UpdatesPlus-Acne & Rosacea - launch of a new monitoring service for dermatology

Pharma Information & Reports is pleased to announce the launch of its UpdatesPlus-Acne & Rosacea service.  To receive this 36 slide report on current Acne & Rosacea R&D, as well as an up to date pipeline and clinical timeline please contact fiona.watts@leaddiscovery.co.uk

The inaugural issue includes

• The current status of the acne/rosacea pipeline and market as well as an overview of key trials
  
• Insight into Valeant's dermatology pipeline including filing plans for WC2055 (a next generation doxycycline calcium salt) and Phase 3 entry of WC3035 (sarecycline)
• An analysis of Galderma's data on the benefit of 40mg modified release doxycycline in acne.  Note that this is the sub-antimicrobial dose in Oracea used for rosacea.  The novelty of the acne data is that efficacy is superior to a higher dose of doxycyline currently employed in acne and with reduced AEs
• Phase 3 data for Galderma's Ivermectin (CD5024) in papulopustular rosacea
• New data on early stage acne products ASC-J9 (a first in class androgen modulator from AndroScience) and SB204 (an NO donor from Novan)
• Novel data from Galderma on the efficacy of adapalene gel against atrophic scarring. We speculate that Galderma could include scarring data in a future regulatory filing for late stage adapalene/BPO combination, potentially offering a competitive advantage
  
• SkinMedica's novel product aimed at treating post-inflammatory hyperpigmentation and erythema in acne patients
• Novel tretinoin delivery technology being developed by Phosphagenics allowing deeper topical penetration with reduced erythema and dryness
  

UpdatesPlus was set up nearly 15 years ago by R&D experts and has since developed into a well respected intelligence tool spanning the immunology and dermatology spectrum. We identify breaking research, clinical trial activity, drug development news and commercial events across multiple therapy areas including psoriasis, IBD, RA and many more.  What makes us really unique is our expert analysis of this information.  This analysis is packaged in monthly reports and ad hoc alerts.

We very rarely issue alerts on case reports but this study of tofacitinib deserves a mention...

This summary is taken from our UpdatesPlus-Psoriasis service - to see an example of our monthly report click here

• Craiglow & King have reported dramatic reversal of  alopecia universalis in a patient with co-morbid psoriasis following tofacitinib treatment
  
• Previous preclinical data has indicated a role for JAK in the development of alopecia universalis,  and its inhibition with tofacitinib.  This may result from the block of IL-15 signalling in the hair follicle
• The patient had reported a gradual development of alopecia areata into alopecia universalis
• Following 2mo treatament with tofacitinib (5mg bid) partial hair regrowth was observed. Dose escalation to 10mg produced full regrowth

Comments:  The response in this one patient is remarkable and demands further investigation.  Of note Pfizer is developing a topical formulation of tofacitinib and it would be of interest to evaluate this formulation as a risk reduction strategy.  It would also be of interest to investigate the efficacy of tofacitinib in patients without psoriasis.  The prevalence of alopecia universalis is approx. 0.1-0.2% and is associated with a higher frequency of other autoimmune diseases.  Treatments are limited

UpdatesPlus-Psoriasis alert - Xenoport advances fumaric acid candidate, XP23829 for psoriasis

This summary is taken from our UpdatesPlus-Psoriasis service - to see an example of our monthly report click here

• Despite early support, fumaric acid esters only became an established  psoriasis therapy in 1994 and then, primarily in Germany as Fumaderm
• XenoPort has been developing an advanced fumarate, XP23829.  This molecule links dimethyl fumarate to a carrier facilitating GI transport
• Phase 1 data reported in 2013 suggested improved PK and tolerability  vs tecfidera (dimethyl fumarate)
• XenoPort has now announced [link] the initiation of a Phase 2 12wk XP23829 study in psoriasis
• Top-line data from 200 patients are expected Q3, 2015
• XP23829 (400 or 800mg qd; or 400mg bid) will be compared to placebo

Comments:  Xenoport has suggested that XP23829 could move straight from the present study into Phase 3.  Successful development would further expand the available options for treatment of psoriasis with orally active products, with apremilast expected to soon receive approval for psoriasis

UpdatesPlus - EULAR - Long term data from ORAL START reports prolonged improvement in patient reported outcomes with Xeljanz

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• The FDA approved an sNDA in Nov 2013 resulting in the inclusion of patient-reported outcomes on the Xeljanz label
• This approval was based on improvements in SF-36 domains at 3 months
  
• Further data were reported at EULAR on 24month outcomes from ORAL Start, a Phase 3 study comparing Xeljanz to MTX in MTX-naive patients
• The SF-36 physical component score improved rapidly with tofacitinib at either dose.  Efficacy was significantly greater than with MTX, remained so for 2 years and was considerably greater than the minimal clinically important difference  
  
• Patient reported disability, pain and fatigue were also significantly improved, although improvement in the SF-36 Mental component score vs MTX was unclear
  

Comments:  The speed and durability of PRO improvement is remarkable.  Explaining the limited improvement in physical component score is difficult but we presume that this reflects variability

UpdatesPlus - EULAR 2014- Further data presented on atacicept from APRIL-SLE

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• Merck Serono's atacicept is an Fc-TACI  fusion protein that neutralizes BAFF and APRIL
• A  lupus nephritis study closed early due to reported cases of severe infection.  A second SLE study evaluating 75mg or 150mg atacicept (APRIL-SLE) continued at the lower dose and was presented at EULAR and ACR in 2013.  This study employed a loading dose regimen (qw over 4wks followed by q2w dosing for the remaining 48wks)
  
• Patients entered a screening period with at least one BILAG A/B score and were treated for flare with steroid.  Steroid dose was then tapered down over approx 10wks and patients who had improved to at least BILAG C/D were randomized to atacicept or control
  
• The primary end-point, (BILAG A/B flare over 52wks) was not met at 75mg (58% vs 54% in placebo arm); however patients receiving 150mg demonstrated a reduction (37%)
• New data presented at EULAR 2014 reported that flares were most often musculoskeletal and mucocutaneous  (lower left in inset)
  
• Data were also reported for SLEDAI flare (upper right) and steroid use (lower right).  SLEDAI flare was clearly reduced at both doses.  The number of patients requiring >20mg/d steroid was reduced by 150mg atacicept but not 75mg.  This was reflected in a reduction in the number of patients requiring an increase in steroid dose from baseline
  
• As previously reported, two fatal infections were reported in the 150mg arm prior to its discontinuation

Comments:  Merck has recently announced continued development of atacicept in SLE in the Phase 2b ADDRESS II study.  Differing from APRIL-SLE, the study has SRI as a primary endpoint rather than BILAG flare. This is important as SRI incorporates disease improvement (SELENA-SLEDAI) as well as no worsening (BILAG flare).  It is unclear what safeguards are in place to mitigate risk of fatal infection reported in earlier studies. We note that ADDRESS II does not have a loading period and this is likely to have some impact. Likewise reduced exposure from 52 to 24wks may also reduce risk

UpdatesPlus- EULAR 2014 - UCB reports durable and predictable response of PsA patients to Cimzia

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• UCB presented new 96wk Cimzia data from RAPID-PsA
• 77% of patients initially randomized to the double blinded phase remained in the study to week 96
• Data presented at EULAR was specifically for those patients randomized to 200mg or 400mg Cimzia (q2w) at baseline
• When reported using an NRI analysis ACR20 rates were 56%/66%/59% at 24/48/96wks demonstrating that efficacy observed at 24wks was sustained over 2yrs, extending previously reported 48wk data 
• Importantly, efficacy was maintained in patients with or without prior TNFi treatment
• In addition to sustaining ACR rates, enthesitis, dactylitis, HAQ-DI and PASI-75/90 responses were also stable over the 96wks
• Safety signals were consistent with previous reports over shorter duration
• Moreover, as reported in a EULAR poster, disease activity during the initial 12wks of treatment may predict long term outcomes

Comments:  Across indications,  UCB has previous focused Cimzia messaging on fast onset of action and predictability.  Predictability is further reinforced here and may offer a powerful message both in terms of cost effectiveness and patient benefit.  Durability of action represents another message that can help UCB develop its positioning further.  Moreover the lack of influence that prior TNFi exposure has on response may be important, positioning Cimzia as a treatment of choice following failure on one of the other TNFis

UpdatesPlus - EULAR 2014 - MTX reportedly increases Humira drug survival in AS

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contactfiona.watts@leaddiscovery.co.uk 

• Approximately 40% AS patients fail to respond to TNFis and the development of  anti-drug antibodies is a risk-factors for treatment failure, particularly in patients treated with Humira
• The CONCERTO study has recently reported that MTX up to 10mg increased Humira serum concentrations and reduced antidrug antibodies
• Current guidelines do not recommend the use of MTX alongside biologics in the treatment of AS
• Taiwanese researchers reported on the survival of Enbrel or Humira treatment using AS data sampled from national insurance records
• The analysis reported that concomitant MTX had no significant effect on Enbrel survival but produced a large increase in Humira retention.  Stratification of the Humira data reported that doses below 10mg/wk were superior to higher doses
  

Comments:  The benefit of concomitant MTX use in Humira treated patients is as expected and consistent with the RA literature.  The MTX dose response is similar and we presume that patients receiving greater than 10mg MTX may have discontinued MTX due to AEs, in turn reducing Humira survival.  Lower doses of MTX are generally used in Asian patients and further study of MTX benefit would be required in a Caucasian cohort

UpdatesPlus- EULAR - Early data suggests c-Kit as a potential target for the treatment of peripheral SpA

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• A small body of data has provided proof of concept for targeting c-Kit inhibition for the treatment of rheumatoid disease
• Two approved molecules from this class include Imatinib (Gleevec) and its more selective successor  Nilotinib (Tasigna).  Both are indicated for the treatment of hematological cancers and in the case of imatinib, gastrointestinal stromal cell tumors
• An early pilot study of 6 SpA patients reported efficacy with imatinib.  A subsequent study suggested that in RA imatinib inhibits mast cell c-Kit tyrosine kinase resulting in apoptosis.  In the CIA model of RA, imatinib was shown to suppress and prevent disease.  Most recently it has been reported that c-Kit-positive mast cells are present in higher numbers in the synovium of SpA vs RA patients.  These cells expressed high levels of IL-17
• With this background data presented for nilotinib at EULAR are of significant interest
• 30 patients with SpA were randomized to nilotinib (at the current approved dose of 400mg bid) or placebo.  After 12wks treatment placebo patients were switched to nilotinib
• Patients with peripheral SpA (n=8) demonstrated a reduction in markers of inflammation, notably MMP-3 in patients with baseline elevation.  This was reflected in a dramatic reduction in patient's global assessment as well as a reduction in physician's global assessment and swollen joint count.  Efficacy was not observed in patients with axial disease (n=17)
  

Comments:  These data are of high interest but must be treated with caution given the small study size. Further we are trying to gain further information on patient type (eg whether patients had psoriatic involvement). In addition the difference in patient and physician global assessment requires greater understanding.  If data can be replicated in a larger study this would support the development of c-Kit inhibitors.  Of note the authors suggest that c-Kit inhibition results in reduced IL-17 release.  Development of nilotinib by Novartis for SpA could offer a franchise building opportunity given current development of secukinumab.  Equally, other companies with c-Kit assets may wish to develop them for SpA.  Finally it is of note that MMP-3 levels were particularly high in some patients with peripheral SpA. MMP-3 has been reported as an early biomarker of peripheral SpA; it will be interesting to determine if high MMP-3 levels could also be a companion biomarker for c-Kit inhibitor use

UpdatesPlus - EULAR - Integrated safety analysis from Xeljanz treated RA patients suggests that serious AE rate does not increase with time

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• In our previous alert we reported on long-term PRO data for Xeljanz from ORAL Start.  A second oral presentation at EULAR on Pfizer's JAK inhibitor described  an integrated safety analysis from cumulative exposure of 12,664 patient-years
• Data were derived from 5671 patients in Phase 2 and 3 RA studies as well as OLEs.  555 patients received treatment for at least 3yrs
• Rates of serious infection were constant over time (overall rate of 2.93/100 pt yrs) with the most frequent pathogens being herpes zoster, UTIs and TB.  TB events were predominantly in regions of high prevalence
• 107 malignancies were reported (excl NMSC) with a stable rate (overall 0.85/100 pt yrs)
• MACE events were reported with an overall rate of 0.46/100 pt yrs.  Rates, when stratified into 6m periods was remarkably variable
  

Comments:  During the Q&A session it was remarked that some AEs may be expected to increase with treatment exposure with the example of serious infection given.  This was not observed.  Conversely an increase in MACE events may be expected due to background aging and against a relatively high risk seen with RA patients.  This was not the case and indeed a trend towards reduced events after 2 years is apparent.  Whether this trend is significant remains to be determined and if so better understood.  One possibility is that the dataset was enriched for healthier patients with time - far more interesting is the possibility that prolonged treatment and reduced inflammatory load reduced CV  risk.  With this in mind adjusting the data for baseline characteristics and stratifying for disease activity may be of use, especially as data continue to accumulate

UpdatesPlus - EULAR - PRIZE data suggests Enbrel dose reduction may be feasible in patients with early RA who achieve rapid remission with Enbrel/MTX

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• In a previous EULAR alert we highlighted data from early RA study, AVERT
  
• In this study an MTX/Orencia combo produced DAS28 CRP remission at 12mo in 61% patients.  Remission was subsequently lost over 6 months following withdrawal of all RA drugs in 85% of these patients
• Data from PRIZE, a second early RA study were also reported last week at EULAR
  
• The study was designed to investigate tapered withdrawal of treatment from patients achieving remission with Enbrel/MTX in an initial open label period (study design is shown bleow left)
  
• Patients who were DAS28-ESR responders (39wks) and remitters (52wks) were then randomized to reduced dose (25mg qw) Enbrel/MTX, MTX alone or drug withdrawal.  All treatment was withdrawn from patients with continued remission at 91wks
  
• Previously reported data include:
• 65% of patients were in remission after 52wks (ACR 2012)
• 64% patients in remission at 52wks remained in remission
• Data were reported on Thursday on predictors of sustained remission.  Of interest there were no baseline predictors however delayed DAS28 remission during the initial period of treatment was a significant predictor of reduced sustained remission.  Indeed 80% patients who achieved remission within 6mo achieved sustained remission after being switched to low dose Enbrel plus MTX

Comments:  The present data suggests that reducing Enbrel dose may offer a realistic approach  to those patients who enter remission early with full dose Enbrel.  This could introduce a significant cost saving.  Further data from the third phase of PRIZE, during which treatment is withdrawn altogether is awaited.  These data will be interesting given that most patients in AVERT for whom treatment was withdrawn from patients in remission relapsed.  In the Q&A following the AVERT presentation it was suggested that less sudden drug withdrawal may be required to maintain remission.  PRIZE may support this concept should reduced Enbrel dosing as a stepping stone to withdrawal is successful

UpdatesPlus - EULAR - 24wk data reported for JAK inhibitor, VX-509 reported in MTX-IR RA patients

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• VX-509 is a selective JAK3 inhibitor developed by Vertex with 25- to 150-fold selectivity vs other JAK isotypes
• The company has publicly commented that it is focusing on its cystic fibrosis activities, waiting for a partner to further develop VX-509
• Phase 2b data were first presented at ACR with ACR20 reach 70% at 12wks with acceptable DAS28-CRP remission (29%). Safety appears quite good in general although triglyceride levels were elevated considerably (30-40mg/dL)
• Vertex subsequently presented 24wk data in a Jan 2014 press release
• These 24wk data were expanded upon at EULAR.  Of note lower doses appeared to accumulate further efficacy between weeks 12 and 24
• AEs were similar although 2 further serious infections accrued in the 150mg dose.  More dramatic increases in moderate lymphopenia and ALT elevation were observed.  Of concern moderate lymphopenia was observed at a similar rate across the dose range
  

Comments:  Vertex has also completed a biomarker study and an open label extension study is now closed for enrollment (presumably from the biomarker and Phase 2b studies).  We understand that further studies will not be initiated until a partner is identified or Vertex dedicates internal resources 

UpdatesPlus - EULAR - Astellas reports for the first time Phase 2b data for JAK inhibitor, ASP015K

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• Astellas is developing a JAK inhibitor, ASP015K (IC50 for JAK1/JAK2/JAK3Tyk2 3.9/5.0/0.7/4.8nM)
  
• We announced in our Jan 2014 issue of UdatesPlus that two Phase 2b studies (monotherapy and MTX add-on) had completed enrollment 6 months earlier than initially expected
• A further Japanese monotherapy study completed late 2013 and was reported at EULAR
• Patients were washed out of DMARDS at least 4wks prior to randomization; 25% were TNFi experienced
• ACR20 rates improved in a dose dependent fashion at 12wks; DAS28-CRP and HAQ-DI values were also improved (-1.80 vs -0.11; 0.16 vs -0.23 at 150mg qd)
• AEs were typical of JAK inhibition
  

Comment: Astellas has previously out-licensed ASP015K to Janssen who recently opened a Phase 2 study in IBD

UpdatesPlus - EULAR 2014 - Further positive Phase 3 data were reported yesterday for Sanofi/Regeneron's sarilumab

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• Sarilumab is, like (Ro)actermra an IL-6R mAb.  Sarilumab is differentiated in that it is fully human leading some to expect improved AEs/reduced AADs
• Sarilumab has been investigated in the Phase 3 SARIL-RA-MOBILITY study in rheumatoid arthritis
  
• MTX-IR patients were randomized to sarilumab (150 or 200mg) or placebo all at q2w sc administration in combination with MTX
• Sanofi/Regeneron reported in 2013 that the 3 co-primary end points, ACR20 (24wks); HAQ-DI (16wks) and mTSS (52wks) had been met.  Our analysis from UpdatesPlus, Dec 2013 is shown below, reporting Sarilumab data at 200mg q2w from SARIL-RA-MOBILITY alongside Brevacta data (with placebo data reported in parentheses)
  

• New data presented at EULAR on Thursday included improvement in major clinical response (ACR70 for >24wks) from 3% to 15% (ACR70 kinetic curves are shown below left).  Durable ACR20 rates were also reported with efficacy maintained to 52wks (below right)
  

• Further data were reported in a poster on Thursday, describing that Sarilumab reduced levels of type1 collagen breakdown products (C1M, C2M and C3M).  This effect was rapid and seen within 2wks
  

Comments:  SARIL-RA-MOBILITY is the first of 5 Sarilumab Phase 3 studies to read out.  Sanofi has previously indicated a filing date of mid 2015.  The durable response along with major clinical response in some patients is promising, as is the reduction in radiographic progression.  The biomarker study is particularly interesting in this context as these molecules are produced upon joint destruction.  Nordic Bioscience is developing an assay to measure C1M/C2M/C3M and we understand that the ability of this assay to predict joint structure outcome is being evaluated in Phase 3 sarilumab studies. Should predictability be established, we believe that this would confer a significant advantage on Sarilumab in terms of cost effectiveness and the ability to help ensure appropriate treatments are delivered to the patients ahead of those less likely to be effective

UpdatesPlus- EULAR 2014 - Achieving new PsA "minimal disease activity"target with Simponi is associated with considerable improvement in disability and joint progression

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• Simponi approval for SpA was supported by GO-REVEAL.  This study compared 50mg or 100mg to placebo
  
• The co-primary endpoints were ACR20 at 14wks and radiographic progression at 24wks.  Thereafter, patients in the placebo arm were allowed to cross over Simponi (50mg)
  
• 5yr data were published May 2014 reporting good patient retention (66%) and durable efficacy ACR20 (primary endpoint measure was 63-70% at 5yrs (data are imputed)
• PASI 75 rates were 60-70%
• Further data reported this morning described the impact of persistent minimal disease activity (MDA) on outcomes.  The definition of MDA has recently been reported
  
• 50% patients achieved MDA (albeit after approximately 3 years).  Patients achieving MDA displayed much improved disability score (HAQ data - top left panel in the figure below), and improved radiographic progression (top right).  Joint structure improvement was optimized with the inclusion of MTX
  
• Achieving MDA confered minimal benefit on PASI score
  

Comments:  This study not only adds further weight to the potential benefits of Simponi but it also offers a validation of the recently agreed MDA definition.  The benefit in terms of joint improvement achieved with MDA supports the use of this target as a treatment goal

UpdatesPlus - EULAR - AVERT data reported - Orencia (abatacept)/MTX demonstrates efficacy in early rheumatoid arthritis

The alert below is from our EULAR 2014 coverage.  We have captured most of the key oral and poster presentations delivered at EULAR and will be analyzing these more comprehensively in upcoming issues of our UpdatesPlus service.  UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the immunology & Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• AVERT was presented last week by Emery
  
• This 351 patients study enrolled patients with early RA (2yrs, anti-ccp, das28 at least 3.2)
  
• Patients were naive to biologics and MTX
• Patients were randomized to receive MTX, Orencia (abatacept; 125mg qw) or a combination of the two treatments
• Baseline characteristics were presented and of note disease activity was particularly high at baseline
• As mentioned in our alert from yesterday, DAS28 CRP remission at 12mo was improved from 45% with MTX alone to 61% with an MTX/Orencia combo
• As shown below, remission was lost over 6 months following the withdrawal of all RA drug therapies (co-primary endpoint) although more patients previously receiving Orencia/MTX remained in remission than those receiving MTX alone (15% vs 8% with MTX alone)
• From the figure below we suggest that the duration over which 50% patients lost remission was approximately 10wks [note that this is our analysis]
• Emery reported that maintained remission was associated with lower baseline DAS28 (CRP); lower HAQ-DI; shorter symptom duration and faster remission

Comments:  We have previously suggested that it would be important to better understand the time to loss of response and biomarkers/baseline characteristics that predict this loss of response.  Both questions were addressed in today's presentation.  We suggest that while some patients with high baseline disease activity may require prolonged biologic treatment, other could be controlled by initial treatment per label but then maintained with reduced treatment frequency.  This would have obvious benefits of reduced cost and improved convenience/safety

Takeda launches Entyvio (vedolizumab) in the US for IBD; Roche opens new Phase 3 etrolizumab study

• Following May 20th approval by the FDA for UC and CD, Takeda has now launched Entyvio in the US [link]
• Like Entyvio, Roche's etrolizumab blocks α4β7, but additional blockade of αEβ7 may produce further immunoregulation and greater efficacy
• A Phase 3 UC program opened in April including a head to head vs infliximab in TNFi naïve patients and a placebo controlled study in experienced or intolerant patients [link]
• Roche has now announced a further Phase 3 study, again in naives but comparing  etrolizumab to adalimumab
• The 350 patient study is investigating induction, with the primary endpoint efficacy vs placebo.  Efficacy compared to adalimumab is a secondary endpoint.  Both endpoints are at 10wks, similar to the previously reported naive study
  
• The study is expected to open Sept 2014, closing Sept 2017 potentially advancing filing as the previously reported studies are due to read out Q4 2018 and Q3 2019 (naives; vs infliximab)

This alert is from Pharma Information & Report's UpdatesPlus service

Comment:  Based on Roche's dates, we estimate a projected recruitment time of approximately 33mo.  This is longer than the 24mo taken to recruit GEMINI I which included more than double the number of patients (inc 689 TNFi naives).  It is unsure whether this duration is conservative and set to shorten; whether Roche believes recruitment will be slower with the added competition of Entyvio or whether it is simply investing less resources in expediting the study.  On a separate note, Roche has indicated Phase 3 CD studies will open but information has yet to be provided

Ahead of tomorrow's oral presentation at EULAR, BMS has announced data from AVERT, its Phase 3b study of Orencia (abatacept)/MTX in early RA

Ahead of tomorrow's oral presentation at EULAR, BMS has announced data from AVERT, its Phase 3b study of Orencia (abatacept)/MTX in early RA [link]

• 351 patients with RA for 2yrs, anti-ccp positive and DAS28 CRP>3.2 were randomized to receive MTX, Orencia (abatacept; 125mg qw) or a combination of the two treatments
  
• Patients were naive to biologics and MTX
• DAS28 CRP remission at 12mo was improved from 45% with MTX alone to 61% with an MTX/Orencia combo
• MRI reported progression (synovitis, osteitis and joint erosion) was also improved with the combination therapy
  
• Maintenance of remission over 6mo following the withdrawal of all RA drug therapies (co-primary endpoint) was also higher in patients previously receiving Orencia/MTX (15% vs 8% with MTX alone)
  

Comments:  Further details will be reported on tomorrow however a number of questions spring to mind.  In particular, what is the mean time to loss of response and are there any biomarkers/baseline characteristics that predict loss of response?  In particular if remission is maintained for a period that is considerably longer than 1wk, maintenance with less frequent Orencia (including the possibility of biomarker tailored injection frequency) may offer potential for future study 

This content is part of UpdatesPlus' coverage of EULAR.  UpdatesPlus provides expert analysis of scientific, clinical, regulatory and commercial information across a range of inflammation therapy areas.  In addition to ad hoc alerts we package all analysis into a monthly PDF.  For details or to register please contact fiona.watts@leaddiscovery.co.uk

UpdatesPlus Alert - Live from EULAR 2014 - 14 Oral presentations to see tomorrow June 12th

As part of our EULAR coverage we have selected out a number of what we consider to be particularly interesting oral presentations relevant to the UpdatesPlus portfolio (for EULAR this includes RA; Lupus; Gout and PsA/AS).  

The presentations to be covered are indicated below.  We intend to cover these presentations and follow up later with full analysis of the data presented.  We will of course be covering posters as well.  Please feel free to pass this information on to your colleagues and if they wish to be placed on our mailing list please contact fiona.watts@leaddiscovery.co.uk 

Rheumatoid Arthritis

• ·     INDUCTION OF CLINICAL REMISSION FOLLOWED BY DRUG-FREE WITHDRAWAL WITH ABATACEPT COMBINATION AND MONOTHERAPY IN EARLY RA: RESULTS FROM THE AVERT STUDY OVER 18 MONTHS
• ·     ITOLIZUMAB, A HUMAN ANTI-CD6 MONOCLONAL ANTIBODY, FOR TREATMENT OF RHEUMATOID ARTHRITIS: RESULTS OF A RANDOMIZED, PLACEBO CONTROLLED, PHASE 2 STUDY
• ·     EFFECTS OF SARILUMAB PLUS MTX ON CLINICAL, RADIOGRAPHIC, AND FUNCTIONAL ENDPOINTS IN PATIENTS WITH MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS: RESULTS OF A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, INTERNATIONAL STUDY
• ·     MRI RESULTS FROM THE AVERT STUDY: A RANDOMIZED, ACTIVE-CONTROLLED TRIAL TO EVALUATE INDUCTION OF REMISSION AND MAINTENANCE OF DRUG-FREE REMISSION USING ABATACEPT IN COMBINATION WITH METHOTREXATE OR AS MONOTHERAPY IN PATIENTS WITH EARLY RA
• ·     IDENTIFICATION OF GENETIC VARIANTS ASSOCIATED WITH RESPONSE TO METHOTREXATE IN PATIENTS WITH EARLY RHEUMATOID ARTHRITIS: RESULTS FROM THE OPTIMA STUDY
• ·     WHEN DOES THE THERAPEUTIC WINDOW OF OPPORTUNITY IN RHEUMATOID ARTHRITIS CLOSE? A STUDY IN TWO EARLY RA COHORTS.
• ·     EARLY RESPONSE TO ETANERCEPT-METHOTREXATE INDUCTION THERAPY PREDICTS SUSTAINED REMISSION WITH REDUCED-DOSE COMBINATION REGIMEN IN THE PRIZE STUDY

 Lupus

• ·     EFFECTS OF ATACICEPT ON DISEASE ACTIVITY IN PATIENTS WITH MODERATE TO SEVERE SYSTEMIC LUPUS ERYTHEMATOSUS: APRIL-SLE RANDOMIZED TRIAL
• ·    A PHASE 2, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PROOF-OF-CONCEPT STUDY TO EVALUATE THE EFFICACY AND SAFETY OF SIRUKUMAB IN PATIENTS WITH ACTIVE LUPUS NEPHRITIS
• ·     OUTCOMES IN SYSTEMIC LUPUS ERYTHEMATOUS (SLE) PATIENTS TREATED WITH BELIMUMAB IN CLINICAL PRACTICE SETTINGS: RESULTS FROM THE OBSERVE STUDY IN GERMANY

 Psoriatic Arthritis

• ·     LONG-TERM SAFETY AND EFFICACY OF CERTOLIZUMAB PEGOL IN PATIENTS WITH PSORIATIC ARTHRITIS WITH AND WITHOUT PRIOR ANTI-TUMOR NECROSIS FACTOR EXPOSURE: 96-WEEK OUTCOMES FROM THE RAPID-PSA TRIAL
• ·    APREMILAST, AN ORAL PHOSPHODIESTERASE 4 INHIBITOR, IS ASSOCIATED WITH LONG-TERM (52-WEEK) IMPROVEMENT IN MEASURES OF DISEASE ACTIVITY IN PATIENTS WITH PSORIATIC ARTHRITIS: RESULTS FROM 3 PHASE 3, RANDOMIZED, CONTROLLED TRIALS
• ·     USTEKINUMAB IS EFFECTIVE IN INHIBITING RADIOGRAPHIC PROGRESSION IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS: INTEGRATED DATA ANALYSIS OF TWO PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED STUDIES
• ·     IMPACT OF PERSISTENT MINIMAL DISEASE ACTIVITY ON LONG-TERM OUTCOMES IN PSORIATIC ARTHRITIS: RESULTS FROM 5 YEARS OF THE LONG TERM EXTENSION OF A RANDOMIZED, PLACEBO-CONTROLLED, STUDY