This is a multicenter prospective and retrospective observational clinical study in patients with primary or post polycythemia vera or post essential thrombocythemia myelofibrosis to test the efficacy of fedratinib in the rea world. Participants will be managed according to the clinical practice of the participating Center. All Centers will be Italian Hematology Units belonging to the GIMEMA Organization in Italy.

开始日期2024-01-29

申办/合作机构

Gruppo Italiano Malattie EMatologiche dell'Adulto

NCT06073847

/ RecruitingN/A

Inrebic® (Fedratinib) Post-Marketing Surveillance in Korean Patients With Myelofibrosis

The purpose of this study is to assess the real-world safety of fedratinib for the treatment of adult participants with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), or post essential thrombocythemia myelofibrosis (post-ET MF) who were previously treated with ruxolitinib. Participants will represent the overall patient population with PMF, post-PV MF or post-ET MF who lost adequate response to and/or are intolerant to ruxolitinib. Inadequate response definitions will follow Ministry of Food and Drug Safety-approved label and reimbursement criteria of the Health Insurance Review & Assessment Service.

开始日期2023-06-13

申办/合作机构

Bristol Myers Squibb Co.

ISRCTN88102629

/ Recruiting临床2期

A phase II study to evaluate the tolerability, safety and activity of fedratinib combined with ropeginterferon alfa-2b in patients with myelofibrosis

开始日期2022-09-12

申办/合作机构

University of Birmingham

100 项与菲卓替尼相关的临床结果

登录后查看更多信息

100 项与菲卓替尼相关的转化医学

登录后查看更多信息

100 项与菲卓替尼相关的专利（医药）

登录后查看更多信息

527

项与菲卓替尼相关的文献（医药）

2025-12-01·Current Hematologic Malignancy Reports

Emerging Therapeutic Approaches for Anemia in Myelofibrosis

Review

作者: Harrington, Patrick ; Palumbo, Giuseppe A ; Chifotides, Helen T ; Duminuco, Andrea ; Torre, Elena ; Bose, Prithviraj ; Vetro, Calogero

PURPOSE OF REVIEW:

In this review, we highlight conventional agents and novel emerging therapeutic strategies to treat anemia in MF.

RECENT FINDINGS:

Anemia is a common and challenging feature of myelofibrosis (MF). The pathobiology of anemia is multifactorial, including progressive bone marrow fibrosis, decreased erythropoiesis due to high hepcidin levels leading to iron sequestration in the reticuloendothelial system, hypersplenism, erythropoiesis inhibition by myelosuppressive JAK inhibitors (ruxolitinib, fedratinib), and others. MF-associated anemia has a negative impact on survival. Conventional agents to manage anemia include erythropoiesis-stimulating agents, danazol, corticosteroids, and immunomodulatory agents, but responses are infrequent and lack durability. Notable advancements have emerged in developing novel treatments for anemia in MF, including the regulatory approval of momelotinib (ACVR1/JAK1/2 inhibitor) in 2023 and development of novel promising agents targeting hemojuvelin and activins. Momelotinib and pacritinib (ACVR1/JAK2 inhibitor) are the preferred JAK inhibitors for patients with cytopenias (anemia, thrombocytopenia). Luspatercept and elritercept are activin receptor ligand traps, promoting erythroid maturation and late-stage erythropoiesis. Currently, luspatercept is being evaluated in a phase 3 trial (INDEPENDENCE™) for anemia in MF patients who are on a JAK2 inhibitor and require transfusions, and in a phase 2 trial (ODYSSEY) in combination with momelotinib in MF patients who are transfusion dependent, whether or not on a JAK inhibitor. Interim results of the RESTORE trial demonstrated that elritercept significantly decreased transfusions in MF patients. DISC-0974 is a first-in-class anti-hemojuvelin (positive hepcidin regulator) monoclonal antibody that decreased hepcidin expression, increased serum iron, and enhanced erythropoiesis in anemic patients with MF in a phase 1b/2 study. Burgeoning studies of novel anemia-targeted agents and combinations are significantly improving the quality of life and outcomes of patients with MF. The recent approval of momelotinib to treat MF with anemia and the emerging novel anemia-directed strategies in early and advanced clinical development have ushered in a new era in the treatment of MF-related anemia.

2025-12-01·CANCER CHEMOTHERAPY AND PHARMACOLOGY

Pharmacokinetics, safety, and tolerability of fedratinib in adults with moderate and severe hepatic impairment: results from the phase 1 FEDR-CP-001 trial

Article

作者: Xue, Yongjun ; Preston, Richard A ; He, Bing ; Smith, William B ; Thomas, Mark ; Thomas, Michael ; Krishna, Gopal ; Marbury, Thomas ; Ghosh, Atalanta ; Ogasawara, Ken ; Attanasio, Massimo ; Chen, Yizhe

PURPOSE:

The FEDR-CP-001 (NCT03983161) trial evaluated the pharmacokinetics (PK) and safety of a single dose of fedratinib in adults with moderate or severe hepatic impairment (HI) compared with matched healthy participants with normal hepatic function.

METHODS:

This was a non-randomized, open-label, multicenter, phase 1 trial. Participants were aged 18-75 years and had a BMI of 18-40 kg/m². HI was determined by Child-Pugh score. Participants were placed into 1 of the following groups: group 1, moderate HI; group 2, healthy participants matched to group 1; group 3, severe HI; and group 4, healthy participants matched to group 3. Participants received a single dose of fedratinib 300 mg (groups 1 and 2) or 200 mg (groups 3 and 4) and were followed for 21 days.

RESULTS:

All participants (N = 38; groups 1, 3, and 4 [n = 8 each], group 2 [n = 14]) completed the trial. Peak and total fedratinib exposures (C_max, AUC_0-∞) were similar between moderate HI versus matched healthy participants. In participants with severe HI, there were lower total exposures compared to the matched healthy participants where the ratios of geometric means for C_max, and AUC_0-∞ were 0.897 and 0.660, respectively, and with large inter-participant variability. Ten participants experienced a treatment-emergent adverse event (all were considered mild), which were evenly distributed across groups.

CONCLUSION:

These data indicate that reducing fedratinib starting doses is not necessary for patients with moderate or severe HI, and support clinicians in regular monitoring of patients with HI taking fedratinib.

MOLECULAR PHARMACEUTICS

Canine Mdr1 Knockout MDCK Cells Reliably Estimate Human Small Intestinal Permeability (P_eff) and Fraction Absorbed (f_a)

Article

作者: Van den Bergh, An ; Park, Seong Hee ; Holm, René ; Yang, Bin ; Beran, Kristian ; Dressman, Jennifer ; Sepassi, Kia ; Hermans, Eline ; Lin, Yanping ; Evers, Raymond

Human intestinal permeability is a key determinant of the oral fraction absorbed (f_a) of active pharmaceutical ingredients (APIs). This study evaluated the ability of an in-house canine Mdr1 (cMdr1) knockout (KO) Madin-Darby Canine Kidney (MDCK) cell line to correlate in vitro apparent permeability (P_app) with human small intestinal permeability (P_eff). In vitro P_app values of 16 reference compounds with high, medium, or low permeabilities were measured in the in-house cMdr1 KO MDCK protocol under pH gradient (6.5 ⇒ 7.4) and pH equivalent conditions (7.4 ⇒ 7.4) and correlations with human P_eff were established (R² > 0.8). The correlations were subsequently used to estimate P_eff and f_a for six test APIs: acetaminophen, voriconazole, fedratinib, voxelotor, lemborexant, and istradefylline. The results for these APIs were compared against literature and permeability data from other methods routinely used in drug discovery and development. The projected P_eff and f_a values for the test APIs aligned well with literature permeabilities derived using other methods and clinical pharmacokinetic studies, respectively. This work highlights the usefulness of cMdr1 KO MDCK cells in permeability classification, especially for highly permeable APIs, and supports its broader use in both research and regulatory contexts.

项与菲卓替尼相关的新闻（医药）

2025-09-03

·PRNewswire

Myelofibrosis Market is Going to Grow at a CAGR of 9% in the Next Ten Years (2025-2034) | DelveInsight

The launch of emerging therapies like BESREMi (PharmaEssentia and AOP Orphan Pharmaceuticals), INCB057643 (Incyte), XPOVIO (Karyopharm Therapeutics), RYTELO (Geron), REBLOZYL (Bristol Myers Squibb), Navtemadlin (Kartos Therapeutics), Pelabresib (Novartis), and others is going to shift the myelofibrosis market. LAS VEGAS, Sept. 3, 2025 /PRNewswire/ -- DelveInsight's Myelofibrosis Market Insights report includes a comprehensive understanding of current treatment practices, emerging myelofibrosis drugs, market share of individual therapies, and current and forecasted myelofibrosis market size from 2020 to 2034, segmented into leading markets (the US, EU4, UK, and Japan). Myelofibrosis Market Summary The total myelofibrosis treatment market size in the leading markets (the US, EU4, UK, and Japan) was USD 2.2 billion in 2024. The United States accounts for the largest market size of myelofibrosis, in comparison to EU4 (Germany, Italy, France, and Spain) and the UK, and Japan. Based on DelveInsight's assessment in 2024, the 7MM had approximately 56K patient pool (prevalent cases) of myelofibrosis. Key myelofibrosis companies, including PharmaEssentia, AOP Orphan Pharmaceuticals, Incyte, Karyopharm Therapeutics, Geron, Bristol Myers Squibb, Kartos Therapeutics, Novartis, Merck, Telios Pharma, Ryvu Therapeutics, Sumitomo Pharma, Syntara, Disc Medicine, Menarini Group, and others, are actively working on innovative myelofibrosis drugs. Some of the key myelofibrosis therapies in clinical trials include BESREMi (ropeginterferon alfa-2b-njft/P-1101), INCB057643, XPOVIO (NEXPOVIO/selinexor/KPT-330), RYTELO (imetelstat), REBLOZYL (luspatercept/ACE-536), Navtemadlin (KRT-232), Pelabresib (DAK539), Bomedemstat (IMG-7289/MK-3543), TL-895, RVU120 ( SEL-120), TP-3654 (nuvisertib), SNT-5505 (PXS-5505), DISC-0974, ELZONRIS (tagraxofusp/SL-401), and others. These novel myelofibrosis therapies are anticipated to enter the myelofibrosis market in the forecast period and are expected to change the market. By 2034, among all the therapies, the highest revenue is expected to be generated by OJJAARA/OMJJARA. Discover which myelofibrosis therapies are expected to grab the largest market share @ Myelofibrosis Market Report Key Factors Driving the Growth of the Myelofibrosis Market Novel Therapies Drive Myelofibrosis Treatment Advancements Currently, four JAK inhibitors have been approved by the US FDA for the treatment of myelofibrosis, including JAKAFI (ruxolitinib), INREBIC (fedratinib), VONJO (pacritinib), and OJJAARA (momelotinib). No drug therapy can cure myelofibrosis. As myelofibrosis primarily affects older adults, stem cell transplantation is not a treatment option for most myelofibrosis patients. The launch of another JAK inhibitor, BESREMi, will further change the dynamics of the myelofibrosis market. Rich clinical pipeline and emerging non-JAK approaches driving the myelofibrosis landscape Beyond JAK inhibitors, active clinical development includes BET inhibitors (Incyte's INCB057643; Novartis' Pelabresib), XPO1 inhibitor (Karyopharm Therapeutics' XPOVIO), Telomerase inhibitor (Geron's RYTELO), MDM2 protein inhibitor (Kartos Therapeutics' Navtemadlin), Tyrosine kinase inhibitors (Telios Pharma's TL-895), PIM1 kinase inhibitor (Sumitomo Pharma's TP-3654), LOX inhibitor (Syntara's SNT-5505), and others, raising market potential by promising new label expansions, second-line options, and higher-value therapies should any prove to be disease-modifying. An aging population & increasing incidence with better survival Myelofibrosis primarily affects older adults; population aging increases the absolute number of patients. As treatments improve symptoms and (in some cases) survival, prevalent patient pools grow, supporting longer-term market demand. In the US in 2024, the 70+ years of age group had the highest number of cases, accounting for approximately 60% of the total prevalent cases, while the ≤39 years of age group accounted for just ~2%. Diagnostic & genomic testing improvements are driving myelofibrosis patient pool, leading to the growth of myelofibrosis market Wider use of molecular profiling (JAK2, CALR, MPL, and others) enables earlier and more accurate MF diagnosis and better patient stratification for targeted therapies. This both expands the diagnosed population and helps match patients to appropriate, often higher-value, treatments. Myelofibrosis Market Analysis JAK inhibitors have become the cornerstone of treatment for patients with myelofibrosis, offering significant benefits such as spleen reduction, symptom relief, and improved quality of life, which can also extend survival in those with advanced disease. All approved JAK inhibitors primarily target JAK2, particularly the wild-type form, but they differ in their activity against other JAK family members. For instance, JAKAFI myelofibrosis inhibits both JAK1 and JAK2; INREBIC selectively inhibits JAK2 while sparing JAK1 and also affects FLT3 and other targets; VONJO myelofibrosis inhibits JAK2 while sparing JAK1 but additionally impacts FLT3, IRAK, and ACVR1; and OJJAARA, approved through a different pathway, targets JAK1/JAK2 and ACVR1, mainly for myelofibrosis patients with anemia. These varying mechanisms lead to distinct patient outcomes. JAKAFI myelofibrosis continues to see strong demand and is expected to grow further, maintaining its position as the standard of care in myelofibrosis. Myelofibrosis will remain the largest segment of JAKAFI's patient population until polycythemia vera cases eventually increase. However, market growth may be limited due to patent expirations of key therapies, with JAKAFI patents set to expire in 2027 for Novartis and 2028 for Incyte, presenting potential opportunities for competitors. In response, Incyte is exploring combination trials with novel drugs to extend JAKAFI's therapeutic lifespan. Learn more about the treatment options for myelofibrosis @ Myelofibrosis Therapy The myelofibrosis treatment landscape offers significant opportunities for innovation, focusing on several key areas: Treating Lower-Risk Patients: Developing safe and effective therapies for patients with lower-risk myelofibrosis, allowing for earlier and more favorable interventions. Enhancing First-Line Treatments: Improving existing first-line therapies for intermediate- to high-risk patients through novel drugs or combination strategies. Managing Cytopenia: Developing targeted therapies to address cytopenia, a significant unmet need in patient care. Myelofibrosis Competitive Landscape The myelofibrosis clinical trial pipeline includes several drugs in mid- and late-stage development that are expected to enter the market during the forecast period. The emerging landscape offers a diverse range of therapeutic alternatives for treatment, including XPOVIO (Karyopharm Therapeutics), Elitracet (Takeda/Keros Therapeutics), Navtemadlin (Kartos Therapeutics), Pelabresib (Novartis), INCB057643 (Incyte), Bomedemstat (Merck), and others, all of which are used in various lines of treatment. The expected launch of these therapies is expected to have a further positive impact on the market. INCB57643 is an orally administered small molecule. Bromodomain and extra-terminal (BET) proteins act as epigenetic readers that control the expression of key oncoproteins implicated in the development of myelofibrosis and other hematologic malignancies, including B-lymphoma-2, nuclear factor kappa, and c-Myc. In a prior Phase I/II clinical trial, the oral BET inhibitor INCB057643, tested both as a monotherapy and in combination with ruxolitinib, demonstrated favorable tolerability and promising clinical activity in patients with advanced cancers. In its Q2 2025 financial report, the company announced that the combination of INCB057643 with ruxolitinib and INCB57643 (a JAK1/JAK2 and BET inhibitor) is currently being evaluated in a Phase II trial for myelofibrosis. RYTELO (imetelstat) is an investigational telomerase inhibitor that targets telomerase, selectively eliminating malignant stem and progenitor cells in the bone marrow, which drive diseases like myelodysplastic syndromes (MDS) and myelofibrosis. By blocking the proliferation of these malignant cells, imetelstat supports the recovery of healthy bone marrow and blood cell production and has shown disease-modifying effects and clinical benefits in Phase III trials for myelofibrosis. This mechanism sets imetelstat apart from other approved or investigational therapies for these blood cancers. In January 2025, Geron reported achieving 75% enrollment in the Phase III IMpactMF trial, which is comparing imetelstat to Best Available Therapy (BAT) in intermediate-2 or high-risk myelofibrosis patients who have relapsed or are refractory to JAK inhibitor treatment. Elritercept is a late-stage investigational activin inhibitor aimed at treating anemia associated with hematologic malignancies, including MDS and myelofibrosis. It is currently undergoing Phase II evaluation in patients with myelofibrosis. In December 2024, Keros Therapeutics presented updated data from this ongoing Phase II trial at ASH 2024. Additionally, in December 2024, Takeda announced an exclusive licensing agreement with Keros to further develop, manufacture, and commercialize elritercept globally, excluding mainland China, Hong Kong, and Macau. The anticipated launch of these emerging myelofibrosis therapies are poised to transform the myelofibrosis market landscape in the coming years. As these cutting-edge myelofibrosis therapies continue to mature and gain regulatory approval, they are expected to reshape the myelofibrosis market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth. To know more about new myelofibrosis treatment, visit @ Myelofibrosis Treatment Market Recent Developments in the Myelofibrosis Market In July 2025, Incyte announced that the Phase I data in patients with myelofibrosis as monotherapy and in combination with ruxolitinib are anticipated in the second half of 2025. In June 2025, QIAGEN and Incyte announced a new global collaboration to develop a novel diagnostic panel to support Incyte's extensive portfolio of investigational therapies for patients with myeloproliferative neoplasms (MPNs), including Incyte's monoclonal antibody INCA033989. In January 2025, Karyopharm Therapeutics stated that it expects to report top-line results from the Phase III SENTRY trial in the second half of 2025, which could represent a potentially transformative opportunity to establish a new treatment paradigm in myelofibrosis. What is Myelofibrosis? Myelofibrosis is a rare blood cancer marked by the accumulation of scar tissue, or 'fibrosis', in the bone marrow. This excess scar tissue prevents the bone marrow from producing enough healthy blood cells. It belongs to a group of blood cancers called 'myeloproliferative neoplasms (MPNs)', in which the blood cells produced by the bone marrow grow and function abnormally. When myelofibrosis arises independently, without being caused by another bone marrow disorder, it is referred to as primary myelofibrosis. In other cases, it can develop from another MPN, such as polycythemia vera or essential thrombocythemia. When this occurs, it is called secondary myelofibrosis, sometimes specifically termed post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. Myelofibrosis Epidemiology Segmentation The myelofibrosis epidemiology section provides insights into the historical and current myelofibrosis patient pool and forecasted trends for the leading markets (the US, EU4, UK, and Japan). It helps recognize the causes of current and forecasted patient trends by exploring numerous studies and views of key opinion leaders. The myelofibrosis market report proffers epidemiological analysis for the study period 2020–2034 in the leading markets (the US, EU4, UK, and Japan) segmented into: Total Prevalent Cases of Myelofibrosis Type-specific Cases of Myelofibrosis Myelofibrosis Cases Based on Risk Stratification Age-specific Prevalent Cases of Myelofibrosis Myelofibrosis Cases Based on Molecular Alterations Download the report to understand which factors are driving myelofibrosis epidemiology trends @ Myelofibrosis Treatment Drugs Scope of the Myelofibrosis Market Report Myelofibrosis Therapeutic Assessment: Myelofibrosis current marketed and emerging therapies Myelofibrosis Market Dynamics: Conjoint Analysis of Emerging Myelofibrosis Drugs Competitive Intelligence Analysis: SWOT analysis and Market entry strategies Myelofibrosis Market Unmet Needs, KOL's views, Analyst's views, Myelofibrosis Market Access and Reimbursement Discover more about myelofibrosis drugs in development @ Myelofibrosis Clinical Trials Table of Contents Related Reports JAK Inhibitors Market JAK Inhibitors Market Size, Target Population, Competitive Landscape, and Market Forecast – 2034 report delivers an in-depth understanding of the market trends, market drivers, market barriers, and key JAK inhibitors companies, including Pfizer, AbbVie, Galapagos, Sierra Oncology, Theravance Biopharma, Dizal Pharmaceutical, Aclaris Therapeutics, Celon Pharma, Incyte Corporation, Gilead Sciences, Reistone Biopharma, Jiangsu Hengrui Medicine Co., MaxiNovel Pharmaceuticals, among others. Myelofibrosis Clinical Trial Analysis Myelofibrosis Pipeline Insight – 2025 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key myelofibrosis companies, including Geron Corporation, Merck, Ryvu Therapeutics SA, Morphic Therapeutic, iOnctura, Pharmaxis, Nippon Shinyaku, Active Biotech, Incyte Corporation, Sumitomo Pharma America, Inc., Cellenkos, Disc Medicine, among others. Polycythemia Vera Market Polycythemia Vera Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key polycythemia vera companies, including Incyte, Novartis, PharmaEssentia, AOP Orphan Pharmaceuticals, Protagonist Therapeutics, Merck (Imago BioSciences), Italfarmaco, Ionis Pharmaceutical, Silence Therapeutics, Perseus Proteomics, AbbVie, Johnson & Johnson Innovative Medicine, Mabwell (Shanghai) Bioscience, Disc Medicine, GluBio Therapeutics, among others. Multiple Myeloma Market Multiple Myeloma Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key multiple myeloma companies, including Sanofi, Karyopharm Therapeutics, AbbVie, Takeda Pharmaceutical, Celgene, Bristol-Myers Squibb, RAPA Therapeutics, Pfizer, Array Biopharma, Cellectar Biosciences, BioLineRx, Celgene, Aduro Biotech, ExCellThera, Janssen Pharmaceutical, Precision BioSciences, Takeda, Glenmark (Ichnos Sciences SA), Poseida Therapeutics, Molecular Partners AG, Chipscreen Biosciences, AbbVie, Genentech (Roche), Janssen Biotech, Nanjing Legend Biotech, Merck Sharp & Dohme Corp., 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 . Connect with us on LinkedIn | Facebook | Twitter 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2期引进/卖出临床1期上市批准临床结果

2025-08-28

·PRNewswire

Vanda Pharmaceuticals Announces FDA Granted Orphan Drug Designation for VGT-1849B, a Novel and Selective Candidate for the Treatment of Polycythemia Vera

WASHINGTON, Aug. 28, 2025 /PRNewswire/ -- Vanda Pharmaceuticals Inc. (Vanda) (Nasdaq: VNDA) today announced the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation for VGT-1849B, a selective peptide nucleic acid-based JAK2 inhibitor for the treatment of polycythemia vera (PV). PV is a chronic myeloproliferative disorder characterized by aberrant hematopoiesis of myeloid lineage with exuberant red cell production and increased release of pro-inflammatory cytokines. More than 95% of PV patients harbor the JAK2 V617F gain-of-function mutation leading to aberrant JAK2 production.1 The prevalence of PV in the United States is estimated to affect 44 to 57 per 100,000 people.2 VGT-1849B is an antisense oligonucleotide (ASO) that utilizes a novel backbone chemistry, OliPass Peptide Nucleic Acid (OPNA), that has been derived from peptide nucleic acid (PNA) by rationally introducing cationic lipid moieties onto nucleobases. By covalently attaching cationic lipid groups onto PNA, cell permeability and affinity for RNA are markedly improved. By selectively targeting JAK2 mRNA, VGT-1849B reduces downstream signaling and JAK2V617F-driven autonomous cell proliferation. VGT-1849B targets JAK2 with high precision and effectively reduces JAK2 protein production, without any off-target kinase effects. Inhibiting JAK2 acts to suppress hematopoiesis, consequently reducing red blood cell, neutrophil, platelet, and lymphocyte production. The ability of VGT-1849B to reduce JAK2 protein may alleviate the disease burden that patients with PV face with a favorable safety profile, resulting in a higher quality of life for patients. JAK2 inhibitors have been shown to be efficacious in treating various JAK-dependent hematologic malignancies, including the treatment of PV. While there are several JAK inhibitors available such as Jakafi®, Inrebic®, Ojjaara®, and Vonjo®, none are solely selective to JAK2. Due to the highly conserved structure of the catalytic sites of protein kinases, JAK2 inhibitors may bind to off-target kinases, leading to increased toxicity and a worse overall safety profile. The adverse side effects that may occur from JAK inhibition emphasize the importance of selectively targeting JAK2 while avoiding inhibition of other JAK family members. By specifically targeting JAK2, we aim to reduce the risk of infection and toxic effects that are seen with inhibitors that also block JAK1, JAK3, TYK2, or other kinases outside of the JAK family. If approved, VGT-1849B could offer targeted efficacy with an improved safety profile and convenient infrequent dosing. Orphan Drug Designation is granted by the FDA to investigational therapies addressing rare medical conditions and provides benefits to drug developers. References P. Gou, W. Zhang, and S. Giraudier, "Insights into the Potential Mechanisms of JAK2V617F Somatic Mutation Contributing Distinct Phenotypes in Myeloproliferative Neoplasms," Myeloproliferative Neoplasms. Int. J. Mol. Sci, vol. 2022, p. 1013, 2022, doi: 10.3390/ijms. Grunwald, M. R.; Stein, B. L.; Boccia, R. V.; Oh, S. T.; Paranagama, D.; Parasuraman, S.; Colucci, P.; Mesa, R. Clinical and Disease Characteristics From REVEAL at Time of Enrollment (Baseline): Prospective Observational Study of Patients With Polycythemia Vera in the United States. Clin Lymphoma Myeloma Leuk 2018, 18 (12), 788-795.e2. . About Vanda Pharmaceuticals Inc. Vanda is a leading global biopharmaceutical company focused on the development and commercialization of innovative therapies to address high unmet medical needs and improve the lives of patients. For more on Vanda Pharmaceuticals Inc., please visit and follow us on X @vandapharma. About VGT-1849B VGT-1849B is an antisense oligonucleotide (ASO) that utilizes a novel backbone chemistry, OliPass Peptide Nucleic Acid (OPNA) peptide nucleic acid, and selectively targets JAK2 mRNA, reducing aberrant levels of JAK2 that may cause hematologic malignancies. OPNA was derived from PNA through rational chemical modifications to enhance cell permeability and RNA affinity. For therapeutic intervention, OPNA potently binds to target pre-mRNA, induces exon skipping, and yields an mRNA splice variant. Unlike other types of RNA therapeutics, OPNA does not require formulation aid for in vivo therapeutic activity. OPNA oligonucleotide-based therapeutics have broad applicability in addressing a number of disorders caused by genetic variants. CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS Various statements in this press release, including, but not limited to statements regarding the estimated prevalence of PV in the United States, the potential therapeutic effects of VGT-1849B, the safety profile of VGT-1849B and the potential benefits of VGT-1849B are "forward-looking statements" under the securities laws. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Forward-looking statements are based upon current expectations and assumptions that involve risks, changes in circumstances and uncertainties. Important factors that could cause actual results to differ materially from those reflected in Vanda's forward-looking statements include, among others, the accuracy of the reporting and diagnosis of PV cases, the ability of VGT-1849B to safely and effectively treat PV, the ability of VGT-1849B to provide patients with the anticipated benefits and Vanda's ability to successfully complete the clinical development of, and obtain regulatory approval for, VGT-1849B in the treatment of PV. Therefore, no assurance can be given that the results or developments anticipated by Vanda will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, Vanda. Forward-looking statements in this press release should be evaluated together with the various risks and uncertainties that affect Vanda's business and market, particularly those identified in the "Cautionary Note Regarding Forward-Looking Statements", "Risk Factors" and "Management's Discussion and Analysis of Financial Condition and Results of Operations" sections of Vanda's most recent Annual Report on Form 10-K, as updated by Vanda's subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the U.S. Securities and Exchange Commission, which are available at . All written and verbal forward-looking statements attributable to Vanda or any person acting on its behalf are expressly qualified in their entirety by the cautionary statements contained or referred to herein. Vanda cautions investors not to rely too heavily on the forward-looking statements Vanda makes or that are made on its behalf. The information in this press release is provided only as of the date of this press release, and Vanda undertakes no obligation, and specifically declines any obligation, to update or revise publicly any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law. Corporate Contact: Kevin Moran Senior Vice President, Chief Financial Officer and Treasurer Vanda Pharmaceuticals Inc. 202-734-3400 [email protected] Jim Golden / Jack Kelleher / Dan Moore Collected Strategies [email protected] SOURCE Vanda Pharmaceuticals Inc. WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

孤儿药寡核苷酸

2025-08-07

·精准药物

【综述】丁克、王震等：激酶药物研发30年——进展与挑战

1 引言激酶是一类能够将三磷酸腺苷(adenosine triphosphate, ATP)末端的磷酸基团转移至特定蛋白质或脂质等底物的酶[1]. 激酶介导的磷酸化修饰会导致底物构象变化, 从而影响底物的亚细胞定位、催化活性以及与其他分子的结合能力, 在调控细胞生长、增殖、分化、迁移和凋亡等过程中发挥着关键作用[2]. 激酶包含一个高度保守的ATP结合域, 由一个铰链多肽连接的β-折叠结构域和α-螺旋结构域组成, 是激酶发挥催化活性的中心(图1). 自1956年被Edmond H. Fischer和Edwin G. Krebs发现以来[3,4], 激酶研究迅速发展. 激酶已成为真核生物中第四大基因家族(占比2%), 仅次于C2H2锌指蛋白(3%)、G蛋白偶联受体(G protein-coupled receptors, GPCRs, 2.8%)和主要组织相容性复合体(major histocompatibility complex, MHC)蛋白家族(2.8%)[5]. 人类基因组中约有518种激酶, 包括478种蛋白激酶和40种脂质激酶等, 其功能异常已被证实与癌症、代谢性疾病、神经退行性疾病、免疫性疾病及感染性疾病等多种人类疾病密切相关[6]. 然而, 由于细胞内高浓度ATP的存在、对激酶活性调控机制的认知不足, 以及ATP结合口袋的高度保守性, 靶向ATP结合位点的激酶药物研发最初被视为不可逾越的挑战[7]. 尽管早在1995年, 首个激酶抑制剂法舒地尔(Fasudil)在日本获批上市用于治疗脑血管痉挛, 以及随后在1999年, 西罗莫司(Sirolimus)成为首个在美国获批上市的激酶抑制剂, 但这两种药物的作用靶点(Rho相关激酶(Rho-associated kinase, ROCK)和哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR))均是后期深入的机制研究发现的[8]. 直到2001年, 伊马替尼(Imatinib)获批上市, 成为首个通过靶向特定蛋白激酶(BCR-ABL)开发并获批用于疾病治疗的药物, 其显著的临床疗效成为肿瘤分子靶向治疗领域研究热潮的催化[8]. 到2025年5月31日止, 美国食品药品监督管理局(U.S. Food and Drug Administration, FDA)批准了14种激酶大分子药物和96种激酶小分子药物(图2)[2,8~10]. 其中, 激酶小分子抑制剂最多, 本文采用Roskoski提出的激酶抑制剂分类标准[11], 具体如下. I型抑制剂: 结合于活性激酶的ATP结合口袋; I1/2型与II型抑制剂: 均结合于非活性激酶的ATP结合口袋, 其区别在于非活性构象中DFG基序的取向——I1/2型为“DFG-in”构象, II型为“DFG-out”构象; III型与IV型抑制剂: 指变构抑制剂(非ATP竞争性), 其中III型结合位点毗邻ATP结合位点, IV型则远离该位点; 共价抑制剂: 通过不可逆结合发挥作用, 在此分类体系中单独归类. 本文将归纳总结FDA上市药物的作用靶标、作用模式以及适应证, 并分析探讨了目前激酶药物的研发现状和未来机遇.. 2 FDA批准的激酶药物2.1 FDA批准的小分子激酶药物 1999年, 辉瑞公司的西罗莫司(Sirolimus)获批上市(图3), 用于预防肾移植患者的器官排斥反应. 该药物是一种含有大环内酯结构的天然产物, 是一类变构激酶抑制剂, 通过诱导亲环蛋白FK506结合蛋白12 (FK506-binding protein 12, FKBP12)和mTOR激酶形成复合物, 抑制mTOR的激酶活性及其信号通路从而发挥免疫抑制活性[12,13]. 2001年, 诺华公司的伊马替尼(Imatinib)获批上市, 用于治疗费城染色体阳性的慢性髓性白血病. 该药物是II型ATP竞争性的一代BCR-ABL激酶抑制剂, 通过稳定BCR-ABL的非活性构象抑制其激酶活性发挥从而抑制肿瘤细胞增殖. 该药物也因对KIT激酶的良好抑制活性于2002年获批用于治疗胃肠道间质瘤[12,14,15]. 2003年, 阿斯利康公司的吉非替尼(Gefitinib)获批上市, 用于治疗携带表皮生长因子受体(epidermal growth factor receptor, EGFR) 19号外显子缺失(EGFRDel19)或21号外显子替换突变(EGFRL858R)等激活性突变的非小细胞肺癌. 该药物是I型ATP竞争性的一代EGFR激酶抑制剂, 通过结合活性构象的EGFR抑制其激酶活性发挥从而抑制肿瘤细胞增殖[12,16]. 2004年, 罗氏公司的厄洛替尼(Erlotinib)获批上市, 用于治疗携带EGFRDel19或EGFRL858R等激活性突变的非小细胞肺癌. 该药物属于一代EGFR激酶抑制剂, 既可作为I型ATP竞争性激酶抑制剂结合活性构象的EGFR, 也能以I1/2型结合非活性构象的EGFR来抑制EGFR的激酶活性[12,17,18]. 2005年, 拜耳公司的索拉非尼(Sorafenib)获批上市, 用于治疗肾细胞癌. 该药物是II型ATP竞争性的BRAF激酶抑制剂, 能同时抑制野生型BRAF及其突变体V600E和RAF1等. 该药物还分别于2007年和2013年获批用于治疗肝细胞癌和甲状腺癌[12,19]. 2006年, FDA批准了2款激酶药物, 包括百时美施贵宝公司的达沙替尼(Dasatinib)和辉瑞公司的舒尼替尼(Sunitinib)[12]. 达沙替尼是I型ATP竞争性的二代BCR-ABL激酶抑制剂, 用于治疗对伊马替尼产生耐药的慢性髓性白血病, 对除T315I外的BCR-ABL突变体有良好的抑制效果[20]. 舒尼替尼是I1/2型ATP竞争性的周期蛋白依赖激酶2 (cyclin-dependent kinase 2, CDK2)激酶抑制剂, 同时对KIT、血管内皮细胞生长因子受体2 (vascular endothelial growth factor receptor 2, VEGFR2)和FMS样酪氨酸激酶3 (Fms-like tyrosine kinase, FLT3)等激酶具有良好的抑制活性, 用于治疗对伊马替尼耐药的胃肠道间质瘤和肾细胞癌[14,21]. 2007年, FDA批准了3款激酶药物, 包括葛兰素史克公司的拉帕替尼(Lapatinib)、诺华公司的尼洛替尼(Nilotinib)和辉瑞公司的替西罗莫司(Temsirolimus)[12]. 拉帕替尼是I1/2型ATP竞争性的EGFR和人表皮生长因子受体2 (human epidermal growth factor receptor 2, HER2)等激酶抑制剂, 用于治疗HER2阳性的乳腺癌[14,22]. 尼洛替尼是II型ATP竞争性的二代BCR-ABL激酶抑制剂, 用于治疗对伊马替尼产生耐药的慢性髓性白血病, 对除T315I外的BCR-ABL突变体有良好的抑制效果[23,24]. 替西罗莫司是一种大环内酯类药物, 是西罗莫司的酯类似物, 同样靶向mTOR激酶, 用于静脉注射治疗肾细胞癌[25]. 2009年, FDA批准了2款激酶药物, 包括诺华公司的依维莫司(Everolimus)和葛兰素史克公司的帕唑帕尼(Pazopanib)[12]. 依维莫司是一种大环内酯类药物, 是西罗莫司的类似物, 同样靶向mTOR激酶, 用于预防移植器官排斥反应以及治疗舒尼替尼或索拉非尼耐药的肾细胞癌[26]. 帕唑帕尼是II型ATP竞争性的泛VEGFR激酶抑制剂, 用于治疗肾细胞癌. 该药物于2012年被获批用于治疗软组织肉瘤[27]. 2011年, FDA批准了4款激酶药物, 包括辉瑞公司的克唑替尼(Crizotinib)、Incyte公司的鲁索利替尼(Ruxolitinib)、阿斯利康公司的凡德他尼(Vandetanib)和罗氏公司的维莫非尼(Vemurafenib)[12]. 克唑替尼是I1/2型ATP竞争性的间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)、ROS1和间质表皮转化因子(mesenchymal to epithelial transition factor, MET)等激酶抑制剂, 用于治疗ALK阳性或ROS1阳性的非小细胞肺癌[25,28]. 鲁索利替尼是I型ATP竞争性的JAK1和JAK2等激酶抑制剂, 是首个获批用于治疗骨髓纤维化的药物[29,30]. 凡德他尼是I型ATP竞争性的RET、VEGFR和EGFR等激酶抑制剂, 用于治疗甲状腺癌[31,32]. 维莫非尼是I1/2型ATP竞争性的BRAF激酶抑制剂(对BRAFV600E活性更优), 用于治疗携带BRAFV600E突变的黑色素瘤, 是首个针对致癌性BRAF的抑制剂[14,33]. 2012年, FDA批准了6款激酶药物, 包括辉瑞公司的阿昔替尼(Axitinib)、博舒替尼(Bosutinib)、托法替尼(Tofacitinib)、Exelixis公司的卡博替尼(Cabozantinib)、武田公司的普纳替尼(Ponatinib)和拜耳公司的瑞戈非尼(Regorafenib)[12]. 阿昔替尼是II型ATP竞争性的VEGFR激酶抑制剂, 用于治疗肾细胞癌[14,34]. 博舒替尼是I型ATP竞争性的二代BCR-ABL激酶抑制剂, 用于治疗费城染色体阳性的慢性髓性白血病[23,35]. 托法替尼是I型ATP竞争性的泛JAK激酶抑制剂, 用于治疗类风湿关节炎、银屑病关节炎和溃疡性结肠炎[36,37]. 卡博替尼是MET、VEGFR2和RET等激酶抑制剂, 用于治疗甲状腺髓样癌和索拉非尼耐药的肾细胞癌和肝细胞癌[38]. 普纳替尼是II型ATP竞争性的第三代BCR-ABL抑制剂, 用于治疗携带BCR-ABLT315I突变的慢性髓性白血病[39]. 瑞戈非尼是II型ATP竞争性的VEGFR、血小板衍生生长因子受体(platelet-derived growth factor receptor, PDGFR)、成纤维细胞生长因子受体(fibroblast growth factor receptor, FGFR)、BRAF、TIE2、RAF1、KIT和RET等激酶抑制剂, 用于治疗结直肠癌、胃肠道间质瘤和肾细胞癌[40]. 2013年, FDA批准了4款激酶药物, 包括勃林格殷格翰公司的阿法替尼(Afatinib)、葛兰素史克公司的达拉非尼(Dabrafenib)、曲美替尼(Trametinib)和强生公司的伊布替尼(Ibrutinib)[12] (图4). 阿法替尼是二代EGFR激酶抑制剂, 也是首个与ATP结合口袋的Cys797形成共价键的共价EGFR抑制剂, 用于治疗携带EGFRDel19或EGFRL858R等激活性突变的非小细胞肺癌[41]. 达拉非尼是I1/2型ATP竞争性的BRAF激酶抑制剂, 用于治疗携带BRAFV600E的黑色素瘤[42,43]. 曲美替尼是III型MEK1/2变构激酶抑制剂, 用于治疗携带BRAFV600E或BRAFV600K的黑色素瘤[44,45]. 伊布替尼是共价布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase, BTK)激酶抑制剂, 用于治疗套细胞淋巴瘤、慢性淋巴细胞白血病、华氏巨球蛋白血症、慢性移植物抗宿主病和边缘区淋巴瘤[46,47].. 2014年, FDA批准了3款激酶药物, 包括诺华公司的色瑞替尼(Ceritinib)、吉利德公司的艾代拉利司(Idelalisib)和勃林格殷格翰公司的尼达尼布(Nintedanib)[12]. 色瑞替尼是I1/2型ATP竞争性的二代ALK抑制剂, 用于治疗ALK阳性的非小细胞肺癌, 对克唑替尼耐药患者有效[25,48]. 艾代拉利司是I型ATP竞争性的磷脂酰肌醇3-激酶δ (phosphoinositide 3-kinase δ, PI3Kδ)抑制剂, 也是首个上市的PI3K选择性抑制剂, 联合利妥昔单抗治疗慢性淋巴细胞白血病以及治疗B细胞非霍奇金淋巴瘤和小淋巴细胞性淋巴瘤[49,50]. 尼达尼布是II型ATP竞争性的泛VEGFR激酶抑制剂, 用于治疗特发性肺纤维化[14,51]. 2015年, FDA批准了5款激酶药物, 包括罗氏公司的阿来替尼(Alectinib)、考比替尼(Cobimetinib)、卫材公司的仑伐替尼(Lenvatinib)、阿斯利康公司的奥希替尼(Osimertinib)和辉瑞公司的哌柏西利(Palbociclib)[12]. 阿来替尼是I1/2型ATP竞争性的ALK和RET等激酶抑制剂, 也是二代ALK抑制剂, 用于治疗对克唑替尼耐药的ALK阳性的非小细胞肺癌[52]. 考比替尼是III型的MEK1/2变构激酶抑制剂, 该药联合维莫非尼用于治疗携带BRAFV600E或BRAFV600K的黑色素瘤[53]. 仑伐替尼是I1/2型ATP竞争性的VEGFR、RET、PDGFR和KIT等激酶抑制剂, 用于治疗甲状腺癌、肝细胞癌和肾细胞癌[54]. 奥希替尼是三代共价EGFR抑制剂, 用于治疗携带EGFRT790M突变的非小细胞肺癌[55]. 哌柏西利是I型ATP竞争性CDK4和CDK6等激酶抑制剂, 与来曲唑联用治疗激素受体阳性和HER2阴性乳腺癌[56]. 2017年, FDA批准了8款激酶药物, 包括礼来公司的阿贝西利(Abemaciclib)、阿斯利康公司的阿卡替尼(Acalabrutinib)、武田公司的布加替尼(Brigatinib)、拜耳公司的可泮利塞(Copanlisib)、诺华公司的米哚妥林(Midostaurin)、瑞波西利(Ribociclib)、辉瑞公司的来那替尼(Neratinib)和Aerie公司的奈舒地尔(Netarsudil)[12]. 阿贝西利是I型ATP竞争性的 CDK4和CDK6等激酶抑制剂, 联合芳香化酶抑制剂或氟维司群治疗激素受体阳性和HER2阴性的乳腺癌[56]. 阿卡替尼是共价BTK激酶抑制剂, 用于治疗套细胞淋巴瘤、慢性淋巴细胞白血病和小淋巴细胞性淋巴瘤[57]. 布加替尼是I型ATP竞争性的ALK激酶抑制剂, 用于治疗对克唑替尼耐药的ALK阳性的非小细胞肺癌[58]. 可泮利塞是I型ATP竞争性的泛PI3K激酶抑制剂, 用于治疗滤泡性淋巴瘤[59]. 米哚妥林是I型ATP竞争性的蛋白激酶C (protein kinase C, PKC)、FLT3和KIT等激酶抑制剂, 用于治疗FLT3突变的急性髓细胞性白血病、侵袭性系统性肥大细胞增多症、系统性肥大细胞增多症. 伴相关血液系统肿瘤和肥大细胞白血病[60]. 瑞波西利是I1/2型ATP竞争性的CDK4和CDK6等激酶抑制剂, 联合芳香化酶抑制剂治疗激素受体阳性和HER2阴性的乳腺癌[11]. 来那替尼是共价HER2和EGFR等激酶抑制剂, 用于治疗HER2阳性的乳腺癌[16]. 奈舒地尔是ATP竞争性的ROCK激酶抑制剂, 作为滴眼液用于治疗开角型青光眼或高眼压症[61]. 2018年, FDA批准了9款激酶药物, 包括礼来公司的巴瑞替尼(Baricitinib)、辉瑞公司的比美替尼(Binimetinib)、达可替尼(Dacomitinib)、康奈非尼(Encorafenib)、洛拉替尼(Lorlatinib)、Secura公司的度维利塞(Duvelisib)、Rigel公司的福坦替尼(Fostamatinib)、安斯泰来公司的吉瑞替尼(Gilteritinib)和拜耳公司的拉罗替尼(Larotrectinib)[12] (图5). 巴瑞替尼是I型ATP竞争性的Janus激酶1 (Janus kinase 1, JAK1)和JAK2等激酶抑制剂, 用于治疗类风湿性关节炎[30]. 比美替尼是III型的MEK1/2变构激酶抑制剂, 联合康奈非尼治疗携带BRAFV600E或BRAFV600K的黑色素瘤或非小细胞肺癌[25]. 达可替尼是二代共价EGFR激酶抑制剂, 用于治疗携带EGFRDel19或EGFRL858R等激活性突变的非小细胞肺癌[62]. 康奈非尼是BRAFV600E/K激酶抑制剂, 联合比美替尼治疗携带BRAFV600E或BRAFV600K的黑色素瘤或非小细胞肺癌, 以及联合西妥昔单抗治疗携带BRAFV600E的结直肠癌[42]. 洛拉替尼是I型大环类ALK和ROS1等激酶抑制剂, 用于治疗ALK阳性的非小细胞肺癌[63]. 度维利塞是I型ATP竞争性的PI3Kδ和PI3Kγ等激酶抑制剂, 用于治疗慢性淋巴细胞白血病、小淋巴细胞性淋巴瘤和滤泡性淋巴瘤[64]. 福坦替尼是I型ATP竞争性的脾酪氨酸激酶(spleen tyrosine kinase, Syk)抑制剂的口服前药, 用于治疗慢性免疫性血小板减少症[65]. 吉瑞替尼是II型ATP竞争性的FLT3和AXL等激酶抑制剂, 用于治疗携带FLT3致癌突变的急性髓系白血病[66]. 拉罗替尼是原肌球蛋白受体激酶A/B/C (tropomyosin receptor kinase A/B/C, TRKA/B/C)等激酶抑制剂, 是首个获得美国FDA“组织不确定”突破性疗法认定的小分子药物, 用于治疗神经营养性酪氨酸受体激酶(neurotrophic tyrosine receptor kinase, NTRK)基因融合的实体瘤[25]. 2019年, FDA批准了7款激酶药物, 包括诺华公司的阿培利司(Alpelisib)、罗氏公司的恩曲替尼(Entrectinib)、强生公司的厄达替尼(Erdafitinib)、赛诺菲公司的菲卓替尼(Fedratinib)、第一三共公司的培西达替尼(Pexidartinib)、艾伯维公司的乌帕替尼(Upadacitinib)和百济神州公司的泽布替尼(Zanubrutinib)[12]. 阿培利司是I型ATP竞争性的PI3Kα激酶抑制剂, 联合氟维司群治疗激素受体阳性、HER2阴性和携带PIK3CA突变的乳腺癌[67]. 恩曲替尼是I1/2型ATP竞争性的TRKA/B/C、ROS1和ALK等激酶抑制剂, 用于治疗携带NTRK基因融合的实体瘤和ROS1阳性的非小细胞肺癌[68]. 厄达替尼是I1/2型ATP竞争性的泛FGFR激酶抑制剂, 用于治疗携带FGFR基因改变的尿路上皮癌[69]. 菲卓替尼是I型ATP竞争性的JAK2激酶抑制剂, 用于治疗骨髓纤维化[30]. 培西达替尼是II型ATP竞争性的集落刺激因子1受体(colony stimulating factor 1 receptor, CSF1R)激酶抑制剂, 用于治疗腱鞘巨细胞瘤[70]. 乌帕替尼是I型ATP竞争性的JAK1抑制剂, 用于治疗类风湿关节炎、银屑病和特应性皮炎[71]. 泽布替尼是共价BTK激酶抑制剂, 选择性优于伊布替尼, 用于治疗套细胞淋巴瘤[72]. 2020年, FDA批准了8款激酶药物, 包括Blueprint Medicines公司的阿伐替尼(Avapritinib)、普拉替尼(Pralsetinib)、诺华公司的卡马替尼(Capmatinib)、Incyte公司的佩米替尼(Pemigatinib)、Deciphera公司的瑞派替尼(Ripretinib)、礼来公司的塞普替尼(Selpercatinib)、阿斯利康公司的司美替尼(Selumetinib)和辉瑞公司的妥卡替尼(Tucatinib)[12]. 阿伐替尼是I型ATP竞争性的KIT和PDGFRA等激酶抑制剂, 用于治疗携带PDGFRA外显子18突变的胃肠道间质瘤[73]. 普拉替尼是I型ATP竞争性的RET激酶抑制剂, 治疗RET融合的非小细胞肺癌、RET突变的甲状腺髓样癌或RET融合的甲状腺癌[74]. 卡马替尼是ATP竞争性的MET激酶抑制剂, 用于治疗携带MET基因14号外显子跳跃突变的非小细胞肺癌[75]. 佩米替尼是ATP竞争性的泛FGFR激酶抑制剂, 用于治疗FGFR2融合或其他重排的胆管癌[76]. 瑞派替尼是II型ATP竞争性的KIT和PDGFR等激酶抑制剂, 用于治疗胃肠道间质瘤[77]. 塞普替尼是I型ATP竞争性的RET激酶抑制剂, 用于治疗RET融合的非小细胞肺癌、RET突变的甲状腺髓样癌或RET融合的甲状腺癌[74]. 司美替尼是III型的MEK1变构激酶抑制剂, 用于治疗神经纤维瘤[78]. 妥卡替尼是ATP竞争性的HER2激酶抑制剂, 联合曲妥珠单抗和卡培他滨治疗HER2阳性乳腺癌[79]. 2021年, FDA批准了8款激酶药物, 包括默克公司的特泊替尼(Tepotinib)、TG Therapeutics公司的厄布利塞(Umbralisib)、G1 Therapeutics公司的曲拉西利(Trilaciclib)、诺华公司的英菲格拉替尼(Infigratinib)、赛诺菲公司的贝舒地尔(Belumosudil)武田公司的莫博替尼(Mobocertinib)、Aveo公司的替沃扎尼(Tivozanib)和诺华公司的阿西米尼(Asciminib)[12] (图6). 特泊替尼是I型ATP竞争性的MET激酶抑制剂, 用于治疗携带MET外显子14跳跃突变的非小细胞肺癌[80]. 厄布利塞是PI3Kδ和酪蛋白激酶1ε (casein kinase 1ε, CK1ε)双靶抑制剂, 用于治疗边缘区淋巴瘤或滤泡性淋巴瘤[81]. 曲拉西利是静脉给药的CDK4/6激酶抑制剂, 是首款骨髓保护疗法, 用于减少广泛期小细胞肺癌患者接受大剂量化疗所导致骨髓抑制频率[82]. 英菲格拉替尼是ATP竞争性的泛FGFR激酶抑制剂, 用于治疗携带FGFR2融合或其他重排的胆管癌[83]. 贝舒地尔是ROCK2激酶抑制剂, 用于治疗慢性移植物抗宿主病[84]. 莫博替尼是EGFR外显子20激活突变体抑制剂, 是首个用于治疗携带EGFR外显子20激活突变的非小细胞肺癌[85]. 替沃扎尼是II型ATP竞争性的泛VEGFR激酶抑制剂, 用于治疗肾细胞癌[34]. 阿西米尼是IV型的BCR-ABL变构激酶抑制剂, 通过结合BCR-ABL融合蛋白特有的肉豆蔻酰口袋来发挥作用, 用于携带BCR-ABLT315I的慢性髓性白血病[86]. 2022年, FDA批准了5款激酶药物, 包括辉瑞公司的阿布昔替尼(Abrocitinib)、百时美施贵宝公司的氘可来昔替尼(Deucravacitinib)、Tiaho公司的福巴替尼(Futibatinib)、Sobi公司的帕克替尼(Pacritinib)和Agios公司的米他匹伐(Mitapivat)[12]. 阿布昔替尼是I型ATP竞争性的JAK1激酶抑制剂, 是首个用于治疗特应性皮炎的激酶抑制剂[87]. 氘可来昔替尼是IV型的TYK2变构激酶抑制剂, 通过结合TYK2的假激酶口袋发挥作用, 用于治疗银屑病, 是首个结构中包含氘原子的激酶抑制剂[88]. 福巴替尼是共价泛FGFR激酶抑制剂, 用于治疗FGFR2融合的肝内胆管癌[89]. 帕克替尼是I型ATP竞争性的选择性JAK2激酶抑制剂, 用于治疗骨髓纤维化[90]. 米他匹伐是丙酮酸激酶(pyruvate kinase, PK)变构激活剂, 用于治疗溶血性贫血[91]. 2023年, FDA批准了8款激酶药物, 包括阿斯利康公司的卡匹色替(Capivasertib)、和记黄埔的呋喹替尼(Fruquintinib)、葛兰素史克公司的莫洛替尼(Momelotinib)、礼来公司的吡托布鲁替尼(Pirtobrutinib)、第一三共公司的奎扎替尼(Quizartinib)、百时美施贵宝公司的瑞普替尼(Repotrectinib)、辉瑞公司的利特昔替尼(Ritlecitinib)和Pharming公司的莱尼奥利西布(Leniolisib)[12]. 卡匹色替是I型ATP竞争性的AKT激酶抑制剂, 用于治疗激素受体阳性和HER2阴性的乳腺癌[92]. 呋喹替尼是ATP竞争性的VFGFR2激酶抑制剂, 用于治疗结直肠癌[93]. 莫洛替尼是I型ATP竞争性的JAK1/2激酶抑制剂, 用于治疗骨髓纤维化[90]. 吡托布鲁替尼是I1/2型ATP竞争性的BTK激酶抑制剂, 用于治疗套细胞淋巴瘤、慢性淋巴细胞白血病和小淋巴细胞淋巴瘤[94]. 奎扎替尼是II型ATP竞争性的FLT3激酶抑制剂, 用于治疗FLT3内部串联重复的急性髓性白血病[95]. 瑞普替尼是I型ATP竞争性的ROS1和TRK双靶激酶抑制剂, 用于治疗ROS1阳性的非小细胞肺癌[96]. 利特昔替尼是I型ATP竞争性的JAK3激酶抑制剂, 用于治疗斑秃[97]. 莱尼奥利西布是ATP竞争性的选择性PI3Kδ激酶抑制剂, 用于治疗PI3Kδ过度活化综合征[98]. 2024年, FDA批准了5款激酶药物, 包括Sun公司的氘代芦可替尼(Deuruxolitinib)、贝达药业的恩沙替尼(Ensartinib)、强生公司的拉泽替尼(Lazertinib)、Day One公司的托沃拉非尼(Tovorafenib)、基因泰克公司的伊那利塞(Inavolisib)[12]. 氘代芦可替尼是ATP竞争性的JAK1/2激酶抑制剂, 用于治疗斑秃[99]. 恩沙替尼是ATP竞争性的ALK激酶抑制剂, 用于治疗ALK阳性的非小细胞肺癌[100]. 拉泽替尼是I1/2型ATP竞争性的三代EGFR激酶抑制剂, 用于治疗携带EGFRDel19或EGFRL858R等激活性突变的非小细胞肺癌患者[101]. 托沃拉非尼是II型ATP竞争性的B-Raf激酶抑制剂, 用于治疗儿童低恶性胶质瘤[102]. 伊那利塞是ATP竞争性的PI3Kα激酶抑制剂, 用于治疗具有PI3Kα基因突变、激素受体阳性(HR+)、HER2阴性、局部晚期或转移性乳腺癌的成年患者[103]. 2025年(截至5月31日), FDA批准了4款激酶药物, 包括SpringWorks公司的米尔德替尼(Mirdametinib)、小野制药的维姆塞替尼(Vimseltinib)和Verastem公司的艾沃美替尼(Avutometinib)、地法替尼(Defactinib)[12]. 米尔德替尼是III型的MEK变构激酶抑制剂, 用于治疗I型神经纤维瘤[45]. 维姆塞替尼是II型ATP竞争性的CSF1R激酶抑制剂, 用于治疗腱鞘巨细胞瘤[104]. 艾沃美替尼通过诱导MEK与RAF形成非活性复合物, 抑制MEK/RAF活性, 用于治疗KRAS突变的低级别浆液性卵巢癌[105]. 地法替尼是I型ATP竞争性的FAK激酶抑制剂, 用于治疗KRAS突变的低级别浆液性卵巢癌[106].2.2 大分子激酶药物(抗体) 1998年, 罗氏公司的曲妥珠单抗(Trastuzumab)获批上市, 用于治疗HER2阳性乳腺癌, 是首个应用于实体肿瘤的人源化单抗. 该药物是抗HER2的单克隆抗体, 通过结合到HER2的胞外结构域IV, 阻止其与其他HER2形成同源二聚体, 从而抑制下游的信号传导路径, 阻止肿瘤细胞的增殖, 以及引发抗体依赖的细胞毒作用[12,107]. 2004年, 默克公司的西妥昔单抗(Cetuximab)获批上市, 用于治疗结肠直肠癌和头颈癌. 该药物是抗EGFR的单克隆抗体, 与EGFR胞外域结合, 阻断其二聚活化, 抑制细胞增殖, 以及引发抗体依赖的细胞毒作用[12,108]. 2006年, 安进公司的帕尼单抗(Panitumumab)获批上市, 用于治疗结直肠癌. 该药物也是抗EGFR的单克隆抗体[12,109]. 2012年, 罗氏公司的帕妥珠单抗(Pertuzumab)获批上市, 用于治疗HER2阳性乳腺癌. 该药物也是抗HER2单克隆抗体, 结合到HER2的胞外结构域II, 阻止HER2与其他EGFR家族受体(HER1、HER3、HER4)形成二聚体, 抑制肿瘤细胞增殖[12,110]. 2013年, 罗氏公司的恩美曲妥珠单抗(Trastuzumab-emtansine)获批上市, 用于治疗HER2阳性乳腺癌. 该药物是由抗HER2靶向药物曲妥珠单抗与抑制微管聚集的化疗药物美坦新通过硫醚连接子连接而成的抗体偶联物(antibody-drug conjugate, ADC)[12,111]. 2014年, 礼来公司的雷莫芦单抗(Ramucirumab)和尼妥珠单抗(Nimotuzumab)获批上市[12]. 雷莫芦单抗是抗VEGFR2单克隆抗体, 结合VEGFR2胞外域的末端, 诱导受体构象的改变, 阻止配体与VEGFR2结合, 从而抑制下游信号传导, 用于治疗胃癌或胃食管交界处癌[112]. 尼妥珠单抗也是一种EGFR单克隆抗体, 用于与放疗联合治疗EGFR阳性的鼻咽癌[113]. 2016年, 礼来公司的奥拉单抗(Olaratumab)获批上市, 用于治疗软组织肉瘤. 该药物是PDGFRα单克隆抗体, 结合人PDGFRα并阻断其与配体PDGFs结合, 抑制下游信号通路[12,114]. 2019年, 第一三共公司的德曲妥珠单抗(Trastuzumab-Deruxtecan)获批上市, 用于治疗HER2阳性的乳腺癌和胃癌. 该药物是一种ADC, 由抗HER2单克隆抗体与DNA拓扑异构酶I抑制剂依沙替康衍生物组成[12,115]. 2020年, MacroGenics公司的马吉妥昔单抗(Margetuximab)获批上市, 用于治疗HER2阳性乳腺癌. 该药物是一种抗HER2的单克隆抗体[12,116]. 2021年, 强生公司的埃万妥单抗(Amivantamab)获批上市, 用于治疗EGFR外显子20插入突变的非小细胞肺癌. 该药物是一种直接针对EGFR和MET的双特异性抗体, 可以与EGFR和MET的胞外域结合, 同时抑制EGFR和MET信号通路[12,117]. 2024年, 百济神州公司的泽尼达妥单抗(Zanidatamab)和Merus公司的泽妥珠单抗(Zenocutuzumab)获批上市[12]. 泽尼达妥单抗是HER2双特异性抗体, 用于治疗HER2阳性胆道癌. 该抗体可同时与HER2上两个不同表位结合, 既可以阻断HER2信号, 也可以促进内化, 导致肿瘤细胞表面受体减少从而抑制肿瘤细胞增长[118]. 泽妥珠单抗是靶向HER2/HER3的双特异性抗体, 用于治疗非小细胞肺癌和胰腺癌. 该药物通过阻止NRG1与HER3结合, 抑制HER2/HER3二聚化并诱导NRG1基因融合肿瘤细胞死亡[119]. 2025年, 艾伯维的特立妥珠单抗(Telisotuzumab)获批上市, 用于治疗c-Met高表达的非鳞状非小细胞肺癌. 该抗体由c-Met靶向抗体、可裂解连接子和单甲基奥瑞他汀E (MMAE)载荷组成的ADC. 针对肿瘤细胞表面的c-Met突变进行追踪, 并释放抗有丝分裂药物MMAE抑制肿瘤细胞增长[12,120]. 3 总结与展望从1995年第一个激酶抑制剂法舒地尔获批30年以来, FDA共批准了110个激酶药物, 包括96个小分子药物和14个大分子药物. 分析这96个激酶小分子药物, 我们得到如下结论. (1) 在这96种药物中, 除了有95种不同类型的激酶抑制剂, 还包含1个丙酮酸激酶变构激活剂米他匹伐. 尽管目前仅有一款激酶激活剂获批用于疾病治疗, 但这有力证实了激活相关激酶是治疗疾病的可行策略, 拓展了激酶药物研发的空间. (2) 53种药物靶向受体酪氨酸激酶, 22种药物抑制非受体酪氨酸激酶, 14种药物拮抗丝氨酸/苏氨酸激酶, 6种药物靶向双特异性蛋白激酶(MEK1/2), 以及1种药物激动糖酵解过程相关的丙酮酸激酶. 由此可知, 尽管在蛋白激酶中, 大部分为丝氨酸/苏氨酸激酶, 但酪氨酸激酶仍然是大部分激酶药物的作用对象. 这可能是因为酪氨酸激酶的病理作用更明确、致癌驱动突变集中, 如EGFR、ALK、BCR-ABL等酪氨酸激酶的突变或融合是多种癌症的直接驱动因素, 而丝氨酸/苏氨酸激酶更多作为下游信号节点(如mTOR、AKT). 另外, 丝氨酸/苏氨酸激酶(如CDKs、PKC)常参与细胞周期、代谢等基础生命活动, 抑制后易导致广泛毒性. 但随着变构调节、蛋白降解及相关生物学技术的发展, 丝氨酸/苏氨酸激酶抑制剂研究将会得到极大助力. (3) 在被批准上市药物的结合模式中, 以吉非替尼为代表的I型ATP竞争性抑制剂达30种, 其结合特点为嘌呤类核心骨架模拟ATP与铰链区形成氢键作用, α-C螺旋处于活性位置(α-C螺旋上的保守谷氨酸与β3折叠上的保守赖氨酸形成离子键), DFG基序为“in”活性构象. 以伊马替尼为代表的II型ATP竞争性抑制剂有15种, 与I型抑制剂不同的是, 其DFG基序为“out”非活性构象. 该构象往往会产生一个新的疏水口袋, 为高选择性化合物的产生带来新的机会. 除去经典的I型或II型结合模式外, 以舒尼替尼为代表的14种药物呈现I1/2型结合模式, 其结构特征为α-C螺旋处于非活性位置, DFG基序为“in”活性构象. 此外, 上市药物还包括以曲美替尼为代表的5种III型变构抑制剂, 以阿西米尼为代表的2种IV型变构抑制剂和以阿法替尼为代表的11种共价抑制剂. 因此, 我们看到激酶抑制剂的作用模式呈现出丰富的多样性. 特别值得注意的是, 近些年上市的药物中, 以艾沃美替尼为代表, 通过诱导形成新蛋白-蛋白相互作用, 从而抑制激酶活性的小分子药物或将成为激酶药物开发的全新方向. (4) 从化学结构多样性角度分析, 上市激酶药物主要可以分为三类: 以首个激酶抑制剂法舒地尔为代表的六元稠环骨架, 包括喹啉、异喹啉及喹唑啉类, 共计20个; 六元芳环氨基嘧啶、氨基吡啶、氨基哒嗪已成为最常用的ATP模拟物骨架, 以伊马替尼为代表的上市药物共计26个; 第三类骨架为五元并六元稠环骨架, 包括吡咯并嘧啶、嘌呤、氧杂吲哚、吡咯或咪唑三嗪等, 共计23个. 其余抑制剂骨架还包括五元并六元稠环的氨基类似物, 非芳香的羧酰胺结构. 由此可见, 目前激酶抑制剂使用的骨架仍然比较局限. 但随着近些年化学合成特别是手性合成的巨大进步, 具有更加立体特性的新型激酶抑制剂骨架有望得到拓展. (5) 1999~2012年间, 有22个激酶小分子药物获批, 在随后的五年(2013~2018)间, 有29个激酶小分子药物上市, 从2019年之后, 药物获批速度进一步加快, 总计45个激酶小分子药物获批上市, 凸显了激酶药物研发的加速趋势. (6) 在适应证上, 81种激酶抑制剂获批用于治疗实体瘤或者非实体瘤. 其中依维莫司和伊布替尼也被用于预防移植物抗宿主病. 17种药物被用于治疗非肿瘤类疾病. 例如, 托法替尼、尼达尼布、阿布希替尼、氘可来昔替尼等用于治疗类风湿性关节炎、肺纤维化、特应性皮炎、银屑病等免疫性疾病. 这些非肿瘤激酶药物的获批, 证实激酶药物的广泛应用价值, 也为激酶药物的应用空间拓展提供了充分的依据. 相信未来我们将看到激酶药物用于更多其他非肿瘤疾病的治疗. (7) 给药方式上, 93种小分子抑制剂采用口服给药的方式, 只有替西罗莫司与曲拉西利采用静脉注射给药方式, 奈舒地尔由于适应证为眼部疾病, 采用滴眼液给药方式. 因此, 口服因其便捷性仍然是激酶药物优选服药方式. 值得一提的是, 截至2025年5月31, 中国国家药品监督管理局(National Medical Products Administration, NMPA)批准上市的国产原研激酶药物也达40个(表1), 包括我们团队研发的奥雷巴替尼和利厄替尼. 在临床肿瘤治疗中, 激酶靶点的选择大致遵循两种策略: 首先, 重点关注已获批激酶抑制剂靶点突变耐药的患者, 开发对突变型激酶具有良好活性的下一代药物. 其次, 针对全新致病激酶靶点, 开发全新的激酶抑制剂. 我国在对现有靶点的下一代药物开发中取得了重要进展, 以奥雷巴替尼为例, 该药物对携带BCR-ABLT315I突变的慢性髓性白血病患者显示出了良好效果, 接连获得美国FDA和欧洲药品管理局孤儿药认可. 但对于针对全新靶点的激酶药物, 我国临床转化领域仍存在较大空白, 亟需针对尚未探索的激酶开发首创小分子调节剂. 另外, 近年来, 更多的FDA批准的激酶药物被应用于非肿瘤类疾病治疗, 包括类风湿性关节炎、肺纤维化、特应性皮炎、银屑病等免疫性疾病, 而我国批准的激酶药物仍集中于癌症, 亟需往更多非癌疾病拓展. Table 1 NMPA-approved domestically developed original kinase-targeted drugs 上市时间药品名(商品名) 靶标批准适应证原研公司 2011 埃克替尼(凯美纳) EGFR 非小细胞肺癌贝达药业 2014 阿帕替尼(艾坦) VEGFR-2 胃癌; 肝细胞癌江苏恒瑞 2018 安罗替尼(福可维) VEGFR/PDGFR/FGFR/C-KIT 非小细胞肺癌正大天晴 2018 吡咯替尼(艾瑞妮) HER2 乳腺癌江苏恒瑞 2018 呋喹替尼(爱优特) VEGFR 结直肠癌和记黄埔 2019 泽布替尼(百悦泽) BTK 套细胞淋巴瘤; 慢性淋巴细胞白血病/小淋巴细胞淋巴瘤百济神州 2019 氟马替尼(豪森昕福) BCR-ABL 费城染色体阳性的慢性髓性白血病翰森制药 2020 阿美替尼(阿美乐) EGFR-T790M 非小细胞肺癌豪森药业 2020 恩沙替尼(贝美纳) ALK 非小细胞肺癌贝达药业 2020 奥布替尼(宜诺凯) BTK 套细胞淋巴瘤; 慢性淋巴细胞白血病/小淋巴细胞淋巴瘤北京诺诚健华 2021 索凡替尼(苏泰达) CSF-1R/FGFR1/VEGFR 神经内分泌瘤和记黄埔 2021 伏美替尼(艾弗沙) EGFR-T790M 非小细胞肺癌艾力斯医药 2021 多纳非尼(泽普生) 多激酶肝细胞癌; 甲状腺癌苏州泽璟 2021 赛沃替尼(沃瑞沙) MET 非小细胞肺癌和记黄埔 2021 奥雷巴替尼(耐立克) BCR-ABL-T315I 耐药慢性髓细胞白血病亚盛医药 2022 林普利塞(因他瑞) PI3Kδ 滤泡性淋巴瘤上海璎黎 2023 谷美替尼(海益坦) c-MET 非小细胞肺癌上海海和 2023 伏罗尼布(伏美纳) 多激酶肾细胞癌; 多癌症贝达药业 2023 舒沃替尼(舒沃哲) EGFR 非小细胞肺癌迪哲医药 2023 贝福替尼(赛美纳) EGFR-T790M 非小细胞肺癌贝达药业 2023 伯瑞替尼(万比锐) c-MET 非小细胞肺癌; 脑胶质瘤北京浦润奥 2023 伊鲁阿克(启欣可) ALK, ROS1 非小细胞肺癌齐鲁制药 2024 妥拉美替尼(科露平) MEK1/2 黑色素瘤科州制药 2024 安奈克替尼(安柏尼) ROS1, ALK, c-Met 非小细胞肺癌正大天晴 2024 瑞齐替尼(瑞必达) EGFR-T790M 非小细胞肺癌上海倍而达 2024 氟泽雷塞(达伯特) KRAS-G12C 非小细胞肺癌信达生物 2024 依奉阿克(安洛晴) ALK 非小细胞肺癌正大天晴 2024 瑞厄替尼(圣瑞沙) EGFR-T790M 非小细胞肺癌圣和药业 2024 戈利昔替尼(高瑞哲) JAK1 外周T细胞淋巴瘤迪哲医药 2024 佐利替尼(泽瑞尼) EGFR-19del/L858R 非小细胞肺癌江苏晨泰医药 2024 他雷替尼(达伯乐) ROS1 非小细胞肺癌葆元生物 2025 利厄替尼(奥壹新) EGFR-T790M 非小细胞肺癌奥赛康 2025 艾玛昔替尼(艾速达) JAK1 强直性脊柱炎江苏恒瑞 2025 吡洛西利(轩悦宁) CDK4/6 乳腺癌轩竹生物 2025 来罗西利(汝佳宁) CDK4/6 乳腺癌嘉和生物 2025 伏维西利(复妥宁) CDK4/6 乳腺癌复星医药/奥鸿药业 2025 法米替尼(艾比特) 多靶点(RTKs) 宫颈癌江苏恒瑞 2025 芦沃美替尼(复迈宁) MEK1/2 朗格汉斯细胞组织细胞增生症; 组织细胞肿瘤; 神经纤维瘤(儿童/青少年) 复星医药 2025 吉卡昔替尼(泽普平) JAK, ACVR1 骨髓纤维化苏州泽璟 2025 戈来雷塞(艾瑞凯) KRAS-G12C 非小细胞肺癌加科思/艾力斯医药总的来说, 30年来的激酶药物研发取得了丰硕成果. 但激酶领域仍然有许多问题值得进一步研究, 如提高激酶抑制剂选择性、克服激酶抑制剂耐药性以及靶向激酶的非酶功能等. 综合采用共价结合、蛋白降解、变构调节等多种策略, 以及结合组学和人工智能技术进行激酶小分子调节剂研究是解决这些需求的重要路径. 基于此, 我们认为, 激酶仍然是未来药物研发的重要方向. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

上市批准

100 项与菲卓替尼相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	菲卓替尼	L01XE57	DB12500

研发状态

批准上市

10 条最早获批的记录,

后查看更多信息

适应症	国家/地区	公司	日期
原发性血小板增多症后骨髓纤维化	欧盟	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性血小板增多症后骨髓纤维化	冰岛	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性血小板增多症后骨髓纤维化	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性血小板增多症后骨髓纤维化	挪威	Bristol-Myers Squibb Pharma EEIG	2021-02-08
真性红细胞增多症后骨髓纤维化	欧盟	Bristol-Myers Squibb Pharma EEIG	2021-02-08
真性红细胞增多症后骨髓纤维化	冰岛	Bristol-Myers Squibb Pharma EEIG	2021-02-08
真性红细胞增多症后骨髓纤维化	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2021-02-08
真性红细胞增多症后骨髓纤维化	挪威	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性骨髓纤维化	欧盟	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性骨髓纤维化	冰岛	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性骨髓纤维化	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2021-02-08
原发性骨髓纤维化	挪威	Bristol-Myers Squibb Pharma EEIG	2021-02-08
脾肿大	欧盟	Bristol-Myers Squibb Pharma EEIG	2021-02-08
脾肿大	冰岛	Bristol-Myers Squibb Pharma EEIG	2021-02-08
脾肿大	列支敦士登	Bristol-Myers Squibb Pharma EEIG	2021-02-08
脾肿大	挪威	Bristol-Myers Squibb Pharma EEIG	2021-02-08
骨髓纤维化	美国	Bristol Myers Squibb Co.	2019-08-16
真性红细胞增多症	美国	Bristol Myers Squibb Co.	2019-08-16
原发性血小板增多症	美国	Bristol Myers Squibb Co.	2019-08-16

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
血液肿瘤	临床3期	美国	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	澳大利亚	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	奥地利	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	比利时	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	巴西	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	加拿大	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	法国	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	德国	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	匈牙利	Bristol Myers Squibb Co.	2011-12-01
血液肿瘤	临床3期	爱尔兰	Bristol Myers Squibb Co.	2011-12-01

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ASCO2025	N/A	骨髓纤维化 JAK2 \| FLT3	960	Fedratinib after Ruxolitinib	齋觸積製醖餘淵積範鹹(艱網餘範衊餘簾膚鬱積) = 31.2% (C.I. 0.27-0.36, p < 0.001) 製網窪遞繭餘艱網夢獵 (鬱鏇鏇製製衊憲鏇範糧 ) 更多	积极	2025-05-30
				Ruxolitinib alone
NCT03952039 (FREEDOM2, Pubmed \| Lancet Haematol) 人工标引	临床3期	骨髓纤维化二线	201	Fedratinib 400 mg per day	衊築鹽選鏇鹽鑰觸簾簾(獵廠廠鑰壓蓋窪鹽糧壓) = 衊鏇鹹網鹹壓製鑰窪鑰選襯範壓製淵鬱製憲築 (範構構壓廠觸範鹹鹽蓋 ) 更多	积极	2024-09-01
				Best Available Therapy (BAT)	衊築鹽選鏇鹽鑰觸簾簾(獵廠廠鑰壓蓋窪鹽糧壓) = 繭淵構醖衊鏇廠衊壓憲選襯範壓製淵鬱製憲築 (範構構壓廠觸範鹹鹽蓋 ) 更多
NCT03755518 (FREEDOM, Pubmed \| Leuk Lymphoma)	临床3期	骨髓纤维化	38	Fedratinib	願淵窪醖鏇顧範範鹽築(築窪鏇製選繭蓋鹹製範) = 蓋糧夢簾遞壓顧簾鏇淵築鑰鑰製糧顧選淵築遞 (襯遞遞淵鹽觸選醖廠顧, 12.5 ~ 43.3) 更多	积极	2024-07-28
NCT03952039 (FREEDOM2, EHA2024) 人工标引	临床3期	骨髓纤维化二线	201	Fedratinib 400mg daily	積願鏇遞糧網窪糧鹹鑰(鏇蓋壓範憲觸廠鹹衊簾) = 簾築夢繭壓蓋簾鑰壓鹽遞鑰窪夢製範廠糧窪鏇 (製廠積簾觸網製憲觸衊 ) 更多	积极	2024-05-14
				Best Available Therapy (BAT)	積願鏇遞糧網窪糧鹹鑰(鏇蓋壓範憲觸廠鹹衊簾) = 壓願餘艱選襯蓋衊夢憲遞鑰窪夢製範廠糧窪鏇 (製廠積簾觸網製憲觸衊 ) 更多
Tandem Meetings ASTCT and CIBMTR2024	N/A	骨髓纤维化	18	Fedratinib 400 mg once daily	範醖積網製鹽願選顧膚(積蓋餘築顧觸獵蓋構願) = n=4 (22.2%) deaths were recorded as of May 2023. Two of the 4 deaths were related to MF and both patients had disease transformation to blast phase MPN before HSCT. A median duration of 14.5 months elapsed between FEDR initiation and death among these 4 patients 選憲積鬱顧鏇齋蓋鹹鬱 (艱鏇衊衊衊蓋壓製膚觸 ) 更多	积极	2024-02-01
NCT03952039 (FREEDOM2, CTgov)	临床3期	原发性血小板增多症后骨髓纤维化 \| 真性红细胞增多症后骨髓纤维化 \| 原发性骨髓纤维化	202	Best Available Therapy (BAT)	鹹鏇鏇蓋襯艱繭夢壓遞 = 構鹹獵選鹽觸膚構夢壓遞夢衊壓築選簾衊蓋襯 (遞願繭糧繭築鬱襯繭壓, 構鹽顧憲膚繭觸淵壓膚 ~ 衊憲獵淵壓齋糧網鏇淵) 更多	-	2024-01-30
NCT03952039 (FREEDOM2, ASH2023)	临床3期	骨髓纤维化	201	Fedratinib 400 mg/day	繭鬱夢遞壓選繭獵簾觸(廠獵築餘淵醖選窪簾糧) = 廠遞憲齋鏇構糧獵築選醖鬱繭願選蓋簾觸襯鹹 (築淵願窪窪淵範遞餘顧 ) 更多	积极	2023-12-10
				Best Available Therapy (BAT)	繭鬱夢遞壓選繭獵簾觸(廠獵築餘淵醖選窪簾糧) = 醖顧壓範遞鏇夢窪憲觸醖鬱繭願選蓋簾觸襯鹹 (築淵願窪窪淵範遞餘顧 ) 更多
NCT04817007 (CA011-023, ASH2023)	临床1/2期	原发性骨髓纤维化	40	BMS-986158+Ruxolitinib	夢鬱蓋觸鏇醖衊蓋醖構(範壓製簾網蓋積構鬱壓) = 窪鏇選窪顧齋築窪襯願鹹醖衊構繭鹽構遞鏇廠 (選顧齋積糧鑰醖糧願蓋 )	-	2023-12-10
				BMS-986158+Fedratinib	夢鬱蓋觸鏇醖衊蓋醖構(範壓製簾網蓋積構鬱壓) = 鏇製鏇範廠餘膚艱壓選鹹醖衊構繭鹽構遞鏇廠 (選顧齋積糧鑰醖糧願蓋 )
NCT05177211 (ASH2023)	临床2期	慢性中性粒细胞白血病 \| 骨髓增生性疾病	10	Fedratinib	憲齋獵願鏇簾築餘窪製(鹽壓憲築繭網觸築簾網) = 餘憲餘廠憲憲齋選鑰淵襯蓋願鏇夢構蓋範製窪 (築衊選範窪網淵網鏇襯 ) 更多	-	2023-12-09
ASH2023	N/A	原发性骨髓纤维化	58	Fedratinib	範繭積糧夢鹽餘鬱窪鑰(餘夢製鑰製觸醖糧願範) = 蓋膚蓋鑰獵窪蓋鏇鏇艱醖觸網選遞製齋憲壓憲 (齋簾繭顧鏇遞艱齋衊蓋 )	-	2023-12-09