If you asked readers of the Journal what they considered the most pressing unmet need in COPD to be today, I think it likely that most would answer “an anti-inflammatory agent that addresses the type of inflammation present in COPD.” To date, I have not touched this area in a very detailed manner, which for a column entitled ‘The COPD Pipeline’ reveals our problem: the lack of much to say on the matter. However, after digging a little, I think that may be undeservedly pessimistic. The PDE4 inhibitor roflumilast, a putative anti-inflammatory agent, has made it all the way through pivotal Ph III studies to an NDA. An FDA determination is expected in May 2010. Additionally, preclinical work and even some early phase clinical studies are being done on several other potential anti-inflammatory drugs for COPD. Therefore, in this and subsequent columns I will review what I have been able to discover or has been reported about new chemical entities (NCEs) to address COPD inflammation. In this one I will deal with a few receptor antagonists that one hopes will have efficacious anti-inflammatory actions.
FX125L, one of a new group of broad spectrum chemokine inhibitors (BSCIs), has completed a Ph I study. BSCIs are a novel class of synthetic small, orally active molecules that exert broad anti-inflammatory actions by inhibiting leukocyte migration, -a relevant target for COPD inflammation. The rationale for BSCIs is that inhibitors of single chemokines such as anti-TNF-alpha and anti-IL8 have been shown to be less than optimally effective, presumably because inflammatory pathways have great redundancy and can bypass inhibition at just a single or a few steps. FX125L inhibits granulocyte and monocyte migration in vitro in response to several pro-inflammatory chemokines, -MCP-1, RANTES, MIP-1α and IL-8, while not affecting migration due to other chemoattractants like fMLP and C5a.
It acts at nanomolar concentrations and its target is not a traditional chemokine receptor but a “well-characterized BSCI receptor” which is abundant on monocytes, macrophages and neutrophils, but sparse on T and B lymphocytes. Details of this “well-characterized BSCI receptor” are, presumably, a trade secret. “The result is an anti-inflammatory agent which powerfully inhibits pathogenic inflammatory signals, while leaving the adaptive immune system intact” according to the sponsors, Funcxional Therpeutics, a UK biotech company. In the completed Ph I trial, the drug was well tolerated over a range of doses and consistent with once daily oral dosing; -no efficacy information yet. The manufacturers believe it will be as effective as corticosteroids, but safer. Among the indications it will be developed for are a range of inflammatory disorders including COPD. The only other reports of its actions I could find are in Ann Thorac Surg 2003;75:1118–22.
The chemokine receptors fall into 4 families of which 2, the CXC and CC chemokines, are understood to play roles in COPD inflammation. The CXC receptors, CXCR1 and CXCR2, bind IL-8, an important mediator of COPD inflammation, by being chemotaxic for neutrophils which they also activate. The CXC receptors regulate neutrophil responses to IL-8, and there is some evidence they may be over-expressed in COPD. They are therefore targets for the development of specific antagonists/inhibitors. Several small molecule CXCR inhibitors have been characterized in experimental systems, but few seem to have made it “into man”. GlaxoSmithKline is developing a CXCR1 antagonist for COPD with the number SB-656933-AAA. This agent completed a Ph I study in 2009 (NCT00504439), but no more information has been published.
The CC receptors CCR1 and CCR2 bind a variety of inflammatory chemokines and chemoattractants for monocytes and macrophages, and are therefore also potential targets for the development of antagonists. AstraZeneca has a CCR1 inhibitor, AZD-4818, which completed a Ph II study in 2008. In addition, a patent was recently issued for a combination of what appears to be AZD-4818 with an ICS, suggesting the product will be developed.
When meshed with ‘COPD’, the terms ‘CC’ or ‘CXC’ generate only one clinical trial on the clinicaltrials.gov website, -a trial of GSK's CXCR2 antagonist, SB-656933, mentioned above.
Always hoping for new anti-inflammatory agents that might be effective in COPD, one comes across reports of novel FLAP inhibitors. One is familiar with FLAP inhibitors for asthma, however two events seem to have propelled their possibilities into new areas. First there have been indications that FLAP may play a role in the generation of atherosclerosis which, as we now understand, has an important inflammatory component. Secondly, the recent determination of the 3-dimensional molecular structure of FLAP has opened the door to the design and synthesis of a series of potential inhibitors which can be screened in vitro. Merck has been active in this area for at least 5 years and, according to the journal Expert Opinion on Therapeutic Patents, has applied for several FLAP-inhibitor patents. Other pharmas also have recent patents and the field must be regarded as ‘hot’ once again. In addition to asthma and atherosclerosis, COPD is claimed as a target for these agents. It is also reported that another unnamed company, which I think must be Amira, has two FLAP inhibitors in clinical development. Amira, a small molecule pharma focused on treatments for inflammatory diseases, announced in 2008 that they had an agreement with GSK to develop two oral FLAP inhibitors, AM103 and AM803, which had successfully completed Phase I trials, and are now in Ph II. But clinicaltrials.gov does not have information of any trials of FLAP inhibitors in COPD.
Merck, as reported in the October 2009 update of their pipeline, revealed an oral CXCR2 antagonist, MK-0893, in PhII. (They also have a 5LO inhibitor, MK-0633, which has been in Ph II for both asthma and COPD indications for some time).
If I may editorialize briefly on the anti-inflammatory receptor-antagonist field as it relates to COPD, some features strike one. Given the complexity of the area, the apparent redundancy in the immune system, our fragmentary knowledge of its workings (to say nothing of the eternal difficulty of predicting an anti-inflammatory outcome in the clinic from pre-clinical in vitro data), any of the above approaches, singly or in combination, could be the disease-modifying treatment we so sorely need. However, one is mindful that the chemotherapies of many complex diseases, -malignancies, HIV and tuberculosis, hypertension, type II diabetes, -were only poorly effective until combinations of 2, 3, and even more agents were introduced, after which outcomes were markedly improved. Isn't it likely that COPD inflammation requires a similar approach?
As we know all too well, corticosteroids, whether inhaled or by mouth, are not nearly as effective in COPD as in asthma. Corticosteroids switch off inflammatory genes, among other actions, by recruiting histone deacetylase (HDAC) to the inflammatory gene complex. It has been postulated for some years (mainly by the group of Peter Barnes) that the relatively weaker efficacy of corticosteroids in COPD is due to a reduction in HDAC activity found in COPD (but not to the same extent in asthma). Theophylline activates HDAC; suggesting that it could augment corticosteroid actions at the gene level in COPD.
Moreover, it does so at blood levels achievable by moderate dosage, levels which are below those that inhibit PDE's (Peter Barnes's group again). This provides a rationale for the co-administration of low-dose theophylline with a corticosteroid in COPD. Two small proof-of-concept trials (Thorax 2009;64:424–9; ERJ 2009;33:1010–9) showed trends towards potentiation of the anti-inflammatory effects of a corticosteroid when combined with modest doses of oral theophylline. This concept has been taken up by Argenta Discovery Ltd, which is developing an inhalational theophylline budesonide compound. A Phase II study of twice-daily inhaled theophylline (12.5 mg) co-administered with budesonide (1 mg) was compared to placebo-budesonide co-administration in COPD over 4 weeks. The combination treatment resulted in significant improvements in lung function, and trends towards beneficial changes in inflammatory cells in sputum and bronchial biopsies as compared to the budesonide monotherapy group (NCT00634413). The small inhaled dose of theophylline was apparently well tolerated.
Larger, longer trials will be necessary for confirmation of the concept, but the results, which were presented at the 2009 ERS meeting in Vienna, are encouraging, and support the concept that combination chemotherapies will be needed to suppress COPD inflammation.
New COPD drug trials initiated in October and November 2009
According to BioPharma, 5 new COPD drug trials were initiated in October and November 2009. GSK's 642444 is a once-a-day LABA that was the subject of 2 new trials, -a Ph III study for a monotherapy COPD treatment, and a Ph I –II study of the same drug in combination with an inhaled corticosteroid. Biotie, a Finish biotech, initiated a Ph II study of its PDE4 inhibitor, ELB353. Kamada initiated another Ph III trial with its alpha-1 replacement therapy, and Schering-Plough initiated a study with Sch527123. Medicinova has a novel, “highly selective” ß2-adrenergic receptor agonist MN-221 that is entering Ph II for the treatment of exacerbations of COPD. Interestingly, the same drug is also being developed for a delay-of-pre-term-labor indication, as are some other LABAs in development. The drug has completed Ph I.
Another site with the name “New Medicines Database” published by PHRMA, lists 35 newly revealed study agents with a COPD indication, http://newmeds.phrma.org/results.php?drug=&indication=58&camp;ompany=&status=
I have reported on some of these already, and there is the usual crop of ‘me-too’ LAMAs, LABAs, ICSs and combinations thereof. Here is some information I was able to find about a few of the others.
AER 002 is an Aerovance product for both CF and COPD indications. The agent is a serine protease, Prostatin, that regulates Na+ channel activity and, thus, mucus rheology and mucociliary clearance (a rationale somewhat similar to that of Bronchitol, a dry powder form of mannitol, that I reported on in the Pipeline III report). Phase II studies showed that the agent was “biologically active” (not listed in clinicaltrials.gov). An AECOPD indication is also mentioned on the Aerovance web site.
AM 211 is Amira's lead DP2 (CRTH2) antagonist. A once-daily oral agent that completed a Phase I study in June 2009 (not listed in clinicaltrials.gov). There are currently no DP2 antagonists in late stage development for a COPD indication that I know of.
BIO-11006 is a dual-mechanism inhibitor of the secretion of mucus and inflammatory mediators from airway epithelial cells. The developer, BioMarck Pharmaceuticals, states that “Inhibition is mediated via inhibition of the myristoylated alanine-rich C-kinase substrate (MARCKS) protein, a required element of the secretory machinery of airway and inflammatory cells.” A Phase II study in COPD patients (NCT0064824) is expected to complete in Q3 20101.
Canakinumab, otherwise known as Ilaris, an orphan drug monoclonal directed against IL-1β is already approved for treating two rare autoimmune disorders. As an anti-inflammatory agent its use is being explored in other inflammatory disorders such as gout, rheumatoid arthritis, diabetes, neonatal onset multisystem inflammatory disease, and COPD for which indication it is in Phase I (NCT00648245).
EPI 12323 is a small molecule anti-inflammatory being developed by Epigenesis for both asthma and COPD. Not a corticosteroid, the drug “delete(s) adenosine pools”. It is delivered by inhalation, possibly once a day, and has demonstrated anti-eosinophil and anti-neutrophil properties in animal models. It is currently in Phase II for a COPD indication (not listed in clinicaltrials.gov).
Prochymal is an adult mesenchymal-stem-cell culture developed by Osiris and delivered by intravenous infusion (NCT00683722). The randomized, placebo-controlled study aims to show disease modification of COPD over 1 year and safety over 2 years.
I will address other “disease modification” trials in more detail in a future column, as well as the remainder of PHRMA's “New Medicines Database”.
Ted C Murphy PhD of BioMarck Pharmaceuticals kindly provided information on the agent BIO-11006.