Roxadustat

日前，默沙东（MSD）公布，其小分子疗法Welireg（belzutifan）在两项3期临床试验LITESPARK-011与LITESPARK-022中，用于治疗肾细胞癌（RCC）患者取得积极结果。基于上述数据，公司已向美国FDA递交相关监管申请。 肾细胞癌是最常见的肾癌类型，约90%的肾癌确诊病例为RCC。2022年，全球约新增43.5万例肾癌病例，约15.6万例患者死于该疾病。RCC在男性中的发病率约为女性的两倍。多数RCC病例是在针对其他腹部疾病进行影像学检查时偶然发现的，约30%的患者在确诊时已处于疾病晚期，治疗选择相对有限。 LITESPARK-011是一项随机、开放标签的3期临床试验，旨在评估Welireg联合卫材（Eisai）旗下酪氨酸激酶抑制剂（TKI）Lenvima（lenvatinib）这一双口服方案，与已获批激酶抑制剂cabozantinib相比，用于治疗在抗PD-1/PD-L1治疗期间或之后出现进展的晚期透明细胞RCC患者的疗效与安全性。该研究设有两个主要终点：由盲态独立中心评审（BICR）依据实体瘤疗效评价标准1.1版（RECIST v1.1）评估的无进展生存期（PFS）和总生存期（OS）。关键次要终点包括客观缓解率（ORR）、缓解持续时间（DOR）及安全性。试验共入组747例患者，随机接受每日一次口服Welireg（120 mg）联合Lenvima（20 mg），或每日一次口服cabozantinib（60 mg）治疗。 在预设的中期分析中，中位随访时间为29.0个月（范围：19.3-49.2）。与活性对照相比，Welireg联合Lenvima在主要终点PFS方面取得统计学显著且具有临床意义的改善，将疾病进展或死亡风险降低30%（HR=0.70，95% CI：0.59-0.84，p=0.00007）。联合治疗组的中位PFS为14.8个月（95% CI：11.2-16.6），对照组为10.7个月（95% CI：9.2-11.1）。在另一主要终点OS方面，联合治疗亦呈现改善趋势（HR=0.85，95% CI：0.68-1.05，p=0.06075）。Welireg联合Lenvima组的中位OS为34.9个月（95% CI：27.5-NR），对照组为27.6个月（95% CI：24.0-31.4）。该研究仍在进行中，OS结果将按照方案在后续分析中进一步评估。 此外，在首次中期分析中，中位随访19.6个月时（范围：9.9-39.8），Welireg联合Lenvima在ORR方面达到主要终点，与活性对照相比显示出统计学显著改善。联合组的确认ORR为52.6%（95% CI：47.3-57.7），对照组为39.6%（95% CI：34.6-44.8）。在第二次中期分析中，联合组的中位DOR为23.0个月（95% CI：2.0-44.3+），对照组为12.3个月（95% CI：1.8-35.9+）。 安全性方面，≥3级治疗相关不良事件（TRAEs）在Welireg联合Lenvima组的发生率为71.6%，对照组为65.8%。因不良事件导致治疗中止的比例分别为11.1%和11.3%。严重不良事件发生率分别为51.6%和43.9%。不良事件导致死亡的比例分别为5.4%（其中2例与治疗相关：血栓性微血管病[n=1]和肺炎[n=1]）和3.2%（其中1例与治疗相关：咯血[n=1]）。 基于上述结果，美国FDA已受理寻求批准Welireg联合Lenvima，用于治疗既往接受PD-1或PD-L1抑制剂、伴透明细胞成分的晚期RCC成人患者的补充新药申请（sNDA）。FDA已将sNDA的PDUFA目标审评日期定为2026年10月4日。 图片来源：123RF 除晚期治疗领域外，LITESPARK-022这一关键3期试验则将Welireg推进至RCC早期治疗领域。该研究评估默沙东抗PD-1疗法Keytruda（pembrolizumab）联合Welireg，用于肾切除术后透明细胞RCC患者的辅助治疗效果。 在首次预设中期分析中，中位随访为28.4个月（范围：15.0-40.1）。与Keytruda联合安慰剂相比，Keytruda联合Welireg显著改善了无病生存期（DFS）这一主要终点，将疾病复发或死亡风险降低28%（HR=0.72，95% CI：0.59-0.87，p=0.0003）。两组的中位DFS均尚未达到；联合组估算的24个月无病生存率为80.7%（95% CI：77.7-83.2），对照组为73.7%（95% CI：70.6-76.6）。联合方案的安全性特征与既往研究一致，未观察到新的安全性信号。 根据新闻稿，这是Welireg在早期疾病阶段取得的首个积极3期临床结果，也是HIF-2α抑制剂与免疫治疗联合方案的首个积极3期结果。基于这些数据，美国FDA已受理Welireg联合Keytruda用于特定RCC患者辅助治疗的监管申请，并授予优先审评资格。 ▲Welireg的作用机制（图片来源：参考资料[3]） Welireg是默沙东研发的“first-in-class”口服低氧诱导因子2α（HIF-2α）抑制剂。HIF-2α是参与氧感应的重要分子。氧感应通路是细胞感知并响应氧浓度变化的关键机制，在低氧适应、代谢调节、血管生成及肿瘤发生等生理与病理过程中发挥重要作用。2019年诺贝尔生理学或医学奖授予Peter Ratcliffe、Gregg Semenza和William Kaelin，以表彰他们在揭示氧感知信号通路方面的突出贡献。诺贝尔委员会指出，其研究不仅揭示了生命的重要适应性机制，也为开发治疗贫血、癌症等疾病的创新药物奠定了基础。 2021年8月，美国FDA批准Welireg上市，用于治疗VHL疾病相关肿瘤，包括肾细胞癌、中枢神经系统血管母细胞瘤和胰腺神经内分泌肿瘤（pNET），成为首个获批上市的HIF-2α抑制剂。2023年，FDA进一步批准其扩展适应症，用于既往接受PD-1/PD-L1抑制剂和血管内皮生长因子酪氨酸激酶抑制剂（VEGF-TKI）治疗后疾病进展的晚期RCC患者。 目前，除belzutifan外，基于“氧感知通路”开发的创新疗法也已陆续获批上市，如用于治疗慢性肾病相关贫血的罗沙司他、daprodustat等。同时，针对该通路的在研药物已达数十款，显示出广阔的发展前景。 在这一创新浪潮中，药明康德多年来依托其一体化、端到端的CRDMO平台，为包括氧感知通路靶向药物在内的广泛新药研发项目，提供从药物研究（R）、开发（D）到商业化生产（M）的全流程支持，助力全球合作伙伴加速推进突破性疗法的研发进程。展望未来，药明康德将继续发挥其一体化CRDMO平台优势，推动更多科学突破转化为临床价值，造福全球患者。 参考资料： [1] WELIREG® (belzutifan) Plus LENVIMA® (lenvatinib) Reduced the Risk of Disease Progression or Death by 30% Compared to Cabozantinib in Certain Previously Treated Patients With Advanced Renal Cell Carcinoma (RCC). Retrieved March 2, 2026 from https://www.merck.com/news/welireg-belzutifan-plus-lenvima-lenvatinib-reduced-the-risk-of-disease-progression-or-death-by-30-compared-to-cabozantinib-in-certain-previously-treated-patients-with-advanced-renal-ce/ [2] KEYTRUDA® (pembrolizumab) Plus WELIREG® (belzutifan) Given as Adjuvant Therapy Reduced the Risk of Disease Recurrence or Death by 28% Compared to KEYTRUDA Monotherapy in Certain Patients With Earlier-Stage Renal Cell Carcinoma (RCC). Retrieved March 3, 2026 from https://www.merck.com/news/keytruda-pembrolizumab-plus-welireg-belzutifan-given-as-adjuvant-therapy-reduced-the-risk-of-disease-recurrence-or-death-by-28-compared-to-keytruda-monotherapy-in-certain-patients-with/ [3] Choi, et al. (2023) Belzutifan (MK-6482): Biology and Clinical Development in Solid Tumors. Curr Oncol Rep, https://doi.org/10.1007/s11912-022-01354-5 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

While AZ has undergone an audit of its Saphnelo datasets to regain the agency’s trust, GSK faces a more daunting challenge: proving that Exdensur actually works in CRSwNP. The FDA is providing more insight into the rejections it recently handed two pharma giants, publishing the complete response letters (CRLs) sent to AstraZeneca and GSK that highlight shortfalls in the data included in their application packages.In a scathing rebuke (PDF) to AstraZeneca, the FDA cited “critical data quality issues that affect key analyses, including the primary endpoint” within a dataset for Saphnelo (anifrolumab) for the drug’s proposed use in systemic lupus erythematosus (SLE). Separately, the agency rejected (PDF) GSK’s Exdensur (depemokimab) for chronic rhinosinusitis with nasal polyps (CRSwNP), ruling that the clinical data failed to provide “adequate evidence” of efficacy, casting doubts on the drug’s potential expansion in that use.The publication of the rejection letters underscores the FDA’s promise of “radical transparency” regarding its drug review process. While AZ has undergone an audit of its Saphnelo datasets to regain the agency’s trust, GSK faces a more daunting challenge: proving that Exdensur actually works in CRSwNP.For AZ, the CRL was issued on Oct. 10, 2025, according to the FDA’s database. But the company didn’t disclose it until Feb. 3, 2026. At that time, the company said it had submitted the information requested by the FDA in the CRL, and that a decision on the updated application was expected in the first half of this year. AZ’s initial submission was based on an interim analysis of the phase 3 Tulip-SC trial, which showed a reduction in disease activity for subcutaneous Saphnelo versus placebo as measured using the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at week 52. However, in the CRL, the FDA flagged that AZ had submitted a “corrected” dataset for the study late in the review cycle after initially making “errors” in the application.As a result, the FDA asked AZ to provide, among other things, a “corrected interim clinical study report” and corrected raw datasets for both the interim and final analyses, presented in formats standard for regulatory reviews. Additionally, the FDA asked the company to “provide a detailed discussion of what led to the errors in the locked database being found,” as well as “a subject-level listing of all the changes in all the datasets along with the reason for each change.”Two months following the FDA’s rejection, European regulators authorized subcutaneous Saphnelo in SLE. This is not the first time that AZ has found itself dealing with data quality issues in a drug application for a kidney disease treatment. Back in 2021, AZ’s then-partner FibroGen filed for an FDA approval but then admitted to manipulating the safety data of roxadustat in chronic kidney disease-related anemia, data that the two firms unveiled to much fanfare in 2019.Roxadustat has since been rejected by the FDA, and AZ exited the collaboration in the U.S. in 2024. Efficacy questions for GSK Meanwhile, GSK faces a different hurdle for Exdensur, as the FDA has asked for “new evidence” that can demonstrate a treatment effect of greater magnitude to prove that the antibody drug provides a “statistically persuasive and clinically meaningful” benefit to CRSwNP patients. In its CRL to GSK, the FDA acknowledged that the co-primary endpoints of the Anchor-1 and -2 trials were met, showing statistically significant improvements for Exdensur versus placebo on nasal polyp scores and nasal obstruction scores. However, on the nasal obstruction score measure, the FDA found the outcomes were “not robust to sensitivity analyses for missing data and handling of intercurrent events.” The FDA views results from the patient-reported endpoint “especially important for assessing benefit-risk because they are a direct reflection of the clinically meaningful effects for patients.”The magnitude of the effects for both primary endpoints was “numerically small,” so the FDA questioned their clinical meaningfulness.The agency’s review team also looked at secondary endpoints, including additional patient-reported symptom scores, the need for nasal sinus or polyp surgery, and oral corticosteroid use. However, because of the statistical design of the studies, none of those endpoints met statistical significance, despite trends favoring Exdensur.The FDA went on further to suggest that a higher dose than the 100 mg selected by GSK “may provide a greater treatment effect,” faulting GSK for not running phase 2 dose-ranging trials specifically in CRSwNP.To tip the review balance further against GSK, the FDA said the every-half-year dosing—a long-acting feature that GSK has touted—means that non-responders would either have to wait a long time to switch to another drug, or risk any issues from taking two biologic therapies while Exdensur is still present in their bodies. “Given the small effect size for depemokimab with lack of robustness on tipping point analysis, the benefit-risk in the setting of a six-month duration of action is not favorable,” the FDA concluded. While the FDA declined to approve Exdensur in CRSwNP, the agency approved the long-acting IL-5 agent as an add-on maintenance treatment for severe asthma with an eosinophilic phenotype. The drug is approved in the EU for both indications.“We remain confident in the benefit Exdensur could bring for patients with CRSwNP and are continuing discussions with the FDA,” a GSK spokesperson told Fierce Pharma. GSK’s focus in the U.S. is on severe asthma, which affects about two million Americans with more than half uncontrolled on current therapy, as well as chronic obstructive pulmonary disease (COPD), the spokesperson added.Exdensur is a key element of GSK's plan to reach more than 40 billion pounds sterling in annual revenue by 2031, a task that has recently fallen on the shoulders of new CEO Luke Miels. In a more important indication than CRSwNP, GSK is testing Exdensur in three phase 3 trials in COPD.