Treatment of rheumatoid arthritis with a Syk kinase inhibitor: a twelve-week, randomized, placebo-controlled trial.
OBJECTIVE
Spleen tyrosine kinase (Syk) has been identified as an important modulator of immune signaling in B cells and cells bearing Fcgamma-activating receptors. R788, a prodrug of active metabolite R406, has been shown to be an inhibitor of Syk kinase, active in a variety of in vitro and in vivo models, suggesting potential activity in the treatment of rheumatoid arthritis (RA).


METHODS
We enrolled 189 patients with active RA despite methotrexate therapy in a 3-month, multicenter, ascending-dose, double-blind, placebo-controlled trial. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12.


RESULTS
Twice-daily oral doses of 100 mg and 150 mg of R788 were significantly superior to placebo or twice-daily oral doses of 50 mg at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57% versus 19% and 17% of patients, respectively) and ACR70 (achieved in 33% and 40% versus 4% and 2% of patients, respectively) scores showed a similar pattern. Clinical effect was noted as early as 1 week after initiation of therapy. Reductions in serum interleukin-6 and matrix metalloproteinase 3 levels also occurred as early as week 1 in the groups receiving 100 mg and 150 mg R788. The major adverse effects were gastrointestinal side effects (predominantly diarrhea) and neutropenia (<1,500/mm3), both of which were dose related.


CONCLUSIONS
These results indicate that an inhibitor of Syk kinase produces significant clinical benefits at 12 weeks in a population of patients with active RA receiving methotrexate therapy. Syk kinase may be an important new therapeutic target in RA and related autoimmune conditions.
Weinblatt
Michael E
ME
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Kavanaugh
Arthur
A
Burgos-Vargas
Ruben
R
Dikranian
Ara H
AH
Medrano-Ramirez
Gabriel
G
Morales-Torres
Jorge L
JL
Murphy
Frederick T
FT
Musser
Theresa Kane
TK
Straniero
Nicholas
N
Vicente-Gonzales
Angela V
AV
Grossbard
Elliott
E
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000631:Aminopyridines; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000097:blood; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines; D000072377:Syk Kinase
D000631:Aminopyridines; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011355:Prodrugs; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D019278:Matrix Metalloproteinase 3; C523665:fostamatinib; D008727:Methotrexate