Maria Juarez1, Nieves Diaz1, Geoffrey I Johnston1, Saba Nayar2, Andrew Payne3, Eric Helmer4, Dionne Cain5, Paulette Williams6, Valerie Devauchelle-Pensec7, Benjamin A Fisher8,9, Roberto Giacomelli10, Jacques-Eric Gottenberg11, Giuliana Guggino12, Marika Kvarnström13, Xavier Mariette14, Wan Fai Ng15, José Rosas16, Juan Sánchez Bursón17, Giovanni Triolo12, Francesca Barone2, Simon J Bowman8. 1. Translational Medicine, UCB Pharma, Slough, UK. 2. Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK. 3. Discovery Biology, Slough, UK. 4. Quantitative Clinical Pharmacology, Slough, UK. 5. Global Clinical Sciences and Operations, UCB Pharma, Slough, UK. 6. Statistical Science and Innovation, UCB Pharma, Raleigh, NC, USA. 7. Department of Rheumatology, Brest University, Cavale Blanche Hospital, Brest, France. 8. National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. 9. Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK. 10. Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. 11. Department of Rheumatology, National Reference Centre For Rare Systemic Auto-Immune Diseases, Strasbourg University Hospital, University of Strasbourg, IBMC, CNRS UPR 3572, Strasbourg, France. 12. Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Palermo, Italy. 13. Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden. 14. Université Paris-Saclay, INSERM, CEA, Centre de recherche en Immunologie des Infections Virales et des Maladies auto-Immunes, AP-HP.Université Paris-Saclay, Hôpital Bicêtre, Rheumatology Department, Le Kremlin Bicêtre, France. 15. Translational and Clinical Research Institute, Newcastle University & NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK. 16. Department of Rheumatology, Hospital Marina Baixa, Villajoyosa, Spain. 17. Department of Rheumatology, Infanta Luisa Hospital, Sevilla, Spain.
Abstract
OBJECTIVES: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS). METHODS:Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. RESULTS:Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. CONCLUSION: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT02610543.
RCT Entities:
OBJECTIVES: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS). METHODS: Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies. RESULTS: Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo. CONCLUSION: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation. TRIAL REGISTRATION: https://clinicaltrials.gov, NCT02610543.
Authors: Xavier Mariette; Raphael Porcher; Raphaele Seror; Gabriel Baron; Marine Camus; Divi Cornec; Elodie Perrodeau; Simon J Bowman; Michele Bombardieri; Hendrika Bootsma; Jacques-Eric Gottenberg; Benjamin Fisher; Wolfgang Hueber; Joel A van Roon; Valérie Devauchelle-Pensec; Peter Gergely Journal: Ann Rheum Dis Date: 2022-04-07 Impact factor: 27.973
Authors: Bart Vanhaesebroeck; Matthew W D Perry; Jennifer R Brown; Fabrice André; Klaus Okkenhaug Journal: Nat Rev Drug Discov Date: 2021-06-14 Impact factor: 112.288