Lebrikizumab

Eli Lilly and AstraZeneca landed at the top of IDEA Pharma's annual Innovation Index and Invention Index rankings, respectively. As Eli Lilly and Novo Nordisk continue to go in opposite directions in their diabetes and obesity market rivalry, so too have they changed positions in the annual IDEA Pharma Innovation Index, which ranks (PDF) the most transformative companies in the biopharma industry.While Lilly advanced from fourth place in 2024 to the top spot this year, it has supplanted last year's champion Novo, which tumbled all the way to eighth place. It’s a familiar perch for Lilly, which earned IDEA’s No. 1 slot in 2019 and 2021.This is the 14th year that IDEA, a pharmaceutical industry consulting firm based in London, has conducted the analysis. In 2019, IDEA added an annual Invention Index, which was topped by AstraZeneca for the third time in the last four years.In conducting its Innovation ranking, IDEA asks two questions: Who in the industry is at the forefront of innovation and what are they doing to achieve this? Additionally, if two biopharma companies were given the same molecule in early phase, which would better develop and launch it and why?In ranking Lilly No. 1, IDEA cited the FDA approvals of obesity drug Zepbound for obstructive sleep apnea, Kisunla for Alzheimer’s disease and Ebglyss for atopic dermatitis, each of which came in the second half of 2024.IDEA also recognized Lilly’s $3.2 billion buyout of Morphic to expand its immunology portfolio and its creation of the LillyDirect platform, which “reflects the company’s commitment to improving patient access and affordability by streamlining therapy delivery and reducing insulin costs.”On the flip side, in addition to falling into No. 8 on the Innovation Index, Novo plummeted to last place in the Invention Index. In both categories, IDEA ranks the industry’s top 30 companies.Novo’s declining fortunes are reflected in a market cap slide from $640 billion in July of last year to its present figure of $293 billion. Last week, the company announced the departure of eight-year CEO Lars Fruergaard Jørgensen.  Also receiving high marks in the Innovation rankings were No. 2 Merck, which jumped from the 10th slot largely because of the continued progression of the development of megablockbuster Keytruda. Third-place AZ and fourth-place Roche rose from Nos. 7 and 8, respectively, while Pfizer, which claimed consecutive titles in 2022 and 2023 for its rapid development of COVID-19 products, came in at No. 5. Also making notable jumps were No. 6 Regeneron, from 15th place, No. 7 UCB, which vaulted from outside of the top 20, and No. 10 Novartis, which was up from 17th place.UCB’s leap was fueled by “significant advancements in immunology, neurology and rare diseases,” IDEA wrote, citing advancements with Bimzelx in inflammatory conditions. "With a pipeline that spans high-need therapeutic areas, UCB has re-established itself as a resilient and innovative player, leveraging differentiated biologics and cutting-edge research to address unmet patient needs,” IDEA CEO Mike Rea said in a release.While IDEA’s Innovation Index measures how well companies perform in bringing new medicines to market and commercializing them, its Invention Index examines the breadth and depth of novel agents currently being developed within the top 30 pharma pipelines. The Invention Index provides a more forward-looking view of who is developing medicines that matter, embracing science and innovations in R&D. AZ’s recent dominance of the category is owed to its deep portfolio across several disease areas, including oncology, evidenced by the success and additional potential of blockbusters Tagrisso, Imfinzi and Enhertu across multiple cancer types.AZ replaced Johnson & Johnson in the top spot, with J&J falling to second place this year, one notch in front of Moderna. As they did in the Innovation Index, Roche and Regeneron also made significant leaps, from No. 17 and No. 8, respectively, last year, to tie for fourth place. Jumping from the teens into the top 10 were No. 8 GSK, as well as BeiGene and Boehringer Ingelheim, which tied for 10th place. Others in the Invention Index top 10 were No. 6 Lilly, No. 7 Merck and No. 9 Pfizer.In addition to Novo placing last in the Invention Index, others who performed poorly in the rankings were Merck KGaA, which placed No. 30 in Innovation and No. 26 in Invention. Takeda also was in the bottom five in both categories. Bayer, Biogen, AbbVie and Otsuka were in the bottom 10 in both categories.

1整体表现LLY在连续两个季度不及预期造成的股价大跌之后，原本依靠Orforglipron的临床读出形成了一波强力反弹到$800b以上，然而这个季报一出瞬间又掉到$750b。一季度收入同比增长45%，净利润同比增长29%，虽然看起来增收不增利，不过这里要考虑到收购Scorpion的每股$1.72的IPR&D负面影响，其实利润增长相当够看。自从24Q4美欧日市场均价下降后，这个季度的降价幅度继续扩大，看起来以价换量带来了效果，销量同比增长飞快，主要都来自Mounjaro的增长；而中国的Mounjaro上市后因供货短缺尚未放量，公司预计将在25H2增加供应。在2024年指引过于激进而错失后，公司2025年初的指引就已经相对理性，而这个季度的指引更新中，收入预期维持在$58-61b、也说明公司认为本季度表现符合预期，而利润预期因收购的IPR&D影响略有下调。2Tirzepatide众所周知，笔者长期以GLP1“吹哨人”自居（参见我是不是可以自称GLP1“吹哨人”了？），自然要不停审视这一观点的可靠性，同时随时做好自我打脸的准备。Tzp这个季度实现了$6.2b销售额，同比增速165%看似固然势不可挡，而环比增速13%基本坐实了逐步走平的预期。拆细来看，Mounjaro在美国市场的增长几乎已经触顶，近几个季度的增长主要依靠Mounjaro在欧日以及Zepbound来驱动。在与Sema的角力中，Tzp已经全面占据上风（这一趋势早在24年初就已明朗，参见【医苑观畴】2024年一季度海外药企进展更新：礼来LLY）。在T2D市场，Tzp的总处方量和新处方量份额分别达到39%和46%，正式完成对Sema的逆转；在减肥市场，Tzp的总处方量和新处方量份额更是分别高居60%和74%，形成对Sema的碾压之势。于是，GLP-1市场已经正式从双寡头齐头并进跑马圈地，向Tzp蚕食Sema份额的状态过渡，这对于高速增长的赛道而言应该是一个引起高度重视的前置信号。甚至对于LLY反复提及的Zepbound Vial剂型，确实在推动处方量提升和争抢份额中起了积极作用（须注意的是上图处方量增长应有相当一部分恰是vial贡献），但对整个市场空间而言也未见得是多么重大的正面作用，毕竟只有在看到增量边界的情况下才会注重存量优化。面对攻守易型，NVO不得不率先变阵、而且很鸡贼地选择就卡在两家公司公布季报之前官宣，包括CVS Caremark决定将Wegovy作为首选GLP-1药物、以及与Hims&Hers达成合作等，这也是导致LLY当天大跌的最直接因素。对此，管理层在电话会上面对汹涌而来的提问，并没有给出任何令人信服的策略（当然要考虑到给他们的反应时间太短），特别是对于是否会做出应对性的降价、乃至进入价格战，基本都不置可否，摆出了一副“别慌我们能赢”“对手先乱所以优势在我”“我有Orfo我怕谁”的姿态。那么就带来一个问题，GLP1市场是否确实接近天花板、乃至即将陷入价格绞杀的阶段呢？笔者目前仍维持谨慎悲观的态度，至少近几个季度从两家巨头的言行来看，已经不复一年前的星辰大海之态。3其他已上市产品在Tirzepatide历史级的增长面前，似乎讨论LLY的业绩就只需要关注这个单品，而我们同时也应注意到，整个公司其他产品线的表现也相当可圈可点，除了Dulaglutide属于内部自我迭代以外，主力品种几乎全都处在成长轨道，特别是诸如Abemaciclib和Empagliflozin等的增量贡献放在全市场来看也已经处于顶流水平（毕竟有很多MNC的最大单品在LTM也拿不出$1b以上的增量）。除了Tzp以外，这样全面和坚实的成长性，才是LLY值得高估值青睐的核心原因。除了Tzp以外的其他代谢基本盘中，Empagliflozin的惊艳还在持续，单季突破$1b大关、LTM累计达到$3.4b。肿瘤板块可能会成为较早进入增长放缓的产品线，Abemaciclib在刨掉年底年初的库存影响后已经基本走平，单季维持在$1.3b上下，市场份额也开始下滑；BTK C481S抑制剂Pirtobrutinib爬坡也相当乏力，单季仍然挣扎在$100m上下。自免板块基本维持着此前的趋势，IL-17A单抗Ixekizumab维持爬坡态势（刨去年底年初的存货影响），LTM累计超过$3.4b，仍在同靶点霸主Secukinumab的50%左右；不过剩下确实难成气候，JAK抑制剂Baricitinib看起来都很难上$1b了、与隔壁Upadacitinib的差距越拉越大，新晋的Lebrikizumab和Mirikizumab的爬坡还需要更多时间。其他唯一的看点CGRP单抗Galcanezumab本季度突然被腰斩，连带着对整个偏头痛市场的空间都要打问号；而万众瞩目的Aβ单抗Donanemab，上市后第三个季度只爬到$22m，总让人怀疑这几十年和几百亿是不是值得……4在研管线近期LLY与NVO双雄争霸的局面逆转，除了Tzp对Sema以外，更多是GLP-1领域的后续管线呈现一枯一荣。与隔壁的Amylin铩羽相比（参见【药海听涛】Amylin这是刚火就要凉了？CagriSema公布第二个临床三期结果），LLY可谓春风得意，小分子Orforglipron读出了首个三期临床ACHIEVE-1试验的积极结果：在559例T2D换着中，给药40周后，Orfo的36/12/3mg剂量组与安慰剂组相比，A1c警服分别为1.5%/1.6%/1.3%/0.1%，体重降幅则分别为7.9%/6.1%/4.7%/1.6%、且尚未达到减重平台期；安全性方面，四个组的腹泻发生率26%/21%/19%/9%、恶心发生率16%/18%/13%/2%、因AE而停药比例8%/4%/6%/1%，未观察到肝脏毒性，应该说是在预期范围内。公司宣布，将在25年底前向提交减重的NDA，在26年提交T2D的NDA，给NVO施加的压迫感简直拉满。不过在Tzp的重要适应症HFpEF上，LLY遭遇了与NVO类似的情况，将24年11月提交该适应症上市申请撤回，看起来FDA要求补充临床试验（虽然公司表示可能可以由其他试验提供数据），这样本以为在这个适应症上相对Sema的优势又被拉回来了。除了GLP-1，代谢管线也进展频频，继上个季度小分子Lp(a)抑制剂Muvalaplin的二期读出后，同靶点siRNA药物Lepodisiran也在NEJM上发布了二期临床ALPACA试验结果，该试验共入组320例高Lp(a)患者，分别在基线和180天接受安慰剂、两次Lepodisiran 16/96mg、Lepodisiran 400mg和安慰剂各一次、两次Lepodisiran 400mg，在60-180天范围内Lepodisiran的16/96/400mg剂量组的Lp(a)平均降幅分别为40.8%/75.2%/93.9%，在第30-360天范围内上述四个组的Lp(a)平均降幅分别为41.2%/77.2%/88.5%/94.8%；安全性方面，需要注意的是Lepodisiran组的注射反应发生率为8.1%-11.6%、肝酶升高发生率为2.7%-5.8%。https://doi-org.libproxy1.nus.edu.sg/10.1056/NEJMoa2415818除此以外，值得关注的进展还包括：Donanemab在欧洲批准遇阻、主要还是源于对ARIA风险的顾虑，JAK抑制剂Baricitinib公布青少年斑秃的三期临床结果。看了医药武林中GLP-1双雄这么久的激烈争斗，虽然这一代看起来胜负已分，但也有惨胜的苗头，于是LLY在面对竞争问题时动辄就王顾左右把Orfo抬出来说事，特别是在NVO后续管线凋敝的情况下。这种态度，是不是让人联想起大理段氏皇位之争到了最后，段延庆对段正淳的心理优势最终落脚在：“我有儿子呀！”礼来LLY往期季报分析：【医苑观畴】主流技术方向谁说了算：2022年上半年全球大药企核心产品管线进展总览【医苑观畴】主流技术方向谁说了算：2022年下半年全球大药企核心产品管线进展总览【医苑观畴】2023年上半年全球大药企核心进展总览【医苑观畴】2024年一季度海外药企进展更新：礼来LLY【医苑观畴】2024年二季度海外药企进展更新：礼来LLY【医苑观畴】2024年三季度海外药企进展更新：礼来LLY【医苑观畴】2024年全年及四季度海外药企进展更新：礼来LLY