Effective "activated PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib.

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Rao VK, Webster S, Dalm VASH, Sediva 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 PI3Kdelta syndrome"-targeted therapy with the PI3Kdelta inhibitor leniolisib.

Blood. 2017 Nov 23;130(21):2307-2316. doi: 10.1182/blood-2017-08-801191. Epub 2017 Sep 29.

PubMed ID

28972011 [ View in PubMed

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Abstract

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase delta (PI3Kdelta) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kdelta syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kdelta inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kdelta in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kdelta inhibitor, caused dose-dependent suppression of PI3Kdelta pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110delta variants and in T-cell blasts derived from patients. A clinical trial with 6 APDS patients was conducted as a 12-week, open-label, multisite, within-subject, dose-escalation study of oral leniolisib to assess safety, pharmacokinetics, and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naive B cells, reduction in PD-1(+)CD4(+) and senescent CD57(+)CD4(-) T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon gamma, tumor necrosis factor, CXCL13, and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean; range, 26%-57%) and 40% (mean; range, 13%-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kdelta as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kdelta pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

DrugBank Data that Cites this Article

Drugs

Leniolisib

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Leniolisib	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform	Protein	Humans	Yes	Inhibitor	Details