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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 Santilli, Michaela Semeraro, Alessandra Simonetti, Felipe Suarez, Marina Cavazzana and Sven Kracker
J Immunol December 1, 2020, 205 (11) 2979-2987; DOI: https://doi.org/10.4049/jimmunol.2000326
Nieves Diaz
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Maria Juarez
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Caterina Cancrini
†Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
‡Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children’s Hospital Bambino Gesù, 00165 Rome, Italy;
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Maximilian Heeg
§Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, 79106 Freiburg, Germany;
¶Center for Pediatrics, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
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Pere Soler-Palacín
‖Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Catalonia, Spain;
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Andrew Payne
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Geoffrey I. Johnston
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Eric Helmer
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Dionne Cain
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Joanne Mann
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Daisy Yuill
*UCB Pharma, Slough SL1 3WE, United Kingdom;
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Francesca Conti
†Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
‡Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children’s Hospital Bambino Gesù, 00165 Rome, Italy;
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Silvia Di Cesare
†Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
‡Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children’s Hospital Bambino Gesù, 00165 Rome, Italy;
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Stephan Ehl
§Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, 79106 Freiburg, Germany;
¶Center for Pediatrics, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
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Marina Garcia-Prat
‖Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Catalonia, Spain;
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Maria Elena Maccari
§Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center – University of Freiburg, 79106 Freiburg, Germany;
¶Center for Pediatrics, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany;
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Andrea Martín-Nalda
‖Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d’Hebron University Hospital, 08035 Barcelona, Catalonia, Spain;
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Mónica Martínez-Gallo
#Immunology Division and Diagnostic Immunology Research Group, Vall d’Hebron University Hospital, Vall d’Hebron Research Institute, 08035 Barcelona, Catalonia, Spain;
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Despina Moshous
**Pediatric Immunology, Haematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Center – University of Paris, 75743 Paris, France;
††Imagine Institute, INSERM UMR 1163, University of Paris, 75015 Paris, France;
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Veronica Santilli
‡Unit of Immune and Infectious Diseases, Academic Department of Pediatrics, Children’s Hospital Bambino Gesù, 00165 Rome, Italy;
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Michaela Semeraro
‡‡Imagine Institute, INSERM UMR 1163 et CNRS ERL 8254, University of Paris, 75015 Paris, France;
§§Academic Department of Pediatrics, Clinical Trial Unit, Children’s Hospital Bambino Gesù, 00165 Rome, Italy;
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Alessandra Simonetti
†Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
§§Academic Department of Pediatrics, Clinical Trial Unit, Children’s Hospital Bambino Gesù, 00165 Rome, Italy;
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Felipe Suarez
‡‡Imagine Institute, INSERM UMR 1163 et CNRS ERL 8254, University of Paris, 75015 Paris, France;
¶¶Adult Haematology Department, Haematology and Rheumatology Unit, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Center – University of Paris, 75743 Paris, France;
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Marina Cavazzana
‖‖Biotherapy Clinical Investigation Center, University Hospitals Paris West, Assistance Publique-Hôpitaux de Paris, INSERM, 75004 Paris, France;
##Imagine Institute, University of Paris, 75015 Paris, France;
***Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; and
†††Biotherapy Department, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Center – University of Paris, 75015 Paris, France
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Sven Kracker
##Imagine Institute, University of Paris, 75015 Paris, France;
***Laboratory of Human Lymphohematopoiesis, INSERM UMR 1163, Imagine Institute, 75015 Paris, France; and
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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.

This article is featured in Top Reads, p.2939

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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The Journal of Immunology: 205 (11)
The Journal of Immunology
Vol. 205, Issue 11
1 Dec 2020
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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 Santilli, Michaela Semeraro, Alessandra Simonetti, Felipe Suarez, Marina Cavazzana, Sven Kracker
The Journal of Immunology December 1, 2020, 205 (11) 2979-2987; DOI: 10.4049/jimmunol.2000326

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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 Santilli, Michaela Semeraro, Alessandra Simonetti, Felipe Suarez, Marina Cavazzana, Sven Kracker
The Journal of Immunology December 1, 2020, 205 (11) 2979-2987; DOI: 10.4049/jimmunol.2000326
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