TY - JOUR
T1 - Seletalisib for Activated PI3Kδ Syndromes
T2 - Open-Label Phase 1b and Extension Studies
AU - Diaz, Nieves
AU - Juarez, Maria
AU - Cancrini, Caterina
AU - Heeg, Maximilian
AU - Soler-Palacín, Pere
AU - Payne, Andrew
AU - Johnston, Geoffrey I.
AU - Helmer, Eric
AU - Cain, Dionne
AU - Mann, Joanne
AU - Yuill, Daisy
AU - Conti, Francesca
AU - Di Cesare, Silvia
AU - Ehl, Stephan
AU - Garcia-Prat, Marina
AU - Maccari, Maria Elena
AU - Martín-Nalda, Andrea
AU - Martínez-Gallo, Mónica
AU - Moshous, Despina
AU - Santilli, Veronica
AU - Semeraro, Michaela
AU - Simonetti, Alessandra
AU - Suarez, Felipe
AU - Cavazzana, Marina
AU - Kracker, Sven
N1 - Publisher Copyright:
Copyright © 2020 by The American Association of Immunologists, Inc.
Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85096815565&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.2000326
DO - 10.4049/jimmunol.2000326
M3 - Article
C2 - 33115853
AN - SCOPUS:85096815565
SN - 0022-1767
VL - 205
SP - 2979
EP - 2987
JO - Journal of immunology (Baltimore, Md. : 1950)
JF - Journal of immunology (Baltimore, Md. : 1950)
IS - 11
ER -