Iptacopan

2026年3月29日，诺华公司宣布了其口服药物Fabhalta®（iptacopan）用于治疗原发性免疫球蛋白A肾病的三期临床试验APPLAUSE-IgAN的两年最终研究结果。数据显示，与安慰剂相比，Fabhalta将患者肾功能下降速度显著减缓了49.3%，并将进展至肾脏衰竭复合终点的风险降低了43%。这些具有高度统计学显著性和临床意义的数据同步发表于国际顶级医学期刊《新英格兰医学杂志》，并在2026年世界肾脏病大会上作为最新突破性数据进行展示。基于此强劲数据，美国食品药品监督管理局已授予Fabhalta用于此适应症的优先审评资格，旨在将其目前的加速批准转为完全批准。这标志着针对IgA肾病这一长期缺乏靶向疗法的自身免疫性肾脏疾病，一种通过精准抑制补体系统来延缓疾病进展的创新治疗方案获得了坚实证据。一、 疾病背景：未被满足的巨大医疗需求 IgA肾病是一种进行性自身免疫性肾脏疾病，其病理特征为免疫球蛋白A在肾脏肾小球系膜区异常沉积，引发炎症反应，进而导致肾脏滤过单位持续受损。据文档引用数据，全球每年每百万人中约有25例新确诊患者。该疾病具有高度致残性，其导致的肾脏内部炎症、尿液中过量蛋白质（蛋白尿）以及估算肾小球滤过率的逐渐下降，共同构成了疾病进展的核心路径。 尤为严峻的是，文档指出，有多达50%的持续性蛋白尿患者会在确诊后的10至20年内进展至肾脏衰竭，从而不得不依赖长期透析或肾移植来维持生命，这为患者及其家庭带来了沉重的长期疾病管理负担。此外，IgA肾病患者还常面临精神与社会层面的多重挑战。长期以来，支持性护理（主要为降压治疗，如使用血管紧张素转换酶抑制剂或血管紧张素II受体阻滞剂）未能针对疾病根本病因，往往无法有效延缓疾病进程。因此，医学界对能够靶向疾病核心驱动因素、有效保护肾功能的新型疗法存在迫切需求。二、 药物机制：精准抑制替代补体通路 Fabhalta（iptacopan）是一种首创的口服小分子药物，其作用机制直指IgA肾病发病环节中的关键炎症通路。它是一种高选择性、高效的因子B抑制剂。因子B是补体系统替代激活途径中的关键丝氨酸蛋白酶。 在IgA肾病中，异常沉积的IgA免疫复合物可以激活补体系统，尤其是替代途径，导致膜攻击复合物的形成，从而对肾小球细胞造成直接攻击和炎症损伤，这是驱动疾病持续进展的核心机制之一。Fabhalta通过特异性抑制因子B，精准阻断补体替代途径的过度活化，旨在从源头上减少补体介导的肾脏炎症与损伤，从而有望延缓肾功能衰退的进程。这种针对特定补体通路的口服靶向治疗，为IgA肾病患者提供了一种全新的治疗选择。三、 APPLAUSE-IgAN临床试验：设计与核心数据解读 APPLAUSE-IgAN是一项全球性、随机、双盲、安慰剂对照的三期临床试验。研究入组了经肾活检确诊为IgA肾病、且在优化支持性护理后仍存在持续性蛋白尿的成年患者。患者以1:1的比例被随机分配接受Fabhalta或安慰剂治疗，并接受了长达24个月的随访观察。1. 研究终点设定 试验的主要终点是24个月期间的年度化总估算肾小球滤过率斜率。eGFR是评估肾功能的核心指标，其斜率（下降速度）是预测终末期肾脏病风险的强有力标志，斜率越平缓，意味着肾功能衰退越慢。关键次要终点包括：至首次发生复合肾脏衰竭事件的时间，以及治疗9个月时蛋白尿的变化。复合肾脏衰竭事件是一个硬终点，包含以下任一情况：相对于基线eGFR持续下降≥30%、eGFR持续低于15 mL/min/1.73 m²、开始维持性透析、接受肾移植、或因肾脏衰竭死亡。2. 两年核心疗效结果 研究达到了主要终点和所有关键次要终点，Fabhalta在所有评估的肾脏结局指标上均一致且显著地优于安慰剂。主要终点：肾功能下降速度减缓近一半 治疗24个月后，Fabhalta组患者的eGFR年平均下降速度为-3.10 mL/min/1.73 m²，而安慰剂组为-6.12 mL/min/1.73 m²。两组间的差异为3.02 mL/min/1.73 m²/年。这意味着，Fabhalta将肾功能下降的速度减缓了49.3%。这一数据从动态功能学角度证实了Fabhalta强大的肾脏保护作用。关键次要终点：显著降低进展至严重肾脏事件的风险 在为期两年的观察中，Fabhalta组有21.4%的患者经历了复合肾脏衰竭事件，而安慰剂组这一比例为33.5%。统计分析显示，Fabhalta治疗使患者发生此类事件的风险比降低了43%。这直接证明了Fabhalta能够有效延缓疾病向需要透析或移植的终末期阶段发展。蛋白尿缓解：深度且持久的达标率 蛋白尿水平是IgA肾病预后的另一重要预测指标。数据显示，在治疗两年时，有40.7%的Fabhalta治疗患者实现了24小时尿蛋白肌酐比持续低于1 g/g的深度缓解目标，而在安慰剂组中，仅有23.7%的患者达到此目标。这进一步支持了Fabhalta对肾脏病理活动的持续抑制效果。3. 安全性特征 文档指出，Fabhalta在两年治疗期间的安全性特征与既往研究结果一致。不良事件发生率及因不良事件导致的治疗中止率均较低，且在Fabhalta组与安慰剂组之间相似。最常见的不良事件主要为轻至中度感染（如COVID-19和上呼吸道感染）、头痛、腹泻和高脂血症。四、 临床意义与未来展望 APPLAUSE-IgAN研究的两年阳性结果，为Fabhalta在IgA肾病治疗中的地位提供了决定性证据。新南威尔士大学医学教授、APPLAUSE-IgAN研究指导委员会联合主席Vlado Perkovic博士评价道：“持续性肾脏炎症是IgA肾病的标志，也是疾病进展的关键驱动力。这些结果至关重要，因为它们表明Fabhalta能够降低疾病进展风险，帮助保护肾脏健康，并改善与长期疾病负担相关的结局。” 此前，Fabhalta已基于APPLAUSE-IgAN研究的预设中期分析结果，在美国和中国获得了用于减少IgA肾病患者蛋白尿的加速批准。此次公布的两年完整数据已提交给美国FDA，用于寻求将加速批准转为基于替代终点临床获益验证的完全批准。FDA授予的优先审评资格，反映了对该药物创新作用机制和数据强度的认可。 诺华全球心血管、肾脏及代谢开发负责人Ruchira Glaser博士表示：“两年的结果证明，Fabhalta能持续且有意义地延缓高危IgA肾病患者的肾功能衰退。这一进展反映了多年来专注的研究，也支持我们努力推进更靶向的治疗方案，以帮助IgA肾病患者保护肾脏健康。” 立即扫码加入药事纵横交流群

Basel, March 29, 2026 – Novartis today announced final two-year results from the Phase III APPLAUSE‑ IgAN study of Fabhalta ( iptacopan ) in IgA nephropathy (IgAN). Fabhalta demonstrated a statistically significant, clinically meaningful improvement in estimated glomerular filtration rate (eGFR) slope, a key marker of kidney function, compared with placebo 1 . Fabhalta consistently outperformed placebo across key kidney outcomes over two years, demonstrating a slowing of disease progression and the potential to preserve kidney function in IgAN 1 . Fabhalta lowered likelihood of progression to kidney failure by 43% in APPLAUSE-IgAN study 1 40.7% of patients on Fabhalta demonstrated sustained reduction of protein in urine over two years 1 Fabhalta granted priority review by FDA for traditional approval The results were published in the New England Journal of Medicine and simultaneously presented as late‑breaking data at the 2026 World Congress of Nephrology (WCN). “Persistent kidney inflammation is a hallmark of IgAN, and a key driver of disease progression, leading to ongoing kidney damage and loss of function over time,” said Vlado Perkovic, MD, Professor of Medicine and Provost, University of New South Wales, and Steering Committee Co‑Chair of the APPLAUSE‑IgAN study. “These results are important because they show that Fabhalta can reduce the risk of disease progression, help preserve kidney health, and address outcomes associated with long-term disease burden.” Key efficacy results over two years 1 Endpoint Fabhalta Placebo Effect vs. placebo Kidney function (eGFR slope) –3.10 mL/min/1.73 m²/yr –6.12 mL/min/1.73 m²/yr 3.02 mL/min/1.73 m 2 / yr (49.3% slower decline) Composite kidney failure events * † 21.4% 33.5% HR 0.57 (43% lower likelihood) Proteinuria † (24-hour UPCR <1g/g) 40.7% achieved target 23.7% achieved target — * Composite kidney failure endpoint: reaching either sustained ≥30% decline in eGFR relative to baseline, sustained eGFR <15 mL/min/1.73 m², initiation of maintenance dialysis, kidney transplant, or death from kidney failure † As measured by p ercentage of patient s “The two-year results demonstrate that Fabhalta consistently and meaningfully slows kidney function decline in high-risk patients with IgAN,” said Ruchira Glaser, MD, MS, Global Head, Cardiovascular, Renal and Metabolic Development, Novartis. “This progress reflects years of focused research and supports our efforts to advance more targeted treatment options to help preserve kidney health in people living with IgAN.” The safety profile of Fabhalta over two years was consistent with previous findings. Rates of adverse events and treatment discontinuation were low and similar between Fabhalta and placebo 1 ,2 . Fabhalta received accelerated approval in the U.S. and China for proteinuria reduction in adults with IgAN based on data from a prespecified interim analysis of the APPLAUSE-IgAN study 2,3 . The two-year data were submitted to the U.S. Food and Drug Administration for traditional approval. Fabhalta was granted priority review based on the novel mode of action and the strength of the data. Alongside Fabhalta, Novartis continues to advance its multi-asset IgAN portfolio, which also includes Vanrafia ® (atrasentan) and investigational compound zigakibart. About IgAN IgAN is a progressive autoimmune kidney disease, with approximately 25 people per million worldwide newly diagnosed each year 4,5 . IgAN is highly debilitating as it leads to inflammation in the small filters of the kidneys, excess protein in urine, and a gradual decline in eGFR 6 . Up to 50% of patients with persistent proteinuria progress to kidney failure within 10 to 20 years of diagnosis, often requiring dialysis or kidney transplantation as part of long-term disease management 5-10 . Furthermore, people living with IgAN often face mental and social challenges 6 - 9 . Supportive care has not addressed the underlying causes of the disease and often fails to slow disease progression, reinforcing the need for more targeted therapies for IgAN 7 -1 2 . About APPLAUSE-IgAN APPLAUSE-IgAN (NCT04578834) is a global, randomized, double-blind, placebo-controlled Phase III study evaluating Fabhalta in adults with biopsy-confirmed IgAN and persistent proteinuria despite optimized supportive care. Patients were randomized 1:1 to receive Fabhalta or placebo and were followed for up to 24 months 1 1 . The primary endpoint was the annualized total eGFR slope over 24 months. Key secondary endpoints included time to first composite kidney failure event and changes in proteinuria over 9 months 1 . The most common adverse events with Fabhalta were mainly mild-to-moderate infections (such as COVID-19 and upper respiratory tract infection), headache, diarrhea, and hyperlipidemia, with overall adverse event rates comparable to placebo 1 . About Fabhalta ® (iptacopan) Fabhalta (iptacopan) is an oral Factor B inhibitor designed to selectively target the alternative complement pathway, one of several key drivers of inflammation and kidney damage in IgAN 4 ,12,13 . By inhibiting Factor B, Fabhalta aims to reduce ongoing complement-mediated injury and slow disease progression. Fabhalta has received regulatory approvals in multiple complement-mediated diseases, including IgAN, and is being evaluated across a range of rare kidney conditions. Novartis’ commitment to kidney diseases Building on a legacy of more than 40 years that began in transplant, Novartis is on a mission to empower breakthroughs and transform care in kidney health, starting with kidney conditions that have significant unmet need. Historically, these conditions have had considerably less funding and research, leading to a treatment landscape largely focused on reactive or end-stage disease management, often with significant physical, emotional, and financial burdens. Our portfolio targets the underlying causes of disease, with an aim to protect kidney health and delay or prevent dialysis and/or transplantation. Our goal is to help patients get back to living life on their terms - whether at work, in school, or with loved ones, and by partnering with patients, advocates, clinicians and policymakers, we aim to raise awareness, accelerate diagnosis, and get patients the right care, sooner. Disclaimer This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. 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In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise. About Novartis Novartis is an innovative medicines company. Every day, we work to reimagine medicine to improve and extend people’s lives so that patients, healthcare professionals and societies are empowered in the face of serious disease. Our medicines reach more than 300 million people worldwide. Reimagine medicine with us: Visit us at https://www.novartis.com and connect with us on LinkedIn , Facebook , X/Twitter and Instagram . References Novartis. Data on file Novartis Pharmaceuticals Corporation. Novartis receives FDA accelerated approval for Fabhalta ® (iptacopan), the first and only complement inhibitor for the reduction of proteinuria in primary IgA nephropathy (IgAN) (2024). Available at: https://www.novartis.com/news/media-releases/novartis-receives-fda-accelerated-approval-fabhalta-iptacopan-first-and-only-complement-inhibitor-reduction-proteinuria-primary-iga-nephropathy-igan . Accessed March 2026 Novartis China. Novartis’ innovative medicine Fabhalta ® (iptacopan) approved in China for a new indication. Novartis China website (in Mandarin). Available at: https://www.novartis.com.cn/news/nuohuazaiyingshenzangjibingzhiliaolingyulichengbeichuangxinyaowufeihedayansuanyipukepanjiaonangigashenbingshiyingzhengzaizhongguohuopi . Accessed March 2026 Rizk DV, Maillard N, Julian BA, et al. The emerging role of complement proteins as a target for therapy of IgA nephropathy. Front Immunol 2019;10:504. Cheung C, Barratt J. The rapidly changing treatment landscape of IgA nephropathy. Semin Nephrol . 2025;44:151573. Kwon CS, Daniele P, Forsythe A et al. A systematic literature review of the epidemiology, health-related quality of life impact, and economic burden of immunoglobulin a nephropathy. J Health Econ Outcomes Res . 2021;8:36–45. Pitcher D, Braddon F, Hendry B et al. Long-term outcomes in IgAN. Clin J Am Soc Nephrol . 2023;18:727–8. Mohd R, Mohammad Kazmin NE, Abdul Cader R, et al. Long-term outcome of immunoglobulin A (IgA) nephropathy: a single center experience. PLoS One . National Kidney Foundation. The voice of the patient (2020). Available at: https://igan.org/wp-content/uploads/2021/01/VOP_IgAN_12-7-20__FNL.pdf . Accessed March 2026. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int . 2021;100:S1–276. Clinicaltrials.gov. NCT04578834. Study of Efficacy and Safety of LNP023 in Primary IgA Nephropathy Patients (APPLAUSE-IgAN). Available at: https://clinicaltrials.gov/study/NCT04578834 . Accessed March 2026. Perkovic V, Barratt J, Rovin B, et al. Alternative complement pathway inhibition with iptacopan in IgA nephropathy. N Engl J Med . 2025;392:531–543. Chiu YL, Lin WC, Shu KH, et al. Alternative complement pathway is activated and associated with galactose-deficient IgA(1) antibody in IgA nephropathy patients. Front Immunol 2021;12:638309. Source: Novartis