1. A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome
- Author
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Maria Juarez, Saba Nayar, Payne Andrew Charles, Wan-Fai Ng, Nieves Diaz, Juan Sanchez Burson, Dionne Cain, Paulette Williams, Marika Kvarnström, Benjamin A Fisher, Valérie Devauchelle-Pensec, José Rosas, Giovanni Triolo, Simon J. Bowman, Xavier Mariette, Jacques-Eric Gottenberg, Giuliana Guggino, Roberto Giacomelli, Francesca Barone, Geoffrey I Johnston, Eric Helmer, UCB Pharma Slough, University of Birmingham [Birmingham], Emory Chemical Biology Discovery Center, Emory University [Atlanta, GA], Quantitative Clinical Pharmacology, UCB Pharma Raleigh, CHRU Brest - Service de Rhumatologie (CHU - BREST - Rhumato), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Clinical Unit of Rheumatology, L'Aquila, Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Rheumatology Unit, Department of Internal Medicine, University of Palermo, Palermo, Italy, Karolinska Institutet [Stockholm], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Newcastle upon Tyne Hospitals [Newcastle, UK], NIHR Biomedical Research Centre, Hospital Marina Baixa, Villajoyosa, Infantaluisa Hospital, Sevilla, Juarez M., Diaz N., Johnston G.I., Nayar S., Payne A., Helmer E., Cain D., Williams P., Devauchelle-Pensec V., Fisher B.A., Giacomelli R., Gottenberg J.-E., Guggino G., Kvarnstrom M., Mariette X., Ng W.F., Rosas J., Sanchez Burson J., Triolo G., Barone F., and Bowman S.J.
- Subjects
Male ,0301 basic medicine ,Saliva ,medicine.medical_specialty ,Pyridines ,primary Sjögren’s syndrome ,Administration, Oral ,primary Sjogren's syndrome ,Placebo ,Proof of Concept Study ,Gastroenterology ,Salivary Glands ,histology ,seletalisib ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Rheumatology ,Internal medicine ,proof-of-concept ,medicine ,Humans ,Pharmacology (medical) ,Adverse effect ,030203 arthritis & rheumatology ,Salivary gland ,biology ,Surrogate endpoint ,business.industry ,Middle Aged ,medicine.disease ,Sialadenitis ,phosphatidylinositol 3-kinase delta (PI3K delta) ,primary Sjögren's syndrome ,3. Good health ,Sjogren's Syndrome ,030104 developmental biology ,medicine.anatomical_structure ,Tolerability ,Immunoglobulin M ,Antirheumatic Agents ,phosphatidylinositol 3-kinase delta (PI3Kδ) ,Quinolines ,biology.protein ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,business - 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.
- Published
- 2020