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更新于：2026-01-17
Mupadolimab
更新于：2026-01-17
概要
基本信息
非在研机构- |
最高研发阶段临床1期 |
首次获批日期- |
最高研发阶段(中国)临床1期 |
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结构/序列
Sequence Code 21946295L
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Sequence Code 21946296H
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关联
4
项与 Mupadolimab 相关的临床试验CTR20223326
CPI-006及其联用帕博利珠单抗治疗晚期实体瘤患者以评估安全性、耐受性及药代动力学特征的多中心I/Ib期临床研究
剂量递增阶段主要目的： 1)评价CPI-006及其联用帕博利珠单抗在晚期实体瘤患者中的安全性和耐受性； 2)评价CPI-006及其联用帕博利珠单抗在晚期实体瘤患者中的最大耐受剂量（MTD）或Ⅱ期推荐剂量（RP2D），为后续临床研究提供依据
剂量扩展阶段主要目的：
评价CPI-006联用帕博利珠单抗在晚期非小细胞肺癌（Non-Small Cell Lung Cancer，NSCLC）、头颈部鳞状细胞癌（Head and Neck Squamous Cell Carcinoma，HNSCC）、鼻咽癌（Nasopharyngeal Carcinoma，NPC）患者中的安全性和耐受性。
开始日期2023-02-16 |
申办/合作机构 |
NCT04734873
Phase 3, Randomized, Placebo Controlled, Double-blind, Multicenter, Stratified Study of CPI-006 Plus Standard of Care Versus Placebo Plus Standard of Care in Mild to Moderately Symptomatic Hospitalized Covid-19 Patients
This is a phase 3, randomized, placebo controlled, double-blind, multicenter, stratified study of CPI-006 plus standard of care (SOC) versus placebo plus SOC in mild to moderately symptomatic hospitalized Covid-19 patients with the primary objective to compare the proportion of participants alive and respiratory failure free between CPI-006 plus SOC versus placebo plus SOC.
开始日期2021-02-25 |
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NCT04464395
Immunotherapy of COVID-19 With B-Cell Activating CPI-006 Monoclonal Antibody
This Phase 1 single-dose, dose-escalation study is an open label trial evaluating the safety of CPI-006, a humanized monoclonal antibody targeting the CD73 cell-surface ectonucleotidase, as immunotherapy for stable hospitalized mild or moderately symptomatic COVID-19 patients with a parallel non-randomized Control Arm for treatment with standard of care only.
开始日期2020-07-01 |
申办/合作机构 |
100 项与 Mupadolimab 相关的临床结果
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100 项与 Mupadolimab 相关的转化医学
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100 项与 Mupadolimab 相关的专利（医药）
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50
项与 Mupadolimab 相关的新闻（医药）2025-10-18
·核药文献
题名：Development of CD73 Inhibitors in Tumor Immunotherapy and Opportunities in Imaging and Combination Therapy
作者：Chunyang Bi 1 2, Jimmy S Patel 1 3, Steven H Liang 1 4
出处：Review J Med Chem. 2025 Apr 10;68(7):6860-6869.
DOI: 10.1021/acs.jmedchem.4c02151
重要性
免疫疗法如今已成为肿瘤治疗的重要组成部分。通过针对不同途径来丰富免疫疗法，将有助于未来患者的治疗。了解CD73 抑制的机制是生成有关其与其他全身性疗法协同作用假设的关键所在。此外，对现有 CD73 抑制剂的回顾可能会为科学家提供宝贵见解，从而探索未开发的化学空间并推进药物研发。
简介
免疫检查点蛋白在调节免疫细胞对各种内在和外在刺激的激活、分化和功能方面发挥着关键作用。（1,2）这些蛋白受到严格调控，其表达的任何破坏都可能导致免疫反应发生显著变化，尤其会影响肿瘤微环境（TME）中的 T 细胞。（3，4）科学家们利用免疫检查点级联反应中各种成分的机制，包括细胞毒性 T 淋巴细胞抗原 4（CTLA-4）、程序性细胞死亡蛋白 1（PD-1）及其配体程序性细胞死亡配体 1（PD-L1），开发出了新型免疫检查点抑制剂（ICIs），从而彻底改变了癌症免疫疗法。（5）自 2010 年以来，美国食品药品监督管理局（FDA）已成功批准了一种 CTLA-4 抑制剂（伊匹单抗）、三种 PD-1 抑制剂（纳武单抗、帕博利珠单抗和西米普利单抗）以及三种 PD-L1 抑制剂（阿特珠单抗、度伐利尤单抗和阿维鲁单抗）。（6）
近年来，分化簇73、外切 5′-核苷酸酶（CD73）已成为新型免疫疗法的一个潜在靶点。（7 - 9）CD73 是一种表面酶，可水解细胞外的腺苷酸（AMP），生成具有抗炎和免疫抑制作用的腺苷（ADO）。（10，11）它在人体多种组织中均有表达，在维持正常生理功能方面发挥着作用，比如抗痛觉、中枢神经系统（CNS）抗炎损伤保护以及脑、心、肝、肾的缺血再灌注损伤保护。（12）对癌症基因组图谱（The Cancer Genome Atlas）的 RNA 测序数据进行分析发现，许多（14）肿瘤样本中 CD73 的表达量高于相邻的正常组织。（13）这一发现突显了 CD73 作为恢复抗肿瘤免疫反应和支持癌症治疗的新靶点的潜力。（14 - 16）例如，CD73 在多种癌症类型中均成为广泛靶向的对象，包括膀胱癌、肺癌、乳腺癌、胆囊癌、胃肠道癌、结直肠癌、前列腺癌、头颈部鳞状细胞癌、胰腺导管腺癌、黑色素瘤、胶质母细胞瘤和慢性淋巴细胞白血病。（17，18）大量研究已强调 CD73 作为肿瘤免疫系统中一种新型免疫检查点蛋白具有显著的负面作用（图 1）。（19,20）CD73 在调节血管通透性和血液中白细胞迁移方面，在内皮细胞表面高度表达。（21）尽管黑色素瘤细胞内皮细胞中 CD73 的缺失并未直接显示出对肿瘤生长和转移的影响，但 CD73 在这些细胞中的过表达已被证明会阻碍 T 细胞穿过血管壁，并促进肿瘤血管生成。（22−24）缺氧通过缺氧诱导因子 -1α（HIF-1α）在肿瘤微环境中强有力地诱导外核苷酸酶，HIF-1α 负责氧气的输送和利用，HIF-1α 的上调直接促进 CD73 的表达从而生成腺苷。（25）随后，HIF-1α 激活血管内皮生长因子（VEGF）以诱导血管生成并抑制免疫反应。（26）在乳腺癌小鼠模型中观察到，抗 CD73 疗法能有效抑制肿瘤血管生成并减少 VEGF 的产生。此外，CD73 在肿瘤相关成纤维细胞（CAFs）中也高度表达，而 CAFs 构成了反应性肿瘤基质的主要成分。CAFs 分泌免疫调节因子，抑制 T 细胞反应，并招募 M2 巨噬细胞、髓源性抑制细胞和调节性 T 细胞（Tregs），从而在肿瘤进展中发挥关键作用。（28，29）抑制 CD73 或其他与 CAFs 相互作用的检查点蛋白的过度表达，正日益被视为肿瘤免疫治疗的一种新策略。在过去 3 年中，已出现了超过 10 种针对 CD73 的单克隆抗体（mAbs）、双功能抗体和小分子药物。这些药物目前正作为针对各种肿瘤疾病的新型免疫疗法在临床 I、II 和 III 期研究中进行评估。图 1
图1. 针对肿瘤微环境中 CD73 的免疫疗法。缩写：ADA，腺苷脱氨酶；ADO，腺苷；ADP，二磷酸腺苷；AMP，一磷酸腺苷；ATP，三磷酸腺苷；CAF，癌相关成纤维细胞；CD39，外核苷三磷酸二磷酸水解酶 - 1；CD73，分化簇 73，外 5′- 核苷酸酶；DC，树突状细胞；EC，内皮细胞；HIF-1α，缺氧诱导因子 - 1α；INO，次黄嘌呤核苷；M1，M1 巨噬细胞；M2，M2 巨噬细胞；MDSC，髓源性抑制细胞；N1，N1 中性粒细胞；N2，N2 中性粒细胞；NK 细胞，自然杀伤细胞；Treg，调节性 T 细胞；VEGF，血管内皮生长因子。
1. 已报道的抑制剂
1.1. 核苷酸/核苷
自2015 年以来，基于核苷酸的结构活性关系（SARs），已报道了众多高效的 CD73 抑制剂（30）。这些核苷酸衍生的 CD73 抑制剂中的大多数是竞争性核苷亚甲基二磷酸盐（AMPCP 衍生物和类似物），包括 AMPCP（1）、（30）PSB-12379（2）、（30）PSB-12489（3）、（31）AB680（4）、（32）以及化合物 5。（33）此外，化合物 6、（34）OP-5244（7）、（35）8、（36）和 ORIC-533（9）（37）也被确定为新型核苷酸衍生的 CD73 抑制剂（图 2）。
图2. 具代表性的源自核苷酸的 CD73 抑制剂
在已报道的CD73 抑制剂中，基于 AMPCP 框架（30,31,38）的 AB680（4）表现出强大的活性，清除率低且半衰期长（32），使其成为很有前景的候选药物，目前正处于 III 期临床试验评估阶段。先前的研究还强调了 PSB-12379（2）和 PSB-12489（3）作为强效、选择性且代谢稳定的 CD73 抑制剂的重要性（30，31）。化合物 5 是一种嘧啶核苷亚甲基二磷酸酯衍生物，后来被确认为一种新型 CD73 抑制剂，在体外对人头颈部鳞状细胞癌表现出浓度依赖性抑制作用（33）。将亚甲基二磷酸基团分别替换为未修饰和修饰的亚甲基磷酸基团，得到了化合物 6 和 OP-5244（7）。引入相对极性的芳基基团则开发出了化合物 8。这些新型核苷酸衍生的 CD73 抑制剂极大地丰富了小分子 CD73 抑制剂的种类（34，35）。例如，化合物 6，一种亚甲基磷酸的类似物，在体内表现出高活性、高选择性、低清除率和长半衰期。（34）在化合物 6 的磷onic 酸α位引入羟甲基和甲氧基甲基基团，得到了 OP-5244（7），其口服生物利用度提高，并且对 CD73 具有抑制作用。（35）在临床前研究中，OP-5244 能够完全抑制 H1568 非小细胞肺癌细胞和 CD8+T 细胞中腺苷的生成，并且在体内通过调节 AMP→ADO 通路逆转免疫抑制。（35）最新的 CD73 抑制剂化合物 8 在临床前体外/体内研究中，无论是作为单药治疗还是与化疗（奥沙利铂、多柔比星或多西他赛）或检查点抑制剂联合使用，都能有效抑制 AMP 介导的 CD8+T 细胞和肿瘤生长。（36）此外，ORIC-533（9）作为一种新型的小分子抑制剂，其效力超过了 AB680，目前正处于治疗复发或难治性多发性骨髓瘤的 I 期临床试验阶段，是首个口服 CD73 抑制剂。（37）作为一种新型核苷酸，ORIC-533 被报道具有较高的代谢稳定性，在小鼠体内半衰期为 2.98 小时，并且与 CD73 的解离速度较慢。（39，40）这些特性使其能够有效地恢复 CD8+T 细胞的细胞因子分泌，并且当作为单一药物口服给药时能够抑制肿瘤生长。（41）
1.2. CD73 核苷酸/核苷抑制剂的构效关系概述
AMPCP 作为 CD73 抑制剂开发的基础骨架，最初由 Müller 研究小组提出，已衍生出众多 Ki 值处于低纳摩尔范围的衍生物和类似物。（30−32，34，35）以 AMPCP 为中心的构效关系分析总结见图 3。
图3. 源自 AMPCP 的 CD73 抑制剂的结构 - 活性关系总结
腺苷环的2 位是生成新型核苷酸抑制剂的关键位点。在大多数情况下，小且极性的取代基，如卤素、CF3、CH3、OCH3、NH2 和 NHNH2 都能很好地耐受。（32，38）尽管近期文献通常倾向于将氯作为 2 位的首选取代基，但仍需进一步研究以比较其与其他卤素的效力。（32，34−36）在所有位置中，N6 位由于合成的便利性和高抑制效力而经常被选作修饰位点。在 N6 位，亲脂性取代基，如 2-苯乙基和环己基，通常也能很好地耐受。（32，34）1-N 或 7-N 用 CH 取代以及 7-和 8-位之间 N 和 CH 的交换通常也是可以耐受的，从而得到的吡唑并嘧啶核苷酸和吡唑并吡啶核苷酸与腺嘌呤核苷酸相当。（32）高活性的嘧啶核苷酸 MRS4620（5）偏离了传统的 AMPCP 结构，突显了嘧啶核苷酸与腺嘌呤核苷酸的可比性。（33,42）核糖上的任何羟基残基或整个二醇基团的缺失均无法被接受，但将 2′-OH 残基替换为氟原子则能很好地被接受。（42−44）
磷酸酯部分在维持基于核苷酸的CD73 抑制剂的效力方面起着关键作用，大多数结构活性关系（SAR）都涉及至少一个磷酸基团。值得注意的是，亚甲基二磷酸酯的活性明显优于单、二和三磷酸酯。（30，45）这种差异被认为是由α-和β-P 原子之间的亚甲基连接子的存在所导致的，这使得磷酸酯相对稳定，不易水解。另外的数据表明，在亚甲基连接子上引入卤素（如溴或氯）或羟基和甲基残基会导致活性降低。（30）另一方面，将强效 AMPCP 衍生物的 5-O′原子替换为更稳定的 CH2 可能会增强其活性。将α-P 原子或α-P 和β-P 原子都替换为 S 会显著降低活性。（44）后续的研究广泛地将亚甲基二磷酸酯部分替换为其他磷酸盐和酸性极性残基，如亚甲基磷酸酯（34、35、46）和丙二酸酯（36、47）。有趣的是，在这些替换中产生的酸性残基似乎表现出与亚甲基二磷酸酯相当的稳定性。总的来说，将来自两种或多种 CD73 核苷酸抑制剂的不同强效取代基进行组合，被证明是一种增强活性的有效策略。通常，这种方法会得到一种活性优于任何单一取代前体的核苷酸。总之，在腺嘌呤核苷酸或吡唑并嘧啶/吡唑并吡啶核苷酸的 N6 位置引入亲脂性取代基，并在 2 位置引入小且极性的取代基，可开发出最有效的 CD73 抑制剂，例如 AB680 和 PSB-12489（30−32、34、35）。
1.3. 非核苷酸类抑制剂
目前报道的非核苷酸类抑制剂对CD73 的抑制作用较核苷酸类抑制剂弱，大多数的 IC50 值处于微摩尔范围。（18,48）然而，非核苷酸类 CD73 抑制剂的酸性降低以及膜通透性的改善使得制剂能够增强口服吸收。此外，大多数非核苷酸类抑制剂具有中等的亲脂性、电中性和相对较低的分子量，这增强了它们穿过血脑屏障（BBB）的潜力。一些具有强抑制活性的代表性非核苷酸类 CD73 抑制剂包括 PSB-0963（10），（49）化合物 11（50）和 12，（51）LY3475070（13），（52）以及化合物 14，（53）15，（54）16，（54）17，（54）和 18（55）（图 4）。
图4. 具代表性的非核苷酸来源的 CD73 抑制剂
Müller 团队之前的研究表明，蒽氨基取代衍生物 PSB-0963（10）对 CD73 和 CD39 具有良好的抑制作用（Ki = 2.59 μM）。（49）在构效关系分析中，磺酸基团被确定为 PSB-0963 维持其抗 CD73 或抗 CD39 活性的关键取代基，这促使后续合成了一系列包含磺酸基团的 PSB-0963 衍生物。（56，57）化合物 11 和 12 由葛兰素史克（GSK）获得专利，表现出显著的活性，其中化合物 12 在所有已报道的非核苷酸抑制剂中表现最佳。（50，51）由礼来公司获得专利的 LY3475070 是唯一一种已进入临床研究（一期）的非核苷酸 CD73 抑制剂。（52）在最近的一项研究中，Lai 团队选择 LY3475070 作为先导化合物，通过在 LY3475070 的吡啶嗪环上进行各种取代基修饰，开发了一系列 CD73 抑制剂。其中，化合物 14 成为肿瘤免疫治疗中最强效的非竞争性抑制剂之一，在体外/体内实验中表现出无明显细胞毒性、出色的代谢稳定性（t1/2 = 3.37 小时）和良好的口服生物利用度（F = 50.24%）。Lawson 团队通过在超过 20 万种化合物的库中进行高通量筛选，发现了中等效力的 CD73 抑制剂 A0001999（15），随后的结构修饰产生了另外两种化合物 16 和 17，它们对 CD73 表现出高活性，但代谢稳定性较差。化合物 17 与人 CD73 共结晶，揭示了竞争性结合模式。基于化合物 16 和 17，李团队进一步进行结构修饰，生成了化合物 18，其代谢稳定性得到改善（t1/2 = 1.2 小时），在小鼠同基因淋巴瘤模型中与 PD-L1 抑制剂 KN035 联合使用时表现出优异的疗效和免疫抑制逆转作用。与主要基于 AMPCP 框架的核苷酸修饰相比，非核苷酸抑制剂的开发在结构修饰方面具有更大的灵活性。尽管目前还没有关于非核苷酸来源的 CD73 抑制剂的系统性总结，但一些趋势已经显现。亲水性药效团，如羧酸、磺酸盐和磺酰胺，在 CD73 分子对接研究中表现出良好的特性。（49，55，58）例如，化合物 18 中的酸性基团与 CD73 闭合形式中的二锌催化中心形成离子键，其活性与核苷酸抑制剂相当，这表明核苷酸抑制剂的腺苷骨架可以被具有生物活性的酸性基团所替代。（55）关键酸性基团的存在已成为核苷酸来源和非核苷酸来源的 CD73 抑制剂之间的共同特征。
这些广泛的临床前研究提高了非核苷类抑制剂的成药性，并为后续非核苷类来源的CD73 免疫治疗药物的开发奠定了基础。此外，天然产物及其类似物也作为非核苷类来源的 CD73 抑制剂出现，其中许多含有活性羧酸基团，IC50 值在微摩尔范围内。例如桦木酸、桦木酮酸和 ZM557 等化合物可能为新型抗 CD73 抑制剂的设计和开发提供有价值的结构见解。（59,60）
然而，开发非核苷酸CD73 抑制剂面临着与结构靶向、选择性和药代动力学相关的重大挑战。CD73 的活性位点高度优化，以结合其天然核苷酸底物 AMP，这使得非核苷酸分子难以实现有效抑制，除非模仿核苷酸结构。虽然靶向别构位点可以规避这一问题，但识别此类位点需要对酶的构象动力学有深入的了解。实现选择性是另一个关键障碍，因为抑制剂必须避免对结构相似的酶（如碱性磷酸酶）产生脱靶效应，同时在不同物种中保持效力以实现转化应用。此外，优化非核苷酸抑制剂的药代动力学特性尤其具有挑战性，因为这些分子必须具有良好的吸收、分布、代谢和排泄（ADME）特性，同时保持稳定性，并在必要时具备穿透血脑屏障的能力。
2. 临床试验与联合疗法
迄今为止，包括奥莱克鲁单抗、BMS-986179、CPI-006、NZV930、TJ004309、HLX23、AK119、IPH5301、PT199、Sym024、IBI325、CPI-006 和 NZV930 在内的 13 种单克隆抗体，以及一种双功能抗体（达鲁特拉夫单抗）和四种小分子药物（奎米克鲁司他、LY3475070、ORIC-533 和 ATG 037）已进入临床试验阶段。这些药物正在作为单一疗法或与其他治疗方式联合使用，以针对各种癌症进行研究。
与传统化疗和靶向治疗相比，免疫疗法彻底改变了癌症治疗，并成为多种肿瘤治疗的基石方法。（9,61）免疫检查点抑制剂（ICIs）因其持续的反应性和良好的疗效而在不同癌症中得到广泛应用。然而，免疫检查点抑制剂单药治疗的反应率通常有限，总体反应率通常在 20% 至 40% 之间。（62）目前，大多数活跃的 CD73 试验涉及与其他癌症疗法的联合使用，包括免疫肿瘤学疗法、化疗、靶向治疗或放疗。在已注册的涉及 CD73 的临床联合治疗方案中，约 89% 融入了最常用的免疫肿瘤疗法，其中约 33% 使用了帕博利珠单抗、度伐利尤单抗和纳武利尤单抗。此外，约 22% 的这些方案涉及紫杉醇、卡铂和吉西他滨等化疗药物。
抗CD73 抗体奥莱克鲁单抗与 PD-L1 抑制剂度伐利尤单抗的联合疗法目前是 III 期研究中的主要抗肿瘤联合疗法。此前，该联合疗法在 II 期临床研究中作为 III 期非小细胞肺癌的巩固治疗进行了探索。值得注意的是，联合疗法所达到的客观缓解率（30.0%）和 12 个月无进展生存率（62.6%）均超过了度伐利尤单抗单药治疗（分别为 17.9% 和 33.9%）。（63）除了与 CD73 抗体的组合，小分子 CD73 抑制剂的加入也能显著增强针对其他免疫检查点（如 PD-1 和 CTLA-4）的免疫疗法。（9）此外，某些检查点联合疗法也已显示出对 CD73 的有效性。例如，Mittal 等人报告称，涉及 A2A 受体拮抗剂（SCH58261）和免疫检查点阻断（抗 CTLA-4、抗 PD-1 或抗 Tim-3 单克隆抗体）的联合免疫疗法在抑制肿瘤细胞上 CD73 的高表达方面，比任何单一疗法都更有效。（64）有关临床 CD73 抑制剂和联合疗法的全面汇总见表 1。
表1. CD73 抑制剂的临床研究总结
3. CD73 PET 成像潜力
正电子发射断层扫描（PET）属于放射性药物成像范畴，能够实现对病理生理过程的无创可视化。（65−69）在肿瘤学领域，PET 成像常用于肿瘤定位、分期以及治疗反应评估。（70，71）
在当前针对CD73 的临床肿瘤学研究中，用于成像和放射免疫治疗的放射性药物报道明显不足，这表明该领域存在迫切需求。Cho 等人报告称，与 FDG 相比，11C 标记的腺苷酸在多种细胞系中的摄取显著更高（10 至 100 倍）。值得注意的是，放射性示踪剂的摄取显著且正向地受到 CD73 表达的影响。（72，73）CD73 抑制剂如 AMPCP 能以剂量依赖的方式阻断 11C 标记的腺苷酸摄取，而不影响标记腺苷的摄取。（72）这一观察结果促使通过分析其对 [11C]AMP 摄取的影响来评估 CD73 抑制剂对肿瘤的靶向作用。对 CD73 抑制剂进行直接放射性标记可能是一种潜在策略，可用于识别表达 CD73 的肿瘤，并评估针对 CD73 的特异性治疗的反应。此外，开发针对 CD73 和 PD-1 等免疫检查点蛋白的特定 PET 配体，能够无创地监测全身和肿瘤内的免疫变化，在临床应用中具有重要且不断扩大的价值。（74）
然而，开发CD73 放射性示踪剂存在若干挑战。实现对 CD73 的高特异性至关重要，以避免与类似酶的非特异性结合，这可能会损害图像采集。因此，用于放射性标记的前体必须对 CD73 具有一定的内在选择性和特异性。此外，药代动力学优化对于平衡快速的血液清除以减少背景噪声和在靶点部位的足够保留至关重要。高血浆蛋白结合会降低示踪剂的有效成像可用性。另外，如果需要对脑部的 CD73 进行成像，放射性示踪剂必须能够穿透血脑屏障，鉴于对亲脂性和分子大小的严格要求，这是一项艰巨的任务。当考虑到大多数临床进展最快的 CD73 抑制剂的核苷酸基结构时，所有这些都可能具有挑战性。最后，放射性标记本身也存在一系列挑战，因为合成过程必须保持一定的效率，以便及时生产并给予患者。我们推测，如上所述对 CD73 抑制剂的关键结构方面进行讨论，可能会帮助药物化学家设计策略来应对这些挑战。
4. 总结与未来方向
免疫疗法是肿瘤治疗领域的一项突破性方法，主要集中在免疫检查点抑制剂（ICIs）和 T 细胞疗法上。（75，76）然而，迫切需要开发下一代免疫检查点及其对应的 ICIs，以解决目前免疫疗法疗效有限和肿瘤耐药性的问题。在肿瘤微环境中，腺苷是成功抗肿瘤免疫反应的关键介质，通过腺苷定量具有预后潜力。（77）CD73 在各种肿瘤学研究中逐渐成为潜在靶点，并已被用作或考虑作为评估生存、肿瘤转移和预后意义的有效临床肿瘤生物标志物，在多种癌症免疫疗法中发挥作用。（78−80）通过分析腺苷嘌呤能通路以及抗 CD73 免疫疗效在肿瘤微环境中的机制，我们能够更深入地了解 CD73 与肿瘤的关系，并设计新的诊断和治疗方法。
根据对CD73 结构和已发表的核苷类药物结构活性关系（SARs）的分析，我们有机会设计和开发高效的小分子 CD73 抑制剂。目前，大量针对 CD73 的临床研究主要集中在针对各类癌症的单克隆抗体免疫疗法上，其中新兴的研究涉及一种双功能抗体（达鲁特拉夫单抗）。这些临床试验大多探索与其他疗法的联合治疗，例如其他检查点免疫疗法、化疗、靶向治疗或放疗。对 CD73 联合疗法的分析表明，在肿瘤的不同阶段选择不同的联合疗法能够优化治疗效果。正电子发射断层扫描（PET）成像是一种评估治疗效果的强大方法，能够精确观察药物与肿瘤的相互作用，并加快药物研发进程。在 CD73 研究中，[11C]AMP 作为放射性示踪剂的潜在应用为敏感的 PET 肿瘤成像提供了有前景的途径。此外，高活性的 CD73 抑制剂有望开发为 PET 示踪剂，从而开展药代动力学和生物分布研究，以筛选药物疗效并评估免疫治疗反应。另一个例子是，一项新颖的研究展示了两种氟-18 标记的 PET 示踪剂 [18F]PSB-19427 和 [18F]MRS-4648 的开发和评估，用于成像侵袭性癌症（如三阴性乳腺癌和胰腺癌）中 CD73 的表达。该研究证明，[18F]PSB-19427 在成像上述癌症方面优于 [18F]FDG，因为其特异性更高且保留时间更长，这表明它有可能成为实体瘤的更优 PET 成像剂，甚至可用于治疗监测。（81）人们热切期待 CD73 PET 成像的未来发展。
总之，我们概述并分析了当前CD73 相关抑制剂的现状及其治疗潜力，并勾勒出了 CD73 研究的未来方向。CD73 在肿瘤免疫学中作为癌症治疗的有前景靶点脱颖而出。新型、高效 CD73 抑制剂的发现有望扩大肿瘤免疫学研究中的候选药物库。
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免疫疗法
2024-11-12
Soquelitinib Atopic Dermatitis Phase 1 Clinical Trial Enrolling Patients in Second Dosing Cohort
Interim Data from Atopic Dermatitis Trial Expected to be Announced December 2024
Registration Phase 3 Clinical Trial of Soquelitinib in Peripheral T Cell Lymphoma (PTCL) Enrolling with Multiple Clinical Sites Open
Conference call today at 4:30 p.m. ET / 1:30 p.m. PT
BURLINGAME, Calif., Nov. 12, 2024 (GLOBE NEWSWIRE) -- Corvus Pharmaceuticals, Inc. (Corvus or the Company) (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, today provided a business update and reported financial results for the third quarter ended September 30, 2024.
“There is strong interest from clinicians and patients in both of our clinical programs for soquelitinib – the registration Phase 3 clinical trial in PTCL and the Phase 1 clinical trial in atopic dermatitis – and we are pleased with ongoing enrollment in these trials,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “ITK inhibition offers a novel mechanism of action that inhibits multiple parallel signaling pathways that modulate T cell function and immunity, giving it broad potential across a range of indications in oncology and immune disease. Its clinical potential has already been demonstrated in PTCL and we look forward to presenting interim data from our Phase 1 clinical trial in atopic dermatitis in December. We are excited for the potential of ITK inhibition to provide a new oral treatment option for atopic dermatitis, with the potential for improved efficacy, and with a more convenient and tolerable profile than biologics.”
Business Update and Strategy
Prioritized Program: Soquelitinib (Corvus’ selective ITK inhibitor)
Soquelitinib for Immune Diseases
Corvus continues to enroll patients at multiple clinical sites in its randomized, placebo-controlled Phase 1 clinical trial of soquelitinib in patients with moderate to severe atopic dermatitis. The trial is planned to enroll 64 patients that have failed at least one prior therapy across four different 28-day dosing regimens of soquelitinib compared to a placebo group. Patients are followed for an additional 30 days after completing the 28 day course of therapy. The endpoints include safety and improvement in the Eczema Area and Severity Index. Patients and physicians are blinded to the treatment assignment. Enrollment in the first cohort (100 mg, twice per day) has been completed and the data review committee has met and found no safety signals. The second cohort (200 mg, once-daily) is now enrolling patients.
Corvus plans to announce interim data from the Phase 1 clinical trial in December 2024.
In November, Corvus plans to present new preclinical data highlighting the potential of soquelitinib to prevent lung damage, inflammation and pulmonary hypertension caused by systemic sclerosis at ACR Convergence 2024, the annual meeting of the American College of Rheumatology.Corvus continues to advance its next-generation ITK inhibitor preclinical product candidates, which were designed to deliver precise T-cell modulation that is optimized for specific immunology indications.
Soquelitinib for T Cell Lymphoma
Corvus continues to enroll patients in a registrational Phase 3 clinical trial of soquelitinib in patients with relapsed PTCL at multiple sites. This randomized controlled trial is anticipated to enroll a total of 150 patients with relapsed PTCL and is evaluating soquelitinib versus physicians’ choice of either belinostat or pralatrexate. The primary endpoint of the trial is progression free survival.There are no FDA fully approved agents for the treatment of relapsed PTCL and the FDA has granted soquelitinib Orphan Drug Designation for the treatment of T cell lymphoma and Fast Track designation for treatment of adult patients with relapsed or refractory peripheral T cell lymphoma after at least 2 lines of systemic therapy.
Collaboration with Kidney Cancer Research Consortium: Ciforadenant (adenosine A2a receptor inhibitor)
Corvus is collaborating with the Kidney Cancer Research Consortium in a Phase 1b/2 clinical trial evaluating ciforadenant as a potential first line therapy for metastatic renal cell cancer (RCC) in combination with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The efficacy endpoint for the trial is deep response rate, defined as CR plus PRs of greater than 50% tumor volume reduction. The clinical trial is expected to enroll up to 60 patients and as of September 30, 2024, a total of 46 patients were enrolled in the trial. The protocol defined, interim pre-specified statistical threshold for efficacy is a 50% increase above the 32% deep response rate seen with previous ipilimumab/nivolumab combination trials in RCC conducted by investigators at the Kidney Cancer Research Consortium. The analysis of the clinical trial continues to meet the threshold for efficacy and therefore enrollment continues. Along with our partners at the Kidney Cancer Research Consortium, we have decided to continue our follow-up of patients on the trial before presenting the data. Therefore, we will not be presenting this data at the GU Malignancy conference taking place in late November and will instead target a presentation sometime in 2025.The Phase 1b/2 clinical trial in patients with metastatic RCC is supported by data presented in November at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting highlighting the potential of ciforadenant to overcome immunotherapy resistance in metastatic castration resistant prostate cancer.
Financial Results
As of September 30, 2024, Corvus had cash, cash equivalents and marketable securities of $41.7 million as compared to $27.1 million as of December 31, 2023. In October 2024, a holder of 1,677,220 common stock warrants early exercised all of their warrants resulting in cash proceeds of approximately $5.9 million. Corvus expects full year 2024 net cash used in operating activities to be between approximately $25 million and $26 million, resulting in a projected cash balance of between approximately $38 million and $39 million at December 31, 2024. Based on its current plans, Corvus expects its cash to fund operations into 2026.
Research and development expenses for the three months ended September 30, 2024 totaled $5.2 million compared to $4.0 million for the same period in 2023. The increase of approximately $1.2 million was primarily due to higher clinical trial costs associated with the development of soquelitinib.
The net loss for the three months ended September 30, 2024 was $40.2 million compared to a net loss of $6.0 million for the same period in 2023. Total stock compensation expense for the three months ended September 30, 2024 was $0.7 million compared to $0.5 million for the same period in 2023 and the non-cash loss from Corvus’ equity method investment in Angel Pharmaceuticals was $0.7 million for the three months ended September 30, 2024 compared to a loss of $0.9 million for the same period in 2023. In addition, the Company recorded a non-cash loss of $32.8 million related to an increase in the fair value of its warrant liability during the three months ended September 30, 2024 due an increase in the Company’s stock price from $1.82 at June 30, 2024 to $5.28 at September 30, 2024. The Company issued approximately 17.1 million common stock warrants in its May 2024 registered direct offering with an exercise price of $3.50 per common stock warrant. After the October 2024 early exercise of 1,677,220 common stock warrants, approximately 15.4 million common stock warrants remain outstanding. The common stock warrants expire on June 30, 2025.
Conference Call DetailsCorvus will host a conference call and webcast today, Tuesday, November 12, 2024, at 4:30 p.m. ET (1:30 p.m. PT), during which time management will provide a business update and discuss the third quarter 2024 financial results. The conference call can be accessed by dialing 1- 800-717-1738 (toll-free domestic) or 1- 646-307-1865 (international) or by clicking on this link for instant telephone access to the event. The live webcast may be accessed via the investor relations section of the Corvus website. A replay of the webcast will be available on Corvus’ website for 90 days.
About Corvus PharmaceuticalsCorvus Pharmaceuticals is a clinical-stage biopharmaceutical company pioneering the development of ITK inhibition as a new approach to immunotherapy for a broad range of cancer and immune diseases. The Company’s lead product candidate is soquelitinib, an investigational, oral, small molecule drug that selectively inhibits ITK. Its other clinical-stage candidates are being developed for a variety of cancer indications. For more information, visit www.corvuspharma.com.
About SoquelitinibSoquelitinib (formerly CPI-818) is an investigational small molecule drug given orally designed to selectively inhibit ITK (interleukin-2-inducible T cell kinase), an enzyme that is expressed predominantly in T cells and plays a role in T cell and natural killer (NK) cell immune function. Based on interim results from a Phase 1/1b clinical trial in patients with refractory T cell lymphomas, which demonstrated tumor responses in very advanced, refractory, difficult to treat T cell malignancies, the Company initiated a registrational Phase 3 clinical trial of soquelitinib in patients with relapsed PTCL. Soquelitinib also is now being investigated in a randomized placebo controlled phase 1 clinical trial in patients with atopic dermatitis. The immunologic effects of soquelitinib lead to what is known as Th1 skewing and inhibition of Th2 and Th17 cells. Research on soquelitinib’s mechanism of action suggests that it has the potential to control differentiation of normal T helper cells and enhance immune responses to tumors by augmenting the generation of cytotoxic killer T cells and the production of cytokines that inhibit cancer cell survival. Soquelitinib has also been shown to prevent T cell exhaustion, a major limitation of current immunotherapy and CAR-T therapies. Soquelitinib has been shown to affect T cell differentiation and induce the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and production of their secreted cytokines. Th1 T cells are required for immunity to tumors, viral infections and other infectious diseases. Th2 and Th17 helper T cells are involved in the pathogenesis of many autoimmune and allergic diseases. The Company believes the inhibition of specific molecular targets in T cells may be of therapeutic benefit for patients with cancers, including solid tumors, and in patients with autoimmune and allergic diseases.
About Peripheral T Cell LymphomaPeripheral T cell lymphoma is a heterogeneous group of malignancies accounting for about 10% of non-Hodgkin’s lymphomas (NHL) in Western populations, reaching 20% to 25% of NHL in some parts of Asia and South America. The most common subtypes are PTCL-not otherwise specified (PTCL-NOS) and T follicular helper cell lymphoma. First line treatment for these diseases is typically combination chemotherapy, however, approximately 75% of patients either do not respond or relapse within the first two years. Patients in relapse are treated with various chemotherapy agents but have poor overall outcomes with median progression-free survival in the three to four month range and overall median survival of six to 12 months. There are no approved drugs in relapsed PTCL based on randomized trials.
PTCL is a disease of mature helper T cells that express ITK, often containing numerous genetic mutations and frequently associated with viral infection. Most often the malignant cells of PTCL express a Th2 phenotype.
About Atopic DermatitisAtopic dermatitis, also called eczema, is a chronic disease that can cause inflammation, redness, scaly patches, blisters and irritation of the skin. It affects up to 20% of children and up to 10% of adults, and treatments include topical therapies, oral therapies and systemic injectable biologic therapies. It is frequently associated with other allergic disorders such as food allergies and asthma. Atopic dermatitis, like asthma and allergy, involves the participation of Th2 lymphocytes which secrete cytokines that result in inflammation. Soquelitinib has been shown in preclinical studies to inhibit cytokine production from Th2 lymphocytes.
About CiforadenantCiforadenant (CPI-444) is an investigational small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine to immune cells present in the tumor microenvironment. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2a receptor present on immune cells and block their activity. Ciforadenant has been shown to block the immunosuppressive effects of myeloid cells present in tumors and preclinical studies published in 2018 demonstrated synergy with combinations of anti PD1 and anti-CTLA4 antibodies.
About MupadolimabMupadolimab (CPI-006) is an investigational, potent humanized monoclonal antibody that is designed to react with a specific site on CD73. In preclinical studies, it has demonstrated immunomodulatory activity resulting in activation of lymphocytes, induction of antibody production from B cells and effects on lymphocyte trafficking. While there are other anti-CD73 antibodies and small molecules in development for treatment of cancer, such agents react with a different region of CD73. Mupadolimab is designed to react with a region of the molecule that acts to stimulate B cells and block production of immunosuppressive adenosine. Mupadolimab is being studied in combination with pembrolizumab in a Phase 1b/2 clinical trial in patients with advanced head and neck cancers and in patients with NSCLC that have failed chemotherapy and anti-PD(L)1 therapy. It is postulated that the activation of B cells will enhance immunity within the tumors of these patients, leading to improved clinical outcomes.
About Angel PharmaceuticalsAngel Pharmaceuticals is a privately held biopharmaceutical company developing a pipeline of precisely targeted investigational medicines for cancer, autoimmune, infectious and other serious diseases in China. Angel Pharmaceuticals was launched through a collaboration with U.S.-based Corvus and investments from investors in China. Angel Pharmaceuticals licensed the rights to develop and commercialize Corvus’ three clinical-stage candidates – soquelitinib, ciforadenant and mupadolimab – in greater China and obtained global rights to Corvus’ BTK inhibitor preclinical programs. Under the collaboration, Corvus currently has a 49.7% equity stake in Angel Pharmaceuticals excluding 7% of Angel’s equity reserved for issuance under the Angel ESOP, and Corvus has designated three individuals on Angel’s five-person Board of Directors. For more information, visit www.angelpharma.com.
Forward-Looking StatementsThis press release contains forward-looking statements, including statements related to the potential safety and efficacy of the Company’s product candidates including soquelitinib, ciforadenant and mupadolimab; the potential use of soquelitinib to treat a variety of hematological cancers and autoimmune diseases; the potential of ciforadenant to overcome immunotherapy resistance in metastatic castration resistant prostate cancer; the potential of ITK inhibition to provide a new oral treatment option for atopic dermatitis; the Company’s ability and its partners’ ability, as well as the timing thereof, to develop and advance product candidates into and successfully complete preclinical studies and clinical trials, including the Company’s registrational Phase 3 clinical trial for PTCL with soquelitinib and its Phase 1 clinical trial for atopic dermatitis with soquelitinib; the timing of and the Company’s ability to launch clinical trials, including the soquelitinib Phase 1 clinical trial for solid tumors; the design of clinical trials, including the timeline for initiation, target or expected number of patients to be enrolled, expected number of sites and certain other product development milestones, including in regards to the Phase 1 clinical trial for atopic dermatitis with soquelitinib and the registrational Phase 3 clinical trial for PTCL with soquelitinib; the availability and timing of clinical and preclinical data announcements and clinical readouts, including interim data from the Phase 1 clinical trial for atopic dermatitis with soquelitinib and preclinical data highlighting the potential of soquelitinib to prevent lung damage, inflammation and pulmonary hypertension caused by systemic sclerosis; the estimated amount of net cash used in operating activities for 2024 and its ability to fund operations into 2026. All statements other than statements of historical fact contained in this press release are forward-looking statements. These statements often include words such as “believe,” “expect,” “anticipate,” “intend,” “plan,” “estimate,” “seek,” “will,” “may” or similar expressions. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond the Company’s control. The Company’s actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to, risks detailed in the Company’s Quarterly Report on Form 10-Q for the three months ended September 30, 2024, filed with the Securities and Exchange Commission on or about the date hereof, as well as other documents that may be filed by the Company from time to time with the Securities and Exchange Commission. In particular, the following factors, among others, could cause results to differ materially from those expressed or implied by such forward-looking statements: the Company’s ability to demonstrate sufficient evidence of efficacy and safety in its clinical trials of soquelitinib and its other product candidates; the accuracy of the Company’s estimates relating to its ability to initiate and/or complete preclinical studies and clinical trials and release data from such studies and clinical trials; the results of preclinical studies and interim data from clinical trials not being predictive of future results; the Company’s ability to enroll sufficient numbers of patients in its clinical trials; the unpredictability of the regulatory process; regulatory developments in the United States, and other foreign countries; the costs of clinical trials may exceed expectations; the Company’s ability to accurately estimate the amount of net cash used in operating activities for 2024 and cash on hand providing funding into 2026 and the Company’s ability to raise additional capital. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the events and circumstances reflected in the forward-looking statements will be achieved or occur, and the timing of events and circumstances and actual results could differ materially from those projected in the forward-looking statements. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and the Company undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise. The Company’s results for the quarter ended September 30, 2024 are not necessarily indicative of its operating results for any future periods.
CORVUS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except share and per share data)
Three Months Ended September 30, Nine Months Ended September 30,
2024 2023 2024 2023
(unaudited) (unaudited)Operating expenses:
Research and development $5,222 $3,965 $13,411 $12,527 General and administrative 2,033 1,595 6,032 5,229 Total operating expenses 7,255 5,560 19,443 17,756 Loss from operations (7,255) (5,560) (19,443) (17,756)Interest income and other expense, net 566 425 1,316 1,204 Change in fair value of warrant liability (32,846) — (31,030) — Sublease income - related party — — — 56 Loss from equity method investment (682) (865) (1,023) (3,880)Net loss $(40,217) $(6,000) $(50,180) $(20,376)Net loss per share, basic and diluted$(0.60) $(0.12) $(0.86) $(0.43)Shares used to compute net loss per share, basic and diluted 66,701,086 48,971,246 58,513,303 47,683,792
CORVUS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands)
September 30,December 31, 2024 2023 (unaudited) Assets Cash, cash equivalents and marketable securities$41,651 $27,149Operating lease right-of-use asset 284 1,149Other assets 1,693 1,132Investment in Angel Pharmaceuticals 15,187 16,123Total assets$58,815 $45,553Liabilities and stockholders' equity Accounts payable and accrued liabilities and other liabilities$6,088 $5,495Operating lease liability 354 1,374Warrant liability 39,964 —Stockholders' equity 12,409 38,684Total liabilities and stockholders' equity$58,815 $45,553
INVESTOR CONTACT:Leiv LeaChief Financial OfficerCorvus Pharmaceuticals, Inc.+1-650-900-4522llea@corvuspharma.com
MEDIA CONTACT:Sheryl SeapyReal Chemistry+1-949-903-4750sseapy@realchemistry.com
临床1期临床3期免疫疗法临床结果快速通道
2024-08-06
Early Results from Soquelitinib Phase 1 Randomized Trial in Atopic Dermatitis Demonstrate Clinical Activity and Corresponding Changes in Cytokine Levels Consistent with ITK Inhibition Mechanism of Action Soquelitinib Registration Phase 3 Trial in Peripheral T Cell Lymphoma (PTCL) Advancing Toward Initial Enrollment in Q3 2024; New Complete Response Achieved in Ongoing Phase 1/1b Clinical Trial Conference call today at 4:30 p.m. ET / 1:30 p.m. PT BURLINGAME, Calif., Aug. 06, 2024 (GLOBE NEWSWIRE) -- Corvus Pharmaceuticals, Inc. (Corvus or the Company) (Nasdaq: CRVS), a clinical-stage biopharmaceutical company, today provided a business update and reported financial results for the second quarter ended June 30, 2024. “We have seen growing evidence supporting the central role of ITK in T cell biology and the significant potential of ITK inhibition as a new mechanism to treat a broad range of immune diseases and cancers,” said Richard A. Miller, M.D., co-founder, president and chief executive officer of Corvus. “This includes early data from our Phase 1 clinical trial of soquelitinib in atopic dermatitis and our ongoing preclinical work exploring ITK inhibition in autoimmunity and inflammation. Based on this, we are increasingly optimistic that our ITK platform has the potential to improve clinical outcomes for a range of indications as an oral medication with an attractive tolerability profile. We have leveraged our experience in T cell lymphomas which has allowed us to gain a deeper understanding of the role of ITK in T cell biology that we can now apply to immune diseases. We remain on track to initiate a Phase 3 registrational trial in PTCL in the third quarter.” Business Update and Strategy Prioritized Program: Soquelitinib (formerly CPI-818, Corvus’ selective ITK inhibitor) Soquelitinib for Immune Diseases Corvus continues to enroll patients at multiple clinical sites in its randomized, placebo-controlled Phase 1 clinical trial of soquelitinib in patients with moderate to severe atopic dermatitis. The trial is planned to enroll 64 patients that have failed at least one prior therapy across four different 28-day dosing regimens of soquelitinib compared to a placebo group. The endpoints include safety and improvement in Eczema Area and Severity Index. Patients and physicians will be blinded to treatment assignment. Initial results, as of July 31, 2024, from three evaluable patients in the first cohort of the trial that completed the 28-day dosing regimen and follow-up visit demonstrated signs of clinical activity and corresponding changes in serum cytokine levels that are consistent with soquelitinib’s mechanism of action. These patients received a dose of 100 mg two-times a day, the lowest dose level planned for the study. Corvus anticipates interim data from the Phase 1 clinical trial will be presented in the fourth quarter of 2024. Recent published data from researchers at Cornell University demonstrated that ITK controls the fate of inflammatory Th17 cells. When ITK is inhibited by soquelitinib, the Th17 cells convert or switch to Treg cells that suppress inflammation. Soquelitinib treatment in an asthma model of mice with allergic airway inflammation significantly reduced the percentage of Th17 cells in the lung resulting in an increase in the ratio of Treg to Th17 cells. These studies confirm our understanding of the role of specific ITK inhibition in inflammation and are relevant to many immune diseases.Corvus continues to advance its next-generation ITK inhibitor preclinical product candidates, which were designed to deliver precise T-cell modulation that is optimized for specific immunology indications. The next-generation ITK inhibitor candidates are part of the Company’s ongoing business development efforts to maximize the potential of the Company’s ITK inhibitor programs in immune diseases and cancers. Soquelitinib for T Cell Lymphoma Corvus continues to follow patients with relapsed T cell lymphoma in its Phase 1/1b clinical trial (no longer enrolling new patients) evaluating single agent therapy with soquelitinib. Updated interim data as of July 16, 2024: A total of 25 patients were enrolled in the Phase 1/1b trial at the optimum 200 mg two-times a day dose and meet the eligibility criteria for the planned registrational Phase 3 clinical trial based on ≥1 and ≤3 prior therapies, including 23 evaluable patients.For the 23 evaluable patients, objective responses (complete response, CR plus partial response, PR) were seen in nine patients (39%), including six CRs (26%) and three PRs. Compared to the prior data reported as of May 3, 2024, one patient with continued tumor regression achieved a CR that previously had a PR at the first follow up visit. See waterfall plot below.Disease control (CR, PR and stable disease) was seen in 14 of 23 patients (61%). The stable disease group included five patients who achieved tumor reductions that did not meet the criteria for a PR. Corvus anticipates initiating a registrational Phase 3 clinical trial of soquelitinib in patients with relapsed PTCL in the third quarter of 2024. There are currently no FDA fully approved agents for the treatment of relapsed PTCL and the FDA has granted Orphan Drug Designation for soquelitinib for the treatment of T cell lymphoma. Recently, the Company received a Pediatric Waiver from the FDA indicating that it would not be required to conduct clinical trials in a pediatric population for this indication.As recently announced, soquelitinib has received Fast Track designation for treatment of adult patients with relapsed or refractory peripheral T cell lymphoma after at least 2 lines of systemic therapy. Waterfall Plot for Patients in the 200 mg Dose Cohort of the Soquelitinib Phase 1/1b Clinical Trial for Peripheral T Cell Lymphoma. The plot shows the best percent change in tumor volume in the 23 evaluable patients (eligible patient population), as of July 16, 2024, that were measurable by CT scan or by Modified Severity-Weighted Assessment Tool (mSWAT) for patients with cutaneous involvement. PTCL-NOS, peripheral T cell lymphoma not otherwise specified; CTCL, cutaneous T cell lymphoma of either Sezary or mycosis fungoides type; NKTCL, natural killer cell T cell lymphoma; ALCL, anaplastic large cell lymphoma; AITL, angioimmunoblastic T cell lymphoma.
Collaboration with Kidney Cancer Research Consortium: Ciforadenant (adenosine A2a receptor inhibitor) Corvus is collaborating with the Kidney Cancer Research Consortium in a Phase 1b/2 clinical trial evaluating ciforadenant as a potential first line therapy for metastatic renal cell cancer (RCC) in combination with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The efficacy endpoint for the trial is deep response rate, defined as CR plus PRs of greater than 50% tumor volume reduction. The clinical trial is expected to enroll up to 60 patients and as of May 31, 2024 a total of 32 patients were enrolled in the trial. The protocol defined, interim pre-specified statistical threshold for efficacy is a 50% increase above the 32% deep response rate seen with previous ipilimumab/nivolumab combination trials in RCC conducted by investigators at the Kidney Cancer Research Consortium. As of May 31, 2024, the interim analysis of the clinical trial has met the threshold for efficacy and therefore enrollment continues.In July 2024, a new U.S. patent was issued (United States Patent No. 12,023,337) by the U.S. Patent and Trademark Office that covers the use of ciforadenant for the treatment of cancer; foreign counterparts are pending. Partner Led Program: Mupadolimab (anti-CD73) Angel Pharmaceuticals, Corvus’ partner in China, is enrolling patients in an expansion cohort of a Phase 1/1b clinical trial of mupadolimab in patients with relapsed non-small cell lung cancer (NSCLC). In this clinical trial, patients will receive mupadolimab monotherapy. Financial Results As of June 30, 2024, Corvus had cash, cash equivalents and marketable securities of $47.2 million as compared to $27.1 million as of December 31, 2023. During the quarter ended June 30, 2024, the Company completed a registered direct offering in which it sold shares of common stock, pre-funded warrants and common warrants, generating $30.3 million in net proceeds. Corvus expects full year 2024 net cash used in operating activities to be between approximately $24 million and $27 million, resulting in a projected cash balance of between approximately $31 million and $34 million at December 31, 2024. Based on its current plans, Corvus expects its cash to fund operations into the fourth quarter of 2025. Research and development expenses for the three months ended June 30, 2024 totaled $4.1 million compared to $4.0 million for the same period in 2023. The increase of $0.1 million was primarily due to higher clinical trial costs associated with the development of soquelitinib. The net loss for the three months ended June 30, 2024 was $4.3 million compared to a net loss of $6.5 million for the same period in 2023. Total stock compensation expense for the three months ended June 30, 2024 was $0.8 million compared to $0.5 for the same period in 2023 and the non-cash loss from Corvus’ equity method investment in Angel Pharmaceuticals was $0.6 million for the three months ended June 30, 2024 compared to a loss of $1.3 million for the same period in 2023. In addition, the Company recorded a non-cash gain of $1.8 million from the change in fair value of its warrant liability during the three months ended June 30, 2024 due to the warrants issued in the registered direct offering. Conference Call DetailsCorvus will host a conference call and webcast today, Tuesday, August 6, 2024, at 4:30 p.m. ET (1:30 p.m. PT), during which time management will provide a business update and discuss the second quarter 2024 financial results. The conference call can be accessed by dialing 1- 800-717-1738 (toll-free domestic) or 1- 646-307-1865 (international) or by clicking on this link for instant telephone access to the event. The live webcast may be accessed via the investor relations section of the Corvus website. A replay of the webcast will be available on Corvus’ website for 90 days. About Corvus PharmaceuticalsCorvus Pharmaceuticals is a clinical-stage biopharmaceutical company pioneering the development of ITK inhibition as a new approach to immunotherapy for a broad range of cancer and immune diseases. The Company’s lead product candidate is soquelitinib, an investigational, oral, small molecule drug that selectively inhibits ITK. Its other clinical-stage candidates are being developed for a variety of cancer indications. For more information, visit www.corvuspharma.com. About SoquelitinibSoquelitinib (formerly CPI-818) is an investigational small molecule drug given orally designed to selectively inhibit ITK (interleukin-2-inducible T cell kinase), an enzyme that is expressed predominantly in T cells and plays a role in T cell and natural killer (NK) cell immune function. Based on interim results from a Phase 1/1b clinical trial in patients with refractory T cell lymphomas, which demonstrated tumor responses in very advanced, refractory, difficult to treat T cell malignancies, the Company plans to initiate a registrational Phase 3 clinical trial of soquelitinib in patients with relapsed PTCL. Soquelitinib also is now being investigated in a randomized placebo controlled phase 1 clinical trial in patients with atopic dermatitis. The immunologic effects of soquelitinib lead to what is known as Th1 skewing and inhibition of Th2 and Th17 cells. Research on soquelitinib’s mechanism of action suggests that it has the potential to control differentiation of normal T helper cells and enhance immune responses to tumors by augmenting the generation of cytotoxic killer T cells and the production of cytokines that inhibit cancer cell survival. Soquelitinib has also been shown to prevent T cell exhaustion, a major limitation of current immunotherapy and CAR-T therapies. Soquelitinib has been shown to affect T cell differentiation and induce the generation of Th1 helper cells while blocking the development of both Th2 and Th17 cells and production of their secreted cytokines. Th1 T cells are required for immunity to tumors, viral infections and other infectious diseases. Th2 and Th17 helper T cells are involved in the pathogenesis of many autoimmune and allergic diseases. The Company believes the inhibition of specific molecular targets in T cells may be of therapeutic benefit for patients with cancers, including solid tumors, and in patients with autoimmune and allergic diseases. About Peripheral T Cell LymphomaPeripheral T cell lymphoma is a heterogeneous group of malignancies accounting for about 10% of non-Hodgkin’s lymphomas (NHL) in Western populations, reaching 20% to 25% of NHL in some parts of Asia and South America. The most common subtypes are PTCL-not otherwise specified (PTCL-NOS) and T follicular helper cell lymphoma. First line treatment for these diseases is typically combination chemotherapy, however, approximately 75% of patients either do not respond or relapse within the first two years. Patients in relapse are treated with various chemotherapy agents but have poor overall outcomes with median progression-free survival in the three to four month range and overall median survival of six to 12 months. There are no approved drugs in relapsed PTCL based on randomized trials. PTCL is a disease of mature helper T cells that express ITK, often containing numerous genetic mutations and frequently associated with viral infection. Most often the malignant cells of PTCL express a Th2 phenotype. About Atopic DermatitisAtopic dermatitis, also called eczema, is a chronic disease that can cause inflammation, redness, scaly patches, blisters and irritation of the skin. It affects up to 20% of children and up to 10% of adults, and treatments include topical therapies, oral therapies and systemic injectable biologic therapies. It is frequently associated with other allergic disorders such as food allergies and asthma. Atopic dermatitis, like asthma and allergy, involves the participation of Th2 lymphocytes which secrete cytokines that result in inflammation. Soquelitinib has been shown in preclinical studies to inhibit cytokine production from Th2 lymphocytes. About CiforadenantCiforadenant (CPI-444) is an investigational small molecule, oral, checkpoint inhibitor designed to disable a tumor’s ability to subvert attack by the immune system by blocking the binding of adenosine to immune cells present in the tumor microenvironment. Adenosine, a metabolite of ATP (adenosine tri-phosphate), is produced within the tumor microenvironment where it may bind to the adenosine A2a receptor present on immune cells and block their activity. Ciforadenant has been shown to block the immunosuppressive effects of myeloid cells present in tumors and preclinical studies published in 2018 demonstrated synergy with combinations of anti PD1 and anti-CTLA4 antibodies. About MupadolimabMupadolimab (CPI-006) is an investigational, potent humanized monoclonal antibody that is designed to react with a specific site on CD73. In preclinical studies, it has demonstrated immunomodulatory activity resulting in activation of lymphocytes, induction of antibody production from B cells and effects on lymphocyte trafficking. While there are other anti-CD73 antibodies and small molecules in development for treatment of cancer, such agents react with a different region of CD73. Mupadolimab is designed to react with a region of the molecule that acts to stimulate B cells and block production of immunosuppressive adenosine. Mupadolimab is being studied in combination with pembrolizumab in a Phase 1b/2 clinical trial in patients with advanced head and neck cancers and in patients with NSCLC that have failed chemotherapy and anti-PD(L)1 therapy. It is postulated that the activation of B cells will enhance immunity within the tumors of these patients, leading to improved clinical outcomes. About Angel PharmaceuticalsAngel Pharmaceuticals is a privately held biopharmaceutical company developing a pipeline of precisely targeted investigational medicines for cancer, autoimmune, infectious and other serious diseases in China. Angel Pharmaceuticals was launched through a collaboration with U.S.-based Corvus and investments from investors in China. Angel Pharmaceuticals licensed the rights to develop and commercialize Corvus’ three clinical-stage candidates – soquelitinib, ciforadenant and mupadolimab – in greater China and obtained global rights to Corvus’ BTK inhibitor preclinical programs. Under the collaboration, Corvus currently has a 49.7% equity stake in Angel Pharmaceuticals excluding 7% of Angel’s equity reserved for issuance under the Angel ESOP, and Corvus has designated three individuals on Angel’s five-person Board of Directors. For more information, visit www.angelpharma.com. Forward-Looking StatementsThis press release contains forward-looking statements, including statements related to the potential safety and efficacy of the Company’s product candidates including soquelitinib, ciforadenant and mupadolimab; the potential use of soquelitinib to treat a variety of hematological cancers and autoimmune diseases; the Company’s ability and its partners’ ability, as well as the timing thereof, to develop and advance product candidates into and successfully complete preclinical studies and clinical trials, including the Company’s Phase 1 clinical trial for atopic dermatitis with soquelitinib; the timing of and the Company’s ability to launch clinical trials, including the soquelitinib registrational Phase 3 clinical trial for PTCL; the design of clinical trials, including the timeline for initiation, target or expected number of patients to be enrolled, expected number of sites and certain other product development milestones, including in regards to the Phase 1 clinical trial for atopic dermatitis with soquelitinib; the availability and timing of clinical and preclinical data announcements and clinical readouts, including early data from the Phase 1 clinical trial for atopic dermatitis with soquelitinib and preclinical data supporting the broad potential of ITK inhibition in immune and inflammatory disease; the estimated amount of net cash used in operating activities for 2024 and its ability to fund operations into the fourth quarter of 2025. All statements other than statements of historical fact contained in this press release are forward-looking statements. These statements often include words such as “believe,” “expect,” “anticipate,” “intend,” “plan,” “estimate,” “seek,” “will,” “may” or similar expressions. Forward-looking statements are subject to a number of risks and uncertainties, many of which involve factors or circumstances that are beyond the Company’s control. The Company’s actual results could differ materially from those stated or implied in forward-looking statements due to a number of factors, including but not limited to, risks detailed in the Company’s Quarterly Report on Form 10-Q for the three months ended June 30, 2024, filed with the Securities and Exchange Commission on or about the date hereof, as well as other documents that may be filed by the Company from time to time with the Securities and Exchange Commission. In particular, the following factors, among others, could cause results to differ materially from those expressed or implied by such forward-looking statements: the Company’s ability to demonstrate sufficient evidence of efficacy and safety in its clinical trials of soquelitinib and its other product candidates; the accuracy of the Company’s estimates relating to its ability to initiate and/or complete preclinical studies and clinical trials and release data from such studies and clinical trials; the results of preclinical studies and interim data from clinical trials not being predictive of future results; the Company’s ability to enroll sufficient numbers of patients in its clinical trials; the unpredictability of the regulatory process; regulatory developments in the United States, and other foreign countries; the costs of clinical trials may exceed expectations; the Company’s ability to accurately estimate the amount of net cash used in operating activities for 2024 and cash on hand providing funding into the fourth quarter of 2025 and the Company’s ability to raise additional capital. Although the Company believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee that the events and circumstances reflected in the forward-looking statements will be achieved or occur, and the timing of events and circumstances and actual results could differ materially from those projected in the forward-looking statements. Accordingly, you should not place undue reliance on these forward-looking statements. All such statements speak only as of the date made, and the Company undertakes no obligation to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise. The Company’s results for the quarter ended June 30, 2024 are not necessarily indicative of its operating results for any future periods.
CORVUS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS (in thousands, except share and per share data)
Three Months Ended June 30, Six Months Ended June 30, 2024 2023 2024 2023 (unaudited) (unaudited)Operating expenses:
Research and development $4,114 $3,968 $8,189 $8,562 General and administrative 1,821 1,654 3,999 3,634 Total operating expenses 5,935 5,622 12,188 12,196 Loss from operations (5,935) (5,622) (12,188) (12,196)Interest income and other expense, net 434 403 750 779 Change in fair value of warrant liability 1,816 — 1,816 — Sublease income - related party — — — 56 Loss from equity method investment (577) (1,284) (341) (3,015)Net loss $(4,262) $(6,503) $(9,963) $(14,376)Net loss per share, basic and diluted $(0.07) $(0.14) $(0.18) $(0.31)Shares used to compute net loss per share, basic and diluted 59,710,265 47,497,414 54,374,423 47,029,396
CORVUS PHARMACEUTICALS, INC.CONDENSED CONSOLIDATED BALANCE SHEETS (in thousands)
June 30, December 31, 2024 2023 (unaudited) Assets Cash, cash equivalents and marketable securities $47,246 $27,149 Operating lease right-of-use asset 578 1,149 Other assets 1,333 1,132 Investment in Angel Pharmaceuticals 15,404 16,123 Total assets $64,561 $45,553 Liabilities and stockholders' equity Accounts payable and accrued liabilities and other liabilities $5,517 $5,495 Operating lease liability 700 1,374 Warrant liability 7,118 — Stockholders' equity 51,226 38,684 Total liabilities and stockholders' equity $64,561 $45,553
INVESTOR CONTACT:Leiv LeaChief Financial OfficerCorvus Pharmaceuticals, Inc.+1-650-900-4522llea@corvuspharma.com MEDIA CONTACT:Sheryl SeapyReal Chemistry+1-949-903-4750sseapy@realchemistry.com A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/a451d560-a41c-4487-99ca-cd7de11e4274
临床1期临床结果免疫疗法临床3期孤儿药
100 项与 Mupadolimab 相关的药物交易
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
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| 新型冠状病毒感染 | 临床3期 | 美国 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 阿根廷 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 巴西 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 加拿大 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 智利 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 哥伦比亚 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 德国 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 意大利 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 墨西哥 | 2021-02-25 | |
| 新型冠状病毒感染 | 临床3期 | 秘鲁 | 2021-02-25 |
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| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床3期 | 46 | (Treatment A: CPI-006 2 mg/kg + SOC) | 顧築構艱鏇壓憲選積壓 = 願願夢夢鑰獵餘網膚蓋 遞繭糧鹽獵糧蓋範衊獵 (衊鑰蓋糧鏇顧蓋衊窪餘, 鬱築鑰鏇齋積範糧鏇衊 ~ 築衊鹹顧淵遞鏇鏇襯鏇) 更多 | - | 2022-08-23 | ||
(Treatment B: CPI-006 1 mg/kg + SOC) | 顧築構艱鏇壓憲選積壓 = 願構鹽範餘衊襯獵艱遞 遞繭糧鹽獵糧蓋範衊獵 (衊鑰蓋糧鏇顧蓋衊窪餘, 廠醖齋鑰積鏇廠繭壓顧 ~ 淵簾選製窪鑰衊壓蓋餘) 更多 | ||||||
临床1期 | 新型冠状病毒感染 CD73 | anti-SARS-CoV-2 antibodies | 10 | 齋獵網糧衊鹹顧糧願構(遞鹽鏇鹽網構顧顧夢積) = 餘觸窪獵鬱廠網淵鹽鹹 範築製鏇齋製淵觸廠製 (鑰壓衊衊觸繭鹽簾鏇襯, 1–21) 更多 | 积极 | 2020-12-10 | ||
临床1期 | 15 | (0.3 mg/kg) | 衊簾淵範壓選鹹艱夢觸(齋糧構膚襯醖蓋襯蓋蓋) = 膚窪憲構顧鏇鏇築淵醖 鹹艱選繭窪艱遞顧遞齋 (築顧遞鹹鏇襯鹹網齋鹽 ) 更多 | 积极 | 2020-10-05 | ||
(1.0 mg/kg) | 衊簾淵範壓選鹹艱夢觸(齋糧構膚襯醖蓋襯蓋蓋) = 壓鹽網獵艱艱鹽淵廠觸 鹹艱選繭窪艱遞顧遞齋 (築顧遞鹹鏇襯鹹網齋鹽 ) 更多 | ||||||
临床1期 | 17 | 糧簾築繭壓繭遞壓遞範(選鑰憲鬱構繭築範醖製) = increased 構淵醖壓願鹹醖繭獵鹹 (顧積簾夢鹹構鹹簾築顧 ) 更多 | 积极 | 2019-05-26 | |||
临床1期 | - | 5 | 構積選餘鹹選艱簾網窪(顧鹽願憲範遞糧夢範鏇) = induced B lymphocyte activation leading to ERK phosphorylation and increased CD69, CD25, and CD83 expression 觸願艱獵艱衊築網鹽願 (遞淵網鬱築範選淵夢網 ) 更多 | 积极 | 2018-11-06 |
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