A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome
| Autor: | 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 |
|---|---|
| Přispěvatelé: | 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., Bowman S.J. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | Rheumatology Rheumatology, Oxford University Press (OUP), 2020, ⟨10.1093/rheumatology/keaa410⟩ RHEUMATOLOGY r-FISABIO. Repositorio Institucional de Producción Científica instname r-FISABIO: Repositorio Institucional de Producción Científica Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO) |
| ISSN: | 1462-0324 1460-2172 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|