Background/Purpose

Primary Sjogren’s syndrome (pSS) is a systemic, progressive autoimmune disease characterized by formation of ectopic germinal centers in exocrine glands and secretory gland dysfunction. A subset of patients also develops extraglandular manifestations. CFZ533 is a novel monoclonal antibody that potently and 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, multi-centric, partial cross-over Phase IIa Proof of Concept (PoC) study to evaluate the safety, tolerability and efficacy of CFZ533 in patients with pSS.

Methods

Clinically active (EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI]≥6) pSS patients were randomized to receive four doses of 3 mg/kg s.c. CFZ533 or placebo (2:1, Cohort 1) or 10 mg/kg i.v. CFZ533 or placebo (2:1, Cohort 2) over 12 weeks in Period 1. Four additional doses of 3 mg/kg s.c. CFZ533 or 10 mg/kg i.v. CFZ533, respectively, were administered in an open label extension (Period 2) for 12 weeks. Key outcomes included safety and efficacy as assessed by change in ESSDAI after 12 weeks treatment. In addition, measurements of pharmacokinetics and pharmacodynamics (PK/PD) of CFZ533, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), Multi-dimensional Fatigue Inventory (MFI), Physician’s Global Assessment, Patient’s Global Assessment, SF-36, and biomarkers of pSS were monitored.

Results

Forty-four patients were enrolled: 8 patients received 3 mg/kg s.c. CFZ533 and 4 placebo in Cohort 1 and 21 received 10 mg/kg i.v. CFZ533 and 11 placebo in Cohort 2. While PK/PD was as expected in the CFZ533 10 mg/kg i.v. cohort based on healthy volunteer data from the first in human trial, CFZ533 exposure appeared lower than expected in the 3 mg/kg s.c. cohort, likely due to target mediated disposition. Overall, CFZ533 was safe and well tolerated, and the majority of AEs were mild or moderate. There was a single serious AE (bacterial conjunctivitis) in the 3 mg/kg s.c. cohort that was not related to study drug. In Cohort 1, ESSDAI was observed to improve by approximately 2 points from mean baseline scores of approximately 12 in both placebo and 3 mg/kg s.c. groups, with therefore no evidence of treatment difference (ΔESSDAI=0.68, 95% CI = -4.71 – 6.46). However in Cohort 2, the improvement in ESSDAI from mean baselines of approximately 11 was observed to be 6.35 in the 10 mg/kg i.v. group compared to 1.27 in the placebo group, with the modelled difference between groups of ΔESSDAI=5.64 (95% CI=1.02 – 10.58) strongly favoring the CFZ533 i.v. treatment. Improvements in other measures such as ESSPRI, MFI, Physician’s Global Assessment, and Patient’s Global Assessment and decreases in the germinal center-related serum biomarker CXCL13 were also observed in the 10 mg/kg i.v. CFZ533 group.

Conclusion

In this proof of concept study, testing a blocking, non-depleting anti-CD40 antibody for the first time in primary Sjögren`s syndrome, results suggest that CFZ533 may offer a new treatment modality in clinically active pSS.