Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the Phase 3 DEFINE and CONFIRM studies.
BACKGROUND
Delayed-release dimethyl fumarate (DMF) is an approved oral treatment for relapsing forms of multiple sclerosis (MS). Preclinical studies demonstrated that DMF activated the nuclear factor E2-related factor 2 (Nrf2) pathway. DMF and its primary metabolite monomethyl fumarate (MMF) were also shown to promote cytoprotection of cultured central nervous system (CNS) cells via the Nrf2 pathway.


OBJECTIVE
To investigate the activation of Nrf2 pathway following ex vivo stimulation of human peripheral blood mononuclear cells (PBMCs) with DMF or MMF, and in DMF-treated patients from two Phase 3 relapsing MS studies DEFINE and CONFIRM.


METHODS
Transcription of Nrf2 target genes NADPH:quinone oxidoreductase-1 (NQO1) and heme-oxygenase-1 (HO1) was measured using Taqman® assays. RNA samples were isolated from ex vivo-stimulated PBMCs and from whole blood samples of 200 patients each from placebo, twice daily (BID) and three times daily (TID) treatments.


RESULTS
DMF and MMF induced NQO1 and HO1 gene expression in ex vivo-stimulated PBMCs, DMF being the more potent inducer. Induction of NQO1 occurred at lower DMF concentrations compared to that of HO1. In DMF-treated patients, a statistically significant induction of NQO1 was observed relative to baseline and compared to placebo. No statistical significance was reached for HO1 induction.


CONCLUSIONS
These data provide the first evidence of Nrf2 pathway activation from two large pivotal Phase 3 studies of DMF-treated MS patients.
Biogen, Inc., Cambridge, MA, USA.
Sreeja
S
Gopal
Biogen, Inc., Cambridge, MA, USA.
Alvydas
A
Mikulskis
St. Josef Hospital, Ruhr University Bochum, Bochum, Germany.
Ralf
R
Gold
Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA.
Robert J
RJ
Fox
Biogen, Inc., Cambridge, MA, USA.
Katherine T
KT
Dawson
Biogen, Inc., Cambridge, MA, USA.
Lakshmi
L
Amaravadi
D000328:Adult; D003692:Delayed-Action Preparations; D000069462:Dimethyl Fumarate / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
D003692:Delayed-Action Preparations; D005650:Fumarates; D007166:Immunosuppressive Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000069462:Dimethyl Fumarate
Dimethyl fumarate; HO1; NQO1; Nrf2 pathway; antioxidant response; monomethyl fumarate