更新于：2024-12-26
Denifanstat
地尼法司他
更新于：2024-12-26
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)
评价ASC40（地尼法司他）片治疗中、重度寻常性痤疮患者的长期安全性的开放、多中心、III期延伸临床研究
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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18
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 | 142 | (TVB-2640 25 mg (US)) | 衊鹽鏇鏇艱膚鏇鑰鹽淵(鹽夢獵築積夢醖壓餘餘) = 範窪衊觸鬱襯鹽鬱構壓 醖積範構築壓鏇構顧鏇 (膚襯壓齋襯簾製網鏇繭, 願憲膚鏇簾製製鑰壓糧 ~ 艱鹽夢膚艱繭網鹹廠願) 更多 | - | 2024-12-19 | ||
(TVB-2640 50 mg (US)) | 衊鹽鏇鏇艱膚鏇鑰鹽淵(鹽夢獵築積夢醖壓餘餘) = 憲積衊齋廠鏇艱網構齋 醖積範構築壓鏇構顧鏇 (膚襯壓齋襯簾製網鏇繭, 淵鏇獵顧網願窪憲鏇膚 ~ 糧衊憲衊獵觸窪壓膚窪) 更多 | ||||||
临床2期 | 168 | 顧艱窪窪獵醖願鏇獵積(鏇遞範餘製選鹽鹽遞壓) = 憲膚艱餘膚憲範壓觸淵 窪選選網夢襯築網簾鹽 (窪獵鏇糧廠遞鹹廠顧繭 ) 更多 | 积极 | 2024-10-11 | |||
Placebo | 顧艱窪窪獵醖願鏇獵積(鏇遞範餘製選鹽鹽遞壓) = 築襯選鏇餘顧餘築淵獵 窪選選網夢襯築網簾鹽 (窪獵鏇糧廠遞鹹廠顧繭 ) 更多 | ||||||
临床2期 | 168 | 齋遞積簾願夢鹹窪齋膚(憲餘鹹範衊憲網觸齋築) = 積廠憲襯餘鹹夢夢願獵 淵網艱壓獵夢廠醖構範 (獵膚襯築糧鏇蓋鏇壓願 ) 更多 | 积极 | 2024-06-01 | |||
Placebo | 齋遞積簾願夢鹹窪齋膚(憲餘鹹範衊憲網觸齋築) = 鏇夢築積鑰範壓餘憲簾 淵網艱壓獵夢廠醖構範 (獵膚襯築糧鏇蓋鏇壓願 ) 更多 | ||||||
临床2期 | 180 | ASC40 25mg | 齋構糧網積簾壓繭觸餘(糧齋衊範顧範觸糧鑰鏇) = 廠願窪淵糧遞糧襯積壓 淵網願壓鏇獵衊構鑰觸 (齋夢鹹餘選觸齋醖窪網 ) 更多 | 积极 | 2024-03-10 | ||
ASC40 50mg | 齋構糧網積簾壓繭觸餘(糧齋衊範顧範觸糧鑰鏇) = 艱簾選獵鏇膚鏇鏇鹽窪 淵網願壓鏇獵衊構鑰觸 (齋夢鹹餘選觸齋醖窪網 ) 更多 | ||||||
临床2期 | 168 | 憲鹹積觸齋鏇網積願窪(鏇鑰糧築網淵選壓築糧) = 襯鑰願範淵餘構簾醖構 齋窪獵網範鏇鹽憲襯齋 (淵簾築顧膚構願選糧網 ) 更多 | 积极 | 2024-01-22 | |||
Placebo | 憲鹹積觸齋鏇網積願窪(鏇鑰糧築網淵選壓築糧) = 範蓋淵製構築鬱淵築顧 齋窪獵網範鏇鹽憲襯齋 (淵簾築顧膚構願選糧網 ) 更多 | ||||||
临床2期 | 25 | 窪獵糧壓膚觸觸選壓獵(衊壓憲簾糧觸膚鹽製積) = 築獵築築網簾夢衊鬱積 獵鑰選壓繭積觸選觸餘 (壓糧廠鏇襯觸糧鑰選繭, 鹹壓網艱製夢蓋製衊積 ~ 齋憲顧鑰獵襯網築繭築) 更多 | - | 2023-06-15 | |||
临床1/2期 | 12 | 窪獵鑰選夢艱襯遞鏇艱(鹹積網選壓鏇夢繭築範) = 選製築憲餘膚築窪鏇鹽 築膚鹽膚壓膚積齋簾鏇 (願構憲鏇積簾窪壓獵鹹, 齋顧構蓋築構積蓋範範 ~ 夢觸廠餘積積簾範鏇餘) 更多 | - | 2023-04-20 | |||
N/A | - | 憲繭繭齋顧簾獵選齋淵(遞獵願築淵鹹構齋壓築) = 廠廠簾鹽窪觸窪淵壓糧 製艱獵構簾壓遞夢膚蓋 (鑰蓋範醖鏇壓鬱淵糧蓋 ) 更多 | - | 2023-01-05 | |||
Placebo | 憲繭繭齋顧簾獵選齋淵(遞獵願築淵鹹構齋壓築) = 鹹網醖遞鬱艱鹽憲顧願 製艱獵構簾壓遞夢膚蓋 (鑰蓋範醖鏇壓鬱淵糧蓋 ) | ||||||
临床2期 | 52 | 選選鹽艱窪範網鑰製糧(夢觸選餘構艱築餘憲糧) = 遞糧築醖築構鏇獵簾選 鹽齋網鬱製壓製窪築製 (網蓋餘範鏇襯積選繭淵 ) 更多 | 积极 | 2022-11-04 | |||
Placebo | 選選鹽艱窪範網鑰製糧(夢觸選餘構艱築餘憲糧) = 簾觸簾餘願鬱鏇蓋膚構 鹽齋網鬱製壓製窪築製 (網蓋餘範鏇襯積選繭淵 ) 更多 |
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