司来利塞(Seletalisib) - 药物靶点：PI3Kδ_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PI3Kδ

作用机制

PI3Kδ抑制剂(磷脂酰肌醇-3激酶δ抑制剂)

治疗领域

免疫系统疾病遗传病与畸形其他疾病+ [4]

在研适应症-

非在研适应症

激活PI3K-δ综合征银屑病关节炎斑块状银屑病+ [2]

原研机构

UCB SA

在研机构-

非在研机构

UCB Celltech

UCB SA

UCB Pharma GmbH

最高研发阶段终止临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (欧盟)

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结构

分子式C23H14ClF3N6O

InChIKeyLNLJHGXOFYUARS-OAQYLSRUSA-N

CAS号1362850-20-1

关联

9

项与司来利塞相关的临床试验

EUCTR2014-004523-51-GR / Not yet recruiting临床2期

A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF UCB5857 OVER 12 WEEKS IN SUBJECTS WITH PRIMARY SJOGREN’S SYNDROME

开始日期2017-02-14

申办/合作机构

UCB Celltech

EUCTR2015-005541-30-ES / Not yet recruiting临床3期

AN OPEN-LABEL, EXPLORATORY, MULTICENTER, EXTENSION STUDY TO EVALUATE THE LONG-TERM SAFETY, TOLERABILITY, PHARMACOKINETICS AND EFFICACY OF UCB5857 IN SUBJECTS WITH ACTIVATED PHOSPHOINOSITIDE 3 KINASE (PI3K) DELTA SYNDROME (APDS)

开始日期2016-06-08

申办/合作机构

UCB Biopharma SRL

EUCTR2015-002900-10-DE / Not yet recruiting临床1期

AN OPEN-LABEL EXPLORATORY STUDY OF UCB5857 IN SUBJECTS WITH ACTIVATED PHOSPHOINOSITIDE 3 KINASE (PI3K) DELTA SYNDROME (APDS)

开始日期2015-12-21

申办/合作机构-

100 项与司来利塞相关的临床结果

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100 项与司来利塞相关的转化医学

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100 项与司来利塞相关的专利（医药）

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12

项与司来利塞相关的文献（医药）

2022-08-24·Journal of Leukocyte Biology3区 · 医学

The phosphoinositide-3-kinase (PI3K)-delta inhibitor seletalisib impairs monocyte-derived dendritic cells maturation, APC function, and promotes their migration to CCR7 and CXCR4 ligands

3区 · 医学

Article

作者: Scopelliti, Fernanda ; Cavani, Andrea ; Costanzo, Gianfranco ; Madonna, Stefania ; Cattani, Caterina ; Dimartino, Valentina ; Albanesi, Cristina ; Mercurio, Laura ; Mirisola, Concetta

AbstractPI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders.

2021-03-02·Rheumatology2区 · 医学

A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome

2区 · 医学

Article

作者: Gottenberg, Jacques-Eric ; Sánchez Bursón, Juan ; Nayar, Saba ; Helmer, Eric ; Giacomelli, Roberto ; Payne, Andrew ; Rosas, José ; Guggino, Giuliana ; Cain, Dionne ; Johnston, Geoffrey I ; Fisher, Benjamin A ; Mariette, Xavier ; Bowman, Simon J ; Devauchelle-Pensec, Valerie ; Ng, Wan Fai ; Barone, Francesca ; Diaz, Nieves ; Juarez, Maria ; Triolo, Giovanni ; Williams, Paulette ; Kvarnström, Marika

AbstractObjectivesThis phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren’s syndrome (PSS).MethodsAdults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies.ResultsTwenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: –2.59 (95% CI: –7.30, 2.11; P=0.266) and –1.55 (95% CI: –3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo.ConclusionDespite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation.Trial registrationhttps://clinicaltrials.gov, NCT02610543.

2020-12-01·The Journal of Immunology2区 · 医学

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies

2区 · 医学

Article

作者: Juarez, Maria ; Helmer, Eric ; Moshous, Despina ; Simonetti, Alessandra ; Martín-Nalda, Andrea ; Heeg, Maximilian ; Mann, Joanne ; Cancrini, Caterina ; Garcia-Prat, Marina ; Cavazzana, Marina ; Cain, Dionne ; Soler-Palacín, Pere ; Johnston, Geoffrey I. ; Martínez-Gallo, Mónica ; Conti, Francesca ; Payne, Andrew ; Ehl, Stephan ; Diaz, Nieves ; Santilli, Veronica ; Maccari, Maria Elena ; Semeraro, Michaela ; Kracker, Sven ; Di Cesare, Silvia ; Yuill, Daisy ; Suarez, Felipe

AbstractMutations in two genes can result in activated PI3Kδ syndrome (APDS), a rare immunodeficiency disease with limited therapeutic options. Seletalisib, a potent, selective PI3Kδ inhibitor, was evaluated in patients with APDS1 and APDS2. In the phase 1b study (European Clinical Trials Database 2015-002900-10) patients with genetic and clinical confirmation of APDS1 or APDS2 received 15–25 mg/d seletalisib for 12 wk. Patients could enter an extension study (European Clinical Trials Database 2015-005541). Primary endpoints were safety and tolerability, with exploratory efficacy and immunology endpoints. Seven patients (median age 15 years; APDS1 n = 3; APDS2 n = 4) received seletalisib; five completed the phase 1b study. For the extension study, four patients entered, one withdrew consent (week 24), three completed ≥84 wk of treatment. In the phase 1b study, patients had improved peripheral lymphadenopathy (n = 2), lung function (n = 1), thrombocyte counts (n = 1), and chronic enteropathy (n = 1). Overall, effects were maintained in the extension. In the phase 1b study, percentages of transitional B cells decreased, naive B cells increased, and senescent CD8 T cells decreased (human cells); effects were generally maintained in the extension. Seletalisib-related adverse events occurred in four of seven patients (phase 1b study: hepatic enzyme increased, dizziness, aphthous ulcer, arthralgia, arthritis, increased appetite, increased weight, restlessness, tendon disorder, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (aphthous ulcer). Serious adverse events occurred in three of seven patients (phase 1b study: hospitalization, colitis, and potential drug-induced liver injury) and one of four patients had adverse events in the extension (stomatitis). Patients with APDS receiving seletalisib had improvements in variable clinical and immunological features, and a favorable risk–benefit profile was maintained for ≤96 wk.

100 项与司来利塞相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12706

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
激活PI3K-δ综合征	临床3期	法国	UCB SA	2016-06-08
原发性干燥综合征	临床3期	瑞典	UCB Celltech	2015-10-01
原发性干燥综合征	临床3期	西班牙	UCB Celltech	2015-10-01
原发性干燥综合征	临床3期	意大利	UCB Celltech	2015-10-01
原发性干燥综合征	临床3期	法国	UCB Celltech	2015-10-01
原发性干燥综合征	临床3期	英国	UCB Celltech	2015-10-01
银屑病关节炎	临床3期	英国	UCB Pharma GmbH	2013-08-01
斑块状银屑病	临床3期	英国	UCB SA	-
干燥综合征	临床3期	希腊	UCB SA	-

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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


NCT02610543 (Pubmed \| Rheumatology (Oxford)) 人工标引	临床2期	原发性干燥综合征	27	seletalisib	(鹹鏇範齋構廠遞蓋鑰築): Difference = -2.59 (95% CI, 2.11 ~ 7.30), P-Value = 0.266 更多	积极	2021-03-02
				Placebo
NCT02610543 (Phase II, EULAR2019)	临床2期	原发性干燥综合征 EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI)	27	Seletalisib	(網簾鹹艱鏇憲網鹽憲鬱) = 構願顧壓網襯夢壓築顧製鬱糧膚鹽構鹹遞鬱簾 (網繭淵憲獵製願淵窪艱, 1.7) 更多	积极	2019-06-12
				Placebo	(網簾鹹艱鏇憲網鹽憲鬱) = 築築餘鬱製積衊選淵鑰製鬱糧膚鹽構鹹遞鬱簾 (網繭淵憲獵製願淵窪艱, 1.5) 更多
NCT02207595 \| NCT02303509 (Pubmed \| Eur J Clin Pharmacol) 人工标引	临床1期	炎症 \| 免疫系统疾病	-	seletalisib (90 mg QD)	(獵顧願範積夢憲觸構餘) = 範繭衊構築網鑰淵觸顧簾獵構構鹽廠壓獵鏇襯 (鏇鏇淵壓艱壓顧積選糧 )	积极	2017-05-01
				seletalisib (30 mg BID)	(獵顧願範積夢憲觸構餘) = 餘齋糧襯鑰選築鹽憲願簾獵構構鹽廠壓獵鏇襯 (鏇鏇淵壓艱壓顧積選糧 )