UpdatesPlus- EULAR - Early data suggests c-Kit as a potential target for the treatment of peripheral SpA

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• A small body of data has provided proof of concept for targeting c-Kit inhibition for the treatment of rheumatoid disease
• Two approved molecules from this class include Imatinib (Gleevec) and its more selective successor  Nilotinib (Tasigna).  Both are indicated for the treatment of hematological cancers and in the case of imatinib, gastrointestinal stromal cell tumors
• An early pilot study of 6 SpA patients reported efficacy with imatinib.  A subsequent study suggested that in RA imatinib inhibits mast cell c-Kit tyrosine kinase resulting in apoptosis.  In the CIA model of RA, imatinib was shown to suppress and prevent disease.  Most recently it has been reported that c-Kit-positive mast cells are present in higher numbers in the synovium of SpA vs RA patients.  These cells expressed high levels of IL-17
• With this background data presented for nilotinib at EULAR are of significant interest
• 30 patients with SpA were randomized to nilotinib (at the current approved dose of 400mg bid) or placebo.  After 12wks treatment placebo patients were switched to nilotinib
• Patients with peripheral SpA (n=8) demonstrated a reduction in markers of inflammation, notably MMP-3 in patients with baseline elevation.  This was reflected in a dramatic reduction in patient's global assessment as well as a reduction in physician's global assessment and swollen joint count.  Efficacy was not observed in patients with axial disease (n=17)
  

Comments:  These data are of high interest but must be treated with caution given the small study size. Further we are trying to gain further information on patient type (eg whether patients had psoriatic involvement). In addition the difference in patient and physician global assessment requires greater understanding.  If data can be replicated in a larger study this would support the development of c-Kit inhibitors.  Of note the authors suggest that c-Kit inhibition results in reduced IL-17 release.  Development of nilotinib by Novartis for SpA could offer a franchise building opportunity given current development of secukinumab.  Equally, other companies with c-Kit assets may wish to develop them for SpA.  Finally it is of note that MMP-3 levels were particularly high in some patients with peripheral SpA. MMP-3 has been reported as an early biomarker of peripheral SpA; it will be interesting to determine if high MMP-3 levels could also be a companion biomarker for c-Kit inhibitor use