Thursday, January 08, 2015

Arena Pharmaceuticals advances S1P1 modulator APD334 into Phase 2 for autoimmune disease - ulcerative colitis and Crohn's disease initial targets

  • Sphingosine 1-phosphate (S1P) receptors are involved in T cell migration out of lymph nodes and S1P1 receptor blockers have therefore been investigated for the treatment of various autoimmune diseases
  • The best known S1P receptor blocker is Gilenya (fingolimod), which was approved for the treatment of multiple sclerosis.  Despite efficacy, Gilenya is associated with significant AEs including dyspnea, bradycardia and ALT elevation
  • Multiple S1P receptors have been identified and the AEs associated with Gilenya appear to be related to poor selectivity vs other receptor subtypes
  • Next generation S1P antagonists are therefore being developed by a number of companies to improve the therapeutic margin seen with Gilenya
  • Most recently in UpdatesPlus-Lupus, we highlighted Mitsubishi's efforts to develop MT-1303 as a candidate treatment of Lupus.  This candidate is also being investigated for multiple sclerosis, IBD (both Crohn's Disease and Ulcerative Colitis) and psoriasis.  Receptos is also developing an S1P blocker (RPC1063) for multiple sclerosis and IBD (Ulcerative Colitis), while Actelion was developing ponesimod for psoriasis, although we understand the company has been evaluating next generation S1P blockers in an attempt to screen out AEs
  • Arena has now announced its development of APD334, a selective S1P1 modulator that dose-dependently lowers lymphocyte counts in healthy volunteers.  In the Phase 1b study announced today, APD334 reduced plasma lymphocyte count by up to 69% without producing CV, hepatic or pulmonary AEs.  
  • Arena now plans to open ulcerative colitis and Crohn's disease studies

This alert will be featured in:

  • UpdatesPlus-Psoriasis
  • UpdatesPlus-Rheumatoid Arthritis 
  • UpdatesPlus-IBD

UpdatesPlus represents a leading monitoring and intelligence service offering up to date analysis of breaking research, trials and drug development news.  For further information on this service please click here

CommentsBuzard et al have recently reported the development of APD334.  This molecule has good CNS penetration supporting additional development for multiple sclerosis.  Efficacy was also observed in rodent models of rheumatoid arthritis.  In addition, the elimination half life is considerably shorter than that of Gilenya.  This is important as lymphocyte recovery following withdrawal of Gilenya can take up to 5wks, potentially increasing risk in the context of opportunistic infection 

Figure:  APD334 demonstrated therapeutic efficacy in a mouse model of multiple sclerosis.  APD334 was administered at day 18 just before disease activity peaks (after Buzard et al)

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