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更新于：2024-12-31
Tempol
更新于：2024-12-31
概要
基本信息
药物类型 小分子化药 |
别名 APC-400、APC-410、MBM-01 + [8] |
作用机制 Hypoxia-inducible factor 1调节剂(缺氧诱导因子1调节剂)、活性氧抑制剂 |
在研适应症 |
非在研适应症 |
最高研发阶段临床3期 |
首次获批日期- |
最高研发阶段(中国)- |
特殊审评快速通道 (美国)、孤儿药 (美国)、孤儿药 (欧盟) |
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结构/序列
分子式C9H18NO2 |
InChIKeyUZFMOKQJFYMBGY-UHFFFAOYSA-N |
CAS号2226-96-2 |
关联
14
项与 Tempol 相关的临床试验NCT06424756
Role of Mitochondria-derived Oxidative Stress on Microvascular Endothelial Function in Healthy Non-Hispanic Black and White Adults
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, and the non-Hispanic Black (NHB) population is disproportionately affected. Our research has previously demonstrated that oxidative stress may contribute to reduced vascular function in otherwise healthy NHB adults, potentially predisposing them to the development of hypertension and CVD. This study is designed to examine whether the mitochondria are an important source of oxidative stress-induced vascular dysfunction in healthy NHB adults.
开始日期2024-07-01 |
申办/合作机构 |
NCT05085561
A Two-Part Study of REC-994 in the Treatment of Adults With Symptomatic Cerebral Cavernous Malformation (CCM); Part 1: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety, Efficacy and Pharmacokinetics of Two Doses of REC-994; Part 2: A Long-Term Blinded Extension Clinical Trial to Evaluate Long-Term Safety Tolerability and Efficacy of REC-994
This is a two-part, multi-center, randomized, double-blind, placebo-controlled study to investigate the safety, efficacy and pharmacokinetics of REC-994 (200 mg and 400 mg) compared to placebo in subjects with symptomatic cerebral cavernous malformation (CCM).
开始日期2022-03-17 |
NCT04729595
A Phase 2/3, Adaptive, Randomized, Double-Blind, Placebo-Controlled Study to Examine the Effects of Tempol (MBM-02) in Subjects With COVID-19 Infection
An Adaptive, Randomized, Double-blind, Placebo-controlled study to examine the Effects of Tempol in subjects with COVID-19 infection.
开始日期2021-09-01 |
申办/合作机构- |
100 项与 Tempol 相关的临床结果
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100 项与 Tempol 相关的转化医学
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100 项与 Tempol 相关的专利（医药）
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1,908
项与 Tempol 相关的文献（医药）2025-01-01·AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Reduced microvascular flow-mediated dilation in Syrian hamsters lacking δ-sarcoglycan is caused by increased oxidative stress
Article
作者: Richard, Alexis ; Belin de Chantemèle, Eric ; Fassot, Céline ; Loufrani, Laurent ; Mongue-Din, Héloïse ; Henrion, Daniel ; Toutain, Bertrand ; Retailleau, Kevin ; Guihot, Anne-Laure ; Fromes, Yves ; Bocquet, Arnaud
This study suggests that the sarcoglycan complex is selectively involved in flow-mediated dilation, thus highlighting its role in endothelial responsiveness to shear stress and amplifying tissue damage in myopathy.
2024-12-31·CLINICAL AND EXPERIMENTAL HYPERTENSION
Uric acid mediates kidney tubular inflammation through the LDHA/ROS/NLRP3 pathway
Article
作者: Gan, Yumei ; Ouyang, Jun ; Wang, Hui ; Huang, Jiangnan
PURPOSE:
Hyperuricemia (HUA) is an important factor leading to chronic kidney disease (CKD). The kidney tubular inflammatory response is activated in HUA. This study aimed to investigate whether lactate dehydrogenase A (LDHA) is involved in mediating uric acid-induced kidney tubular inflammatory response.
METHODS:
In vivo, an HUA mouse model was established by continuous intraperitoneal injection of potassium oxonate (PO) for one week. A total of 18 C57BL/6J male adult mice were divided into three groups: control group, HUA group, and HUA+oxamate group, with six mice in each group. Oxamate was intraperitoneally injected into the mice one hour after PO injection. In vitro, an HUA model was simulated by stimulating HK-2 cells with uric acid. Oxamate and tempol inhibited LDHA and reactive oxygen species (ROS) in HK-2 cells.
RESULTS:
In HUA mice, blood uric acid levels were significantly elevated. LDHA in kidney tubular cells was significantly increased in both in vivo and in vitro HUA models, accompanied by an increase in kidney tubular inflammation and ROS. Mechanistically, LDHA mediates uric acid-induced inflammation to kidney tubular cells through the ROS/NLRP3 pathway. Pharmacologic inhibition of LDHA or ROS in kidney tubular cells can significantly ameliorate inflammation response caused by uric acid.
CONCLUSIONS:
LDHA in kidney tubular cells significantly was increased in HUA models. LDHA mediates kidney inflammation response induced by uric acid through the ROS/NLRP3 pathway. This study may provide a new intervention target for preventing kidney tubular inflammation caused by uric acid.
2024-12-31·CLINICAL AND EXPERIMENTAL HYPERTENSION
Gestational diabetes causes hyperactivity of the sympathetic nervous system and hypertension in adult mice offspring
Article
作者: Wang, Chunxiang ; Luo, Hao ; Zhu, Jun ; Yang, Li ; Zhu, Xingyu ; Hu, Zegang ; Bai, Xue
BACKGROUND:
Gestational diabetes can lead to increased blood pressure in offspring, accompanied by impaired renal sodium excretion function and vasoconstriction and diastole dysfunction. However, there are few studies on whether it is accompanied by increased sympathetic nerve activity.
METHODS:
Pregnant C57BL/6 mice were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at day 0 of gestation. The mice of control mother offspring (CMO) and diabetic mother offspring (DMO) at 16 weeks of age were infused with vehicle (artificial cerebrospinal fluid, aCSF, 0.4 μL/h) or tempol (1 mmol/L, 0.4 μL/h) into the bilateral paraventricular nucleus (PVN) of mice for 4 weeks, respectively.
RESULTS:
Compared with CMO group, SBP and peripheral sympathetic nerve activity (increased heart rate, LF/HF and plasma norepinephrine and decreased SDNN and RMSSD) were increased in DMO group, which was accompanied by increased angiotensin II type-1 receptor (AT1R) expression and function in PVN. The increase in AT1R expression levels was attributed to a decrease in the methylation level of the AT1R promoter region, resulting in an increase in AT1R mRNA levels in PVN of DMO. Moreover, compared with CMO group, the levels of oxidative stress were increased and DNMT1 expression was decreased in PVN of DMO. Bilateral PVN infusion of tempol attenuated oxidative stress increased the level of DNMT1 expression and the binding of DNMT1 to the AT1R promoter region, which reduced mRNA and protein expression level of AT1R, heart rate and SBP in DMO, but not in CMO.
CONCLUSIONS:
The present study provides evidence for overactive sympathetic nervous systems in the pathogenesis of gestational diabetes-induced hypertension in offspring. Central antioxidant intervention in the PVN may be an important treatment strategy for fetal-programmed hypertension.
59
项与 Tempol 相关的新闻（医药）2024-12-18
·药学进展
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张齐雄
电子科技大学附属四川省人民医院副研究员，硕士生导师。陆军军医大学药剂学博士，师从张建祥教授，从事智能药物递送领域研究工作。入选四川省“卫生健康英才计划”中青年骨干人才、 四川省人民医院首批“双百工程”和“优博计划”。担任四川省国际医学交流促进会合理用药分会常务委员。主持承担国家自然科学基金、四川省自然科学基金等多项科研项目。以第一或通信作者发表SCI论文20余篇，其中12篇影响因子大于10，1篇入选ESI前0.1%热点论文，总他引超700次，H指数12。授权发明专利5项。
李姗姗
西南民族大学副教授，硕士生导师，四川大学-墨尔本大学联合培养博士。现主持国家自然科学基金1项、四川省科技厅自然科学基金项目1项、个体化药物治疗四川省重点实验室开放课题 1 项、西南民族大学人才引进项目1项，中央高校基本科研业务费专项项目1项。申请授权发明专利4项， 以第一/通信作者在J Control Release、Theranostics 和 Acta Biomater 等国际主流学术期刊发表论文30余篇，总影响因子超200。
活性氧响应性递药系统在抗炎治疗中的研究进展 PPS
李鹏程1，杨颜睿1，杜宇航1，焦玉1，黄秋映1，张辉辉1，张齐雄2*，李姗姗1**
（1. 西南民族大学药学与食品学院，四川 成都 610225；2. 四川省医学科学院 四川省人民医院，四川 成都 610072）
[摘要] 活性氧是细胞正常生理功能的重要调节因子，而在炎症反应中，过量的活性氧会破坏氧化-还原平衡，进而引发细胞和组织损伤，导致疾病的发生。利用炎症部位高活性氧水平的特性，活性氧响应性递药系统可以实现药物的靶向控释，在抗炎治疗领域应用潜力巨大。综述了基于不同类型活性氧响应性材料（包括含硫类化合物、含硒/碲化合物、苯硼酸酯类化合物及脯氨酸低聚物等）的递药系统在抗炎治疗中的研究进展，旨在为用于治疗炎症性疾病的智能递药系统的深度开发提供思路与参考。
1
引言
活性氧（reactive oxygen species，ROS）是一类具有高反应性的氧基化合物，其种类繁多，包括超氧阴离子（O2-）、过氧化氢（H2O2）、单线态氧（1O2） 和羟基自由基（·OH）等[1]。内源性ROS主要形成于线粒体内膜的氧化磷酸化过程。在此过程中， 电子通过电子传输链传递，部分电子提前与氧分子结合形成O2- [1-2]。O2- 反应性极高，可进一步转化为 H2O2 和·OH等其他类型的ROS。外源衍生性ROS 主要来源于辐射、空气污染物或异生素等[3]。一般情况下，ROS是细胞正常生理功能的重要调节因子， 参与信号传递、细胞分裂和免疫反应过程[4-6]。但在氧化应激条件下，过量的ROS会破坏氧化-还原平衡，对蛋白质、脂质、DNA等生物分子造成损伤， 从而引发疾病[7]。例如癌症、心血管疾病、神经退行性疾病、炎症性疾病等的发生发展过程都与ROS 水平的失衡密切相关[5, 8-10]。
炎症，作为机体对抗感染与组织伤害的自然防御机制，旨在清除病原体与促进组织修复。然而，当炎症反应过度或持久不息时，其反而会加剧组织损伤，推动疾病恶化。炎症反应过程中ROS的产生显著增加，扮演着双刃剑的角色。一方面，ROS是免疫系统抗击病原体的有力武器；另一方面，它也是导致细胞损伤和炎症加剧的关键因素。研究显示， 正常人血浆中H2O2的平均浓度为3 μmol · L-1，而在肺部炎症性疾病和脑缺血发生时，H2O2浓度可分别升高至20和100 μmol · L-1 [11]。在炎症部位，免疫细胞的活跃与病理环境的刺激共同促进了ROS的大量生成[12]，形成高氧化应激微环境。近年来，利用该微环境的特异性，设计并构建ROS响应性智能载体进行药物递送的研究备受关注。新兴的ROS敏感材料种类众多，在生物医学领域展现出巨大的发展潜力。常见的ROS响应材料包括含硫化合物、含硒 （Se）聚合物、含碲（Te）聚合物、含苯基硼酸（或 苯基硼酸酯）聚合物、L-脯氨酸聚合物等。相较于传统递药系统，ROS响应性递药系统能够识别炎症部位高ROS环境并精准释放药物，治疗效率更高， 毒副作用更低，为炎症性疾病的治疗开辟了新途径。本文对基于ROS响应性材料的递药系统在抗炎治疗中的研究进展进行综述，以期为炎症性疾病的治疗研究提供新的视角和启示。
2
基于ROS响应性材料的递药系统及其在抗炎治疗中的研究
2.1 基于含硫化合物的递药系统
硫醚基氧化敏感材料是目前广泛研究的ROS响应性材料之一[13-14]，研究发现其对H2O2、·OH、 有机过氧化物、次氯酸（HClO）、过氧亚硝基阴离子（ONOO-）敏感。在这些ROS的作用下，疏水的含硫醚基化合物被氧化为亲水的砜/亚砜化合物， 水溶性的显著增加使得该材料所包裹的疏水药物得以释放[15]。例如，聚丙烯硫醚（PPS）是一种常用 的含硫醚基的疏水性聚合物，在氧化环境下，疏水性PPS可以转变为强亲水性的聚丙烯砜/亚砜，在高ROS浓度的炎症部位有效释放药物，从而降低 ROS 水平，实现抗炎治疗。2004年，Napoli等[16] 利用PPS的ROS响应性，首次合成了基于聚乙二醇（PEG）和PPS的ABA型三嵌段共聚物，其中PEG是亲水性A段，PPS是疏水性B段。研究表明， 这种共聚物在水中能自组装成稳定的球形或长圆形单层囊泡。在0.03%的H2O2溶液中处理10 d，共聚物未能完全氧化；但在10% H2O2溶液中处理10 h， 囊泡迅速溶解并破坏，显示出了显著的高H2O2浓度响应性。这一发现展示了PPS在基于ROS响应性材料的递药系统[特别是用于递送氧化应激相关疾病（如炎症、癌症等）治疗药物的系统]开发中的潜力。此外，Poole等[17]通过PPS包埋抗炎抗氧化分子姜黄素（Cur）制成微粒，旨在治疗糖尿病相关的外周动脉疾病。PPS-Cur微球颗粒平均直径为 （1.33±0.55）μm，载药量和包封率分别为49%和 40%。研究表明，PPS-Cur微球的细胞相容性良好， 在高ROS浓度环境中通过“疏水-亲水”相变机制， 可靶向释放Cur，从而有效清除被脂多糖与干扰素激活的巨噬细胞产生的ROS，并降低糖尿病小鼠外周动脉疾病后肢缺血模型组织中的ROS水平。有趣 的是，由于PPS具有ROS清除作用，空白PPS微球在体外也显示出一定的治疗特性。
ROS响应性结构片段也可与其他类型刺激响应性结构片段相结合，开发出同时具有多重响应特性的递药系统。例如，聚硫醚缩酮中的硫醚基团具有 ROS 响应性，在ROS作用下被氧化，将聚合物主链由疏水性转变为亲水性；而缩酮基团具有pH响应性，在弱酸性环境中快速降解。Mahmoud等[18] 以聚硫醚缩酮为原料制备了纳米颗粒（平均粒径约 200 nm），发现其只有在同时存在氧化应激（100 mmol · L-1 H2O2 ）和酸性的条件下（pH 5），才会完全降解。相较而言，在100 mmol · L-1 H2O2/pH 7.4条 件下，纳米颗粒仅发生膨胀而不降解，使得小分子物质的释放率高，而大分子物质的释放率有限。因此对于蛋白质等大分子的递送，具有双重响应特性的聚硫醚缩酮材料具有显著的优势，研究结果也证实基于该材料的递送系统所负载的卵清蛋白在氧化应激/酸性条件下，24 h内的释放效率比氧化应激/ 中性条件下更高。pH降低和ROS水平升高是炎症组织的典型特征[19-20]，以聚硫醚缩酮制备的递药系统基于硫醚基团的ROS响应性和缩酮基团的pH响应性，有望实现炎症性疾病的有效靶向治疗。
硫缩酮是由缩酮与硫醇在路易斯酸条件下合成的ROS响应性结构，研究发现其对H2O2、O2-、 ·OH、1O2敏感。硫缩酮结构对生物体内的酶、酸性或碱性环境稳定，在健康的细胞或组织中，含硫缩酮的递药体系保持稳定，不会诱导细胞毒性[21]。但在ROS的作用下，硫缩酮可迅速降解成无毒的硫醇与酮类[22]。因此，含有硫缩酮结构的聚合物材 料可作为优异的递药载体，利用炎症部位的高ROS 微环境，使载药材料降解，实现药物的定点靶向释 放[23-25]。例如，针对促炎性细胞因子的小干扰RNA （siRNA）有潜力治疗肠道炎症相关疾病，但多种口服递药策略均无法保护siRNA免受胃肠道黏液的破坏。Wilson 等[26] 构建的基于硫缩酮的纳米颗粒可包裹siRNA，克服胃肠道中的不利因素，选择性地在高ROS浓度环境中降解，将纳米颗粒负载的 siRNA 定点释放于肠道炎症部位，从而抑制炎症相关靶基因的表达。Li等[27]也以芳香化硫缩酮作为连接子，将抗炎药物布地奈德与抗氧化剂Tempol偶联，制备成具有ROS响应性的前药。基于芳香化硫缩酮之间的π-π堆积以及疏水作用力，前药可自组装成纳米颗粒。该纳米颗粒可以靶向递送至小鼠结肠炎病灶部位，经微环境中的ROS裂解并释放药物， 在抗炎和抗氧化的双重作用下，发挥治疗效果。
除肠道炎症外，基于硫缩酮的抗炎药物递送系统还可用于肺部炎症、骨关节炎和皮肤炎症等疾病的治疗。Zhai等[28]将醋酸地塞米松包裹于含硫缩酮的聚合物载体中，制得载药纳米颗粒。纳米颗粒在急性肺损伤部位的高ROS水平作用下裂解并快速释放醋酸地塞米松，从而减少促炎细胞因子的产生，减少肺损伤。骨关节炎是临床上常见的退行性关节疾病之一，其发病进程与氧化应激状态密切相关[29]。为了同时实现对ROS的响应性清除和药物的靶向递送，Xiong 等[30] 以聚硫缩酮和甲氧基聚乙二醇-丙烯酸酯为原料，合成了一种高药物负载能力的新型 聚合物。以该聚合物包载天然抗氧化剂虾青素所制得的载药纳米颗粒，可在高ROS病灶部位精准释药， 从而有效减少ROS的产生，达到高效治疗骨关节炎症的效果。含硫缩酮基质材料(如凝胶或薄膜)还可应用于伤口愈合。Patil等[31]合成了含硫缩酮结构的聚氨酯，将其作为伤口修复支架，并通过改变硫缩酮键两侧基团来调节支架的亲水性。其中硫缩酮键两侧均为7个乙二醇单元（EG7）基团的支架亲水性最强、与ROS反应活性最高。在猪皮肤伤口愈合实验中，该支架能更有效地促进组织浸润、细胞 外基质沉积及表皮再生，这得益于敷料中硫缩酮结构对ROS的清除作用，以及EG7对有利于皮肤再生和修复的相关免疫细胞群的招募作用。
除了常见的含硫醚基类和硫缩酮类ROS响应性材料，目前还有许多其他对ROS敏感的含硫化合物 （如二烷基硫烯、亚砜、二硫化物及寡硫化物）受到研究人员关注[32]。Sun等[33]发现经二硫键桥接的前药具有ROS响应性，其响应机制与硫醚键类似， 即通过将二硫键氧化为亲水性砜或亚砜，并进一步促进结构中相邻酯键的水解，达到快速释放药物的效果。Lee等[34] 研究发现作为寡硫化物之一的二烯丙基三硫醚可以减少脂多糖诱导的ROS增加。脂多糖是关键的炎症反应引发剂，可激活多种细胞因子进而诱导炎症反应[35]。因此，二烯丙基三硫醚是一 种可应用于炎症治疗的ROS响应性材料。
2.2 基于含硒/碲化合物的递药系统
硒作为人体必需的微量矿物元素，通过氧化还原反应，在人体内发挥着重要的生物活性，对细胞代谢和DNA修复等多种生理过程产生深远影响[36]。硒与硫均为氧族元素，具有相似的化学性质。但相较于硫原子，硒原子的半径更大，电负性更低，导致其化合物的键能更低，对氧化刺激更敏感。在 ROS环境下，疏水性的单硒基团可以转化为亲水性的硒砜，双硒键可被氧化裂解为硒酸[37]，从而达到响应性释药的效果。Fan等[38]合成了维生素E琥珀酸酯-聚（乳酸-羟基乙酸）-Se-Se-甲氧基聚乙二醇 （VES-PLGA-Se-Se-mPEG）共聚物，利用透析法制备了VES-PLGA-Se-Se-mPEG 包裹小檗碱的载药胶束BPseP（见图1）。动态光散射（dynamic light scattering，DLS）结果显示，BPseP 呈均匀球形， 平均粒径153 nm，Zeta电位5.12 mV，且包封率高达86.25%。由 于 BPseP中的双硒键具有ROS响应性， 该载药胶束能优先与炎症组织的线粒体结合，释放出局部高浓度的小檗碱，表现出比单独使用小檗碱高10倍的抗炎效果，具有应用于类风湿性关节炎治疗的潜力。
碲作为氧族元素中最后一个非金属元素，比硫、 硒具有更大的原子半径和更低的电负性，使得碲参与形成的化学键键能更低，低价态的含碲分子对氧化刺激更加敏感，从而加大了研究难度。因此，含碲化合物的研究进展相比于含硫和含硒化合物较慢[39]。Fang 等 [40] 在合成的含碲两亲性超支化聚合物胶束 HBPTe1900 中加入100 μmol · L-1 H2O2 溶液，观察聚合物对ROS的敏感性。透射电子显微镜分析结果显示，HBPTe1900结构中的碲醚被氧化成亚碲砜之后， 材料亲水性和胶束粒径显著增加。24 h内，粒径从最初的（28±7）nm膨胀至（66±5）nm，扩大到约2.4 倍，这一结果表明HBPTe1900对低浓度ROS 环境具有良好的响应性。据文献报道，炎症部位的 ROS 浓度通常为50 ~ 100 μmol · L-1，一些含碲聚合物胶束甚至可以在H2O2浓度低至50 μmol · L-1的环境中响应[41]。因此，含碲多聚物被视为一种极具潜力的ROS响应性载药材料。
2.3 基于苯硼酸酯类化合物的递药系统
苯硼酸酯（phenylborate ester，PBAE）具有结构易修饰和生物相容性良好的优点，是常见的ROS 敏感材料之一。PBAE类材料包载药物形成纳米颗粒的方式主要有2种：一是基于PBAE聚合物材料的疏水性，将疏水性药物以游离状态包载于纳米颗粒核心；二是利用药物或载体材料中的1，2-或1，3- 二羟基结构与苯硼酸结构形成苯硼酸酯键，从而运载药物[42]。PBAE 在ROS环境中能被氧化成苯酚和硼酸，从而由疏水性转变为亲水性。由于PBAE 与ROS反应一定程度上会消耗ROS，PBAE聚合物载体不仅具有ROS高度敏感性，其本身就有一定的抗炎抗氧化效果[43]。近年来，基于PBAE的 ROS 响应性载药系统在炎症相关疾病的靶向治疗研究中显示出了巨大的潜力。例如，含PBAE结构的水凝胶伤口敷料除具有抗菌和抗氧化活性外，还具有抑制炎症和促进血管生成的作用，可用于慢性伤口的修复[44-45]。Wu 等[46] 利用苯硼酸与邻苯二酚结构成酯的原理，合成了基于咖啡酸接枝ε-聚赖氨酸（EC）与苯硼酸接枝氧化葡聚糖（POD）交联的可注射糖肽水凝胶。将具有促血管生成作用的芒果苷（MF）包封于pH响应胶束（MIC）中形成 载药胶束MIC@MF。最后，将具有抗炎活性的双氯芬酸钠（DS）与MIC@MF共同嵌入水凝胶中， 构建了一个时空可控的pH/ROS双重响应载药系统 DS&MIC@MF（见图2）。该水凝胶具有良好的生 物降解性、稳定的流变性和自愈合能力，可实现DS 和MF的时空顺序递送。实验结果表明，这种新型糖肽水凝胶抗感染、抗氧化、抗炎效果良好，为慢性糖尿病患者伤口的修复提供了一种新策略。Qiao 等[47] 利用化学交联法，使透明质酸接枝的3-氨基苯硼酸（HA-PBA）与聚乙烯醇（PVA）间形成苯硼酸酯键，制备了ROS敏感的HA-PBA/PVA（HPA） 水凝胶。将具有抗炎功能的疏水性的Cur与Pluronic F127（PF）混合，形成包载Cur的PF胶束（Cur PF），最后将Cur-PF胶束与亲水性抗生素莫西沙星（M）装入HPA 水凝胶（HPA/M&Cur-PF）中。由于两种药物的亲疏水性以及存在形式不同，HPA/ M&Cur-PF 水凝胶可在36 h内释放80%以上的莫西沙星，达到快速抗感染的效果，并在288 h内释放 Cur，达到持续抗炎的效果。在耐甲氧西林金黄色葡 萄球菌（MRSA）感染的小鼠皮肤伤口模型中进行的研究显示，与单一药物递送组（HPA/M和HPA/ Cur-PF）相比，HPA/M&Cur-PF 可更显著地降低炎 症水平和促进血管再生，使伤口愈合更快，炎症更轻， 胶原沉积更多。
基于PBAE的ROS响应性纳米递药系统在治疗动脉粥样硬化（atherosclerosis，AS）等炎症性疾病方面也具有显著效果。业内学者对于AS形成的复杂病理过程曾提出过多种理论，包括氧化应激理论、脂质浸润理论、氧化假说理论等。其中将脂质氧化、炎症与AS联系起来的“氧化假说”理论认为，AS是血管壁中低密度脂蛋白被ROS氧化修饰的结果[48-49]。因此，利用病灶部位高浓度ROS精准递药并清除ROS，对于 AS治疗至关重要。Wang等[50] 将一种超氧化物歧化酶模拟剂tempol和可以消耗 H2O2 的PBAE化合物共价偶联到β-环糊精上，制备得到具有ROS响应性的功能化环糊精（TPCD）。再将TPCD与卵磷脂、二硬脂酰基磷脂酰乙醇胺-甲氧基聚乙二醇2000（DSPE-PEG2000）进行自组装， 得到纳米颗粒TPCD NP。在ROS的作用下，TPCD NP 裂解，通过释放tempol使得ROS水平降低并抑制细胞对低密度脂蛋白的摄取，从而抑制泡沫细胞的形成，缓解AS病症。Zhang等[51]合成了5种不同结构的含PBAE的β-环糊精衍生物OxbCD，辅以卵磷脂和DSPE-PEG自组装成纳米颗粒，并考察了不同材料在ROS敏感性和生物安全性方面的差异。选取性质优异的OxbCD-2和OxbCD-5作为纳米载体包载地塞米松或吲哚美辛，在1 mmol · L-1 H2O2作 用下，载药纳米颗粒6 h内的累积释药率为80%， 能够通过抑制炎症细胞分泌肿瘤坏死因子（TNF）-α、 白细胞介素（IL）-1β、IL-6等炎症因子和单核细胞 趋化蛋白（MCP）-1、巨噬细胞炎性蛋白（MIP）-2、 IL-8 等炎症趋化因子来达到抗炎效果。
2.4 基于脯氨酸低聚物的递药系统
在多肽链的构成中，各类氨基酸残基普遍具有较高的氧化裂解敏感性，然而，脯氨酸（proline） 作为自然界中唯一能够与其他分子形成叔胺键的氨基酸，展现出了独特的性质。在富含ROS的环境下，叔胺键比仲胺键更容易被氧化，因此，脯氨酸低聚物凭借其出色的生物相容性和生物可降解性， 成为了ROS敏感性药物载体研发或前药改造的优选材料。慢性炎症介导的氧化应激是植入体排异和失败的关键。Yu 等[52]将PEG和聚ε-己内酯（PCL） 二嵌段共聚物羧化，然后将该聚合物与双胺化的 PEG-Pn-PEG 链交联（Pn 表示脯氨酸低聚物），得到具有ROS响应性的聚合物支架。研究表明，该聚合物支架在ROS作用下缓慢降解，孔隙率增加，有望实现炎症部位靶向持续释药。随后，Gupta等[53] 采用生物偶联法和可逆加成-断裂链转移聚合法 （reversible addition-fragmentation chain-transfer polymerization，RAFT polymerization）相结合的方法， 合成了一种运载质粒DNA（pDNA）的聚合物—— mPEG113-b-CP5K-b-PDMAEMA42-b-P[(DMAEMA22-co-BMA40-co-PAA24)]（PPDDBP，其中mPEG 为甲氧基聚乙二醇、CP5K为半胱氨酸-五聚脯氨酸-赖氨酸、PDMAEMA为聚甲基丙烯酸N，N-二甲氨基乙酯、DMAEMA为甲基丙烯酸N，N-二甲氨基乙酯、 BMA为甲基丙烯酸丁酯、PAA为2-丙基丙烯酸）。该聚合物的第一部分结构mPEG可形成冠状的亲水区块，以保护阳离子聚合物PDMAEMA部分，避免其与血液和组织成分的非特异性相互作用；第二部分结构CP5K可在ROS作用下断裂，从而导致 mPEG 外壳脱落，增加纳米粒在富ROS环境中的细胞摄取率；第三部分结构为亲水的PDMAEMA， 其含有带正电荷的叔胺，可与带负电荷的pDNA 相互作用，增加核酸的载量；第四部分结构为 DMAEMA、BMA和PAA 组成的三元共聚物，其在内涵体的低pH条件下正电荷增加，促使内涵体膜破裂，增加纳米载体的内涵体逃逸。在体外人类冠状动脉平滑肌细胞炎症模型中，PPDDBP聚合物表现出良好的pH和ROS双响应性。这种新型纳米载 体系统是一种极具开发前景的基因递送工具，有望应用于动脉粥样硬化的预防与治疗。
3
结语与展望
ROS 响应性递药系统是一种针对ROS的水平变化实时释放药物的智能系统，当细胞内的ROS水平异常升高时，药物会被释放。炎症是众多疾病共有的病理过程，其典型特征是微环境中ROS水平远高于正常组织。因此，ROS响应性递药系统可在抗炎治疗中实现药物的靶向输送和精准控释，具有广泛的应用前景。ROS响应性递药系统使用ROS敏感材料作 为载体，包括含硫化合物（如硫醚类化合物、硫缩酮类化合物、二硫化合物等）、含硒/碲化合物、苯硼酸酯类化合物以及脯氨酸低聚物等，响应机制多为通过改变材料亲疏水性，或使材料氧化降解而释药。
尽管目前ROS响应性递药系统在抗炎治疗研究中展现出优异的性能，但其临床应用仍面临诸多挑战。首先，用于递药系统的载体材料直接与复杂的生理环境接触，应具有高度的生物相容性，以避免引起炎症反应。其次，由于生物体内存在众多生物活性分子和酶，可能会干扰药物的释放和疗效。除此之外，ROS响应性递药材料的敏感性以及药物释放的稳定性仍是需要考虑的问题。期待在不久的将来，ROS响应性递药系统在抗炎治疗领域中能够克服这些挑战，实现突破与创新，为人类健康事业做出重要贡献。
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感谢您阅读《药学进展》微信平台原创好文，也欢迎各位读者转载、引用。本文选自《药学进展》2024年第11期。
《药学进展》杂志由国家教育部主管、中国药科大学和中国药学会共同主办，中国科技核心期刊（中国科技论文统计源期刊）。刊物以反映药学科研领域的新方法、新成果、新进展、新趋势为宗旨，以综述、评述、行业发展报告为特色，以药学学科进展、技术进展、新药研发各环节技术信息为重点，是一本专注于医药科技前沿与产业动态的专业媒体。
《药学进展》注重内容策划、加强组稿约稿、深度挖掘、分析药学信息资源、在药学学科进展、科研思路方法、靶点机制探讨、新药研发报告、临床用药分析、国际医药前沿等方面初具特色；特别是医药信息内容以科学前沿与国家战略需求相合，更加突出前瞻性、权威性、时效性、新颖性、系统性、实战性。根据最新统计数据，刊物篇均下载率连续三年蝉联我国医药期刊榜首，复合影响因子1.216，具有较高的影响力。
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2024-11-20
Recursion unveils post-combination technology-enabled portfolio with more than 10 clinical and preclinical programs, 10 advanced discovery programs, and more than 10 partnered programsPlatform will focus on first and best-in-class drug discovery and development, demonstrating the ability to find novel insights and dramatically reduce the time and cost of discoveryRecursion will host an update call today, November 20, 2024 at 7:30 a.m. ET / 5:30 a.m. MT / 12:30 p.m. GMT on LinkedIn, X and Youtube SALT LAKE CITY, Nov. 20, 2024 (GLOBE NEWSWIRE) -- The business combination of two AI-powered drug discovery and development companies, Recursion (Nasdaq: RXRX) and Exscientia has been completed, with Exscientia becoming a wholly owned subsidiary of Recursion creating a vertically-integrated and technology-enabled drug discovery platform. Exscientia ADSs (Nasdaq: EXAI) ceased trading and will be delisted from Nasdaq. “I believe the combination of the incredible teams and platforms at Exscientia and Recursion position us as the leader of the AI-enabled drug discovery and development space,” said Chris Gibson, Ph.D., Co-Founder and CEO of Recursion. “With more than 10 clinical and preclinical programs in the internal pipeline, more than 10 partnered programs and over $450M in upfront and realized milestone payments received from partners to date out of more than $20B possible, we are advancing a flywheel of discovery and creating value in our pipeline through technology.” “The combination of our platforms and people make us the company to beat,” said David Hallett, Ph.D., former CSO and Interim CEO of Exscientia and newly appointed Chief Scientific Officer at Recursion. “With our combined strength of real-world proprietary data and the models we’ve created – hypothesizing, testing and learning in a continuous loop – we're redefining the space by shrinking timelines and costs, identifying and optimizing lead candidates faster than traditional methods.” The Company is pleased to share updates on the combined entity’s pipeline, partnerships, and platform below: Pipeline The combined pipeline represents more than 10 clinical and preclinical programs. In addition there are approximately 10 advanced discovery programs in the current pipeline. Updated guidance is bulleted below as well as a snapshot of our pipeline: REC-617 (CDK7 inhibitor; Advanced Solid Tumors): Initial Phase 1 monotherapy safety and PK/PD data expected at the AACR Special Conference on December 9th 2024, and a webinar to follow on December 10th 2024.REV102 (ENPP1 inhibitor; Hypophosphatasia): Development candidate nomination expected in Q4 2024REC-4881 (MEK1/2 inhibitor, Familial Adenomatous Polyposis): Phase 1b/2 safety and early efficacy data expected in H1 2025REC-2282 (pan-HDAC inhibitor; Neurofibromatosis Type 2): PFS6 futility analysis expected by H1 2025REC-3565 (MALT1 inhibitor, B-Cell Malignancies): Phase 1 first patient dosed (FPD) expected in Q1 2025REC-4539 (LSD1 inhibitor, Small-Cell Lung Cancer): Phase 1 first patient dosed (FPD) expected in H1 2025REC-994 (Superoxide scavenger, Cerebral Cavernous Malformation): Further data to be shared at an upcoming medical conference / publication / webinar in H1 2025; regulatory update expected by H2 2025REC-394 (C. difficile Toxin B selective inhibitor, C. difficile): Phase 2 update expected in Q1 2026REC-1245 (RBM39 degrader; Solid Tumors and Lymphoma): Phase 1 dose-escalation data update expected in H1 2026REC-4209 (undisclosed target; Idiopathic Pulmonary Fibrosis): IND-enabling studies are ongoingREC-4881 in APC/AXIN1 indications have been deprioritized as part of a disciplined strategic prioritization of the portfolio. Study status will be updated on clinicaltrials.gov Partnerships The combined company’s therapeutic partnerships represent more than 10 partnered programs in areas such as oncology and immunology. The combined company has received approximately $450M in upfront and milestone payments from partnerships to date. Through these partnerships, we have the potential to receive more than approximately $20B in additional milestone payments before royalties. Platform With chemical design and synthesis methods from Exscientia and over 60 petabytes of proprietary data generated in house or licensed from partners like Helix and Tempus, the combined entity will strengthen the Recursion OS to be a first-in-class and best-in-class drug discovery and development platform. The platform will continue to drive iterative loops of hypotheses and active learning all the way from research to development, with the goal of eventually creating virtual cells that will allow the company to execute clinical trials at scale. Company, Board, and Leadership Updates The combined company will have approximately 800 employees with the headquarters remaining in Salt Lake City, and primary offices in Toronto, Montreal, Milpitas, New York, the Oxford area, and London. Individual board and executive leadership changes of Recursion, effective as of November 20, 2024, are summarized below: Franziska Michor, a former member of the Board of Directors of Exscientia, was appointed as a Class II Director of the Board of Directors of Recursion, with her initial term to extend until the 2026 Annual Meeting of Stockholders of Recursion.Ben Taylor, former Chief Financial and Strategy Officer of Exscientia, was appointed as the Chief Financial Officer of the Company and President of Recursion UK.Dave Hallett, former Interim Chief Executive Officer of Exscientia, was appointed as Chief Scientific Officer of the Company.Kristen Rushton, Chief Business Operations Officer of the Company, was promoted to Chief Operating Officer of the Company.Matthew Kinn, Senior Vice President, Business Development and Corporate Initiatives of the Company was promoted to serve as Chief Business Officer of the Company.Lina Nilsson, Senior Vice President, Emerging Technologies of the Company, was promoted to serve on the executive team as Senior Vice President, Head of Platform of the Company.Michael Secora, Tina Marriott, and Laura Schaevitz will transition from their executive roles into advisor roles for the combined company. All three have provided many years of dedicated service to the Company and we wish to express our heartfelt gratitude for each of them. Recursion would not be where it is today without their dedication and efforts. Update Call Information Recursion will host an update call today at 7:30 a.m. ET / 5:30 a.m. MT / 12:30 p.m. GMT. The Company will broadcast the live stream from Recursion’s X (formerly Twitter), LinkedIn and YouTube accounts, and on Exscientia’s LinkedIn account. Questions can be submitted via this link ahead of time or during the livestream. About Recursion Recursion is a leading, clinical-stage TechBio company decoding biology to industrialize drug discovery. Central to its mission is the Recursion Operating System (OS), a platform built across diverse technologies that continuously expands one of the world’s largest proprietary biological, chemical and patient-centric datasets. Recursion leverages sophisticated machine-learning algorithms to distill from its dataset a collection of trillions of searchable relationships across biology and chemistry unconstrained by human bias. By commanding massive experimental scale—up to millions of wet lab experiments weekly—and massive computational scale—owning and operating one of the most powerful supercomputers in the world—Recursion is uniting technology, biology, chemistry and patient-centric data to advance the future of medicine. Recursion is headquartered in Salt Lake City, where it is a founding member of BioHive, the Utah life sciences industry collective. Recursion also has other primary offices in Toronto, Montreal, the San Francisco Bay Area, New York, the Oxford area, and London. Recursion Investor Relationsinvestor@recursion.com Recursion Mediamedia@recursion.com Forward Looking Statements Statements contained herein which are not historical facts may be considered forward-looking statements under federal securities laws and may be identified by words such as “anticipates,” “believes,” “estimates,” “expects,” “intends,” “plans,” “potential,” “predicts,” “projects,” “seeks,” “should,” “will,” or words of similar meaning and include, but are not limited to, statements regarding the leadership position of the combined company and its impact on the industry; the ability for the combined business to accelerate the discovery of better solutions for patients; the timing of IND submissions and IND enabling studies; the potential to receive upfront, milestone, and royalty payments and work on over 60 therapeutic programs; the strengthening of the Recursion OS through the combined company; the continued learning of Recursion’s platform and the creation of virtual cells to enable execution of clinical trials at scale; Recursion’s achievement of efficiencies; the continuous expansion of the Recursion OS datasets; and advancing the future of medicine; the outlook for Recursion’s future business and financial performance; and others. Such forward-looking statements are based on the current beliefs of Recursion’s management as well as assumptions made by and information currently available to them, which are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict. Actual outcomes and results may vary materially from these forward-looking statements based on a variety of risks and uncertainties including: the ability of the combined company to retain key personnel; the ability to realize the benefits of the combination, including cost synergies; the ability to successfully integrate Exscientia's business with Recursion’s business, at all or in a timely manner; the amount of the costs, fees, expenses and charges related to the combination; the effect of economic, market or business conditions, including competition, regulatory approvals and commercializing drug candidates, or changes in such conditions, have on the combined company’s operations, revenue, cash flow, operating expenses, employee hiring and retention, relationships with business partners, the development or launch of technology enabled drug discovery, and commercializing drug candidates; the risks of conducting business internationally; the impact of changes in interest rates by the Federal Reserve and other central banks; the impact of potential inflation, volatility in foreign currency exchange rates and supply chain disruptions; the ability to maintain technology-enabled drug discovery in the biopharma industry; and risks relating to the market value of Recursion’s Class A common stock. Other important factors and information are contained in Recursion’s most recent Annual Report on Form 10-K, including the risks summarized in the section entitled “Risk Factors,” Recursion’s subsequent Quarterly Reports on Form 10-Q, the joint definitive proxy statement filed by Recursion and Exscientia on October 10, 2024, as amended by the supplemental disclosures filed by Recursion on November 6, 2024, and each of Recursion’s other filings with the U.S. Securities and Exchange Commission (the “SEC”), which can be accessed at https://ir.recursion.com, or www.sec.gov. All forward-looking statements are qualified by these cautionary statements and apply only as of the date they are made. Recursion undertakes no obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Photos accompanying this announcement are available athttps://www.globenewswire.com/NewsRoom/AttachmentNg/359d7cd4-0ccf-4210-938d-f585a9b073eehttps://www.globenewswire.com/NewsRoom/AttachmentNg/a94dc301-518d-48a8-b8d3-430cd726d651https://www.globenewswire.com/NewsRoom/AttachmentNg/57cb9454-a7a7-4abf-a76f-82356a3682ac
临床1期高管变更
2024-11-06
Multiple clinical trial milestones were achieved, including encouraging topline data for a Phase 2 trial in CCM, the first patient dosed for a Phase 2 trial in recurrent C. difficile infection, and IND clearance for a Phase 1/2 trial in biomarker-enriched solid tumors and lymphoma (Target RBM39), which highlight a growing number of potential clinical program catalystsOur first neuroscience phenomap was optioned by Roche-Genentech for $30 million as part of a fee structure that could exceed a total of $500 million across multiple maps before program-specific milestones or royaltiesEntered into an expanded collaboration with Google Cloud to leverage technologies to support our drug discovery platform, which continues to highlight Recursion’s close partnership with leading technology companies like Google, NVIDIA, Tempus, and othersThe potential business combination with Exscientia continues to advance towards close with a special shareholder meeting to be held on November 12, 2024 and an expected date for the scheme of arrangement to be November 20, 2024 SALT LAKE CITY, Nov. 06, 2024 (GLOBE NEWSWIRE) -- Recursion (Nasdaq: RXRX), a leading clinical stage TechBio company decoding biology to industrialize drug discovery, today reported business updates and financial results for its third quarter ending September 30, 2024. “We are excited to continue to drive rapidly towards the closure of our proposed business combination with Exscientia in a matter of weeks, ahead of the original guidance,” said Chris Gibson, Ph.D., Co-founder and CEO of Recursion. "We believe the combination with Exscientia will help to build a robust and diverse portfolio of tech-enabled clinical and near-clinical programs, significant value-creation opportunities through multiple transformational partnerships with both biopharma and technology companies, and the industry’s first full-stack technology-enabled small molecule discovery platform. Ultimately, we have never been more confident in our ability to translate our work into potential medicines for patients. These developments will drive additional value beyond the clinical trial catalysts we’ve seen in the last few months, including encouraging data from our Phase 2 trial in CCM, the first patient dosed in our Phase 2 trial in C. difficile infection, and our IND clearance for a Phase 1/2 trial in biomarker-enriched solid tumors and lymphoma (Target RBM39)." Summary of Business Highlights Pipeline Cerebral Cavernous Malformation (CCM) (REC-994): In September, we announced that our Phase 2 SYCAMORE clinical trial, which is a randomized, double-blind, placebo-controlled, study of two doses of REC-994 in participants with CCM, met its primary endpoint of safety and demonstrated encouraging trends in objective MRI-based exploratory efficacy measures at the highest dose, seeing reductions in lesion volume and hemosiderin ring size. We plan to meet with the FDA and advance the development of REC-994 for the potential treatment of symptomatic CCM in subsequent studies. We also plan to present the Phase 2 data at a medical conference and publish results in a peer reviewed scientific journal.Neurofibromatosis Type 2 (NF2) (REC-2282): Our adaptive Phase 2/3 POPLAR clinical trial is an open label, two part study of REC-2282 in participants with progressive NF2-mutated meningiomas. Part 1 of the study explores two doses of REC-2282 in adult and pediatric participants. Enrollment of adult patients in Part 1 of the study is complete (n=24). We expect to share an update in Q4 2024.Familial Adenomatous Polyposis (FAP) (REC-4881): Our Phase 1b/2 TUPELO clinical trial is an open label, multicenter, two part study of REC-4881 in participants with FAP. Part 1 is complete and enrollment in Part 2 has commenced. We expect to share Phase 2 safety and preliminary efficacy data in H1 2025.APC or AXIN1 Mutant Cancers (REC-4881): Our Phase 2 LILAC clinical trial is an open label, multicenter study of REC-4881 in participants with unresectable, locally advanced or metastatic cancer with AXIN1 or APC mutations. We expect to share Phase 2 safety and preliminary efficacy data in H1 2025.Clostridioides difficile Infection (REC-3964): In October, we announced the first patient dosed in our Phase 2 clinical study of REC-3964, a potential first-in-class, oral, non-antibiotic small molecule for recurrent Clostridioides difficile infection. Our Phase 2 ALDER clinical trial is an open-label, multicenter randomized study designed to evaluate rates of recurrence with REC-3964 at two doses compared with an observational cohort after patients have achieved initial cure with vancomycin. We expect a preliminary readout by the end of 2025.Biomarker-Enriched Solid Tumors and Lymphoma, Target RBM39 (REC-1245): In October, we announced FDA clearance of an IND for REC-1245, a potential first-in-class RBM39 degrader for biomarker-enriched solid tumors and lymphoma. RBM39 is a novel CDK12-adjacent target identified by the Recursion OS. We plan to initiate dosing of Phase 1/2 in Q4 2024 to evaluate REC-1245. Phase 1 data from the dose-escalation portion of the study is expected by the end of 2025.Undisclosed Indication in Fibrosis, Target Epsilon: We are advancing our lead candidate and expect an IND submission in early 2025. Partnerships Transformational Collaborations: We continue to advance efforts to discover potential new therapeutics with our strategic partners in the areas of undruggable oncology (Bayer) as well as neuroscience and a single indication in gastrointestinal oncology (Roche-Genentech). In August, our first neuroscience phenomap was optioned by Roche-Genentech for $30 million as part of a fee structure that could exceed a total of $500 million across multiple maps. In the near-term, there is the potential for option exercises associated with partnership programs and map building initiatives or data sharing. Platform Google Cloud Collaboration: We entered into an expanded collaboration with Google Cloud in order to leverage Google Cloud's technologies to support our drug discovery platform. This strategic partnership includes exploring generative AI capabilities, including Gemini models, to support the RecursionOS, drive improved search and access with BigQuery, and help scale compute resources. In addition, we will also explore making some of our AI models available on Google Cloud. Additional Corporate Updates Combination with Exscientia: A special shareholder meeting will be held on Nov 12, 2024 at 5:00 pm Eastern Time / 3:00 pm Mountain Time in order to vote on Recursion’s proposed combination with Exscientia. Shareholders may vote in advance of this meeting by telephone, mail, or online at www.virtualshareholdermeeting.com/RXRX2024SM. Following this shareholder meeting, we expect the date of the scheme of arrangement to be Nov 20, 2024.L(earnings) Call: We will not host a L(earnings) Call in relation to the business updates and financials for the third quarter. Instead, we expect to host an Update Call around the date of the scheme of arrangement which is expected to be Nov 20, 2024. We will broadcast the live stream from Recursion’s X (formerly Twitter), LinkedIn, and YouTube accounts and there will be opportunities to ask questions of the company.Chief People & Impact Officer: In October, Erica Fox joined Recursion as its Chief People & Impact Officer. Ms. Fox has over 20 years experience as a people and systems strategist having previously led various human resource functions at technology companies Primer.ai and Google. Third Quarter 2024 Financial Results Cash Position: Cash and cash equivalents were $427.6 million as of September 30, 2024.Revenue: Total revenue was $26.1 million for the third quarter of 2024, compared to $10.5 million for the third quarter of 2023. The increase was due to revenue recognized from our partnership with Roche & Genentech and the $30.0 million acceptance fee for the completion of a neuroscience phenomap.Research and Development Expenses: Research and development expenses were $74.6 million for the third quarter of 2024, compared to $70.0 million for the third quarter of 2023. The increase in research and development expenses was driven by our platform and personnel costs as we continue to expand and upgrade our platform, including our chemical technology, machine learning, and transcriptomics platform.General and Administrative Expenses: General and administrative expenses were $37.8 million for the third quarter of 2024, compared to $29.2 million for the third quarter of 2023. The increase in general and administrative expenses compared to prior period was primarily driven by an increase in software and lease expense.Net Loss: Net loss was $95.8 million for the third quarter of 2024, compared to a net loss of $93.0 million for the third quarter of 2023.Net Cash: Net cash used in operating activities was $59.2 million for the third quarter of 2024, compared to $72.9 million for the third quarter of 2023. The change in net cash used in operating activities compared to the same period last year was the net result of the $30.0 million acceptance fee received during the third quarter of 2024, partially offset by the higher operating costs incurred for research and development and general and administrative activities. About RecursionRecursion is a clinical stage TechBio company leading the space by decoding biology to industrialize drug discovery. Enabling its mission is the Recursion OS, a platform built across diverse technologies that continuously expands one of the world’s largest proprietary biological, chemical and patient-centric datasets. Recursion leverages sophisticated machine-learning algorithms to distill from its dataset a collection of trillions of searchable relationships across biology and chemistry unconstrained by human bias. By commanding massive experimental scale — up to millions of wet lab experiments weekly — and massive computational scale — owning and operating one of the most powerful supercomputers in the world, Recursion is uniting technology, biology, chemistry and patient-centric data to advance the future of medicine. Recursion is headquartered in Salt Lake City, where it is a founding member of BioHive, the Utah life sciences industry collective. Recursion also has offices in Toronto, Montreal, the San Francisco Bay Area, and London, UK. Learn more at www.Recursion.com, or connect on X (formerly Twitter) and LinkedIn. Media ContactMedia@Recursion.com Investor ContactInvestor@Recursion.com Recursion Pharmaceuticals, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss (unaudited)(in thousands, except share and per share amounts) Three months ended Nine months ended September 30, September 30,Revenue 2024 2023 2024 2023 Operating revenue$26,082 $10,102 $53,977 $33,252 Grant revenue - 431 316 432 Total revenue 26,082 10,533 54,293 33,684
Operating costs and expenses
Cost of revenue 12,079 10,877 32,444 32,706 Research and development 74,600 70,007 216,087 171,744 General and administrative 37,757 29,199 100,998 80,364 Total operating costs and expenses 124,436 110,083 349,529 284,814
Loss from operations (98,354) (99,550) (295,236) (251,130) Other income, net 2,679 6,533 9,347 16,060 Loss before income tax benefit (95,675) (93,017) (285,889) (235,070) Income tax benefit (167) - 1,134 - Net loss and comprehensive loss$(95,842)$(93,017) $(284,755)$(235,070)
Per share data
Net loss per share of Class A, B and Exchangeable common stock, basic and diluted$(0.34)$(0.43) $(1.12)$(1.16)Weighted-average shares (Class A, B and Exchangeable) outstanding, basic and diluted 282,583,048 214,327,186 253,447,099 203,090,637
Recursion Pharmaceuticals, Inc.Condensed Consolidated Balance Sheets (unaudited)(in thousands)
September 30,December 31, 2024 2023 Assets Current assets Cash and cash equivalents$427,647 $391,565 Restricted cash 1,555 3,231 Other receivables 2,255 3,094 Other current assets 42,715 40,247 Total current assets 474,172 438,137
Restricted cash, non-current 6,629 6,629 Property and equipment, net 84,410 86,510 Operating lease right-of-use assets 47,882 33,663 Financing lease right-of-use assets 26,897 - Intangible assets, net 34,093 36,443 Goodwill 52,056 52,056 Other assets, non-current 360 261 Total assets$726,499 $653,699
Liabilities and stockholders’ equity Current liabilities Accounts payable$2,260 $3,953 Accrued expenses and other liabilities 40,597 46,635 Unearned revenue 49,579 36,426 Operating lease liabilities 8,233 6,116 Notes payable and financing lease liabilities 8,219 41 Total current liabilities 108,888 93,171
Unearned revenue, non-current 15,712 51,238 Operating lease liabilities, non-current 53,663 43,414 Notes payable and financing lease liabilities, non-current 20,510 1,101 Deferred tax liabilities 168 1,339 Other liabilities, non-current 2,999 - Total liabilities 201,940 190,263
Commitments and contingencies
Stockholders’ equity Common stock (Class A, B and Exchangeable) 3 2 Additional paid-in capital 1,776,933 1,431,056 Accumulated deficit (1,252,377) (967,622) Total stockholder's equity 524,559 463,436
Total liabilities and stockholders’ equity$726,499 $653,699
Forward-Looking StatementsThis document contains information that includes or is based upon "forward-looking statements'' within the meaning of the Securities Litigation Reform Act of 1995, including, without limitation, those regarding expectations related to early and late stage discovery, preclinical, and clinical programs, including timelines for enrollment in studies, data readouts, and progression toward IND-enabling studies; the timing and likelihood of completing the proposed business transaction with Exscientia plc; the impact of the Google Cloud agreement on our drug discovery platform; the option exercise by Roche-Genentech and the potential future revenue related to the potential creation, delivery, and option of future maps; the completion and uses of additional maps being built; our anticipated meeting with the FDA regarding REC-994; plans to present SYCAMORE trial data at a medical conference and submit the data for publication; developments with Recursion OS and other technologies, including construction of foundation models and augmentation of our dataset; developments of our transcriptomics technology, including the timing of development of a whole-genome knockout transcripts map; expectations and developments with respect to licenses and collaborations, including option exercises by partners and additional partnerships; prospective products and their potential future indications and market opportunities; expectations for business and financial plans and performance, including cash runway; Recursion’s plan to maintain a leadership position in data generation and aggregation and advancing the future of medicine; and all other statements that are not historical facts. Forward-looking statements may or may not include identifying words such as “plan,” “will,” “expect,” “anticipate,” “intend,” “believe,” “potential,” “could,” “continue,” and similar terms. These statements are subject to known or unknown risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements, including but not limited to: challenges inherent in pharmaceutical research and development, including the timing and results of preclinical and clinical programs, where the risk of failure is high and failure can occur at any stage prior to or after regulatory approval due to lack of sufficient efficacy, safety considerations, or other factors; our ability to leverage and enhance our drug discovery platform; our ability to obtain financing for development activities and other corporate purposes; the success of our collaboration activities; our ability to obtain regulatory approval of, and ultimately commercialize, drug candidates; our ability to obtain, maintain, and enforce intellectual property protections; cyberattacks or other disruptions to our technology systems; our ability to attract, motivate, and retain key employees and manage our growth; inflation and other macroeconomic issues; and other risks and uncertainties such as those described under the heading “Risk Factors” in our filings with the U.S. Securities and Exchange Commission (the “SEC”), including in the definitive joint proxy statement related to the proposed business combination filed with the SEC on October 10, 2024, our most recent Annual Report on Form 10-K, and our subsequent Quarterly Reports on Form 10-Q. All forward-looking statements are based on management’s current estimates, projections, and assumptions, and Recursion undertakes no obligation to correct or update any such statements, whether as a result of new information, future developments, or otherwise, except to the extent required by applicable law. Additional Information and Where to Find ItThis communication relates to the proposed business combination by and between Recursion and Exscientia plc. Recursion and Exscientia have delivered a definitive joint proxy statement related to the proposed business combination to Recursion’s stockholders and Exscientia’s shareholders, which was also filed with the SEC on October 10, 2024. The definitive joint proxy statement provides full details of the proposed business combination and the attendant benefits and risks, including the terms and conditions of the Scheme of Arrangement and the other information required to be provided to Exscientia’s shareholders under the applicable provisions of the United Kingdom Companies Act 2006. This communication is not a substitute for the definitive joint proxy statement or any other document that Recursion or Exscientia may file with the SEC or send to their respective security holders in connection with the proposed business combination. Security holders are urged to read the definitive joint proxy statement and all other relevant documents filed with the SEC or sent to Recursion’s stockholders or Exscientia’s shareholders as they become available because they will contain important information about the proposed business combination. All documents, when filed, will be available free of charge at the SEC’s website (www.sec.gov). You may also obtain these documents by contacting Recursion’s Investor Relations department at investor@recursion.com; or by contacting Exscientia’s Investor Relations department at investors@exscientia.ai. This communication does not constitute an offer to sell or the solicitation of an offer to buy any securities or a solicitation of any vote or approval. INVESTORS AND SECURITY HOLDERS ARE URGED TO READ THE DEFINITIVE PROXY STATEMENT (WHICH INCLUDES AN EXPLANATORY STATEMENT IN RESPECT OF THE SCHEME OF ARRANGEMENT OF EXSCIENTIA, IN ACCORDANCE WITH THE REQUIREMENTS OF THE UNITED KINGDOM COMPANIES ACT 2006) AND ANY OTHER RELEVANT DOCUMENTS THAT MAY BE FILED WITH THE SEC, AS WELL AS ANY AMENDMENTS OR SUPPLEMENTS TO THESE DOCUMENTS, CAREFULLY AND IN THEIR ENTIRETY IF AND WHEN THEY BECOME AVAILABLE BECAUSE THEY CONTAIN OR WILL CONTAIN IMPORTANT INFORMATION ABOUT THE PROPOSED TRANSACTION. Participants in the SolicitationThe Company, Exscientia and their respective directors and executive officers may be deemed to be participants in any solicitation of proxies in connection with the proposed business combination. Information about Recursion’s directors and executive officers is available in Recursion’s proxy statement dated April 23, 2024 for its 2024 Annual Meeting of Stockholders. Information about Exscientia’s directors and executive officers is available in Exscientia’s Annual Report on Form 20-F dated March 21, 2024. Other information regarding the participants in the proxy solicitation and a description of their direct and indirect interests, by security holdings or otherwise, is contained in the definitive joint proxy statement. Investors are urged to read the definitive joint proxy statement and any other relevant materials to be filed with the SEC regarding the proposed business combination when they become available, carefully before making any voting or investment decisions. No Offer or SolicitationThis communication is not intended to and shall not constitute an offer to buy or sell or the solicitation of an offer to buy or sell any securities, or a solicitation of any vote or approval, nor shall there be any offer, solicitation or sale of securities in any jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such jurisdiction. The Company securities issued in the proposed business combination are anticipated to be issued in reliance upon an available exemption from such registration requirements pursuant to Section 3(a)(10) of the Securities Act of 1933, as amended. A photo accompanying this announcement is available at https://www.globenewswire.com/NewsRoom/AttachmentNg/3213e888-501b-4736-adad-9672e8e8792a
临床2期临床1期临床结果财报临床申请
100 项与 Tempol 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 放射性皮炎 | 临床3期 | 美国 | 2022-01-30 | |
| 新型冠状病毒感染 | 临床3期 | 美国 | - | 2021-09-01 |
| 中枢神经系统海绵状血管瘤 | 临床2期 | 美国 | 2022-03-17 | |
| 放射性口腔黏膜炎 | 临床2期 | 美国 | 2022-01-30 | |
| 共济失调毛细血管扩张 | 临床2期 | 美国 | 2021-07-01 | |
| 多形性胶质母细胞瘤 | 临床2期 | 美国 | 2021-06-01 | |
| 非转移性前列腺癌 | 临床2期 | 美国 | 2021-05-30 | |
| 复发性前列腺癌 | 临床2期 | 美国 | 2021-05-30 | |
| 食管癌 | 临床2期 | 美国 | 2019-05-13 | |
| 粘膜炎 | 临床2期 | 美国 | 2019-05-13 |
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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 |
|---|
N/A | 毒性 superoxide dismutase | oxidative stress | - | 50 mM tempol | 觸網選夢範願鑰遞遞鏇(鑰餘築顧觸夢顧淵憲齋) = 鬱願繭鬱衊繭鏇構積繭 繭觸憲觸憲願憲壓築餘 (壓鹹壓範壓製襯鹽鬱齋 ) | 积极 | 2013-06-01 | |
N/A | - | - | (Control) | 餘醖構顧範願廠觸鑰鑰(廠簾築壓鏇願鑰範遞獵) = 衊構餘積觸網窪獵鑰簾 範構憲鑰鬱衊齋鏇艱觸 (憲築壓夢觸網鏇壓醖廠 ) | - | 2012-10-17 | |
(Restraint-stress) | 餘醖構顧範願廠觸鑰鑰(廠簾築壓鏇願鑰範遞獵) = 鹽願顧壓夢窪鬱蓋構艱 範構憲鑰鬱衊齋鏇艱觸 (憲築壓夢觸網鏇壓醖廠 ) | ||||||
N/A | - | 11 | TEMPOL at 100mg/kg | 襯艱繭鹽願窪衊窪顧艱(遞顧蓋觸餘膚遞膚選鹽) = 網顧鏇齋鏇觸糧衊鹽齋 鏇鏇鏇淵餘構積遞夢齋 (襯窪襯鬱遞襯繭築顧醖, 29) 更多 | 积极 | 2008-05-01 | |
Saline | 襯艱繭鹽願窪衊窪顧艱(遞顧蓋觸餘膚遞膚選鹽) = 遞積築鹽齋憲窪顧襯淵 鏇鏇鏇淵餘構積遞夢齋 (襯窪襯鬱遞襯繭築顧醖, 10) 更多 |
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