生物活性

• 描述Leniolisib is a selective PI3Kδ inhibitor with IC50 values of 0.205, 0.087, 0.128, 0.064 and 0.05μM for PI3K wt, PI3K N334K, E525K, E1021K and C416R mutant, most commonly described in APDS (activated PI3Kδ syndrome). It led a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T-cell blasts derived from patients. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. The elevated serum levels of CXCL13, CXCL10, IFNγ, and TNF in APDS patients were reduced by leniolisib treatment to levels measured in healthy volunteers. Also it improved lymphadenopathy, splenomegaly and cytopenias in APDS patients^[3].

• 动物研究
  剂量	Rat: 10 mg/kg[2] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[2] Dogs[2] Monkeys[2] Dose 1 mg/kg (i.v.) 30 mg/kg (p.o.) 0.1 mg/kg (i.v.) 0.3 mg/kg (p.o.) 0.1 mg/kg (i.v.) 0.3 mg/kg (p.o.) Administration i.v. p.o. i.v. p.o. i.v. p.o. Cmax, norm 334 nM (p.o.) 3410 nM (p.o.) T1/2 1.8 h (i.v.) 1.5 h (i.v.) 0.7 h (i.v.) Tmax <0.25 h (p.o.) 0.7 h (p.o.) <0.5 h (p.o.) CL 28 ml/min/kg (i.v.) 2 ml/min/kg (i.v.) 17 ml/min/kg (i.v.) Cmax 213 nM (p.o.) BAV >100% 58% (p.o.) 13% (p.o.) AUCnorm 20120 nM·h (i.v.) 11690 nM·h (p.o.) Vss 3.1 L/kg (i.v.) 0.3 L/kg (i.v.) 0.6 L/kg (i.v.) AUC(normalized to 1 mg/kg) 1355 nM·h (i.v.) 2107 nM·h (p.o.) 2250 nM·h (i.v.) 297 nM·h (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02435173	Common Variable Immunodeficien... more >>cy (CVID) More Specifically Activated PI3Kdelta Syndrome (APDS) p110delta-activating Mutation Causing Senescent T Cells Lymphadenopathy and Immunodeficiency (PASLI) Collapse <<	Phase 2 Phase 3	Recruiting	February 6, 2020	United States, Maryland ... more >> National Institute of Health NIH Recruiting Bethesda, Maryland, United States, 20814 Contact: Sharon Webster    301-496-2771    Sharon.webster@nih.gov    Czechia Novartis Investigative Site Recruiting Prague 5, Czechia, 150 00 Ireland Novartis Investigative Site Recruiting Dublin, Ireland Italy Novartis Investigative Site Recruiting Brescia, Italy, 25123 Netherlands Novartis Investigative Site Recruiting Rotterdam, Netherlands, 3000 CA Russian Federation Novartis Investigative Site Recruiting Moscow, Russian Federation, 117198 United Kingdom Novartis Investigative Site Recruiting Belfast, United Kingdom, BT9 7AB Novartis Investigative Site Recruiting London, United Kingdom, NW3 2PF Collapse <<

• 参考文献

• [1] Rao VK, Webster S, et al. Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316.

  [2] Hoegenauer K, Soldermann N, et al. Discovery of CDZ173 (Leniolisib), Representing a Structurally Novel Class of PI3K Delta-Selective Inhibitors. ACS Med Chem Lett. 2017 Aug 25;8(9):975-980.

  [3] Rao VK, Webster S, Dalm VASH, Šedivá A, van Hagen PM, Holland S, Rosenzweig SD, Christ AD, Sloth B, Cabanski M, Joshi AD, de Buck S, Doucet J, Guerini D, Kalis C, Pylvaenaeinen I, Soldermann N, Kashyap A, Uzel G, Lenardo MJ, Patel DD, Lucas CL, Burkhart C. Effective "activated PI3Kδ syndrome"-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29. PMID: 28972011; PMCID: PMC5701526.