FDA approves Cosentyx for the treatment of ankylosing spondylitis and psoriatic arthritis

Analysis from UpdatesPlus-Spondyloarthropathy - Industry's source for market intelligence and monitoring

• We reported in November that the EMA had approved Cosentyx for the treatment of psoriatic arthritis and ankylosing spondylitis.  This coincided with impressive data reported at ACR
• In particular, for ankylosing spondylitis Cosentyx efficacy in MEASURE 2 (dosing with the approved sc induction regimen) was maintained for 52wks and was associated with long term prevention of radiographic progression in MEASURE 1.  An observation that the presenters differentiated from a lack of TNFi effect
  
• For psoriatic arthritis notable data included long term benefit including 104wk data from FUTURE 1 (iv induction) and 52wk data for FUTURE 2 (approved sc induction).  Cosentyx demonstrated efficacy in FUTURE 2 irrespective of TNF treatment history or MTX background, although 300mg produced an improved effect (vs 150mg) in TNF-IRs or those patients with skin involvement.  The involvement of IL-17 in enthesitis, and the importance of enthesitis in psoriatic arthritis were stand out messages at ACR and Cosentyx produced a considerable improvement in this measure
• The Cosentyx SPC was since updated.  Importantly Cosentyx is specifically approved with or without MTX for psoriatic arthritis in DMARD-IRs without specifying conventional or biologic DMARD.  This opens the way for possible first line biologic use.  300mg Cosentyx is indicated in TNF-IRs and those with moderate to severe plaque psoriasis, but 150mg is indicated in others.  This reflects FUTURE 2 and importantly could offer a  cost benefit for pre-TNFi use.  Of note the label included a considerable amount of data on enthesitis.  For ankylosing spondylitis, the indicated dose is 150mg for all with no guidance offered on line of treatment or MTX background.  Radiographic data were not included, possibly because 104wk data reporting progression were not available at the time of filing
• The FDA has now reportedly approved Cosentyx for the treatment of both ankylosing spondylitis and psoriatic arthritis.  Further detail are yet to be disclosed

US Patent office rejects Amgen's petition against Humira formulation patents potentially delaying market entry of ABP 501

• One strategy through which companies have been attempting to gain biosimilar market entry utilizes IPR (Inter Partes Review) Petitions
  
• IPRs offers a legal strategy whereby a biosimilar developer can test the validity of innovator patents prior to filing
  
• This strategy is increasingly being adopted.  Amgen filed IPR petitions in Jun 2015 against Humira US formulation patents: 8,916,157 and 8,916,158
• Coherus subsequently filed IPR Petitions against AbbVie patents claiming 40mg q2w dosing for rheumatoid arthritis (8,889,135, 9,017,680, 9,073,987).  Boehringer Ingelheim also attacked this dosing strategy, petitioning 8,889,135 in Dec 2015
• A legal decision on the Coherus petition is expected mid-2016, however in the meantime Amgen’s initial petitions have now been rejected by the patent office

Comments:  Amgen filed ABP 501, its biosimilar adalimumab, in the US on Nov 25th.  This is believed to be the first adalimumab biosimilar filed in the US.  Abbvie has previously commented that one of its biosimilar defense strategies will include patent defense, including a broad estate of relatively recent, method of use, dosing and formulation patents.  The patents that Amgen petitioned were two of these formulation patents and by rejecting the company's IPRs the Patent Office has maintained one barrier to Amgen finding a way through Abbvie's IP estate.  Claims in the two patents are of interest.  In particular, we understand that these patents claim formulations which support a longer shelf life, stability if frozen, an absence of citric acid and the possibility of neutral pH.  These properties are distinct from the Humira formulation currently available in the US and if the Patent Office had decided the claims were indeed unpatentable, Amgen would not only have been offered a route to early market entry, they may also been offered a competitive advantage over Humira.  In this respect Abbvie has developed a new formulation Humira.  This has recently been approved in the US and EU and is characterized by low volume/high concentration and also reduced injection site pain (due to the lack of citric acid).  This new formulation appears to have different characteristics to those claimed in the patents petitioned by Amgen and may represent a next level of Abbvie's defense if Amgen (or others) launch a biosimilar adalimumab.  For the moment however Amgen will have to develop new strategies, one of which is contesting the patents through the court system.  This however will take a number of years

UpdatesPlus Alert: GSK announces positive topline data from Phase 3 sirukumab program

Source:  UpdatesPlus-Rheumatoid Arthritis - for a full and in depth analysis of all key developments in rheumatoid arthritis R&D contact jon.goldhill@leaddiscovery.co.uk

• Sirukumab is a human anti-IL-6 mAb being developed by J&J and GSK.  This is differentiated from (Ro)Actemra and more recently sarilumab which target the IL-6 receptor
  
• A 2 part Phase 2 MTX-IR study of sirukumab opened in 2008.  Part A evaluated q2w sirukumab (100mg sc).  Part B subsequently evaluated q2w (100mg) or q4w dosing (25, 50 or 100mg)
• Data presented at ACR 2011 reported high efficacy (see below) with 100mg q2w producing an ACR50 response of 27% vs 3% with placebo.  Continued treatment with sirukumab increased ACR50 rates further to 60% by 24wks (note that placebo treated patients switched to sirukumab at 12wks preventing placebo correction; the uncorrected rates in corresponding (Ro)Actemra studies were however 30-45%).  It has previously been commented that the high efficacy of sirukumab may reflect the lower expression of ligand vs receptor and/or the high affinity of sirukumab
• Sirukumab entered Phase 3 in 2012.  The program comprises a DMARD-IR and TNFi-IR study (see below).  A head to head comparison with Humira has also been conducted.  Although the
  DMARD-IR study is showing on clinicaltrials.gov as reaching its primary endpoint time frame in 2016, the study stopped enrolling in Oct 2014 with primary endpoints at 16wk for ACR 20 and 52wk for radiographic progression
• GSK has today announced that it has received positive top-line results from the Phase 3 program.  There were reportedly no unexpected safety findings and filing is anticipated for 2016

Comments:  We note that GSK did not specify in its press release that positive data had been received from all of the Phase 3 studies; simply the Phase 3 program.  We have no reason to suspect that any of the three pivotal studies produced negative data although it is possible that 52wk radiographic data have yet to be analyzed from SIRROUND-D.  Also of note, GSK failed to give any any idea of efficacy.  Further data may not become available until EULAR (June 2016) by which time we expect filing to have taken place

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.