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]

Biogen licenses S1P modulator MT-1303 from Mitsubishi for the development in multiple sclerosis, IBD (crohn's disease and ulcerative colitis) and more

Biogen licenses S1P modulator MT-1303 from Mitsubishi [Link]

• Biogen will receive worldwide development and commercialization rights to MT-1303, excluding Asia for $60M plus further milestone payments of up to $484M
• MT-1303 is an oral S1P modulator which halts T cell exit from lymph nodes and hence their movement to disease sites
• The lead indication for MT-1303 is multiple sclerosis for which a Phase 2 study has been successfully completed and Biogen is now set to accelerate development for this indication
• Biogen will also develop the molecule for inflammatory bowel disease, initiating an ulcerative colitis study with the  existing Crohn’s disease program to advance to Phase 3
• Mitsubishi has the right to participate in Biogen’s global clinical trials and has co-promote non-multiple sclerosis indications in the US

Note that post is from our UpdatesPlus service offering ad hoc analaysis and in depth monthly reports of breaking R&D spanning IBD, Lupus, Psoriasis and much more.  For further information and sample reports please contact  jon.goldhill@leaddiscovery.co.uk

Comments: Biogen is a field leader in the development of multiple sclerosis treatments (contact us for a full landscape of the multiple sclerosis area) and it is not surprising that it has secured this acquisition.  Gilenya has already established proof of concept for the development of S1P modulators for this indication.  AEs associated with Gilenya have prompted the development of more selective molecules from this class.  MT-1303 is quite far advanced but still behind Ozanimod (RPC1063).  Receptos developed this molecule prior to the company's acquisition by Celgene which completed  two weeks ago.  Celgene expects approval for Ozanimod in 2018 meaning that Biogen would have to significantly accelerate its own Phase 3 program to be competitive

In addition to multiple sclerosis, S1P modulators are in development for lupus, IBD and psoriasis.  Data are especially encouraging for IBD.  Again, Ozanimod leads the field with TOUCHSTONE, which was reported at ECCO and DDW this year, demonstrating improved rates of clinical remission in ulcerative colitis patients. Mucosal healing was also improved.  A Phase 3 Ozanimod study in ulcerative colitis opened May 2015.  Again, Biogen will have to accelerate development to compete with Ozanimod

Biogen's licensing activity is also of interest in terms of its activity in the broader autoimmune space.  While the company is an player established in multiple sclerosis, it has limited activity in other autoimmune diseases with the exception of lupus.  This suggests Biogen may accelerate MT-1303 development for lupus as well as leverage its acquisition of MT-1303 to gain a broader footprint in immunology.  Of note, Biogen is developing a biosimilar portfolio with Samung and developing a combination of established biologics alongside next generation small molecules could not only be attractive commercially but also allow rapid franchise expansion

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)