PMID- 32949140 OWN - NLM STAT- MEDLINE DCOM- 20210629 LR - 20210629 IS - 1462-0332 (Electronic) IS - 1462-0324 (Linking) VI - 60 IP - 3 DP - 2021 Mar 2 TI - A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjogren's syndrome. PG - 1364-1375 LID - 10.1093/rheumatology/keaa410 [doi] AB - OBJECTIVES: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kdelta inhibitor, in patients with moderate-to-severe primary Sjogren'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 Sjogren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjogren'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. CI - (c) The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com. FAU - Juarez, Maria AU - Juarez M AD - Translational Medicine, UCB Pharma, Slough, UK. FAU - Diaz, Nieves AU - Diaz N AD - Translational Medicine, UCB Pharma, Slough, UK. FAU - Johnston, Geoffrey I AU - Johnston GI AD - Translational Medicine, UCB Pharma, Slough, UK. FAU - Nayar, Saba AU - Nayar S AD - Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK. FAU - Payne, Andrew AU - Payne A AD - Discovery Biology, Slough, UK. FAU - Helmer, Eric AU - Helmer E AD - Quantitative Clinical Pharmacology, Slough, UK. FAU - Cain, Dionne AU - Cain D AD - Global Clinical Sciences and Operations, UCB Pharma, Slough, UK. FAU - Williams, Paulette AU - Williams P AD - Statistical Science and Innovation, UCB Pharma, Raleigh, NC, USA. FAU - Devauchelle-Pensec, Valerie AU - Devauchelle-Pensec V AD - Department of Rheumatology, Brest University, Cavale Blanche Hospital, Brest, France. FAU - Fisher, Benjamin A AU - Fisher BA AD - National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. AD - Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK. FAU - Giacomelli, Roberto AU - Giacomelli R AD - Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy. FAU - Gottenberg, Jacques-Eric AU - Gottenberg JE AD - Department of Rheumatology, National Reference Centre For Rare Systemic Auto-Immune Diseases, Strasbourg University Hospital, University of Strasbourg, IBMC, CNRS UPR 3572, Strasbourg, France. FAU - Guggino, Giuliana AU - Guggino G AD - Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Palermo, Italy. FAU - Kvarnstrom, Marika AU - Kvarnstrom M AD - Department of Medicine, Rheumatology Unit, Karolinska Institutet, Stockholm, Sweden. FAU - Mariette, Xavier AU - Mariette X AD - Universite Paris-Saclay, INSERM, CEA, Centre de recherche en Immunologie des Infections Virales et des Maladies auto-Immunes, AP-HP.Universite Paris-Saclay, Hopital Bicetre, Rheumatology Department, Le Kremlin Bicetre, France. FAU - Ng, Wan Fai AU - Ng WF AD - Translational and Clinical Research Institute, Newcastle University & NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, UK. FAU - Rosas, Jose AU - Rosas J AD - Department of Rheumatology, Hospital Marina Baixa, Villajoyosa, Spain. FAU - Sanchez Burson, Juan AU - Sanchez Burson J AD - Department of Rheumatology, Infanta Luisa Hospital, Sevilla, Spain. FAU - Triolo, Giovanni AU - Triolo G AD - Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, Rheumatology Section, University of Palermo, Palermo, Italy. FAU - Barone, Francesca AU - Barone F AD - Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK. FAU - Bowman, Simon J AU - Bowman SJ AD - National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. LA - eng SI - ClinicalTrials.gov/NCT02610543 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - England TA - Rheumatology (Oxford) JT - Rheumatology (Oxford, England) JID - 100883501 RN - 0 (Antirheumatic Agents) RN - 0 (Pyridines) RN - 0 (Quinolines) RN - 64CW205BDD (seletalisib) SB - IM MH - Administration, Oral MH - Antirheumatic Agents/administration & dosage/adverse effects/*therapeutic use MH - Double-Blind Method MH - Female MH - Humans MH - Male MH - Middle Aged MH - Proof of Concept Study MH - Pyridines/administration & dosage/adverse effects/*therapeutic use MH - Quinolines/administration & dosage/adverse effects/*therapeutic use MH - Salivary Glands/pathology MH - Sjogren's Syndrome/*drug therapy/pathology OTO - NOTNLM OT - histology OT - phosphatidylinositol 3-kinase delta (PI3Kdelta) OT - primary Sjogren's syndrome OT - proof-of-concept OT - seletalisib EDAT- 2020/09/20 06:00 MHDA- 2021/06/30 06:00 CRDT- 2020/09/19 08:33 PHST- 2020/03/03 00:00 [received] PHST- 2020/05/08 00:00 [revised] PHST- 2020/09/20 06:00 [pubmed] PHST- 2021/06/30 06:00 [medline] PHST- 2020/09/19 08:33 [entrez] AID - 5908809 [pii] AID - 10.1093/rheumatology/keaa410 [doi] PST - ppublish SO - Rheumatology (Oxford). 2021 Mar 2;60(3):1364-1375. doi: 10.1093/rheumatology/keaa410.