Pemigatinib

2025年6月16日，美国旧金山和中国苏州——信达生物制药集团（香港联交所股票代码：01801），一家致力于研发、生产和销售用于治疗肿瘤、自免、代谢、眼科等重大疾病领域创新药物的生物制药公司，宣布：胰高血糖素（GCG）/胰高血糖素样肽-1（GLP-1）双受体激动剂玛仕度肽在中国患有中重度阻塞性睡眠呼吸暂停（OSA）且肥胖（BMI≥28kg/m2）的受试者中完成首例受试者给药。这也是玛仕度肽开展的第七项III期临床研究，持续探索其在肥胖及一系代谢相关综合症管理中的潜力，为临床应用提供更全面完整的高质量循证医学证据。本研究是一项在中国患有中重度阻塞性睡眠呼吸暂停（OSA）且肥胖（BMI≥28kg/m2）受试者中比较玛仕度肽9mg与安慰剂的有效性和安全性的多中心、随机、开放标签的III期临床研究（NCT06931028）。研究的主要终点是第48周时呼吸暂停低通气指数（AHI）自基线变化的幅度。全球30岁至69岁人群中约有4.25亿人群患有中重度OSA，其中中国受影响人数最多，约有6,600万中重度OSA患者1。中国OSA诊断率不足1%，美国也仅有20%的诊断率2,3。OSA在肥胖人群中的患病率约为40%，在接受减重手术的人群中OSA 患病率高达80.5%4,5。OSA与各种不良心血管疾病事件（CVD）的发生密切相关，诸如高血压、心律失常、卒中、代谢综合征等，并发症的负担随着OSA严重程度而逐渐增加6,7。气道正压通气（PAP）是OSA的一线治疗手段，虽然许多患者能从中获得显著获益，但仍有部分患者因治疗负担难以坚持或完全拒绝使用PAP。尽管PAP治疗可改善OSA症状，但现有证据并不充分支持其对心脏代谢结局（死亡率、高血压、心肌梗死、卒中）的长期益处8。GLP-1/GIP双受体激动剂替尔泊肽（Zepbound®）已经于2024年12月在美国获批，是首个也是唯一用于治疗中重度阻塞性睡眠呼吸暂停（OSA）合并肥胖症成人患者的处方药9，但目前国内尚无治疗OSA具有明确疗效的药物1。因此，在OSA治疗领域仍存在巨大的未满足的医学需求。相关文献提示10,11,12，体重减轻10%可预测AHI下降26%，BMI每降低1个单位可预测AHI就会降低2、3个单位。因此，以GLP-1类为代表的减重药物治疗，在治疗OSA将有较大的空间和潜力。本项研究的主要研究者北京大学第三医院洪天配教授表示：“未治疗的OSA患者发生心血管疾病、代谢性疾病、神经认知障碍以及交通事故的风险显著增加，且OSA患者的劳动能力和生活质量明显下降。这部分患病人群在肥胖患者中所占的比例相当高，且呈持续增加趋势，但目前国内缺乏有效的药物治疗方案13。玛仕度肽在III期研究GLORY-114中展现出强大的减重疗效及多重心血管代谢改善，且安全性良好，有望成为全球首个针对OSA合并肥胖人群的GCG/GLP-1双靶药物。我将与GLORY-OSA的所有研究者一起同心协力推进并高质量完成此项研究，在获得高质量的临床研究证据的同时，为中国中重度OSA合并肥胖人群提供更优的治疗选择。”信达生物制药集团临床开发高级副总裁钱镭博士表示：“我们开发玛仕度肽不同剂量和给药方案，为不同适应症的患者群体提供更理想的治疗选择。玛仕度肽在OSA适应症的开发针对中国BMI在28 kg/m2以上的中重度OSA患者的治疗需求，在肥胖患者群体的II期研究中，玛仕度肽9 mg治疗48周取得了相较安慰剂18.6%的体重降幅和多项心血管代谢获益，且安全性好，滴定步骤简捷。我期待玛仕度肽在GLORY-OSA研究中充分展现其强大的疗效和良好的安全性，尽快为中重度OSA合并肥胖患者带来相比PAP更理想的药物治疗选择和安全有效的长期管理方案。” 关于玛仕度肽（IBI362）- 滑动查看更多介绍 -玛仕度肽（IBI362）是信达生物与礼来制药共同推进的一款GCG/GLP-1双受体激动剂。作为一种哺乳动物胃泌酸调节素（OXM）类似物，玛仕度肽除了通过激动GLP-1R促进胰岛素分泌、降低血糖和减轻体重外，还可通过激动GCGR增加能量消耗增强减重疗效，同时改善肝脏脂肪代谢。玛仕度肽已在多项临床研究中展现出优秀的减重和降糖疗效，以及降低腰围、血脂、血压、血尿酸、肝酶及肝脏脂肪含量，以及改善胰岛素敏感性，带来多重代谢获益。 玛仕度肽当前共有两项NDA获NMPA受理审评，包括： 用于成人肥胖或超重患者的长期体重控制； 用于成人2型糖尿病患者的血糖控制。 玛仕度肽当前共开展了七项III期临床研究，包括： 在中国超重或肥胖受试者中开展的III期临床研究（GLORY-1）； 在中国中重度肥胖受试者中开展的III期临床研究（GLORY-2）； 在中国超重或肥胖合并MAFLD受试者中开展的对比玛仕度肽和司美格鲁肽的III期临床研究（GLORY-3）; 在中国OSA合并肥胖受试者中开展的III期临床研究（GLORY-OSA）;在初治的中国2型糖尿病患者中开展的III期临床研究（DREAMS-1）； 在口服药物治疗血糖控制不佳的中国2型糖尿病受试者中开展的对比玛仕度肽和度拉糖肽的III期临床研究（DREAMS-2）； 在中国2型糖尿病合并肥胖的受试者中开展的对比玛仕度肽和司美格鲁肽的III期临床研究（DREAMS-3）。 其中，GLORY-1、DREAMS-1和DREAMS-2研究均已达成终点，另外四项研究进行中。 此外，玛仕度肽的多项新临床研究正在进行中或计划启动，其中包括治疗青少年肥胖的III期临床研究，以及治疗代谢相关脂肪性肝炎（MASH）、射血分数保留心力衰竭（HFpEF）、更高剂量头对头替尔泊肽治疗中重度肥胖等新临床研究。 关于信达生物- 滑动查看更多介绍 -“始于信，达于行”，开发出老百姓用得起的高质量生物药，是信达生物的使命和目标。信达生物成立于2011年，致力于研发、生产和销售肿瘤、自身免疫、代谢、眼科等重大疾病领域的创新药物，让我们的工作惠及更多的生命。公司已有15个产品获得批准上市，它们分别是信迪利单抗注射液（达伯舒®），贝伐珠单抗注射液（达攸同®），阿达木单抗注射液（苏立信®），利妥昔单抗注射液（达伯华®），佩米替尼片（达伯坦®），奥雷巴替尼片（耐立克®），雷莫西尤单抗注射液（希冉择®），塞普替尼胶囊（睿妥®），伊基奥仑赛注射液（福可苏®），托莱西单抗注射液（信必乐®）, 氟泽雷塞片（达伯特®），匹妥布替尼片（捷帕力®），己二酸他雷替尼胶囊（达伯乐®）和利厄替尼片（奥壹新®）和替妥尤单抗N01注射液（信必敏®）。目前，同时还有3个品种在NMPA审评中，4个新药分子进入III期或关键性临床研究，另外还有15个新药品种已进入临床研究。公司已与礼来、罗氏、赛诺菲、Incyte和MD Anderson癌症中心等国际合作方达成30多项战略合作。信达生物在不断自研创新药物、谋求自身发展的同时，秉承经济建设以人民为中心的发展思想。多年来，始终心怀科学善念，坚守“以患者为中心”，心系患者并关注患者家庭，积极履行社会责任。公司陆续发起、参与了多项药品公益援助项目，让越来越多的患者能够得益于生命科学的进步，买得到、用得起高质量的生物药。截至目前，信达生物患者援助项目已惠及20余万普通患者，药物捐赠总价值36亿元人民币。信达生物希望和大家一起努力，提高中国生物制药产业的发展水平，以满足百姓用药可及性和人民对生命健康美好愿望的追求。详情请访问公司网站：www.innoventbio.com或公司领英账号：Innovent Biologics。声明：1.信达不推荐任何未获批的药品/适应症使用。2.雷莫西尤单抗注射液（希冉择®），塞普替尼胶囊（睿妥®）和匹妥布替尼片（捷帕力®）由礼来公司研发。前瞻性声明本新闻稿所发布的信息中可能会包含某些前瞻性表述。这些表述本质上具有相当风险和不确定性。在使用“预期”、“相信”、“预测”、“期望”、“打算”及其他类似词语进行表述时，凡与本公司有关的，均属于前瞻性表述。本公司并无义务不断地更新这些预测性陈述。这些前瞻性表述是基于本公司管理层在做出表述时对未来事务的现有看法、假设、期望、估计、预测和理解。这些表述并非对未来发展的保证，会受到风险、不确性及其他因素的影响，有些是超出本公司的控制范围，难以预计。因此，受我们的业务、竞争环境、政治、经济、法律和社会情况的未来变化及发展的影响，实际结果可能会与前瞻性表述所含资料有较大差别。本公司、本公司董事及雇员代理概不承担 (a) 更正或更新本网站所载前瞻性表述的任何义务;及 (b) 若因任何前瞻性表述不能实现或变成不正确而引致的任何责任。参考文献：1.Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med. 2019;7(8):687-698. doi:10.1016/S2213-2600(19)30198-52.Zhang Y, et al. Underdiagnosis of Sleep Apnea in China: A Call for Public Health Action. Chest. 2022;161(2):418-426.3.Kapur VK, et al. Underdiagnosis of Sleep Apnea in U.S. Adults. Am J Respir Crit Care Med. 2017;196(3):285-286.4.成人阻塞性睡眠呼吸暂停高危人群筛查与管理专家共识.中华健康管理学杂志, 2022,16(8) : 520-528.5.成人阻塞性睡眠呼吸暂停基层诊疗指南. 中华全科医师杂志，January 2019, Vol. 18, No.16.肖毅. 中华结核和呼吸杂志, 2019,42(8) : 561-563.  7.Alakörkkö I, et al. The economic cost of obstructive sleep apnea: A systematic review. Sleep Med Rev. 2023 Dec;72:101854.8.Malhotra A, Bednarik J, Chakladar S, et al. Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial. Contemp Clin Trials. 2024;141:107516. doi:10.1016/j.cct.2024.1075169.https://lilly.mediaroom.com/2024-12-20-FDA-approves-Zepbound-R-tirzepatide-as-the-first-and-only-prescription-medicine-for-moderate-to-severe-obstructive-sleep-apnea-in-adults-with-obesity10.Araghi MH, et al. Sleep. 2013 Oct 1;36(10):1553-62, 1562A-1562E.11.Peppard PE, et al. JAMA. 2000 Dec 20;284(23):3015-21.12.Romero-Corral A, et al. Chest. 2010 Mar;137(3):711-9.13.Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004–1814.Ji L, et al. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight. N Engl J Med. 2025 Jun 12;392(22):2215-2225. doi: 10.1056/NEJMoa2411528.

The fibroblast growth factor receptor (FGFR) family consists of transmembrane receptor tyrosine kinases that regulate a broad range of biological processes, including embryonic development, wound healing, and angiogenesis. Upon binding of FGFs (fibroblast growth factors) to their corresponding FGFRs, downstream signaling pathways—such as RAS-RAF-MAPK, PI3K-AKT/mTOR, STATs, and PLCγ/PKC—are activated, orchestrating cellular proliferation, survival, migration, and differentiation. In oncology, aberrant activation of FGFR signaling is considered a key oncogenic driver, with FGFR alterations identified in approximately 7% of human cancers. These alterations contribute to uncontrolled cell behavior and disease progression, making small-molecule FGFR inhibitors a hot area of research in targeted cancer therapy. Biological Functions of FGFR SignalingThe FGFR family comprises four highly conserved transmembrane receptor tyrosine kinases—FGFR1 through FGFR4. Upon ligand binding with specific FGFs, these receptors form ternary complexes that initiate complex intracellular signaling cascades. FGFRs play crucial roles in morphogenesis during embryogenesis and are also involved in adult tissue repair, angiogenesis, and the maintenance of stem cell pluripotency, thus serving as a vital bridge between normal physiology and disease states. Mechanisms of oncogenic fibroblast growth factor receptor signalling1Upon FGF-FGFR interaction, multiple downstream signaling pathways are activated. These include: ·RAS-RAF-MAPK, primarily driving mitogenic signaling; ·PI3K-AKT/mTOR, which promotes cell survival and metabolic regulation; ·STATs, acting as transcription factors that modulate gene expression in response to extracellular stimuli and participate in immune and inflammatory responses; ·PLCγ/PKC, which regulate calcium signaling and cytoskeletal remodeling, essential for cell motility and morphological changes. Structure of fibroblast growth factor receptor1While FGFR signaling maintains homeostasis under physiological conditions, dysregulation due to genetic mutations or environmental stress can lead to pathological consequences. In cancer, FGFR pathway dysregulation is recognized as a major oncogenic mechanism. Alterations—including gene amplification, point mutations, and chromosomal rearrangements—are found in about 7% of human cancers. These result in elevated FGFR expression or constitutive activation, driving uncontrolled proliferation, apoptosis resistance, invasiveness, and metastatic potential. FGFR signaling is also implicated in promoting epithelial–mesenchymal transition (EMT), a process contributing to cancer cell migration and therapy resistance. Therapeutic Strategies Targeting FGFR PathwaysGiven its pivotal role in various cancers, the FGFR signaling pathway has become a prominent target for therapeutic intervention. Several selective FGFR tyrosine kinase inhibitors (TKIs) have progressed into clinical trials and demonstrated promising anti-tumor efficacy. For instance, Erdafitinib became the first FDA-approved FGFR inhibitor for the treatment of locally advanced or metastatic urothelial carcinoma harboring specific FGFR2 or FGFR3 mutations. A number of other selective FGFR inhibitors are also in various stages of development, aiming to provide more precise and tolerable alternatives to conventional chemotherapy. Beyond direct inhibition, combination therapies targeting FGFR signaling alongside other pathways are under active investigation to enhance efficacy and delay resistance. Mechanisms of resistance to fibroblast growth factor receptor inhibitors1Mutations or overexpression of FGFR genes result in hyperactivation of the FGFR signaling cascade, promoting tumorigenesis. These genetic alterations—such as amplifications, point mutations, or rearrangements—lead to elevated FGFR protein levels or constitutive signaling activity, fueling malignant behaviors like proliferation, survival, invasion, metastasis, and therapy resistance. According to an analysis of 4,853 solid tumor samples, FGFR alterations were identified in 7.1% of cases. Among these: ·Gene amplification was the most prevalent form (66%), ·Followed by point mutations (26%), ·And chromosomal rearrangements (8%). FGFR1 aberrations were the most common, accounting for approximately 49% of all FGFR alterations, followed by FGFR3 (26%), FGFR2 (19%), and FGFR4 (7%). These findings underscore the relevance of FGFR-targeted therapies in precision oncology across multiple tumor types. Research and Development Progress of FGFR InhibitorsGiven the critical role of the FGFR signaling pathway in tumorigenesis, scientists have been actively engaged in the development of FGFR inhibitors. These inhibitors are typically highly selective and specific, designed to precisely block the aberrant signaling mediated by FGFR while minimizing effects on non-target tissues. Currently, several selective FGFR inhibitors have entered clinical trials, and some have even received regulatory approval. 1. ErdafitinibErdafitinib (brand name Balversa) is the first selective pan-FGFR inhibitor approved by the U.S. Food and Drug Administration (FDA). It is specifically indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) harboring specific FGFR3 or FGFR2 mutations. These patients often experience disease progression during or after platinum-containing chemotherapy, indicating poor response or acquired resistance to standard therapies. As an oral medication, erdafitinib effectively targets and inhibits the activity of FGFR1 through FGFR4, thereby counteracting abnormal cell proliferation and survival driven by dysregulated FGFR signaling. The mechanism of action of erdafitinib involves its specific binding to the ATP-binding pocket of FGFR family kinases, thereby inhibiting the functions of these receptor tyrosine kinases. When the FGFR signaling pathway is aberrantly activated due to genetic mutations or other causes, it can promote tumor cell growth, survival, and migration. By blocking this abnormal signaling, erdafitinib helps to slow or even halt tumor progression, and it may induce tumor shrinkage. This mechanism makes erdafitinib an ideal treatment option for patients with specific FGFR alterations, offering a critical alternative for individuals who have failed to respond to conventional therapies. Erdafitinib Dosage2Initially, erdafitinib received FDA accelerated approval in April 2019 based on the results of the Phase II BLC2001 clinical trial, which demonstrated significant efficacy in patients with FGFR3 or FGFR2 mutations. Subsequently, on January 19, 2024, the FDA granted full approval for erdafitinib in the treatment of adult patients with locally advanced or metastatic urothelial carcinoma harboring susceptible FGFR3 or FGFR2 alterations, following disease progression after platinum-containing chemotherapy. In China, the National Medical Products Administration (NMPA) officially approved erdafitinib tablets, developed by Johnson & Johnson, on January 13, 2024. The indication is for adult patients with unresectable locally advanced or metastatic urothelial carcinoma carrying susceptible FGFR3 mutations who have experienced disease progression during or after prior therapy with at least one line of anti-PD-1 or anti-PD-L1 inhibitors. Clinical Data of Erdafitinib2The Phase III THOR (BLC3001) trial demonstrated erdafitinib's outstanding performance in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Compared with chemotherapy, erdafitinib showed a statistically significant improvement in OS. The median OS for the erdafitinib group was 12.1 months versus 7.8 months in the chemotherapy group (HR=0.64; 95% CI, 0.47–0.88; p=0.0050), indicating that erdafitinib reduced the risk of death by 36% compared to chemotherapy. Furthermore, the median PFS in the erdafitinib group was 5.6 months, compared with 2.7 months in the chemotherapy group. The ORR with erdafitinib was also higher at 35.3%, compared with 8.5% in the chemotherapy group. Despite the promising clinical benefits of erdafitinib, its use may be associated with certain adverse events. The most common adverse reactions (≥20%) include hyperphosphatemia, diarrhea, stomatitis, dry mouth, decreased appetite, dry skin, anemia, and constipation. To ensure safe and effective treatment, physicians should closely monitor patients' health and adjust the dosage or provide supportive care as necessary to manage side effects. 2. PemigatinibPemigatinib (brand name: Pemazyre) is a highly selective FGFR1-3 inhibitor. It received accelerated approval from the U.S. Food and Drug Administration (FDA) for the treatment of pre-treated advanced cholangiocarcinoma patients with FGFR2 fusions or rearrangements. These patients often experience disease progression following first-line standard therapy and face significant unmet medical needs due to the lack of effective second-line or later therapeutic options. The advent of pemigatinib offers new hope for these patients. Pemigatinib specifically binds to the ATP-binding pocket of FGFR, thereby inhibiting receptor tyrosine kinase autophosphorylation and downstream signaling pathways. This inhibits tumor cell growth and dissemination. This targeted therapeutic approach allows precise action on tumor cells with specific genetic alterations, reducing the impact on normal cells and improving treatment efficacy and safety. Clinical Trials of Pemigatinib3The approval of pemigatinib was based on data from the FIGHT-202 trial, a Phase II, single-arm, open-label clinical study in patients with locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements, who had previously received systemic therapy and whose tumors were unresectable. In cohort A of the trial, which included patients with FGFR2 fusions or rearrangements, the median follow-up was 15 months. Pemigatinib monotherapy achieved an overall response rate (ORR) of 36%, with 4 cases of complete response (3.7%) and 36 cases of partial response (33.3%). The median duration of response (DoR) was 9.1 months. Furthermore, the study demonstrated good tolerability consistent with the mechanism of action of pemigatinib. Common adverse events included hyperphosphatemia (58.5%), alopecia, diarrhea, nail toxicity, and fatigue. In terms of safety, pemigatinib exhibited relatively favorable tolerability. Approximately 68.7% of the participants experienced Grade 3 or higher adverse events, but most could be managed by dose adjustments or supportive care measures. The most common Grade 3 or higher adverse events included hypophosphatemia (14.3%) and other significant side effects such as arthralgia and oral mucositis (6.1% each), abdominal pain, fatigue, and hyponatremia (5.4% each). Palmar-plantar erythrodysesthesia syndrome and hypotension were less frequently observed. Notably, ocular toxicity represents a potential risk with the use of pemigatinib, necessitating regular ophthalmologic monitoring to detect or manage any eye-related issues. In addition to its approval in the United States, pemigatinib has also been authorized for the treatment of FGFR2 fusion-positive unresectable biliary tract cancer (BTC) patients who have progressed after chemotherapy in Japan. In Europe, it is approved for adult patients with locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements, whose disease has progressed following at least one prior systemic therapy. In China, Innovent Biologics has submitted a new drug application for pemigatinib, and this has been accepted by the National Medical Products Administration (NMPA), signaling an active evaluation of the drug's suitability for Chinese patients. 3. Other Selective FGFR Inhibitors Under DevelopmentIn addition to the two aforementioned selective FGFR inhibitors that have been approved, several other small-molecule compounds are undergoing clinical development at various stages. For instance, BGJ398 is a highly selective tyrosine kinase inhibitor targeting FGFR1 that has demonstrated effective inhibition of acute myeloid leukemia cell lines in vitro. Similarly, Irpagratinib (ABSK011), an orally active FGFR4 inhibitor, has been shown to effectively suppress tumor growth in FGFR4-driven liver cancer models in vivo. The development of these new agents not only broadens the application scope of FGFR-targeted therapies but also provides potential solutions to address emerging resistance issues. ConclusionIn summary, the FGFR signaling pathway is not only critical for normal physiological processes but also acts as a driver for the development of many cancers when dysregulated. By specifically blocking abnormal FGFR-mediated signaling cascades, next-generation selective FGFR inhibitors such as erdafitinib and pemigatinib have demonstrated remarkable efficacy in clinical trials and received regulatory approval for the treatment of specific types of advanced cancers. These drugs not only offer new therapeutic options for patients harboring specific FGFR alterations but also advance the field of precision medicine. With further accumulation of clinical data and technological progress, FGFR-targeted therapies are expected to expand their application scope in the future, improving patient outcomes and quality of life. Moreover, ongoing research will help address potential resistance issues, ensuring sustained therapeutic efficacy over the long term. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery! Reference 1.Babina IS, Turner NC. Advances and challenges in targeting FGFR signalling in cancer. Nat Rev Cancer. 2017 May;17(5):318-332. doi: 10.1038/nrc.2017.8. Epub 2017 Mar 17. 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