BI 655066 alert - Phase 3 psoriasis studies announced as Boehringer reports further impressive Phase 2 data for its IL-23 mAb

This exert is from our live coverage of EADV - for comprehensive coverage contact leaddisc@leaddiscovery.co.uk

• Boehringer presented Phase 2 proof of concept data for IL-23 mAb, BI 655066 at EADV 2014
• BI 655066 targets the p19 subunit of the IL-23 receptor, while Stelara targets the p40 subunit which is shared by the IL-12 and IL-23 receptor
  
• A  single dose produced 58% PASI90 across doses.  Durability of response was remarkable with PASI100 at 12wks maintained to 41-66wks
• A Phase 2 dose ranging study reported at AAD confirmed efficacy
• At 90mg or 180mg (0, 4 and 16wks) BI 655066 produced  PASI90 rates of 66% and 86% at 24wks
  
• New data from the follow up period were reported this week at EADV (see below)
  
• PASI90 rates remained very high at 20 wks after the last treatment with 90mg or 180mg (ie at 36wks).  Rates were 69% and 81% respectively vs 30% for Stelara which started to drop off rapidly from 8wks after the last dose
• The time to reach PASI90 was presented and this was twice as fast with BI 655066 (57d).  Of interest, the speed of response was related to dose
  
• For those patients who achieved PASI 90 a KM curve analysis reported a dramatic increase in the time to PASI90 loss.  This was 169d with Stelara; for 180mg BI 655066, 60% of patients still had PASI90 at the end of follow up (169d after the final dose) and hence a value could not be calculated

Comments:  The data continue to be very impressive for BI 655066, with most opinion leaders at EADV expressing considerable excitement around the molecule.  The consensus opinion appears to be that the high level of efficacy is due to the mode of action rather than long half life or other physio-chemical attributes of BI 655066.  This is interesting because the thinking to date has been that Stelara targets both IL-23 and IL-12 and that the latter is a bystander.  The present data suggests that IL-12 may exert some degree of beneficial effect, and hence the net benefit of blocking IL-23 and IL-12 is less than selectively targeting IL-23 alone.  Alternatively the p19 subunit of IL-23 which is targeted by BI 655066 is a component of another receptor which does not include p40, and hence untouched by Stelara.  A further possibility is that for some unknown reason BI 655066 is able to deplete target cells, whereas Stelara cannot. This is all conjecture and the key points remains that the high efficacy continues to be shown and the progress to Phase 3 which we will describe in our next alert

FDA accepts Sandoz's application for biosimilar Etanercept despite Amgen maintaining Enbrel exclusivity to 2029

• Sandoz has announced it is seeking approval for all indications included in the Enbrel label
• The is first time the FDA has accepted a submission for a biosimilar version of etanercept
• Filing is supported by studies including EGALITY which enrolled patients with psoriasis
• Sandoz recently launched Zarxio, a biosimilar filgrastim

For our coverage of EADV next week please contact leaddisc@leaddiscovery.co.uk

Comments:  This filing is interesting for a number of reasons but we believe the fact that etanercept is administered sc over chronic periods makes this particularly interesting.  For the first time in the US there will there be a good opportunity for a biosimilar company to test the waters with a product that can be differentiated by administration device and also by patients support programs.  It will be intriguing to see how Sandoz handles this.  This is all the more notable given that its parent company, Novartis has recently launched Cosentyx for psoriasis with a state of the art device which could be potentially used to differentiate Sandoz's etanercept from Enbrel and the Enbrel pen.  The timing of Sandoz's announcement is also convenient with EADV coming up next week.  Perhaps the most interesting aspect of today's news is that the general assumption has been Amgen's exclusivity on Enbrel runs to 2029 in the US.  A key question is therefore, why exactly has Sandoz chosen to file now.

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

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

AstraZeneca suggests that it will be proceeding with brodalumab development

• AstraZeneca held its Q2 results call yesterday and hinted at continued development of brodalumab
• The future of brodalumab had been put in doubt earlier this year with Amgen announcing that it was no longer going to develop brodalumab in the US [see our earlier post]
  
• Amgen consequently transitioned rights to AstraZeneca
• Amgen stated its decision was due to reported suicidality and ideation of suicide in brodalumab trials
• While Amgen has yet to disclose the level of risk, it commented that there was a fear of labelled monitoring requirements diminishing the competitiveness of brodalumab
• During the company's comments AstraZeneca commented that an initial evaluation of data suggested that suicidality was likely unrelated to brodalumab
• It was also commented that it had received multiple partnering offers but that it was completing data analysis prior to selecting a partner
• On the slide deck accompanying the results call, brodalumab filing continues to be listed as 2015

Comments: The full reasons behind Amgen's decision to abandon brodalumab continue to be elusive.  The fact that AstraZeneca is muting possible licensing suggests others are less concerned that FDA requirements will reduce the competitiveness of brodalumab however a 2015 filing would seem unlikely in the US unless AstraZeneca opts for a commercial license handling  submission itself


Call quotes:  As for brodalumab we have conducted an initial evaluation of the data, which confirms that broda demonstrated strong efficacy in psoriasis and indicates that the observations of suicide or ideation are unlikely to be causally related to brodalumab therapy....we've actually had several expression of [partnering] interest. In fact we've already received offers, and we are considering those and engaging in discussions with potential partners. But it was really encouraging to see that we didn't get one, we got several expressions of interest from a variety of partners...But the key is really first of all to go through the data in more details, and that's what we are still doing. And secondly decide how we progress this together with the partner that we would select.

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

Celgene takes PKCθ (PKC theta) inhibitor into the clinic as candidate first in class treatment of psoriasis

This is an extract from UpdatesPlus-Psoriasis, our regular report analyzing breaking development across the field of psoriasis research and development - for further information and sample copies please contact Dr Jon Goldhill

• The protein kinase C (PKC) family comprises 12 isoforms including T cell modulators, PKCθ and PKCα
• Both isoforms are anti-inflammatory targets although PKCα inhibition carries a risk of CV AEs
  
• PKCθ mediates the response to TCR activation including IL-2 production, cellular expansion, and activation
• Proof of concept exists to support the development of PKCθ inhibitors for rheumatoid arthritis as knock-out mice do not develop disease in experimental models (Healy et al).  PKCθ inhibition also apparently enhances functionality of rheumatoid arthritis Treg cells (Zanin-Zhorov)
  
• Novartis was developing sotrastaurin which inhibits PKCθ with nM potency.  Inhibition was relatively unselective, which likely contributed to the termination of it's development. 
  
• Abbvie also reported earlier this year efforts to develop PKCθ inhibitors with low nM potency, but with ≈100-fold selectivity over PKCα.  A representative molecule from this series was active in a model of rheumatoid arthritis however we are unaware of Abbvie advancing this class into the clinic yet
  
• Celgene has also previously indicated its involvement in PKCθ inhibitor development and has now opened a Phase 1b study of CC-90005 including the enrollment of psoriasis patients
• The study is evaluating oral dosing.  Data should be available by Oct 2016.  Although the study is primarily a safety and PK trial, efficacy will also be investigated

Amgen pulls out of brodalumab development amongst fears of suicidality - bad luck, bad target or victim of brodalumab's efficacy

This content is sampled from our UpdatesPlus service. UpdatesPlus-Psoriasis is a regular monitoring and analysis service from our inflammation and dermatology collection. Reports are accompanied by ad hoc e-mail alerts providing near real time analysis of key breaking events.  This alert along will all other recent events will be analyzed in our next issue of UpdatesPlus.  Please contact jon.goldhill@leaddiscovery.co.uk - or access our UpdatesPlus product brochure for further details 

Update [31st July 2015]:  AstraZeneca seems likely to continue brodalumab development with new partner [more]

• Amgen and AstraZeneca has been collaborating since 2012 on the development of 4 mAbs from Amgen's inflammation portfolio including IL-17R mAb, brodalumab
• Amgen has however now announced that it will be terminating development of brodalumab
• Brodalumab was in development for psoriasis, psoriatic arthritis, and axial spondyloarthritis
• The decision was based on suicidal ideation and behavior.  Amgen believes this would have restricted labeling
• The company has commented that "During our preparation process for regulatory submissions, we came to believe that labeling requirements likely would limit the appropriate patient population for brodalumab"
  
• Amgen is now starting to transition the brodalumab program to AstraZeneca who now has the right to file (outside of Asia where Kyowa Hakko Kirin has rights)

Comments:  Despite high efficacy in Phase 3 studies, whispers of suicidality associated with brodalumab started to emerge at AAD.  At the time Amgen suggested this was related to disease however the company refused to comment on total rates and whether events were seen across arms.  At the time we commented that Amgen's suggestion that suicidality related to disease rather than drug was curious.   If this had have been the case events would have been expected to be skewed towards placebo groups where patients would have been less likely to achieve skin clearance.  In turn Amgen would have been expected to clarify this to protect brodalumab.  This was not the case.  Since suicide ideation is increased in patients with psoriasis, we agree with Amgen that a labelled warning of this adverse event could have been detrimental (although we note that this is a labelled warning for Otezla which has had a good launch).  The question is whether Amgen is being hyper-cautious or whether the risk of suicidality is especially concerning.  Questions also emerge around the cause of risk - is this a spurious cluster of events unrelated to brodalumab; is suicidality perhaps related to relapse from the excellent efficacy associated with brodalumab after withdrawal (remember most patients exhibited at least PASI 90 on treatment but durability was very poor upon withdrawal); or perhaps suicidality is related to blocking the IL-17RA (note that suicidality has not to our knowledge been reported for the IL-17A ligand mAb Cosentyx).  Questions also relate to whether AstraZeneca will file brodalumab.  Against the exceptional performance of Consentyx and also ixekizumab, as well as the apparently inferior durability of broadulamab vs  IL-17 ligand mAbs and now the possibility of suicide ideation warnings, the fate of brodalumab remains to be seen.  One final point is whether regulators will now reevaluate suicide risk of IL-17 related molecules as a class - much greater clarity of brodalumab data is required to make a judgement