This phase I/II trial tests the safety, side effects, and best dose of tazemetostat and umbralisib and whether tazemetostat in combination with umbralisib and ublituximab works to shrink tumors in patients with follicular lymphoma that has come back (relapsed) or does not respond to treatment (refractor). Tazemetostat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Umbralisib may help block the formation of growths that may become cancer. Ublituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving tazemetostat in combination with umbralisib and ublituximab may work better in treating follicular lymphoma.

开始日期2023-05-01

申办/合作机构

City of Hope National Medical Center

[+1]

NCT04635683 / Withdrawn临床1期

A Phase I Trial of Lenalidomide, Umbralisib and Ublituximab in Patients With Relapsed or Refractory Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma

This phase I trial studies the safety and how effective the combination of ublituximab, umbralisib, and lenalidomide is in certain types of indolent (slow-growing) non-Hodgkin's lymphoma or mantle cell lymphoma. Lenalidomide may stimulate the immune system in different ways and stop cancer cells from growing. Lenalidomide may also stop the growth of non-Hodgkin's lymphoma by blocking blood flow to the cancer. Umbralisib is designed to block a protein called PI3 kinase in order to stop cancer growth and cause changes in the immune system that may allow the immune system to better act against cancer cells. Ublituximab is an antibody that attaches to the lymphoma cells and triggers immune reactions that may result in the death of the targeted lymphoma cells.

开始日期2022-09-30

申办/合作机构

Ohio State University Comprehensive Cancer Center

NCT04692155 / Terminated临床1/2期IIT

Phase Ib/II Trial of Ublituximab and Umbralisib With CHOP (U2-CHOP) Followed by U2 Maintenance (U2-CHOP-U2) in Previously Untreated Mantle Cell Lymphoma (MCL)

This is a single arm, multi-center, open label Phase Ib/II trial in adult patients with newly diagnosed Mantle Cell Lymphoma (MCL)(Stage II-IV). The Diagnosis of MCL (Stage II, III, IV) is supported by histology and over expression of cyclin D1 or by FISH (fluorescent in situ hybridization). In the proposed study, the primary endpoint is to estimate the biological response rate of the combination of Umbralisib at dose 800 mg with Ublituximab (900mg)-Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP), but a phase Ib portion with dose de-escalation at two does level (800 and 600 mg) will be built in to further confirm its safety and tolerability. Treatment will be administered on an outpatient basis in 3-week (21 day) cycles. Once Umbralisib dose is defined in phase Ib, the study will expand to phase II portion after SMC/DSMB (Safety monitoring committee/Data Safety Monitoring Committee) agreement.

开始日期2021-08-31

申办/合作机构

The University of Alabama at Birmingham

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100 项与厄布利塞相关的专利（医药）

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项与厄布利塞相关的文献（医药）

2024-09-03·CLINICAL CANCER RESEARCH

PI3K Inhibitors in Hematology: When One Door Closes…

Review

作者: Skånland, Sigrid S. ; Okkenhaug, Klaus ; Davids, Matthew S.

Abstract:

The PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan–class I inhibitor copanlisib (2017), the dual PI3Kγ/δ inhibitor duvelisib (2018), and the PI3Kδ and casein kinase 1ε inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, whereas idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates; however, follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression-free survival when compared with chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3Kis. In this study, we review the development and current status of PI3Kis in hematology, limitations to their use, and our perspective on whether there is a future for PI3Kis in hematology.

2024-09-01·CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY

Safety profile of first-line targeted therapies in elderly and/or comorbid chronic lymphocytic leukaemia patients (unfit subpopulation). A systematic review and network meta-analysis

Review

作者: Reczek, Monika ; Stożek-Tutro, Anita ; Kawalec, Paweł

This systematic literature review (CRD42023393903) and a Bayesian network meta-analysis (NMA) aimed to assess the relative safety profile of first-line targeted therapies (acalabrutinib, ibrutinib, obinutuzumab, ofatumumab, pirtobrutinib, ublituximab, umbralisib, venetoclax, zanubrutinib) in chronic lymphocytic leukaemia (CLL) patients with advanced age and/or comorbidities. The NMA revealed that zanubrutinib was the safest treatment option in terms of the overall safety profile (e.g., serious adverse events [AEs] grade 1-5), followed by venetoclax-obinutuzumab, which showed an advantage in terms of AEs grade 1-5. The use of Bruton's tyrosine kinase inhibitor (BTKi) monotherapy was more favourable in terms of the risk of haematological AEs, but chemoimmunotherapy showed advantages in terms of cardiovascular, gastrointestinal, and infectious AEs. The risk of secondary cancers was similar between treatments. In conclusion, targeted therapies are associated with variable and clinically relevant AEs. The therapies appear to be safer when used as monotherapy rather than in combination with immunological agents in naïve CLL patients with advanced age and/or comorbidities.

2024-05-01·Anti-cancer agents in medicinal chemistry

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021)

Review

作者: Gupta, Ghanshyam Das ; Jain, Ankit ; Vishakha, S ; Navneesh, N ; Verma, Sant Kumar ; Patel, Preeti ; Kurmi, Balak Das

Abstract::

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

项与厄布利塞相关的新闻（医药）

2024-09-19

·PRNewswire

Mantle Cell Lymphoma Clinical Trial Pipeline Insights Featuring 20+ Companies | DelveInsight

Mantle cell lymphoma is a rare and aggressive type of non-Hodgkin lymphoma originating from B-cells in the "mantle zone" of the lymph nodes. The development of novel targeted therapies and immunotherapies, such as Bruton's tyrosine kinase (BTK) inhibitors, is improving treatment outcomes and driving market growth for Mantle cell lymphoma. LAS VEGAS, Sept. 19, 2024 /PRNewswire/ -- DelveInsight's ' Mantle Cell Lymphoma Pipeline Insight 2024 ' report provides comprehensive global coverage of pipeline mantle cell lymphoma therapies in various stages of clinical development, major pharmaceutical companies are working to advance the pipeline space and future growth potential of the mantle cell lymphoma pipeline domain. Key Takeaways from the Mantle Cell Lymphoma Pipeline Report DelveInsight's mantle cell lymphoma pipeline report depicts a robust space with 20+ active players working to develop 22+ pipeline therapies for mantle cell lymphoma treatment. Key mantle cell lymphoma companies such as AbbVie, Adicet Bio, InnoCare Pharma Inc., Guangzhou Lupeng Pharmaceutical Company LTD., BeiGene, Nurix, LegoChem Biosciences, Xynomic Pharmaceuticals, Merck & Co, Incyte Corporation, TG Therapeutics, Janssen/Pharmacyclics, Eternity Bioscience, Traws Pharm, Advenchen Laboratories, and others are evaluating new mantle cell lymphoma drugs to improve the treatment landscape. Promising mantle cell lymphoma pipeline therapies such as Venetoclax, ADI-001, Orelabrutinib, LP-168, BGB-11417, NX 2127, LCB 71, NX 5948, Abexinostat, Pembrolizumab, Parsaclisib, Umbralisib, Ibrutinib, Edralbrutinib, Narazaciclib, Lucitanib, and others are under different phases of mantle cell lymphoma clinical trials. In May 2024, AstraZeneca had announced positive interim results from the Phase III ECHO clinical trial, which evaluated Bruton's tyrosine kinase (BTK) inhibitor Calquence (acalabrutinib) in combination with standard chemoimmunotherapy for treating mantle cell lymphoma (MCL). In March 2024, BeiGene, Ltd. announced the presentation of emerging oncology pipeline data at the American Association for Cancer Research (AACR) Annual Meeting. Additional highlights include preclinical characterization data for an investigational BTK degrader, BGB-16673, currently in clinical development for B-cell malignancies, including mantle cell lymphoma In October 2023, Ascentage Pharma announced that it has entered into a clinical collaboration with AstraZeneca Investment. The two companies will jointly conduct a registrational Phase III study of the Bcl-2 inhibitor, APG-2575 (lisaftoclax), in combination with AstraZeneca's Bruton's tyrosine kinase (BTK) inhibitor, CALQUENCE® (acalabrutinib), in treatment-naive patients with first-line chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). In January 2023, the FDA granted an orphan drug designation to LP-284, a novel small-molecule, next-generation acylfulvene, for the treatment of mantle cell lymphoma (MCL), a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL), according to an announcement from Lantern Pharma. Request a sample and discover the recent advances in mantle cell lymphoma treatment drugs @ Mantle Cell Lymphoma Pipeline Report The mantle cell lymphoma pipeline report provides detailed profiles of pipeline assets, a comparative analysis of clinical and non-clinical stage mantle cell lymphoma drugs, inactive and dormant assets, a comprehensive assessment of driving and restraining factors, and an assessment of opportunities and risks in the mantle cell lymphoma clinical trial landscape. Mantle Cell Lymphoma Overview Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphomas (NHLs) characterized by the (11,14) translocation, leading to overexpression of the cyclin D1 (CCND1) gene. Its various morphological variants can make diagnosis challenging, though some cases are straightforward. Many individuals with MCL are asymptomatic in the early stages, but may later seek medical attention due to persistent, typically painless swelling of lymph nodes, especially in the neck and throat region (e.g., Waldeyer's ring). MCL is marked by a reciprocal chromosomal translocation t(11;14)(q13;q32), which places the cyclin D1 gene next to the immunoglobulin heavy chain gene, causing continuous cyclin D1 expression. This overexpression contributes to tumor cell proliferation through cell cycle dysregulation, chromosomal instability, and epigenetic changes. Rarely, MCL cases without this translocation may involve CCND2 or CCND3 translocations. Hypothetical molecular subtypes, based on the cell of origin, correlate with clinical phenotypes: classical or aggressive MCL arises from naive B cells lacking or having limited iGVH mutations and expressing SOX11, a neural transcription factor inhibiting terminal B cell differentiation. The indolent variant originates from antigen-experienced B cells with IGVH somatic hypermutations, typically SOX11-negative and genetically stable. Diagnosis of MCL involves detailed patient history, thorough clinical evaluation, and specialized tests, including biopsy of an affected lymph node or bone marrow. These tests confirm the NHL type and subtype, assess disease extent, and determine appropriate treatments. Treatment for MCL is multifaceted and tailored to each patient, often including chemotherapy, immunotherapy drugs like rituximab, targeted therapies such as ibrutinib, and stem cell transplants, particularly for aggressive disease or younger patients. Radiation therapy may target specific lymphoma areas. Participation in clinical trials can offer new treatment options. Treatment plans are developed collaboratively by healthcare professionals and patients, considering disease stage, overall health, and personal preferences. Regular monitoring and follow-up care are essential to track treatment response and manage side effects effectively. Find out more about mantle cell lymphoma treatment drugs @ Drugs for Mantle Cell Lymphoma Treatment A snapshot of the Mantle Cell Lymphoma Pipeline Drugs mentioned in the report: Learn more about the emerging mantle cell lymphoma pipeline therapies @ Mantle Cell Lymphoma Clinical Trials Mantle Cell Lymphoma Therapeutics Assessment The mantle cell lymphoma pipeline report proffers an integral view of the mantle cell lymphoma emerging novel therapies segmented by stage, product type, molecule type, mechanism of action, and route of administration. Scope of the Mantle Cell Lymphoma Pipeline Report Coverage: Global Therapeutic Assessment By Product Type: Mono, Combination, Mono/Combination Therapeutic Assessment By Clinical Stages: Discovery, Pre-clinical, Phase I, Phase II, Phase III Therapeutics Assessment By Route of Administration: Oral, Parenteral, Intravenous, Subcutaneous, Topical Therapeutics Assessment By Molecule Type: Recombinant fusion proteins, Small molecule, Monoclonal antibody, Peptide, Polymer, Gene therapy Therapeutics Assessment By Mechanism of Action: Apoptosis stimulants, Proto-oncogene protein c-bcl-2 inhibitors, Proteasome inhibitors, Immunologic cytotoxicity, T lymphocyte replacements, Agammaglobulinemia tyrosine kinase inhibitors Key Mantle Cell Lymphoma Companies: AbbVie, Adicet Bio, InnoCare Pharma Inc., Guangzhou Lupeng Pharmaceutical Company LTD., BeiGene, Nurix, LegoChem Biosciences, Xynomic Pharmaceuticals, Merck & Co, Incyte Corporation, TG Therapeutics, Janssen/Pharmacyclics, Eternity Bioscience, Traws Pharm, Advenchen Laboratories, and others Key Mantle Cell Lymphoma Pipeline Therapies: Venetoclax, ADI-001, Orelabrutinib, LP-168, BGB-11417, NX 2127, LCB 71, NX 5948, Abexinostat, Pembrolizumab, Parsaclisib, Umbralisib, Ibrutinib, Edralbrutinib, Narazaciclib, Lucitanib, and others Dive deep into rich insights for new drugs for mantle cell lymphoma treatment, visit @ Mantle Cell Lymphoma Drugs Table of Contents For further information on the mantle cell lymphoma pipeline therapeutics, reach out @ Mantle Cell Lymphoma Treatment Drugs Related Reports B-Cell Lymphoma Epidemiology B-Cell Lymphoma Epidemiology Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology as well as the B-cell lymphoma epidemiology trends. B-Cell Lymphoma Market B-Cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2032 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key B-cell lymphoma companies, including Vincerx Pharma, Ubix Therapeutics, Biomea Fusion Inc, Shanghai Hengrui Pharmaceutical, BeiGene, Hanmi Pharmaceutical, among others. Diffuse Large B-Cell Lymphoma Pipeline Diffuse Large B-Cell Lymphoma Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key DLBCL companies, including Genmab, Roche, Acerta Pharma, Autolus, Xynomic Pharmaceuticals, Genentech, Celgene, AbbVie, Mabion, among others. Diffuse Large B-Cell Lymphoma Market Diffuse Large B-Cell Lymphoma Market Insights, Epidemiology, and Market Forecast – 2034 report deliver an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key B-cell lymphoma companies, including AbbVie, Genmab, Merck, Roche, Xencor and Janssen, Denovo Biopharma, Calithera Biosciences, IMV, Biogen, Autolus Therapeutics, Allogene Therapeutics, Novartis, Miltenyi Biomedicine, Regeneron Pharmaceuticals, among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

临床3期免疫疗法孤儿药

2024-08-08

·echemi

Regulatory Challenges of Gene Therapy and Cancer Drugs: Industry Trends Behind the Withdrawal of Zydelig and FDA's Response

In 2022, Gilead announced that it would voluntarily withdraw Zydelig from the U.S. market for two lymphoma treatments, a full six years after it suspended the trial due to patient deaths. A Gilead spokesperson clarified that the withdrawal was not due to safety concerns, but rather because of insurmountable obstacles to recruiting subjects for additional research trials required by the FDA. Nevertheless, Zydelig retains its eligibility for the treatment of chronic lymphocytic leukemia and remains on the market for patients. Notably, the withdrawal of Zydelig coincides with the withdrawal of several other PI3K inhibitors used to treat follicular lymphoma: Secura Bio's duvelisib (trade name Copiktra) withdrawn in December 2021, TG's umbralisib (trade name Ukoniq) withdrawn in 2022 (here may be a clerical error, read "February" or adjusted to another month), Bayer's copanlisib (trade name Aliqopa) also withdrew from the market in November 2023. Together, these events outline an industry trend. A study published in JAMA Internal Medicine reveals an interesting data point: Before Gilead decided to withdraw some uses of Zydelig from the U.S. market, its global sales had reached a staggering $842 million. This reflects the wide application and high recognition of the drug in the market, although it ultimately failed to fully meet all expectations for various reasons. Interestingly, the pharmaceutical industry sometimes employs a series of ingenious strategies to speed up the process of bringing a product to market. Eli Lilly, for example, successfully used all four avenues of acceleration to bring oncology product Lartruvo to market in 2016. The key clinical data for the product is based only on the results of a trial involving 133 patients, and while the results showed a possible positive impact on survival outcomes for sarcoma, a cancer that affects muscles and other soft tissues, the specific effect on slowing cancer growth is unclear. However, just over two years later, a larger study revealed that Lartruvo had no significant impact on patient survival, and Eli Lilly had to withdraw it from the market. Despite this, Lartruvo still managed to achieve a whopping $500 million in sales during its short market life. Among the many drugs approved for accelerated marketing, oncology products have become the hardest hit by ineffective drugs. However, as the development of therapies continues to deepen and progress, new questions continue to emerge and are presented to the FDA. In particular, advanced therapies represented by cell and gene therapies, when they meet with the accelerated approval system, have brought unprecedented challenges to this "old revolution". Given the complexity of cell and gene therapies and the relative lack of understanding of their safety, once ineffective advanced therapies are released to the market, the consequences and impacts will be far beyond the scope of small molecule ineffective drugs. For example, the tragic death of a three-year-old boy in a clinical trial of Pfizer's fordadistrogene movaparvovec, a gene therapy for Duchenne muscular dystrophy, highlights the shortcomings and limitations of researchers in predicting the potential for serious adverse events. As vectors of ssRNA (single stranded RNA), viruses (such as AAV) play a critical role in gene therapy, but can also cause a series of serious adverse events including cardiopulmonary failure, myocarditis, thrombotic microangiopathy, and acute liver failure. These potential risks have forced the FDA to be more cautious and rigorous in approving gene therapies. Speaking at the annual meeting of the American Society for Gene and Cell Therapy, CBER director Peter Marks said speeding up the withdrawal of approved gene therapies could be easier and faster than for small-molecule therapies. At the same time, he stressed that "accelerated approval of gene therapy is not a get-out-of-jail-free ticket." The FDA will not hesitate to withdraw accelerated approval of rare disease gene therapies if they fail subsequent confirmatory trials." Marks further points out that the "one-size-fits-all" nature of gene therapy makes confirmatory studies easier to follow and monitor patients over time. It also makes for greater clarity and clarity on the question of whether to withdraw gene therapy. In contrast, there may be more controversy and disagreement in the decision process of withdrawing cancer therapy. Marks, however, said the FDA would only withdraw gene therapy if it was clear that the patient benefit was likely to be "minimal" but the side effects were significant. He cited a case in which Bluebird Bio's sickle cell gene therapy Lyfgenia (lovotibeglogene autotemcel) caused patients to develop myelodysplastic syndrome and leukemia during treatment. The product was approved by the FDA in December 2023 with a boxed warning about hematologic malignancies. Marks said it is unclear whether these malignancies are related to the preconditioning regimen associated with Lyfgenia treatment, the underlying disease, or the gene therapy itself. In addition, the case of drug manufacturers refusing to voluntarily withdraw the market is not unique in the history of FDA accelerated approval. Everything from the withdrawal of Makena, a drug that reduced the risk of preterm birth, after 12 years on the market, to the legal battle between Pepaxto and the FDA highlights the complexity and seriousness of the issue. In the face of these challenges, FDA has to seek the support of legislation to strengthen its regulatory power and capability. Fortunately, the introduction of the FDORA (Comprehensive Food and Drug Reform Act) bill provides the FDA with greater flexibility and autonomy to act without public hearings.

上市批准基因疗法

2024-08-07

·CPHI制药在线

快进快出？每年几十亿美元的无效药物怎么破？

关注并星标CPHI制药在线 “举秀才，不知书；举孝廉，父别居。寒素清白浊如泥，高第良将怯如鸡”。这首西汉《桓灵时谣》放在当今的医药领域竟然仍有警示作用。 1、无效药物现象抬头一款年销量4亿美元的肌萎缩侧索硬化症（ALS）药物被分析师戏谑为“疗效不如薄荷糖”；一款销售量接近8.5亿美元的血癌药物不仅因为不具疗效被勒令撤市，还在几年前因为安全问题导致患者死亡。这只是捭阖医药领域的无效药物的两个缩影而已。据报道，2014 年以来未通过上市后验证性研究的加速批准药物，以及在美国撤市的药物，其全球销售额总计至少达到36亿美元。难怪耶鲁大学公共卫生教授Gregg Gonsalves一阵见血地指出：“我们获得药物的速度越来越快，但对药物的了解却越来越少，支付的费用也越来越多。”图1显示了自从2000以来通过至少一种快速通道（优先审查、加速批准、突破性疗法认定、快速通道、使用优先审评券PRV）获得FDA批准的药物数量与常规批准药物数量的对比。图1. 2000年以来通过至少一条快速通道获得FDA批准的药物数量。（图片来源：Bloomberg）制药公司可以通过多种方式更快地为患者提供治疗，包括“优先审评（priority review）”、“快速通道（fast track）”、“加速批准（accelerated approval）”以及“突破性疗法（breakthrough therapy）认定”。除此之外，这些条件都不符合的项目还可以使用优先审评券（priority review voucher）实现“召为田舍郎，暮登天子堂”的梦想。根据Bloomberg的数据分析显示，美国的大多数新药都是通过其中一种或多种加速途径获得批准的。2023年有三分之二的新药都是通过这种方式进入市场的（图1）。 2、无效药物背后的加持毫无疑问，实现药物快速上市的动机是好的，但问题是将什么样的药物“扶上马，送一程”。就像“让一部分人先富起来”的政策里面是否提到了让什么样的人先富起来，是那些投机倒把的还是真正对社会发展产生促进作用的？FDA庞大的快速审批策略导致的是一番泥沙俱下的场面。但问题的不断滋生动摇了政策的初衷时，就到了物极必反的思考阶段。文章开始处提到的两款药物，分别是肌萎缩侧索硬化症（ALS）药物Relyvrio和吉利德的血癌药物Zydelig。 Amylyx Pharmaceuticals Inc. 的 ALS 药物Relyvrio在 2022 年寻求批准时，它只完成了一项小型试验，而且试验数据更多地指向了这款药物没有显著临床益处的结论。FDA的专家咨询小组先是做出否决该药物的建议，随后又推翻了自己的决定，建议FDA加速批准。这背后有很多力量使然。首先是ALS患者群体倡议者为FDA施加的压力，其次是Amylyx做出的“如果上市后验证性研究失败将主动撤市”的承诺。在通过加速批准上市后，Amylyx的股票飙升50%多，Amylyx为这款由两种非常简单的小分子有效成分构成的药物标出了15.8万美元的“天价”，2023年卖出了3亿美元。之后就是III期研究PHOENIX失败，Amylyx最终将“譬如朝露”的Relyvrio撤市，裁员70%，股价暴跌超过80%。通常来说，FDA只在掌握了充分证据证明药物有效且益处大于风险的情况下，才会对申请开绿灯。但加速批准从最初的非主流逐渐到目前的大行其道，这种变化改变了FDA的审批惯例。这种尺度不一的表现背后，可能是患者群体及其利益倡导者所施加的压力，他们经常通过非盈利组织联合起来，实现药物的迅速批准上市。例如ALS 协会在其年度报告中表示，它“领导了一场活动，鼓励 FDA 采取紧急和灵活的行动”，将 Amylyx 的药物提供给患者。即便在Relyvrio的III期研究失败之后，ALS 协会仍然发表了一份声明，表达了失望之情，并指出他们支持早期批准，因为Relyvrio看起来很安全，而且患者“愿意在结果无效的情况下冒险”。 FDA 加速审批的另外一个问题，在于这可能滋生制药商“王侯将相宁有种乎”的思维方式，导致大批类似药物的集中申请。比如吉利德的 Zydelig （Idelalisib）于 2014 年通过加速批准上市，用于治疗两种类型的淋巴瘤。但两年内，由于严重的副作用和试验中患者死亡，吉利德停止了对该药物的多项研究。FDA也发出了安全警告，但在之后的几年里，FDA继续加速批准了许多类似的药物。其中之一是 TG Therapeutics Inc. 的血癌药物 Ukoniq。该药于 2021 年 2 月获得加速批准，用于治疗两种类型的淋巴瘤。Ukoniq的获批基于小型试验，未评估患者是否寿命更长。由于迅速获得批准，TG Therapeutics股价上涨了 12%。但不到一年后，Ukoniq针对第三种血癌的更大规模研究发现，与接受标准治疗的患者相比，死亡风险可能增加。在 FDA 的敦促下，TG Therapeutics于 2022 年 4 月将该药物撤出市场，并停止寻求针对其他癌症的批准。同年，吉利德宣布将自愿撤回 Zydelig 在美国的两种淋巴瘤用途，此时距离吉利德因患者死亡而停止试验已经过去了六年。吉利德发言人表示，撤回并不是因为安全问题，而是因为在招募人们参加 FDA 要求的额外研究试验方面遇到了挑战。Zydelig仍在市场上使用，保留慢性淋巴细胞白血病适应症。Zydelig的撤回在时间上与其它治疗滤泡性淋巴瘤的PI3K抑制剂的撤回时间吻合：Secura Bio的duvelisib （Copiktra）于 2021 年 12 月撤回，TG 的umbralisib （Ukoniq）于 2022 年 14月撤回，拜耳的copanlisib （Aliqopa）于 2023 年 11 月撤回（图2）。《美国医学会杂志内科医学》的一项研究发现，吉利德在将Zydelig撤回美国的部分用途之前，其全球销售额达到了 8.42 亿美元。图2. 撤回的PI3K抑制剂滤泡性淋巴瘤药物。有趣的是，有时候制药商可以祭出一套组合拳加速他们的产品上市。例如礼来在2016年动用了全部四种加速途径将他们的肿瘤学产品Lartruvo 推向了市场。其关键临床数据只是基于一项133名患者参加的试验结果，显示处对肉瘤（一种影响肌肉和其他软组织的癌症）的生存结果可能产生正面影响，尽管其减缓癌症生长的作用尚不明确。仅仅两年多后，一项更大规模的研究表明Lartruvo对患者的生存没有影响，礼来随即将其从市场上撤下。Lartruvo在其短暂的市场活跃期间收获了5亿美元的销售额。 3、无效获批药物新现象：先进疗法通过加速批准上市的无效药物中肿瘤学产品是重灾区。然而疗法开发的深入进步，也不断地将新问题呈现到FDA面前，细胞和基因疗法为代表的先进疗法，当它们与加速批准“金风玉露一相逢“的话，便给FDA这个“老革命”制造了新问题。尤其是考虑到细胞和基因疗法的“量级”以及人们对其安全性认识的相对不足，无效的先进疗法如果放行进入市场，造成的声响可能要远大于小分子无效药物。例如辉瑞的杜氏肌营养不良症基因疗法fordadistrogene movaparvovec在临床试验中造成一名三岁男童死亡，就凸显了研究者对于基因疗法的潜在严重不良事件预判方面的不足。作为ssRNA（单链RNA）的载体，病毒（例如AAV）有可能引发包括心肺衰竭、心肌炎、血栓性微血管病和急性肝衰竭等严重不良事件。在美国基因与细胞治疗学会年会上，CBER主任 Peter Marks 称，加速批准的基因疗法的撤回将比小分子疗法更容易，同时表态称，基因疗法加速批准并没有免死金牌，如果罕见病基因疗法未能通过验证性试验，FDA将撤回加速批准。Marks认为，基因疗法“一劳永逸”的性质不仅使验证性研究更容易长期跟踪患者，而且在判断是否撤回的问题上更加黑白分明。相对于肿瘤疗法的撤回，基因疗法的撤回将不会引发很大争议。但对于基因疗法的撤回标准，Marks表示，只有当情况非常明确时，FDA才会做出撤回基因疗法的决定。例如对患者的益处可能“微乎其微”，但副作用却很大的情景模式。Marks 列举了Bluebird Bio 的镰状细胞基因疗法 Lyfgenia（lovotibeglogene autotemcel）中患者出现骨髓增生异常综合征和白血病的情况。Lyfgenia该产品于2023年12 月获得FDA批准，并附有关于血液恶性肿瘤的黑框警告。Marks称，目前尚不清楚与 Lyfgenia 治疗相关的预处理方案、潜在疾病还是基因治疗本身导致了恶性肿瘤。 4、骑虎难下？监管机构如何面对无效获批药物制药商拒绝主动撤市的案例在FDA加速批准史中也屡见不鲜。前有Makena（降低早产风险药物）12年后撤市，后有Pepaxto与FDA对簿公堂。FDA的东郭先生在面对中山狼时只得求诸立法。索性的是，FDORA（《食品和药品综合改革法》）法案的出台赋予了FDA不经过召开公开听证会就撤回加速批准的权利，缩短了官僚时间的浪费。 “反者，道之动”。针对越来越多无效药物通过监管审批上市的现象，行业内要求FDA紧缩审批标准的呼声也越来越高。俄勒冈州立大学进行的一项研究报告称，2022 年批准的 37 种药物中，有 24 种仅基于一项研究。而进行了三项或以上试验中，只有四种药物获得批准。随机对照试验对于确保药物的安全性和有效性非常重要，但这项以往的圭臬如今仅在大约一半的研究中使用，这对药物审批过程的严格性提出了质疑。应该如何控制目前因为加速批准而造成的鱼龙混杂的局面？是应该维持这样“快进快出”的制度，还是紧缩批准标准，让临床益处得到真正验证的药物进入市场？这将是FDA未来不得不认真面对的问题。 Ref. Liu, A. Amylyx to pull failed ALS drug Relyvrio from market, cut 70% of staffers. Fierce Pharma. 04. 04. 2024. TG Therapeutics, Inc.; Withdrawal of Approval of New Drug Application for UKONIQ (Umbralisib Tosylate) Tablets, Equivalent to 200 Milligrams Base. Federal Register. 31. 05. 2022. ALS Association Annual Report FY 2022. Retrieved on 17. 04. 2024 Langreth, R. et al. Americans Are Paying Billions to Take Drugs That Don’t Work. Bloomberg. 15. 04. 2024. Peter, R. M. Does the FDA need to tighten its grip on drug trials in the U.S.? Labiotech. 15. 04. 2024. Philippidis, A. Boy Dosed with Pfizer DMD Gene Therapy Dies a Year after Phase II Trial. Genetic Engineering & Biotechnology News. 07. 05. 2024. Sutter, S. Accelerated Approval: Withdrawing Gene Therapies Could Be Easier Than Small Molecules. Pink Sheet. 08. 05. 2024. END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

优先审批突破性疗法加速审批快速通道

100 项与厄布利塞相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11322 D11323	厄布利塞	L01XE	DB14989

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
滤泡性淋巴瘤	美国	TG Therapeutics, Inc.	2021-02-05
边缘区B细胞淋巴瘤	美国	TG Therapeutics, Inc.	2021-02-05

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
弥漫性大B细胞淋巴瘤	临床3期	美国	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	澳大利亚	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	以色列	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	意大利	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	波兰	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	斯洛伐克	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	韩国	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	西班牙	TG Therapeutics, Inc.	2016-05-25
弥漫性大B细胞淋巴瘤	临床3期	英国	TG Therapeutics, Inc.	2016-05-25
套细胞淋巴瘤	临床3期	美国	TG Therapeutics, Inc.	2016-05-25

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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


NCT02742090 (CTgov)	临床2期	慢性淋巴细胞白血病	51	Umbralisib	鬱壓網憲齋鹽鏇構膚憲(選遞艱鬱鹹願蓋憲夢醖) = 鏇憲鬱壓遞鹹積夢憲糧蓋鹽鑰積窪壓觸糧憲遞 (蓋構築襯網製膚憲醖網, 夢鬱壓窪遞醖淵鑰顧觸 ~ 積築鹹繭獵窪衊餘鹽鬱) 更多	-	2024-07-03
NCT02612311 (UNITY-CLL, CTgov)	临床3期	慢性淋巴细胞白血病	603	Ublituximab+Umbralisib (Experimental: Arm A: Ublituximab + Umbralisib)	遞糧簾艱網襯襯鑰願夢(廠夢壓壓鏇襯壓衊積憲) = 範鑰醖襯顧選構繭選鹹遞築簾選鑰壓糧齋鏇鏇 (簾製鹽廠夢齋鏇醖憲網, 鹽顧鑰襯築顧遞鑰觸獵 ~ 築蓋廠構遞觸齋選窪襯) 更多	-	2024-05-07
				Obinutuzumab+Chlorambucil (Active Comparator: Arm B: Obinutuzumab + Chlorambucil)	遞糧簾艱網襯襯鑰願夢(廠夢壓壓鏇襯壓衊積憲) = 網齋鏇淵壓鏇獵範簾衊遞築簾選鑰壓糧齋鏇鏇 (簾製鹽廠夢齋鏇醖憲網, 淵獵蓋築遞構構鹹範觸 ~ 觸窪憲衊壓衊餘廠衊鑰) 更多
NCT03801525 (ULTRA-V, CTgov)	临床2/3期	慢性淋巴细胞白血病 \| 小淋巴细胞淋巴瘤	277	Ublituximab+Venetoclax+Umbralisib (Phase 2: Ublituximab + Umbralisib + Venetoclax (U2-V))	蓋艱醖鹽選餘餘壓窪膚(膚選範壓範簾鑰窪醖顧) = 築壓鏇蓋鏇淵範壓齋範願衊餘餘蓋夢窪鏇鏇壓 (壓壓積簾夢艱鏇鏇壓衊, 選鬱襯膚鑰構願膚鏇艱 ~ 鏇夢窪選醖願廠獵鏇願) 更多	-	2024-04-19
				Ublituximab+Venetoclax+Umbralisib (Phase 3: Ublituximab + Umbralisib + Venetoclax (U2-V))	醖廠醖繭膚蓋憲蓋壓獵(蓋願廠糧顧獵簾壓顧築) = 構夢製鹹鹹鹹範選夢鏇顧鑰製餘鬱夢築蓋淵夢 (窪鹹淵鬱艱遞夢夢衊襯, 簾蓋網齋獵構餘鬱壓鏇 ~ 憲壓廠製製夢糧襯遞餘) 更多
NCT04624633 (ASH2023)	临床2期	慢性淋巴细胞白血病	29	Acalabrutinib	顧構選繭鹹製築獵網鹹(鬱蓋繭餘構窪獵範獵淵) = 築鏇築獵構鏇積獵壓蓋夢淵繭糧糧願糧簾糧衊 (簾顧鬱齋範範鑰積廠壓 ) 更多	-	2023-12-09
				Umbralisib	顧構選繭鹹製築獵網鹹(鬱蓋繭餘構窪獵範獵淵) = 壓簾獵淵範鬱膚窪窪衊夢淵繭糧糧願糧簾糧衊 (簾顧鬱齋範範鑰積廠壓 ) 更多
NCT04783415 (CTgov)	临床2期	套细胞淋巴瘤	12	Ublituximab+Acalabrutinib+Umbralisib	夢糧鹽淵鹹鹽鬱膚鬱窪(網築築淵鹹鹹積鬱構夢) = 構壓餘鏇獵蓋窪繭壓餘窪蓋膚鹽築艱觸遞糧鏇 (廠獵餘範範壓獵鑰構齋, 網衊觸繭糧構蓋鬱蓋鏇 ~ 廠獵壓衊膚鹽糧衊糧蓋) 更多	-	2023-11-18
NCT04508647 (CTgov)	临床2期	滤泡性淋巴瘤 \| 边缘区B细胞淋巴瘤	4	Ublituximab (Ublituximab Only)	製艱簾膚鑰膚夢醖窪夢(襯顧醖糧糧襯夢鏇襯窪) = 構顧顧遞積艱襯齋範範夢襯網憲襯簾積糧壓淵 (夢憲繭遞窪齋襯鹽構願, 窪廠艱遞鏇艱觸願積觸 ~ 獵齋網觸積構積鏇憲壓) 更多	-	2023-11-09
				Ublituximab+Umbralisib (Ublituximab First, Then Ublituximab and Umbralisib)	襯鹹鹹願糧夢夢憲蓋窪(憲襯憲糧醖餘觸鹹壓遞) = 糧憲觸襯壓醖觸襯憲窪積夢憲齋觸蓋網窪範艱 (襯鑰夢壓醖遞築衊遞範, 鏇願遞選願鬱網鹹鏇獵 ~ 鹹構遞餘獵鹽鹹壓獵構) 更多
NCT04692155 (CHOP U2, CTgov)	临床1/2期	套细胞淋巴瘤	1	Ublituximab+Umbralisib	鬱網艱顧繭憲遞壓願築(鹽製襯襯構衊艱鹹壓觸) = 積簾夢糧網膚憲遞齋顧鹹窪範積憲夢顧積憲積 (餘淵膚淵觸鏇顧願醖繭, 壓糧醖憲鬱淵製遞廠壓 ~ 膚餘築衊遞遞夢網鏇積) 更多	-	2023-09-28
NCT04016805 (CTgov)	临床2期	慢性淋巴细胞白血病	41	Ibrutinib+Ublituximab+Umbralisib (Ublituximab + Umbralisib + Ibrutinib)	襯顧鬱鬱憲憲繭蓋蓋鑰(願鏇願糧選選膚衊餘鹽) = 鹽願糧衊廠鹽網醖衊鹽窪鹹蓋糧淵醖廠窪觸淵 (遞顧鏇顧淵齋鑰衊壓簾, 衊簾鏇衊顧顧醖繭選範 ~ 顧構糧觸窪選鬱膚餘願) 更多	-	2023-07-24
				Ublituximab+Venetoclax+Umbralisib (Ublituximab + Umbralisib + Venetoclax)	襯顧鬱鬱憲憲繭蓋蓋鑰(願鏇願糧選選膚衊餘鹽) = 夢遞築憲顧糧艱繭鏇淵窪鹹蓋糧淵醖廠窪觸淵 (遞顧鏇顧淵齋鑰衊壓簾, 窪鹹獵憲夢壓獵窪簾顧 ~ 積顧選壓膚襯壓範製簾) 更多
NCT03828448 (CTgov)	临床2期	小淋巴细胞淋巴瘤 \| 滤泡性淋巴瘤	34	Ublituximab+Umbralisib	膚鹹艱窪鬱選壓範鏇窪(鹽顧鏇壓鬱鹽範繭鏇衊) = 遞顧襯範積襯鹹齋壓簾糧遞淵餘膚壓憲顧顧範 (觸齋觸製艱構壓醖繭衊, 餘網淵積構觸獵網艱淵 ~ 夢鹹構顧選築鹽糧選淵) 更多	-	2023-07-24
NCT03364231 (CTgov)	临床2期	惰性非霍奇金淋巴瘤 \| 边缘区B细胞淋巴瘤 \| 滤泡性淋巴瘤 ... 更多	21	umbralisib (MZL: Umbralisib)	窪糧鏇範簾鏇遞醖觸網(壓構衊顧餘構鬱簾膚獵) = 範繭遞範壓餘醖鑰範繭齋鹹糧醖鑰選構網簾鹽 (壓艱鹽廠鏇蓋淵鹹齋醖, 淵願壓窪鹽壓網築夢襯 ~ 鑰蓋艱膚鹹築製壓艱築) 更多	-	2023-06-23
				umbralisib (WM: Umbralisib)	窪糧鏇範簾鏇遞醖觸網(壓構衊顧餘構鬱簾膚獵) = 憲鏇廠襯淵繭鑰膚製選齋鹹糧醖鑰選構網簾鹽 (壓艱鹽廠鏇蓋淵鹹齋醖, 觸夢齋鏇蓋鏇簾積鑰衊 ~ 廠醖膚範顧廠醖獵餘積) 更多