Infliximab

Recently, Johnson & Johnson (J&J) announced an agreement with Kaken Pharmaceutical of Japan to acquire the global exclusive rights (excluding Japan) to KP-723, a preclinical STAT6 inhibitor. Under the agreement, J&J will pay $30 million upfront, with potential milestone payments of up to $1.2175 billion, and will receive single-digit to low double-digit percentage royalties on future sales of the drug. Kaken Pharmaceutical plans to initiate Phase 1 clinical trials for atopic dermatitis (AD) next year and intends to explore its application in other Th2-mediated diseases, such as asthma. J&J will be responsible for the global clinical development and commercialization of the drug. The significant investment in STAT6 inhibitors stems from their critical role in the JAK/STAT signaling pathway. STAT6, as a downstream target, primarily responds to the stimulation of cytokines IL-4 and IL-13, promoting the expression of Th2-related genes and enhancing immune responses. In diseases such as asthma and AD, the abnormal activation of STAT6 can exacerbate inflammation and worsen disease progression. STAT6 represents a "first-in-class" target for developing novel oral therapies against these diseases. However, as a transcription factor, STAT6 lacks deep binding pockets, making it challenging to develop drugs against. While early attempts at STAT6 inhibitors for autoimmune diseases often failed due to insufficient affinity, the application of PROTAC technology has provided a promising solution. Currently, the most advanced STAT6 inhibitor project is Kymera Therapeutics' KT-621, whose IND application was approved by the U.S. FDA in October this year. In vitro models have shown that KT-621 can completely block the IL-4/IL-13 pathway by degrading STAT6, with efficacy comparable to or better than the monoclonal antibody Dupilumab. Moreover, KT-621 has demonstrated nearly complete degradation of STAT6 at low oral doses and has shown good tolerability in multiple preclinical toxicity studies. Meanwhile, Sanofi is also actively investing in STAT6 inhibitors to protect its Dupilumab market share. Through partnerships with Nurix and Recludix, Sanofi is developing STAT6 protein degraders and small-molecule inhibitors, both in the preclinical stage. The STAT6 inhibitor space has become a hotspot for heavy investment by multinational pharmaceutical companies in the autoimmune field. According to Frost & Sullivan, the global autoimmune drug market is expected to reach $176 billion by 2030, with a compound annual growth rate of 3.6% from 2022 to 2030. In China, the market size is projected to reach $23.1 billion by 2030, with the share of biologics increasing from 32.9% in 2021 to 71.8% by 2030, making it a major growth driver in the global market. J&J has a rich history and extensive product portfolio in the autoimmune drug space, with flagship products like Remicade (Infliximab), Stelara (Ustekinumab), Tremfya (Guselkumab), and Simponi/Simponi Aria (Golimumab). Despite the declining sales of Remicade due to competition from biosimilars (2023 revenue: $1.839 billion), Stelara's 2023 sales exceeded $10 billion for the first time, reaching $10.858 billion, making it the core pillar of J&J's pharmaceutical business. However, Stelara faces patent expiration, with its U.S. patent expiring in September 2023, leading to a 6.6% revenue decline in Q3 2024 to $2.6 billion. Nevertheless, Tremfya, approved for treating psoriasis, received additional approval on September 11 this year for moderate-to-severe active ulcerative colitis (UC), showing potential to succeed Stelara. To solidify its leadership in the autoimmune field, J&J continues to aggressively pursue new products to replace its existing lineup. In the AD field, J&J has made two acquisitions this year, both targeting bispecific antibodies for AD treatment. It acquired Proteologix for $850 million, securing candidates like PX128 and PX130. PX128, a bispecific antibody targeting IL-13/TSLP, is about to enter Phase 1 clinical development, while PX130, targeting IL-13/IL-22, is in preclinical development for moderate-to-severe AD. J&J also entered an agreement with Numab Therapeutics to acquire Yellow Jersey Therapeutics for approximately $1.25 billion, gaining global rights to NM26, a bispecific antibody targeting IL-4Rα and IL-31 for AD. NM26 is currently in Phase 1 trials and about to enter Phase 2 development. In the psoriasis space, J&J has consistently led the way, offering products like Infliximab, Golimumab, Ustekinumab, and Guselkumab. The recent introduction of Icotrokinra (JNJ-2113), an oral IL-23R-targeting peptide licensed from Protagonist, has achieved positive results in pivotal Phase 3 trials for plaque psoriasis, marking the potential launch of the world's first selective oral IL-23 receptor inhibitor, further cementing J&J’s dominance in this space. Additionally, Nipocalimab, an FcRn-targeting monoclonal antibody acquired for $6.5 billion from Momenta, has shown breakthrough potential across various autoimmune diseases. In August 2023, J&J submitted a BLA to the FDA for treating generalized myasthenia gravis (gMG) and received BTD designation for treating Sjögren's syndrome based on the DAHLIAS Phase 2 study. Nipocalimab is projected to have a peak sales potential exceeding $5 billion, despite existing competition from Argenx and UCB in the FcRn space. As a leader in autoimmune disease therapies, J&J faces challenges such as patent expirations for key products and head-to-head competition from first-in-class rivals. However, its proactive acquisitions and investments reflect its determination to open new pathways in the autoimmune space. Whether J&J can maintain its dominant position in the coming decade remains highly anticipated.

12月26日，强生公司宣布与日本药企Kaken Pharmaceutical签订了一项独家许可协议，获得在除日本外的全球开发、制造和商业化用于自身免疫性和过敏性疾病药物KP-723的权利。Kaken将保留在日本的商业化权利，而强生可以选择与Kaken签订共同推广协议。 根据协议条款，强生将向Kaken支付3000万美元预付款、12.175亿美元里程碑金额，以及个位数至低双位数比例的销售分成。Kaken有资格获得强生创新的股权投资。 囊获新型口服STAT6抑制剂KP-723是一款新型口服STAT6抑制剂，处于临床前的在研阶段。Kaken预计将于明年开展针对特应性皮炎（AD）的1期试验，并有可能将该药应用于其他Th2介导的疾病，包括哮喘等，之后强生将在全球范围内进行临床开发和商业化。 特应性皮炎（AD）是一种慢性、复发性、炎症性皮肤病，好发于婴儿和儿童，也可发生于成人。由于患者常合并过敏性鼻炎、哮喘等其他特应性疾病，故被认为是一种系统性疾病。AD 最基本的特征是皮肤干燥、慢性湿疹样皮损和剧烈瘙痒，严重影响患者的生活质量。 数据显示，2022年全球特应性皮炎患者人数达6.8亿人，其中儿童/青少年达3.6亿人，预计到2030年达7.5亿人，其中儿童/青少年达3.8亿例。2022年我国特应性皮炎患者人数达7070万例，其中儿童/青少年达3470万例。预计到2030年达8170万人，其中儿童/青少年达3650万例。 研究发现，特应性皮炎的发病机制与多种细胞因子有关，其中IL-4和IL-13在这一过程中扮演着核心角色。 IL-4和IL-13是2型炎症反应中的关键细胞因子，它们与多种特应性疾病有关，包括AD、哮喘和慢性鼻窦炎伴鼻息肉病（CSwNP）。在AD中，IL-4和IL-13通过与2型IL-4受体（IL-4R）结合发出信号，从而介导炎症反应。它们能够诱导B细胞中免疫球蛋白类别转换为免疫球蛋白E（IgE），并通过IL-4Rα刺激传入神经元，促进瘙痒，这是特应性皮炎病理生理学的一个重要方面。此外，IL-4和IL-13还参与调节皮肤屏障功能，抑制抗菌肽的产生，进一步影响AD的病程。因此，IL-4和IL-13不仅是AD病理生理学的关键因素，也是治疗AD的重要靶点。 STAT6是IL4/IL-13信号通路唯一的特异性转录因子，也是过敏性疾病中Th2炎症的核心驱动因素，在免疫应答、炎症反应以及细胞增殖等多个生理过程中扮演关键角色。 当前，特应性皮炎等Th2介导的疾病存在大量未满足的医疗需求，KP-723的开发有望为这些患者提供新的治疗选择。作为一种口服药物，KP-723也将提供相比于注射或外用药物更为便捷的给药方式，可提高患者的依从性。 通过与Kaken的合作，强生能够利用Kaken在STAT6抑制剂领域的研发成果，加速药物的研发进度。同时，强生也是希望进一步布局STAT6，以强化其在特应性皮炎和哮喘领域的布局。 重仓自免双抗 近年来，自免药物一直是强生的核心业务，Remicade（英夫利昔单抗）、Stelara（乌司奴单抗）、Tremfya（古塞奇尤单抗）、Simponi/ Simponi Aria（戈利木单抗）等产品都为其贡献了重要的收入。 其中，英夫利昔单抗自上市以来，累计为强生贡献了超900亿美元的营收，另一款产品乌司奴单抗在2023年销售额突破百亿美元，也是强生的重磅支柱产品。 然而，这两款产品都面临专利到期问题，为了填补专利悬崖，强生也在积极寻找新的突破。 过去，强生在自免领域的研发策略主要围绕在IL-17和IL-23两个靶点上开发口服小分子药物JNJ-2113和JNJ-1459，并不断迭代疗法，从而优化患者的药物依从性。而现在，强生则开始布局双抗产品组合，以应对多重致病通路。 今年强生的两起自免并购便是从双抗切入Th2迭代赛道。今年5月，强生先后达成两笔收购，先是以8.5亿美元收购Proteologix公司，囊获多款双抗疗法，其中就包括一种靶向IL-13和TSLP的双抗PX128，该双抗即将进入针对中度至重度AD和中度至重度哮喘的I期临床开发。此外，强生还与Numab达成最终协议，以约12.5亿美元的现金，收购Numab子公司Yellow Jersey Therapeutics，获得一款治疗AD的双抗NM26的全球权利。 据不完全统计，目前强生在AD领域布局的药物约10余种。基于多个已经上市的自免产品，强生将不断扩大在此领域的优势，形成集团作战。 除了强生，赛诺菲、艾伯维、葛兰素史克、诺华、福泰制药等大药企也在重点布局自免领域。赛诺菲IL-4R（Th2）、强生IL-12/IL-23（Th17）跻身百亿美元品种，IL-17、IL-23诞生了多款重磅炸弹。葛兰素史克以14亿美元收购Aiolos获得长效TSLP抗体切入Th2赛道。赛诺菲经将自免炎症作为绝对核心，连续展开多项交易。礼来收购DICE从小分子替代角度继续布局IL-17，等等。 与此同时，国内企业也在迅猛发力。据统计，A股和H股上市近80家新药研发企业中，有43家企业均入局自免赛道。尤其是在特应性皮炎、银屑病、类风湿关节炎和系统性红斑狼疮等疾病领域，本土部分药企已取得了初步的研发成效。 随着全球自免领域的BD交易不断达成，国内自免后期管线陆续获批，自免领域的商业化新时代即将开启。未来，在新的市场起点上，谁能“弯道超车”，还待时间考验。