Novartis has announced approval of Cosentyx (secukinumab) for psoriasis and psoriatic arthritis in Japan

The following alert is from our UpdatesPlus service - for a summary of our most recent issue of UpdatesPlus-Psoriasis click here.  This service monitors and analyzes breaking journal articles, clinical trials and R&D news across the inflammatory disease spectrum 

• Approval has been granted for the treatment of adult psoriasis and psoriatic arthritis patients responding inadequately to systemic therapies (link)

• This is significant for three reasons

• Firstly, approval has come in Japan before the EU or the US.  Approval is expected early 2015 in both of these regions

• Secondly, the approved indication in Japan is more conservative than that recommended in the US and EU, where the FDA AdCom and the CHMP both recommended use in patients who are candidates for systemic or photo therapy

• Thirdly, Japanese regulators have simultaneously approved Cosentyx for psoriasis and psoriatic arthritis.  In the EU and US, psoriatic arthritis will be filed for as an sBLA in 2015

Comments:  Recommended indications in the US and EU will allow for first line treatment of patients.  This contrasts with the approved indication in Japan, where patients must first be treated with and shown to be insufficiently responsive to systemic therapies.  We presume that this reflects the more conservative nature of Japanese regulators and in addition the general preference of oral over systemic therapeutics in Japan.  The significance of this difference in indications remains to be seen as we expect payers to resist first line treatment with Cosentyx in the US and EU.  Simultaneous approval of psoriasis and psoriatic arthritis in japan is interesting as there are geographic differences in the prevalence of psoriatic arthritis.  Globally 30% of psoriasis patients have psoriatic arthritis;  in Japan however just 3% of psoriasis patients have psoriatic arthritis (source: Novartis press release).  In the US and EU separate psoriasis and psoriatic arthritis studies are required by regulators.  FUTURE 1 and FUTURE 2 studies which specifically enrolled psoriatic arthritis patients are required to support sBLA applications in these regions.   However, because psoriatic arthritis is such an uncommon condition in Japan we understand that indications for both psoriasis and psoriatic arthritis can be approved based on psoriasis studies alone

Galapagos regains full rights to the entire GPR84 program from Janssen as it plans to open Phase 2 ulcerative colitis studies this month

This alert comes from our UpdatesPlus-IBD service.  Providing ad hoc analysis of breaking events as well as detailed reports on IBD drug development this service is rapidly becoming a valued intelligence resource across the R&D community.  To receive a complimentary copy of our most recent issue please contact fiona.watts@leaddiscovery.co.uk

Galapagos has announced that it is taking back full developmental rights to this program which includes GLPG1205 and its backup GLPG2384.  No further details were disclosed on the reasons for this decision 

GLPG1205 antagonizes GPR84 and has reported good efficacy in models of IBD as well as good Phase 1 safety, PD activity and favorable drug-like properties.  As a result Galapagos announced in its press release that Phase 2 ulcerative colitis studies will start this month 

Comments: GPR84 is a medium chain free fatty acid receptor found on neutrophils, monocytes and macrophages and contributes to chemotaxis and cytokine release. Antagonism limits disease activity in models of IBD. 

Galapagos reported that Phase 1 data were positive almost exactly one year ago. Data were presented in greater detail at UEG a few weeks ago. Safety was in general good with no treatment related AEs observed in a SAD study. In a MAD study events were absent at 50mg and 100mg but at 200mg 2/6 patients reported dehydration, oropharyngeal pain, vomiting and fatigue. We suspect that the same 2 patients exhibited each of these effects as they are all consistent with vomiting. This needs to be confirmed as does the severity of vomiting. 

Crucially however PD data (below) reports near complete inhibition of receptor binding at the lowest dose test. The difference in inhibition across doses is rather modest suggesting the AEs may be off-target. Thus, even if doses under 200mg are deemed excessive for advancement, Galapagos' back up may be devoid of such activity.

Although Galapagos has not provided further details on Janssen's decision, we do not believe safety/efficacy are explanations. It is probably too early to gain a full understanding of efficacy and as mentioned safety/tolerability appears good at appropriate doses. Moreover, Galapagos has consistently stated, even in yesterday's release that ulcerative colitis studies will open this month. It is noteworthy that yesterday's decision came almost 1 year after the data becoming available and it is possible that a "no-development" clause had been triggered

Janssen has now discontinued two Phase 2 ulcerative colitis assets in rapid succession.  Janssen also handed JNJ-54781532 (ASP015K) back to Astellas at the start of the month. This did not come as a surprise to us given data presented at ACR 2014. These data were issued as part of our UpdatesPlus-Rheumatoid Arthritis service and report a very unconvincing dose response curve. Uncertainty in rheumatoid arthritis, the largest JAK market in immunology doubtless contributed to Janssen pulling out of ASP015K development.  Discontinuing the GPR84 program is more surprising

Detailed brodalumab data reported for the first time from AMAGINE-1 at Gene to Clinic - Continued excellent efficacy with IL-17 blockade to drive a new set of clinical challenges

Detailed brodalumab data reported for the first time from AMAGINE-1 at Gene to Clinic - Continued excellent efficacy with IL-17 blockade to drive a new set of clinical challenges


Below is from our UpdatesPlus-Psoriasis service - this service provides expert monitoring and analysis of key breaking data.  Intended for industry and clinicians alike our ad hoc alerts and full monthly reports offer support to all involved in the area.  For further information please contact fiona.watts@leaddiscovery.co.uk

• Amgen and AstraZeneca reported topline data from AMAGINE-1 comparing IL17RA blocker brodalumab to placebo in May of this year. 
  
• Patients were randomized to 210mg or 140mg brodalumab or placebo q2w. The study met its co-primary endpoints (PASI75 and PGA 0/1 at 12wks) at both evaluated doses.  PASI90 and 100 efficacy was also improved.  Efficacy was particularly impressive as the study cohort included 47% biologic experienced
  
• Since then, data have been reported from AMAGINE-2 and -3, demonstrating superiority over Stelara and placebo
• In highlighting each of these studies we have commented on the lack of time course data.  This is important as secukinumab response is rapid and messaged as a key attribute of the molecule. Yesterday, for the first time detailed AMAGINE-1 data were presented at Gene to Clinic, including full kinetics and 52wk data with and without withdrawal
• As previously reported PASI75 rates at 12wks were 83% and 60% at 140mg and 210mg respectively.  PASI 90 and PASI 100 responses were 70% and 42%
• PGA rates have been reported for what we believe is the first time.  This co-primary endpoint was reached in 76% and 54% at the 2 doses.  
• The primary efficacy endpoints increased rapidly during the first 12wks.  We calculate that half maximal efficacy is at approx 3wk.  For reference this is very similar to that reported previously for Cosentyx (secukinumab) and considerably faster than for Enbrel in the same study (3-4wks vs 7wk)
• The design of AMAGINE-1 means that after 12wks, patients achieving PGA under 2 are re-randomized to continue receiving the same dose as during the initial 12wks or switched to placebo.  Patients not achieving PGA under 2 continue on 210mg q2w brodalumab
  
• Two points should be highlighted during the long term follow up.  Firstly almost all (83%) responders over the initial 12wks maintain their response over 1yr (note this is an NRI analysis with patients lost to follow up or discontinuing  included as having a return to disease).  As is becoming apparent for the IL-17 class, persistence does seem very good.  Secondly however, most patients do lose a PGA 0/1 response within 12wks.  The half time for this effect is approx 4-6wks
• Biomarker data were presented describing IL-17A and IL-17C over-expression in plaques. Both mediators returned to levels in non-lesional skin within 12wks.  Cosentyx data suggests an early response to IL-17 blockade involves the depletion of dermal neutrophils.  These cells are large IL-17 reservoirs and migrate to inflamed skin under the control of IL-17 which provokes the release of neutrophil chemotactic agents from keratinocytes.  Breaking this viscous cycle likely contributes to the reduction of IL-17 levels
  
• The safety profile for brodalumab was unremarkable - oral candidiasis was reported in 2.1% patients over the 52wk study however this is similar to that in the Cosentyx Phase 3 program
  

Comments:  The AMAGINE-1 data are promising and as now expected of the IL-17 class.  Efficacy is rapid, high, durable and apparently safe/tolerable.  As the bar for efficacy become increasingly re-established at PASI 90 or PASI 100 we anticipate future challenges being the early identification of the 30-60% of patients who do not achieve this level of efficacy and well as identification of patients whose QoL is not excessively impacted by lower PASI improvement.  The latter may include patients who are most troubled by itch, nail psoriasis, scalp psoriasis or joint co-morbidity etc for whom PASI may not necessarily reflect QoL impairment and for whom agents that may be very effective against these domains (eg Otezla) may offer real hope.  For those patients that require complete skin clearance and who do not achieve PASI 100/PGA 0 with an IL-17 blocker, other options will also be required.

One interesting aspect of Cosentyx efficacy is its apparent biphasic response with a clear accumulation of efficacy observed between 12 and 16wks.  It is not possible from the AMAGINE-1 data presentation to determine if this is the same for brodalumab as patients were re-randomized at 12wks.  The only way to look at this will be to reanalyze the data pooling those patients who remained on 210mg after 12wks (ie ignoring those patients with a PGA under 2 who were re-randomized to placebo).  We look forward to seeing these data to get a clearer idea of efficacy levels with brodalumab but who may take a little longer to reach maximal response

Finally, patients lose response on brodalumab withdrawal.  This has previously been reported for Cosentyx.  This means that lifelong treatment continues to be a likelihood.  Further information is required on the severity of disease following brodalumab withdrawal as there may be the option of patients previously requiring a biologic, gaining adequate efficacy with topical treatment.  Being able to predict flare is required and one discussed at Gene to Clinic.  Alternatively, maybe the next paradigm shift will be to develop therapeutics that can produce durable efficacy even after treatment withdrawal.  IL-23 blockade does appear to fit this need based on preliminary data

An additional objective that continues to emerge is the treatment of co-morbidity.  Cardiometabolic disease, affective disorders and addiction are all emerging as important co-morbidities.  Identifying these patients and more importantly rational treatment using the growing psoriasis treatment armeratarium will become increasingly important.  Otezla has label warning of depression and weight loss and so heavier patients without depression (including those with nail/scalp disease, joint involvement etc) may be a target patient group.  Which treatment options may be most appropriate for patients with CV risk?  There are hints of reduced CV disease in the PSOLAR registry for Stelara but data corrected for baseline parameters are required.  Likewise the Cosentyx registry will be powered to detect reduced CV events.  Is systemic IL-17, TNFalpha or IL-12/23 implicated in CNS disorders?  These are all questions that need to be addressed as treatment options broaden

UpdatesPlus-Psoriasis - An expert analysis of recent events in Psoriasis

Our December issue of UpdatesPlus-Psoriasis is now available.  This 121 slide report analyzes information from over the last couple of months, incorporating EADV presentations.  Key topics are shown below. The executive summary can be found here.  For information on receiving the full report or to meet us at Gene to Clinic this week please contact leaddisc@leaddiscovery.co.uk  

Key topics from the December issue of UpdatesPlus-Psoriasis include

• Current marketed products with sales figures (inc psoriasis splits), life cycle management studies and commercial activity.  In particular we look at Jansen's efforts to capture the market through messaging of Stelara drug survival
• Biosimilar activity as Remsima is filed in the US
  
• Analysis of the next market entries, Cosentyx and Otezla, including a detailed look at regulatory decisions including the surprising first line recommendation by the CHMP for Cosentyx.  We also look at new post hoc analyses, plus the novel SensoReady autoinjector device developed for Cosentyx
• New data on ixekizumab and brodalumab.  This includes new Phase 2 post hoc analyses and the recently announced Phase 3 data.  We take a critical and in depth look at the latter.
  
• The IL-23 class.  We ask if these candidates really offer a paradigm shift in psoriasis treatment in the wake of some astonishing preliminary data on BI 655066
  
• New data on taclonex gel/suspension as Leo fights to grow this segment
• Pipeline entries including novel JAKs, H4 blockers, PI3K
  

As usual we offer fully up to date charts summarizing the psoriasis landscape and clinical trial activity