A Phase 2 Trial to Evaluate Safety, Tolerability, and Efficacy of Bardoxolone Methyl in Patients With Chronic Kidney Disease at Risk of Rapid Progression

This multi-center, randomized, double-blind, placebo-controlled, Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in qualified patients with CKD due to multiple etiologies at risk of rapid disease progression. Approximately 70 patients will be enrolled and randomized 1:1 to either bardoxolone methyl or placebo. Patients with CKD secondary to varying etiologies will be enrolled from age 18-70 years with eGFR ≥ 20 to < 60 mL/min/1.73 m2, and other risk factors for rapid progression of kidney disease.
The maximum target dose will be determined by baseline proteinuria status. Patients with baseline urine albumin to creatinine ratio (UACR) ≤ 300 mg/g will be titrated to a maximum dose of 20 mg, and patients with baseline UACR > 300 mg/g will be titrated to a maximum dose of 30 mg. Qualified patients will be randomized 1:1 to receive either bardoxolone methyl or placebo once daily (preferably in the morning) throughout a 12-week dosing period.
Patients in the study will follow the same visit and assessment schedule. Patients will be assessed during treatment at Day 1, Weeks 1, 2, 4, 6, 8, and 12 and by telephone contact on Days 3, 10, 21, 31, 35, and 45. Date of last dose and the end-of-treatment assessments mark the end of the treatment period. Patients will not receive study drug during a 5-week off-treatment period between Weeks 12 and 17. The off-treatment (OT) period includes 5 visits requiring various assessments to characterize eGFR from the time of study drug discontinuation through Day 35 off-treatment.

开始日期2021-02-09

申办/合作机构

Reata Pharmaceuticals, Inc.

NCT04494646

/ Completed临床2期IIT

BARCONA: A Phase II, Randomized, Double-blind, Placebo-controlled, Multi-center Study of the Effects of Bardoxolone Methyl in Participants With SARS-Corona Virus-2 (COVID-19)

This multi-center, double-blind, placebo-controlled, randomized Phase 2 trial will study the safety, tolerability, and efficacy of bardoxolone methyl in patients hospitalized with confirmed COVID-19. The trial will include approximately 40 patients and is designed to provide an early interim analysis of safety. Patients will be randomized using permuted block randomization in a 1:1 fashion to either once-daily administration of bardoxolone methyl (20 mg) or matching placebo and treatment will be administered for the duration of hospitalization (until recovery), with a maximum treatment duration of 29 days.

开始日期2020-09-08

申办/合作机构

NYU Langone Health

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100 项与甲基巴多索隆相关的临床结果

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100 项与甲基巴多索隆相关的转化医学

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100 项与甲基巴多索隆相关的专利（医药）

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项与甲基巴多索隆相关的文献（医药）

2025-04-01·Health Science Reports

Systematic Review of Management Strategies for Alport Syndrome: Implications for Male Patients

Review

作者: Sarfraz, Muzna ; Khan, Ayesha ; Irfan, Omar ; Liaqat, Maryyam ; Sarfraz, Zouina ; Javad, Faheem ; Saleem, Meher ; Kc, Manish ; Khalid, Musfira ; Khan, Aden ; Sarfraz, Azza

ABSTRACT:

Background and Aims:

Alport Syndrome (AS) is a rare genetic disorder characterized by progressive kidney disease, hearing loss, and ocular abnormalities, with an incidence of approximately 1 in 50,000 newborns. Due to the severity of the disease, particularly in males with X‐linked inheritance, this systematic review consolidates current management strategies, highlighting advancements and existing gaps in treatment options.

Methods:

This systematic review followed a protocol registered on the OSF platform (osf. io/k86ms). A comprehensive search of PubMed, Web of Science, Scopus, Cochrane Library, Embase, ClinicalTrials.gov, and the WHO ICTRP was completed by December 24, 2023. Studies eligible for inclusion were clinical trials or observational studies evaluating AS management. Four clinical trials from six publications and two observational studies met the inclusion criteria. The risk of bias was assessed using the Cochrane ROB 2 tool for clinical trials and the Newcastle–Ottawa Scale (NOS) for observational studies. Key interventions examined included bardoxolone methyl, ramipril, and losartan.

Results:

Bardoxolone methyl, ramipril, and losartan demonstrated potential benefits in slowing renal disease progression in AS. Observational studies indicated that early intervention might delay the need for dialysis and improve life expectancy. However, significant heterogeneity among studies precluded quantitative synthesis. Ongoing studies on AS management encompass 25 trials involving 52,135 participants, reflecting an active area of research.

Conclusion:

Bardoxolone methyl, ramipril, and losartan show promise in delaying renal failure in AS. Nonetheless, the findings highlight the critical need for larger, more diverse trials to validate these therapies and explore additional treatment strategies. Future research must aim to address these evidence gaps, improving treatment efficacy and patient quality of life, particularly for males disproportionately affected by the disease.

Protocol Registration:

The protocol for this systematic review is registered in the Open Science Framework (OSF): osf. io/k86ms.

2025-03-10·ONCOGENE

Discovery of a molecular glue for EGFR degradation

Article

作者: Wang, Zhipeng ; Wang, Rui ; Qi, Xiaowei ; Zhou, Wenshen ; Lai, Ren ; Zou, Li ; Yang, Qin ; Wang, Hui ; Li, Yuanzhen ; Wang, Hairui ; Nie, Jianyun ; Li, Xiyin ; Deng, Li ; Jiao, Baowei

Aberrant expression of epidermal growth factor receptor (EGFR) plays a critical role in the pathogenesis of various tumors, potentially representing a target for therapeutic intervention. Nonetheless, EGFR remains a challenging protein to target pharmacologically in triple-negative breast cancer (TNBC). An emerging approach to address the removal of such proteins is the application of molecular glue (MG) degraders. These compounds facilitate protein-protein interactions between a target protein and an E3-ubiquitin ligase, subsequently leading to protein degradation. Herein, we identified a new MG (CDDO-Me, C-28 methyl ester of 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid), which orchestrated binding between EGFR and KEAP1 (an E3-ubiquitin ligase adapter), thereby initiating the ubiquitination and degradation of EGFR. CDDO-Me directly interacted with the tyrosine kinase (TK) domain of EGFR, resulting in its degradation via an autophagy-dependent lysosomal pathway. Knockdown of KEAP1 decreased the degradation of EGFR by reducing its K63-linked ubiquitination, leading to diminished EGFR colocalization in autophagosomes and lysosomes. Notably, CDDO-Me attenuates TNBC progression by accelerating EGFR degradation in cell-derived xenografts and patient-derived organoid models, highlighting its clinical application potential. Consequently, induction of EGFR degradation through MG degraders represents a viable therapeutic strategy for TNBC.

2025-03-01·Toxicological Research

Oxidative stress and NRF2 signaling in kidney injury

Review

作者: Yanti ; Kwak, Mi-Kyoung ; Ng, Cherry ; Kim, Maxine

Oxidative stress plays a crucial role in the pathogenesis of acute kidney injury (AKI), chronic kidney disease (CKD), and the AKI-to-CKD transition. This review examines the intricate relationship between oxidative stress and kidney pathophysiology, emphasizing the potential therapeutic role of nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of cellular redox homeostasis. In diverse AKI and CKD models, diminished NRF2 activity exacerbates oxidative stress, whereas genetic and pharmacological NRF2 activation alleviates kidney damage induced by nephrotoxic agents, ischemia-reperfusion injury, fibrotic stimuli, and diabetic nephropathy. The renoprotective effects of NRF2 extend beyond antioxidant defense, encompassing its anti-inflammatory and anti-fibrotic properties. The significance of NRF2 in renal fibrosis is further underscored by its interaction with the transforming growth factor-β signaling cascade. Clinical trials using bardoxolone methyl, a potent NRF2 activator, have yielded both encouraging and challenging outcomes, illustrating the intricacy of modulating NRF2 in human subjects. In summary, this overview suggests the therapeutic potential of targeting NRF2 in kidney disorders and highlights the necessity for continued research to refine treatment approaches.

项与甲基巴多索隆相关的新闻（医药）

2025-05-06

·梅斯医学

小便有泡泡不当回事？18岁男生竟查出罕见遗传病，肾坏前早有三大预警！

18岁的小杨最近总觉得有点“怪”：上厕所时泡泡尿越来越多，一天能看好几次，早上起来还有点眼皮肿、腿沉。家里人说是“肾虚”或者“上火”，让他多喝点水就好。他自己也没太放在心上——直到一次学校体检，被查出“尿蛋白2+”，医生建议他去医院进一步检查。血压偏高、尿中蛋白持续升高，还伴随有隐血。医生进一步追问时，他提到近两年听力有点下降，尤其是开会或吵闹环境中听不清人讲话，偶尔还觉得视力模糊，去眼镜店却说配镜也没用。家属这才回忆起来：他爸年轻时也听力不好、40多岁时开始做透析，爷爷还得过“肾病综合征”。医生立刻警觉，安排了肾活检和基因检测，最终确诊为——Alport综合征。定义及分型Alport 综合征是一种临床表现以血尿、蛋白尿、进行性肾功能减退为特征，部分患者合并感音神经性耳聋、眼部病变等肾外表现的综合征。根据患者所携带致病性变异的基因不同，Alport综合征包括XLAS、ARAS、ADAS及近年发现和提出的双基因Alport综合征4种类型。临床表现1. 血尿：血尿是Alport综合征患者最常见的临床表现，为肾小球源性，在各种遗传型中均可出现。XLAS男性患者和ARAS患者几乎100%存在镜下血尿，90%以上的XLAS女性患者存在镜下血尿。2. 蛋白尿：几乎所有XLAS男性患者及ARAS患者均会出现蛋白尿，且随年龄增长表现为持续性蛋白尿，甚至发展为肾病范围蛋白尿。蛋白尿在XLAS女性患者及ADAS患者中也较为常见。3. 肾功能减退：XLAS男性患者肾脏预后极差，几乎所有XLAS男性患者均会在不同时期出现进行性肾功能减退，最终发展至ESKD。约90%的XLAS男性患者将在40岁之前进展至ESKD，且进展为ESKD的速度与COL4A5基因的变异类型有关。而在XLAS女性患者中，16%将在65岁前进展为ESKD。4. 听力障碍：Alport综合征患者听力障碍表现为SNHL，发生于耳蜗部位，最初仅累及高频区，故难以察觉，需进行纯音测听才可发现。听力损失呈进行性加重，随年龄增长逐渐累及全音域，甚至影响日常对话交流。5. 眼部病变：对Alport综合征具有诊断意义的眼部病变包括前圆锥形晶状体、黄斑周围点状和斑点状视网膜病变。6. 其他：弥漫性平滑肌瘤病是Alport综合征少见的临床表现，胃食管、气管和女性生殖道（如阴蒂、大阴唇及子宫）为常见受累部位，并伴随相应症状，如吞咽困难、呼吸困难。家族史家族史对于Alport综合征的确诊、患者预后评估及患病家系遗传咨询十分重要。判断家族史除了详尽询问并绘制系谱图（建议绘制三代及以上）外，应至少对先证者的一级亲属包括父母、子女和兄弟姐妹进行尿常规及尿沉渣检查。Alport综合征诊断临床主要表现为持续性肾小球源性血尿或血尿伴蛋白尿的患者，具有以下任一项即可诊断为Alport综合征：（1）肾组织电镜示GBM致密层撕裂、分层、薄厚不均或篮网状改变；（2）肾脏组织基底膜Ⅳ型胶原α3、α4、α5链免疫荧光染色异常或EBMⅣ型胶原α5链免疫荧光染色异常；（3）基因检测示COL4A3、COL4A4或COL4A5基因具有致病性变异（包括ACMG分级的可能致病性变异）。需要说明极少数XLAS患者同时具有累及COL4A5和COL4A6基因外显子的大片段缺失变异；不推荐仅依据COL4A3或COL4A4基因杂合致病性变异诊断ADAS，建议结合ESKD家族史、SNHL、Alport综合征特异的眼部异常及肾组织电镜GBM改变等临床病理表现进行诊断。Alport综合征的治疗Alport综合征尚无根治或病因性治疗措施。目前Alport综合征的治疗策略旨在通过早期药物治疗减缓疾病的进展，从而延缓ESKD的发生；一旦进展至 ESKD，则需进行肾脏替代治疗。肾素-血管紧张素-醛固酮系统（RAAS）阻断剂是目前延缓Alport综合征肾脏疾病进展的首要推荐药物。其他针对Alport综合征抗炎抗纤维化的治疗药物仍在研发中，部分药物正在进行Ⅲ期临床试验，例如甲基巴多索隆，但尚无充分循证医学证据，目前暂不作建议。参考资料：[1] 沈欣，郑必霞，黄松明. Alport综合征基因治疗进展. 中华儿科杂志，2024，62(07):692-695. DOI:10.3760/cma.j.cn112140-20240222-00118[2]Alport综合征协作组，国家肾脏疾病临床医学研究中心，北京医学会罕见病分会. Alport综合征诊治专家共识（2023版）. 中华医学杂志，2023，103(20):1507-1525. DOI:10.3760/cma.j.cn112137-20230203-00161来源 | 梅斯医学编辑 | wanny神经系统罕见病交流群↓点击下方“阅读原文”，下载梅斯医学APP吧！

2023-12-08

·SYNAPSE

What are Nrf2 inhibitors and how do you quickly get the latest development progress?

Nrf2, or nuclear factor erythroid 2-related factor 2, is a transcription factor that plays a crucial role in the human body's defense against oxidative stress and inflammation. It regulates the expression of various antioxidant and detoxification genes, promoting cellular protection and maintaining redox homeostasis. Nrf2 activation is essential for combating harmful free radicals and reactive oxygen species, which can lead to various diseases, including cancer, neurodegenerative disorders, and cardiovascular conditions. Understanding and harnessing the potential of Nrf2 signaling pathways have become a significant focus in pharmaceutical research, aiming to develop novel therapeutic interventions for oxidative stress-related diseases. Due to the biological characteristics of tumors, multidrug resistance (MDR) is a major cause of chemotherapy failure. Studies have shown that high expression of Nrf2 is found in different types of cancer cells (bladder cancer, lung cancer, pancreatic cancer, liver cancer, and head and neck cancer). Nrf2 can activate the transcription of more than 500 genes in the human genome, most of which have cell protective functions, enhancing the detoxification and excretion of harmful substances and toxic metals, thereby leading to tumor resistance to chemotherapy drugs. Therefore, the development of Nrf2 inhibitors is considered an important strategy to overcome chemotherapy drug resistance. The use of Nrf2 inhibitors as sensitizers in combination with anticancer drugs will reverse tumor resistance and significantly improve the efficacy of chemotherapy drugs. The analysis of the target Nrf2 in the pharmaceutical industry reveals a competitive landscape with companies like Biogen, Inc., Reata Pharmaceuticals, Inc., and Teva Pharmaceutical Industries Ltd. leading the way in R&D progress. Multiple drugs targeting Nrf2 have been approved for indications such as Multiple Sclerosis and Friedreich Ataxia. Small molecule drugs are progressing rapidly, with biosimilars indicating intense competition. The United States is at the forefront of development, followed by the European Union, China, and other countries. The future development of target Nrf2 holds promise for the treatment of various indications and requires continued research and investment in innovative drug development. How do they work?Nrf2 inhibitors are a class of compounds or drugs that specifically target and inhibit the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 is a transcription factor that plays a crucial role in regulating the expression of genes involved in antioxidant response and cellular defense against oxidative stress. From a biomedical perspective, Nrf2 inhibitors are of interest because they have the potential to modulate the Nrf2 pathway and alter the cellular response to oxidative stress. By inhibiting Nrf2, these compounds can prevent the activation of antioxidant genes and disrupt the cellular defense mechanisms against oxidative damage. Nrf2 inhibitors have been studied in various biomedical contexts, including cancer research. In some cancer cells, Nrf2 is overexpressed, leading to increased antioxidant capacity and resistance to chemotherapy or radiation therapy. By inhibiting Nrf2, researchers aim to sensitize cancer cells to treatment and enhance the effectiveness of anticancer therapies. Moreover, Nrf2 inhibitors have also been investigated as potential therapeutic agents for other conditions associated with oxidative stress, such as neurodegenerative diseases, cardiovascular diseases, and inflammatory disorders. By modulating the Nrf2 pathway, these inhibitors may offer a way to restore redox balance and mitigate the detrimental effects of oxidative stress in these conditions. It is important to note that the development and use of Nrf2 inhibitors require careful consideration of their potential side effects and impact on normal cellular functions. While inhibiting Nrf2 may be beneficial in certain disease contexts, it may also disrupt the physiological antioxidant defense mechanisms and have unintended consequences. Therefore, further research and clinical trials are necessary to fully understand the therapeutic potential and safety profile of Nrf2 inhibitors. List of Nrf2 InhibitorsThe currently marketed Nrf2 inhibitors include: OmaveloxoloneMonomethyl fumarateDiroximel fumarateDimethyl fumarateBardoxolone MethylOltipraz10-Nitrooleic acidALZ-001ALZ-002APPAFor more information, please click on the image below. What are Nrf2 inhibitors used for?Nrf2 inhibitors have been studied in various biomedical contexts, including cancer research. For more information, please click on the image below to log in and search. How to obtain the latest development progress of Nrf2 inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of Nrf2 inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

2023-11-18

·动脉网

2023年26家生物制药公司倒在临床阶段，资本寒冬不背锅

纵观整个商业发展史，破产、倒闭是绝大多数创业公司的宿命。但是，上市公司、独角兽、获得过多轮大额融资的明星公司在短期内接连宣布破产，就显得不那么正常了。根据外媒Fierce Biotech统计，截止10月30日，今年已关闭或计划关闭的生物技术公司已有22家，是去年的3倍之多。而且，就在11月，又有新的生物制药企业宣布关闭，未来两月或许还将有其他生物制药企业登上今年的死亡名单。（根据公开报道统计，2023年部分宣布关闭的生物制药企业）事实上，生物制药领域从年初就释放了强烈的悲观信号。1月，7家生物制药企业接连宣布关闭，给刚刚进入新一年的投资人与创业者浇了一盆冷水，行业也因此蒙上了一层阴影。2月，情况丝毫不见好转，甚至更加恶劣，有9家生物制药企业先后宣布关闭或破产清算。在这些企业的关停声明中，大部分公司将关闭原因归咎于“当前充满挑战的融资环境，难以维持公司发展所需的时间和资金”。但是，深究发现，原因并不如此简单。资本寒冬不背锅，这些企业倒闭主要是内因虽然全球资本市场进入了寒冬期，生物制药企业的融资较往年更加困难。但是，融资环境变差并不是这些企业倒闭的主要原因，融资问题在所有倒闭因素中的占比或许都不到10%。通过详细梳理，这些倒闭的生物制药企业，绝大部分都是因为自身因素而关闭。第一，临床试验失败是这些企业决定破产的最主要因素。在统计的30多家企业中，约有50%是因为核心管线的临床试验失败而选择破产清算。例如，生物制药公司Tricida在2022年10月公布其核心管线veverimer的III期临床试验未达到主要终点，后于2023年1月申请破产清算；荷兰生物技术企业Xenikos在2023年1月宣布其抗体组合疗法与Incyte JAK抑制Jakaf的III期临床试验由于达到协议规定的60天死亡率停止边界而终止，并计划关停公司。另外，许多曾备受资本市场关注的生物制药公司也因临床试验失败而倒闭关门。曾获得诺和诺德、辉瑞等知名公司上亿美元投资的Aristea在2023年2月宣布：鉴于正在进行的Ⅱ期临床试验中的安全性结果，已停止RIST4721的开发项目。随着该项目的结束，Aristea也迅速关停。第二，项目推进缓慢，企业融资困难是另一原因。例如，成立于2013年的红细胞疗法（RCT）鼻祖Rubius Therapeuticss，如今已启动清算和解散程序。此前，Rubius曾在七年内完成超7亿美元融资。从2013年到2017年，Rubius几乎都在构建RCT平台。直到2018年，Rubius在完成C轮融资时，其资金用途是加速第一波RCT产品的开发。（Rubius融资历程）基于RCT技术平台，Rubius率先研发了PTX-134，主要针对苯丙酮尿症。但是，RTX-134在苯丙酮尿症的临床I期研究中宣告失败。之后，Rubius宣布停止红细胞疗法在苯丙酮尿症及其他罕见病的临床试验，并将目光转向癌症和自身免疫疾病领域。在癌症领域，Rubius布局研发了针对实体瘤的RTX-224、RTX-240等产品管线，并将其推进到临床I期。但是，2022年，Rubius决定停止这两条已处于临床试验阶段的研发管线，其认为这两款疗法不具备继续投入的前景。在缩减研发管线后不久，Rubius就决定寻求出售或合并。（Rubius此前布局的管线及进展）与Rubius的命运截然相反，Anokion等红细胞疗法的后起之秀发展十分顺利。据了解，Anokion在2022年5月公布了其主要候选药物KAN-101用于治疗乳糜泻的临床I期的积极数据。随后，Anokion在2022年10月获得了辉瑞公司提供的3500万美元股权投资。同时，Anokion与辉瑞达成协议，将利用辉瑞的开发专长和能力支持KAN-101的持续临床开发。红细胞疗法鼻祖与后起之秀的的境遇之差，直教人感叹命运之玄奇。需要说明的是，Rubius的关闭，并不是单一因素导致的，而是由管线失败、推进缓慢、资金不足等多项因素构成的。除上述原因外，商业化、法律诉讼、药监部门监管、投资者意见分歧等因素也迫使一部分企业关停。其中，Goldfinch Bio的核心产品GFB-887已经走到临床II期，但是，由于商业化问题，该公司暂停了该产品的临床试验，并在今年1月初宣布了破产。另外，加拿大公司Medicago推出了植物源重组新冠疫苗Covifenz，但也因商业化问题而关闭。Vyera Pharmaceuticals则是遭遇了法律诉讼。2020年1月，美国联邦贸易委员会对Vyera提起诉讼，指控其哄抬药价（一夜暴涨55倍），以维持弓形虫病药物Daraprim的垄断地位。2021年12月，该诉讼达成和解，和解协议要求Vyera在10年内向消费者提供4000万美元救济，并以生产成本价向仿制药竞争对手提供Daraprim。2023年5月，Vyera申请破产，其将原因归咎于利润下降、仿制药竞争以及关于Daraprim的持续诉讼。药监部门的监管也让一部分企业走向倒闭，如Antios Therapeutics、Athenex等公司。以Athenex为例，Athenex的核心产品口服紫杉醇虽然完成III期临床试验，但FDA却回复拒批。原因是FDA认为口服紫杉醇较静脉注射紫杉醇对患者构成安全风险，并担忧其疗效的不确定性。此后，Athenex将重心转移至细胞疗法，但在2022年3月，其神经母细胞瘤细胞疗法由于在临床I期出现患者死亡事件被FDA紧急叫停，随后在2023年5月宣布破产。还有企业因为投资者意见分歧而关停，如tRNA药物研发公司Theonys。该公司联合创始人Peter Dedon教授表示：“作为一名科学创始人，Theonys的情况让我非常沮丧。Theonys背后的科学技术非常强大，创始人和大部分成员都是tRNA表观转录组学领域的发明人。因此，公司因投资者失误而倒闭，至少可以说是令人难过的。”总的来看，这些生物制药企业倒闭，绝大部分在于内因，资本寒冬、当前的融资环境不能为其倒闭背锅。创业者只有正视这些内因，避开这些问题，才能走得更远。裁员、转型难自救，创新生物制药公司趁机借壳上市面对破产危机，企业决策层自然会尝试各种各样的自救方式。有的企业寄希望于裁员、卖身。如Athenex遭遇危机后，迅速启动裁员，并先后出售位于敦刻尔克的制造工厂和位于中国的API原料药工厂。但最终，Athenex还是以破产离场。曾7年斩获7亿美元融资的红细胞疗法鼻祖Rubius 在核心管线受挫后通过多轮裁员、缩减研发管线等方式自救，但这些动作都是徒劳。其在宣布转型发展新一代红细胞平台后两个月，就匆匆宣布寻求出售或合并。尽管这些危机中的企业多数都走向了关停，但也有少部分企业和其他公司合并，抱团取暖延长了现金流。例如，TCR-T领域企业Adaptimmune在削减产品线、解雇员工后，终于与TCR² Therapeutics战略合并，现金跑道延长至3年以后；Aileron在收购Lung Therapeutics之后，私募所得及收购后现金将满足公司到2024年第四季度的运营和资本支出。除此外，随着大批上市公司倒下，一部分生物制药企业看准时机，趁机“借壳上市”。例如，Angion Biomedica在经历一系列试验失败后，与Elicio于2023年1月完成合并。合并后的公司将以Elicio的名称运营，股票代码也从“ANGN”变为“ELTX”；Magenta在暂停了临床研究后与Dianthus于2023年9月完成合并，合并后公司以Dianthus名称运营，并在纳斯达克以股票代码“DNTH”进行交易。与此类似的还有Cyclo Therapeutics借ATM的壳以“CYTH”代码登陆纳斯达克；DMK Pharmaceuticals借Adamis的壳以“DMK ”代码在纳斯达克资本市场进行交易；Tourmaline借Talaris的壳在纳斯达克以股票代码“TRML”进行交易。对于有较好临床数据但资金不足的生物制药企业，市场通常也会以收购、并购等方式让其体面退场，并继续推进其管线。例如，专攻免疫疗法的Surface Oncology，其在被收购之前，曾于2022年11月宣布其抗体SRF388作为单药治疗非小细胞肺癌患者的积极临床结果。根据积极结果，Surface开始了SRF388与抗PD-1抗体Keytruda组合治疗的临床II期试验。2023年4月，Surface又公布了SRF114的新临床前数据。结果表明，抗CCR8和抗PD-1联合治疗增加了肿瘤免疫细胞的浸润，细胞因子的产生，并改善了检查点抑制剂耐药黑色素瘤模型的总生存率。或许是基于Surface公布的临床数据，Coherus于2023年6月以6500万美元收购了Surface。收购完成后，Coherus新增四个不同临床阶段的资产：Toripalimab、Casdozokitug（SRF388）、CHS-114（SRF114）、CHS-006。再比如2023年2月宣布战略重组的肿瘤免疫疗法公司Apexigen，其在2023年5月被Pyxis Oncology以1600万美元的价格收购，获得其抗体发现平台。Pyxis Oncology在收购前就十分看好Apexigen的核心管线Sotigalimab，其总裁兼首席执行官Lara S. Sullivan表示：“今天是公司的一个重要里程碑，因为我们增加了sotigalimab，这是一种潜在的一流CD40激动剂，对以前使用PD-(L)1抑制剂的患者具有抗癌活性，并增强了我们的ADC能力。”Apexigen也没有辜负期望。就在一个月后，Apexigen就公布了评估Sotigalimab联合dox（多柔比星药品）治疗晚期软组织肉瘤患者的新数据。数据显示：Sotigalimab联合dox是安全的且耐受性良好，患者的总生存期也明显增加。在所有评估的晚期软组织肉瘤患者中，中位总生存期为35.6个月，高于dox单独治疗时患者12.8-20个月的总生存期数据。可以看到，对于有良好临床数据的企业，市场仍然会通过多种方式助力其推进项目。而核心管线遭遇临床试验失败的企业，则是走向破产倒闭。不过，这些破产倒闭的企业中，其中一部分上市公司会将自己唯一有价值的东西——上市公司的身份，一起卖掉。总的来看，大部分走向倒闭的生物制药企业，或许真的不冤。倒闭潮来袭，生物制药企业如何绝境逆袭？从年初至今，全球已有约30家生物制药企业宣布关停。在这一轮的倒闭浪潮中，如何活下来是所有生物制药企业都需考虑的问题。或许，那些从绝境中实现自我拯救的企业可以给我们带来一些启示。在倒闭的生物制药企业中，核心管线的临床试验失败是最主要的因素。成立于2002年的Reata也曾遭遇临床III期失败，但其后来却被渤健溢价59%以73亿美元收购。据悉，Reata此前研发了小分子Nrf2激活剂新药bardoxolone，用于治疗由Alport综合征导致的慢性肾病。基于bardoxolone的前景，雅培在2010年以4.5亿美元获得获得了该药物在美国以外的市场权益。可惜的是，该药物在完成临床III期试验、递交注册申请后，被FDA以临床数据不能说明药物有效性而拒绝。2023年5月，Reata最终宣布停止了bardoxolone管线。与此同时，Reata基于Nrf2激动剂研发出的另一款药物Omaveloxolone（商品名：Skyclarys）在研发九年之后终于在今年作为“First in class”药物获FDA批准上市，用于治疗弗里德赖希氏共济失调症（一种罕见病）。目前，Omaveloxolone在市场上没有竞争对手。或许是基于此，渤健于7月25日宣布溢价59%，以73亿美元收购Reata Pharmaceuticals，以加强其神经和罕见病业务。值得一提的是，Nrf2激动剂可以改善细胞线粒体的功能，这使其可能用于治疗阿兹海默症等神经系统疾病。而Reata基于Nrf2激动剂推出的获批药物Omaveloxolone证明了其实力，未来或将研发出更多基于Nrf2激动剂的药物。疫苗研发商Novava也是一个代表性案例。其在成立34年后，仍然没有一款产品获批上市，且其针对老年人呼吸道合胞病毒的RSV F疫苗在临床III期中未达主要终点，以失败告终。之后，Novava的另一款疫苗ResVax也在临床III期研究中未达到主要临床终点。此时，Novava已经资不抵债，甚至触摸到了破产的开关。但是，转折从2020年开始。随着新冠疫情的爆发，及Novava在疫苗技术上的积累，其迅速从多处获取了资金，并研发出了新冠疫苗。据介绍，其疫苗对于新冠肺炎感染的总体保护率为90.4%，对重症的有效性为100%。同时，其基于重组蛋白技术的疫苗较mRNA疫苗具有易于存储和运输的优势。此种背景下，Novavax从破产边缘崛起，并在2021年一跃成为市值260亿美元的公司。2023年8月，Novavax发布的财报显示：其在第二季度营收4.24亿美元，高于分析师预期的2.4亿美元。10月，Novavax宣布其新冠佐剂疫苗(NVX-CoV2601)已获FDA的紧急使用授权，可用于12岁及以上人群预防新冠肺炎的主动免疫。同时，该疫苗获得了美国疾病控制和预防中心的推荐。从Novavax的案例看，仅有技术，仍会走向破产，如Theonys公司的创始人和大部分成员都是tRNA表观转录组学领域的发明人，拥有强大技术实力，但最后还是关停。而应用场景、产品的选择在商业上至关重要。瞄准合适的场景，基于优秀技术平台研发对应的新产品，更能取得事半功倍的效果。至于开源节流等老生常谈的言论，本文就不再赘述了。相信生物制药企业的创始人们会有更灵敏的感知、更深刻的洞察以及更科学的决策。*封面图片来源：123rf近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

临床3期临床2期

100 项与甲基巴多索隆相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09585	甲基巴多索隆	-	DB05983

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
Alport 综合征	申请上市	欧盟	Reata Pharmaceuticals, Inc.	2021-10-27
慢性肾病	临床3期	美国	Reata Pharmaceuticals, Inc.	2019-03-08
慢性肾病	临床3期	日本	Reata Pharmaceuticals, Inc.	2019-03-08
慢性肾病	临床3期	澳大利亚	Reata Pharmaceuticals, Inc.	2019-03-08
慢性肾病	临床3期	法国	Reata Pharmaceuticals, Inc.	2019-03-08
慢性肾病	临床3期	波多黎各	Reata Pharmaceuticals, Inc.	2019-03-08
慢性肾病	临床3期	西班牙	Reata Pharmaceuticals, Inc.	2019-03-08
常染色体显性多囊肾病	临床3期	美国	Reata Pharmaceuticals, Inc.	2019-03-08
常染色体显性多囊肾病	临床3期	日本	Reata Pharmaceuticals, Inc.	2019-03-08
常染色体显性多囊肾病	临床3期	澳大利亚	Reata Pharmaceuticals, Inc.	2019-03-08

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临床结果

适应症

分期

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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


NCT03918447 (FALCON, CTgov)	临床3期	常染色体显性多囊肾病	667	Placebo oral capsule	壓願齋鹹簾糧遞鬱顧遞(襯壓築觸齋鹹範繭艱鬱) = 憲餘鏇廠觸鏇觸衊膚築觸獵鑰淵壓糧觸壓築膚 (獵鹹齋窪壓衊願憲繭衊, 0.769) 更多	-	2024-06-11
NCT03749447 (EAGLE, CTgov)	临床3期	常染色体显性多囊肾病 \| Alport 综合征 \| 慢性肾病	270	Placebo+Bardoxolone Methyl (Prior Placebo to Bardoxolone Methyl)	衊醖膚餘糧醖憲衊範願 = 憲選鑰窪簾遞築鑰膚鬱鹽襯觸構遞淵製範餘夢 (遞製製築鏇構鹽鏇鏇襯, 餘廠夢構窪壓衊簾遞鹹 ~ 齋積構鹹獵製鹽壓鹹繭) 更多	-	2024-03-19
				Bardoxolone Methyl (Prior Bardoxolone Methyl to Bardoxolone Methyl)	衊醖膚餘糧醖憲衊範願 = 襯醖襯蓋網鬱簾遞積簾鹽襯觸構遞淵製範餘夢 (遞製製築鏇構鹽鏇鏇襯, 膚鹽夢簾願膚繭蓋鏇蓋 ~ 壓遞繭齋膚構襯觸淵鹹) 更多
NCT03068130 (RANGER, CTgov)	临床3期	肺性高血压	261	Bardoxolone Methyl	窪積蓋襯構醖觸襯積壓 = 膚築衊製網廠齋淵蓋構鹹鑰願齋蓋願觸鑰齋窪 (顧齋遞衊窪夢選窪廠膚, 範鑰窪窪夢製繭獵憲艱 ~ 選夢製餘醖餘糧積蓋構) 更多	-	2023-10-12
NCT03019185 (CARDINAL, CTgov)	临床2/3期	Alport 综合征	187	Bardoxolone Methyl (Phase 2 Bardoxolone Methyl)	窪襯鑰積製醖窪窪夢蓋(觸糧鹹遞艱鹹窪艱膚網) = 窪夢襯願範窪繭壓築齋鏇遞製鑰憲膚鹹網窪蓋 (憲餘鬱壓範繭顧積製襯, 1.4111) 更多	-	2023-10-11
				Placebo Oral Capsule (Phase 3 Placebo)	廠艱繭鹹觸襯積積糧網(鬱餘鹹襯繭鏇範鏇願醖) = 簾窪衊鬱顧艱艱製遞範網鏇製觸網齋觸獵艱顧 (鑰醖襯膚艱膚繭觸醖鑰, 1.248) 更多
NCT02657356 (CTgov)	临床3期	结缔组织病 \| 与结缔组织病相关的肺动脉高压	202	Placebo capsules (Placebo Capsules)	壓選壓膚膚艱膚繭鬱選(遞齋範膚醖襯蓋構蓋選) = 餘艱構壓鹹觸觸製齋鬱膚觸願顧積膚鹹簾醖憲 (糧醖觸夢願膚鏇廠憲窪, 4.954) 更多	-	2023-05-19
				Bardoxolone methyl capsules (Bardoxolone Methyl Capsules)	壓選壓膚膚艱膚繭鬱選(遞齋範膚醖襯蓋構蓋選) = 窪築壓壓築艱窪廠獵願膚觸願顧積膚鹹簾醖憲 (糧醖觸夢願膚鏇廠憲窪, 4.952) 更多
NCT04702997 (MERLIN, CTgov)	临床2期	慢性肾病	81	Bardoxolone methyl oral capsule (Bardoxolone Methyl)	網餘遞顧壓醖齋構築窪(糧壓艱遞鏇糧積壓衊築) = 廠簾夢憲艱膚鹽網衊壓艱觸餘顧鬱遞構積艱鹽 (廠壓齋構簾餘獵積蓋淵, 0.925) 更多	-	2022-12-01
				Placebo oral capsule (Placebo)	網餘遞顧壓醖齋構築窪(糧壓艱遞鏇糧積壓衊築) = 壓製顧壓廠選遞憲顧憲艱觸餘顧鬱遞構積艱鹽 (廠壓齋構簾餘獵積蓋淵, 0.868) 更多
NCT03019185 (CARDINAL, Pubmed) 人工标引	临床2/3期	Alport 综合征	157	Bardoxolone Methyl	艱構鏇壓願廠鏇鏇蓋窪(憲築鑰憲鹽鹹選廠鏇艱) = 選蓋廠選繭醖製鹽築醖遞獵餘膚範壓餘憲鏇餘 (觸鬱觸選膚獵鏇憲醖夢 ) 更多	积极	2022-11-21
				Placebo	艱構鏇壓願廠鏇鏇蓋窪(憲築鑰憲鹽鹹選廠鏇艱) = 窪醖鏇廠選膚鑰膚壓壓遞獵餘膚範壓餘憲鏇餘 (觸鬱觸選膚獵鏇憲醖夢 ) 更多
NCT03749447 (EAGLE, ISN WCN2022)	临床3期	Alport 综合征	112	Bardoxolone methyl 5 mg	範夢鹽遞衊膚蓋襯憲窪(襯製繭廠獵糧膚簾衊鑰) = 廠廠鑰簾顧餘壓廠鹹糧鹽憲鹹積壓鑰顧窪廠觸 (鑰簾鏇選齋衊觸鏇遞廠, 11.1)	积极	2022-02-01
NCT03366337 (PHOENIX, CTgov)	临床2期	常染色体显性多囊肾病 \| 1型糖尿病合并糖尿病肾病 \| 局灶性节段性肾小球硬化症 ... 更多	103	Bardoxolone methyl capsules (Bardoxolone Methyl - ADPKD)	廠窪壓夢廠獵壓糧廠遞(築積願觸膚觸廠衊顧範) = 淵範廠餘顧廠膚製艱鏇觸齋選壓齋鹹鑰簾鏇齋 (遞鬱積廠鏇襯糧選醖齋, 1.3743) 更多	-	2022-01-18
				Bardoxolone methyl capsules (Bardoxolone Methyl - IgAN)	廠窪壓夢廠獵壓糧廠遞(築積願觸膚觸廠衊顧範) = 糧鑰糧膚齋遞蓋築鬱製觸齋選壓齋鹹鑰簾鏇齋 (遞鬱積廠鏇襯糧選醖齋, 1.5700) 更多
NCT04494646 (CTgov)	临床2期	新型冠状病毒感染	40	Bardoxolone Methyl (Bardoxolone Methyl)	壓襯衊選顧獵艱範鹽鹹 = 齋壓選顧鏇選製廠積廠鹹遞鹽鑰壓構憲衊醖衊 (鏇蓋齋艱選壓糧簾壓鏇, 齋鏇繭廠鏇膚憲壓窪衊 ~ 願繭窪壓憲構鬱獵膚積) 更多	-	2022-01-12
				Placebo (Placebo)	壓襯衊選顧獵艱範鹽鹹 = 醖積膚壓簾餘膚壓製膚鹹遞鹽鑰壓構憲衊醖衊 (鏇蓋齋艱選壓糧簾壓鏇, 襯顧鬱製簾鑰構壓繭鑰 ~ 鹹鹹鏇餘醖鏇鏇窪廠鑰) 更多