Safety, tolerability, efficacy, and pharmacokinetics of the anti-CD40 antibody iscalimab in patients with primary Sjögren’s syndrome: a multi-center, randomised, double-blind, placebo-controlled, parallel group proof-of-concept study

Research output: Contribution to journalArticle

Authors

  • Antonia Szanto
  • Wan-Fai Ng
  • Michele Bombardieri
  • Maximilian Posch
  • Athena Papas
  • Arwa Farag
  • Thomas Daikeler
  • Bettina Bannert
  • Diego Kyburz
  • Alan Kivitz
  • Steven Carsons
  • David Isenberg
  • Pascal Espie
  • David Floch
  • Cyrielle Dupuy
  • Xiaohui Ren
  • Petra Faerber
  • Andrew Wright
  • Hans-Ulrich Hockey
  • Michael Rotte
  • Julie Milojevic
  • Alexandre Avrameas
  • Marie-Anne Valentin
  • James Rush
  • Peter Gergely

Abstract

Background: Primary Sjögren’s syndrome (pSS) is an autoimmune disease that presents as dryness of the mouth and eyes due to impairment of the exocrine glands, where currently there are no systemic therapies that have demonstrated efficiacy. CD40-CD154 mediated T cell-B cell interactions in pSS contribute to aberrant lymphocyte activation in inflamed tissue leading to sialadenitis and other tissue injury. Therefore, we investigated the role of this costimulatory immune pathway in pSS.

Methods: A multi-center, randomised, double-blind, placebo-controlled, proof-of-concept study including two sequential cohorts was conducted to assess the safety, tolerability, efficacy, and pharmacokinetics of iscalimab (CFZ533), a blocking anti-CD40 antibody in pSS patients, by measuring the change after 12 weeks of treatment in the EULAR Sjögren's syndrome disease activity index (ESSDAI) score compared with placebo (Clinicaltrials.gov identifier: NCT02291029). Cohorts 1 (subcutaneous[SC]) and 2 (intravenous[IV]) underwent a double-blind, placebo-controlled period, where patients were randomised (2:1) to receive either iscalimab or placebo, followed by an open-label period where all patients received iscalimab for an additional 12 weeks.

Findings: AEs were similar between iscalimab treatment and placebo groups and two SAEs were reported to be unrelated to treatment with iscalimab. Furthermore, IV treatment in Cohort 2 resulted in a mean reduction of 5·21 points (95% CI:0·96-9·46; one-sided p=0·009 ) in ESSDAI score versus placebo with some improvements in other pSS relevant outcomes and reductions in levels of the germinal-center biomarker CXCL13 after 12 weeks of treatment.

Interpretation: This is the first randomised, placebo-controlled trial of a new investigational drug for pSS that has met its primary endpoint. Our data suggest a pivotal role of CD40-CD154 interactions in pSS pathology and indicate a therapeutic potential for CD40 blockade in pSS.

Details

Original languageEnglish
JournalLancet Rheumatology
Publication statusAccepted/In press - 5 Dec 2019