UpdatesPlus Substance Use Disorder - breaking information on smoking cessation, reduced harm tobacco and treatment of drug abuse

We are pleased to announce the release of our most recent issue of UpdatesPlus-Substance Use Disorder.  This issue covers smoking cessation, reduced harm tobacco products and treatments of illicit substance abuse.  

For access instructions please contact fiona.watts@leaddiscovery.co.uk

The issue includes

• New data on Champix/Chantix retreatment and the potential for an sNDA, revenue growth and possible fueling of Pfizer's continued direct to consumer strategy.  We also include information on the FDA AdCom meeting announced for Oct 16 to discuss neuropsychiatric risk of Chantix
  
• A look into both the The Tobacco Products Scientific Advisory Committee meeting and the FDA's proposal on regulation of smokeless tobacco products including e-cigarettes
• A full update on e-cigarette/reduced harm products development including a detailed look into PMI's evolving scientific approach
• Activity around alcohol abuse including recommendation of Selincro by NICE and new therapeutic targets including adrenoceptor receptor blockade; GALR3 antagonists
  
• The trials and tribulations of Orexo's launch of Zubsolv (opiate maintenance therapy), apparently negatively affected by Publicis Touchpoint's commercialization efforts; a new partnership with inVentiv Health; generic attack from Actavis; and positive clinical results demonstrating utility as an induction therapy
• PDE4 inhibition as a novel approach to opiate addiction
  
• Significant activity around new naloxone preparations for opiate overdose reversal
• New proof of concept supporting development of mGlu2 PAMs; D3 antagonists and TAAR1agonists as novel approaches to cocaine addiction
  

The issue is made up of 64 slides analyzing recent information released in the area of Substance Use Disorder including commercial activity, up to date pipeline and clinical timeline charts, clinical data and proof of concept papers describing new targets


*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.

Novel approach to psoriasis as GSK takes first in class anti-LAG-3 mAb, GSK2831781 into the clinic

The alert below is from our UpdatesPlus-Psoriasis 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 and Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• LAG-3 (CD223) is a protein specifically expressed by recently activated T cells.  LAG-3 binds MHC class II and plays a central role in the activation of antigen presenting cells 
  
• Selective depletion of cells expressing LAG-3 has been suggested as a therapeutic approach to autoimmune disease and cytotoxic anti-LAG-3 antibodies have been shown to prevent experimental allograft rejection
• GSK has developed GSK2831781, a humanized cytotoxic mAb molecule that targets LAG-3.  This mAb is also able to support antibody dependent cell cytotoxicity and is therefore expected to depleted activated T cells
  
• A healthy volunteer/psoriasis patient trial has now opened, initially testing single ascending doses in healthy volunteers to investigate safety, tolerability and PK/PD of iv GSK2831781
• LAG-3 has been previously shown to  down-regulate tuberculin reactivation of T cells in the skin of BCG inoculated primates.  The study will also determine the effect of GSK2831781 on skin inflammation in healthy subjects previously vaccinated with BCG and challenged topically with tuberculin (Note that this is the Mantoux tuberculin skin test, a standard clinical test of immune response to tuberculosis)
• The second part of the study will enroll psoriasis patients
• Skin biopsies, systemic biomarkers and clinical response endpoints will allow both MOA investigation (including depletion of T cells).  Moreover the identification of systemic biomarkers will drive future studies in indications where biopsies are more challenging to collect
• The study is indicated as running from July 2014 to August 2016

Comments:  The development of this target represents an exciting advance potentially depleting T cells in a targeted fashion.  We expect that GSK2831781 will be targeted to multiple therapy areas in addition to psoriasis if safe.  Antibodies which support antibody dependent cell cytotoxicity have previously been developed successfully (eg Rituxan and Herceptin).  Of note the GSK mAb is de-fucosylated.  This is expected to both enhance cytotoxicity and reduce the risk of anti-drug antibody formation.  We congratulate GSK on its novel translational approach through the use of the Mantoux test.  This represents an ingenious approach to better understanding the potential of GSK2831781.  This also however raises concerns over the safety of GSK2831781 - specifically, if GSK2831781 reduces the response to tuberculin, we ask whether it may also limit the protective role of BCG vaccination and raise the risk of tuberculosis infection.  Given that GSK2831781 is advancing into the clinic, we assume that GSK has preclinical data to suggest that this is not the case

Celgene opens Phase 2 study of CC-220 in SLE

The alert below is from our UpdatesPlus-Lupus 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 and Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• CC-220 is a small molecule developed by Celgene that has previously been reported to bind cereblon.  This intracellular protein forms part of the E3 ubiquitin ligase, a multi-protein complex responsible for protein degradation. Thalidomide also binds cereblon and this is believed to produce its well known teratogenic activity by inhibiting the ubiquitination process and in turn reducing FGF levels

• When incubated with SLE monocytes, CC-220 reduces IRF-4, BLIMP-1, XBP-1 levels, and blocks immunoglobulin production suggesting it may share the immunomodulatory activity of thalidomide and related IMiDs

• Following two earlier Phase 1 studies Celgene has now opened a does ranging study in SLE patients

• The study will randomize 140pts with skin involvement to placebo or 4 dosing regimens

• The study will be in two parts, the first will evaluate safety and PK activity in 40pts

• The second part of the study will be initiated once safety has been demonstrated and will aim to demonstrate improvement in skin manifestations

• Celgene also plans to open studies in sarcoidosis and systemic sclerosis

Comments:   The risk of teratogenicity and venous thrombosis with thalidomide and its analogues is well recognized, however It has previously been suggested that the therapeutic and teratogenic effects of these agents can be dissociated.  It is unclear whether the molecular mode of action of CC-220 allows this dissociation, in turn supporting the immunomodulatory effects of the IMiDs without the AEs.  We presume that since Celgene is developing CC-220, it has identified a mechanism suggestive of an increase in therapeutic index

Pfizer announces new head to head study of Xeljanz with or without MTX vs Humira/MTX

The alert below is from 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 and Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• Pfizer has announced ORAL STRATEGY [link], a new efficacy and safety study comparing Xeljanz with or without MTX and Humira/MTX

• The Phase 4 study is large, aiming to enroll 1080 MTX-IR patients across the three treatment arms

• The primary endpoint is ACR50

• The study is intended to provide new answers to two questions:  1) What impact does MTX have on the response to Xeljanz and; 2) How does the safety/efficacy of Xeljanz monotherapy compare to Humira/MTX

Comments:  We believe this to be an important study, and as indicated by title it should provide valuable information on the strategic use of Xeljanz.  Firstly, in MTX-IR patients can MTX be withdrawn with the introduction of Xeljanz without losing efficacy?  This would be attractive to patients and physicians, reducing monitoring and avoiding AEs/tolerability issues associated with MTX.  Secondly, with regards to selection of Xeljanz vs Humira, the two options have already been compared head to head in ORAL Standard.  The two strategies produced similar efficacy when administered on a background of MTX.  ORAL STRATEGY will provide information on whether Xeljanz produces similar efficacy even in the absence of MTX.  If use of Xeljanz monotherapy does not come at the expense of a loss of efficacy vs Humira/MTX, the rational for switching MTR-IRs to Xeljanz monotherapy rather than to Humira/MTX will be strengthened.  There will still be the open question of whether MTX-IR patients should be better switched to (Ro)Actemra

Liposome Bupivacaine for Postsurgical Analgesia in Adult Patients Undergoing Laparoscopic Colectomy: Results from Prospective Phase IV Sequential Cohort Studies Assessing Health Economic Outcomes

Corresponding Author:  Keith A. Candiotti

Abstract

Background

Opioid-based postsurgical analgesia exposes patients undergoing laparoscopic colectomy to elevated risk for gastrointestinal motility problems and other opioid-related adverse events (ORAEs). The purpose of our research was to investigate postsurgical outcomes, including opioid consumption, hospital length of stay, and ORAE risk associated with a multimodal analgesia regimen, employing a single administration of liposome bupivacaine as well as other analgesics that act by different mechanisms.

Methods

We analyzed combined results from 6 Phase IV, prospective, single-center studies in which patients undergoing laparoscopic colectomy received opioid-based intravenous patient-controlled analgesia (PCA) or multimodal analgesia incorporating intraoperative administration of liposome bupivacaine. As-needed rescue therapy was available to all patients. Primary outcome measures were postsurgical opioid consumption, hospital length of stay, and hospitalization costs. Secondary measures included time to first rescue opioid use, patient satisfaction with analgesia (assessed using a 5-point Likert scale), and ORAEs.

Results

Eighty-two patients underwent laparoscopic colectomy and did not meet intraoperative exclusion criteria (PCA n = 56; multimodal analgesia n = 26). Compared with the PCA group, the multimodal analgesia group had significantly lower mean total postsurgical opioid consumption (96 vs 32 mg, respectively; P < 0.0001) and shorter median postsurgical hospital length of stay (3.0 vs 4.0 days; P = 0.0019). Geometric mean costs were $11,234 and $13,018 in the multimodal analgesia and PCA groups, respectively (P = 0.2612). Median time to first rescue opioid use was longer in the multimodal analgesia group versus PCA group (1.1 hours vs 0.6 hours, respectively; P=0.0003). ORAEs were experienced by 41% of patients receiving intravenous opioid PCA and 8% of patients receiving multimodal analgesia (P = 0.0019). Study limitations included use of an open-label, nonrandomized design; small population size; and the inability to isolate treatment-related effects specifically attributable to liposome bupivacaine.

Conclusions

Compared with intravenous opioid PCA, a liposome bupivacaine-based multimodal analgesia regimen reduced postsurgical opioid use, hospital length of stay, and ORAEs, and may lead to improved postsurgical outcomes following laparoscopic colectomy.

Source: Current Therapeutic Research, Volume 76, December 2014, Pages 1–6

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Further Comments

This paper reports results from a prospective, multicenter, open-label study of liposome bupivacaine (known as the IMPROVE or Extended PaIn Relief Trial Utilizing the Infiltration of a Long-Acting Multivesicular LiPosome FoRmulation Of BupiVacaine, Exparel  trial) that evaluated opioid burden and health economic outcomes in patients undergoing laparoscopic colectomy who were treated with either a multimodal analgesic regimen that included a single intraoperative administration of liposome bupivacaine 266 mg (n=26) or a standard of care, opioid-based analgesic regimen (n=56). The mean total amount of opioids consumed (morphine equivalents) after surgery was 32 mg in the liposome bupivacaine-based multimodal analgesia group versus 96 mg in the IV opioid/PCA group (P less than 0.0001). Median durations of hospital stay were 3.0 days versus 4.0 days (P=0.002) in the multimodal and IV opioid PCA groups, respectively; total cost of hospitalization was $11,234 and $13,018 (P=0.26), respectively. Opioid-related adverse events were experienced by 2 (8%) patients in the multimodal analgesia group versus 23 (41%; P=0.002) in the IV opioid PCA group. These results equate to a statistically-significant 67% reduction in mean total amount of opioids consumed after surgery, a median postsurgical length of hospital stay that was shorter by 1 day, and an 80% reduction in the proportion of patients experiencing opioid-related adverse events.

 

UpdatesPlus - Atopic Dermatitis - an analysis of recent advances

UpdatesPlus-Atopic Dermatitis has now been launched. The inaugural issue evaluates recently released commercial, clinical and scientific advances including:

• We evaluate recent commercial data on topical calcineurin inhibitors as Valeant grows its share of the US market to 48% share of this segment, although Astellas' Protopic remains the market leader, at least until loss of exclusivity later this year
• We also discuss Valeant's M&A activity as the company continues to drive dermatology franchise expansion through a period of acquisitions
• The AAD has released a new series of atopic dermatitis guidelines - we summarize these and identify areas of potential importance to R&D activity
  
• Significant activity has been seen around PDE4 inhibitors, including Anacor's initiation of Phase 3 AN2728 studies as well as data release on Eisai's E6005.  While we question the level of efficacy seen for E6005, Eisai has reported some elegant data directly measuring sensory afferent discharge and related scratching activity.  In contrast to AN2728 and E6005 which are topical, Celgene is developing apremilast as an oral PDE4i for atopic dermatitis.  We report on the start of Phase 2 studies
• Dupilumab, Sanofi/Regeneron's IL-4Ralpha mAb is also highlighted - we describe Phase 2a data as the companies prepare to announce Phase 2b data and open a Phase 3 program (we will issue an alert on this as soon as information is available)
  
• In our "new target" section we look at potentially important proof of concept data on H4 antagonists.  Janssen has published promising data on a now discontinued H4 antagonist.  The company has a second candidate in development for rheumatoid arthritis without the structural issues that are proposed to have lead to the AEs of the initial compound.  This back up could cross over into atopic dermatitis.  Likewise, Ziarco Pharma is the new kid on the block.  Managed by ex-Pfizer personnel the company has raised capital to take its H4 antagonist into the clinic for atopic dermatitis
• Another molecular target with promise is CX3CR1.  Blockade has been shown to be efficacious in models of atopic dermatitis, possibly offering benefit against co-morbid airway hyperreactivity.  Antagonists have yet to enter the clinic although AstraZeneca is developing this class for immunology including multiple sclerosis
  

In addition, we provide a fully up to date atopic dermatitis pipeline and clinical timeline.  To receive the entire 33 page report please contact fiona.watts@leaddiscovery.co.uk

Gilead has announced a Phase 1b study of its MMP-9 (Matrix metallopeptidase 9) inhibitor in Rheumatoid Arthritis patients

This alert is part of our UpdatesPlus-Rheumatoid Arthritis service.  To get further analysis of this study and a full overview of research and drug development activity in rheumatoid arthritis please contact fiona.watts@leaddiscovery.co.uk

• MMP-9 (Matrix metallopeptidase 9, type IV collagenase, gelatinase) is an extra cellular matrix degrading enzyme which is implicated in various inflammatory diseases
• Gilead has developed a mAb against this enzyme, GS-5745 which is currently being evaluated in patients with IBD, COPD and also cancer
• To our knowledge this is the first MMP-9 candidate that has entered clinical development for any indication
• Development in IBD is supported by consistent upregulation of MMP-9 in several animal models of colitis as well as in patients with IBD.  Moreover, deletion of MMP-9 protects against murine colitis
• MMP-9 has also been associated with RA, with levels increased in the synovial fluid of patients.  Moreover, only last month de Rooy et al suggested that genetic variation close to the MMP-9 gene is related to joint progression
• In addition to IBD and COPD studies, Gilead has now announced a small study in 20 RA patients to investigate the safety and PK profile of iv GS-5745 [link]
• The study should read out by the end of 2014