Tofacitinib demonstrates efficacy in Phase 3 ulcerative colitis induction trials

Source:  UpdatesPlus-IBD

• Pfizer has announced topline results from two identical OCTAVE induction studies
• Both studies met their primary endpoints (remission at 8wks) The two studies evaluated oral tofacitinib (10mg BID) in 1139 patients with moderate/severe ulcerative colitis
• Patients must have been previously been intolerant or unresponsive to corticosteroids, azathioprine/6 MP), or a TNFi
  
• Pfizer's press release comments that that are no new AEs
  
• A third study, OCTAVE Sustain investigating maintenance treatment with tofacitinib is anticipated by the end of 2016

Comments:  Obviously further data are required before tofacitinib can be more fully evaluated as an option in ulcerative colitis patients.  Safety is one issue, particularly as a 10mg dose was employed rather than the 5mg dose of tofacitinib approved as Xeljanz in the US for rheumatoid arthritis.  The absence of new AEs is promising, however it will be important to know the rate of known AEs.  This is not only important for ulcerative colitis; safety data may be important for use in psoriasis as well, since treatment with 10mg tofacitinib is required to produce non-inferior efficacy to that of Enbrel in the psoriasis study, OPT Compare.  The degree of efficacy in ulcerative colitis remains to be seen and particularly whether prior treatment history affects tofacitininb response.  It is unclear if OCTAVE will be presented at UEGW in October, from where we will be reporting.  The late breaker deadline was August 25. [Contact us if you are interested in our conference reporting service]

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

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Comments:  Buzard 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)