Lipoic acid choline ester

By the time 2023 is over, Novartis expects to be moving much lighter: It will have spun out its generics subsidiary Sandoz, completed layoffs of thousands of staffers worldwide and put in new internal structures for running the company. And it will be ready to hunt for blockbusters. CEO Vas Narasimhan underscored Novartis’ upcoming transformation into a “pure-play” company, reiterating across a series of calls — one with reporters, two with investors and analysts — that the new structure would boost its R&D productivity and sharpen its focus on big, new medicines. “Our focus now is to improve the value per asset,” he said on Q4 and full year 2022 earnings call, “identifying assets earlier that have significant potential, investing in those assets more aggressively, pursuing more lifecycle management indications — with a goal to increase the success rate and reduce the cycle time and generate larger assets.” Despite a decline in sales and operating income compared to 2021, Narasimhan called 2022 a “pivotal year” that sets Novartis up for growth in 2023. Novartis highlighted five drugs as key drivers of growth in the last quarter of last year: Entresto (heart failure, +44%), Kesimpta (multiple sclerosis, +157%), Kisqali (breast cancer, +33%). Although Cosentyx recorded lower sales in Q4, the company also spotlighted the anti-inflammatory drug as a top product, alongside the radioligand therapy Pluvicto. Back in June, Novartis detailed plans to lay off 8,000 of its more than 100,000 employees around the world. More than seven months later, Narasimhan said his team is continuing to make “very good progress.” In fact, he said, the restructuring is a little ahead of plan at the moment. Overall, the company is on track to complete the major reorg by the end of the year, he added. For context, CFO Harry Kirsch noted that while 8,000 is a large number, it’s actually similar to Novartis’ annual attrition of about 7,000 — meaning there’s room for redeployment for the impacted employees. Narasimhan added that part of the restructuring translated to a “big simplification” on a country level, eliminating levels, layers, therapeutic divisions and “complex conglomerate structures” within each country. Marie-France Tschudin, president of Novartis Pharmaceuticals, noted that it’s all about having agility to make decisions quickly. “We’ve set up a model that is a single model that works on the continuum from end to end of really tying the relationship with our development unit, with our research unit, with our commercial units,” she said. “So that we are one team and we’re all talking and speaking the same language.” Looking to Eli Lilly and Novo Nordisk as successful examples of “pure-play” companies, Narasimhan said the idea that having a broader set of businesses could offer a buffer to innovative R&D hasn’t been borne out. Having these businesses, in fact, “has not actually reduced volatility of anything.” “It’s very hard to allocate capital and to make good decisions and invest people, energy across very diverse businesses,” he said on stage at a press conference. “If you’re going to try to be in contact lenses and generics, while also trying to be at the leading edge of RNA therapeutics it’s very challenging.” Like many of its pharma brethren, Novartis said it continues to “actively evaluate” M&A deals, with the sweet spot still in the $4 to $5 billion range — and a sharp eye for high quality data. “Valuations, of course, have come down,” Narasimhan said on the media call. “But in and of itself, that’s not enough. We want attractive valuations, but more importantly, very compelling science.” What about megamergers? Don’t hold your breath, Narasimhan suggested. Those may be the distant memories of older times. “You have a set of companies now that are very scaled,” he said, with 75,000 people even after streamlining operations and spinning off Sandoz. “So we don’t need to do M&A to get more scale.” Then there’s the consideration that historically most large mergers have led to significant disruptions that resulted in reduced R&D productivity, he said. Couple that with the increasing pushback from antitrust regulators, and the idea of two huge companies merging simply isn’t that appealing. “I don’t have perfect information, of course. Things will change,” he said. “But I think those are some of the considerations that make it harder than maybe it was a decade or two ago, when you saw many more of these combinations happening — smaller, relatively smaller companies coming together to try to get significant scale out. Now you have eight to 10 very skilled players, and so the combinations become hard to really make sense.” Restructuring and impairments were both big factors leading to lower operating income in 2022, Novartis noted. The implementation of the restructuring cost $1.2 billion; the company also wrote off $1 billion in value for previously acquired assets that didn’t pan out. Kirsch noted in the press conference that the key program here was UNR844, a presbyopia drug from the 2016 buyout of Encore Vision. Novartis recorded a $600 million hit after “The Phase IIb didn’t work out,” he said. “There was another attempt at it, and then finally, we stopped. There’s another couple of these which were more at the 200 million range.”

原本获FDA加速批准上市，却在确证性研究中折戟，GSK的BCMA ADC药物Blenrep在多发性骨髓瘤III期研究中未达主要终点而失败一事令人惋惜。不仅是GSK，今年下半年以来，MNC企业宣布临床试验失败、或未达到临床试验主要终点的案例不在少数。例如，默沙东K药经典“可乐组合”再度“翻车”；辉瑞嗅到“没戏”危机，在III期临床中期试验结果不理想时，果断放弃曾重金收购来的p38 MAPK口服小分子抑制剂；诺华亦斩掉曾收购来的产品临床试验；赛诺菲药物研发仍屡屡受挫……战战兢兢、如履薄冰，这可能是所有MNC新药临床研发时共有的状态。01默沙东：K药组合疗法遭遇“滑铁卢”2022年前三季度，K药（帕博利珠单抗）的销售额达154.61亿美元，有望成为全球突破200亿美元大关的超级重磅炸弹药物。然而，第三季度K药相关临床试验“翻车”频频。8月，知名“可乐组合”——K药与Lenvima(仑伐替尼/乐伐替尼)进行的组合疗法，在晚期肝癌一线治疗上熬过了一、二期临床试验，却在第三季度遭遇了“滑铁卢”。默沙东/卫材宣布，K药联用仑伐替尼一线治疗晚期不可切除肝细胞癌(uHCC)患者的III期LEAP-002研究未达到总生存期(OS)和无进展生存期(PFS)的双重主要终点。此前，可乐组合还在非小细胞肺癌、尿路上皮癌的研究中未达到主要临床终点。针对肝细胞癌适应症，目前有多家药企正在进行PD-1与仑伐替尼的联合试验。其中“T+A”(阿替利珠单抗+贝伐珠单抗)和“双达组合”(信达的信迪利单抗+贝伐珠单抗)均已获得国家药监局批准，用于既往未接受过系统治疗的不可切除或转移性肝细胞癌的一线治疗。除此之外，君实生物在开展特瑞普利单抗注射液(JS001)或安慰剂联合仑伐替尼一线治疗晚期肝细胞癌的临床试验；康方生物在开展卡度尼利单抗注射液单药或联合乐伐替尼治疗晚期肝细胞癌的临床试验。除此之外，K药联合多西他赛治疗转移性去势抵抗性前列腺癌(mCRPC)患者的III期KEYNOTE-921研究未达到总生存期(OS)和影像学无进展生存期(rPFS)的双重主要终点，这也是今年K药联合治疗在mCRPC失败的第2个III期研究。7月，K药联合放化疗（CRT）用于未切除的局部晚期头颈部鳞状细胞癌（HNSCC）患者的III期KEYNOTE-412研究未达到改善无事件生存期（EFS）的主要终点。值得注意的是，在HNSCC疾病领域，MacroGenics和天境生物联合开发的靶向CD276的依布妥组单抗由于在双臂中出现7例可能与出血事件相关的死亡事件后，终止了依布妥组单抗联合PD-1单抗retifanlimab或PD1/LAG3双特异性抗体特泊利单抗用于HNSCC治疗的II期研究。此外，Brooklyn ImmunoTherapeutics开发的IRX-2也未达到临床研究主要终点。02辉瑞：削减3条管线，果断停止PF-07265803III期临床8月3日，辉瑞宣布，通过对PF-07265803治疗LMNA扩张型心肌病（DCM）全球III期临床（REALM-DCM）的中期结果分析发现，该试验在完成后不太可能达到主要研究终点。因此，辉瑞决定停止PF-07265803的III期临床，并放弃其进一步开发。PF-07265803（ARRY-797）是辉瑞在2019年6月以114亿美元收购Array BioPharma时获得的一款p38 MAPK口服小分子抑制剂，曾在II期临床中证明其对LMNA心肌病患者有功能能力（6MWT）的改善。据辉瑞披露信息，自7月份最后一次信息更新以来，已从其管线中削减了三个项目，其中便包括PF-07265803。此外，辉瑞还停掉了处于I期治疗特应性皮炎的局部软JAK抑制剂PF-07259955；结束了在研CDK2抑制剂PF-07104091与Ibrance在转移性乳腺癌中的I期联合研究，然而，辉瑞的产品线更新表明，无论是单独使用还是与实验性CDK4阻滞剂PF-07220060联合使用，以及作为卵巢癌的单一疗法，候选药物仍在针对这一适应症进行评估。辉瑞首席执行官表示，在未来8个月内，预计将有多达19种新产品或适应证进入市场，“从临床角度来看，其中许多项目在很大程度上能成功上市。”03罗氏：T药抢夺肾癌适应证受挫今年前三季度，罗氏的T药阿替利珠单抗（Tecentriq）销售额达26.92亿瑞士法郎，同比增长10%。今年第三季度，Tecentriq在皮下注射剂III期临床试验 IMscin001中收获了积极结果，预计将在年内递交二线治疗NSCLC的上市申请，成为欧美首个拥有关键临床积极结果的PD-(L)1皮下注射产品，另外两项针对早期肝细胞癌和非小细胞肺癌辅助治疗的关键III期临床试验预计在今年完成，头颈部鳞状细胞癌的相关数据要推迟至2023年公布。不过，7月21日，罗氏业务负责人Bill Anderson在投资者会议上透露，Tecentriq在肾癌辅助治疗的IMmotion010研究中未能达到主要终点。目前，Tecentriq获批的适应证主要包括膀胱癌、非小细胞肺癌、小细胞肺癌、三阴性乳腺癌、肝细胞癌、黑色素瘤这几个瘤种，尚未在肾细胞癌适应证上拿到上市资格。当前，获得肾细胞癌适应症的PD-1/PD-L1药物有3款，分别为纳武利尤单抗、帕博利珠单抗和阿维鲁单抗。帕博利珠单抗在2021年11月和2022年1月先后获得FDA和EMA批准用于肾细胞癌的辅助治疗，是首款获得FDA批准辅助治疗肾细胞癌的免疫疗法。在国内，恒瑞的SHR-1701注射液联合甲磺酸仑伐替尼胶囊对比苹果酸舒尼替尼胶囊一线治疗晚期肾细胞癌的多中心、随机、对照、开放的Ⅲ期临床研究，于去年11月获批临床。04诺华：卡那奴单抗再受挫，FIC眼药项目终止在今年内部动作频频的诺华，在重磅产品的研发进度上也受到了挫折。其三季报显示，在肝移植的II期研究中，其抗CD40单克隆抗体iscalimab （CFZ533）与tacrolimus相比，获益/风险状况较差，该项目将被终止。此前该药曾在肾移植的中期试验中失败。另外，由于治疗老花眼的UNR844的IIb期剂量范围研究的中期分析未能达到其主要终点，即在第三个月显示出显著的剂量反应，诺华决定终止该项目，并记录5.68亿美元的相关减值费用。UNR844是诺华于2016年收购Encore Vision 所得，该产品是一种硫辛酸胆碱酯，被视为是或将改变疾病进程的潜在全球首创（first-in-class）的老花眼疗法。除了这两项终止试验之外，在今年8月，由于可能会造成周围神经病变等副作用，诺华宣布将暂时停止branaplam在亨廷顿病中进行的IIb期试验。据了解，Branaplam最初设计用于治疗脊髓性肌萎缩症（SMA），2021年由于branaplam对SMA的疗效不佳，诺华选择完全放弃该产品对于SMA的探索。此外，在过去的第三季度，其canakinumab(卡那奴单抗，ACZ885)在癌症领域的探索再受挫折。今年8月，诺华宣布卡那奴单抗辅助治疗II-IIIA和IIIB期完全切除的非小细胞肺癌(NSCLC)成年患者的III期CANOPY-A研究没有达到无病生存期(DFS)的主要终点。去年3月，该产品联合多西他赛用于既往接受过PD1/PDL1抑制剂和铂类化疗的成人NSCLC患者的III期临床（CANOPY-2）也未达到改善OS的主要终点；10月，卡那奴单抗联合帕博利珠单抗加铂类双药化疗一线治疗局部晚期或转移性NSCLC的III期临床研究（CANOPY-1）也同样未达到改善总生存期(OS)和无进展生存期(PFS)的主要终点。不过这些挫折似乎很难对诺华产生实质性的冲击。在产品管线方面，诺华有149条临床试验项目，其中47款处于临床三期阶段，诺华预测其2026年前获批的产品中，将有20款新药有望成为年销售超过10亿美元的重磅药物。05赛诺菲：仍处研发水逆期继今年3月，BMS宣布偏向性IL-2（Bempegaldesleukin）联合PD-1抗体Opdivo治疗转移性黑色素瘤的三期临床未达到无进展生存期（PFS）和客观缓解率（ORR）的主要终点之后，赛诺菲也传出了坏消息。10月28日，赛诺菲宣布终止偏向性IL-2抗体THOR-707的开发，该药物由赛诺菲于2019年以25亿美元重金收购Synthorx所得。对于该产品，赛诺菲曾充满期待，称之为“一种有可能成为下一代免疫肿瘤联合疗法基础的分子”。不过对于此次临床受挫，赛诺菲表示并未完全放弃，仍会开启新的临床方案。据了解，先声药业、志道生物、恒瑞医药、信达生物等国内药企均在偏向性IL-2赛道有所布局。今年8月，赛诺菲宣布口服选择性雌激素受体降解剂amcenestrant联合哌柏西利治疗ER+/HER2-晚期乳腺癌患者的III期AMEERA-5研究未达主要终点，并宣布终止amcenestrant的全球临床开发计划。而在今年3月，amcenestrant用于激素治疗前后进展的局部晚期或转移性ER+/HER2-乳腺癌患者的II期AMEERA-3研究也以失败告终。另外其肿瘤管线中的PD-1单抗Libtayo（西米普利单抗）的研发进展同样坎坷，在今年年初赛诺菲/再生元自主撤回了Libtayo二线治疗晚期宫颈癌的sBLA。并且对于该产品，这一对老搭档也开始“划清界限”，此前两家公司共同开发并平等共享Libtayo的全球利润，美国市场由赛诺菲/再生元共同负责商业化，美国以外市场由赛诺菲独立负责商业化。但是今年6月赛诺菲宣布将PD-1抗体Libtayo的权益退还给再生元。06GSK：ADC产品血液瘤领域探索受挫近日，在被媒体披露主动终止与Lyell和Adaptimmune在实体瘤细胞免疫疗法项目的合作，退出细胞治疗2.0联盟（此联盟是细胞治疗领域杰出的科学家团队之一）之后，GSK又宣布其BCMA靶向药DREAMM-3，Blenrep单药治疗与泊马度胺联合低剂量地塞米松（PomDex）的III期开放标签、随机头对头临床实验，针对治疗复发或难治性多发性骨髓瘤(RRMM)患者，未能达到无进展生存期(PFS)的主要终点。该试验对Blenrep在美国和欧盟加速/有条件批准下的确认性研究，旨在表明该疗法优于市场上的护理标准。Blenrep于2020年8月获得FDA加速批准，用于五线治疗难治性多发性骨髓瘤成人患者，是FDA批准的世界上首个靶向BCMA的抗体偶联药。即便Blenrep未达到此次试验主要终点，但GSK并未放弃，并对Blenrep以及二线治疗复发/难治性多发性骨髓瘤的联合试验的治疗潜力充满信心。接下来GSK仍会积极与当地监管部门沟通DREAMM-3的数据，推进Blenrep相关的临床试验DREAMM-7、DREAMM-8，并计划于2023年上半年公布DREAMM-7和DREAMM-8的III期数据。据了解，该产品对于GSK一度意义重大，GSK曾期待该产品成长为骨髓瘤的支柱产品，从销售数据来看，2021年Blenrep的销售额为8900万英镑，2022年前3季度的总销售额为9100万英镑。登记邮箱信息订阅E药经理人信息服务扫描二维码