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A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome
- Source :
- 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)
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 14620324 and 14602172
- Database :
- OpenAIRE
- Journal :
- 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)
- Accession number :
- edsair.doi.dedup.....20a4a7a49e1db4568f69115de9d4e12a