Gout - breaking research and drug development

Our most Aug issue of UpdatesPlus - Gout is now available. To receive further information or instruction on how to access the service including our Dec 2013 backgrounder please contact fiona.watts@leaddiscovery.co.uk 

Gout is a highly prevalent condition - recent US figures suggest that gout prevalence has grown 7-fold in the past 50yr to 8.1mn in 2009. The disease is caused by elevated serum uric acid, usually due to its reduced excretion and presents as recurrent inflammatory arthritis with joint destruction, pain and reduced mobility. Symptoms are especially severe in patients with tophi (nodular collections of monosodium urate crystals). Kidney stones are also evident. Gout is, like many chronic inflammatory conditions associated with serious co-morbidities including cardiovascular disease 

Given the seriousness of gout we are always surprised with the limited therapeutic options and also the size of the drug development pipeline, especially given the commercial opportunities for developing companies 

For the above reasons we produced a report at the end of 2013 to present the gout drug development landscape to help companies and physicians understand the gout treat and development landscape. This has now turned into a monthly report within our Updates plus portfolio

This month we analyze: 

• Updated EULAR recommendations on gout treatment which were presented at EULAR 2014 
• A new patient reported outcomes tool evaluating the impact of tophi on QoL
• Takeda's new Phase 2 study of extended release febuxostat as the company prepares for generic incursion towards the end of the decade
• A Menarini sponsored Phase 4 safety study of febuxostat cardiovascular safety 
• Long term data Ilaris data 
• AstraZeneca's development of  Lesinurad 
• Pfizer's new pipeline candidate, PF-06743649   
• Selecta's in-licensing of pegsiticase from 3SBio and the company's development plans     

In addition to this recent news we also present a fully up to date gout landscape and clinical trial landscape

This alert comes from our UpdatesPlus - Gout service, a regular analysis providing depth information on all key recent events in the area. To receive further information or instruction on how to access the service including our Dec 2013 backgrounder please contact fiona.watts@leaddiscovery.co.uk

UpdatesPlus Heart Failure - Amgen on track to potentially launch Ivabradine for chronic heart failure in the US mid-2015

This alert comes from our UpdatesPlus - Heart Failure service, a regular analysis providing depth information on all key recent events in the area.  To receive further information or instruction on how to access the service please contact fiona.watts@leaddiscovery.co.uk

• Ivabradine (Procoralan) approval was granted to Servier by the EMA in 2005, however outside of the EU, ivabradine has yet to gain FDA approval

• Servier licensed US rights to Amgen in July 2013.  Amgen has previously commented that NDA filing is targeted for 2014, and that the FDA has awarded ivabradine fast track status

• We issued an alert earlier this month that Amgen filed its NDA.  At the time we indicated that the FDA would likely expedite review because of the fast track status.  This has now been confirmed lining up review for Q1 2015

Comment:  We previously suggested that an FDA decision could be expected early 2015.  This now appears to be the case with possible launch mid 2015.  Although the speed of development has obvious advantages it should be considered that Amgen will be new to the CV market.  Amgen has previously announced that a CV team will handle the launch of ivabradine as well as its PCSK9 inhibitor Evolocumab.  We expect a BLA to be filed for this second candidate during this quarter and as a result this new CV team could find itself handling 2 major launches in a similar time frame.  Whether this would introduce risks remains to be seen

UpdatesPlus - Rheumatoid Arthritis August research and development issue now available

The August issue of UpdatesPlus - Rheumatoid Arthritis is now available, offering a top to bottom analysis of research and development activity from the rheumatoid arthritis arena.  This 100 slide issue provides analysis of commercial/life cycle management activity around the biologics all the way down through recent launches such as Xeljanz, late clinical candidates such as sarilumab and preclinical proof of concept data on new targets such as HDAC.  We also provide a full analysis of biosimilar activity as it relates to rheumatoid arthritis

To receive the full report please contact fiona.watts@leaddiscovery.co.uk

Analysis included in this issue includes:

• A look at Q2 2014 sales of the biologics which we estimate to have reached $4.7B for rheumatoid arthritis and $9.6B across all indications.  We look at regulatory activity including EU approval of RoActemra sc and monotherapy, as well as well as J&J's decision to withdrawn its MAA for iv Simponi.  With regards to life cycle management, data have been presented on early rheumatoid arthritis as stakeholders battle for this segment.  We analyze new data from key studies such as PRIZE and AVERT
• Xeljanz is one of the highest profile recent launches.  In the early stages of its roll out we look at new analysis of key studies such as ORAL START and new studies including ORAL STRATEGY
• As the sale of current biologics continues to grow so to do biosimilars advance.  We analyze recent activity including the important news that Celltrion has filed Remsima in the US.  Four other biosimilars have also entered Phase 3 for rheumatoid arthritis over recent weeks
• We also analyze news around the development of the new IL-6 biologics.  Most activity exists around sarilumab as Sanofi approaches its targeted launch in 2015.  As hinted in our blogs earlier this week we understand that although development proceeds well, a key study may have been stopped.  New data have also been released on IL-6 receptor antibodies, sirukumab and clazakizumab.  Efficacy looks good and we analyze this data
• With regards to other mechanisms of action, much has happened over past weeks. Three of four Phase 3 baricitinib studies are now fully enrolled with data expected between Sept 2014 and  Feb 2015.  A fourth, RA-BEAM is still enrolling as Lilly prepares to launch in the US, EU and Japan simultaneously in 2016.  Earlier in development Novartis' NURTURE 1 study of secukinumab is now fully enrolled. 24wk endpoints should be reached by the end of 2014, providing important proof of concept data in the IL-17 field.  AstraZeneca has announced promising data on its GM-CSF candidate, Mavrilimumab with Phase 3 decisions expected in 2015
• As usual we also trawl preclinical data, looking for possible areas of future development.  This month we have identified data suggesting IL-17 blockade may limit breast cancer metastasis.  This may be particularly interesting if NURTURE 1 establishes proof of concept for IL-17 mAbs as anti-inflammatories in the rheumatoid arthritis setting.  We also describe convincing new preclinical data establishing HDAC6 as a therapeutic target and med chem activity from Abbvie describing new PKCθ inhibitors

This is just a small look at what this issue of UpdatesPlus Rheumatoid Arthritis is looking at. We believe that we have covered all key information released in the area over the past few weeks.  Our formula is simple - for the past 8 years our researchers continuously monitor company websites and presentations, trial data bases and journal articles and use their expertise to provide analysis in one easy to read slide deck.  To receive the full report please contact fiona.watts@leaddiscovery.co.uk

Update on sarilumab in rheumatoid arthritis

Yesterday we wrote on Sanofi's COMPARE study of sarilumab in rheumatoid arthritis.  We believe that this is an important study, comparing sarilumab to Enbrel in rheumatoid arthritis patients who have not responded sufficiently to Humira.  We feel that this is an important study, alongside TARGET which is comparing sarilumab to placebo in TNF-IR patients.  TARGET could support the use of sarilumab in this cohort, while COMPARE is important commercially, potentially helping Sanofi to establish sarilumab as a second line biologic.  Given the high cycling rate of biologics in rheumatoid arthritis, this represents a key objective

Based on a change in COMPARE status on clinicaltrials.gov we understood that the study had completed early, and formed the conclusion that this important data may be ready for submission along with Sanofi's overall regulatory dossier next year

Since writing it has come to our attention that although COMPARE is now listed as "ongoing, but not recruiting participants" on clinicaltrials.gov, Sanofi may not have followed convention in updating this entry.  Usually this statement infers that the target patient number has been reached.  In contrast if a study has been stopped early for commercial reason, slow enrollment, adverse events etc, then this would be specified.  The situation regarding this trial is fluid and the above analysis will be updated if anything changes

In the meantime please feel free to contact us (fiona.watts@leaddiscovery.co.uk) for further information on the above

News on sarilumab development is also now available through our monthly UpdatesPlus Rheumatoid Arthritis report

Rheumatoid arthrtitis alert - Sanofi announces full enrollment of key Sarilumab study in rheumatoid arthritis earlier than expected

This alert is an extract from our 100+ slide UpdatesPlus-Rheumatoid Arthritis report due out later today or tomorrow (now available).  This report provides full analysis of key information released in the rheumatoid arthritis arena over the past few months.  The report also provides a fully up to data rheumatoid arthritis landscape and clinical trials timeline. For further information please contact fiona.watts@leaddiscovery.co.uk

• Sanofi/Regeneron intends to file IL-6R mAb Sarilumab for rheumatoid arthritis in 2015
• Registration will be supported by MOBILITY in MTX-IRs. TARGET and COMPARE will provide efficacy data in TNF-IR patients
  
• Commercially, COMPARE is possibly more important than TARGET as it is comparing Sarilumab and Enbrel in Humira-IRs
• Initially COMPARE was expected to read out after registration but Sanofi has now announced full enrollment likely allowing it to support registration

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

Comments: We believe that the Sarilumab data package may be a little patchy at launch.  The rheumatoid arthritis market for biologics is currently fragmented into monotherapy, MTX-IR and TNF-IR.  Increasingly, early RA is proving an attractive cohort. 

Roche has been aggressively positioning (Ro)Actemra around monotherapy efficacy supporting use in MTX-unable patients.  Sanofi's SARIL-RA-ONE is expected to complete in time for filing supporting monotherapy.  Disappointingly however, SARIL-RA-ONE  is focusing on immunogenicity rather than also evaluating efficacy.  This will limit competitiveness in the monotherapy setting.  MOBILITY is in MTX-IR patients and may therefore support use as a 1st line biologic.  The study is however placebo controlled, and comparative data supporting 1st line (MTX-IR) biologic use will be limited. 

Sanofi's clinical program seems most directed towards TNF-IR patients.  ASCERTAIN is comparing Sarilumab and (Ro)Actemra in this cohort but this is a safety study.  Unless important differences are revealed, Sanofi may have difficulty competing with (Ro)Actemra.  TARGET and COMPARE are probably more important commercially, and especially COMPARE which will allow Sarilumab to compete with Enbrel as a 2nd line biologic.  Early completion of COMPARE is therefore important.  Sanofi's targeting of TNF-IR patients is not too surprising for a new molecule, and indeed this strategy may allow higher pricing.  If approved Sanofi may then choose to rapidly follow up with further studies comparing Sarilumab with (Ro)Actemra, especially if SARIL-ONE reports particularly low immunogenicity, or if ASCERTAIN suggests improved safety vs (Ro)Actemra     

Stop press:  Since the above blog was written it seems that although COMPARE is now listed as "ongoing, but not recruiting participants" on clinicaltrials.gov, Sanofi may not have followed convention in updating this entry.  Usually this statement infers that the target patient number has been reached.  In contrast if a study has been stopped early for commercial reason, slow enrollment, adverse events etc, then this would be specified.  The situation regarding this trial is fluid and the above analysis will be updated if anything changes

Alert: UpdatesPlus-Psoriasis - Lilly reports impressive Phase 3 data for ixekizumab

This alert comes from our UpdatesPlus-Psoriasis service, a regular analysis providing depth information on all key recent events in the area.  To receive further information or instruction on how to access the service please contact fiona.watts@leaddiscovery.co.uk [for a summary of our most recent full report click here]

• Lilly has reported superiority of ixekizumab to Enbrel and to placebo in the company's UNCOVER program

• UNCOVER comprises 3 studies: UNCOVER-1 (placebo controlled) and UNCOVER-2 and -3 (placebo and Enbrel controlled)

• All primary and key secondary measures were met, including superiority to etanercept

• At 12wks PASI75 rates ranged from 78-90%, while 31-41% of patients achieved PASI100 (complete skin clearance)

• Improvements in skin clearance were reported within 1wk

• Lilly has indicated that it plans to file H1 2015

• AEs were reportedly comparable to etanercept

Comments:  Few have doubted that ixekizumab would generate impressive PASI100 data given previously reported results from across the IL-17 class.  As a point of reference PASI100 rates recently reported for secukinumab were 24-29% at the highest dose tested (300mg qw for 4wk followed by q4w doses).  We presume that the 41% referred to in the Lilly press release relates to the higher dose of ixekizumab (80mg q2w).  In this instance ixekizumab efficacy appears nominally higher than secukinumab although the usual cautions of cross study comparison apply.  Lilly's success will depend in part on speed of response - Novartis has specifically reported this (see Langley et al linked to above) and it will be interesting to see similar data from the UNCOVER program.  Lilly reports efficacy from 1wk however further analysis is obviously required to establish speed of response.  One advantage of ixekizumab is that at the higher dose, just one injection is required.  This contrasts with secukinumab where two injections are required.  Just how much of an impact this will have in terms of injection site reaction and patient convenience remains to be seen.  The profile of the autoinjectors being developed for the two candidates will impact on this.  A further differentiators that Lilly will likely use is the ability to reduce dosing frequency to q12w in some patients after the initial 12wks of treatment.  The feasibility of this approach remains unknown as further data from after the initial 12wks of treatment is awaited

UpdatesPlus-Lupus (August) - Analysis of breaking research and development in lupus

We are pleased to announced the most recent issue of UpdatesPlus-Lupus.  This regular analysis provides in depth information on all key recent events in SLE and lupus nephritis.  To receive further information or instruction on how to access the full report please contact fiona.watts@leaddiscovery.co.uk

Amongst the analysis presented in this issue we analyze the following:

• Upcoming changes in clinical practice following the release of new data describing the impact of treatment withdrawal, especially of conventional immunosuppressants and how this may be done most efficaciously. We also look at treat to target strategies for lupus similar to other chronic autoimmune diseases such as RA.  
• Benlysta development:  We report on the most recent sales figures and also on potentially important data from the German real world study, OBSErve.  GSK is moving towards sc Benlysta, expected in 2016.  We update clinical development to support this activity including the launch of a new autoinjector study. Potentially as important is  treatment holiday study and new data on a PRO instrument developed using Benlysta data 
• Advanced clinical candidates: We update the clinical progress of the lupus pipeline including new activity around UCB's CD22 antibody, Epratuzumab; Merck Serono's BAFF/APRIL biologic, Atacicept; and the IFN blocker class which has seen significant recent activity
• New proof of concept data supporting the development of low dose topoisomerase 1 inhibitors for the treatment of lupus nephritis as well as new data suggesting IL-17 blockade may offer an approach to lupus

The present issue of UpdatesPlus is 34 slides and as usual provides a fully updated clinical pipeline and timeline

AstraZeneca has reported positive Phase 3 data for gout candiate lesinurad

This alert comes from our UpdatesPlus-Gout service, a regular analysis providing depth information on all key recent events in the area.  To receive further information or instruction on how to access the full report please contact fiona.watts@leaddiscovery.co.uk [for a summary of our most recent full report click here]

• AstraZeneca has reported topline data for its URAT1 inhibitor from three gout studies, CLEAR1, CLEAR2 and CRYSTAL
• In CLEAR1 and CLEAR2 daily lesinurad (200 or 400mg) in combination with the xanthine oxidase inhibitor allopurinol increased the proportion of patients reaching the target sUA goal (less than 6.0mg/dL) after 6mo
  
• CRYSTAL studied lesinurad at the same dose in combination with a second xanthine oxidase inhibitor, febuxostat in patients with tophi.  The target sUA goal was slightly lower at less than 5.0mg/dL and this was met at 400mg after 6mo but not 200mg (superiority was however observed at other earlier and later time points)
• Of note, in CRYSTAL,  renal-related adverse events and incidence of kidney stones was increased at the higher 400mg dose

Comments:   The company has commented that it is preparing for regulatory submissions but at the lower 200mg dose.  We expect filing to also be this year, approximately in line with earlier expectations.  A fourth study, LIGHT was reported in 2013 demonstrating efficacy at 400mg as a monotherapy in gout patients unable to take an xanthine oxidase inhibitor.  In this study renal AEs were also elevated. We presume that the 400mg dose is not being submitted due to AEs and this may limit the potential of lesinurad, especially as approval will likely not be for monotherapy.   Given that submission will be limited to 200mg, the degree of efficacy at this dose will be important.  AstraZeneca has indicated that full data are expected later this year. 

UpdatesPlus-Psoriasis alert - Guselkumab moves into Phase 3 development

This alert comes from our UpdatesPlus-Psoriasis service, a regular analysis providing depth information on all key recent events in the area.  To receive further information or instruction on how to access the full report please contact fiona.watts@leaddiscovery.co.uk [for a summary of our most recent full report click here]

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• Janssen has announced two Phase 3 Guselkumab studies, VOYAGE 1 and VOYAGE 2

• Both studies will compare Guselkumab (100mg sc), adalimumab and placebo

• Guselkumab will be injected at wks 0, 4 and q8w.  VOYAGE 2 will include a treatment withdrawal protocol

• Co-primary endpoints are IGA 0/1 and PASI90 at 16wks

• Key secondary endpoints include nail and scalp psoriasis scores

• VOYAGE 2 will include additional psychiatric QoL scores (ie SF-36, anxiety)

• 1750 patients will be enrolled in total from Q3 2014 with the primary endpoint date expected in Sept-Oct 2015

• Patients will be recruited in Taiwan, Germany and Poland

Comments:  Phase 2b data reported from X-PLORE at AAD earlier this year demonstrated superior efficacy of Guselkumab vs adalimumab.  This study evaluated q8w and q12wk dosing.  At q8w, 100mg was the highest dose investigated and continuation at this dose in VOYAGE is consistent with the benign AE profile in X-PLORE.  Of note, 3 MACE events were reported, but after 28wks and in patients with at least 3 CV risk factors.  q12w dosing (200mg) was investigated in X-PLORE but this did not appear to improve efficacy over 100mg q8w.  Advancing q8w rather than q12w dosing does place Guselkumab at a slight disadvantage to Stelara although this is likely to be of limited importance.  Of greater interest perhaps is how Janssen intends to differentiate Guselkumab and Stelara.  Stelara targets the shared p40 subunit of IL-12/23 while Guselkumab targets p19 and therefore offer more selective blockade of IL-23.  The biological implications of this remain unclear although further Phase 3 studies are inevitable and these may shed light on the relative positioning of the two Janssen products.   For example, does Janssen believe Guselkumab may provide improved efficacy and therefore conduct a head to head vs Stelara, or could Guselkumab carry a reduced risk of infectious and therefore conduct a study in a high risk cohort?  The former could create internal competition between the two Janssen products and we therefore doubt this strategy would be followed.  The latter is also questionable given the low rate of infection with Stelara in long-term studies. Differentiation of Guselkumab and Stelara therefore remains unclear.  Also unclear is why the CTG entry indicates that multiple sites have withdrawn from VOYAGE studies - whether this is a temporary issue and what the reasons are require further understanding

UpdatesPlus-Psoriasis (July 31st) - Analysis of breaking research and development in psoriasis

We are pleased to announced the most recent issue of UpdatesPlus-Psoriasis.  This regular analysis provides in depth information on all key recent events in the area.  To receive further information or instruction on how to access the full report please contact fiona.watts@leaddiscovery.co.uk

This issue includes analysis of the following:

The biologic market: Sales for biologics approved for psoriasis continue to expand across all indications.  Q2 sales were $8.6B, an 18% increase over Q2 2013.  Of this we estimate that sales for psoriasis were $2B.  Stelara sales continue to accelerate dramatically.  Amgen has indicated that Enbrel sales are being threatened as a result and that new DTC activity will be initiated to counter this threat.  Biosimilar threat is also growing with Sandoz and Coherus both advancing candidates supported specifically by psoriasis data. A further interesting advance is the clinical development of sub-dermal etanercept by ASIS.  

Humira sales have also grown, but like other biologics, biosimilar threat is growing with Amgen completing enrollment of a Phase 3 ABP 501 study.  Recruitment to a Phase 3 PsO study has completed.  Amgen has previously indicated that its biosimilars will launch from 2017 onwards. Infliximab is the only biosimilar launched for psoriasis and roll out continues with the most recent approvals being in Turkey and Japan

IL-17s:  This novel class continues to move forward with EMA and FDA opinion on secukinumab expected Q4 2014/Q1 2015. CLEAR (H2H vs Stelara) is fully enrolled and on track to read out in 2015.  Positive data will have important pricing and launch implications. Following the read out of top line brodalumab data from AMAGINE-1, Amgen has confirmed AMAGINE-2/3 (vs Stelara) will read out in Q4.  We presume that filing will be Q2 2015, just before that of Lilly's Ixekizumab

Other biologics: UCB and Dermira have announced a collaboration on the development of Cimzia for psoriasis.  Earlier in the pipeline, GSK has taken first in class LAG-3 candidate into the clinic

Methotrexate:  Competition for sc MTX formulations has increased with the approval of Medac's Rasuvo. This follows earlier approval of Antares' Otrexup which has been launched in the dermatology space by Leo

Small molecules:  Celgene has confirmed that Otezla is on track for EU/US launch around the end of 2014.  Pfizer's Tofacitinib is also approaching the market following positive data from OPT Pivotal #1 and #2.  We expect filing in the US early 2015, at around the same time as an sNDA for Pfizer's qd formulation.  We speculate positive psoriasis data may also trigger a combined filing in the EU for psoriasis and RA.  Pfizer is also developing PF-06263276, a broad spectrum JAK/TYK2 inhibitor. Pfizer has opened a patient study which, interestingly compares this candidate to topical tofacitinib and daivonex

Other candidates we report on in the present issue include GSK/Galapagos' JAK inhibitor GSK2586184; Can-Fite' adenosine receptor modulator, CF101 and a novel candidate being developed by Kadmon.  Finally, Xenoport is developing a novel fumarate prodrug

Steroids and Vitamin D derivatives:   As competition grows for share of the pediatric market, Leo has reported full results on one of its large Phase 3 pediatric studies of Taclonex,. Galderma has also opened a Phase 4 pediatric study of calcitriol ointment, Silkis/Vectical. In contrast to the Leo study of 12-18 year olds, Galderma's trial is enrolling 2-12 year olds

To receive further information or instruction on how to access the full report please contact fiona.watts@leaddiscovery.co.uk