AT ACR 2017

SAN DIEGO (FRONTLINE MEDICAL NEWS) Multiple doses of the investigational agent CFZ533 administered for 24 weeks in patients with primary Sjögren’s syndrome were safe and well tolerated, according to results of a proof-of-concept study.

CFZ533 is a novel monoclonal antibody being developed by Novartis that potently and selectively blocks CD40, a costimulatory pathway receptor essential for germinal center reactions and other immune-mediated functions implicated in primary Sjögren’s syndrome pathogenesis.

“Sjögren’s syndrome is characterized by focal infiltration of lymphocytes in a periductal distribution in exocrine glands,” lead study author Benjamin Fisher, MD , said at the annual meeting of the American College of Rheumatology.

“These lymphocytic foci often show organization and a proportion will show a germinal center formation. The lymphocytic infiltrates are associated with profound dryness, conjunctival erosions, fatigue that’s disabling, and in at least one-third of patients, systemic manifestations. There are no proven immunomodulatory treatments for this Sjögren’s syndrome. The lymphocytic infiltrates are also characterized by the expression of the costimulatory molecule CD40 and its ligand, also known as CD154,” he said.

Dr. Fisher, of the Rheumatology Research Group at the University of Birmingham (England), noted that the CD40 costimulation pathway has important roles at a number of levels within the immune system, including activating antigen-presenting cells such as dendritic cells. “As a result, the dendritic cells upregulate other costimulatory molecules and cytokines,” he said. “The end result is that they activate rather than tolerize T cells. The CD40 pathway also has important roles in the interaction between B and T cells, and it will result in B-cell activation. That is important for B cell differentiation, germinal center formation, antibody production, affinity maturation, and isotype switching. Our hypothesis is that therapeutic blockade of the CD40 pathway would inhibit the immune processes that underlie pathology in Sjögren’s syndrome.”

For the study, subjects with an ESSDAI (EULAR Sjögren’s Syndrome Disease Activity Index) score of 6 or more were randomized 2:1 to receive 10 mg/kg of CFZ533 or placebo over a 12-week period. Four additional doses were administered in an open-label extension for 12 weeks. The primary goals were to evaluate the drug’s safety and tolerability as assessed by adverse events, and also to assess disease activity, with the primary outcome being the ESSDAI score. “The proof-of-concept criteria were stringent,” Dr. Fisher said. They “required a reduction in the ESSDAI score after 12 weeks to be 5 or more points greater in the CFZ533 group than the placebo group. The minimal clinically important difference is 3 points.”

He reported results from 21 patients in the CFZ533 and 11 in the placebo group. The baseline ESSDAI scores were 10.6 and 11 in the CFZ533 group and placebo groups, respectively. Patients also showed high symptomatic burden as assessed by the ESSPRI (EULAR Sjögren’s Syndrome Patient Reported Index), which measures dryness, fatigue, and pain on a 0-10 scale (mean scores of 6.7 and 7.2, respectively).

At 24 weeks, CFZ533 was found to be well tolerated, with no unexpected safety findings. “There were no serious infectious complications and there were no thromboembolic events,” Dr. Fisher said. “We did have one serious adverse event at the end of the open-label period. It occurred on the last day of that subject’s follow-up period. This was a case of atrial fibrillation. However, the patient had a predisposing medical condition and it was thought to be unrelated to the study drug.” Evaluation of pharmacokinetic data revealed that plasma levels throughout the study were above the level which previous data suggest is associated with inhibition of the CD40 pathway in tissue. “These plasma levels are also associated with inhibition of germinal center formation and with inhibition of T-dependent antigen response,” he said.

At the end of 12 weeks, CFZ533 was associated with a statistically significant reduction in ESSDAI scores, compared with the placebo group. The difference between groups was 5.6 points, which exceeded the proof-of-concept criteria. “This response was maintained through the open-label period,” Dr. Fisher said. “We also saw a reduction in the placebo group once they’d been switched to CFZ533 in the open-label period.”

The researchers also observed clinically meaningful improvements in other measures that favored CFZ533 over placebo, including the Physician Global Assessment, the physician and patient ratings on the Visual Analog Scale, and the Short Form–36 physical and mental health measures. “These data support continuation of the CFZ533 clinical program in primary Sjögren’s syndrome,” Dr. Fisher concluded.

Novartis sponsored the study. Dr. Fisher disclosed having received research support from Novartis, Roche, Bristol-Myers Squibb, and Virtualscopics.