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


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• 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