A Phase I/Ib, Open-label, Multi-center Study of DFF332 as a Single Agent and in Combination With Everolimus or IO Agents in Patients With Advanced/Relapsed ccRCC and Other Malignancies With HIF2α Stabilizing Mutations

This is first in human study of DFF332, a small molecule that targets a protein called HIF2α. By acting on HIF2α, DFF332 may be able to stop the growth of certain types of cancer. DFF332 will be tested at different doses as single agent and in combination with Everolimus (RAD001, an mTOR inhibitor), and also in combination with Spartalizumab (PDR001, an anti-PD1) plus Taminadenant (NIR178, an adenosine A2A receptor antagonist), in patients with advanced clear cell renal cell carcinoma and other malignancies with HIF stabilizing mutations.

开始日期2021-11-30

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT04237649 / Terminated早期临床1期

A Phase I/Ib, Open-label, Multi-center, Study of KAZ954 as a Single Agent and in Combination With Spartalizumab, NZV930 and NIR178 in Patients With Advanced Solid Tumors

The primary objective of the trial was to characterize the safety, tolerability, and maximum tolerated dose (MTD)/recommended dose (RD) for expansion of single agent KAZ954 and KAZ954 in combination with PDR001, NIR178 and NZV930.

开始日期2020-02-20

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT03742349 / Terminated临床1期

A Phase Ib, Multicenter, Open-label Dose Escalation and Expansion Platform Study of Select Immunotherapy Combinations in Adult Patients With Triple-negative Breast Cancer

This is a Phase Ib, open label, dose escalation study of spartalizumab + LAG525 in combination with NIR178, capmatinib, MCS110, or canakinumab, followed by a dose expansion in adult patients with advanced or metastatic TNBC.
During the dose-escalation part of each treatment arm, patients will be treated with fixed doses of spartalizumab + LAG525 in combination with partner investigational drugs to be escalated until the MTD is reached or a lower RDE is established: NIR178, capmatinib, MCS110, or canakinumab. It is anticipated that other partner study drugs may be added in the future by protocol amendment.
After the determination of the MTD/RDE for a particular treatment arm, dose expansion may begin in that arm in order to further assess safety, tolerability, PK/PD, and anti-tumor activity of each combination at the MTD/RDE. Dose expansion arms may initiate only after consideration by the Investigators and Novartis of all available toxicity information, the assessment of risk to future patients from the BLRM, and the available PK, preliminary efficacy, and PD information. There is no requirement for dose-escalation treatment arms reaching an MTD/RDE to proceed to dose expansion.

开始日期2019-01-31

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 NIR-178 相关的临床结果

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100 项与 NIR-178 相关的转化医学

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100 项与 NIR-178 相关的专利（医药）

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项与 NIR-178 相关的文献（医药）

2023-04-28·Cancers

Early Adverse Event Derived Biomarkers in Predicting Clinical Outcomes in Patients with Advanced Non-Small Cell Lung Cancer Treated with Immunotherapy.

Article

作者: Chiappori, Alberto ; Chen, Dung-Tsa ; Thapa, Ram ; Gray, Jhanelle E. ; Saltos, Andreas N. ; Rose, Trevor ; Thompson, Zachary J.

RATIONALE:

Adverse events (AEs) have been shown to have clinical associations, in addition to patient safety assessments of drugs of interest. However, due to their complex content and associated data structure, AE evaluation has been restricted to descriptive statistics and small AE subset for efficacy analysis, limiting the opportunity for global discovery. This study takes a unique approach to utilize AE-associated parameters to derive a set of innovative AE metrics. Comprehensive analysis of the AE-derived biomarkers enhances the chance of discovering new predictive AE biomarkers of clinical outcomes.

METHODS:

We utilized a set of AE-associated parameters (grade, treatment relatedness, occurrence, frequency, and duration) to derive 24 AE biomarkers. We further innovatively defined early AE biomarkers by landmark analysis at an early time point to assess the predictive value. Statistical methods included the Cox proportional hazards model for progression-free survival (PFS) and overall survival (OS), two-sample t-test for mean difference of AE frequency and duration between disease control (DC: complete response (CR) + partial response (PR) + stable disease (SD)) versus progressive disease (PD), and Pearson correlation analysis for relationship of AE frequency and duration versus treatment duration. Two study cohorts (Cohort A: vorinostat + pembrolizumab, and B: Taminadenant) from two immunotherapy trials in late-stage non-small cell lung cancer were used to test the potential predictiveness of AE-derived biomarkers. Data from over 800 AEs were collected per standard operating procedure in a clinical trial using the Common Terminology Criteria for Adverse Events v5 (CTCAE). Clinical outcomes for statistical analysis included PFS, OS, and DC.

RESULTS:

An early AE was defined as event occurrence at or prior to day 30 from initial treatment date. The early AEs were then used to calculate the 24 early AE biomarkers to assess overall AE, each toxicity category, and each individual AE. These early AE-derived biomarkers were evaluated for global discovery of clinical association. Both cohorts showed that early AE biomarkers were associated with clinical outcomes. Patients previously experienced with low-grade AEs (including treatment related AEs (TrAE)) had improved PFS, OS, and were associated with DC. The significant early AEs included low-grade TrAE in overall AE, endocrine disorders, hypothyroidism (pembrolizumab's immune-related adverse event (irAE)), and platelet count decreased (vorinostat related TrAE) for Cohort A and low-grade AE in overall AE, gastrointestinal disorders, and nausea for Cohort B. In contrast, patients with early development of high-grade AEs tended to have poorer PFS, OS, and correlated with PD. The associated early AEs included high-grade TrAE in overall AE, gastrointestinal disorders with two members, diarrhea and vomiting, for Cohort A and high-grade AE in overall AE, three toxicity categories, and five related individual AEs for Cohort B. One low-grade TrAE, alanine aminotransferase increased (vorinostat + pembrolizumab related), was an irAE and correlated with worse OS in Cohort A.

CONCLUSIONS:

The study demonstrated the potential clinical utility of early AE-derived biomarkers in predicting positive and negative clinical outcomes. It could be TrAEs or combination of TrAEs and nonTrAEs from overall AEs, toxicity category AEs, to individual AEs with low-grade event leaning to encouraging effect and high-grade event to undesirable impact. Moreover, the methodology of the AE-derived biomarkers could change current AE analysis practice from a descriptive summary into modern informative statistics. It modernizes AE data analysis by helping clinicians discover novel AE biomarkers to predict clinical outcomes and facilitate the generation of vast clinically meaningful research hypotheses in a new AE content to fulfill the demands of precision medicine.

2022-06-01·CLINICAL CANCER RESEARCH1区 · 医学

Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non–Small Cell Lung Cancer

1区 · 医学

Article

作者: Hurtado, Felipe K. ; Aregay, Mehreteab ; Tanvetyanon, Tawee ; Thapa, Ram ; Manenti, Luigi ; Beg, Amer A. ; Barlow, Margaret L. ; Morgan, Liza ; Antonia, Scott ; Chen, Zhihua ; Creelan, Ben ; Boyle, Theresa A. ; Haura, Eric B. ; Chen, Dung Tsa ; Castro, Julio ; Morris, Erick ; Gray, Jhanelle E. ; Chiappori, Alberto A.

Abstract:

Purpose::

The adenosine 2A receptor (A2AR) mediates the immunosuppressive effects of adenosine in the tumor microenvironment and is highly expressed in non–small cell lung cancer (NSCLC). Taminadenant (PBF509/NIR178) is an A2AR antagonist able to reactivate the antitumor immune response.

Patients and Methods::

In this phase I/Ib, dose-escalation/expansion study, patients with advanced/metastatic NSCLC and ≥1 prior therapy received taminadenant (80–640 mg, orally, twice a day) with or without spartalizumab (anti–programmed cell death-1, 400 mg, i.v., every 4 weeks). Primary endpoints were safety, tolerability, and feasibility of the combination.

Results::

During dose escalation, 25 patients each received taminadenant alone or with spartalizumab; 19 (76.0%) and 9 (36.0%) had received prior immunotherapy, respectively. Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea [n = 1 (4.0%) each; 640 mg], and in the combination group were pneumonitis [n = 2 (8.0%); 160 and 240 mg] and fatigue and alanine/aspartate aminotransferase increase [n = 1 (4.0%) each; 320 mg]; pneumonitis cases responded to steroids rapidly and successfully. Complete and partial responses were observed in one patient each in the single-agent and combination groups; both were immunotherapy naïve. In the single-agent and combination groups, 7 and 14 patients experienced stable disease; 7 and 6 patients were immunotherapy pretreated, respectively.

Conclusions::

Taminadenant, with and without spartalizumab, was well tolerated in patients with advanced NSCLC. The maximum tolerated dose of taminadenant alone was 480 mg twice a day, and 240 mg twice a day plus spartalizumab. Efficacy was neither a primary or secondary endpoint; however, some clinical benefit was noted regardless of prior immunotherapy or programmed cell death ligand-1 status.

2020-10-01·Biomedical chromatography : BMC4区 · 医学

Development and validation of an LC–MS/MS method for the quantitative analysis of the adenosine A2a receptor antagonist NIR178 and its monohydroxy metabolite in human plasma: Application to clinical pharmacokinetics

4区 · 医学

Article

作者: Picard, Franck ; Hatsis, Panos ; Wu, Shari ; Heudi, Olivier ; Flarakos, Jimmy ; Aumonier, Celine ; Winter, Serge ; Hurtado, Felipe K. ; Plaud, Nathalie

Abstract:

We report a selective LC–MS/MS method for the simultaneous quantitative determinations of the adenosine A2a receptor antagonist NIR178 (NIR178) and its major metabolite NJI765 in human plasma. Sample preparation steps involved protein precipitation, sample evaporation and reconstitution using a plasma sample volume of 0.1 ml plasma. Separation was achieved in 10 min on an Acquity UPLC BEH C18 1.7 μm, 2.1 × 50 mm column heated at 60°C with a gradient elution at 0.6 ml/min mobile phase made of water and acetonitrile both acidified with 0.1% formic acid. The detection was performed in positive ion mode and quantification based on multiple reaction monitoring. The linear response range was 1.00–1,000 ng/ml using a 1/x2 weighting factor. The intra‐ and inter‐day accuracies (bias %) and intra‐ and inter‐day precisions (CV, %) obtained for NIR178 and NJI765 were within the acceptance criteria. The normalized NIR178 and NJI765 matrix factor calculated from six lots of normal, lipemic and hemolyzed plasmas ranged from 0.97 to 1.05. The normalized recoveries of both NIR178 and NJI765 compared with their internal standards were consistent and reproducible with a CV ≤8.0. This method was successfully applied to support pharmacokinetic studies in adult patients with cancer.

项与 NIR-178 相关的新闻（医药）

2024-05-12

·药事纵横

8家跨国药企，砍掉40多条管线（2024 Q1）

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。面对新药研发困难、销售业绩下滑等压力冲击，药企巨头也不得不做出管线调整、裁员的决定。跨国大药企的斧头快速抡起，消减研发管线，聚焦更有前景的资产，为的是保持竞争优势。让我们一起来看看2024年第一季度都有哪些跨国药企削减了管线项目。一、罗氏：砍掉6条管线4月24日，罗氏在2024年第一季度财报中披露：削减6项临床项目，分别为用于实体肿瘤的camonsertib和belvarafenib；用于结直肠癌的双特异性抗体RG6286；用于精神疾病的RG6163以及用于尿路感染的LepB抑制剂RG6319。大部分处于1期开发阶段。camonsertib是一款潜在的BIC口服ATR抑制剂，用于治疗具有特定合成致死基因组改变的肿瘤，包括ATM基因改变。今年1月份，II期 TAPISTRY研究中第1名患者接受了Camonsertib治疗，由此触发了一个4000万美元的里程碑付款。但情况突然急转而下，半个月后罗氏突然宣布将终止协议，罗氏给出的理由是：出于对罗氏的管线和不断变化的外部因素进行审查后的结果。belvarafenib是一款选择性泛RAF激酶抑制剂，目前处于2项临床，但已停止患者招募，即使已从管线移除此项目，但公司将继续提供研究治疗并监测已入组患者。2016年，Genentech从韩国公司Hanmi Pharmaceutical中引入该药物，获得该药物在除韩国之外的全球权益。Hanmi因此获得8000万美元预付款，以及高达8.3亿美元的开发、监管和商业化里程碑费用等。在交易时，Belvarafenib开发正处于I期阶段。双特异性抗体RG6286可与T细胞上的结直肠癌抗原LY6G6D和CD3结合。I期临床试验预计将于2026年初完成。基因泰克于2020年开始在结直肠癌患者中测试该候选药物（也称为 BLYG8824A）。此外，放弃了用于精神疾病的RG6163以及用于尿路感染的LepB抑制剂RG6319，而转向推进一种名为RG6436的替代性LepB抑制剂。在此过程中，罗氏产品线的平衡从神经科学和肿瘤学（较小程度）转向了免疫学、心血管和代谢疾病领域。神经科学项目的数量从18个降至12个，尽管其中一个项目被转移到了研发管线的另一部分。自2023年第3季度以来，罗氏为重点关注影响力大的项目，已终止了20%的管线。首席执行官Thomas Schinecker表示：“罗氏的目标是使其产品线中80%为最佳管线或一流资产。确定优先次序和不断重新分配是正常业务的一部分，确保其拥有的资金其用于患者和公司的最佳用途。”二、BMS：砍掉12条管线4月25日，百时美施贵宝(BMS)在2024年第一季度财报中披露：BMS正在施行一项全面成本削减计划，到2025年底，该计划将节省约15亿美元的成本，大部分将用于再投资以资助创新和推动增长。作为计划的一部分将从其产品线中削减大约12个项目，还包括裁员约2200人，约占其全球员工总数的6%。BMS在决定停止药物开发时考虑的因素包括公司是否认为某个项目的数据可以击败现有药物或其他在研药物，某个项目是否会成为潜在的增长动力，以及是否可以成为 "同类第一"或 "同类最佳"。涉及的一些实验性药物包括抗CTLA-4项目、抗SIRPα抗体和BET抑制剂。抗CTLA-4和抗SIRPα的研究可能无法击败Yervoy。BET抑制剂（BMS-986158）被取消的原因是，虽然该药显示了良好的数据，但没有达到成为增长动力的门槛。在周四早盘交易中，该公司股价$BMY下跌超过8%。根据Endpoints News对其2023年第四季度和2024年第一季度报告的审查，百时美施贵宝总体上从1期开发中撤消了8个项目，从2期开发中撤消了6个项目。该公司还增加了五个进入1期的项目，同时将一种药物从1期推进到2期，将两种药物从1期推进到3期。最近收购的Karuna和RayzeBio公司的两个项目也进入了 3 期开发阶段。三、吉利德：砍掉10条管线4月22日，吉利德在2024年第一季度财报中披露：共砍掉10条管线。其中，吉利德终止2个细胞疗法项目：分别为自体抗CD19 CAR-T细胞疗法Brexucabtagene autoleucel (ZUMA-25)治疗罕见B细胞恶性肿瘤的2期试验和CLL-1 (KITE-222)治疗复发难治性急性髓系白血病的1期试验。剔除了CD47单抗magrolimab联合疗法治疗头颈部鳞状细胞癌、三阴性乳腺癌、结直肠癌等实体瘤的6项研究。2月7日，吉利德宣布，终止magrolimab所有血液瘤项目开发，而此次6项试验从管线中移除意味着吉利德彻底放弃该款药物的开发。此外，吉利德还停止与Arcus合作的PD-1单抗zimberelimab联合抗TIGIT抗体domvanalimab±化疗用于一线非小细胞肺癌的2个项目。在研产品管线方面，吉利德在肿瘤、抗病毒、免疫疾病领域将继续打造丰富的产品储备。目前，吉利德已有54款项目进入临床研究阶段，同时还有10款可供临床阶段选择的资产。四、赛诺菲：砍掉3条管线4月25日，赛诺菲在2024年第一季度财报中披露：放弃了部分免疫学及神经学管线适应症项目，包括自免赛道的CD40L抗体Frexalimab在干燥综合征上的2期研究、RIPK1抑制剂Oditrasertib治疗肌萎缩性侧索硬化症（ALS）的2期研究、一项用于治疗罕见遗传性疾病GM2神经节脂质沉积症的分子Venglustat的2期研究。Frexalimab：由于2期研究数据未达到“必要的疗效结果”，赛诺菲暂停开发治疗Sjögren综合征的CD40L抗体药物Frexalimab。不过，Frexalimab其他适应症不会受影响，公司继续进行多发性硬化症和继发性进展性多发性硬化症(SPMS)的3期试验，以及1型糖尿病和系统性红斑狼疮的2期试验。Oditrasertib：赛诺菲停止了RIPK1抑制剂Oditrasertib治疗肌萎缩性侧索硬化症（ALS）的2期研究，因其未能达到基于ALS功能评定量表修订的主要改善终点。赛诺菲将在即将召开的医学会议上分享完整的安全性和有效性数据，并继续在多发性硬化症患者中进行Oditrasertib的2期研究。Venglustat：用于治疗罕见遗传性疾病GM2神经节脂质沉积症的分子Venglustat的2期研究因试验的临床终点“缺乏积极趋势”而被终止。五、阿斯利康：砍掉7条管线4月25日，阿斯利康在2024年第一季度财报中披露：将放弃4款早期药物涉及7条管线：口服Porcupine抑制剂AZD5055，该药物用于特发性肺纤维化，由AZ于2020年8月以1700万美元首付、3.6亿美元的潜在里程碑从Redx Pharma引进，目前阿斯利康由于战略投资组合优先顺序而终止其在健康志愿者中的两项I期试验；反义寡核苷酸药物AZD7503：由于战略投资组合优先顺序而终止该药物用于治疗非酒精性脂肪性肝炎的两项1期试验和健康志愿者中测试安全性和耐受性的一项1期试验；LOX-1靶向单克隆抗体MEDI6570：该药物旨在阻断LOX-1受体的多种配体。由于战略投资组合优先顺序，阿斯利康终止了其正在进行的一项名为GOLDILOX的2b期临床试验；口服D因子抑制剂Vemircopan（维米克泮）：终止其用于治疗全身性重症肌无力的一项2期研究，其用于治疗狼疮性肾炎的2期试验和治疗肝功能受损的1期试验还在进行中；六、诺华：砍掉2条管线与上一季度对比来看，诺华砍掉了一项早期资产CD73拮抗剂NZV930和一项2期临床资产CSF-1R抑制剂BLZ945。诺华此前在开展NZV930单独使用以及与PDR001和/或 NIR178联合使用对晚期癌症患者的安全性、耐受性和初步抗肿瘤活性的I/Ib期、开放标签、多中心研究（NCT03549000）。对于BLZ945，此前在一项开展ALS患者在多次服用 BLZ945 后的安全性、耐受性和脑小胶质细胞反应的II期试验（NCT04066244），和一项口服BLZ945单药或与PDR001静脉注射联合用于晚期实体瘤成年患者中的安全性、耐受性、药代动力学（PK）、药效学和抗肿瘤活性的I/II 期研究（NCT02829723）。七、辉瑞：砍掉4条管线5月1日，辉瑞发布了2024 Q1业绩报告。在管线方面，公司停止了VTX-801的开发，VTX-801是一款重组AAV基因疗法，用于治疗罕见遗传性疾病威尔逊氏症，该疗法是辉瑞与Vivet Therapeutics共同开发的。辉瑞于2019年3月收购了Vivet的少数股权，并正在为1/2期研究生产该疗法的载体。此外，辉瑞还取消了其溃疡性结肠炎药物Velsipity（etrasimod）在特应性皮炎和斑秃中的两个潜在新适应症，以及口服Zavzpret（zavegepant）的偏头痛预防项目。这三项研究均已进入第二阶段。总体而言，辉瑞的研发管线在过去三个月中净增加了一个项目，从112个增加到113个。除了削减的4个项目外，辉瑞还增加或推进了10个项目，并在美国和欧盟获得了5项批准。八、强生：砍掉2条管线与2023年12月的管线对比发现，强生2024Q1砍掉了两个肿瘤的I期项目，一个是JNJ-8114 (PSMA/CD3)，一个是JNJ-4916溶瘤病毒。强生的创新药业务主要聚焦于免疫调节、抗感染、神经系统、肿瘤、肺动脉高压和心血管六大管线。目前强生管线中共有95个项目，包括23个1期项目，20个2期项目，39个3期项目和13个项目处于上市申报阶段。总结仅在2024年Q1就有8家药企巨头就已砍了40多条管线，终止原因多因疗效数据不及预期临床失败，或因市场变化进行战略调整。对于跨国药企来说，加速从不具优势的领域抽身，从原计划试验中节约的资金将用于加速推进其全球首创或同类最佳候选药物，是公司研发战略调整的重要部分。不过，管线项目的消失仍浪费了大量资源和精力，因此这提醒了药企应该更加注重风险管理和决策的科学性，以减少砍掉管线造成的损失。参考资料：各公司官网

引进/卖出财报临床1期ASH会议临床2期

2023-10-07

·药时代

实体瘤领域“大撤退”，诺华在想什么

在创新药生态中，制药巨头的一举一动无疑是风向标一般的存在。只要盯住巨头在做什么、追赶什么，就能描绘制药行业风起云涌、潮涨潮落的晴雨表。过去一年中，诺华的管线变动，向我们传递了一个隐秘的真相：诺华对于实体瘤的兴趣正在变淡。从2022年二季度到2023年二季度，一年时间里，诺华管线中的实体瘤药物从42款被削减到了28款，实体瘤产品在诺华管线中的比重也从28%下降到了21%。事实上，即便不看整体管线的变动，诺华在实体瘤领域的撤退也有迹象可循。在最近几个月时间里，诺华先后终止与三家药企合作的实体瘤疗法。在全球大部分药企正朝着实体瘤高歌猛进的时候，诺华却在逆行业潮流而行。作为全球TOP10制药巨头之一，诺华在实体瘤领域的“掉头”，究竟是嗅到了什么先机？还是纯粹而决绝地抛弃了自己并不占优势的领域？/ 01 /“重灾区”，1/3实体瘤管线被砍在过去一年里，诺华在实体瘤领域的投入以肉眼可见的速度缩水。尤其是早期管线，更是“重灾区”。具体来看，诺华砍掉了9款处于一期临床阶段实体瘤管线，其中大多数是成药不确定性较高的新兴靶点。比如，被砍掉的TNO115是一款SHP2抑制剂。SHP2是一种蛋白酪氨酸磷酸酶，由于磷酸酶催化域高度保守，催化位点抑制剂普遍缺乏选择性，使磷酸酶临床开发大大受限于毒性反应，难度较高。此前，艾伯维、赛诺菲纷纷放弃这一靶点的药物研发，在这样的背景下，诺华选择放弃并不奇怪。再比如，另一款被砍掉的TGFβ抑制剂NIS793，同样前路未知。此前，临床上靶向TGF-β通路的药物存在小分子、抗体、配体、寡核苷酸等，通通遭遇失败或毒副作用，尤其是默克PD-L1/TGF-β双抗失败，更是为TGFβ添上了一抹阴霾。由于药物的有效性和安全性尚未确定，所以诺华停止了与Xoma合作开发NIS793的计划，彻底放弃了TGFβ靶点，针对这一药物的一期临床及三期临床试验均被画上了句号。这两个靶点之外，诺华终止的早期临床产品还有新兴免疫调节剂、Porcupine抑制剂、IL-15和IL-15α重组异二聚体、KRAS抑制剂针对KRAS G12C突变的一项实体瘤临床试验，以及两款未披露靶点的产品。在二期临床药物上，诺华仅砍掉了一款A2aR抑制剂药物NIR178。在实体瘤的三期临床管线上，除了上文所述的NIS793，与百济神州合作的替雷利珠单抗、ACZ885均被砍掉。其中，ACZ885是一款IL-1b抑制剂，诺华曾在一项针对心血管疾病开展的III期CANTOS试验事后分析中发现，肺癌死亡率随着药物剂量增加而显著降低，基于此诺华启动了该药促肿瘤炎症转变的概念验证。不幸的是，在两项针对NSCLC的临床III期研究中，均未达到改善OS的主要终点。在这一药物无力回天后，诺华决定放弃。总体来看，实体瘤领域虽然仍是诺华布局的五大领域之一，但与过去相比，诺华在这一领域的投入明显缩减。/ 02 /在不占优势的热门领域后退看到这里，你可能有疑问，为什么诺华在实体瘤领域的探索愈发保守？要知道，肿瘤可是创新药第一大市场，据WHO数据，2021年全球新发癌症1975.8万例，其中血液瘤新发患病例约130.5万例，占比不到10%。剩下的90%，都是新发实体瘤患者。有机构预测，到2030年，全球肿瘤市场规模预计高达2900亿美元。在这一领域，已经诞生了不少重磅炸弹药物。在当前35种重磅炸弹中，排名前10的肿瘤学药企贡献了其中的31种。因此，几乎所有排名靠前的全球大药企，都在围绕着肿瘤领域展开全方位的布局。典型如阿斯利康，品尝过DS-8201带来的胜利果实后，阿斯利康通过自研+引进，正全面布局实体瘤研发。诺华却逆行业潮流而行，其对外表示，这是因为美国医保谈判带来的压力。上述靶点未明确的药物研发风险本就高，而在美版医保谈判出炉后，这些药物可能面临着上市后还未赚回研发投入，就被纳入谈判的情况，诺华很有可能连研发投入都赚不回来。但除此之外，诺华在实体瘤上的撤退更深层的原因或许是公司整体策略的转向。此前，在电话会议中，诺华表示产品管线的去留是根据研发和治疗战略的匹配程度、商业潜力和整体价值以及竞争格局来决定。若是从这几个维度来分析，诺华在实体瘤上的后退选择不难理解。从治疗战略匹配程度来看，诺华现有管线实际上与肿瘤药物的协同性并不强。与阿斯利康手握DS-8201、默沙东手握K药不同，在肿瘤领域，诺华并没有太多的超级重磅产品。根据诺华2022年财报，8款核心产品中只有Kisqali和Pluvicto两款产品针对实体瘤，整体实体瘤板块为公司带来的收入也仅占比11%。尤其是在IO疗法的布局上，由于诺华已经基本放弃了自研的PD-1抑制剂 spartalizumab，那么,在许多以PD-1为基石的疗法疗法的布局上，诺华也就难以占据优势地位。因此，对诺华来说，继续推进以PD-1为首组合的IO疗法，可能并不是一个合适的策略。诺华全球药品开发总裁兼首席医学官Shreeram Aradhye此前曾对外表示，公司缩减管线主要基于两方面的考量，一方面，确定核心治疗领域；另一方面，能将资源和人力最大程度地聚焦在最关注的治疗领域上，借此进一步加强研发成功率。/ 03 /在优势领域的创新布局更进一步当然，诺华在实体瘤领域投入的资源减少，必然会在其他领域加大资源投入。事实上，近些年来诺华积极投身于新兴技术平台。目前公司已经拥有5大技术平台，包括靶向蛋白质降解技术、细胞疗法、基因疗法、放射性配体疗法以及RNA疗法。其中，多个领域，诺华均处于领先地位。比如在小核酸领域，诺华的布局在各大药企中最为靠前。早在1998年，诺华与ionis合作研发的ASO药物fomivirsen已经获批上市，成为全球第一款上市的ASO药物。虽然这款药物最终因为销售额过低而退市，但是诺华在这一领域的布局从未停止。2021年12月，诺华的siRNA疗法Leqvio获批上市，成为全球首个能够降低低密度脂蛋白胆固醇（LDL-C）的siRNA疗法。在放射性核素领域，诺华也是当之无愧的领军企业。2022年3月，诺华核素药物Pluvicto获得FDA批准，用于PSMA阳性转移性去势抵抗性前列腺癌三线治疗，成为了全球首款靶向PSMA的放射性配体疗法。为了巩固自己在核药领域的领先地位，诺华不断加码研发。今年以来，其先后与Bicycle、3BP达成合作，开发双环肽和成纤维细胞活化蛋白（FAP）靶向放射性疗法。近两年以来，诺华的并购交易也多是围绕着AAV基因疗法、体内基因编辑疗法、RNAi疗法等新兴技术。看起来，相比于在不占优势的肿瘤领域内卷，诺华更倾向于在新兴领域打造一条属于自己的护城河，从而形成更具优势的研发能力和生产规模。/ 04 /追逐安全感和确定性事实上，不只是诺华，最近两年在宏观经济压力、政策调整等大环境的影响下，不少大药企都开始在战略层面倾向于聚焦优势领域。在过去的2022年，制药业务收入全球排名前10的大药企砍掉的管线超过50项。大药企频频砍管线背后的逻辑均是，从不具优势的领域抽身，让自己更加聚焦、提高投资回报率。毕竟，一家药企的精力总是有限的，人、财、物的资源也是有限的，想要把有限的资源发挥出最大的效果，必须要集中起来使用，也就是将资源集中到优势领域，不断寻求实质性的突破、增强竞争优势，进而拓宽自己的护城河。考虑到当前这个不确定的环境下，即便是更具资源优势的大药企，也开始未雨绸缪，更在意安全感和确定性。回到国内来说，如何进一步聚焦优势产品，以及构建筛选市场切实需要的管线，也应该是各家需要思考的关键性问题。尤其在当下的生物制药寒冬里，聚焦优势战略更是适用于大部分biotech。在当下，守住核心产品，砍掉一些当下不能带来业绩、未来预期有限或渺茫的产品，才能拥有更大的可能，成功穿越这场漫长的寒冬。封面图来源：123rf偶联药物家族成员盘点，除了ADC还有哪些？武田：莫博赛替尼，决定撤市DRUGTIMES点击在看共济新药研发浪潮

临床3期临床1期临床终止寡核苷酸临床2期

2022-11-16

·FierceBiotech

Novartis halts phase 1 cancer trial of CD73 antagonist over efficacy, but combo studies continue

A failed study of Novartis' CD73 antagonist enrolled 127 participants with advanced malignancies who received NZV930 either as a monotherapy or in combination. Novartis has halted a phase 1 trial of its CD73 antagonist due to a low likelihood of efficacy, although the Big Pharma will continue to explore the therapy’s potential as part of a combo regimen. The trial of NZV930 was “terminated early because data review showed low likelihood of efficacy in the patients recruited in that clinical setting,” a Novartis spokesperson confirmed to Fierce Biotech. The decision was not safety-related, they added. The study, which began in July 2018, enrolled 127 participants with advanced malignancies who received NZV930 either as a monotherapy or in combination with Novartis’ checkpoint inhibitor spartalizumab or its adenosine A2a receptor antagonist NIR178, according to ClinicalTrials.gov. Novartis will continue to evaluate whether NZV930 is effective when used in combination with other investigational agents, the spokesperson told Fierce. They pointed to an ongoing phase 1 trial of KAZ954 in advanced solid tumors that includes a cohort receiving the investigational therapy in combination with NZV930. The aim of CD73 antagonists is to block the CD73 enzyme from producing adenosine, which can suppress the body’s immune response to cancer. Novartis is not alone in exploring this mechanism: I-Mab’s uliledlimab showed promise alongside Junshi Bioscience’s PD-1 inhibitor toripalimab in initial phase 2 data, while AstraZeneca’s CD73 antagonist oleclumab is in phase 2 trials for pancreatic cancer and phase 3 trials for lung cancer, including in combination with Imfinzi.

临床2期临床1期临床失败临床3期临床终止

100 项与 NIR-178 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床2期	美国	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	日本	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	阿根廷	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	澳大利亚	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	奥地利	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	比利时	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	捷克	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	法国	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	德国	Novartis Pharmaceuticals Corp.	2017-08-28
晚期恶性实体瘤	临床2期	意大利	Novartis Pharmaceuticals Corp.	2017-08-28

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03207867 (ESMO_IO2022) 人工标引	临床2期	三阴性乳腺癌 ER Negative \| PR Negative \| HER2 Negative	30	taminadenant 160 mg+spartalizumab 400 mg	廠淵網觸淵齋餘鏇艱範(築獵淵膚醖範範構鹹醖) = 艱艱網艱網醖齋餘願獵鹽遞網艱壓淵夢衊夢繭 (廠鬱淵簾觸築艱鹹餘鏇 ) 更多	积极	2022-12-08
NCT03549000 (AACR2022) 人工标引	临床1期	肿瘤	105	NZV930(60-1000 mg Q2W) or NZV930(200-600 mg Q2W) + spartalizumab (400 mg Q4W) or NZV930(200-600 mg Q2W) + taminadenant (80-240 mg Q2W) or NZV930(200-600 mg Q2W) + spartalizumab (400 mg Q4W) + taminadenant (80-240 mg BID)	範壓鹽選淵繭蓋壓製衊(鹹衊憲糧築簾膚鏇願簾) = 壓選鏇憲蓋簾鏇築齋廠觸選糧齋艱築糧選衊餘 (鏇獵糧膚選獵壓壓製廠 ) 更多	积极	2022-04-08
NCT02403193 (Pubmed \| Clin Cancer Res)	临床1期	晚期非小细胞肺癌	25	Taminadenant alone	衊鏇餘鏇壓壓窪夢鏇衊(鑰夢網築壓築壓製夢餘) = Dose-limiting toxicities (all Grade 3) with taminadenant alone were alanine/aspartate aminotransferase increase and nausea (n=1 [4.0%] each; 640 mg) and in the combination group were pneumonitis (n=2 [8.0%]; 160 and 240 mg), fatigue and alanine/aspartate aminotransferase increase (n=1 [4.0%] each; 320 mg); pneumonitis cases responded to steroids rapidly and successfully. 鏇願窪築齋構壓壓選願 (製壓襯鏇糧襯範衊願衊 )	-	2022-03-07
NCT02403193 (Pubmed \| Clin Cancer Res)	临床1期	晚期非小细胞肺癌	25	Taminadenant with Spartalizumab		-	2022-03-07
NCT03207867 (ESMO2021) 人工标引	临床2期	转移性微卫星稳定结直肠癌 Microsatellite Stable (MSS)	58	taminadenant + spartalizumab	鏇鬱齋衊衊蓋網夢壓蓋(積網淵壓餘壓觸獵獵壓) = 鬱簾積獵願鹹獵簾夢願鏇蓋襯衊選鏇鹹衊憲鏇 (獵網獵簾艱觸鏇蓋遞廠, 0.0 ~ 9.2) 更多	积极	2021-09-16
NCT02403193 (ASCO2018) 人工标引	临床1/2期	非小细胞肺癌二线	24	NIR178	窪網齋餘願艱繭餘網淵(積積齋鹹範襯獵積窪艱) = none 製鬱蓋鹹構遞壓齋鏇糧 (觸窪蓋願廠顧齋築鑰憲 ) 更多	积极	2018-06-03