Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies
| Autor: | Andrea Martín-Nalda, Maria Juarez, Pere Soler-Palacín, Francesca Conti, Eric Helmer, Caterina Cancrini, Geoffrey I Johnston, Marina Cavazzana, Dionne Cain, Nieves Diaz, Marina Garcia-Prat, Despina Moshous, Maria Elena Maccari, Payne Andrew Charles, Felipe Suarez, Michaela Semeraro, Sven Kracker, Mónica Martínez-Gallo, Daisy Yuill, Silvia Di Cesare, Stephan Ehl, Maximilian Heeg, Joanne Mann, Alessandra Simonetti, Veronica Santilli |
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| Přispěvatelé: | UCB Pharma, Slough SL1 3WE, United Kingdom |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Class I Phosphatidylinositol 3-Kinases Pyridines [SDV]Life Sciences [q-bio] Immunology Arthritis CD8-Positive T-Lymphocytes Gastroenterology Young Adult 03 medical and health sciences 0302 clinical medicine Internal medicine medicine Humans Immunology and Allergy Young adult Colitis Child Adverse effect Stomatitis ComputingMilieux_MISCELLANEOUS business.industry Precursor Cells B-Lymphoid Immunologic Deficiency Syndromes medicine.disease 3. Good health Clinical trial Settore MED/01 Tolerability Mutation aphthous ulcer Quinolines Female business 030215 immunology |
| Zdroj: | Journal of Immunology Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2020, pp.ji2000326. ⟨10.4049/jimmunol.2000326⟩ |
| ISSN: | 0022-1767 1550-6606 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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