Ranibizumab (Genentech)

Despite a 108% increase in sales from its blockbuster macular degeneration drug Vabysmo, Roche saw a 6% slide in revenue in the first quarter, credited largely to a decrease in sales of COVID products. It’s been eight months since Regeneron secured approval for a high-dose version of its powerhouse macular degeneration treatment Eylea in the U.S. So how much impact has souped-up Eylea had on the upward trajectory of Roche’s Vabysmo, which was approved 19 months earlier as a longer-acting challenger? Not much, according to sales figures released by Roche on Wednesday morning. In the first quarter of 2024, Vabysmo racked up revenue of 847 million Swiss francs ($927 million), which was up 108% year over year and demolished the analyst consensus of 750 million Swiss francs. It also was a huge leap sequentially from sales of 594 Swiss francs in the fourth quarter of last year. Regeneron and Bayer have yet to report their first-quarter results. Bayer got high-dose Eylea approved in EU in early January. In February, Regeneron reported that Eylea U.S. sales fell from $6.3 billion in 2022 to $5.9 billion in 2023, with high-dose Eylea accounting for $166 million in sales over the last four months of the year. Back then, Regeneron also said that it didn’t expect to see a sales surge for Eylea HD in the first quarter because its permanent J-code would not kick in until April 1. J-codes are part of an identifying system that allows pharmacies, hospitals and physicians to bill for medications, and getting it can be an important step for drug reimbursement.  In a conference call on Wednesday, Roche’s pharma CEO Teresa Graham said the company has not seen any sales impact on Vabysmo since the start of this month. Roche pointed to a network meta-analysis comparing results from seven trials of Vabysmo and Eylea which included more than 5,000 patients and concluded that Vabysmo produced more reduction in central subfield thickness in both age-related macular degeneration (AMD) and diabetic macular edema (DME). “This analysis adds to the growing body of evidence that Vabysmo’s unique [mechanism of action] leads to the superior anatomical outcomes in the drying of eyes, supporting Vabysmo is the preferred choice for first-line treatment in AMD and DME,” Graham said. Graham added that real-world data studies that included more than 50,000 Vabysmo patients will validate Vabysmo’s credentials as “a standard of care,” in AMD and DME. The company will present those results next week in Seattle at the Association for Research in Vision and Ophthalmology conference. Vabysmo continued to grow its market share in the U.S. to 25% in AMD and 18% in DME, which is an increase of 3 percentage points from the previous quarter in both indications, Roche said. Additionally, Vabysmo also has already grabbed an 8% share of the retinal vein occlusion market since the FDA signed off on the label expansion in October of last year. Roche added that more than 40% of Vabysmo patients are new to eye treatments, compared to a 10% figure for treatment-naïve patients in the first quarter of last year. The company is targeting Q3 to re-launch wet AMD treatment Susvimo. The medicine approved for use in Susvimo is a customized formulation of ranibizumab, but at a different concentration than what is used for eye injections with Lucentis (ranibizumab injection). Additionally, in the second half of this year, Roche hopes to file for diabetic macular edema and diabetic retinopathy as new indications for Susvimo which was originally approved in October of 2021 but recalled by the company a year later because of a leakage issue. Overall, for the first quarter, Roche reported sales of 14.4 billion Swiss francs ($15.8 billion), which was a 6% decline from revenue of 15.3 billion Swiss francs ($16.8 billion) in the first quarter of 2023 and a 2% drop sequentially. Roche blamed the declines on the loss of revenue from its COVID-19 products but CEO Thomas Schinecker said that those effects will end in the second quarter, setting the company up for a return to revenue growth. Excluding COVID products, Roche’s sales were up 7% in the quarter, supporting the company’s guidance to mid-single-digit growth in 2024, which the company confirmed on Wednesday. Roche’s top product, multiple sclerosis treatment Ocreuvus, rang up sales of 1.66 billion Swiss francs ($1.82 billion) in the quarter,  good for 8% growth year over year. With an approval expected for its injectable version of Ocrevus, Roche expects a blockbuster-sized bump in sales, “upwards of the $2 billion range,” Graham said. Making major sales gains in the period were blood cancer treatment Polivy, which was up 70% year-over-year to 387 million Swiss francs ($424 million) and breast cancer drug Phesgo, which increased sales 81% to 249 million Swiss francs ($273 million). Polivy was approved in 2019 and Phesgo made the grade in 2020.

2024年2月1日，默沙东公布2023年业绩，其当家花旦Keytruda（帕博利珠单抗，俗称K药）迎来历史性高光时刻，全年营收250.11亿美元，荣登2023年“药王”宝座。不过默沙东并非高枕无忧。一方面，诺和诺德的司美格鲁肽2023年销售额已达212亿美元，且增长势头强劲，未来极有可能超越K药成为新药王。另一方面，K药的一些关键专利将在2028年到期，目前其生物类似药来势汹汹，布局厂家不乏安进、山德士等巨头。内忧外患下，K药有可能成为史上“最短命药王”。那么，默沙东为保卫K药做了哪些尝试？虎视眈眈的生物类似药据不完全统计，目前已有近10家药企的K药生物类似药进入临床试验阶段，最快的已进入III期临床。今年3月15日，安进在Clinicaltrials.gov网站上注册了K药生物类似药ABP 234的III期临床试验。该研究计划入组927例晚期或转移性非鳞状非小细胞肺癌（NSCLC）患者，预计2027年10月完成。无独有偶，去年12月1日，仿制药巨头山德士登记了一项K药生物类似药GME751与K药的头对头临床试验，将在需要K药辅助治疗的已切除晚期黑色素瘤患者中对GME751与K药进行比较。同年12月7日，山德士再次登记了一项GME751的III期头对头试验，该试验旨在比较GME751和K药在未经治疗的转移性非鳞状NSCLC患者中的有效性、安全性和免疫原性。试验计划入组720例患者，按1:1的比例随机接受GME751或K药联合化药治疗。以上两项试验均预计将于2026年完成。另外，三星Bioepis也加入了K药生物类似药的竞争行列。三星Bioepis原由三星生物与渤健公司共同成立，后渤健公司将三星Bioepis股权出售给三星生物。三星Bioepis主要聚焦于生物类似药研发，目前产品已经覆盖依那西普、英夫利西单抗、阿达木单抗、曲妥珠单抗、贝伐珠单抗、雷珠单抗等6大品类。今年2月21日，三星Bioepis宣布启动K药生物类似药SB27的I期临床试验，旨在比较SB27与K药在完全切除和辅助铂类化疗后的II-IIIA期NSCLC患者中的药代动力学、疗效、安全性等。视线回到国内，今年2月底，百奥泰在Clinicaltrials.gov网站上注册了K药生物类似药BAT3306一线治疗非鳞状NSCLC的III期临床试验，计划入组676例NSCLC患者，试验主要终点包括药代动力学、临床等效性等，预计将于2027年初步完成该试验。去年12月，齐鲁制药也在Clinicaltrials.gov网站上注册了其K药生物类似药QL2107的I期临床试验，该试验计划入组168例健康志愿者，预计2024年6月完成。除此之外，复宏汉霖也申报了K药类似药HLX17的临床试验。目前无论是海外还是国内，盯着K药生物类似药的企业都不在少数。倘若未来几年生物类似药产品顺利上市，K药的市场份额将很快被蚕食，K药保卫战迫在眉睫。那么为保药王之位，默沙东做了哪些尝试？拓展适应症事实上，自2014年K药首次获FDA批准以来，默沙东一直不曾停下拓展其适应症的脚步。截至目前，K药已在美国获批约40项适应症，覆盖黑色素瘤、肺癌、肝癌、头颈癌等多个瘤种，在中国也获批十余项适应症。K药在国内获批的适应症来源：公开资料打造K药基石属性，探索联合治疗模式在拓展适应症过程中，联合疗法是重要维度。据悉，默沙东在高达1600多项临床试验中研究K药联合各种治疗方案在不同瘤种中的作用，包括与溶瘤病毒、ADC、mRNA肿瘤疫苗等的联合使用。2020年7月，默沙东与溶瘤病毒领域明星公司Oncorus开展临床试验合作，以评估Oncorus的ONCR-177联合K药治疗晚期和/或难治性皮肤、皮下或转移性淋巴结实体瘤患者的效果。不过该联用疗法的I期临床试验结果并不尽如人意，随后该管线被砍。在与ADC联合方面，K药联合安斯泰来的靶向Nectin-4 ADC产品维恩妥尤单抗（Padcev），在一线治疗尿路上皮癌中降低53%的死亡风险，佐证了K药与ADC联合的效果。目前，该联合方案用于一线治疗局部晚期或转移性尿路上皮癌（la/mUC）的补充生物制品许可申请（sBLA）获FDA优先审评，PDUFA日期为2024年5月9日。由于ADC联用可成为K药的强力辅助，因此默沙东将重金砸向ADC领域。于是就有了默沙东与科伦博泰的3次牵手，以及与第一三共220亿美元的合作。围绕ADC，默沙东共达成了8项交易。日前，默沙东在Clinicaltrials.gov网站上注册了两项MK-2870的全球III期临床试验，分别用来评估MK-2870单药或联用K药在特定类型乳腺癌和NSCLC患者中的疗效。MK-2870是科伦博泰研发的一款靶向Trop2的ADC 产品，由靶向Trop2的人源化单克隆抗体、可酶促裂解的连接子和新型拓扑异构酶I抑制剂组合而成。此次注册的两项临床试验分别是将MK-2870与K药联用头对头对比K药，用于辅助治疗既往接受新辅助K药与含铂双药化疗且手术后未达到病理完全缓解的NSCLC患者（可切除的II期-IIIB期），计划入组780例患者，预计2034年2月初步完成。另一项研究则是评估MK-2870单药或联合K药治疗局部晚期或转移性HR+/HER2-乳腺癌的全球Ⅲ期临床试验，计划入组1200例患者，预计在2027年7月初步完成。除了上述两项联用疗法外，K药还与吉利德的Trop2 ADC Trodelvy联用开展一线治疗三阴性乳腺癌（TNBC）和NSCLC的临床试验。2022年，K药又再次联手阿斯利康/第一三共的Trop2 ADC DS-1062（Dato-DXd），冲击PD-L1低表达NSCLC。值得一提的是，这些研究的对照组均为K药单药。未来K药将与ADC擦出什么样的火花，值得期待。在与mRNA肿瘤疫苗联用方面，2023年12月，默沙东宣布启动III期INTerpath-002研究，该研究旨在评估Moderna的肿瘤mRNA疫苗mRNA-4157联合K药辅助治疗完全切除的II、IIIA或IIIB期NSCLC患者的有效性与安全性。mRNA独有的优势在肿瘤领域极具想象空间，与K药联合，或许可成为下一个癌症治疗范式。除此之外，肿瘤电场、TIL（肿瘤浸润淋巴细胞疗法）、微生物、CAR-M（嵌合抗原受体巨噬细胞）等前沿疗法也出现在K药联用方案中。向疾病早期迈进，加注辅助治疗赛道2023年10月，默沙东发布了K药在早期NSCLC治疗的III期临床数据。在这项名为KEYNOTE-671的III期临床试验中，K药用于可切除的II期、IIIA 期或IIIB期NSCLC围手术期治疗达到了主要终点OS。基于此项研究，FDA批准了K药与含铂化疗联用作为术前新辅助治疗，并在术后单药作为辅助治疗，用于治疗可切除NSCLC患者。此外，默沙东还在黑色素瘤、肾细胞癌、TNBC等领域进一步探索K药早期治疗的潜力。K药迈入疾病早期阶段，预示着其适应症范围进一步扩大。如今看来，默沙东已把持续拓宽K药联用疗法，作为K药破局的“利器”。最终能在多大程度上延长K药的生命周期，仍待观察。总之，K药的卫冕之路仍任重道远。参考来源1.clinicaltrials.gov2.医麦客《默沙东K药的“药王保卫战”：物尽其用、联合百搭》3.FDA grants priority review to Merck’s application for Keytruda plus Padcev (enfortumab vedotin-ejfv) for the first-line treatment of patients with locally advanced or Metastatic Urothelial Cancer.4.新康界《准药王”突围战：默沙东“K药”推进早期肺癌治疗》