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ACR 2017 | Daily Highlights
The Novel Anti-CD40 Monoclonal Antibody CFZ533 Shows Beneficial Effects in Patients with Primary Sjögren’s Syndrome: A Phase IIa Double-Blind, Placebo-Controlled Randomized Trial
Authors: Benjamin Fisher1, Margit Zeher2, Wan-Fai Ng3, Michele Bombardieri4, Maximilian Posch5, Athena S Papas6, Arwa M Farag6, Thomas Daikeler7, Bettina Bannert8, Alan J. Kivitz9, Steven E. Carsons10, David A. Isenberg11, Francesca Barone12, Simon Bowman13, Pascal Espie14, Grazyna Wieczorek14, Pierre Moulin14, David Floch14, Cyrielle Dupuy14, Xiaohui Ren14, Petra Faerber14, Andrew M Wright15, Hans Ulrich Hockey15, Michael Rotte14, James S. Rush15 and Peter Gergely14, 1Rheumatology Research Group, University of Birmingham, Birmingham, United Kingdom, 2Division of Clinical Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary., Debrecen, Hungary, 3Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom, 4Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK, London, United Kingdom, 5Charité Research Organisation GmbH, Berlin, Germany, 6Tufts University, Boston, MA, 7Rheumatology, University Hospital Basel, Basel, Switzerland, 8University Hospital Basel, Basel, Switzerland, 9Department of Rheumatology, Altoona Center for Clinical Research, Duncansville, PA, 10NYU Winthrop University Hospital, Department of Medicine, Mineola, NY, 11Centre for Rheumatology, Division of Medicine, University College London, London, United Kingdom, 12Institute of Inflammation and Ageing (IIA), University of Birmingham, Birmingham, United Kingdom, 13Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK, Birmingham, United Kingdom, 14Novartis Institutes for Biomedical Research, Basel, Switzerland, 15Novartis Pharmaceuticals Corporation, Basel, Switzerland
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.
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.
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.
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.
B. Fisher, Novartis, Roche, Virtualscopics, 5; M. Zeher, None; W. F. Ng, Pfizer, UCB, MedImmune, Takeda and Sanofi, 5; M. Bombardieri, GSK, Amgen/MedImmune and UCB, 5; M. Posch, None; A. S. Papas, None; A. M. Farag, None; T. Daikeler, None; B. Bannert, None; A. J. Kivitz, Sanofi, Pfizer, Roche, and UCB, 5; S. E. Carsons, None; D. A. Isenberg, EMD Serono, Inc, 5; F. Barone, None; S. Bowman, AstraZeneca/Meddimmune, BMS, Celgene, Eli Lilly, Glenmark, GSK, MTPharma, Novartis, Ono, Takeda, UCB, XLT Bio., 5; P. Espie, Novartis Pharmaceutical Corporation, 3; G. Wieczorek, Novartis Pharmaceutical Corporation, 3; P. Moulin, Novartis Pharmaceutical Corporation, 3; D. Floch, Novartis Pharmaceutical Corporation, 3; C. Dupuy, Novartis Pharmaceutical Corporation, 3; X. Ren, Novartis Pharmaceutical Corporation, 3; P. Faerber, Novartis Pharmaceutical Corporation, 3; A. M. Wright, Novartis Pharmaceutical Corporation, 3; H. U. Hockey, Novartis Pharmaceutical Corporation, 3; M. Rotte, Novartis Pharmaceutical Corporation, 3; J. S. Rush, Novartis Pharmaceutical Corporation, 3; P. Gergely, Novartis Pharmaceutical Corporation, 3.
The study is one of several currently ongoing trials in the area of connective tissue diseases and Sjögren syndrome with biologics and small molecular inhibitors. In some of the connective tissue diseases these trials are already in their final stages before registration, others, like the one presented here, are currently presenting results of proof of concept studies. The rapid development in this area was possible because of improved tools for preclinical characterization and definition and validation of endpoints for clinical trials.
In this regard, this abstract has two major messages: First, it provides a template for the design of proof of concept studies in Sjögren syndrome. The study was feasible with a short study duration, tested several doses as required by agencies like the FDA, and was able to show differences in efficacy with a validated endpoint. The second message is that a CD40 targeting therapy appears to be a valuable approach for the treatment of Sjögren’ s syndrome. There were clear differences in the ESSDAI activity score with the 10mg/kg iv dose of the CD40 antibody, supported by similar trends in additional secondary endpoints. These results now have to be confirmed in a larger phase 3 trial.
Prof. Dr. Oliver Distler