Background Primary Sjogren's syndrome is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands. To our knowledge, no systemic therapies for primary Sjogren's syndrome have shown efficacy. CD40-CD154-mediated T cell-B cell interactions in primary Sjogren's syndrome contribute to aberrant lymphocyte activation in inflamed tissue, leading to sialadenitis and other tissue injury. Therefore, we investigated the safety and preliminary efficacy of iscalimab (CFZ533), a novel anti-CD40 monoclonal antibody, in patients with primary Sjogren's syndrome. Methods This multicentre, randomised, double-blind, placebo-controlled, proof-of-concept study took place at ten investigational sites across Europe (UK, n=4; Germany, Switzerland, and Hungary, n=1 each) and the USA (n=3). Eligible patients were aged 18-75 years and fulfilled the 2002 American European consensus group diagnostic dassification criteria for primary Sjogren's syndrome. In the double-blind phase of the trial, patients were randomly assigned (2:1) via computer-generated unique randomisation numbers to receive subcutaneous iscalimab (3 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 1) or intravenous iscalimab (10 mg/kg) or placebo at weeks 0, 2, 4, and 8 (cohort 2). Randomisation was stratified according to baseline intake of oral corticosteroids. At week 12, patients in both cohorts received open-label iscalimab (same dose and route) for 12 weeks. The primary objectives of the study were to assess the safety, tolerability, and efficacy of multiple doses of iscalimab in the two sequential dose cohorts. Safety and tolerability were assessed by adverse events and efficacy of iscalimab versus placebo was assessed by dinical disease activity, as measured by the change in European League Against Rheumatism Sjogren's syndrome disease activity index (ESSDAI) score after 12 weeks of treatment. Analyses were done on a per-protocol basis. The trial was registered with ClinicalTrials.gov, NCT02291029. Findings Between Oct 22, 2014, and June 28, 2016, we assessed 82 patients for eligibility (25 for cohort 1 and 57 for cohort 2). 38 patients were excluded because of ineligibility. In cohort 1, 12 patients were randomly assigned to receive either 3 mg/kg doses of iscalimab (n=8) or placebo (n=4), and in cohort 2, 32 patients were randomly assigned to receive either intravenous 10 mg/kg doses of iscalimab (n=21) or placebo (n=11). Adverse events were similar between iscalimab treatment groups and placebo groups, with adverse events occurring in all patients in cohort 1, and in 52% and 64% of the iscalimab and placebo groups, respectively, in cohort 2. Two serious adverse events were reported (one case of bacterial conjunctivitis in cohort 1 and one case of atrial fibrillation in cohort 2), which were unrelated to treatment with iscalimab. Intravenous treatment with iscalimab resulted in a mean reduction of 5.21 points (95% CI 0.96-9.46; one-sided p=0.0090) in ESSDAI score compared with placebo. There was no signficiant difference in ESSDAI score between subcutaneous iscalimab and placebo. Interpretation To our knowledge, this is the first randomised, placebo-controlled proof-of-concept study of a new investigational drug for primary Sjogren's syndrome that indicates preliminary efficacy. Our data suggest a role of CD40-CD154 interactions in primary Sjogren's syndrome pathology and the therapeutic potential for CD40 blockade in this disease should be investigated further. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Background: Primary Sjögren’s syndrome (pSS) is a systemic progressive autoimmune disease characterised by formation of lymphoid structures and germinal centres within glandular tissue. Iscalimab (CFZ533) is a novel monoclonal antibody that potently and selectively blocks CD40, a co-stimulatory pathway receptor important for germinal centre reactions and B cell activation. Iscalimab showed clinical efficacy in a Proof of Concept randomised controlled trial at a dose of 10 mg/kg intravenously (IV), whereas subcutaneous (SC) dosing at 3 mg/kg was associated with unexpectedly low plasma concentrations and reduced efficacy, likely due to efficient pre-systemic target-mediated clearance. Objectives: To test IV versus SC loading doses of iscalimab followed by SC maintenance dosing, as a means of achieving target drug exposure and clinical efficacy. Methods: Patients with clinically active pSS [EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) ≥6] were randomised to receive either 600 mg SC iscalimab weekly on 4 occasions, followed by 300 mg SC weekly until week 12, or a single IV dose of 10 mg/kg iscalimab on study Day 1, followed by 300 mg SC weekly until week 12. Subjects and investigator staff remained blinded to study treatment allocation until first dosing. Results: Twenty-five patients were randomised; 13 in the SC loading and 12 in the IV loading arms. Baseline characteristics were similar to the previous phase IIa cohorts with mean ESSDAI scores of 12.7 (SD 6.1) and 10.4 (5.9) in the SC and IV loading arms respectively. In Arm 1 (SC) and Arm 2 (IV), the mean trough plasma concentrations were 169 μg/mL (SD 64.1, CV 38%) and 135 μg/mL (SD 70.9, CV 53%) on Day 85, respectively. Both values were well above levels previously reported to be sufficient for suppression of germinal centre development and T dependent antigen responses in cynomolgus monkeys. Consistent with this finding, clinically important improvements were seen in both arms with a mean decrease in ESSDAI scores of -5.5 (+/- SD: 5.5) and -7.6 (+/- 7.1) points from baseline to Day 85 in the SC and IV dosing arms. Improvements were also seen in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) scores: -1.67 (+/- 1.8) and -1.17 (+/- 2.3), respectively. Other secondary efficacy outcomes showed similar patterns of improvement. Treatment with iscalimab was associated with a reduction in the germinal centre-related serum biomarker CXCL13 in both groups. Overall, iscalimab was safe and well-tolerated with no new safety signal emerging. One subject experienced three SAEs (hemarthrosis, worsening of right knee pain and swelling requiring arthroscopy) in the safety follow-up period, all unrelated to study drug. Conclusion: These results further support the safety and efficacy of iscalimab in pSS and the suitability of SC dosing for future development. Disclosure of Interests: Benjamin Fisher Consultant for: Novartis, Roche, MedImmune, Bristol-Myers Squibb, Antónia Szántó: None declared, Wan Fai Ng: None declared, Michele Bombardieri Grant/research support from: Celgene, Consultant for: Medimmune, Maximilian Posch: None declared, Athena Papas Grant/research support from: Novartis, Consultant for: Novartis, Arwa Farag: None declared, Thomas Daikeler: None declared, Bettina Bannert: None declared, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Steven Carsons Grant/research support from: Novartis, David Isenberg: None declared, Francesca Barone Grant/research support from: GlaxoSmithKline, Roche, UCB Pharma, Actelion, ONO Pharmaceutical, Consultant for: GlaxoSmithKline, Roche, Actelion, ONO Pharmaceutical, Simon J. Bowman Grant/research support from: Previously UCB Pharma (to University of Birmingham) and Roche, Consultant for: 2016-7: Novartis, Mitsubishi Tanabe Pharma 2017-8: AstraZeneca, MedImmune, GFK, Xtlbio, ONO Pharmaceutical 2018-9: Novartis, AstraZeneca, UCB Pharma, Pascal Espie Employee of: Novartis, Grazyna Wieczorek Employee of: Novartis, Pierre Moulin Employee of: Novartis, David Floch Employee of: Novartis, Cyrielle Dupuy Employee of: Novartis, Amanda Nguyen Employee of: Novartis, Andrew Wright Shareholder of: Novartis, Employee of: Novartis, Michael Rotte Employee of: Novartis, James Rush Employee of: Novartis, Peter Gergely Employee of: Novartis

s Committee: Chair: Kentaro Ikeda, DDS, MPH Co-Chair: Bhavik Desai, DMD, PhD #11 – 3:00-3:10pm The Parotid Gland in Primary Sjögren’s Syndrome: Association of Ultrasound, Histopathology and Saliva Production in the Diagnostic Work-up *Konstantina Delli, Esther Mossel, Erlin Haacke, Bert van der Vegt, Suzanne Arends, Uzma Nakshbandi, Jolien F van Nimwegen, Alja J Stel, Fred KL Spijkervet, Frans GM Kroese, Arjan Vissink, Hendrika Bootsma University Medical Center Groningen, Netherlands Objectives: The parotid glands are commonly involved in primary Sjögren’s syndrome (pSS). The aim of this study was to assess the diagnostic accuracy of ultrasound of the parotid glands (PSGUS) compared with the parotid histopathology and parotid saliva production. Methods: We included consecutive patients suspected with pSS. All patients underwent a full diagnostic work-up according to ACR-EULAR criteria, including PSGUS, parotid gland biopsy and collection of stimulated parotid saliva. For PSGUS, the average score of hypoechogenic areas in both parotid glands was applied (range 0-3). On H&E stained sections from parotid gland biopsies, focus score, presence of lymphoepithelial lesions (LELs) and germinal centers (GCs) were assessed. The area of lymphocytic infiltrate was calculated digitally on CD45 stained sections. The relative increase of IgG expressing plasma cells (≥30%) was evaluated on sections stained for IgA and IgG. PSGUS score was associated with focus score, percentage of infiltrate and saliva flow and compared with plasma cell shift, LELs and GCs by calculating the percentage of absolute agreement, sensitivity and specificity. Results: In total, of the 111 included patients, 53 fulfilled the ACR-EULAR classification criteria for pSS. PSGUS score showed moderate correlation with focus score (ρ=0.494, p<0.001) and percentage of lymphocytic infiltrate (ρ=0.575, p<0.001). There was a moderate to good absolute agreement between PSGUS and focus score (78.5%), plasma cell shift (79.8%), LELs (81.4%) and GCs (82.7%). ‘Presence of hypoechogenic areas’ was not very sensitive to predict focus score (69.2%), plasma cell shift (45.8%), LELs (61.5%) or GCs (34.6%). Interestingly, almost all patients with <25% presence of hypoechogenic areas in glandular parenchyma were also negative for GCs (98.7%). A substantial amount of these patients did not have a positive focus score (81.4%), plasma cell shift (90.7%) or LELs (87.8%). There was a fair reversed correlation between PSGUS and stimulated parotid saliva flow (ρ=-0.259, p=0.07). Conclusions: This is the first study comparing the diagnostic accuracy of PSGUS with histopathology and salivary secretion in detail. PSGUS and histopathology are stronger associated than PSGUS and parotid secretion. Specificity of PSGUS increases when results are compared to plasma cell shift, LELs and GCs, instead of focus score. #12 – 3:10-3:20pm Novel Anti-CD40 Monoclonal Antibody CFZ533 in Patients with Primary Sjogren Syndrome: A Phase IIa Double-Blind, Placebo–Controlled Randomized Trial *Arwa Farag, Athena Papas, Benjamin Fisher, Margit Zeher, Wan-Fai Ng, Michele Bombardieri, Maximilian Posch, Thomas Daikeler, Bettina Bannert, Alan Kivitz, Steven Carsons, David Isenberg, Francesca Barone, Simon Bowman, Pascal Espie, Grazyna Wieczorek, Pierre Moulin, David Floch, Cyrielle Dupuy, Xiaohui Ren, Petra Faerber, Andrew Wright, Hans Ulrich Hockey, Michael Rotte, James Rush, Peter Gergely Tufts University School of Dental Medicine, USA

Objectives: Primary Sjogren syndrome (pSS) is a progressive autoimmune disease characterized by formation of ectopic germinal centers in exocrine glands and secretory gland dysfunction with subset of patients developing extraglandular manifestations. CFZ533 is a novel monoclonal antibody that selectively blocks CD40, a co-stimulatory pathway receptor essential for germinal center reactions and other immune-mediated functions implicated in pSS pathogenesis. We conducted a randomized, double-blind, placebo-controlled, multicentric, partial crossover, Phase IIa Proof of Concept (PoC) study to evaluate the safety, tolerability and efficacy of CFZ533 in patients with pSS.