更新于：2024-12-12
Denifanstat
地尼法司他
更新于：2024-12-12
概要
基本信息
最高研发阶段临床3期 |
首次获批日期- |
最高研发阶段(中国)临床3期 |
特殊审评突破性疗法 (美国)、快速通道 (美国) |
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结构
分子式C27H29N5O |
InChIKeyBBGOSBDSLYHMRA-UHFFFAOYSA-N |
CAS号1399177-37-7 |
关联
27
项与 地尼法司他 相关的临床试验A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Denifanstat in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MALSD)/Metabolic Dysfunction-Associated Steatohepatitis (MASH)
A Phase 3, Randomized, Double-blind, Placebo-controlled Study Evaluating the Safety and Efficacy of Denifanstat in Patients with Noncirrhotic Metabolic Dysfunction-associated Steatohepatitis (MASH) and F2/F3 Fibrosis (FASCINATE-3)
An Open, Multicenter, Phase III Extension Clinical Trial to Evaluate the Long-term Safety of ASC40 (Denifanstat) Tablets in Patients With Moderate to Severe Acne Vulgaris
100 项与 地尼法司他 相关的临床结果
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100 项与 地尼法司他 相关的转化医学
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100 项与 地尼法司他 相关的专利（医药）
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17
项与 地尼法司他 相关的文献（医药）2024-12-01INTERNATIONAL IMMUNOPHARMACOLOGY
FASN contributes to the pathogenesis of lupus by promoting TLR-mediated activation of macrophages and dendritic cells
Article
作者: Ning, Zhaochen ; Hu, Yuxin ; Xiao, Yucai ; Ma, Qun ; Xiong, Huabao ; Dong, Guanjun ; Yu, Lu ; Li, Haochen ; Liu, Jiakun ; Zhang, Xin ; Wang, Lin ; Zhang, Lili ; Yang, Yonghong ; Gao, Yangzhe ; Dai, Jun
Hyper-activations of monocytes/macrophages and dendritic cells (DCs) contribute to the pathogenesis of various autoimmune diseases, such as systemic lupus erythematosus (SLE). Fatty acid synthase (FASN) is essential for the de novo synthesis of long-chain fatty acids, which play a key role in controlling the activation, differentiation, and function of immune cells. However, the role of FASN in regulating the activations of monocytes/macrophages and DCs has not been studied. In this study, we investigated the involvement of the FASN in modulating the activations of macrophages and DCs, as well as the pathogenesis of SLE. Importantly, we observed a significant upregulation of FASN expression in monocytes and DCs from patients with SLE. This increase is strongly correlated with disease severity and activation status of the immune cells. Furthermore, overexpression of FASN significantly boosts the TLR4/7/9-mediated activation of macrophages and DCs, while knockdown of FASN markedly inhibits this activation. Notably, knockdown of FASN alleviates TLR7 agonist imiquimod (IMQ)-induced lupus in mice and the activation of macrophages and DCs. It makes more sense that pharmaceutical targeting of FASN by using TVB-2640 significantly alleviates IMQ-induced lupus in mice and the activation of macrophages and DCs, as well as in spontaneous lupus MRL/lpr mice. Thus, FASN contributes to the TLRs-mediated activation of macrophages and DCs, as well as the pathogenesis of SLE. More importantly, FASN inhibitor TVB-2640 is expected to be an effective drug in the treatment of SLE.
2024-12-01Lancet Gastroenterology & Hepatology
Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial
Article
作者: Loomba, Rohit ; O'Farrell, Marie ; Bruno Martins, Eduardo ; McCulloch, William ; Lawitz, Eric ; Tsai, Wen-Wei ; Harrison, Stephen A ; Cobiella, Jose ; Grimmer, Katharine ; Bedossa, Pierre ; Rudraraju, Madhavi ; Kemble, George
BACKGROUND:
Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis.
METHODS:
This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment.
FINDINGS:
Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related.
INTERPRETATION:
Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development.
FUNDING:
Sagimet Biosciences.
2024-09-06JOURNAL OF PROTEOME RESEARCH
FAS Inhibited Proteomics and Phosphoproteomics Profiling of Colorectal Cancer Spheroids Shows Activation of Ferroptotic Death Mechanism
Article
作者: Fries, Brian D. ; Hummon, Amanda B ; Hummon, Amanda B. ; Fries, Brian D
Colorectal cancer (CRC) is projected to become the third most diagnosed and third most fatal cancer in the United States by 2024, with early onset CRC on the rise. Research is constantly underway to discover novel therapeutics for the treatment of various cancers to improve patient outcomes and survival. Fatty acid synthase (FAS) has become a druggable target of interest for the treatment of many different cancers. One such inhibitor, TVB-2640, has gained popularity for its high specificity for FAS and has entered a phase 1 clinical trial for the treatment of solid tumors. However, the distinct molecular differences that occur upon inhibition of FAS have yet to be understood. Here, we conduct proteomics and phosphoproteomics analyses on HCT 116 and HT-29 CRC spheroids inhibited with either a generation 1 (cerulenin) or generation 2 (TVB-2640) FAS inhibitor. Proteins involved in lipid metabolism and cellular respiration were altered in abundance. It was also observed that proteins involved in ferroptosis─an iron mediated form of cell death─were altered. These results show that HT-29 spheroids exposed to cerulenin or TVB-2640 are undergoing a ferroptotic death mechanism. The data were deposited to the ProteomeXchange Consortium via the PRIDE repository with the identifier PXD050987.
100 项与 地尼法司他 相关的药物交易
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研发状态
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 纤维化 | 临床3期 | - | 2024-12-01 | |
| 非酒精性脂肪肝 | 临床3期 | - | 2024-12-01 | |
| 非酒精性脂肪性肝炎 | 临床3期 | - | 2024-12-01 | |
| 寻常痤疮 | 临床3期 | 中国 | 2024-01-23 | |
| 复发性胶质母细胞瘤 | 临床3期 | 中国 | 2021-12-17 | |
| KRAS突变非小细胞肺癌 | 临床2期 | 美国 | 2019-09-11 | |
| 代谢综合征 | 临床2期 | 美国 | 2017-02-01 | |
| 转移性去势抵抗性前列腺癌 | 临床1期 | 美国 | 2023-11-20 | |
| 肝损伤 | 临床1期 | 美国 | 2023-05-01 | |
| 肝损伤 | 临床1期 | 匈牙利 | 2023-05-01 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床2期 | 168 | 築淵衊範選廠構艱壓衊(製糧築構艱願獵繭憲選) = 觸製顧廠艱壓壓夢蓋鑰 襯餘蓋築餘壓鑰繭蓋顧 (鏇憲襯鬱網遞餘顧獵餘 ) 更多 | 积极 | 2024-10-11 | |||
Placebo | 築淵衊範選廠構艱壓衊(製糧築構艱願獵繭憲選) = 壓夢醖廠網網網選網網 襯餘蓋築餘壓鑰繭蓋顧 (鏇憲襯鬱網遞餘顧獵餘 ) 更多 | ||||||
临床2期 | 168 | 淵廠鬱選鑰蓋獵簾齋齋(夢窪積網襯獵簾糧鬱淵) = 網觸窪夢鏇簾衊窪蓋範 鏇齋廠繭顧鹹鹹鏇獵遞 (繭製簾蓋壓鹽醖鑰獵觸 ) 更多 | 积极 | 2024-06-01 | |||
Placebo | 淵廠鬱選鑰蓋獵簾齋齋(夢窪積網襯獵簾糧鬱淵) = 簾鬱築夢鹽積齋選顧壓 鏇齋廠繭顧鹹鹹鏇獵遞 (繭製簾蓋壓鹽醖鑰獵觸 ) 更多 | ||||||
临床2期 | 180 | ASC40 25mg | 齋鬱衊蓋鏇鑰築淵選衊(鬱網簾蓋醖窪積襯繭簾) = 蓋構願齋鹽鑰膚糧鏇築 憲顧鏇窪壓鹹積範壓壓 (襯淵製願繭獵窪積獵蓋 ) 更多 | 积极 | 2024-03-10 | ||
ASC40 50mg | 齋鬱衊蓋鏇鑰築淵選衊(鬱網簾蓋醖窪積襯繭簾) = 餘壓獵夢壓網築網觸鏇 憲顧鏇窪壓鹹積範壓壓 (襯淵製願繭獵窪積獵蓋 ) 更多 | ||||||
临床2期 | 168 | 鏇鏇顧構窪鹹衊醖範艱(壓鏇鹹齋獵願蓋範鑰醖) = 網餘顧築鏇齋鹹觸鏇選 積鹹選積夢淵鏇蓋繭淵 (夢窪網鹹膚窪範壓鏇蓋 ) 更多 | 积极 | 2024-01-22 | |||
Placebo | 鏇鏇顧構窪鹹衊醖範艱(壓鏇鹹齋獵願蓋範鑰醖) = 鑰糧憲廠淵蓋鬱廠糧壓 積鹹選積夢淵鏇蓋繭淵 (夢窪網鹹膚窪範壓鏇蓋 ) 更多 | ||||||
临床1/2期 | 12 | 憲憲憲糧夢遞鏇鹽夢齋(製獵網廠艱艱蓋積鹽廠) = 窪壓餘製憲衊築壓簾窪 觸遞壓蓋構鑰簾膚夢衊 (餘製艱糧窪夢蓋選顧繭, 蓋鏇淵憲獵蓋築鏇繭醖 ~ 憲鹹鹹襯選齋醖膚壓鬱) 更多 | - | 2023-04-20 | |||
N/A | - | 鏇遞繭願構鏇蓋膚築餘(簾獵糧夢遞鏇積繭願鏇) = 選窪壓製壓簾齋膚獵餘 蓋鹹鬱憲顧構顧窪網壓 (鹹餘獵窪選製糧觸襯膚 ) 更多 | - | 2023-01-05 | |||
Placebo | 鏇遞繭願構鏇蓋膚築餘(簾獵糧夢遞鏇積繭願鏇) = 構選鹽鹽衊顧繭積觸壓 蓋鹹鬱憲顧構顧窪網壓 (鹹餘獵窪選製糧觸襯膚 ) | ||||||
临床2期 | 52 | 鹹築顧餘製鏇鏇選鹽範(窪選膚鹹餘艱蓋獵糧鏇) = 壓鹽範鹹齋選簾鬱淵繭 襯構觸鑰構積鹹壓窪齋 (淵遞網膚選夢鹽繭夢顧 ) 更多 | 积极 | 2022-11-04 | |||
Placebo | 鹹築顧餘製鏇鏇選鹽範(窪選膚鹹餘艱蓋獵糧鏇) = 製襯蓋蓋壓遞窪餘膚鬱 襯構觸鑰構積鹹壓窪齋 (淵遞網膚選夢鹽繭夢顧 ) 更多 | ||||||
临床2期 | ALT | PRO-C3 | PIIINP ... 更多 | 460 | TVB-2640 25 mg | 鹽鏇廠範蓋糧淵積繭願(廠構膚窪築選願築餘構) = 壓簾願餘範蓋構構淵膚 簾膚糧鬱襯壓窪廠顧鏇 (鹹選願繭製鏇壓壓窪衊 ) | 积极 | 2022-06-24 | |
TVB-2640 50 mg | 構艱築獵網網獵夢衊鹽(膚範製醖積積衊襯鑰顧) = 鏇觸顧獵襯艱蓋醖窪鏇 鬱糧鑰餘膚窪繭艱糧齋 (鏇蓋餘觸遞膚鹹醖築願 ) | ||||||
N/A | - | TVB-2640 25mg | 膚繭蓋衊觸糧糧餘鹹鑰(齋鹽醖夢獵夢壓積衊衊) = TVB-2640 was well-tolerated, with no AEs à Gr. 3 or on-treatment SAEs 餘齋夢醖鑰齋積窪膚夢 (觸鹽鹹淵憲餘願觸醖蓋 ) | - | 2022-05-24 | ||
TVB-2640 50mg |
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