ABSTRACTCancer therapies include several immune checkpoint or anticytokine therapies whereas ulcerative colitis treatments consist of anticytokine therapies. The development of tolerance and immunogical effects of these agents in people living with HIV are not well assessed as these persons are often excluded from clinical trials. Herein, we report a case of a Caucasian woman who received multiple sequential immunotherapies for severe ulcerative colitis. Due to steroid-refractory disease, receipt of maximal doses of mesalamine and initial repeated decline of surgical intervention, she went on to receive biologic immune inhibitors like tumor necrosis fator-α blockers infliximab and adalimumab, the α4β7integrin blocker vedolizumab, anti-interleukin 12/23 blocker ustekinumab and Janus Kinase inihibitor tofacitinib without achieving remission. Only minor infectious complications were encountered and no significant changes in CD4 count nor CD4/CD8 ratio occurred. This case provides support for the safety and tolerability of the above immunotherapies in people living with HIV with suppressed viral load on antiretroviral therapy.

2019-10-01·Diabetes, Obesity and Metabolism2区 · 医学

Commentary: SGLT inhibitors in type 1 diabetes: Place in therapy and a risk mitigation strategy for preventing diabetic ketoacidosis ‐ the STOP DKA protocol

2区 · 医学

Article

作者: Rendell, Marc S.

AbstractIn the accompanying article, Goldenberg et al. review the promotion of diabetic ketoacidosis by SGLT2 inihibitors. They have carried out a metanalysis showing a 3.5‐fold increase in the risk of diabetic ketoacidosis (DKA) in patients with type 1 diabetes under treatment with SGLT2 inhibitors. They make a number of suggestions for attempting to mitigate the risk of DKA in these patients, notably including blood ketone monitoring and the use of supplemental carbohydrates with additional insulin when ketones suggest incipient DKA. Their proposal merits evaluation in a clinical trial involving type 1 diabetes, which should also assess the possible cardiorenal benefits demonstrated with treatment with SGLT2 inhibitors in type 2 diabetes.

2015-08-01·Archives of Endocrinology and Metabolism

The evolving field of thyroid cancer: refinement of old and creation of new paradigms

Article

作者: Hoff, Ana O.

Since the landmark paper by Mazzaferri and Jhiang (1) indicating the benefit of adequate surgery and postoperative radioactive iodine treatment in patients with well-differentiated thyroid cancer (DTC), a lot has been learned about prognostic factors associated with disease recurrence and mortality and the risks and benefits of treatment. In addition, over the past 3 decades we have experienced a dramatic improvement in imaging and laboratorial techniques resulting in highly sensitive and specific studies for disease detection, and have observed a significant advance in the understanding of the molecular pathogenesis of thyroid cancer. This accumulated knowledge has confirmed a few paradigms and has provided im portant insights that have refined the treatment of thyroid cancer. First, surgery is the mainstay treatment of thyroid cancer and therefore an experienced surgeon and an adequate surgical treatment have the highest impact in cure. Second, the major roles and best responses of radioactive iodine treatment are in reducing recurrence rate in high-risk patients and in treating young patients with micronodular lung metastases and; third, the development of kinase inhibitors has been a major breakthrough in treating metastatic thyroid cancer, not only DTC but also medullary thyroid cancer (MTC). In this issue of Archives of Endocrinology and Metabolism three papers describe different facets of thyroid cancer treatment. On one side of the spectrum, Furtado and cols. demonstrate the low incidence of persistent (3.5%) and recurrent disease (2.5%) in patients with papillary thyroid cancer with less than 5 lymph nodes detected only at the operative procedure and without other poor prognostic factors (2). As expected, these patients have low risk of recurrence raising the question whether radioactive iodine treatment provides any benefit, a situation in which the disease could be less harmful than the treatment. Interestingly, in the 2009 American Thyroid Association guidelines, all patients with lymph node (LN) metastases (N1 disease), regardless of number and size of LN, were considered intermediate risk and adjuvant radioactive iodine treatment was recommended (3). However, data have accumulated demons trating that the risk of recurrence is significantly lower in patients with small LNs de tected pathologically when compared to pre-operatively detected lymph nodes (4-6), findings confirmed in the study by Furtado and cols. On the other side of the spectrum, two papers describe the “good and bad” of tyrosine kinase inhibitors. In one paper, Pitoia and cols. report a patient with advanced MTC and ectopic Cushing’s syndrome in whom treatment with vandetanib resulted in rapid resolution of hypercortisolism (7). Ectopic ACTH syndrome is rarely obser ved in MTC but is usually associated with extensive disease and significant symptoms. The control of cortisol hypersecretion results in symptomatic relief and better quality of life. This is an important observation that has been also demonstrated with sorafenib and sunitinib and expands the known effects of kinase inihibitors. In a second

项与 SAR-502250 相关的新闻（医药）

2024-02-11

·药渡

药渡Cyber解析脑渗透性咪唑[1,2-b]哒嗪类糖原合成激酶（GSK-3β）抑制剂的设计思路和优化过程

感谢关注转发，欢迎学术交流请点击此处链接观看CyberSAR系统详细使用教程糖原合成酶激酶-3 （GSK-3）是一种丝氨酸/苏氨酸激酶，调节多种细胞过程并与多种疾病相关。其中，GSK-3β（GSK-3的异构体之一）与阿尔茨海默病相关的神经原纤维缠结的形成有关，这主要是由于Tau蛋白的过度磷酸化导致。本文描述了一系列作为GSK-3β抑制剂的咪唑[1,2-b]哒嗪类衍生物的设计和合成，并指明构效关系。此外，体内研究进一步表明，化合物47具有脑渗透性，口服利用度较高，并将显著降低磷酸化Tau蛋白的水平，这为阿尔兹海默症的治疗提供了新思路。GSK-3在组织中普遍表达，在中枢神经系统（CNS）呈现高表达，分为GSK-3α（51kDa）和GSK-3β（47kDa）两种异构体，二者在催化区域上的同源性高达98%。研究发现，GSK-3β以主要亚型存在于CNS的大多区域。GSK-3β过度激活，一方面将导致tau蛋白的过度磷酸化，进一步导致细胞内神经元纤维缠结（NFTs）的聚集以及β淀粉样蛋白（Aβ）的增加，另一方面，也可能促进β、γ分泌酶活性，导致Aβ肽的累积，从而促进Aβ斑块形成。而Aβ与NFT被认为是阿尔茨海默病等神经退行性疾病的潜在致病原因。由此可见，GSK-3抑制剂具有作为阿尔茨海默病治疗药物的潜力。现阶段被评估用作阿尔茨海默病治疗的GSK-3β抑制剂如图1所示。Tideglusib1是一种非ATP竞争性GSK-3抑制剂，已完成阿尔茨海默病的II期研究。对应地，芳基马来酰亚胺2（SB-216763）则作为一种ATP竞争性GSK-3抑制剂。苯并呋喃化合物3具有脑渗透性，吡唑4具有口服性，化合物5（UDA-680）在小鼠体内的研究表明，它具有显著抑制tau磷酸化的母体结构，氨基吡啶6对激酶表现出良好的选择性。BMS公司首先针对以上发现，系统地探索了相应母核周围的化学空间，在此基础应用构效关系（SAR）研究发现了基于异烟碱酰胺的GSK-3β抑制剂7，不仅表现出良好的激酶选择性，并且具有较好的口服生物利用度。随后展开了一系列基于化合物7的衍生物研究（如化合物8）。图1.代表性GSK-3β抑制剂环丙基羧酰胺部分是该化学型中最受青睐的酰胺之一，具有平衡效力和代谢稳定性的作用。然而，当7的类似物8在小鼠血清中37℃孵育时，在3小时内观察到环丙基羧酰胺基团24%的裂解，在人血清中也检测到微量的裂解。此外，由于一份报告表明，如果环丙羧酸在体内从母体化合物中释放出来，可能会产生特异性毒性，因此是否能够使用其他酰胺或替代基团取代异烟酰胺化学型中的环丙基羧胺部分成为研究新方向。BMS公司在SAR研究与X射线共晶分析时发现：环丙基羧酰胺羰基和上层酰胺NH之间形成的水桥氢键，可能使分子在能量上倾向于生物活性构象，也就是说，环丙基羧酰胺具有平衡效力和代谢稳定性的作用。据此，BMS公司设想将下层酰胺以杂环回接（图2B中红色虚线表示），其中氮取代羰基氧，通过形成更倾向于生物活性构象的内部氢键（图2B中蓝色虚线表示）以及更有利的偶极子排列（图2B蓝色箭头所示）得到新型咪唑[1,2-b]哒嗪环体系，以此作为研发GSK-3β抑制剂的一个有吸引力的杂环支架，见图3。图2.（A）通过分子模拟程序添加氢后，GSK-3β（PDB ID: 8DJD）激酶结构域9的X射线共晶结构。配体以棒状模型表示，绿色的碳原子和黑色虚线表示的氢键。与配体形成氢键的氨基酸残基显示为棒状。在环丙酰胺羰基和酰胺NH之间观察到一个水桥氢键。（B）咪唑[1,2- B]哒嗪基GSK-3β抑制剂支架的原理。红色虚线表示建议的回接以形成一个五元环。蓝色虚线表示内部氢键。所需的酰胺构象与相邻的咪唑[1,2-b]吡啶环系统具有良好的偶极子排列，如蓝色箭头所示。图3.咪唑[1,2-b]哒嗪类GSK-3β抑制剂设计方案构效关系与X射线晶体研究在1型咪唑[1,2-b]哒嗪嘧啶系列中，对吡啶环4位的SAR进行了研究，结果见表1。化合物19对GSK-3β酶的IC50值为220nM。当吡啶在4位上被甲基取代时，效价提高了3.5倍（20），当甲基被异丙醚取代时，效价又提高了10倍（比较21和20）。含有苯基（22）或六元环杂环（23-24）的类似物的效价与化合物21相似。4,4-二氟哌啶基类似物（25）是该组中最有效的类似物（GSK-3β IC50=0.87nM）。总的来说，表1所示化合物对GSK-3β和GSK-3α的效价相差在3倍以内。表3.GSK-3β和GSK-3α对化合物53-57的抑制活性a除非另有说明，数值是两个测定值的平均值。b值是至少三次测定的平均值±SD。化合物22结合在GSK-3β催化结构域的X射线共晶结构如图4所示。蛋白质结晶为二聚体，在每个结合口袋中具有相似的配体相互作用。咪唑[1,2-b]哒嗪吡啶六元环的sp2氮和环丙基甲基胺取代基的氨基在GSK-3β催化结构域的铰链区与Val135（分别为2.5和2.1Å）形成氢键。吡啶部分的sp2氮与Lys85胺形成氢键（1.9Å）。酰胺羰基与Asp200的主链NH之间存在水介导的氢键。苯基占据了核糖结合位点，分子的这个区域提供了一种优化这种化学型效力的方法，因为它与蛋白质有良好的范德华接触。与表1中的化合物19和20相比，类似物21-25的效力有所提高，这可归因于吡啶环上4位取代基与核糖体结合位点上蛋白质的良好相互作用。在咪唑[1,2-b]哒嗪吡啶环体系中，酰胺NH与N1氮之间存在内部氢键。图5. 化合物47的S对映体结合在GSK-3β激酶结构域（PDB ID: 8DJC）的X射线共晶结构。（A）配体以绿色碳原子的棒状模型表示，氢键以黑色虚线表示。与配体相互作用的残基显示为棒状。2-甲基吗啉基团占据了核糖结合位点。（B）与GSK-3β的ATP结合位点结合的S -对映体47蛋白的表面表示。在2型咪唑[1,2-b]哒嗪吡啶环体系的2位与苯基或环丙基取代基结合，探索吡啶环4位的SAR，结果如表2和表3所示。对亲本无取代吡啶基类似物19和36的比较表明，后者的效价是19的11倍（GSK-3β IC50分别为20nM和220nM）。BMS公司发现该系列中R1处的苯基取代类似物的效力比表1中相应的类似物高5-20倍（分别比较37、38、45和47与20、21、23和24）。在吡啶环的4位加入一个甲基（37）得到一个GSK-3β IC50值为3.5nM的化合物。中等较大基团（38-40）的化合物的GSK-3β IC50值为~1nM或更低。在R2（41和42）处含有苯基的类似物被证明是有效的（GSK-3β IC50分别=3.6和1.6nM）。此外，六元杂环取代苯基提供了更高效的化合物，大多数GSK-3β IC50值在亚纳摩尔范围内（43-47）。用手性色谱法将化合物47分离成对映体后，结果表明(S)-47的效价比(R)-47高6倍。在R1的苯基环上加成一个邻甲氧基或对三氟甲氧基取代基是可行的（比较48和49至47以及比较50至45）。还研究了吡啶在R3和R4上的取代。在R3上有甲氧基的类似物比未取代的吡啶类似物的效力低近2倍（比较51和36）。在R4处的氯取代导致效力降低35倍（对比52和44）。表2所示化合物对GSK-3β和GSK-3α具有选择性，其效价差异在3-4倍之内。表2.化合物36-52对GSK-3β和GSK-3α抑制活性a除非另有说明，数值是两个测定值的平均值。b值是至少三次测定的平均值±SD。c值是单次判断的结果。相应地，咪唑[1,2-b]哒嗪吡啶的2位苯基被环丙基取代后，类似物的效力通常与在该位置具有苯基的相应化合物相当（分别比较54和55与44和42），见表3。化合物53的效力略低于47。化合物53和54的效价与表1中相应的类似物相当（分别为24和25），尽管在铰链区域失去了一个与Val135的经典氢键。然而，当去除咪唑[1,2-b]吡啶的2位苯基时（分别比较56和57与47和44），由于苯基失去了与蛋白质邻近氨基酸残基的疏水接触，观察到效力降低了10倍。表3.化合物53-57对GSK-3β和GSK-3α的抑制活性a除非另有说明，数值是两个测定值的平均值。b值是至少三次测定的平均值±SD。化合物47结合在GSK-3β催化位点的X射线共晶结构如图5所示。化合物47的S-对映体与蛋白质的配合作用更强。重要的氢键相互作用的细节如图5A所示。在咪唑[1,2-b]哒嗪的，并与蛋白质进行有利的疏水相互作用，从而增强其效力。在咪唑[1,2-b]哒嗪吡啶环体系中，酰胺NH与N1氮之间存在一个内部氢键。图5.化合物47的S对映体结合在GSK-3β激酶结构域（PDB ID: 8DJC）的X射线共晶结构（A）配体以绿色碳原子的棒状模型表示，氢键以黑色虚线表示。与配体相互作用的残基显示为棒状。2-甲基吗啉基团占据了核糖结合位点。（B）与GSK-3β的ATP结合位点结合的S-对映体47蛋白的表面表示。化合物在细胞试验中进行测试，其中GSK-3β抑制剂在短暂转染Tau蛋白的U2OS细胞中通过高含量成像试验测量其调节Tau蛋白S396磷酸化的能力。化合物25、38、41、44、45、47、(S)-47、(R)-47、48、49、53和54的实验结果见表4。结论如下：（1）在本实验中测试的化合物的pTau IC50值遵循GSK-3β酶实验中观察到的相同趋势；（2）在R2上含有4,4-二氟哌啶或吗啉的化合物在pTau测定中是最有效的（44、45和47）；（3）化合物41（R2=Ph）在R2（例如，45和47）时的效力比含啉基团的类似物低15-20倍；（4）化合物42在pTau测定中的效价无法确定，可能是由于在测定条件下溶解度差；（5）化合物(S)-47是该组中最有效的化合物。表4.咪唑类[1,2-b]哒嗪类GSK-3β抑制剂的pTau抑制活性a值是两个决定的平均数。b值是至少三次测定±SD的平均值。c值是单次测定的结果。体外分析-激酶选择性评估用412种激酶pp (Ambit/DiscoverX/Eurofins)对化合物进行广泛的激酶选择性筛选。单点检测板，设对照组，化合物浓度为1μM，结果如图6所示。对化合物44、45和47的激酶选择性谱的比较表明，与44和45相比，47有提高激酶选择性的趋势。GSK-3和CDKs是CMGC激酶家族的成员。而化合物47对与GSK-3最相似的激酶CDK2（IC50=1.4μM）的选择性超过1900倍，对CDK5（IC50=6.4μM）的选择性超过8700倍。图6.化合物44、45和47的边界径向图每条线表示在1μM测试化合物存在下单个激酶的剩余活性。单个激酶被分成不同的家族，用不同的线条颜色表示。从中心开始，圆圈表示控制绑定剩余的83%、33%和0%。SI33是在1μM的测试化合物存在下，具有≤33%对照结合的激酶的百分比。对于44、45和47,SI33分别= 5.3、5.8和4.1。化合物41、42、44、45、47和53的其他体外分析数据见表5。通过在人和小鼠肝微粒体中共温孵来评估化合物的代谢稳定性，结果表明41和42具有较高的代谢稳定性（10分钟后母体化合物的残留率>75%），而44、45、47和53具有较低的代谢稳定性（10分钟后母体化合物的残留率<50%）。研究表明，这是由于吡啶-2-甲基吗啉部分在自身发生氧化、开环和脱氢反应的同时，也易被肝微粒体氧化和双氧化。实验未观察到谷胱甘肽（GSH）偶联。然而，值得注意的是，在体外代谢稳定性测定中获得的结果并不一定能预测该化学型在小鼠药代动力学研究中化合物的体内分布。尽管这些化合物的血浆蛋白结合率很高，但化合物41、42和44与小鼠0.2-0.3% 无血浆部分的蛋白也表现出较高的结合。化合物45和47在小鼠血浆中的未结合部分也比44高几倍。特别地，用环丙基（53）取代47中的苯基导致未结合部分的额外增加，这可归因于该化合物的亲脂性降低。化合物53在人和小鼠中无血浆含量分别为1.5%和3.1%。平行人工膜透性试验（PAMPA）用于测定膜间被动透性。表5所示的结果表明，这些化合物具有高渗透性。在Caco-2细胞中也测量了通透性，Caco-2细胞中存在转运蛋白和外排蛋白。化合物45、47和53在Caco-2细胞中表现出高通透性，44也表现出高通透性，但比前三种化合物稍差。从B−A/A−B比值（<1）可以看出，这些化合物不是P-糖蛋白（P-gp）底物（表5）。表5中化合物的cLog P值范围为1.6至3.5，tPSA范围为72至85Å，是穿透血脑屏障的理想范围。化合物45、47和53的配体效率（LE）分别为0.43、0.40和0.42，亲脂配体效率（LLE）分别为6.88、6.14和6.98。在pH 1和pH 7.4、禁食状态模拟肠液（FaSSIF，pH 6.5）和进食状态模拟肠液（FeSSIF，pH 5）的溶解度分别为1.22、0.014、0.021和0.788mg/mL。表5.化合物41、42、44、45、47和53的体外分析数据a人（H）和小鼠（M）肝微粒体代谢稳定性；数值为孵育10分钟后母体残留的百分比。ND=未确定。体内药代动力学研究为了解化合物45、47和53在体内的分布，在雄性C57BL6小鼠中进行了药代动力学研究，结果见表6。当以2mg/kg静脉给药时，化合物45和47的清除率较低（分别为10.6和3.8 mL min-1kg-1）。化合物45的半衰期为3.1h，而化合物47的半衰期较长，为5.2h。化合物45和化合物47的分布体积（Vss）超过了体内总水量。当以10mg/kg的剂量作为溶液口服时，化合物45和47都被很好地吸收，并表现出较高的口服生物利用度（F%=~100和64%）。当静脉给药时，化合物53表现出中等清除率（49.5 mL min-1kg-1），半衰期短，为1.1h。当化合物53口服给药时，暴露量低于45和47，口服生物利用度为37%。化合物45、47和53的体外代谢稳定性和体内药代动力学特征之间的脱节可能归因于这些化合物的高血浆蛋白结合。然而，更高的内在清除率会导致更高的体内清除率，因此血浆蛋白结合的程度在体内化合物的清除率中也起着重要作用，并且可以改变相对于体外代谢稳定性结果上可能预期的药代动力学特征。在小鼠体内研究中，较差的水溶性妨碍了对41、42和44的评价。表6.化合物45、47和53在小鼠体内的药动学参数a静脉注射剂量2mg/kg，载体:40%聚乙二醇（PEG）400/35% 50mM柠檬酸盐（pH 4）/15%羟丙基β环糊精（HP-β-CD）/10%二甲基乙酰胺（DMAC，n=3）。b PO剂量10mg/kg，载体:83.3%聚乙二醇400/14.7% 50mM柠檬酸盐（pH 4）/2%聚维酮（PVP）-K30， (n=3)。抑制Tau磷酸化在上述药代动力学研究的3种化合物中，化合物47在小鼠药代动力学研究中清除率最低。进一步对化合物47在LaFerla 3xTg-C57BL6小鼠的三重转基因小鼠阿尔茨海默病模型中进行了评价。LaFerla 3xTg-C57BL6小鼠过度磷酸化的Tau（pTau）蛋白水平升高，并逐渐形成斑块和缠结，证明阿尔茨海默病造模成功。以剂量为250mg/kg （ip）的氯化锂作为阳性对照组，以30mg/kg（n=6）的剂量口服47作为实验组，实验结果显示化合物47导致pTau396减少52%。这种效果与用氯化锂观察到的还原水平相当，见图7。实验结束时（5h）测量了终端血浆和脑暴露，发现化合物47以3.8± 0.8μM的水平浓度暴露在血浆和1.3±0.4μM的浓度存在于脑中，脑-血浆（B/P）比为0.34。小鼠脑组织匀浆中47的未结合分数（fu,b）为0.9%，与小鼠血浆中未结合分数相当，未结合的脑与未结合的血浆比（Kp,uu）为0.34。图7.三转基因小鼠阿尔茨海默病模型的体内实验结果在LaFerla 3xTg-C57BL6小鼠（n=6）中，以30mg/kg剂量（83.4% PEG 400/14.7% 50mM柠檬酸盐（pH 3）/2% PVP-K30）。以250mg/kg（ip）剂量口服氯化锂作为阳性对照，口服化合物47可使pTau396减少52%。在给药后5h得到结果。数据采用方差分析（ANOVA）和Dunnett事后检验进行分析，**与对照比较P<0.01结论抑制GSK-3β是治疗阿尔茨海默病的一种潜在方法。这篇报道描述了一类新的咪唑[1,2-b]哒嗪基GSK-3β抑制剂，并发现了具有亚纳摩尔GSK-3β酶抑制剂效力的高效类似物。SAR研究结合X射线共晶结构结果表明，只需在激酶的铰链结合区与Val135进行一次经典的氢键相互作用，GSK-3β就能获得优异的效价。在X射线共晶结构中，咪唑[1,2-b]吡啶环体系的酰胺NH与N1氮之间存在内部氢键。这种内部氢键以及有利的偶极相互作用使酰胺有利于生物活性构象。该化学型化合物在PAMPA和Caco-2检测中表现出高通透性。在包含412个激酶的Ambit面板和大约30个激酶的内部面板中筛选选定的化合物表明，具有良好的总体激酶选择性，对CDK2具有出色的选择性。在体内对化合物47进行了评估，发现该化合物在小鼠药代动力学研究中具有较高的口服生物利用度，并在三重转基因小鼠阿尔茨海默病模型中显着降低了tau磷酸化。对47的血浆和脑水平的测量表明，该化合物是一种中等脑渗透GSK-3β抑制剂。总之，本研究结果为进一步优化该类GSK-3β抑制剂化合物的物理化学和药代动力学性质提供了基础。文章来源J. Med. Chem. 2023, 66, 4231−4252请点击此处链接观看CyberSAR系统详细使用教程1.药渡CyberSAR结合药物设计思想，挖掘了文献及专利报道的活性的结构，通过CyberSAR以方便快速获得研发人员兴趣靶向结构，以供开拓思路，就GSK-3β抑制剂举例如下：2.在靶点界面选中“化学空间”选项标签下级联“聚类结构视图”选项卡，可以将CyberSAR平台收录的文献和专利具有关于GSK-3β相关实验测试活性的分子以“母核结构聚类”的形式展示。其中绿色字体“高亮的”为文献报道的体外酶、细胞活性测试实验中IC50<100nM的活性分子结构、具体实验、实验结果及实验来源。3.在靶点界面选中“化学空间”选项标签下级联“原始结构视图”选项卡，可以将CyberSAR平台收录的文献具有关于GSK-3β相关实验测试活性的分子以“研发阶段时光轴“的形式展示。登录方式CyberSAR在电脑浏览器端登录网址：https://data.pharmacodia.com/cybersar/，欢迎猛烈试用。请点击此处链接观看CyberSAR系统详细使用教程如需进一步沟通，请扫码添加微信联系药渡赵博士或药渡CyberSAR沟通群。

临床终止临床1期临床结果临床2期

2023-01-18

·GlobeNewswire-Health Care

Junshi Biosciences Announces Toripalimab as Perioperative Treatment for Operable NSCLC Patients Met Primary Endpoint in Phase 3 Clinical Study

SHANGHAI, China, Jan. 18, 2023 (GLOBE NEWSWIRE) -- Shanghai Junshi Biosciences Co., Ltd (“Junshi Biosciences”, HKEX: 1877; SSE: 688180), a leading innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of novel therapies, announced today that a randomized, double-blind, placebo-controlled, multi-center phase III clinical study (“Neotorch”, NCT04158440) of the company’s anti-PD-1 monoclonal antibody, toripalimab, in combination with platinum-containing doublet chemotherapy as perioperative treatment for operable non-small cell lung cancer (“NSCLC”) patients, has finished the pre-specified interim analysis. The Independent Data Monitoring Committee (IDMC) has determined that the primary endpoint of event-free survival (“EFS”) has met the pre-defined efficacy boundary. Junshi Biosciences will communicate with regulatory authorities regarding matters related to the supplemental New Drug Application in the near future. Lung cancer is currently the second most prevalent type of cancer with the highest mortality rate in the world. According to data released by the World Health Organization, in 2020, the number of new lung cancer cases in China amounted to 816,000 and accounted for 17.9% of all new cancer cases in China. In the same year, the number of lung cancer deaths in China amounted to 715,000 and accounted for 23.8% of all cancer deaths in China. NSCLC is a major subtype of lung cancer, accounting for approximately 85% of all cases. Amongst these patients, 20%-25% are surgically resectable at first diagnosis, but even after radical surgical treatment, 30%-55% of such patients will suffer from post-surgical recurrence and death. Radical surgery in combination with chemotherapy is a way to prevent recurrence, but chemotherapy, as preoperative neoadjuvant or postoperative adjuvant therapy, has limited clinical benefit and can only raise the 5-year survival rate of patients by approximately 5%. Immuno-oncology (I-O) therapy, a type of treatment best represented by PD-(L)1 inhibitors, can provide patients with long-term tumor control or elimination. By relieving the immune suppression of immune cells caused by cancer cells, PD-(L)1 inihibitors reactivate the patients’ own immune system to destroy cancer. At present, the global community has accumulated sufficient clinical evidence proving that I-O can significantly improve the overall survival of patients with advanced NSCLC. However, the research on patients with operable NSCLC began relatively recently and focused solely on preoperative neoadjuvant or postoperative adjuvant I-O therapy. Perioperative I-O therapy covering the whole process, including pre- and post-surgery, is expected to be a better treatment model for patients. Neotorch is the world’s first phase III registered study of perioperative I-O therapy for lung cancer with a positive EFS result. Led by Professor Shun LU of Shanghai Chest Hospital as primary researcher, the study is a randomized, double-blind, placebo-controlled, multicenter phase III clinical study aiming to compare the efficacy and safety of toripalimab in combination with platinum-containing doublet chemotherapy versus placebo in combination with platinum-containing doublet chemotherapy for patients with operable NSCLC. The primary endpoints are EFS as assessed by researchers and major pathological remission rate (“MPR rate”) as assessed by the Blind Independent Pathology Review Committee (“BIPR”). The secondary endpoints include pathological complete remission rate (pCR rate) as assessed by BIPR and researchers, EFS as assessed by Independent Review Committee (“IRC”), and disease free survival (DFS), overall survival (OS) and safety as assessed by IRC and researchers, etc. The study was launched in 56 centers nationwide. Patients with operable NSCLC received toripalimab/placebo in combination with platinum-containing doublet chemotherapy as neoadjuvant and adjuvant therapy, and received toripalimab monotherapy as consolidation therapy after postoperative adjuvant therapy. Platinum-containing doublet chemotherapy was selected by researchers according to treatment practices of therapeutic institutions, of which paclitaxel in combination with cisplatin was for patients with squamous NSCLC, while pemetrexed in combination with cisplatin was for non-squamous NSCLC. Based on the interim analysis, compared with chemotherapy alone, toripalimab in combination with chemotherapy as perioperative treatment for phase III operable NSCLC patients and toripalimab monotherapy for consolidation therapy thereafter may significantly extend EFS of patients. The safety data of toripalimab is in line with known risks, with no new safety signals identified. About Toripalimab Toripalimab is an anti-PD-1 monoclonal antibody developed for its ability to block PD-1 interactions with its ligands, PD-L1 and PD-L2, and for enhanced receptor internalization (endocytosis function). Blocking PD-1 interactions with PD-L1 and PD-L2 promotes the immune system’s ability to attack and kill tumor cells. More than thirty company-sponsored toripalimab clinical studies covering more than fifteen indications have been conducted globally by Junshi Biosciences, including in China, the United States, Southeast Asia, and European countries. Ongoing or completed pivotal clinical trials evaluating the safety and efficacy of toripalimab cover a broad range of tumor types including cancers of the lung, nasopharynx, esophagus, stomach, bladder, breast, liver, kidney and skin. In China, toripalimab was the first domestic anti-PD-1 monoclonal antibody approved for marketing (approved in China as TUOYI®). Currently, there are six approved indications for toripalimab in China: unresectable or metastatic melanoma after failure of standard systemic therapy;recurrent or metastatic NPC after failure of at least two lines of prior systemic therapy;locally advanced or metastatic urothelial carcinoma that failed platinum-containing chemotherapy or progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy;in combination with cisplatin and gemcitabine as the first-line treatment for patients with locally recurrent or metastatic NPC;in combination with paclitaxel and cisplatin in first-line treatment of patients with unresectable locally advanced/recurrent or distant metastatic ESCC;in combination with pemetrexed and platinum as the first-line treatment in EGFR mutation-negative and ALK mutation-negative, unresectable, locally advanced or metastatic non-squamous non-small cell lung cancer (“NSCLC”). The first three indications have been included in the National Reimbursement Drug List (NRDL) (2021 Edition). Toripalimab is the only anti-PD-1 monoclonal antibody included in the NRDL for treatment of melanoma and NPC. In the United States, the Food and Drug Administration (FDA) is reviewing the Biologics License Application (BLA) resubmission for toripalimab in combination with gemcitabine and cisplatin as first-line treatment for patients with advanced recurrent or metastatic NPC and for toripalimab monotherapy for the second-line or later treatment of recurrent or metastatic NPC after platinum-containing chemotherapy. The FDA has granted Breakthrough Therapy designations for toripalimab in combination with chemotherapy for the first-line treatment of recurrent or metastatic NPC as well as for toripalimab monotherapy in the second or third-line treatment of recurrent or metastatic NPC. Additionally, the FDA has granted Fast Track designation for toripalimab for the treatment of mucosal melanoma and Orphan Drug designations for the treatment of esophageal cancer, NPC, mucosal melanoma, soft tissue sarcoma, and small cell lung cancer (SCLC). In Europe, marketing authorization applications (MAA) were submitted to the European Medicines Agency (EMA) and the United Kingdom’s Medicines and Healthcare products Regulatory Agency (MHRA) in November 2022 for: 1) toripalimab combined with cisplatin and gemcitabine for the first-line treatment of patients with locally recurrent or metastatic NPC and 2) toripalimab combined with paclitaxel and cisplatin for the first-line treatment of patients with unresectable locally advanced/recurrent or metastatic ESCC. In December 2022, the EMA accepted the MAA. About Junshi BiosciencesFounded in December 2012, Junshi Biosciences (HKEX: 1877; SSE: 688180) is an innovation-driven biopharmaceutical company dedicated to the discovery, development, and commercialization of innovative therapeutics. The company has established a diversified R&D pipeline comprising over 50 drug candidates, with five therapeutic focus areas covering cancer, autoimmune, metabolic, neurological, and infectious diseases. Junshi Biosciences was the first Chinese pharmaceutical company that obtained marketing approval for anti-PD-1 monoclonal antibody in China. Its first-in-human anti-BTLA monoclonal antibody for the treatment of various cancers was the first in the world to be approved for clinical trials by the FDA and NMPA and has since entered Phase Ib/II trials in both China and the US. Its anti-PCSK9 monoclonal antibody was the first in China to be approved for clinical trials by the NMPA. In the face of the pandemic, Junshi Biosciences’ response was strong and immediate, joining forces with Chinese and international scientific research institutions and enterprises to develop an arsenal of drug candidates to combat COVID-19, taking the initiative to shoulder the social responsibility of Chinese pharmaceutical companies by prioritizing and accelerating COVID-19 R&D. Among the many drug candidates is JS016 (etesevimab), China’s first neutralizing fully human monoclonal antibody against SARS-CoV-2 and the result of the combined efforts of Junshi Biosciences, the Institute of Microbiology of the Chinese Academy of Science and Lilly. JS016 administered with bamlanivimab has been granted Emergency Use Authorizations (EUA) in over 15 countries and regions worldwide. As of December 3 2021, over 700,000 patients have been treated with bamlanivimab or bamlanivimab and etesevimab, potentially preventing more than 35,000 hospitalizations and at least 14,000 deaths. Meanwhile, VV116, a new oral nucleoside analog anti-SARS-CoV-2 drug designed to hinder virus replication, is in global Phase III clinical trials. The JS016 and VV116 programs are a part of the company’s continuous innovation for disease control and prevention of the global pandemic. Junshi Biosciences has more than 3,100 employees in the United States (San Francisco and Maryland) and China (Shanghai, Suzhou, Beijing, Guangzhou, etc). For more information, please visit: http://junshipharma.com. Junshi Biosciences Contact InformationIR Team:Junshi Biosciencesinfo@junshipharma.com+ 86 021-6105 8800 PR Team:Junshi BiosciencesZhi Lizhi_li@junshipharma.com+ 86 021-6105 8800

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适应症	最高研发状态	国家/地区	公司	日期
阿尔茨海默症	药物发现	法国	Sanofi SA	-
2型糖尿病	药物发现	法国	Sanofi SA	-
2型糖尿病	药物发现	日本	Mitsubishi Pharma Corp.	-
精神分裂症	药物发现	法国	Sanofi SA	-
精神分裂症	药物发现	日本	Mitsubishi Pharma Corp.	-