Key Points
Seletalisib, a PI3Kδ inhibitor, was evaluated in seven patients with APDS1 and APDS2.
Following treatment, patients had improvements in clinical and immunological features.
Seletalisib had a favorable risk–benefit profile in a phase 1b study up to 96 wk.
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.
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Footnotes
This work was supported by UCB Pharma, Brussels, Belgium, including the design and conduct of the studies, the collection, analysis, and interpretation of the data, and the preparation, review, and approval of the manuscript.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- AKT
- protein kinase B
- ALT
- alanine aminotransferase
- APDS
- activated PI3Kδ syndrome
- HSCT
- hematopoietic stem cell transplantation
- IGRT
- Ig replacement therapy
- mTOR
- mammalian target of rapamycin
- pAKTS473
- AKT phosphorylated at Ser473
- PhGADA
- physician’s global assessment of disease activity
- p-S6
- phospho-S6 ribosomal protein
- PtGADA
- patient/caregiver’s global assessment of disease activity
- SAE
- serious treatment–emergent adverse event
- TEAE
- treatment-emergent adverse event.
- Received March 30, 2020.
- Accepted September 22, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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