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

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

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2979-2987
Number of pages9
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume205
Issue number11
DOIs
Publication statusPublished - 1 Dec 2020

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