Acalabrutinib

iStock, leolintang Wegovy and Zepbound are just the latest drug dyads to face-off in the competitive pharma market, continuing a legacy of rivalry that includes blockbuster drugs Keytruda, Humira and Eliquis. Obesity is the most competitive space in biopharma right now. The two frontrunners, Novo Nordisk and Eli Lilly, are locked in a very tight fight for leadership in a market that by some estimates could reach a jaw-dropping $150 billion in the next few years. Novo moved first. Its GLP-1 analog semaglutide was first cleared by the FDA in 2017 as Ozempic for type 2 diabetes. Some four years later, in July 2021, semaglutide won another approval as Wegovy , this time specifically indicated for chronic weight management. Lilly’s weight-loss blockbuster tirzepatide, in comparison, is a relative late-comer, first reaching the U.S. market in 2022 as Mounjaro for type 2 diabetes Then in November 2023, the FDA approved the drug as Zepbound for obesity , setting up the head-to-head battle with Wegovy in the massive and swiftly growing weight loss market. Despite being years behind, Lilly is chipping away at Novo’s lead. Costanza Alciati, pharma analyst at GlobalData, told BioSpace in an email that tirzepatide’s efficacy edge has helped Lilly catch up. Broadly speaking, according to Alciati, the safety profiles of Zepbound and Wegovy are similar, with both drugs sharing common side effects like nausea and vomiting. Both products are also matched in terms of the route and frequency of administration. However, Zepbound’s “weight loss efficacy seems to be higher than Wegovy’s,” Alciati said, adding that “according to trials, there seems to be less muscle mass loss associated with Zepbound’s treatment than Wegovy’s.” Currently, Novo’s first-mover advantage and sprawling global footprint has allowed it to maintain a slight lead over Lilly. Last year, the Danish pharma logged roughly $26 billion in sales for Ozempic and Wegovy worldwide, while Lilly’s tirzepatide franchise brought in nearly $16.5 billion globally. But with an aggressive commercial strategy, Lilly is quickly gaining ground. “Eli Lilly’s drug has now been launched in all major markets,” Alciati said. Last month, the Indianapolis pharma launched Mounjaro in India, beating Novo to tap the market of the world’s most populous country. Aside from Wegovy and Zepbound, pharma has witnessed many other dramatic drug rivalries play out over the years, from Keytruda’s comeback and subsequent dominance over Opdivo and the burgeoning competition between Leqembi and Kisunla. In this article, BioSpace looks at some of the biggest pharma face-offs. Cancer: Merck’s Keytruda vs BMS’ Opdivo In the oncology arena, few drugs can hope to stand up against Merck’s blockbuster PD-1 inhibitor Keytruda, which has become a cornerstone of cancer care since its first approval in September 2014. As of writing, Keytruda has more than 41 approvals under its belt. These include several forms of melanoma, hepatocellular carcinoma, breast cancer and, crucially, lung cancer. For the last two years, it has also been the pharma’s top-selling product , bringing in $29.5 billion in 2024. But it wasn’t always that way. Keytruda once played second fiddle to Bristol Myers Squibb’s PD-1 blocker Opdivo. Approved in December 2014, just months behind Keytruda, Opdivo initially took a sizeable lead in the market, bringing in $942 million in 2015 versus Keytruda’s $566 million. “Initially, Bristol Myers Squibb was dominating that race,” William Blair partner Matt Phipps told BioSpace in an interview last month. “They had broader approvals and bigger indications.” Merck, according to Phipps, “completely overtook” BMS due to better trials and crucial approvals in lung cancer. Opdivo never recovered. Last year, the drug brought in $9.3 billion —less than a third of Keytruda’s sales. Still, BMS continues to carve out a cancer niche for Opdivo. In January, BMS won the race to bring a subcutaneous PD-1 treatment to the market, with the FDA signing off on a new formulation of Opdivo that can be delivered with an injection under the skin. Merck’s application for subcutaneous Keytruda is still under review. Meanwhile, an NSCLC approval in October 2024 made Opdivo the first PD-1 blocker that can be used both before and after surgery. Cardio: BMS, Pfizer’s Eliquis vs Bayer, J&J’s Xarelto Two blood thinners brought by four of the biggest pharmas are battling it out in cardiovascular disease. Bristol Myers Squibb and Pfizer’s oral anticoagulant Eliquis is the stronger competitor. Despite being approved more than a decade ago, Eliquis’ market presence continues to grow, surging 9% year-on-year to bring in $13.3 billion in 2024. Meanwhile, its closest competitor is a distant second. Though it won the FDA’s blessing a year ahead of Eliquis in 2011 , Bayer and Johnson & Johnson’s Xarelto has fallen behind its competitor in terms of market share. The drug peaked in 2021 when it earned J&J $2.44 billion in the U.S. and Bayer just over $5 billion in international markets, for a total of around $7.5 billion. Last year Bayer reported roughly $3.85 billion in international sales for Xarelto, while J&J recorded $2.37 billion in the U.S.—a total of over $6.2 billion. There are likely several reasons for why Eliquis has cleanly outperformed Xarelto, and one of them might be a question of clinical value. A 2021 study published in JAMA showed that in a Medicare population of more than 580,000 patients with atrial fibrillation, Xarelto was associated with significantly elevated risks of major ischemic or hemorrhagic events, such as fatal bleeding, as compared with Eliquis. Total mortality was also worse with Xarelto. Similarly, a 2023 study in Circulation found that Xarelto significantly heightened the risk of ischemic stroke and major bleeding versus Eliquis in patients in the Optum Clinformatics Data Mart database. There have been no well-designed and well-controlled head-to-head trials to compare the drugs. Alzheimer’s: Biogen, Eisai’s Leqembi vs Lilly’s Kisunla Decades of dispiriting clinical failures have finally produced two winners in Alzheimer’s disease. A tough market showdown has followed. In one corner is Biogen and Eisai’s embattled Leqembi and on the other is Eli Lilly’s newer challenger Kisunla. The anti-amyloid antibody Leqembi first won regulatory clearance in January 2023 under the FDA’s accelerated pathway before becoming the industry’s first fully approved Alzheimer’s therapy in July 2023. The buzz around Leqembi was strong, despite questions about the strength of the efficacy results and whether the benefits outweighed the risks. Phase III data presented in September 2022 helped revitalize the anti-amyloid theory, experts said at the time. In June 2023, an FDA advisory committee unanimously endorsed Leqembi’s full approval. Meanwhile, Kisunla’s path to approval was more fraught. In January 2023, the FDA turned down Lilly’s bid for accelerated approval, citing the need for more data from patients who had been treated for at least 12 months. The drug eventually won the regulator’s blessing in July 2024 , almost a year to the day behind Leqembi. Now, however, Leqembi’s edge doesn’t seem so large. Biogen and Eisai have struggled to get the drug off the ground and have been forced at least twice to lower their sales projection for the asset. In March, for instance, Eisai revealed that it expects Leqembi to bring in from ¥250 billion to ¥280 billion (approximately $1.7 billion to $1.9 billion) in its fiscal year 2027—a roughly 50% decline from a prior projection. For fiscal year 2024, which ends this month, the Japanese firm expects full-year sales of around $280 million for Leqembi. Lilly has already launched Kisunla in the U.S. but has yet to report sales figures. But both drugs have faced concerns about side effects called ARIA, which can signal bleeding or swelling in the brain. They have also faced slow uptake as physicians and health systems struggle to adapt to the new treatment paradigm. I&I: AbbVie’s Humira vs J&J’s Stelara Two pharma giants are duking it out in the immunology space with blockbuster drugs that are past their prime. AbbVie’s Humira was for six straight years the world’s best-selling drug. The biologic peaked in 2022 , bringing in $21.2 billion. But since losing key patent protections in 2023, its sales have declined steeply : last year, Humira made just under $9 billion . On the other hand, J&J’s Stelara never reached the same sales heights as Humira. At its peak in 2023, Stelara raked in $10.86 billion before dipping 4.6% to $10.34 billion last year. Like AbbVie’s biologic, Stelara is contending with copycat competitors. After it lost market exclusivity in 2023, several biosimilars have entered the U.S. market, including Amgen’s Wezlana and Sandoz’s Pyzchiva . Both Humira and Stelara work by tamping down the inflammatory response and share a substantial overlap in their indications, including psoriatic arthritis, plaque psoriasis, Crohn’s disease and ulcerative colitis. The specific mechanisms by which the drugs exert their therapeutic effects differ, however. Humira targets TNF-alpha, while Stelara acts on IL-12 and IL-23. All three molecules are crucial parts of the inflammatory cascade and often act synergistically, with slight differences in functionality. IL-12 and IL-23 explicitly encourage inflammation, for instance, while TNF-alpha can have both pro- and anti-inflammatory effects. In May 2021, a head-to-head study showed that despite these mechanistic nuances, Stelara and Humira are largely clinically similar. In patients with Crohn’s disease, Stelara induced a 64.9% clinical remission rate at 52 weeks, while Humira achieved a 61% remission rate at the same time point—a difference that failed to reach statistical significance. Lymphoma: AstraZeneca’s Calquence vs AbbVie’s, J&J’s Imbruvica The blood cancer field is witness to a BTK inhibitor battle between AbbVie and J&J’s Imbruvica, the first-comer, and AstraZeneca’s Calquence, which entered the ring four years later. The bad blood between the two goes way back to the biotech days, when Pharmacyclics developed what would become Imbruvica and rival Acerta Pharma championed Calquence. The rivalry was chronicled in Nathan Vardi’s book For Blood and Money: Billionaires, Biotech, and the Quest for a Blockbuster Drug . Both drugs work by blocking the Bruton’s tyrosine kinase, an enzyme that plays a crucial signaling role in the proliferation and activity of B cells. Because they share a mechanism of action, the two products also have wide overlap in their indications. Imbruvica and Calquence are both approved for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Currently, Imbruvica has a slight edge. Last year, AbbVie reported nearly $3.35 billion in worldwide sales for the drug, as opposed to Calquence’s $3.13 billion. Imbruvica also has broader coverage: Aside from the indications that it shares with Calquence, it is also approved for chronic graft versus host disease and the rare blood cancer Waldenström’s macroglobulinemia. But Calquence is quickly gaining ground. In 2024, AstraZeneca’s asset grew 24% year-on-year, while Imbruvica slid 6.9%. Calquence is also catching up clinically. A May 2024 readout showed that AstraZeneca’s drug, when combined with standard chemoimmunotherapy, can boost progression-free survival in untreated patients with mantle cell lymphoma (MCL). AbbVie and J&J had pulled Imbruvica’s accelerated approval in this indication nearly a year before. Calquence remains approved for MCL under the FDA’s accelerated pathway. Meanwhile, real-world data presented at the 2024 Congress of the European Hematology Association showed that patients with CLL or SLL who were treated with Calquence had longer time to discontinuation or death than comparators on Imbruvica. Time to next treatment was also longer in the Calquence group, as reported by OncLive at the time.

国产BTK赛道持续开大。根据百济神州的财报数据，2024年，泽布替尼的销售额达到26.44亿美元（约合192亿元人民币），同比增长105%，成为首个年销售额超百亿元人民币的国产BTK抑制剂。诺诚健华发布的2024年年度报告显示，其主打产品BTK抑制剂奥布替尼的全年销售收入首次突破十亿元大关，达到10.09亿元人民币，同比增长36.68%。01BTK抑制剂市场分析BTK（Bruton's tyrosine kinase，布鲁顿酪氨酸激酶）抑制剂是一类靶向药物，通过抑制BTK的活性来阻断B细胞受体下游信号通路，从而诱导恶性B细胞凋亡，主要用于治疗B细胞恶性肿瘤和某些自身免疫性疾病。自2013年首款药物伊布替尼问世以来，彻底改变了部分血液肿瘤和自身免疫性疾病的治疗格局。历经十余年的发展，BTK抑制剂领域涌现出多款创新药物，市场规模持续扩张，竞争格局日趋复杂。目前全球已上市多款BTK抑制剂，包括第一代不可逆的伊布替尼，第二代选择性更高的不可逆抑制剂如阿可替尼、泽布替尼和奥布替尼，以及第三代可逆的匹妥布替尼等。其中，第二代BTK抑制剂凭借更高的选择性和安全性，逐步蚕食第一代伊布替尼的市场份额。第三代可逆抑制剂的上市，为耐药患者提供了新的治疗选择。根据结合方式的不同，BTK抑制剂可分为共价不可逆抑制剂，如伊布替尼、阿可替尼和泽布替尼，通过与BTK的C481残基形成共价键，产生持久的抑制作用。非共价可逆抑制剂，如匹妥布替尼，与BTK的ATP结合位点形成非共价键，抑制作用是可逆的。这类抑制剂旨在克服共价抑制剂产生的C481突变耐药问题。目前，BTK抑制剂的临床研究不仅集中在已获批的血液肿瘤领域，还在积极探索在其他血液肿瘤和自身免疫性疾病中的应用。同时，BTK抑制剂与化疗、其他靶向药物和免疫疗法的联合治疗策略也备受关注。根据市场调研机构的数据显示，2024年，全球BTK抑制剂市场规模约为94亿美元。预计2025年将达到219亿美元，到2030年有望增长至251-289亿美元。中国BTK抑制剂市场增速更快，预计2025年将达到131亿元人民币，2030年将达到178-225亿元人民币。驱动市场增长的主要因素包括：广泛的适应症：BTK抑制剂已获批用于多种B细胞恶性肿瘤，并且在自身免疫性疾病领域展现出潜力。临床疗效显著：BTK抑制剂在许多患者中表现出良好的疗效，提高了患者的生存期和生活质量。新一代药物的上市：选择性更高、安全性更好的第二代和能够克服耐药性的第三代BTK抑制剂的推出，进一步推动了市场增长。联合治疗策略的进展：BTK抑制剂与其他疗法的联合应用有望扩大其治疗范围和提高疗效。本土创新药的崛起：以泽布替尼和奥布替尼为代表的国产创新BTK抑制剂凭借其疗效、安全性以及价格优势，迅速占领市场份额。未满足的临床需求：尽管已有药物上市，但在某些疾病亚型和耐药患者群体中，仍存在显著的未满足临床需求。同时仍存在一定的市场限制因素，包含以下几方面：药物价格和可及性：尽管医保政策有所改善，但BTK抑制剂的价格仍然较高，尤其是一些尚未纳入医保的进口药物，限制了部分患者的可及性。不良反应和安全性问题：第一代BTK抑制剂存在一定的脱靶毒性，新一代药物虽然有所改善，但仍可能出现不良反应，影响患者的耐受性和依从性。耐药性的产生：长期使用共价BTK抑制剂可能导致耐药性，特别是C481突变的发生，限制了药物的长期疗效。市场竞争加剧：随着更多BTK抑制剂和同靶点药物的上市，市场竞争日益激烈，对新进入者的市场份额构成挑战。02BTK抑制剂竞争格局分析全球BTK抑制剂市场的主要参与者包括艾伯维/强生的伊布替尼（Imbruvica），是首个上市的BTK抑制剂，拥有广泛的适应症和较长的市场积累。然而，其脱靶毒性和耐药性问题以及专利即将到期是其面临的主要挑战。阿斯利康的阿可替尼（Calquence），一种选择性更高的第二代共价BTK抑制剂，在特定适应症上展现出优势。百济神州的泽布替尼（Brukinsa），一款具有高选择性的第二代共价BTK抑制剂，在全球市场表现强劲，尤其在中国市场后来居上。礼来的匹妥布替尼（Jaypirca），首个获批的非共价可逆BTK抑制剂，为C481突变耐药患者提供了新的治疗选择。诺诚健华的奥布替尼（Orelabrutinib），一款国产第二代共价BTK抑制剂，在中国市场取得了显著的商业化成功。中国BTK抑制剂市场竞争格局正在经历深刻的变化，主要特点是本土创新药的快速崛起，其中伊布替尼最早进入中国市场，曾占据主导地位。目前，国产创新药正在强势崛起，泽布替尼和奥布替尼凭借其临床数据、价格优势以及医保支持，迅速抢占市场份额，2023年其全球销售额突破13亿美元大关，成为首个国产“十亿美元分子”。泽布替尼已在多个适应症上获得批准，并在头对头临床试验中展现出优于伊布替尼的疗效。奥布替尼在边缘区淋巴瘤等适应症上具有独特优势，并实现了快速放量。匹妥布替尼进入耐药市场，作为首个在中国获批的非共价BTK抑制剂，匹妥布替尼有望在经历过其他BTK抑制剂治疗的复发或难治性MCL患者中占据市场份额。此外，伊布替尼的专利即将到期，预计将有大量仿制药上市，进一步加剧市场竞争。国内多家药企正在积极研发新一代BTK抑制剂，未来市场竞争将更加激烈。随着BTK抑制剂市场的持续发展和竞争的加剧，未来几年将呈现以下趋势：新一代BTK抑制剂持续涌现：更多具有更高选择性、更好安全性和克服耐药性潜力的BTK抑制剂将进入市场。如蛋白水解靶向嵌合体（PROTACs）是一种新兴的药物研发策略，它通过招募E3泛素连接酶到靶蛋白附近，诱导靶蛋白的泛素化和蛋白酶体降解。BTK-PROTACs有望实现对BTK的更深层次抑制，并可能克服传统小分子抑制剂的耐药性问题。目前，一些公司正在积极探索BTK-PROTACs的研发。联合治疗成为趋势：BTK抑制剂与其他靶向药物、免疫疗法等的联合应用将成为重要的研究方向，以期提高疗效和克服耐药性。自身免疫性疾病领域潜力巨大：目前获批的BTK抑制剂主要集中在血液肿瘤领域，但在类风湿关节炎、系统性红斑狼疮等自身免疫性疾病中也显示出治疗潜力，未来有望成为新的增长点。国际化进程加速：以泽布替尼为代表的国产BTK抑制剂已开始走向国际市场，未来将有更多中国创新药参与全球竞争。结论BTK抑制剂行业正处于快速发展和变革的时期。随着对BTK在疾病发生发展中作用的深入理解和技术的不断进步，新一代BTK抑制剂和创新的治疗策略将持续涌现，为B细胞恶性肿瘤和自身免疫性疾病患者带来更多希望。市场竞争将日益激烈，但同时也为具有创新能力和差异化优势的企业提供了广阔的发展空间。期待下一个国产BTK抑制剂大药。识别微信二维码，添加抗体圈小编，符合条件者即可加入抗体圈微信群！请注明：姓名+研究方向！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点，不代表本站立场。