞因子释放综合征（CRS），即CAR-T细胞输注至体内后，被激活、增殖时引发细胞因子级联释放，介导多种免疫反应，从而引起发热、低血压、呼吸困难、凝血障碍、终末器官障碍等临床表现，甚至可能危机生命。 免疫效应细胞相关神经毒性综合征（ICANS）是另一类常见的CAR-T治疗副作用，这些患者会出现一系列神经系统异常的临床表现，包括头痛、谵妄、震颤、精神状态改变、注意力下降、语言障碍等，其机制可能与治疗过程中单核细胞或巨噬细胞活化介导的大量炎症因子释放有关。 在这一部分，文章分别针对小分子药物和单克隆抗体，探讨了潜在的联合治疗策略。 ▲降低CAR-T毒性的联合疗法策略（图片来源：参考资料[1]） 1. 小分子药物 在小分子药物方面，文章介绍了3种候选药物在降低CAR-T疗法毒性方面的临床前潜力。目前，针对这些药物的临床试验正在进行中。 首先是伊他替尼（itacitinib），作为JAK1激酶的选择性抑制剂，伊他替尼可以调节由IL-6和IFN-γ等细胞因子激活的信号通路。在临床前研究中，伊他替尼的使用下调了CRS/ICANS相关细胞因子，并且保持了CAR-T细胞的抗肿瘤活性。 另一种有望降低CAR-T细胞疗法毒性的候选药物是度维利塞（duvelisib），作为全球首个获批的磷脂酰肌醇-3-激酶PI3K-δ和PI3K-γ口服双重抑制剂，其对PI3K激酶的抑制会影响T细胞和其他免疫细胞的功能与存活，进而减少可导致CRS/ICANS的细胞因子的产生。 最后，达沙替尼（dasatinib）作为一种酪氨酸激酶抑制剂，还会抑制对T细胞活化与功能至关重要的激酶，因此能够调节T细胞的激活与增殖。临床前研究表明，达沙替尼在控制CAR-T细胞毒性以及抵消CAR-T细胞衰竭方面具有潜在效用。 2. 单克隆抗体 由于靶向CRS/ICANS相关细胞因子的抗体可以控制CAR-T治疗的毒性，因此单克隆抗体成为降低副作用的另一种联合治疗策略。 其中，靶向IL-6R的托珠单抗（tocilizumab）是目前唯一获批的CRS疗法；而现阶段的临床试验主要集中在解决ICANS上。目前，研究正在探索分别在CAR-T细胞输注之前或之后施用另一种IL-6靶向抗体司妥昔单抗（siltuximab）。 最近的研究还指出，髓系细胞是CRS/ICANS相关促炎性细胞因子的重要生产者。作为一种靶向粒细胞-巨噬细胞集落刺激因子（GM-CSF）的拮抗剂，lenzilumab展现出减少CRS和ICANS、提升CAR-T疗效的潜力。 ▲正在临床试验阶段，旨在降低CAR-T毒性的联合疗法盘点（数据来源：参考资料[1]；数据截至2024年4月11日/制图：药明康德内容团队） 文章指出，除了上面详细介绍的疗法，还有一些有望增强疗效的联合疗法尚未进入临床试验阶段，包括STING激动剂，靶向LAG-3、TIM-3和TIGIT的免疫检查点抑制剂等。此外，HDAC和EZH2抑制剂等表观遗传调节剂可能通过重编程TME，增加肿瘤抗原表达并减少免疫抑制，从而增强CAR-T细胞疗法的功效。同时，一些旨在提高CAR-T细胞安全性的组合疗法也尚未在临床试验中进行验证，包括靶向IFNγ的单克隆抗体。 正如这篇评论文章所述，将CAR-T与其他疗法相结合有着巨大的潜力。目前，在临床和临床前阶段的持续研究对于充分发挥组合CAR-T细胞疗法在癌症治疗中的潜力，找到最佳的给药方案、尽可能降低毒性等至关重要。我们期待从这些联合疗法中，能够诞生有效治疗实体瘤，以及长期缓解血液癌症的强大疗法。 参考资料： [1] Ugur Uslu et al., CAR T cell combination therapies to treat cancer. Cancer Cell (2024). DOI:https://doi-org.libproxy1.nus.edu.sg/10.1016/j.ccell.2024.07.002 本文来自药明康德内容微信团队，欢迎转发到朋友圈，谢绝转载到其他平台。如有开设白名单需求，请在“学术经纬”公众号主页回复“转载”获取转载须知。其他合作需求，请联系wuxi_media@wuxiapptec.com。 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。