1. Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies.
- Author
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Diaz N, Juarez M, Cancrini C, Heeg M, Soler-Palacín P, Payne A, Johnston GI, Helmer E, Cain D, Mann J, Yuill D, Conti F, Di Cesare S, Ehl S, Garcia-Prat M, Maccari ME, Martín-Nalda A, Martínez-Gallo M, Moshous D, Santilli V, Semeraro M, Simonetti A, Suarez F, Cavazzana M, and Kracker S
- Subjects
- Adolescent, Adult, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes metabolism, Child, Female, Humans, Immunologic Deficiency Syndromes metabolism, Male, Mutation drug effects, Precursor Cells, B-Lymphoid immunology, Precursor Cells, B-Lymphoid metabolism, Young Adult, Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors, Immunologic Deficiency Syndromes drug therapy, Pyridines therapeutic use, Quinolines therapeutic use
- Abstract
Mutations 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., (Copyright © 2020 by The American Association of Immunologists, Inc.)
- Published
- 2020
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