Hormonal transition periods during the menstrual cycle may predispose women to mental disorders. Hormonal fluctuations provide specific neuroendocrine conditions that modulate brain structure and function and these actions affect cognitive and emotional behaviors and affect energy and mood homeostasis. It is thought that these changes are driven by altered dopamine transmission. Here, the investigators aim to examine (1) how sex hormones and dopamine are linked and also (2) how hormonal changes affect motivation, mood, and energy homeostasis.
To this end, dopamine intervention will be tested on effort-based decision-making and motivational circuits in three hormonal stages (i.e., women in early-follicular phase (EF), women in mid-luteal phase (ML), and men). Additionally, the effects of hormonal status on metabolic indices will be tested, and its effects on mood fluctuations in a period of a month.
The investigator hypothesizes that women in EF cycle phase (1) have naturally less dopamine and show less effort, and (2) they show greater improvement in effort-based decision-making after Levodopa administration. The investigator has exploratory outcomes about (3) sex differences in reward-learning with and without Levodopa administration and explores if these differences correlate with elevated female sex hormone levels. Moreover, it is hypothesized that (4) hormonal fluctuations affect energy homeostasis, thus women in their EF cycle phase have higher energy expenditure and (5) they report more negative mood than in their mid-luteal (ML) cycle phase.

开始日期2024-05-01

申办/合作机构

University Hospital Tuebingen

[+2]

CTRI/2024/02/062899 / RecruitingN/A

Efficacy and safety of levodopa in dystonia due to neurological Wilson disease, an open labeled placebo controlled randomized controlled trial

开始日期2024-03-04

申办/合作机构-

IRCT20230505058093N1 / Recruiting临床3期IIT

The efficacy of Lavandula stoechas product on motor symptoms of patients with Parkinson's disease treated with levodopa : A double-blind clinical trial

开始日期2023-12-22

申办/合作机构

Kerman Medical University

100 项与左旋多巴相关的临床结果

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100 项与左旋多巴相关的转化医学

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100 项与左旋多巴相关的专利（医药）

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23,550

项与左旋多巴相关的文献（医药）

2024-12-31·Fly

Ribose-cysteine and levodopa abrogate Parkinsonism via the regulation of neurochemical and redox activities in alpha-synuclein transgenic Drosophila melanogaster models

Article

作者: Oremosu, Ademola A ; Idowu, Olumayowa K ; Dosumu, Olufunke O ; Mohammed, Abdullahi A

Parkinson's disease (PD), the most prevalent type of parkinsonism, is a progressive neurodegenerative condition marked by several non-motor and motor symptoms. PD is thought to have a complex aetiology that includes a combination of age, genetic predisposition, and environmental factors. Increased expression of α-synuclein (α-Syn) protein is central to the evolvement of neuropathology in this devastating disorder, but the potential of ribose-cysteine and levodopa in abating pathophysiologic changes in PD model is unknown. Crosses were set up between flies conditionally expressing a pathological variant of human α-Syn (UAS-α-Syn) and those expressing GAL4 in neurons (elav-GAL4) to generate offspring referred to as PD flies. Flies were randomly assigned to five groups (n = 40) from the total population of flies, with each group having five replicates. Groups of PD flies were treated with either 500 mg/kg ribose-cysteine diet, 250 mg/kg levodopa diet, or a combination of the two compounds for 21 days, whereas the control group (w¹¹¹⁸) and the PD group were exposed to a diet without ribose-cysteine or levodopa. In addition to various biochemical and neurochemical assays, longevity, larval motility, and gravitaxis assays were carried out. Locomotive capability, lifespan, fecundity, antioxidant state, and neurotransmitter systems were all significantly (p < 0.05) compromised by overexpression of α-Syn. However, flies treated both ribose cysteine and levodopa showed an overall marked improvement in motor functions, lifespan, fecundity, antioxidant status, and neurotransmitter system functions. In conclusion, ribose-cysteine and levodopa, both singly and in combination, potentiated a therapeutic effect on alpha-synuclein transgenic Drosophila melanogaster models of Parkinsonism.

2024-12-01·Applied microbiology and biotechnology

Novel recombinant aminoacylase from Paraburkholderia monticola capable of N-acyl-amino acid synthesis

Article

作者: Bongaerts, Johannes ; Oyen, Sven ; Schörken, Ulrich ; Jaeger, Karl-Erich ; Siegert, Petra ; Jolmes, Tristan ; Haeger, Gerrit

Abstract:

N-Acyl-amino acids can act as mild biobased surfactants, which are used, e.g., in baby shampoos. However, their chemical synthesis needs acyl chlorides and does not meet sustainability criteria. Thus, the identification of biocatalysts to develop greener synthesis routes is desirable. We describe a novel aminoacylase from Paraburkholderia monticola DSM 100849 (PmAcy) which was identified, cloned, and evaluated for its N-acyl-amino acid synthesis potential. Soluble protein was obtained by expression in lactose autoinduction medium and co-expression of molecular chaperones GroEL/S. Strep-tag affinity purification enriched the enzyme 16-fold and yielded 15 mg pure enzyme from 100 mL of culture. Biochemical characterization revealed that PmAcy possesses beneficial traits for industrial application like high temperature and pH-stability. A heat activation of PmAcy was observed upon incubation at temperatures up to 80 °C. Hydrolytic activity of PmAcy was detected with several N-acyl-amino acids as substrates and exhibited the highest conversion rate of 773 U/mg with N-lauroyl-L-alanine at 75 °C. The enzyme preferred long-chain acyl-amino-acids and displayed hardly any activity with acetyl-amino acids. PmAcy was also capable of N-acyl-amino acid synthesis with good conversion rates. The best synthesis results were obtained with the cationic L-amino acids L-arginine and L-lysine as well as with L-leucine and L-phenylalanine. Exemplarily, L-phenylalanine was acylated with fatty acids of chain lengths from C8 to C18 with conversion rates of up to 75%. N-lauroyl-L-phenylalanine was purified by precipitation, and the structure of the reaction product was verified by LC–MS and NMR.

Key points:

• A novel aminoacylase from Paraburkholderia monticola was cloned, expressed in E. coli and purified.• The enzyme PmAcy exhibits exceptional temperature and pH stability and a broad substrate spectrum.• Synthesis of acyl amino acids was achieved in good yields.

2024-05-01·Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology

Objective assessment of the effects of opicapone in Parkinson’s disease through kinematic analysis

Article

作者: Colella, Donato ; Guerra, Andrea ; Birreci, Daniele ; Paparella, Giulia ; Fabbrini, Giovanni ; Costa, Davide ; Cannavacciuolo, Antonio ; Angelini, Luca ; Antonini, Angelo ; Bologna, Matteo ; Berardelli, Alfredo

Abstract:

Background:

Opicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson’s disease (PD) patients.

Objectives:

In this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements.

Methods:

We enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3).

Results:

Movement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0–T3 was significantly lower in the L-DOPA + OPC than L-DOPA session.

Conclusions:

This study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

415

项与左旋多巴相关的新闻（医药）

2024-06-28

·PRNewswire

Mitsubishi Tanabe Pharma America to Present Latest Parkinson's Disease Research at the 10th Congress of the European Academy of Neurology

JERSEY CITY, N.J., June 28, 2024 /PRNewswire/ -- Mitsubishi Tanabe Pharma America, Inc. (MTPA) today announced three presentations on investigational ND0612 in Parkinson's disease (PD) will be shared at the 10th Congress of the European Academy of Neurology (EAN), being held in Helsinki, Finland, June 29 – July 2. "We are excited to be at EAN this year to showcase our ongoing research and engage with the scientific community," said Gustavo A. Suarez Zambrano, M.D., Vice President of Medical Affairs, MTPA. "These findings highlight our dedication to advancing the understanding of investigational ND0612 and our commitment to recognizing the unmet needs of people living with Parkinson's disease." Presentation Details: Presentations include findings from subgroup analyses of the pivotal Phase 3 multi-center, randomized, double-blind double-dummy BouNDless trial (NCT04006210) evaluating the efficacy, safety and tolerability of investigational ND0612 in people with PD experiencing motor fluctuations, as well as a secondary analysis from a Phase 2 study (NCT02577523), which evaluated the onset of efficacy with ND0612 utilizing patient and clinical global ratings. Additionally, findings from an analysis characterizing infusion site reactions in patients who received 24-hour subcutaneous infusion of ND0612 will be shared. Subgroup Analyses of a Phase 3, Randomized Study of Levodopa/Carbidopa Infusion (ND0612) for Parkinson's Patients (Nelson Lopes, M.D.; NeuroDerm) ePresentation Session: "Movement Disorders 1" (EPR-082): 2:10 p.m. – 2:15 p.m. CEST, June 29 Onset of Efficacy with Levodopa/Carbidopa Infusion (ND0612) for Parkinson's Patients (Nelson Lopes, M.D.; NeuroDerm) ePresentation Session: "Movement Disorders 1" (EPR-083): 2:15 p.m. – 2:20 p.m. CEST, June 29 Characterization of Infusion Site Reactions With 24-hour Subcutaneous Infusion of ND0612 (Nelson Lopes, M.D.; NeuroDerm) ePresentation Session: "Movement Disorders 1" (EPR-084): 2:20 p.m. – 2:25 p.m. CEST, June 29 About ND0612 ND0612 is an investigational drug-device combination therapy – a 24-hours/day, continuous subcutaneous (SC) infusion of liquid levodopa/carbidopa (LD/CD) for the treatment of motor fluctuations in people with Parkinson's disease (PD). Development of investigational ND0612 is being led by NeuroDerm, Ltd., a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation (MTPC). About Mitsubishi Tanabe Pharma America, Inc. Based in Jersey City, N.J., Mitsubishi Tanabe Pharma America, Inc. (MTPA) is a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation (MTPC). It was established by MTPC to develop and advance our pipeline as well as commercialize approved pharmaceutical products in North America. For more information, please visit or follow us on X (formerly Twitter), Facebook and LinkedIn. About Mitsubishi Tanabe Pharma Corporation Mitsubishi Tanabe Pharma Corporation (MTPC), the pharma arm of Mitsubishi Chemical Group (MCG), is one of the oldest pharmaceutical companies in the world, founded in 1678. MTPC is headquartered in Doshomachi, Osaka, the birthplace of Japan's pharmaceutical industry. MCG has positioned health care as its strategic focus in its management policy, "Forging the future". MTPC sets the MISSION of "Creating hope for all facing illness". To that end, MTPC is working on the disease areas of central nervous system, immuno-inflammation, diabetes and kidney, and cancer. MTPC is focusing on "precision medicine" to provide drugs with high treatment satisfaction and additionally working to develop "around the pill solutions" to address specific patient concerns based on therapeutic medicine, including prevention of diseases, pre-symptomatic disease care, prevention of aggravation and prognosis. For more information, go to . About NeuroDerm, Ltd. NeuroDerm, Ltd. is a wholly-owned subsidiary of Mitsubishi Tanabe Pharma Corporation (MTPC), based in Israel, inspired to reduce disease burden and improve the quality of life of patients and their families through innovative drug-device combination therapies and technologies. NeuroDerm is an integrated pharmaceutical and medical technology company developing central nervous system (CNS) product candidates. For additional information, please visit NeuroDerm's website at or follow the Company on LinkedIn. Media inquiries: [email protected] SOURCE Mitsubishi Tanabe Pharma America

临床2期临床3期

2024-06-28

·echemi

AbbVie's Persistent Pursuit of a Revolutionary Parkinson's Treatment: Navigating FDA Challenges and Industry Competition

After being rejected by the US Food and Drug Administration (FDA) over a year ago, the world's leading biopharmaceutical company AbbVie did not give up, but instead tried to launch a revolutionary Parkinson's disease drug, ABBV-951, again, aiming to provide patients with a more convenient treatment option to replace their current carbidopa and levodopa formulation. However, the FDA's rejection has brought new challenges and tests for AbbVie. The FDA's complete response letter (CRL) detailed the observations made during the inspection of third-party manufacturers for AbbVie's drug application. Although AbbVie stressed that these factories' inspections did not involve ABBV-951 or any of AbbVie's drugs, the FDA's decision undoubtedly cast a shadow over this highly anticipated new drug. AbbVie's forward-looking therapy is a combination of foscarbidopa and foslevodopa, which are the precursors of carbidopa and levodopa, respectively, included in AbbVie's Parkinson's treatment drug Duopa, approved in 2015. Precursors, as a special form of drugs, enter the body and are converted into active drug components once inside. This design aims to improve the drug's bioavailability and reduce side effects, providing better treatment outcomes for patients. Despite the FDA's rejection, which left AbbVie deeply disappointed, the company has not given up on its collaboration with the FDA and continues to advance the development of ABBV-951. AbbVie Senior Vice President and Global Therapy Chief Medical Officer Dr. Roopal Thakkar stated in a statement, "We will continue to work closely with the FDA to address the current issues and strive to bring ABBV-951 to market as soon as possible." The FDA's rejection did not involve the safety, effectiveness, or labeling issues of ABBV-951, including the drug's subcutaneous pump device. In the past, this device did give some pharmaceutical companies trouble, but AbbVie has conducted thorough research and validation to ensure its safety and effectiveness. Last March, ABBV-951 was rejected by the FDA for the first time, due to the need for additional information about the candidate drug's delivery device. However, AbbVie did not give up, but instead made comprehensive improvements and supplements in response to the FDA's requirements. Today, ABBV-951 is delivered through a pump under the skin, providing patients with a more convenient and comfortable treatment option. Evercore ISI analysts have high hopes for ABBV-951 and praised it as one of AbbVie's "biggest new products to launch in the next one to two years." Analysts believe that ABBV-951's design is intended to provide convenience advantages over Duopa, which has been on the market for nearly a decade in a gel form and must be administered via a feeding tube. This new method of drug delivery will greatly reduce the burden on patients and improve their quality of life. However, AbbVie stated in its press conference on Tuesday that it would not conduct any additional efficacy or safety trials for the candidate drug or its delivery device. This decision has drawn widespread attention from the industry, but AbbVie's confidence and determination in its products has not wavered. Wall Street analysts had previously estimated that ABBV-951's peak sales could reach $1 billion, but the Evercore team said last year that they "would not be surprised" if the drug ultimately exceeded the $2 billion mark. This is enough to demonstrate the industry's expectations and confidence in ABBV-951. Meanwhile, AbbVie's Parkinson's disease prodrug combination is also facing challenges from competitors. Mitsubishi Tanabe Pharma's nd-0612 is also a continuous subcutaneous infusion of liquid levodopa and carbidopa, and the Japanese company acquired NeuroDerm for $1.1 billion in 2017. However, Mitsubishi Tanabe revealed in a recent filing that nd-0612 had also been subject to an FDA CRL attack earlier this month. The details behind the rejection are scarce, but the company said it would review the complete response and work with the FDA to address the regulator's concerns. In other areas, the pump-based therapy has also posed problems for other pharmaceutical companies developing Parkinson's disease drugs. For example, in April this year, Supernus' SPN-830 application was rejected for the third time due to product quality and syringe master file issues. These problems indicate that while new modes of administration offer convenience and comfort to patients, they also bring new challenges and tests. Although AbbVie encountered setbacks in the development of ABBV-951, the company has not given up its exploration and innovation in Parkinson's disease treatment. AbbVie will continue to work with the FDA to advance the development and marketing of ABBV-951, bringing better treatment outcomes and quality of life to patients. At the same time, AbbVie will also keep track of its competitors' dynamics and market changes, continuously adjust and optimize its product line to maintain its leading position in Parkinson's disease treatment.

上市批准并购

2024-06-27

·E药经理人

全球首个HER3 ADC上市卡壳！礼来、艾伯维曾陷类似窘境，什么拦住了默沙东的FIC？

生产方面的缺陷为何到了FDA审查环节才被发现？撰文| Kathy 编辑| 润屿顿河就差临门一脚！凭着优异临床数据拿到优先审批资格，翘首以盼半年，默沙东和第一三共等来的却是一纸延迟批准的CRL（完整回复函）。本该摘下全球首个HER3成药光环的默沙东与第一三共，却在PDUFA（FDA对新药申请的目标批准日期）当日，遭遇反转。 6月26日，默沙东和第一三共宣布，其HER3 ADC药物Patritumab Deruxtecan基于第三方生产原因，被FDA延迟批准用于既往至少接受过两种系统治疗的EGFR突变型局部晚期或转移性非小细胞肺癌。 FDA的完整回复函中提到，延迟审批的原因来自于第三方制造设施检查相关的调查结果。作为全球首款申报上市的HER3 ADC，Patritumab Deruxtecan既承载着“全球首个HER3成药”的希望，更担着“默沙东的第一个ADC”的“重任”。不幸之中的万幸是，CRL表示，Patritumab Deruxtecan疗效和安全性数据并未存在问题。但隐藏于这番“侥幸”之下的，是越来越多好不容易迈过“十年十亿美元”研发难关的创新药，筑起千里之堤后，倏然“卡在”了生产方面的缺陷——一个或许最不该成为掣肘的环节上。打破成药黑洞只差最后一脚 73亿美元，这大概就是10个月前默沙东打包第一三共三款在研ADC产品权益时，HER3-DXd一条管线的价值，可想这含金量。具体而言，根据双方协议，双方达成合作时，默沙东一次性支付给第一三共7.5亿美元（约合54亿元）预付款用于HER3 ADC产品。待合作12个月后，继续支付7.5亿美元。预付款合计15亿美元。 HER3的竞争虽不及HER2激烈，但靶点被发现三十余年来，始终未能成药，谁能拔得头筹？备受瞩目。原本一路领跑的默沙东与第一三共，突然卡在终点线前，不禁让人惋惜。 Patritumab Deruxtecan原本是全球研发进展最快的HER3靶点药物。去年12月时，FDA受理了该药的BLA并给予优先审评，用于治疗EGFR突变的局部晚期或转移性非小细胞肺癌（NSCLC）且在接受第三代酪氨酸激酶抑制剂（TKI）和铂类药物治疗期间或之后出现疾病进展的患者。 Patritumab Deruxtecan递交的BLA是基于HERTHENA-Lung01关键性II期试验的主要结果和IASLC 2023世界肺癌大会（#WCLC23）上公布的数据结果，这些结果同时发表在《临床肿瘤学杂志》上。 HERTHENA-Lung01研究结果显示：在EGFR TKI和铂类化疗后疾病进展的225例EGFR突变局部晚期或转移性NSCLC患者中，Patritumab Deruxtecan治疗的客观缓解率（ORR）为29.8%（95%CI：23.9-36.2），包括1例完全缓解和66例部分缓解。中位缓解持续时间为6.4个月（95%CI：4.9-7.8）。细看FDA这次发出的CRL显示，被延期的原因主要是由于第三方制造设施检查相关的调查结果。让人稍感安慰的是，FDA表示疗效和安全性数据并未存在问题。这也意味着，待解决制造问题后，HER3 DXD ADC依然有希望成为照进黑洞的第一缕光，在ADC领域砸下重金的默沙东，依然还有拿下第一名的机会。然而，也极有可能的是，Patritumab Deruxtecan的第一名宝座会被摘得竞争对手弯道超车而抢占。双抗与ADC是近年来靶向HER3治疗中最有希望成药的两大赛道。就在上月，Merus公司的HER2/HER3双抗Zenocutuzumab上市申请已获FDA受理，并被授予了优先审评资格。此前有分析指出，若一切顺利，Zenocutuzumab有可能在今年11月获批。默沙东/第一三共与Merus，分别代表了ADC与双抗，双方正在首个HER3成药的审批上“暗暗较劲”，而在他们身后，处在研发阶段的企业也在奋力冲刺、虎视眈眈。百利天恒与BMS潜在总交易额高达84亿美元的项目BL-B01D1，同样是HER3靶点ADC，为EGFR×HER3双抗ADC。值得注意的是，Patritumab Deruxtecan与BL-B01D1是唯二处于临床III期的HER3 ADC。也难怪BMS此前不惜砸下重金。从研发进展来看，百利天恒已经在国内启动三项Ⅲ期临床与多项II期临床，同时BL-B01D1的Ⅰ/Ⅱ期探索性临床正在对十余个潜在适应证进行验证。此外，BL-B01D1正在开展全球多中心I期临床研究（BL-B01D1-LUNG101），根据此前披露，BMS及百利天恒将陆续启动在肺癌、乳腺癌领域的全球注册临床。就像Patritumab Deruxtecan此前曾多次遭遇临床研究失败一样，正处在II期阶段的另一款研发进展较为靠前的宜联生物HER3 ADC在上周被FDA叫停。 BioNTech在上周披露了一份SEC公告文件，其中显示FDA已部分暂停了其合作伙伴宜联生物的HER3 ADC BNT326/YL202的多中心、开放标签、首次人体I期临床（NCT05653752）。具体来看，由于试验过程中已有三位患者因药物副作用死亡，FDA表示了担忧，即在较高剂量下，可能会使人类受试者面临不合理和重大的疾病或伤害风险。究竟谁能打破HER3靶点被发现超过30年，却至今未有成药的尴尬现实？推荐阅读 * 曾10年蝉联榜首，今400亿美元围猎ADC，默沙东能重回全球药企TOP1吗？ * 全球TOP10药物大变！K药最"短命"，罗氏砍8大项目，AZ 、辉瑞停GLP-1，默沙东研发费用300亿…… 生产缺陷“害惨”了谁被延迟批准的FIC，Patritumab Deruxtecan不是第一个。上一个与其经历类似的选手Zolbetuximab，花费了近4个月的时间重新向FDA递交BLA，PDUFA也因此推迟了10个月。与HER3的相似，成名于2016年ASCO的Zolbetuximab是全球进展最快的Claudin 18.2靶点药物，一举一动同样全球瞩目。 2023年7月时，FDA基于安斯泰来提交的Zolbetuximab的优异的临床数据，授予其用于一线治疗不可切除、局部晚期或转移性、HER2阴性、胃或胃食管交界处 (GEJ) 患者的优先审批资格，PDUFA日期为2024年1月12日。同样在万众期待之下，安斯泰来收到的也是一封延迟审批CRL。在CRL信函中，FDA指出了Zolbetuximab第三方生产工厂未解决的缺陷，因此不能在原定的PDUFA日期前批准该药上市。历史总是惊人的相似，和Patritumab Deruxtecan目前的境况一样，FDA也未对Zolbetuximab的临床数据提出任何疑问，也没有要求安斯泰来开展额外的临床试验。虽然因生产缺陷暂时折戟FDA，Zolbetuximab今年3月在日本获批上市，成为全球首款且目前唯一获批的靶向CLDN18.2阳性、不可切除、晚期或复发性胃癌患者的治疗方案。在今年5月，安斯泰来重新向FDA递交了Zolbetuximab的BLA。根据处方药用户费用法案（PDUFA），FDA将新审批日期设定为今年的11月9日。一个第三方生产工厂的缺陷，让一款FIC药物上市后独占市场的时间减少至少十个月。安斯泰来与默沙东、第一三共的遭遇并非个案。包括艾伯维、礼来、诺和诺德、再生元在内的全球巨头，抑或是Biotech公司，都倒在了生产核查环节。来自生产方面的缺陷，在FDA发出CRL并延迟审批/拒绝其NDA/BLA申请的比例越来越高，甚至有企业连续四次都无法通过FDA的检查。 FDA签发CRL中所涉及的缺陷，一般分为7大类，即一般缺陷、药效、安全性、临床药理学、非临床研究、生产制造、标签。虽然药效、安全性仍然是FDA“说不”的最主要原因，但与生产制造相关问题的比例近年来明显攀升。公开数据统计，仅2023年，FDA共发出36封CRL（包含小分子及大分子药物），存在生产方面缺陷的CRL达到18封，占比已经高达50%。与药物安全性、有效性出现缺陷相比，生产方面相关的问题或许不是致命性的，但却同样会让一款药物的上市计划被搁置，轻则股价波动、重则商业化停滞、失去市场先机。艾伯维就在近日因为第三方生产商的问题第二次被FDA拒绝，股票在当日早盘交易中小幅下跌。 6月25日，艾伯维收到FDA就ABBV-951（foslevodopa / foscarbidopa）用于晚期帕金森病运动症状波动（motor fluctuations）的新药上市申请（NDA）发出的完整回复函（CRL）。时隔一年多再次被FDA拒绝批准的原因主要在于第三方生产商。 FDA列出了在对第三方合同生产组织检查中观察到的结果，不涉及ABBV-951及设备，也未提及ABBV-951（包括该组合的皮下注射泵装置）安全性、有效性、标签相关的任何问题，且没有要求艾伯维补充额外的疗效和安全性试验。不过艾伯维依然没有放弃，表示会继续与FDA保持积极合作，尽早为帕金森病患者提供该创新疗法。 MNC或许还能快速应对，对于抗风险能力较弱的Biotech公司来说，可能带来“灭顶之灾”。 Spectrum Pharmaceuticals就曾在收到FDA关于其Rolontis用于治疗接受骨髓抑制性癌症药物的患者的中性粒细胞减少证申请的CRL后，股价应声下跌了近30%，CRL信中提到因生产制造方面的缺陷，有必要对韩国的Hanmi Bioplant公司进行重新检查。比Spectrum处境更糟糕的ImmunityBio，其膀胱癌治疗药物Anktiva因第三方合同制造商存在缺陷而收到CRL，市值蒸发60%。一封CRL还带来了更严重的“后遗症”，此后ImmunityBio宣布裁员以简化运营，专注于当前的业务战略并降低成本。或许越来越多生产制造缺陷带来的CRL与警告信，正在给药物研发公司敲个警钟：在递交上市申请前，不论是自有工厂生产或委托第三方生产，都要进行风险评估与系统检查，对产品设计、生产工艺、设施等等全流程进行更严格的核查。生产方面的缺陷到了FDA审查才被发现，是否太晚了？回复“逆商”，了解电子期刊详情精彩推荐 CM10 | 集采 | 国谈 | 医保动态 | 药审 | 人才 | 薪资 | 榜单 | CAR-T | PD-1 | mRNA | 单抗 | 商业化 | 国际化｜猎药人系列专题 | 出海启思会 | 声音·责任 | 创百汇 | E药经理人理事会 | 微解药直播 | 大国新药 | 营销硬观点 | 投资人去哪儿 | 分析师看赛道 | 药事每周谈 | 医药界·E药经理人 | 中国医药手册创新100强榜单 | 恒瑞 | 中国生物制药 | 百济 | 石药 | 信达 | 君实 | 复宏汉霖｜翰森 | 康方生物 | 上海医药 | 和黄医药 | 东阳光药 | 荣昌 | 亚盛医药 | 齐鲁制药 | 康宁杰瑞 | 贝达药业 | 微芯生物 | 复星医药｜再鼎医药｜亚虹医药跨国药企50强榜单 | 辉瑞 | 艾伯维 | 诺华 | 强生 | 罗氏 | BMS | 默克 | 赛诺菲 | AZ | GSK | 武田 | 吉利德科学 | 礼来 | 安进 | 诺和诺德 | 拜耳 | 莫德纳 | BI | 晖致 | 再生元

抗体药物偶联物优先审批临床2期引进/卖出申请上市

100 项与左旋多巴相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00059	左旋多巴	N04BA01	DB01235

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
帕金森病	美国	Shire Development LLC	1970-06-04
帕金森病	美国	Hoffmann-La Roche, Inc.	1970-06-04

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
运动失调	临床3期	美国	AbbVie, Inc.	2009-06-01
运动失调	临床3期	德国	AbbVie, Inc.	2009-06-01
运动失调	临床3期	新西兰	AbbVie, Inc.	2009-06-01

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临床结果

适应症

分期

评价

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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


MDS2023	N/A	肌张力障碍	-	Pre-levodopa administration	憲築願夢簾構鬱艱網鹽(觸獵憲窪齋選積構餘繭) = 獵醖衊壓糧憲遞餘膚簾鹹鏇簾襯艱觸顧壓選獵 (齋齋蓋製壓網鏇遞餘網 )	-	2023-08-27
				Post-levodopa administration	憲築願夢簾構鬱艱網鹽(觸獵憲窪齋選積構餘繭) = 蓋鹽積積範窪壓壓襯鹹鹹鏇簾襯艱觸顧壓選獵 (齋齋蓋製壓網鏇遞餘網 )
PD MED early disease randomisation (MDS2023)	N/A	帕金森病	1,593	Levodopa-sparing therapy (dopamine agonist or monoamine oxidase B inhibitor)	簾鹹淵築淵醖繭觸獵鹽(窪夢網顧鏇範膚艱積積): P-Value = 0.84 更多	积极	2023-08-27
				Levodopa alone
INVEST study (MDS2023)	N/A	帕金森病	-	Continuous intrajejunal levodopa infusion (CILI)	鏇範窪膚廠鹹齋積壓製(願餘艱壓鬱鹹醖繭蓋餘) = 製窪廠網夢築繭壓艱壓淵襯膚積衊網鹹築遞簾 (艱製餘築鹹齋衊壓簾壓, -2.9 ~ 11.0)	-	2023-08-27
MDS2023	N/A	-	110	LD/DCI	醖蓋壓淵範糧艱齋齋繭(淵廠顧繭壓醖積夢遞醖) = 選鹽膚糧膚窪蓋簾膚衊憲艱願艱顧襯鹽獵鬱壓 (糧餘鏇夢顧積遞艱鏇糧 ) 更多	积极	2023-08-27
				LD/DCI+COMT-I	醖蓋壓淵範糧艱齋齋繭(淵廠顧繭壓醖積夢遞醖) = 遞壓積願鹽積夢構獵襯憲艱願艱顧襯鹽獵鬱壓 (糧餘鏇夢顧積遞艱鏇糧 ) 更多
MDS2023	N/A	帕金森病 calpains	16	Without levodopa	製憲構蓋獵餘築憲餘膚(窪獵遞鏇選網鹽鏇觸餘) = 糧餘範積糧蓋憲積蓋鑰蓋憲衊顧壓繭繭顧鏇願 (範壓糧餘糧顧簾淵餘憲, - 0.11)	积极	2023-08-27
				Daily dose up to 600 mg	製憲構蓋獵餘築憲餘膚(窪獵遞鏇選網鹽鏇觸餘) = 構簾網襯範醖鑰窪築醖蓋憲衊顧壓繭繭顧鏇願 (範壓糧餘糧顧簾淵餘憲, - 0.16)
MDS2023	N/A	帕金森病	-	levodopa	窪襯範襯憲壓鏇遞鹹膚(簾範襯繭艱餘餘蓋積觸) = 範襯積簾艱觸願繭繭壓願糧鑰觸積觸鹹衊窪窪 (夢憲鬱選鏇餘壓築醖構 )	积极	2023-08-27
				levodopa	壓願壓衊築構夢網齋構(製廠艱積選製願淵積餘) = 獵襯築鏇鑰憲艱醖獵鏇繭醖網製淵醖獵鬱齋鑰 (繭鬱夢襯製觸齋憲蓋廠 ) 更多
MDS2023	N/A	帕金森病	3	Levodopa intake	鹹願簾襯範蓋製繭艱廠(蓋齋簾鏇獵觸選積積襯) = 襯範範蓋廠鹽選繭遞廠蓋築製鏇鑰窪衊獵觸願 (積糧範廠願襯網糧遞簾, 57.2)	积极	2023-08-27
MDS2023	N/A	帕金森病	-	Levodopa/Benserazide	鏇範鏇醖願蓋製構鑰餘(簾憲鬱鹽顧糧網鬱選鏇) = 醖製糧鏇製餘獵鬱鑰鏇醖憲窪窪鹽鹽築鑰願膚 (廠淵窪選淵膚壓壓鹹獵 )	不佳	2023-08-27
				Placebo	鏇範鏇醖願蓋製構鑰餘(簾憲鬱鹽顧糧網鬱選鏇) = 鏇糧蓋簾鹽網壓築獵鑰醖憲窪窪鹽鹽築鑰願膚 (廠淵窪選淵膚壓壓鹹獵 )
Parkinson’s Progression Markers Initiative (PPMI) (MDS2023)	N/A	帕金森病	428	levodopa	蓋範衊鑰願遞獵簾顧淵(餘顧艱衊鹹夢膚築鹽鹽) = 遞構選簾遞膚廠製範壓願鏇顧範鏇鬱糧繭淵鏇 (壓壓鹽壓選構獵願觸積 )	-	2023-08-27
				levodopa	蓋範衊鑰願遞獵簾顧淵(餘顧艱衊鹹夢膚築鹽鹽) = 廠艱窪夢鑰觸夢範衊廠願鏇顧範鏇鬱糧繭淵鏇 (壓壓鹽壓選構獵願觸積 )
ARVO2023	N/A	年龄相关性黄斑变性	21	Levodopa	願淵廠淵鹹願壓憲遞夢(範糧糧膚醖鏇齋襯壓遞) = 鹹鑰窪膚積衊構窪壓壓窪製夢網築衊廠夢製廠 (壓選鹹簾廠製壓餘淵願 ) 更多	-	2023-06-01
				Other Dopamine Agonists (ropinirole, pramipexole, bupropion, amantadine, bromocriptine)	築觸廠膚淵夢鏇壓製製(遞壓糧膚顧壓構選鹽築) = 繭簾鹽齋觸鏇壓襯構觸膚艱鹹壓壓範選艱襯醖 (選憲願簾範齋遞淵淵鑰 ) 更多