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]

Disappointing Phase 2 psoriasis data reported for the monomethyl fumarate prodrug, XP23829

• Despite early support, fumaric acid esters only became an established  psoriasis therapy in 1994 and then, primarily in Germany as Fumaderm.  This product is a combination of dimethylfumarate and monoethylfumarate salts
  
• Tecfidera (dimethyl fumarate, DMF) is a prodrug developed by Biogen Idec.  This molecule is converted to monomethyl fumarate (MMF) prodrug and has been approved for multiple sclerosis but is associated with common AEs (eg 18% abdominal pain; 40% flushing)
• XenoPort has developed XP23829, another MMF prodrug using technology linking DMF to a carrier facilitating GI transport.  This improves PK and potentially reduces AEs
• Positive top-line results have now been presented from a Phase 2 study of XP23829 in 200 moderate-to-severe psoriasis patients [see today's presentation]
  
• XP23829 at both 800mg QD and 400mg BID met its primary endpoint, improvement from baseline to 12wks in PASI score (see figure below).  A responder analysis reported PASI75 rates of 22% vs 9% at 400mg BID
  
• Efficacy was considerably greater in biologic naive patients (eg mean PASI change of 59% vs 38% at 400mg BID for naives and experienced respectively).  Of note PASI75 rates were similar irrespective of treatment history
  
• There were two SAEs potentially attributed to XP23829: acute cholecystitis and enterocolitis.  GI AEs were relatively high, especially at 400mg bid and within the range seen in Phase 3 studies of Tecfidera.  Flushing AEs were however reduced considerably compared to Tecfidera
• Phase 3 studies are expected to open in 2016 with Xenoport suggest QD dosing would be the regimen of choice
  

Comments:  The development of XP23829 appears to have reduced the flushing AEs seen with Tecfidera.  Our concern however is that GI AEs remain present.  This is despite titration to target dose over the initial 3wks.  Xenoport suggested that this may reflect in part observer bias given that the drug class has been previously associated with GI AEs.  We are also concerned that the PASI75 efficacy rates were relatively low, reaching just 22%.  With the advent of IL-17 mAbs, very high rates of skin clearance can now be expected and PASI75 rates now exceed 80%.  There remains a place for molecules with lower efficacy rates.  For example, the oral treatment Otezla has shown good uptake.  This PDE4 inhibitor produces PASI75 rates of approximately 30% at 16wks although like  XP23829 efficacy is quite slow in onset.  Showing further similarity, Otezla is also associated with GI AEs although the rate of diarrhea appears considerably higher with XP23829.  Although Xenoport is planning Phase 3 studies, we believe limited efficacy and at best similar tolerability vs Otezla will present challenges given that the two would likely compete compete should XP23829 enter the market.  Of note Xenoport shares fell 25% today suggest the market likewise believes XP23829 may struggle in the competitive psoriasis market.  Xenoport did stress the point that XP23829 efficacy is expected to accumulate slowly and suggested that it would be competitive when followed for longer periods; it remains to be seen whether this is indeed the case

AstraZeneca further ups its biologics manufacturing capacity - further evidence of future brodalumab production?

In our recent alert announcing Valeant's decision to in-license psoriasis candidate, brodalumab from AstraZeneca we commented that the deal may suffer from a lack of manufacturing capacity for biologics.  AstraZeneca appears to be making a concerted effort to expand manufacturing capacity potentially addressing this

• AstraZeneca has recently invested $285M in its Swedish biologics facility.  Capacity at an existing Maryland site is also to be expanded (see our original alert below)
  
• Now AstraZeneca has announced  the purchase of a biologics bulk manufacturing facility from Amgen in Colorado
• AstraZeneca reportedly plans to start staffing the facility immediately to support refurbishment and infrastructure improvements
• Once complete, the site is expected to be operational and licensed for commercial production by late 2017
• The facility will eventually double AstraZeneca's biologics manufacturing capacity in the US.

Comments:  Across the AstraZeneca/Medimmune pipeline at least 6 mAbs may be in a position to launch in the near term (Durvalumab, Moxetumomab and Tremelimumab for oncology and brodalumab, Benralizumab and Tralokinumab for immunology).  New capacity will be required to meet this over demand.  Although it is unclear whether AstraZeneca will be responsible for brodalumab manufacture under its deal with Valeant,  today's new makes it increasingly likely that it will be able to do so if necessary.  Furthermore until Amgen's recent decision to drop brodalumab it may have even been the intent to manufacture commercial supply at the Colorado site suggesting that processes are up and ready to rapidly meet demand

For detailed analysis of immunology pipelines, R&D activity and commercial activity ask us about UpdatesPlus - sample 100 page reports available on request

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

Valeant in-licenses global rights to brodalumab outside of Japan and other Asian geographies as it further grows into the dermatology space

Valeant in-licenses global rights to brodalumab

From: UpdatesPlus-Psoriasis our regular psoriasis monitoring and analysis service

• Just a few weeks ago we reported that AstraZeneca seemed likely to continue brodalumab development and that a new partner was being sought to replace Amgen
• Amgen had earlier decided to discontinue development due to concerns over labelling relating to suicidality (See Amgen pulls out of brodalumab development amongst fears of suicidality - bad luck, bad target or victim of brodalumab's efficacy)
• Valeant has now announced that it will in-license global rights to brodalumab from AstraZenecca.  
• Valeant will make an upfront payment of $100M to AstraZeneca, with another $170M in prelaunch milestones and up to $175M following launch
• Valeant will license exclusive global development and commercialization rights to brodalumab with the exception of Japan and certain other Asian countries where rights are held by Kyowa Hakko Kirin under a prior arrangement with Amgen
  
• After approval, AstraZeneca and Valeant will share profits although the profit split has not to our knowledge been disclosed
  
• EU and US filing is expected Q4 2015
• Valeant will assume all development costs associated with the regulatory approval for brodalumab

Comments:  Valeant had extensive commercial experience across the dermatology spectrum including actinic keratosis, acne and atopic dermatitis. A Steroid/Retinoid combination is expected to be filed for psoriasis in 2016.  Acquiring brodalumab could significantly expand Valeant's position in dermatology.  Under the terms of the current deal it seems that AstraZeneca will not be commercializing brodalumab if approved and instead Valeant will be responsible for this.  With Valeant's existing activity in dermatology and a limited level of AstraZeneca sales activity, this agreement seems logical.  On the other hand the deal will allow AstraZeneca to focus on immuno-oncology.  One barrier Valeant could face is its limited experience in biologics and in this respect it is of interest that AstraZeneca recently announced plans to invest $285M in a new biologics manufacturing facility in Sweden. The new plant will be focused on filling and packaging of protein therapeutics. Clinical trial material will be generated by 2018 with commercial capacity coming on line by 2019.  Biologics capacity at an existing site in Maryland is also reported to be expanded.  It is not known if these sites are to be responsible for brodalumab manufacture/filling - if this is however the case, brodalumab capacity may suffer a lag during the initial role out period (ie 2017/18)

Read more in our next issue of UpdatesPlus-Psoriasis our regular monitoring and analysis service. Reports are accompanied by ad hoc e-mail alerts providing near real time analysis of key breaking events. This alert along with all other recent events will be analyzed in our next issue of UpdatesPlus. Please contact jon.goldhill@leaddiscovery.co.uk