Fourth Phase 3 study reports out for Lilly/Incyte's JAK1/2 inhibitor, baricitinib - RA-BEAM demonstrates superiority over Humira in biologic naive rheumatoid arthritis

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• Lilly has been reading out on its Phase 3 baricitinib program over the past year in preparation for filing expected towards the end of 2015
  
• RA-BEACON (bDMARD-IR) and RA-BUILD (cDMARD-IR) were reported in Q4 2014 and Q1 2015.  More recently, RA-BEGIN demonstrated non-inferiority of baricitinib vs MTX both as monotherapy, mostly in DMARD naïve patients (conventional and biologic)
• A fourth study, RA-BEAM (H2H vs Humira) has now read out.  This study compared baricitinib to placebo or Humira in biologic naive patients
  
• The study met its primary endpoint with ACR20 at 12wk superior to that of placebo.  Radiographic progression at 24wks was also reduced
• Superiority was also demonstrated over Humira (secondary endpoints) on ACR20 and DAS28-hsCRP measures at 24wks.  Superiority was reportedly maintained through 52wk
• Lilly's press release comments that "RA-BEAM is the first study to demonstrate that a once-daily oral treatment was superior in improving signs and symptoms of rheumatoid arthritis compared to the current injectable standard of care".  This refers to the QD dosing regimen for baricitinib vs BID dosing for Xeljanz.  Of note, a modified release QD formulation of the later is currently under regulatory review
• Limited safety data was reported - one case of TB infection was reported each with baricitinib and Humira.  Infection rates were higher for baricitinib and Humira vs placebo although differences between the active groups were not reported
• Lilly suggests RA-BEGIN but not RA-BEAM will be reported at ACR in November
  

Comments:  The topline efficacy reported for RA-BEGIN (DMARD naive) a few weeks ago was important securing a possible first line systemic approach for baricitinib.  Although the degree of efficacy has yet to be reported we expect it to be considerable given that efficacy in RA-BUILD (cDMARD experienced) was impressive and paralleled that reported in similar studies of Xeljanz.  Given the likely cost of baricitinib and limited safety data expected at launch, RA-BUILD is possibly more important than RA-BEGIN, establishing baricitinib as a pre-biologic option between cDMARD and bDMARD.  In exception RA-BEGIN may support early use in patients unwilling or unable to receive MTX.  Today's RA-BEAM data reinforces RA-BUILD, not only supporting pre-biologic use but suggesting baricitinib use instead of Humira after the failure of a cDMARD.  This now given the rheumatologist further interesting  decisions - not only is there a choice between IL-6 blockade through (Ro)Actemra or TNFi, there is also the choice between a JAKi and a biologic.  Data are available to guide most decision points in this increasingly complex treatment paradigm, which is good for the patient.  Further data would however be useful to help guide the future decision between post-cDMARD baricitinib and (Ro)actemra or Enbrel.  In reality with Xeljanz already available as a JAKi, we would expect baricitinib to be reserved at first as a post-biologic option supported by RA-BEACON unless RA-BEAM reveals extraordinarily impressive benefits over Humira

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

Invion's INV102 demonstrates modest increase in smoking cessation but significant potential for harm reduction - opportunities to improve quit rate through biomarker guided Phase 3 selection

From UpdatesPlus Addictive Disorders - your source for intelligence from the smoking cessation and drug addiction research and development arena - to receive our monthly report please contact leaddisc@leaddiscovery.co.uk

• Invion has reported that INV102 increases the rate of smoking cessation from 11% to 19% over 10-12wks
  
• 155 smokers with chronic cough who had previously attempted to quit but relapsed due to their cough were randomized to INV102 or placebo
• The proportion of patients benefiting from a >70% reduction in cigarettes smoked was nearly doubled from 36% to 61%
• INV102 also reduced sputum MUC5AC and ERK1, epithelial biomarkers of mucous metaplasia (ie abnormal build up of mucous).  Chronic cough is thought to be due to mucous secretion
• Further data analysis will attempt to correlate biomarker and smoking cessation data.  This will be used to strengthen Invion's IP position and also guide Phase 3 patient inclusion
• An End of Phase 2 meeting with the FDA has been requested for early 2016 to discuss Phase 3 development.
• INV102 is thought to inhibit the beta arrestin pathway, mucous metaplasia and hence mucus production.  This contributes to "smokers cough" which is a common cause of relapse to smoking

Comments: INV102 is an inverse beta adrenoceptor agonist which is already marketed as Corgard (nadolol) for CV indications.  Nguyen et al (2008) previously reported that nadolol reduces airway inflammation supporting a possible role in asthma and COPD, future indications for INV102.  Despite the relatively poor efficacy in terms of smoking cessation (eg Chantix/Champix supports abstinence rates of 42% in COPD patients [Tashkin]), we find the present study of considerable interest for multiple reasons.  1.  The identification of biomarker reduction offers opportunities to amplify efficacy.  The fact that this may also improve the IP position is an added bonus; 2. The present study did not include the adjunctive use of current smoking cessation products.  Since INV102 has a completely different MOA to current NRTs, the combination of nicotine replacement and INV102 could produce much higher quit rates; 3. The study enrolled patients with chronic cough including those with COPD.  This group is at increased risk of smoking related acceleration of smoking related disease, moreover they are also associated with reduced smoking abstinence using NRT; 4. The rate of smoking reduction appears dramatic (perhaps disproportionately so given the low quit rate).  This may offer significant harm reduction opportunities and hence opportunities for approval especially in the EU; 5. Opportunities for harm reduction may be further enhanced given that nadolol is an anti-hypertensive which may be of CV benefit in long-term smokers.  Moreover there is evidence that ERK1 blockade may both prevent the development of lung cancer and also increase sensitivity to chemotherapies in diagnosed cancers, with the former further offering opportunities for harm reduction.  Invion will be developing INV102 as a treatment of COPD. The possibility of reducing signs and symptoms of COPD alongside reduced smoking, the cause of COPD is highly attractive

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.