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全球畅销药 Keytruda 宛如一位即将走下神坛的武林盟主，2028 年就要失去专利独占权这块 “免死金牌” 啦。BioSpace 如同好奇的江湖小报记者，盯上了五种已然跳下专利悬崖的药物。 药企困境：重磅药专利到期的 “达摩克利斯之剑” 未来几年，大型制药公司就像被 “专利到期” 这把达摩克利斯之剑悬在头顶。默沙东的 Keytruda 那可是如今全球畅销药界的 “扛把子”，2024 年全球销售额蹭蹭蹭快到 300 亿美元了，跟印钞机似的。可谁能想到，2028 年它就要失去专利保护，一下子从特权阶层变成 “平民”。这消息一传出，整个行业都跟打了鸡血似的，纷纷投入生物类似药的研发大战，都想在 PD - 1 这个巨大市场里分一杯羹，就像一群饿狼盯着一块肥肉。 默沙东的 “专利丛林” 战术：能护 Keytruda 周全？ 默沙东就像一位老谋深算的武林高手，面对 Keytruda 即将失去独占权、收入可能大幅缩水的危机，那是绞尽脑汁。自 2014 年 Keytruda 首次获批出道以来，默沙东一口气申请了至少 129 项专利，不过大部分都是关于药物新适应症和新配方的，药物本身倒没怎么动。 这就好比给 Keytruda 打造了一片密密麻麻的 “专利丛林”，理论上能把保护期延长到 2036 年，让对手难以近身。可这一招太狠啦，引来了美国马萨诸塞州民主党参议员伊丽莎白・沃伦办公室的调查，沃伦参议员直接炮轰默沙东拥有 “垄断力量”，这默沙东可算是惹上大麻烦了。 诺和诺德的 “专利网络”：Ozempic 的独家秘籍 另一边，诺和诺德也不甘示弱，玩起了类似的套路。为它家的重磅糖尿病药物 Ozempic 构建了一个由近二十项专利组成的复杂网络，这就像给 Ozempic 织了一张密不透风的 “专利防护网”。Ozempic 去年在最畅销药物排行榜上可是排第二呢，销售额接近 170 亿美元，而且它还有个 “马甲” 叫 Wegovy，专门用来减肥，深受爱美人士喜爱。虽说第一批核心专利 2026 年就要到期，但第二批专利能让诺和诺德在 2033 年之前继续享受独占权，稳稳拿捏市场。 历史经验：失去独占权，药物盈利能力就 “凉凉”？ 不过，历史告诉我们，失去独占权可不一定就意味着药物盈利能力的 “凉凉”。BioSpace 这会儿就像个侦探，开始研究近期重磅药物在失去专利保护前后的销售轨迹，试图在这混乱的药物世界里找到专利到期后的生存规律，看看这些药物巨头们到底能不能在专利悬崖下找到新的生机。 GSK的Advair 适应症：慢性阻塞性肺病和哮喘 最高销售额：2013年的79亿美元 专利到期年份：2010年 在20世纪90年代和2000年代，新一代哮喘和慢性阻塞性肺病治疗药物问世，勃林格殷格翰和阿斯利康凭借其吸入器在全球范围内获得了数十亿美元的销售额。然而，GSK的重磅药物Advair在2000年上市后击败了所有竞争对手，成为当时最畅销的哮喘药物。 该药物在2010年失去了专利保护，但此后仍保持了多年的稳定销售，2013年达到约52.7亿英镑（约合79亿美元）的峰值销售额。GSK的秘诀在于其用于给药的专利Diskus装置，该装置的单独专利一直保护其免受仿制药的冲击直至2019年。仿制药制造商不得不寻找自己的给药装置来与药物匹配，这在数年内被证明是相当困难的。因此，正如分析师保罗·迪格尔在2010年向路透社预测的那样，“这不会是一个典型的仿制药崩盘”，而是一个“相对缓慢的坍塌过程”。相关数据也确实证明了这一点。 艾伯维的Humira 适应症：类风湿性关节炎、银屑病、溃疡性结肠炎及其他免疫相关疾病 最高销售额：2022年的212亿美元 专利到期年份：2022年 在Keytruda创造令人震惊的数字之前，艾伯维的关节炎药物Humira一直是冠军。该药物在2008年获批后，在免疫学领域不断增加适应症，并在2022年达到超过210亿美元的峰值销售额。 该药物的原始专利本应于2016年到期，但多年来艾伯维通过申请大量专利（总计超过250项）来抵御生物类似药，这些专利涵盖了其最初的关节炎适应症之外的各种用途。这使得该药物的独占期延长至2022年，最终在美国失去了独占权。这额外的时间使艾伯维有机会推出两款后续药物：Skyrizi（艾伯维于2016年以5.95亿美元从勃林格殷格翰收购）和Rinvoq（艾伯维自主研发）。 Skyrizi和Rinvoq在2024年的总销售额约为190亿美元，几乎弥补了Humira因失去专利保护而出现的销售下滑。艾伯维预计到2027年，Skyrizi和Rinvoq的总销售额将达到270亿美元。 安进的Neulasta 适应症：化疗患者的免疫刺激 最高销售额：2013年的58亿美元 专利到期年份：2015年 安进的重磅药物Neulasta主要用于刺激化疗患者中性粒细胞的生长，在其独占期的大部分时间里一直是全球十大畅销药物之一，并且一直是安进的畅销产品之一，与安进的关节炎治疗药物Enbrel不相上下。 在2015年专利到期后，安进除了起诉潜在竞争对手Coherus（指控其挖角安进员工以获取有关Neulasta的信息）之外，并未采取任何特别的法律手段来延长该药物的生命周期。安进运气不错，因为那些竞相生产仿制药的公司难以获得FDA的批准。2018年，迈兰终于推出了一款生物类似药，抢占了安进的部分市场份额。2019年，山德士也紧随其后，进一步推动了销售额的下降。 辉瑞的立普妥 适应症：高胆固醇 最高销售额：2006年的129亿美元 专利到期年份：2011年 立普妥对心脏病学领域产生了巨大影响。其所属的他汀类药物在2019年被开具给超过8亿人，其中立普妥及其仿制药占了近3亿。在2011年失去专利后，立普妥几乎完美地从专利悬崖上跌落，仿制药在一年内立即将辉瑞的药物销售额削减了三分之二。 2020年，辉瑞将立普妥和另一款传统药物万艾可分拆到一家名为晖致的新公司，该公司在过去几年中报告称该药物的总销售额每年稳定在约4亿美元。自2011年起，辉瑞开始与沃森制药合作销售自己的立普妥仿制药。 强生的Remicade 适应症：克罗恩病、类风湿性关节炎 最高销售额：2016年的69亿美元 专利到期年份：2016年 TNFα阻断抗体Remicade是强生制药部门杨森的年年重磅药物。它是有史以来最畅销的五种药物之一，在类风湿性关节炎治疗领域，其在2016年达到峰值销售额，与Humira不相上下。 强生几乎在整个药物生命周期内都在拼命维护专利独占权并保护其利润空间。2018年，Brinks Gilson & Lione的两名律师在《国家法律评论》中写道，强生在Remicade专利方面所玩的把戏未能“改写历史”。 与此同时，辉瑞则押注该药物的专利将按计划于2018年到期，并于2016年推出了一款生物类似药。当一名法官暂时撤销Remicade的专利时，辉瑞于2017年起诉强生存在反竞争行为，该诉讼直至2021年才得以解决。最终，Remicade的专利于2018年如期到期，随后一系列额外的生物类似药进入该领域，导致Remicade的销售额暴跌。 参考资料：https://www.biospace.com/business/just-how-steep-is-the-drug-patent-cliff-ask-these-pharmas 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观不本站。

Monte Rosa Therapeutics reported Phase 1 data Thursday morning for a Novartis-partnered program that the companies believe could change the treatment paradigm for some immune-mediated diseases. Though the data come from healthy volunteers, observers are keen to see whether the program known as MRT-6160 can affect certain immunological biomarkers while remaining safe. Other drug classes targeting the immune system, particularly JAK and interleukin inhibitors, can sometimes cause taxing side effects for patients. In the Phase 1 study, researchers tested MRT-6160 in 70 individuals across five single-ascending doses and three multiple-ascending doses. The program degraded a protein called VAV1 by greater than 90% in individuals’ peripheral T cells in all but the lowest dose cohorts, according to SEC documents. The results were also dose-dependent. Monte Rosa also measured VAV1 degradation in peripheral B cells, with MRT-6160 inducing “similar” results to the T cell data — although the company did not report specific figures. On an investor call Thursday morning, Monte Rosa executives were asked how the results might translate to patients, given that the Phase 1 came from ex vivo stimulation of healthy volunteers’ blood cells. CEO Markus Warmuth said it would depend on the disease but the company is confident in how MRT-6160 hit its biomarkers. Following the Phase 1 trials, Novartis is expected to take over development and decide which diseases to test Phase 2. Preparation for Phase 2 studies is ongoing. Warmuth said the final decision on which diseases to test MRT-6160 in Phase 2 has not been made, but hinted at where Monte Rosa and Novartis see the most potential. “We had a very strong preclinical data in [ulcerative colitis], very interesting data in rheumatoid arthritis,” Warmuth said. “There’s related diseases you could think about.” MRT-6160 is designed to target VAV1, which works downstream of T cell and B cell receptors, according to Monte Rosa. The idea is to reduce cytokine proteins that fuel autoimmune conditions when modulated. The data also provide an early snapshot into the potential of molecular glues. The space has grown significantly in the last 18 months, with at least 10 licensing deals signed between biotech and pharma partners. Novartis paid Monte Rosa $150 million upfront for full rights to MRT-6160 in the largest upfront payment for a molecular glue deal in that time frame . Jefferies analyst Kelly Shi previewed the data in a Sunday note, saying the expectation heading into Thursday was VAV1 degradation of about 80%, as well as reducing certain biomarker expression by at least 70%. Such a profile, Shi wrote, could “support its early potential” in both rheumatoid arthritis and inflammatory bowel disease. The four main biomarkers Shi highlighted were CD69, IL-2, IL-6, and IL-17, with the latter three implicated in AbbVie’s JAK inhibitor Rinvoq. IL-17 in particular plays an important role in ulcerative colitis. Another experimental drug, Merck and Prometheus’ anti-TL1A program MK-7240, showed a 50% reduction in IL-17 for IBD patients in a Phase 2 study. Results from the trial showed that in CD69, MRT-6160 suppressed regulation by greater than 90% in certain doses, Monte Rosa said. The program also inhibited IL-2, IFN-γ and IL-17A “by up to 99%.” IL-6 levels were between 60% and 90%. Safety data indicated all side effects were mild or moderate. Monte Rosa’s stock price $GLUE was volatile premarket, going up about 6% and then falling as much as 16% Thursday morning. After the market opened, shares were up about 8%. Separately, Monte Rosa released new Phase 2 data for an oncology program called MRT-2359, which it is developing in-house. This molecular glue aims to degrade the GSPT1 protein in the hopes of improving outcomes for cancer patients with tumors driven by what are known as MYC transcription factors. So far, researchers tested the program in 59 patients with MYC-related malignancies. They found that, among 37 evaluable patients, MRT-2359 induced one partial response in a patient with MYC biomarkers. There was also one unconfirmed partial response in an individual who was biomarker negative. Monte Rosa is opting to deprioritize most indications. Warmuth noted on the call that the partial response occurred in a patient with neuroendocrine bladder cancer. The patient had “extremely high expression” of MYC biomarkers. The lead indication for MRT-2359 will now be castration-resistant prostate cancer, and all lung cancer work will be shelved. Monte Rosa will still enroll patients with HR+ breast cancer. Additional data will be available for both prostate and breast cancer in the second half of the year. Monte Rosa does not yet have data from prostate cancer patients, Warmuth said, because it hasn’t received clear biopsies. When the company reports data later this year, Warmuth said he hopes there will be results from 20 to 30 prostate cancer patients. Monte Rosa also reported its full-year and fourth-quarter earnings Thursday morning, saying its cash runway will extend into 2028. Editor’s note: This article was updated to include additional information from Monte Rosa’s investor call on Thursday morning.