A phase 2 randomized, double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome

TL;DR: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS and demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo.

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 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.

Summary

Introduction

• Primary Sjögren’s syndrome (PSS) is a chronic, inflammatory, autoimmune disease characterised by focal lymphocytic infiltration and progressive functional impairment of the exocrine glands, often associated with systemic symptoms, B-cell hyperactivation, autoantibody formation, and increased risk of lymphoma development (1-3).
• Two controlled trials of rituximab (5, 6) and two studies of abatacept (7, 8) did not meet their primary endpoints.
• Conversely, a small study with a CD40-targeted antibody, CFZ533, reported significant amelioration of European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index , and a trend towards improvement in Sjögren’s Syndrome Patient Reported Index (9).
• In a mouse model of PSS, treatment with seletalisib blocked PI3Kδ activity, demonstrated by significant reduction of pS6 phosphorylation and decreased accumulation of B and T lymphocytes and plasma cells.
• Treatment with seletalisib also reduced autoantibody titres and improved saliva production (3), providing a strong rationale for the evaluation of seletalisib in patients with PSS.

Study design

• 1 to oral seletalisib 45 mg once daily or matching placebo, in addition to current PSS therapy, according to a predetermined randomisation schedule (supplementary materials, section Methods), also known as Patients were randomised 1.
• The study comprised a 12-week treatment period and a 4-week safety follow-up.

Patients

• Eligible patients were aged 18–75 years with moderate-to-severe PSS meeting the American-European Consensus Group criteria (20), total ESSDAI score ≥5, and positive for anti-Sjögren's-syndrome-related antigen A (SSA; Ro) and/or antiSjögren's-syndrome-related antigen B (SSB; La) autoantibodies.
• Eligibility required an unstimulated salivary flow rate of >0 mL/15 min and a salivary gland biopsy in the prior 12 months, or during screening.
• Additional inclusion and exclusion criteria are provided in Supplementary Table S1.
• The study was conducted in accordance with the Declaration of Helsinki and the protocol approved by national or regional independent ethics committees.
• Written informed consent was obtained from all patients before enrolment.

Endpoints

• The primary objectives were safety and tolerability and systemic disease activity.
• Exploratory efficacy endpoints included changes in salivary gland biopsies at Week 12 and those listed in the supplementary materials, section Methods.
• Safety and tolerability assessments included incidence of adverse events, changes in clinical laboratory measurements, vital signs, and 12-lead electrocardiograms (ECGs).
• Staining was detected by immunohistochemistry using the Leica Bond RX automated staining system (Leica Biosystems, Milton Keynes, UK) (21).
• Manual immunofluorescence staining for CD20, CD138, CD3 and pS6 was performed as previously described (3) on sequential sections.

Statistical analysis

• Safety analyses were based on the safety set, which comprised all randomised patients who received at least one dose of study drug.
• Efficacy analyses were based on the full analysis set, which comprised all patients in the safety set who had at least one post-baseline efficacy assessment.
• The primary efficacy endpoint, change from baseline in ESSDAI at Week 12, was analysed by a mixed model for repeated measures (MMRM) to account for missing data, with covariates of treatment, visit, baseline ESSDAI score, and treatment by visit interaction.
• The minimal clinically important improvement in ESSDAI score was defined as a decrease of three points.
• A post-hoc Bayesian analysis was conducted to interpret the results based on the limited observed data (supplementary materials, section Methods).

Patient disposition and demographics

• Fifty-one patients were screened, 27 patients randomised (seletalisib n=13, placebo n=14), and 20 completed the study (Fig. 1).
• Due to enrolment challenges, the study was terminated early; nearly 2 years was needed to recruit the 51 patients.
• Moreover, due to safety concerns related to potential interaction, the number of concomitant medications allowed during the study were limited, further restricting the inclusion criteria.
• Baseline characteristics were generally well balanced between the two groups.

Histology

• Salivary gland biopsies were obtained from consenting patients at baseline (seletalisib n=13, placebo n=13), and Week 12 (seletalisib n=7, placebo n=11).
• Lymphocytic foci, B and T cell segregation, and germinal centres were identified with H&E, CD3/CD20 and CD21 staining, respectively (Fig. 3A, Supplementary Fig. S4).
• At baseline, minor salivary gland biopsies showed broadly similar features between groups although percentage infiltration and focus score were slightly higher in the placebo group.
• Of seletalisibtreated patients with histological data at Week 12, 6/7 were ESSDAI responders (greater than 3-point reduction in ESSDAI score), and also had decreases in infiltration, foci with follicular dendritic cells, segregation, and germinal centres.
• PS6 staining decreased in the seletalisib group versus placebo in B cells, but not in T cells or plasma cells (Supplementary Fig. S6).

Discussion

• PSS still represents an unmet clinical need.
• This reduction may be related to missing data, where two patients receiving placebo trending toward worsening and one patient receiving seletalisib trending toward improvement had missing Week 12 ESSDAI scores.
• The authors also observed significant changes in salivary gland pathology: salivary gland infiltrates from seletalisib-treated patients showed decreases in both the organization and extent of lymphocytic infiltration.
• This suggests that PI3Kδ inhibition affects cell aggregation in the salivary glands, compromising the process of T/B cell activation, as reflected in the observed decrease in immunoglobulins.
• In line with the results in this study, leniolisib, another PI3Kδ inhibitor, also showed a modest improvement in biological endpoints but did not achieve significant clinical results in patients with PSS (23).

Figure legends

• (A) Change from baseline in ESSDAI score; (B) Percentage of patients with a ≥3 point reduction from baseline in ESSDAI score; (C) Change from baseline in ESSPRI score (full analysis set).
• Fig. 3. Histological results from paired minor salivary gland biopsies.
• (A) Representative sections from placebo-treated and seletalisib-treated patients at screening/baseline and Week 12.
• In H&E stained sections, lymphocytic foci are indicated with arrows; margins of the foci are marked with green lines.
• Individual patient data from paired biopsies (at baseline and Week 12) are shown for each group.

Disclosure statement

• MJ, ND, and PW are employees and shareholders of UCB Pharma.
• AP was an employee of UCB Pharma at the time this study was conducted, is currently employed by Exscientia Ltd, and holds share options for UCB Pharma.
• BAF reports personal consultancy fees from BMS, Novartis, and Roche. MK and JSB report no competing interests.
• SJB reports grants from Roche and UCB Pharma and personal consultancy fees from AstraZeneca, BMS, Celgene, GFK, MedImmune, MT Pharma, Novartis, ONO Pharmaceuticals, UCB Pharma, and Xtlbio.

Data sharing statement

• Due to the small sample size in this trial, Individual Patient Data cannot be adequately anonymised and there is a reasonable likelihood that individual participants could be re-identified.
• For this reason, data from this trial cannot be shared.

Figures

Table 1 Patient demographics and baseline characteristics

Table 2 Incidence of adverse eventsa (safety set)

Full text

University of Birmingham
A phase 2 randomised, double-blind, placebo-
controlled, proof-of-concept study of oral seletalisib
in primary Sjögren’s syndrome
Juarez, Maria; Diaz, Nieves; Johnston, Geoffrey; Nayar, Saba; Payne, Andrew; Helmer, Eric;
Cain, Dionne; Williams, Paulette; Devauchelle-Pensec, Valerie; Fisher, Benjamin; Giacomelli,
Roberto; Gottenberg, Jacques-Eric; Guggino, Giuliana; Kvarnstrom, Marika; Mariette, Xavier;
Ng, Wan-Fai; Rosas, Jose; Burson, Juan; Triolo, Giovanni; Barone, Francesca
DOI:
10.1093/rheumatology/keaa410
License:
None: All rights reserved
Document Version
Peer reviewed version
Citation for published version (Harvard):
Juarez, M, Diaz, N, Johnston, G, Nayar, S, Payne, A, Helmer, E, Cain, D, Williams, P, Devauchelle-Pensec, V,
Fisher, B, Giacomelli, R, Gottenberg, J-E, Guggino, G, Kvarnstrom, M, Mariette, X, Ng, W-F, Rosas, J, Burson,
J, Triolo, G, Barone, F & Bowman, S 2020, 'A phase 2 randomised, double-blind, placebo-controlled, proof-of-
concept study of oral seletalisib in primary Sjögren’s syndrome', Rheumatology.
https://doi.org/10.1093/rheumatology/keaa410
Link to publication on Research at Birmingham portal
Publisher Rights Statement:
This is a pre-copyedited, author-produced version of an article accepted for publication in Rheumatology following peer review. The version
of record, Maria Juarez, Nieves Diaz, Geoffrey I Johnston, Saba Nayar, Andrew Payne, Eric Helmer, Dionne Cain, Paulette Williams, Valerie
Devauchelle-Pensec, Benjamin A Fisher, Roberto Giacomelli, Jacques-Eric Gottenberg, Giuliana Guggino, Marika Kvarnström, Xavier
Mariette, Wan Fai Ng, José Rosas, Juan Sánchez Bursón, Giovanni Triolo, Francesca Barone, Simon J Bowman, A phase 2 randomized,
double-blind, placebo-controlled, proof-of-concept study of oral seletalisib in primary Sjögren’s syndrome, Rheumatology, ,keaa410 is
available online at: https://doi.org/10.1093/rheumatology/keaa410
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Download date: 10. Aug. 2022

Seletalisib SS0004 manuscript_Rheumatology
Page 1
A phase 2 randomised, double-blind, placebo-controlled,
proof-of-concept study of oral seletalisib in primary Sjögren’s
syndrome
Maria Juarez,
1
* Nieves Diaz,
1
* Geoffrey I Johnston,
1
Saba Nayar,
2
Andrew Payne,
3†
Eric Helmer,
4†
Dionne Cain,
5
Paulette Williams,
6
Valerie Devauchelle-Pensec,
7
Benjamin A Fisher,
8,9
Roberto Giacomelli,
10
Jacques-Eric Gottenberg,
11
Giuliana
Guggino,
12
Marika Kvarnström,
13
Xavier Mariette,
14
Wan Fai Ng,
15
Jose Rosas,
16
Juan Sanchez Burson,
17
Giovanni Triolo,
12
Francesca Barone,
2
* Simon J Bowman
8
*
*Dr Maria Juarez, Dr Nieves Diaz, Dr Francesca Barone and Professor Simon J
Bowman contributed equally to this paper
†
Employees of UCB Pharma at the time the study was conducted
1
Translational Medicine, UCB Pharma, Slough, UK
2
Institute of Inflammation and Ageing,
University of Birmingham, Birmingham, UK
3
Discovery Biology, UCB Pharma, Slough, UK
4
Quantitative Clinical Pharmacology, UCB Pharma, 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
National Reference Centre For Rare Systemic Auto-Immune Diseases, Department
of Rheumatology, 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

Seletalisib SS0004 manuscript_Rheumatology
Page 2
14
Department of Rheumatology,
Université Paris-Sud, Assistance Publique –
Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, INSERM UMR1184, 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
Corresponding author:
Francesca Barone
Rheumatology Research Group, Institute of Inflammation and Ageing
Queen Elizabeth Hospital
Birmingham B15 2WB, UK
Email: f.barone@bham.ac.uk
ORCiD iD: 0000-0002-5287-9614
Running header: Phase 2 seletalisib study in primary Sjögren’s syndrome
Previous presentations in part: The results have been previously published as
an abstract for EULAR 2019 (Juarez M et al. Ann Rheum Dis. 2019;78[Suppl
2]:1692–1693).
Word count: 3,121

Seletalisib SS0004 manuscript_Rheumatology
Page 3
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 randomised 1:1 to seletalisib 45 mg/day or placebo, in addition
to current PSS therapy. Primary endpoints were safety and tolerability and change
from baseline in ESSDAI score at Week 12. Secondary endpoints included change
from baseline at Week 12 in ESSPRI score and histological features in salivary gland
biopsies.
Results
Twenty-seven patients were randomised (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 versus 1/14 for placebo and
5/13 versus 1/14 discontinued due to AEs, respectively. Serum IgM and IgG
concentrations decreased in the seletalisib group versus 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 organization.
Trial registration number:
NCT02610543

Seletalisib SS0004 manuscript_Rheumatology
Page 4
Keywords
Phosphatidylinositol 3-kinase delta (PI3Kδ); primary Sjögren’s syndrome; seletalisib;
proof-of-concept; histology
Key messages
 Seletalisib demonstrated a trend towards clinical improvement in patients with
PSS despite enrolment-related underpowering
 Histological analyses demonstrated encouraging effects of seletalisib on
salivary gland inflammation and organization
 Seletalisib or other PI3Kδ inhibitors could be new effective drugs in PSS
requiring future development

Frequently asked questions

Q1. What contributions have the authors mentioned in the paper "University of birmingham a phase 2 randomised, double-blind, placebo- controlled, proof-of-concept study of oral seletalisib in primary sjögren’s syndrome" ?

Citation for published version ( Harvard ): Juarez, M, Diaz, N, Johnston, G, Nayar, S, Payne, A, Helmer, E, Cain, D, Williams, P, Devauchelle-Pensec, V, Fisher, B, Giacomelli, R, Gottenberg, J-E, Guggino, G, Kvarnstrom, M, Mariette, X, Ng, W-F, Rosas, J, Burson, J, Triolo, G, Barone, F & Bowman, S 2020, ' A phase 2 randomised, double-blind, placebo-controlled, proof-ofconcept study of oral seletalisib in primary Sjögren ’ s syndrome ', Rheumatology. 

Q2. What future works have the authors mentioned in the paper "University of birmingham a phase 2 randomised, double-blind, placebo- controlled, proof-of-concept study of oral seletalisib in primary sjögren’s syndrome" ?

Larger studies with specific PI3Kδ inhibitors and potentially with patient stratification could be considered in the future.