Sanofi announces new Sarilumab monotherapy study

• Sanofi aims to file its IL-6 mAb, Sarilumab in 2015 and has opened multiple Phase 3 studies to support this
  
• MOBILITY, the key MTX-IR study first read out in 2013 with further data reported at EULAR 2014.  Of interest, analysis has reported that biomarkers of joint destruction were reduced within 2wks.  We understand that these biomarkers are being evaluated as possible prognostic tools to optimize the future use of Sarilumab although this requires validation
  
• Sanofi has also announced two important safety studies. SARIL-RA-ONE is a new immunogenicity study; ASCERTAIN is comparing Sarilumab and (Ro)Actemra in TNF-IR patients
• Sanofi’s focus is on TNF-IR patients and 2 further studies have been initiated: TARGET (vs placebo) and COMPARE (vs Enbrel). COMPARE is comparing Sarilumab and Enbrel in Humira-IR patients and is important to support use in this second line biologic space. Initially this study was expected to read out after the likely registration time-frame but Sanofi has now announced that it is no longer enrolling patients and we expect data to be included in the BLA
  
• Now, Sanofi has announced SARIL-RA-MONARCH.  This 340 patient study aims to demonstrate Sarilumab superiority over Humira in a monotherapy (MTX-free) setting
• The primary endpoint, DAS28 (ESR) at 12wks is expected to read out July 2016

Comments:  This study is similar to ADACTA, which was sponsored by Roche to occupy the MTX-unable space.  ADACTA demonstrated (Ro)Actemra superiority and has since been used to support one of Roche's key messages that MTX cannot be used in a substantial proportion of patients and that (Ro)Actemra offers an attractive first line biologic option in this situation.  We expect Sanofi to file Sarilumab around Q4 2015 suggesting approval late 2016.  If this turns out to be the case then data from SARIL-RA-MONARCH should be available to allow the filing of an sBLA soon after launch.  Data reported in Q4 2016 may prompt Sarilumab use as a monotherapy even prior to approval of an sBLA.  One criticism of ADACTA has been that Humira was dosed q2w despite labels indicating weekly dosing as an option in some patients.  In other words ADACTA was "designed for success".  It seems that SARIL-RA-MONARCH is likewise designed to dose Humira q2w  

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2015 promises to be a good year for psoriatic arthritis and ankylosing spondylitis drug development

We are pleased to announce the release of January's issue of UpdatesPlus-Spondyloarthropathy.  This 74 slide report identifies and analyzes emerging information in areas of psoriatic arthritis, ankylosing spondylitis and non-radiographic spondyloarthropathy.  Information includes papers, new trials, clinical data, conference presentations and company releases.  The report also presents a fully up to date landscape and clinical trial overview

UpdatesPlus-Spondyloarthropathy is a regular report, and is part of our rheumatology and dermatology collection.  Reports are accompanied by ad hoc e-mail alerts providing near real time analysis of key breaking events.  For further information please contact fiona.watts@leaddiscovery.co.uk or see our UpdatesPlus product brochure

Current market leaders in the Spondyloarthropathy segment include Humira, Remicade and Enbrel. Little new activity has been reported around these products although of note, the first biosimilar version of Humira has been launched in India.  Elsewhere Remicade continues to come under biosimilar threat, not least through Remsima filing in the US and the USPO's rejection of one of J&J's Remicade patents.  Remsima is expected to launch in major EU markets this quarter

As a relatively new member of the TNFi class, Simponi continues to grow healthily. Continued read out of long-term psoriatic arthritis (GO-REVEAL) and ankylosing spondylitis (GO-RAISE) data is expected to contribute to clinical confidence given impressive drug survival and durable efficacy.  J&J has also submitted an sBLA for non-radiographic spondyloarthropathy

Most recent noise however is around Otezla (apremilast, PDE4 inhibitor from Celgene) and Cosentyx (secukinumab, IL-17 mAb from Novartis)

Otezla was first approved by the FDA for lead indication, psoriatic arthritis in March 2014.  The FDA has now also approved Otezla for psoriasis.  This was followed by the EMA's CHMP recommending approval for both indications in Europe.  At the same time the FDA AdCom and CHMP have approved Cosentyx for psoriasis

In terms of data flow, ACR 2014 in Boston was a key platform for Celgene with more than 10 psoriatic arthritis presentations delivered.  These reinforced the durability of Otezla  and the apparent accumulation of efficacy with long-term treatment. New 52wk PALACE 4 data (DMARD naïve) were presented.  Overall Otezla has performed well clinically in terms of nail and joint structure improvement.  Drug survival is good, responses are durable and drug safety is to date excellent; the main question mark hangs over efficacy in terms of skin lesions

Cosentyx looks promising across the rheumatology and dermatology spectra. This biologic is set to become the first to market IL-17 mAb for psoriasis having been recommended for FDA and EMA approval at the end of 2014.  Japanese regulators have however trumped western agencies, approved Cosentyx for both psoriasis and psoriatic arthritis.  Cosentyx promises to be a field changer exhibiting high levels of efficacy and good safety. Data were reported in detail for the first time at ACR from FUTURE 1 and FUTURE 2, pivotal psoriatic arthritis studies of Cosentyx.  ACR20 and PASI90 improvement was impressive.  Effects on joint structure appears at least as good as current options while resolution of skin lesions appears competitive.  As reported for psoriasis, adverse events are limited and we expect Novartis' EU and US regulatory filings for psoriatic arthritis (probably early/mid 2015) to be successful

Cosentyx is also performing well in ankylosing spondylitis. MEASURE 2, which enrolled AS patients closed for enrolment H2 2014.  MEASURE 1, also in AS, completed earlier in 2014 and Novartis announced in October that both studies had met their primary endpoint. MEASURE 1 was presented at ACR 2014 and reported impressive ASAS20 rates

For our full report  please contact fiona.watts@leaddiscovery.co.uk 

Arena Pharmaceuticals advances S1P1 modulator APD334 into Phase 2 for autoimmune disease - ulcerative colitis and Crohn's disease initial targets

• Sphingosine 1-phosphate (S1P) receptors are involved in T cell migration out of lymph nodes and S1P1 receptor blockers have therefore been investigated for the treatment of various autoimmune diseases
• The best known S1P receptor blocker is Gilenya (fingolimod), which was approved for the treatment of multiple sclerosis.  Despite efficacy, Gilenya is associated with significant AEs including dyspnea, bradycardia and ALT elevation
  
• Multiple S1P receptors have been identified and the AEs associated with Gilenya appear to be related to poor selectivity vs other receptor subtypes
• Next generation S1P antagonists are therefore being developed by a number of companies to improve the therapeutic margin seen with Gilenya
• Most recently in UpdatesPlus-Lupus, we highlighted Mitsubishi's efforts to develop MT-1303 as a candidate treatment of Lupus.  This candidate is also being investigated for multiple sclerosis, IBD (both Crohn's Disease and Ulcerative Colitis) and psoriasis.  Receptos is also developing an S1P blocker (RPC1063) for multiple sclerosis and IBD (Ulcerative Colitis), while Actelion was developing ponesimod for psoriasis, although we understand the company has been evaluating next generation S1P blockers in an attempt to screen out AEs
• Arena has now announced its development of APD334, a selective S1P1 modulator that dose-dependently lowers lymphocyte counts in healthy volunteers.  In the Phase 1b study announced today, APD334 reduced plasma lymphocyte count by up to 69% without producing CV, hepatic or pulmonary AEs.  
• Arena now plans to open ulcerative colitis and Crohn's disease studies

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• UpdatesPlus-IBD

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Comments:  Buzard et al have recently reported the development of APD334.  This molecule has good CNS penetration supporting additional development for multiple sclerosis.  Efficacy was also observed in rodent models of rheumatoid arthritis.  In addition, the elimination half life is considerably shorter than that of Gilenya.  This is important as lymphocyte recovery following withdrawal of Gilenya can take up to 5wks, potentially increasing risk in the context of opportunistic infection 

Figure:  APD334 demonstrated therapeutic efficacy in a mouse model of multiple sclerosis.  APD334 was administered at day 18 just before disease activity peaks (after Buzard et al)

UpdatesPlus Psoriasis - Leo continues to defend its Taclonex brand by filing NDA for foam formulation of calcipotriene/betamethasone dipropionate

• Leo has submitted an NDA for calcipotriene/betamethasone dipropionate aerosol foam (0.005%/0.064%), LEO 90100 as a treatment of psoriasis [link]
• This is the first aerosol foam formulation of a fixed combination calcipotriene/betamethasone dipropionate
  
• The NDA is supported by the Phase 3a PSO-FAST efficacy/safety and Phase 2 MUSE safety studies
• Regulatory filings in Europe and other countries are planned in 2015/2016

Comments:  Leo has previously marketed calcipotriene/betamethasone dipropionate ointment but the FDA approved Tolmar's generic in Jan 2014 which was launched in partnership with Sandoz on April 1st 2014.  Tolmar's 180d period of exclusivity started at launch and expired Sept 28th 2014.  Perrigo subsequently received approval for a second generic in Dec 2014.  Leo's defense against generic calcipotriene/betamethasone ointments has been to launch a gel formulation which is claimed to be preferred by patients over ointment formulations.  Foam formulations may offer further benefits of improved application without requiring rubbing onto the skin which may reduce irritation to large and sensitive skin surfaces.  We suspect that the gel formulation may be focused on scalp psoriasis, while the foam will be targeted to other areas.  Of note a further Phase 3 study completed enrollment in Dec 2014 and is expected to reach its primary endpoint this month.  This study has an active control arm (contrasting with PSO-FAST which was placebo controlled).  We suggest that this study will be included in the EU regulatory dossier


This alert is from our UpdatesPlus-Psoriasis service.  UpdatesPlus offers A unique and affordable combination of information monitoring and expert analysis across 14 therapy areas [further information]

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Phase 3 Cimzia program opens in psoriasis

• UCB’s sales of Cimzia continue to expand rapidly with YoY growth reaching 28%. Q3 2014 sales were approx $263M
• Unlike other TNFis, Cimzia approval in  dermatology has been limited to psoriatic arthritis however in these patients RAPID reported promising skin improvement.  Likewise, Phase 2 efficacy in psoriasis patients was high with PASI75 rates of 75% reported
  
• Prompted by these data and a need to expand indications to maximize sales, UCB licensed Cimzia to Dermira in 2014 for development in psoriasis.  The license is for the US, Canada and the EU
• Dermira will be responsible for Phase 3 development costs and will receive payments of up to $49.5 million on the achievement of development and regulatory milestones
• Dermira and UCB filed a Phase 3 IND in Sept 2014 and the Phase 3 CIMPASI program has now been announced
  
• CIMPASI-I and CIMPASI-II will each randomize 225 patients to placebo or Cimzia (400mg, q2w, sc).  In one arm patients will be switched to 200mg at week 6, a dosing regimen similar to that approved for psoriatic arthritis.  The primary endpoints will be PASI75 and PGA 0/1 at 16wks.  The primary endpoints will be reached in Q1 2016
  

Comments:  The UCB/Dermira agreement represents a logical move, allowing Dermira to extend from it's traditionally topical approach and for UCB to expand into dermatology where it has limited experience.  Developing Cimzia for psoriasis will however face the obvious challenge of competing with new high efficacy drug classes including the IL-17 mAbs and IL-23 mAbs from 2016 onwards.  It will be interesting to see how this challenge is addressed.  Cimzia has previously been positioned around speed and predictability of response, although of note Cosentyx (Secukinumab) is also remarkable in its speed of response.  Clarification of the CIMPASI study design is required and in particular dose strength after 6wks.  In one arm the dose is reduced to 200mg q2w (similar to the current label for psoriatic arthritis).  It is unclear if the dose strength in the second arm is maintained at 400mg q2w - if this is the case the dose is higher than that currently approved and may have been selected to produce higher efficacy.



This alert is from our UpdatesPlus-Psoriasis service.  UpdatesPlus offers A unique and affordable combination of information monitoring and expert analysis across 14 therapy areas [further information]

To access our most recent 121 slide report on recent advances in psoriasis please contact fiona.watts@leaddiscovery.co.uk

Janssen announces Phase 2 study of IL-23 mAb, Guselkumab in Psoriatic Arthritis

Our next issue of UpdatesPlus-Spondyloarthropathy is due to be released this week - to access this detailed report on recent events in Psoriatic Arthritis and Ankylosing Spondylitis please contact fiona.watts@leaddiscovery.co.uk
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• Janssen is developing IL-23 mAb, guselkumab as a candidate for psoriasis
• Following reports of promising data from Phase 2b X-PLORE at AAD 2014, Janssen opened a Phase 3 psoriasis program
• VOYAGE 1 will compare Guselkumab (100mg sc), Humira and placebo. VOYAGE 2 is similar but with a withdrawal period of up to 48wks.  A second study, NAVIGATE will evaluate guselkumab in Stelara non-responders
• Janssen has now announced an upcoming Psoriatic Arthritis study for guselkumab.  This 150 patient study will compare guselkumab (100mg sc; q8w after initial  injections at 0 and 4wks) and placebo. 
  
• Of interest, patients not demonstrating a sufficient response by 16wks will receive Stelara per label

Comments:  Stelara is viewed as offering good efficacy in psoriasis, with PASI 75 rates approaching those seen with IL-17 blockade.  Skin improvement is also impressive in Psoriatic Arthritis patients albeit falling short of values in psoriasis patients (52% and approx 70% respectively).  ACR 20 rates in Psoriatic Arthritis were similar to those expected for a TNFi.  ACR and PASI scores will be reported in the present guselkumab study and it will be be interesting to compare these to historic Stelara values.  Of note the study has an early escape option if patients achieve less than a 5% improvement in ACR score.  Unfortunately patients will switch to Stelara rather than be re-randomized to Stelara or guselkumab, thereby preventing a direct comparison

This alert is from our UpdatesPlus-Spondyloarthropathy service.  UpdatesPlus offers A unique and affordable combination of information monitoring and expert analysis across 14 therapy areas [further information]

Phase 3 acne program opens for Sarecycline in the US

• Actavis indicated at the end of 2014 that it will initiate a Phase 3 program of Sarecycline
  
• The antibiotic is a dual, narrow-spectrum antibacterial and potent anti-inflammatory activity, being developed for the treatment of acne and rosacea
  
• Shortly before the holidays, two large studies were posted to CTG
• The first study is a 1000 patient US study comparing Sarecycline (1.5mg/kg once daily po) and placebo.  The primary endpoints will be absolute change in inflammatory lesions and Investigator Global Assessment at 12wks and will read out Oct 2015.  The second study is an identical study also being conducted in the US
  

Comment:  Sarecycline was developed from a collaborative agreement signed by Paratek and Warner Chilcott (now Actavis) in 2007.  The current studies are being led by Actavis; of note we understand Paratek still has rights to Sarecycline ex-US.  Further understanding of plans for development in other regions is required.  The narrow spectrum profile of Sarecycline is expected to limit antibiotic resistance.  Actavis and Paratek have also previously commented on the robust oral bioavailability, and favorable pharmacokinetic properties of Sarecycline.  One aspect of the Phase 3 program that is of note is that dosing is weight based and this could lead to a requirement for multiple dose strengths or scored tablets if approved

This alert is from our UpdatesPlus-Acne and Rosacea service.  UpdatesPlus offers A unique and affordable combination of information monitoring and expert analysis across 14 therapy areas [further information]

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Breaking News and Views - Lupus, Gout and Spondyloarthropathy

Pharma Information and Reports is pleased to announce availability of December's issues of the following UpdatesPlus reports:

• UpdatesPlus-Lupus
• UpdatesPlus-Gout
• UpdatesPlus-Spondyloarthropathy (Psoriatic Arthritis, Ankylosis Spondylitis and Axial Spondyloarthropathy)

UpdatesPlus offers A unique and affordable combination of information monitoring and expert analysis across 14 therapy areas [further information]

Top news from lupus

Sifalimumab (IFNα): Phase 2b Sifalimumab data were presented at ACR 2014.  Patients with severe disease at baseline responded to q4w sifalimumab with an increase in SRI-4 rates (45% to 57-60%).  CLASI measures of skin involvement as well as joint disease and fatigue were also improved.  Increased incidence of zoster is, for the moment the AE of greatest concern (8.4% at the highest dose tested vs 0.9% with placebo)

Comments:  SRI rates are still rather modest, albeit higher than those historically reported for Benlysta.  Moreover sifalimumab efficacy was quite flat over a broad dose range (200, 600, 1200mg iv).  This suggests redundancy in inflammatory pathways responsible for lupus, or alternatively sub-populations of patients.  AstraZeneca is developing anifrolumab as well as sifalimumab. Anifrolumab blocks the type 1 IFN receptor and hence a broader spectrum of interferons (IFNα, IFNβ, and IFNω).  If there is redundancy amongst the interferons Anifrolumab may offer greater efficacy.  We suspect AstraZeneca will wait for Phase 2 anifrolumab data expected in 2015 before selecting a Phase 3 candidate.  

To access our full 37 slide report please contact: fiona.watts@leaddiscovery.co.uk

Top news from gout

Lesinurad/RDEA3170: AstraZeneca reported further data from CLEAR1 and CLEAR2 at ACR2014.  Data were initially reported in Aug 2014 .  New data demonstrated stable efficacy of a Lesinurad/allopurinol combo over 12mo 
In addition to lesinurad, AstraZeneca is developing a 2nd generation URAT1 inhibitor, RDEA3170. A Phase 2 monotherapy study is now complete. A Phase 2 febuxostat combination study has also recently been announced and the first patients have now been recruited

Comments:  AstraZeneca had previously indicated that EU and US filings for lesinurad would be submitted in Q4 2014.  At the time of writing it appears that this will more likely be Q1 2015.  Reasons for this are unclear

To access our full 21 slide report please contact: fiona.watts@leaddiscovery.co.uk

Can-Fite moves towards opening Phase 3 study of adenosine A3 receptor agonist, CF101 in rheumatoid arthritis

• Can-Fite is developing A3 agonist, CF101 for rheumatoid arthritis and psoriasis. 
  
• A3 receptors are over-expressed in rheumatoid arthritis and this correlates with lower disease activity suggesting a possible compensatory mechanism
• Can-Fite reported positive top line data from a 12wk Phase 2b monotherapy study of CF101 (1mg bid) in Dec 2013 and then in more detail at ACR 2014
• Of particular interest, in patients with higher baseline A3 expression (greater than 1.5-fold higher than the mean; approx 70% of patients), ACR20 rates reached 50%, and 75% in patients naive to systemic therapy.  These data are particularly impressive given the clean safety profile
  
• Can-Fite has now announced that it has completed the design of its Phase 3, 300 patient study
• The study will evaluate 2mg or 3mg bid, higher doses than those studied in the Phase 2b trial
• A3 receptor expression will be determined prior to dosing and correlated with efficacy.  Of interest, Can-Fite is developing a commercial biomarker blood test kit for the A3 receptor
  

Comments:  Further details on the Phase 3 design are eagerly awaited.  In particular we hope that treatment naive patients will be included given the efficacy in these patients in the Phase 2b study and the potential for CF101, with its excellent safety profile, to occupy an early line treatment option, sparing steroids and avoiding MTX

Stop press:  Since this editorial was initially posted we have been in contact with Can-Fite sources and understand that patients will be both naive to prior treatment and experienced.  Concomitant MTX therapy will not be allowed in the study.  Finally, like the Phase 2b study inclusion will depend on baseline A3R expression

This alert is from our UpdatesPlus service. This service monitors and analyzes breaking journal articles, clinical trials and R&D news across the inflammatory disease spectrum - to access our most issue of UpdatesPlus-Rheumatoid Arthitis including a full development landscape and clinical  timeline please contact fiona.watts@leaddiscovery.co.uk 

Aquinox Pharmaceuticals has opened Phase 2 KINSHIP study of AQX-1125 in atopic dermatitis

The following alert is from our UpdatesPlus service. This service monitors and analyzes breaking journal articles, clinical trials and R&D news across the inflammatory disease spectrum - to access our most recent issue of UpdatesPlus-Atopic Dermatitis including a full development landscape and clinical  timeline please contact fiona.watts@leaddiscovery.co.uk 

• AQX-1125 is an oral SHIP1 activator that has been shown to reduce immune cell activation and migration
• SHIP1 is a protein preferentially expressed in haematopoietic cells and which inhibits the PI3K pathway
  
• The atopic dermatitis study is enrolling 50 adult patients with mild-moderate disease
• The primary endpoint is change in Total Lesion Symptom Score (TLSS) after 12wks.  Data are expected by the end of 2015
  

Link to Aquinox press release

Comments:  AQX-1225 has already demonstrated anti-inflammatory activity in preclinical studies, reducing release of  various cytokines including GM-CSF, IL-6, TNF alpha, IL-2 and IL-4 from splenocytes.  Chemotaxic was also reduced when a range of inflammatory cells and chemotactic agents were probed.  In vivo, AQX-1225 has demonstrated efficacy in experimental models of atopic inflammation (passive cutaneous anaphylaxis and OVA-induced asthma models) and neutrophilic inflammation (cigarette smoke-induced pulmonary inflammation). In the clinic, oral AQX-1225 demonstrated a linear PK profile and good safety.  In addition, efficacy has been demonstrated in a clinical model of COPD.  This model involves administration of LPS to volunteers, which results in neutrophil elevation in the sputum.  AQX-1225 reduced neutrophil counts by 62% [company data].  Since this study, Phase 2 studies have opened for interstitial cystitis/bladder pain syndrome and COPD.  COPD is the lead indication with this study enrolling 400 patients

AQX-1225 has previously demonstrated efficacy in the
PCA model, a simple assay of dermal inflammation