Ryanodine receptor 1 (RyR1) is a Ca²⁺-release channel expressed on the sarcoplasmic reticulum (SR) membrane. RyR1 mediates release of Ca²⁺ from the SR to the cytoplasm to induce muscle contraction, and mutations associated with overactivation of RyR1 cause lethal muscle diseases. Dantrolene sodium salt (dantrolene Na) is the only approved RyR inhibitor to treat malignant hyperthermia patients with RyR1 mutations, but is poorly water-soluble. Our group recently developed a bioassay system and used it to identify quinoline derivatives such as 1 as potent RyR1 inhibitors. In the present study, we focused on modification of these inhibitors with the aim of increasing their water-solubility. First, we tried reducing the hydrophobicity by shortening the N-octyl chain at the quinolone ring of 1; the N-heptyl compound retained RyR1-inhibitory activity, but the N-hexyl compound showed decreased activity. Next, we introduced a more hydrophilic azaquinolone ring in place of quinolone; in this case, only the N-octyl compound retained activity. The sodium salt of N-octyl azaquinolone 7 showed similar inhibitory activity to dantrolene Na with approximately 1,000-fold greater solubility in saline.

2022-10-01·Aesthetic plastic surgery

Efficacy of Topical Losartan in Management of Mammoplasty and Abdominoplasty Scars: A Randomized, Double-Blind Clinical Trial

Article

作者: Nassireslami, Ehsan ; Motavalli Khiavi, Farhad ; Khodaei, Behzad ; Rahmati, Javad ; Seyedpour, Simin ; Haddady Abianeh, Shahriar ; Nasimi, Maryam

BACKGROUND:

Annually, millions of people suffer from skin scars' psychological and physical disadvantages. Pathologic scars prevention is challenging and requires developing feasible and effective therapeutic strategies. Regarding promising results of losartan (an angiotensin 1 receptor inhibitor) on skin scar in preclinical studies, we aimed to assess the losartan ointment's impact on surgical scars in a clinical setting.

MATERIAL AND METHOD:

Twenty-four patients with surgical wounds were enrolled from Razi hospital's plastic and reconstructive surgery department. The patients were trained to apply ointments 14-18 days post-surgery on the determined scar side, twice a day for 6 months. Two dermatologists independently evaluated scar formation at 3 and 6-month follow-ups using the Vancouver Scar Scale (VSS) score.

RESULT:

Twenty-four female patients with cosmetic surgeries were included. The mean VSS score of losartan-treated sides was 7.1 ± 2.06 (at month 3) and 5.21 ± 1.71 (at month 6) that significantly were different from placebo-treated sides (9.77 ± 1.55 and 8.31 ± 1.88 at 3 and 6 months, respectively) (P value < 0.001 and < 0.001, respectively, for months 3 and 6). The subset analysis demonstrated a significant improvement in height (P value < 0.001 at 3 and 6 months), pliability (P value < 0.001 at 3 and 6 months), and vascularity (P value < 0.001 at 3 and 6 months) subsets at losartan compared to placebo-treated side. Losartan ointment was well tolerated with no complication.

CONCLUSION:

Losartan ointment successfully improved scar formation in mammoplasty and abdominoplasty patients. The losartan preventive effect should be confirmed in future large-scale studies with long-term follow-ups.

LEVEL OF EVIDENCE II:

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

2022-03-01·Hypertension research : official journal of the Japanese Society of Hypertension3区 · 医学

Both central sympathoexcitation and peripheral angiotensin II-dependent vasoconstriction contribute to hypertension development in immature heterozygous Ren-2 transgenic rats

3区 · 医学

Article

作者: Vaněčková, Ivana ; Vavřínová, Anna ; Hojná, Silvie ; Rauchová, Hana ; Řezáčová, Lenka ; Behuliak, Michal ; Valovič, Pavol ; Zicha, Josef

Recently, we demonstrated that chronic blockade of the renin-angiotensin system (RAS) lowered the blood pressure (BP) of adult Ren-2 transgenic rats (TGR) mainly through the attenuation of central sympathoexcitation. However, the participation of central and peripheral mechanisms in the development of high BP in immature TGR remains unclear. In the present study, 6-week-old heterozygous TGR males were chronically treated with intracerebroventricular (ICV) or intraperitoneal (IP) infusions of the AT₁ receptor inhibitor losartan (1 or 2 mg/kg/day) for 4 weeks. The influence of these treatments on sympathetic- and angiotensin II-dependent BP components (BP response to pentolinium or captopril, respectively) as well as on BP response to exogenous angiotensin II were determined to evaluate the participation of central and peripheral RAS in hypertension development. Chronic IP losartan administration (1 or 2 mg/kg/day) lowered the BP of immature TGR by reducing both sympathetic and angiotensin II-dependent BP components. The central action of IP-administered losartan was indicated by a reduced BP response to acute ICV angiotensin II injection. Chronic ICV administration of a lower losartan dose (1 mg/kg/day) reduced only the sympathetic BP component, whereas a higher ICV administered dose (2 mg/kg/day) was required to influence the angiotensin II-dependent BP component. Accordingly, chronic ICV losartan administration of 2 mg/kg/day (but not 1 mg/kg/day) attenuated the BP response to acute intravenous angiotensin II application. In conclusion, central sympathoexcitation seems to play an important role in hypertension development in immature TGR. Central sympathoexcitation is highly susceptible to inhibition by low doses of RAS-blocking agents, whereas higher doses also affect peripheral angiotensin II-dependent vasoconstriction.

项与 BMS-986260 相关的新闻（医药）

2023-08-03

·FiercePharma

Bristol Myers, BeiGene end legacy Celgene deal with settlement years after China ban

Bristol Myers Squibb and BeiGene decided to terminate their entire China partnership three years after Chinese authorities put chemotherapy drug Abraxane on an import and sale ban. Back in 2020, a surprise manufacturing shortfall led to an import ban of Bristol Myers Squibb’s Abraxane, sold by BeiGene, in China. Legal finger-pointing ensued, and, now, the companies have decided to scrap their three-drug partnership altogether. BMS and BeiGene on Tuesday agreed to end a China licensing deal that BeiGene signed with Celgene back in 2017 before its acquisition by Bristol, a securities filing shows. In the original deal, Celgene essentially sold its China business, including local rights to cancer drugs Revlimid, Abraxane and Vidaza. Now, to end the deal, BMS will return nearly 23.3 million ordinary shares of BeiGene that Celgene had previously purchased. BeiGene won’t pay anything for those shares. As of Tuesday, BeiGene’s American depositary shares on Nasdaq, each of which represents 13 ordinary shares, were worth more than $200 apiece. The price dropped to below $190 Wednesday amid a marketwide retreat in the U.S. Using that measurement, the total settlement was worth about $340 million. Cracks started to form in the relationship in March 2020. At that time, Chinese authorities put Abraxane on an import and sale ban after spotting manufacturing problems at BMS' contractor Fresenius Kabi’s facility in Phoenix. Because of the quality misstep, BeiGene was disqualified from a national procurement program and banned from participating for two years. BeiGene has recorded no Abraxane sales since then. Hurt by the sanction, BeiGene brought an arbitration case against BMS at the International Chamber of Commerce, accusing the U.S. company of a breach of contract. BMS responded by delivering BeiGene a notice in October 2021 to end the Abraxane collaboration. Now, the two sides have decided to settle the feud by ending the entire legacy Celgene deal, effective at the end of 2023. BeiGene is also allowed to sell all inventory of Revlimid and Vidaza in China until the end of 2024. BeiGene has already shifted its attention from those drugs, which helped catapult the company to the commercial stage in 2017. BeiGene’s BTK inhibitor Brukinsa and PD-1 inhibitor tislelizumab have served as the company’s growth drivers lately. Thanks to a U.S. approval in chronic lymphocytic leukemia, Brukinsa pulled in $308 million sales in the second quarter, up from $211 million in the first quarter. Sales of tislelizumab, which is so far only available in China, came in at $150 million in the second quarter, compared with $115 million in the first quarter. By comparison, Revlimid brought BeiGene $21.8 million in sales and Vidaza $3.9 million during the three months that ended in June. The termination comes as BeiGene and its partner Novartis are about to face off against BMS in the U.S. PD-1 inhibitor market. BeiGene and Novartis are awaiting a long-overdue FDA decision on tislelizumab, which might eventually compete with BMS’ Opdivo. The FDA recently completed a much-delayed manufacturing inspection in China, but the agency hasn’t communicated a new target decision date, according to BeiGene. Meanwhile, BeiGene has been busy bolstering its own manufacturing capabilities. These include a $700 million-plus flagship manufacturing and R&D facility the company is building in Hopewell, New Jersey, which it says will be ready next year. BeiGene is also expanding its biologics facility in Guangzhou, China, and is constructing a new small-molecule campus in Suzhou, China.

引进/卖出上市批准

2023-06-13

·BioSpace

Seagen Touts Adcetris Early-Stage Lymphoma Data with 93% Complete Remission

Pictured: Illustration of a lymphoma cell/iStock, Dr_Microbe Tuesday, Seagen announced results from part C of its three-part Phase II trial in early-stage classical Hodgkin lymphoma, reporting that Adcetris (brentuximab vedotin) used in a combination approach led to complete remission in 93% of 150 patients. Adcetris was given in combination with Bristol Myers Squibb’s PD-1 inhibitor, Opdivo (nivolumab), and standard chemotherapy agents used for frontline treatment in early-stage classical Hodgkin lymphoma (cHL). The Part C results showed a 98% overall response rate at the end of treatment. Results from Part B of the study, which focused on advanced-stage disease, were shared at a European Hematology Association 2023 Congress in Frankfurt, Germany last week. The overall and complete response rates were 95% and 89%, respectively. Early-stage cHL patients have very high cure rates of over 90%, according to the NIH. However, long-term treatment related complications often caused patient deaths down the road. Recent focus for drug development has been on minimizing those risks. Already approved in later stage and high-risk cHL, the goal of ongoing Adcetris studies is to “develop curative treatments that improve survival while also reducing toxicity,” Jeremy Abramson, director of the Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital and principal investigator for the Phase II trial, said in a statement. Seagen won pediatric FDA approval for Adcetris to treat cHL patients aged two and older last November, in combination with standard chemotherapeutic agents. The antibody-drug conjugate works by targeting the CD30 surface protein overexpressed by certain types of cancer cells and releasing its cytotoxic payload once attached. Last week, BMS presented its data at ASCO for Opdivo in advanced, untreated cHL. Results from its Phase III trial SWOG S1826 showed that after a median follow-up of 12.1 months, Opdivo reduced the risk of disease-related death by 52% as compared with Adcetris. Additionally, Opdivo patients saw a 94% progression-free survival rate after one year. The Adcetris arm posted an 86% PFS. The BMS checkpoint inhibitor also appeared to be safer than Seagen’s ADC, with four deaths in the Opdivo arm, three related to adverse events, compared to 11 deaths for Adcetris, seven of which were due to toxicities. Adcetris will be added to Pfizer’s drug portfolio, once its $43 billion buy of Seagen is completed late this year or early next. The drug is by far Seagen's top seller, posting $839 million in sales for 2022. The acquisition will help grow Pfizer’s cancer treatment portfolio as sales from the pharma giant’s biggest sellers—its COVID-19 products—drop off. Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

临床结果上市批准并购抗体药物偶联物临床2期

2023-03-14

·SYNAPSE

挑战PD-(L)1+TKI：罗氏碰壁，BMS绿灯通行

前有恶狼，后有猛虎。这是罗氏的PD-L1单抗Tecentriq（atezolizumab）正在面临的现状。尽管在2022年，Tecentriq全年营收近40亿美元，仍然是超重磅炸弹，但在激烈竞争下，它的销售额增速还是肉眼可见快速下滑。罗氏正在为其寻找新的利润增长点：与其他药物联用，挑战当前标准疗法。去年，在与同为免疫检查点抑制剂的TIGIT单抗联用的系列试验失败后，罗氏的天平重心倒向了另一方——与酪氨酸激酶抑制剂（TKI）联用。只是这一次，开局仍然不顺利，计划试验中的2/3已经宣告失败。 BMS的PD-1单抗Opdivo（nivolumab）给出了正面案例。与罗氏不同，BMS的组合在肾细胞癌（RCC）上一路绿灯通行，在最新的实验中，还加入了免疫检查点CTLA-4抑制剂的联用。希望没有消失，罗氏等待最后一项实验的落槌敲定。而这等待的时间，注定也不会太久。梦碎：罗氏的PD-L1与Cabometyx 以PD-(L)1单抗为代表的免疫检查点抑制剂，重新调动起免疫系统的识别能力，阻断癌细胞免疫逃逸，引发T细胞特异性杀伤肿瘤。基于这种机制，这类药物往往具有广谱抗癌效果。但肿瘤免疫逃逸机制与免疫应答之间关系存在更复杂的关系，使用PD-(L)1单抗单药治疗，患者的应答率往往只有10%-20%。联合用药是大势所趋。与同为免疫检查点抑制剂的TIGIT单抗Tiragolumab联用，罗氏在小细胞肺癌和非小细胞肺癌（NSCLC）上都没有收到很好的疗效。而TKI，作为靶向治疗的经典小分子抑制剂，可有效阻断酪氨酸活性。后者是细胞信号传导途径中的重要因子，参与调节细胞生长、分化和凋亡等多种生理进程，异常活化会导致恶性肿瘤发生。罗氏期待不同机制的TKI能拓展Tecentriq的治疗边界。Exelixis的Cabometyx（cabozantinib）则是承担这一志向的载体。根据临床前研究，Cabometyx能促进“免疫允许环境”，使肿瘤细胞对免疫反应更加敏感。为此，罗氏与Exelixis签署合作协议，推进Tecentriq-Cabometyx组合在NSCLC、转移性去势抵抗性前列腺癌（mCRPC）、RCC等癌种上的应用。 NSCLC成为了第一个梦碎现场。2022年12月，罗氏宣布，在III期CONTACT-01研究中，与Cabometyx和多西他赛的组合相比，联合方案并未改善总生存期（OS）。一次失败问题不大。RCC的III期CONTACT-03研究结果公布紧随其后，然而翘首以盼的结果并不如人意——2023年3月2日，Exelixis宣布该组合未达到无进展生存期（PFS）。这是一项随机和开放标签的研究，评估Tecentriq-Cabometyx组合对发生疾病进展的RCC是否有临床益处。CONTACT-03研究共招募了522名局部晚期、转移性透明/非透明细胞的RCC患者，他们在接受免疫检查点抑制剂治疗期间，或之后出现了疾病进展。这些患者按照1：1比例被随机分到了实验组和Cabometyx单药对照组。安全性方面，没有发现新的安全信号。但从效果上来看，目前信息有限，只知道没有达到主要临床终点，详细信息将在近期医学会议上公布。另外，罗氏还透露，除了PFS以外，CONTACT-03也评估了OS。不过这次失败所引起实际杀伤力并不严重。有分析师认为，NSCLC前车之鉴，RCC失败在意料之中，不会对Cabometyx在2023年15.8亿-16.8亿美元的销售收入指引造成波动。但话说回来，在与Tecentriq联用上，TKI Cabometyx会步TIGIT单抗Tiragolumab的后尘吗？仅存的CONTACT-02试验，还有成功的希望吗？比起Exelixis，罗氏更希望从中获得肯定的回答。绿灯通行：BMS的PD-1与Cabometyx 现实并没有那么悲观。向前看，BMS的PD-1单抗Opdivo方可注入一丝信心——2021年1月，Cabometyx与Opdivo联合疗法获得了FDA批准，用于一线治疗晚期RCC患者。关键III期CheckMate -9ER试验，在651名晚期RCC患者中评估Opdivo-Cabometyx联合疗法和舒尼替尼的疗效对比。根据试验设计，不允许组间交叉治疗和减少Opdivo剂量，但允许减少Cabometyx和舒尼替尼的剂量。舒尼替尼是第一代TKI，是曾经的标准疗法。结果显示，在PFS、OS和客观响应率等关键指标方面，联用组表现出比舒尼替尼更明显的优势。 Opdivo-Cabometyx的中位PFS为16.6月，相比之下，舒尼替尼组为8.3月；在12个月OS方面，联合疗法的数据为85.7%，舒尼替尼组为75.6%。此外，对药物的响应率，联合组也比舒尼替尼组高一倍多，前者为55.7%，后者为27.1%。不仅于此，根据后期结果，与舒尼替尼相比，联合疗法还将死亡风险降低了40%。后续随访中，接受联合组治疗的患者也报告了更好的生活质量。在安全性方面，Opdivo-Cabometyx耐受性良好，任何等级的与治疗相关的AE导致停药的比率为15.3%，高于对照组的8.8%，但整体还是维持在低水平。但因疾病进展而导致治疗终止的比率，联合组要比舒尼替尼低得多，仅为27.8%，而后者为48.1%。今年2月，CheckMate-9ER研究的3年随访数据披露，数据显示，Opdivo-Cabometyx作为一线治疗手段，可以促进RCC的长期生存和响应率。这项试验，将Opdivo-Cabometyx这对组合推向了成为新确诊转移性RCC的标准疗法，也证明了联用TKI的确如猜测般，能够加强免疫检查点抑制作用。 Cabometyx其实早在2017年就获得FDA批准，用于一线治疗晚期RCC患者。在关键试验中，Cabometyx单药和对照组舒尼替尼的中位PFS分别为8.6月和5.3月；ORR分别为20%和9%。由此也可见，Opdivo-Cabometyx这对组合也产生了1+1>2的效果。得益于这项适应症的拓展，Cabometyx的年销售额从2020年的7.9亿美元，上涨到2021年的11.5亿美元，涨幅高达45%。 Exelixis的野心开始膨胀起来。 Exelixis的两出压轴戏与罗氏的联用三部曲中，仅剩未揭幕的CONTACT-02，针对mCRPC。截止目前，Cabometyx获批适应症有晚期RCC、肝细胞癌、甲状腺癌，mCRPC是尚未到达的新大陆。根据美国癌症协会估计，美国每年约有28.8万新发前列腺癌患者。其中，有70%-80%会发生骨转移，目前的主要的治疗方法为雄激素剥夺治疗（ADT），经过ADT后疾病仍然出现进展的前列腺癌即为mCRPC。很可惜，这个数字非常高，绝大多数前列腺癌患者接受内分泌治疗的18-24月后，病情都会进展到mCRPC，这时候相当于半只脚已经踏入了死亡门槛。这是一个庞大且极具潜力的市场，罗氏与Exelixis挑战的是二线疗法。CONTACT-02研究于2020年正式启动，招募了580名mCRPC患者，评估Tecentriq-Cabometyx与激素疗法的疗效对比。其中，PFS和OS为共同主要终点，预计今年下半年就能见到顶线数据。罗氏在等待。另一方的Exelixis还压了一块宝在BMS身上。名为COSMIC-313的试验，意图在更小的区域内迭代CheckMate-9ER试验中所孵化出的标准疗法。这项正在进行中的III期试验，正在评估Cabometyx+Opdivo+Yervoy（ipilimumab）组成的三联方案取代Opdivo+Yervoy的可能性。 Yervoy是全球首个上市的免疫检查点抑制剂，针对T细胞活性的负调节剂CTLA-4起效。Opdivo+Yervoy这对双重检查点抑制剂组合，一直是IMDC中低风险的一线晚期RCC的标准治疗方法。先前CheckMate-9ER试验中，纳入的患者并不限IMDC风险。 2022年的ESMO大会上，COSMIC-313研究的主要终点数据公布。Exelixis很高兴，两年前的成功逻辑仍然行得通——相比对照组的11.3月，三联组显著改善了PFS数据，截至统计日期，尚未达到中位PFS。不过这项获益主要由中风险RCC患者驱动。在这些患者中，三联组的中位PFS未达到，对照组为11.4个月。而在低风险队列中，三联组效果欠佳，中位PFS分别为9.5个月和11.2个月。目前只公布了COSMIC-313研究的主要终点数据，对次要终点OS的随访正在进行中，预计数据结果将于今年下半年公布。对Exelixis来说，与BMS的合作兜了一个底，目前已出的结果都朝向积极态势发展。但对罗氏来说，情况并不友好。虽然距离Tecentriq的专利悬崖还有至少七年时间，但面对PD-(L)1赛道竞争日益强烈，更多平价产品的涌入，罗氏的Tecentriq的销售额增速不可避免开始下滑。 2022年该药物销售额约为39.76亿美元，同比增长9.4%。相比2021年16.8%、2020年61%的增幅，2022年所展现出的增长趋势并不理想。寻求这款收入支柱的另一驱动力，是罗氏当前迫在眉睫的功课。毕竟，如果不抢占市场，立刻会有竞争对手补齐空缺。究竟mCRPC能否给罗氏带来CONTACT系列研究计划中的翻盘？现在只能等待最后结果。参考资料： 1.Roche, Exelixis Suffer Another Late-Stage Cancer Combo Failure；Biospace 2.U.S. Food and Drug Administration Approves OPDIVO® (nivolumab) in Combination with CABOMETYX® (cabozantinib) as First-line Treatment for Patients with Advanced Renal Cell Carcinoma；BMS官网 3.Choueiri TK, Powles T, Burotto M; CheckMate 9ER Investigators. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2021 Mar 4;384(9):829-841. 4.COSMIC-313: Triplet Prolongs PFS vs Doublet in Renal Cell Carcinoma；Cancer Therapy Advisor 5.Exelixis’ Cabometyx R&D On Track Despite Pivotal Kidney Cancer Setback；Scrip

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适应症	最高研发状态	国家/地区	公司	日期
结直肠癌	临床前	美国	Rigel Pharmaceuticals, Inc.	2020-01-28
结直肠癌	临床前	美国	Bristol Myers Squibb Co.	2020-01-28
结直肠癌	临床前	印度	Bristol-Myers Squibb India Pvt Ltd.	2020-01-28