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

New therapeutic candidate enters the lupus pipeline - CD30 indications to spread from oncology to autoimmune disease?

Seattle Genetics to open clinical study of CD30 targeting brentuximab in lupus [link]


From UpdatesPlus-Lupus is our regular report analyzing breaking development across the field of lupus research and development - for further information and sample copies  please contact Dr Jon Goldhill

• Seattle Genetics has successfully developed and launched Brentuximab (SGN-35) as Adcetris for the treatment of  relapsed or refractory CD30+ Hodgkin lymphoma
• Brentuximab consists of an anti-CD30 mAb (SGN-30) conjugated to a cytotoxic agent monomethyl auristatin E
• This allows selective internalization of the cytotoxic by CD30 expressing tumor cells leading to their destruction
  
• CD30 has also been implicated in autoimmune disease
• CD30 and its ligand CD30L are members of the TNF super-family expressed on activated lymphocytes
  
• CD30 over-expression has been reported in lupus.  As long ago as 1995 it was reported that sCD30 levels were increased 10-fold in lupus patients correlating with disease activity 
  
• Over-expression was later confirmed and shown to include SLE and lupus nephritis patients
• More recently SLE patients have been shown to express a high rate of CD30 T cells.  Moreover expression was on CD8 T cells rather than CD4 T cells which preferentially express CD30 under healthy conditions
• Seattle Genetics retrospectively reviewed data from lymphoma patients and concluded that concomitant autoimmune disease was improved in some patients treated with brentuximab
• Seattle Genetics has now announced the initiation of a phase 2 study of brentuximab in SLE
  
• The new study will administer brentuximab to 40 patients (q3w)

Comments:  Given the limited lupus pipeline new candidates entering the clinic are particularly welcome.  This is especially the case when candidates are first in class.  By word of caution however, the brentuximab product label carries a boxed warning of PML and lists a large number of toxicities although it should be noted that trials were in an oncology setting and causality is difficult to conclude.  From a mechanistic perspective we would expect brentuximab to impact both CD4 and CD8 CD30 positive cells although previous data suggest CD8 T cells may be a more relevant target.  Moving forward we also ask if strategies aimed at more selective targeting of CD8 cells could improve the therapeutic index.  For example, OX40 and CD30 reportedly act synergistically to regulate CD8 cells, opening options for bispecific approaches.  Finally, we note that sCD30 has been related to lupus disease activity.  We presume that this is an indirect measure of membrane bound CD30, and that cleavage in turn increases sCD30.  It would be useful to verify however whether sCD30 carries a pathophysiologic role

Anacor reports positive Phase 3 data on PDE4 inhibitor ANA2728 (Crisaborole)

In yesterday's issue of UpdatesPlus-Atopic Dermatitis** we reported that Anacor has fully enrolled two Phase 3 pivotal ANA2728 studies and that data were expected this quarter.  Data were released yesterday [Link]


**UpdatesPlus is our regular report analyzing breaking development across the field of atopic dermatitis research and development - for further information and sample copies  please contact Dr Jon Goldhill

• ANA2728 now known as Crisaborole is a topical PDE4 inhibitor.  The molecule is based on Anacor's boron based chemistry which is intended to increase skin penetration
• Each of the two studies enrolled 750 patients aged 2yo and treated for 1 month
• Patients had mild-moderate dermatitis covering approximately 18% of the skin.  Approximately 60% patients had moderate disease
  
• The primary endpoint (ISGA 0/1 - clear/nearly clear, with a minimum of a 2 grade improvement) was improved in both studies from 25%-18% with vehicle to 33%-31%.  This produced a delta of 7% and 13% in the two studies
  
• During Anacor's investor call, the company highlighted the secondary endpoint, ISGA 0/1 (without a requirement for a 2 grade improvement) as clinically more important.  This was improved from 41-30% to 52%-59% (delta of 11% and 19%)
  
• Efficacy was achieved within 8d (see below).  The safety profile was benign and the only measure worthy of mention is a small increase in application site pain (1.2% vs 4.4%).  Severity of pain was not reported however there was no increase in discontinuation between test and vehicle
• A long term safety study is now underway.  During the results call it was disclosed that 500 patients had enrolled
  

Comments:  During Anacor's call, market research was presented claiming that there is a large unmet need in the atopic dermatitis market with high potency corticosteroids producing excessive adverse events.  The benign safety profile of Crisaborole suggests benefit in this respect although a active control arm allowing comparison of efficacy between the two strategies would have been useful.  On the other hand, low potency corticosteroids are viewed as being insufficient in resolving itch.  The present study suggests that rash is resolved in up to 60% patients.  Again an active comparator arm would have been useful.


Of note one non-steroidal comparator, Elidel (pimecrolimus) produces clear/nearly clear rates of 35% at 6wks.  This is nominally lower than for Crisaborole although the Elidel vehicle response was also markedly lower (18%).  It is unclear at present therefore how much of the power of Crisaborole lies in its vehicle.  Indeed Crisaborole vehicle produced clear/nearly clear rates very similar to Elidel response (30-41% vs 35%).   Quite how important or relevant this is is unclear.  Anacor actively set out to rationally optimize its vehicle.  Moreover the important issue is the degree of efficacy seen with the product in its entirety.  The observation does however suggest the possibility of developing the vehicle alone as a maintenance treatment for some patients.



Data were not reported on itch and this is eagerly awaited.  Of note, in our UpdatesPlus report yesterday we suggests that evidence, particularly from topical tofacitinib studies, suggests a dissociation of rash and itch resolution.  Given the importance of itch as a patient reported out come it will be important to note how Crisaborole improves itch.  The company was asked about this in its call and commented that data were not yet full analyzed but appeared promising, including in terms of speed to response