Safety and in vivo immune assessment of escalating doses of oral laquinimod in patients with RRMS

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Tjalf Ziemssen - , Department of Neurology (Author)
  • Hayrettin Tumani - , Ulm University (Author)
  • Tony Sehr - , Department of Neurology (Author)
  • Katja Thomas - , TUD Dresden University of Technology (Author)
  • Friedemann Paul - , Charité – Universitätsmedizin Berlin, Max Delbrück Center for Molecular Medicine (MDC) (Author)
  • Nils Richter - , Neurologische Gemeinschaftspraxis (Author)
  • Emil Samara - , PharmaPolaris International Consulting (Author)
  • Ofer Spiegelstein - , Teva Pharmaceutical Industries Ltd. (Author)
  • Ella Sorani - , Teva Pharmaceutical Industries Ltd. (Author)
  • Oren Bar-Ilan - , Teva Pharmaceutical Industries Ltd. (Author)
  • Dorit Mimrod - , Teva Pharmaceutical Industries Ltd. (Author)
  • Liat Hayardeny - , Teva Pharmaceutical Industries Ltd., Galmed Pharmaceuticals (Author)

Abstract

Background: Laquinimod is an oral immunomodulator in clinical development to treat relapsing-remitting multiple sclerosis (RRMS). Laquinimod is in clinical development for the treatment of multiple sclerosis and Huntington Disease (HD). The objective of this study is to assess the safety, tolerability, pharmacokinetics (PK) and cytoimmunologic effects following escalating doses of laquinimod in patients with RRMS. Methods: One hundred twelve patients were randomly assigned to laquinimod/placebo in a series of separate dose-escalating cohorts starting from a daily oral dose of 0.9mg/1.2mg escalating to 2.7mg, in 0.3mg increments. Results: Twenty-eight patients received placebo and 84 received laquinimod ranging from 0.9 to 2.7mg. No deaths occurred. One serious adverse event (SAE) of perichondritis was reported, which was unrelated to laquinimod (0.9mg). There was no increased incidence of adverse events (AEs) with escalating doses. Laquinimod-treated patients showed more abnormal laboratory levels in liver enzymes, P-amylase, C-reactive protein (CRP), and fibrinogen, but most shifts were clinically non-significant. The exposure of laquinimod was dose proportional and linear in the tested dose range. An immunological substudy showed significant dose-dependent decreases in 6-sulpho LacNAc + dendritic cell (slanDC) frequency following laquinimod compared to placebo. Conclusion: Laquinimod doses up to 2.7mg were safely administered to patients with RRMS. An in vivo effect of laquinimod on the innate immune system was demonstrated. Trial registration: EudraCT Number: 2009-011234-99. Registered 23 June 2009.

Details

Original languageEnglish
Article number172
JournalJournal of neuroinflammation
Volume14
Issue number1
Publication statusPublished - 31 Aug 2017
Peer-reviewedYes

External IDs

PubMed 28859672
ORCID /0000-0001-8799-8202/work/171553412

Keywords

Keywords

  • Immunology, Laquinimod, Multiple sclerosis, Safety, SlanDC