The Antibacterial Gap. I have written twice before about the coming crisis in the antibiotic pipeline and I make no apology for revisiting the subject, -there is a coming dearth in the continuous supply of the new antibiotics we will always need to keep ahead of the ingenuity of micro-organisms. Partly this problem is due to the marketing concerns of pharmaceutical companies and the regulatory requirements that they feel are unfavorable for the discovery and development of antibiotics (Nature Reviews Drug Discovery 2010;9:675–6; Clin Infect Dis 2009;48:1–12). Only 5 major drug companies have active antibiotic discovery programs, -GSK, Novartis, AstraZeneca, Pfizer, and Merck. But there are other challenges and the good news is that they are being addressed.
The approach to discovery of new agents, almost since the beginning of the antibiotic era, has been to modify a molecule whose initial efficacy against validated bacterial targets has been lost, -retain the scaffold, change the attached side-groups. However, there is a limit to how far this strategy can be exploited and, apparently, that limit is close. Discovering new molecular targets in the worst micro-organisms, which is what is required, has not been much advanced by the advent of microbial genomics so far. Targets can be identified by high through-put screening in acellular assays, but disappointingly few potential antibiotic molecules can reach and inactivate the target inside the bug. However, the new approaches are firstly to screen with whole-cell screens, thus addressing the problem of access of the test molecule to the target within. Secondly, the screened organisms can be engineered to carry the commonest antibiotic resistance genes, -a strategy that eliminates the fortuitous re-discovery of known targets and thus greatly improves the odds of identifying an agent that will be antibacterial through a novel mechanism. Thirdly and possibly most important, the screening libraries are being expanded; molecular libraries used in the past had limited diversity. One other novel approach comes from a “boron chemistry platform” (Anacor Pharmaceuticals) that the company says “confers molecules with certain drug-like properties” http://www.anacor.com/gsk052.php.
In addition, X-ray crystallography is being used to identify small molecules that interact with bacterial targets. Potential ‘fragments’ are then built up into drug-like compounds. GSK has thus identified a new class, the pyrrolamides that bind to DNA gyrase “in a way that is different from quinolones”. They also have another product that inhibits DNA gyrase in both Staph aureus and E coli, GSK299423 (Nature 2010;466:935–40). Let us hope that pharmacologic ingenuity outstrips microbial ingenuity and continues to provide us with tools to conquer the infections we struggle with daily, particularly in our ICU patients.
Bronchitol. In a previous “Pipeline” I described the dry-powder mannitol formulation being developed for delivery to the lower respiratory tract by Pharmaxis Ltd, an Australian company. Its stated indications are for cystic fibrosis and bronchiectasis and it has orphan drug designation in Europe and the US. Two phase III muliticenter international studies in CF were recently completed and showed that the agent increased baseline FEV1 by a significant amount and reduced the number of acute exacerbations despite all usual therapy being permitted. Safety outcomes were also good. The company's portfolio is concentrated in the respiratory area and seems likely (in my opinion) to submit for a COPD indication for its Bronchitol product. (They also have PXS TPI1100, an inhaled PDE4 inhibitor selective for PDE4B, 4D and 7A that addresses neutrophil inflammation in a smoking mouse model. The product will be aimed at a COPD indication as I reported previously (COPD 2009;6: 488–9).
R-Bambuterol. The R- enantiomer of bambuterol, a long-acting beta-2 selective adrenergic agent, entered a Phase I trial in the People's Republic of China. Lotus Pharmaceuticals, the developer, has provided little information about the properties of this new agent, other than that the R- enantiomer “has shown greater efficacy and fewer side effects compared to [racemic] bambuterol in preclinical studies”. China is believed to have 30–40 million patients with obstructive lung diseases and the anti-asthma and chronic obstructive pulmonary disease market in China reached approximately $300 million in 2009. The lineup of once-a-day ultra-LABAs is thus increasing, being led by indacaterol (Onbrez®), with BI1744 (Olodaterol®) and others not far behind.
Anti-inflammatory agents for COPD. Following up on my annual review of the COPD Pipeline in my last column, I have analyzed all agents with a stated indication of COPD that are listed in clinicaltrials.gov as of time of writing (Nov 2010). My interest is to see how many of the ongoing trials are for a drug that is described as anti-inflammatory for COPD. I excluded all trials that were not interventional (e.g. observational trials), and all that were closed. As trials are rarely removed from the site, the majority of drug studies that have ever been listed remain on the site although long-since irrelevant to the pipeline, but this step could have resulted in missing some agents that should have been counted. (Roflumilast, for example, does not come up, as it is not at this point in any ongoing trials). This selection process left 24 trials of drugs that had a stated indication of “COPD OR Emphysema”, that were stated to be for an “anti-inflammatory” indication as well as being interventional and ongoing. Of these, 9 trials were in Phase IV and therefore represent agents already in general use. Every one of these was for one of the ICS-LABA combinations, or a monotherapy formulation of an ICS, LABA or LAMA. Another 11 of the ongoing COPD trials involving an agent described as anti-inflammatory were in Phase III, and 3 more each in Phases II and I.
Expecting to find some trials of new anti-inflammatory agents here, I found only two, both already approved agents, -the TNF antagonist etanercept, and the anti-diabetic agent rosiglitazone. So, every one of the agents listed as anti-inflammatory and for a COPD indication is in fact a “me-too” or a “line extension”, -not a single new molecule or class. I know that some agents that were relevant to my search have been missed because I have found some on Pharma websites and reported them in previous columns. Nevertheless, this reinforces one's perception that Industry's interest is largely in getting a piece of the well established maintenance-treatment-for-COPD pie. Perhaps this is because the route to a disease modifying treatment for COPD is expensive, unpredictable and treacherous. Clearly we need more basic research in this area, but there are many promising leads that hold great possibilities, many of them in the hands of bioscience companies. I will review these again in a future column. But there are also regulatory problems particularly related to the limited acceptability of relevant endpoints.
Dulera. The fixed combination of formoterol and mometasone furoate that is delivered by MDI and known as Dulera that was developed by Schering-Plough and Novartis was approved for asthma in June 2010. It has now completed a Phase III study in patients with COPD (NCT00383721). Presumably it will be coming to the FDA shortly for a COPD indication.
Autophagy and alpha-1 ATD. As we well know, alpha-1 ATD affects the liver because the abnormal Z protein that cannot leave the hepatocyte tends to form aggregates that are retained in the endoplasmic reticulum. Accumulation of these inclusions impairs liver function and can cause problems during the neonatal period and again much later in life. Thus adult patients with alpha-1 ATD often have hepatic failure and/or cirrhosis as well as emphysema. Strategies to eliminate the hepatic problem, although far beyond the horizon at present, are being developed (Marciniak SJ, Lomas DA. N Engl J Med 2010;363:1863–4). The intracellular disposal of abnormal proteins is normally performed by tagging the molecule for degradation by the proteasome, -autophagy, -a process to which the aggregates of Z proteins may not be entirely amenable. However, if the polymerization of the abnormal molecules can be blocked, their autophagy might be enhanced.
How can that be achieved? There are agents that can do this and carbamazepine is one and, being an FDA-approved drug, has extensive safety data in humans. Proof-of-concept has been provided by mice transfected to express the Z form of alpha-1 ATD which accumulates in their livers, mimicking the human disease. Large doses of carbamazepine cleared their hepatic inclusions. Equivalent doses could probably not be given to humans, but autophagy can be stimulated by other approved agents, e.g. sirolimus, lithium or valproic acid. There are at present no trials of such treatments for “COPD”, “emphysema” or “alpha-1 antitrypsin deficiency” listed in clinicaltrials.gov, but one presumes that such trials in humans are being developed.
Recombinant adeno-associated virus vector expressing alpha-1 antitrypsin. Like the trial I mentioned in a previous Pipeline column (COPD 2010;7:76–78), this is an attempt to transfect alpha-1 deficient patients with multiple doses of rAAV1-CB-hAAT vector administered by IM injection. The primary outcome is safety but efficacy will be determined by the appearance of M-specific alpha-1 AT phenotype in the serum. The agent has orphan drug status and first results are due in December this year (NCT01054339).
Rivaroxban. Rivaroxban is a once-daily oral direct factor Xa inhibitor that has been developed to avoid the need for regular INR measurements that are required when patients are placed on warfarin. A recently completed head-to-head trial against warfarin known as ROCKET AF was reported at the American Heart Association meeting in Chicago in November 2010 (http://www.investor.jnj.com/releasedetail.cfm?ReleaseID = 530447). The trial, which was sponsored by the makers of rivaroxban, Johnson & Johnson, included 14,269 patients with atrial fibrillation and a previous history of a stroke. The primary outcome, all systemic embolic events, was slightly but not statistically less than in the warfarin receiving group by intention-to-treat. Mortality, too, was similarly slightly lower. An FDA panel reviewed rivaroxban in March 2009 and recommended approval. At that time there were concerns that the drug's use might be associated with “severe liver injury”. If approved now, it is likely the sponsors will subsequently submit an NDA for a venous thrombo-embolism indication (http://www.drugs.com/clinical_trials/rivaroxaban-successfully-demonstrated-non-inferiority-compared-standard-care-prevention-recurrent-10008.html). The drug which is known as Xarelto has been approved for some post-operative indications by the European agency. Stroke and venous thrombo-embolism indications are also now being sought. Boehringer-Ingelheim's warfarin alternative, Pradaxa, was approved for systemic embolism indications in October 2010 and a venous thrombo-embolism indication is now being sought.
P38 MAP Kinase Inhibitors. Mitogen-activated-protein kinases are a large group of phosphorylases that participate in signaling cascades that transmit information about extracellular events across the cell membrane, through the cytoplasm to the nucleus. The cascades, which can involve the serial activation of many enzymes, can be initiated by a wide variety of stimuli, including inflammatory signals, apoptosis, heat- and osmotic-shock, and similar cellular stresses and, of-course, mitogens. The end result depends on the cellular context but is often the activation of nuclear transcription factors, e.g. NFkB, and a pro-inflammatory response.
Thus, agents that selectively down-regulate MAP kinases are being studied as potential treatments for a variety of inflammatory diseases including COPD. The evidence in support of the concept is, in part, that MAP kinase signaling is reportedly increased in macrophages from COPD patients (Mercer BA, D'Armiento JM Int J Chron Obstruct Pulmon Dis 2006;1:137–50). Very few pharmaceutical companies appear to have MAP kinase development programs with COPD treatment as a goal. Three inhibitors of p38 MAP kinases are SB-706504, SB-681323, and GW856553, all in the GSK portfolio. In in vitro cell cultures, SB-706504 inhibited the expression of inflammatory cytokines, an action that was potentiated by the presence of a corticosteroid (Kent LM, et al. J Pharmacol Exp Ther 2009;328:458–68). I don't find more recent news of its progress (which could mean either that it's showing some promise or that it's not showing enough promise). The second agent, SB-681323, which was in Phase I when GSK released their last pipeline update (Feb 2010), had a successful clinical trial as shown by the inhibition of TNF-alpha production after single oral doses (Singh D, et al J Clin Pharmacol 2010;50:94–100) (NCT00380133, NCT00144859, NCT00439881).
GW856553, also known as losmapimod, appears to be GSK's most developmentally advanced MAP kinase inhibitor. Although it is in Phase II with COPD as a stated indication, GSK has also studied it for neuropathic pain, depression, rheumatoid arthritis and to reduce endothelial inflammation. Apart from some abstracts, I can find no detailed clinical trial results for losmapimod. It will shortly begin a Phase II trial in COPD where 3 oral b.i.d. doses will be compared with placebo and in which a 6 minute walk will be the primary outcome (NCT01218126). Review of the published pipelines of other major pharmaceutical companies does not reveal other MAP kinase inhibitors in development for COPD.
Staying with anti-inflammatories, SCH 527123, a Merck/Schering Plough agent, is in Phase II for COPD. Inhibition of neutrophil migration is a stated action in one of 9 studies listed in clinicaltrials.gov, and an outcome of some of these trials is the change in sputum neutrophil counts. The agent has also been in trials of psoriasis and asthma. Further information, such as its mechanism of action, is not available on the website.
V85546. Vernalis is a UK biotech with a number of interesting molecules but only one that aims for a respiratory indication. V85546 is a selective MMP-12 inhibitor (for which see my column of 2010;6:488–9 in this journal) which one might think is looking for a disease target because it is presently in trials for rheumatoid arthritis, multiple sclerosis, “liver fibrosis”, as well as for COPD. It has completed Phase I and is reportedly “ready for Phase II”. No trials of this agent are listed in clinicaltrials.gov.
CAL263 is an inhibitor of phosphoinositide-3 kinases (PI3K), –a family of enzymes with very diverse cellular functions including cell growth, proliferation, differentiation, motility, survival and intracellular trafficking. The delta isoform of PI3K is involved in the regulation of some immune responses, e.g. on Th2 cytokines, attenuating leukocyte activation, and inhibiting release of inflammatory mediators http://www.calistogapharma.com/asthma_copd.php CAL263 appears to be a relatively specific inhibitor of PI3K-d and thus may have anti-inflammatory actions. In addition to a Phase II trial in COPD (not yet listed in clinicaltrials.gov), the agent is being tested in asthma, rheumatoid arthritis, and allergic rhinitis (NCT01066611).
Omalizumab, the anti-IgE monoclonal (Xolair®) approved for asthma some years ago, has entered a phase II study in COPD patients with elevated IgE levels. The study is sponsored primarily by National Jewish Hospital and the primary outcome is the frequency of acute exacerbations (NCT00851370).
GSK961081. This is a bifunctional or dual-action bronchodilator, -a single synthetic molecule with 2 pharmacophores, -a beta-2 agonist (LABA) and an antimuscarinic (LAMA). Sometimes referred to as MABAs, I wrote about these in a previous column (The COPD Pipeline III. COPD 2010;7:154–56). GSK, in combination with its US partner Theravance has now initiated a Phase IIb study of the agent. In a 28-day double-blind, double-dummy study, it will be given once or twice daily by inhalation to about 425 patients with moderate to severe COPD. The study is not yet listed in clinicaltrials.gov as of this writing. Although other companies have MABAs in development, GSK's 981081 appears to be at the head of the pack.
Stem Cell Therapy. In a previous Pipeline (COPD;2010:7:307–309) I reported on the mesenchymal stem-cell trial for COPD sponsored by Osiris and Genzyme. There is another trial of autologous ‘stem cells’ for severe COPD which has just been reported (João Tadeu Ribeiro-Paes et al. Int J of COPD 2011;6:63–71 DOI 10.2147/COPD.S15292). Bone marrow was obtained from the patients immediately after GMCSF stimulation. The mononuclear cells isolated from the marrow were immediately infused intravenously. The primary outcome was spirometry at 12 months and did not show a significant change in the 4 subjects studied. No adverse events were reported. (NCT01110252). http://www.dovepress.com/article_6046.t3156787
Fidaxomicin. The C. difficile superbug has overtaken MRSA as the commonest hospital-acquired infection in the US; about 500,000 patients are sickened with it each year. In around a quarter of all cases metronidazole and vancomycin either fail to eliminate it or fail to prevent a recurrence when the antibiotic is discontinued. The search for new antibiotics to address this problem has yielded fidaxomicin, an oral inhibitor of bacterial RNA polymerase. The drug is effective when given once daily on two consecutive days, according to reports of 3 trials at the Infectious Diseases Society of America annual meeting in Vancouver BC late last year. Importantly, C. difficile recurrence was cut in half. The manufacturer, Optimer Pharmaceuticals, San Diego, has applied to the FDA for fast-track approval. http://www.nature.com/nm/journal/v17/n1/full/nm0111–10.html
PolyUnsaturatedFattyAcid (PUFA). Endothelial dysfunction has been seen as a feature of some chronic inflammatory diseases including COPD. Recent research suggests that fish oil, specifically its polyunsaturated fatty acid content, improves endothelial dysfunction and lowers levels of inflammatory intermediaries. A pilot study sponsored by Columbia University and supported by NIEHS is enrolling patients with COPD to receive randomly either omega-3-PUFA supplementation (3 gm per day) or a corn oil placebo for 6 months. The primary outcome is “Flow-mediated Dilation” (details not provided). Secondary outcomes include the inflammatory markers LTB4, TNF-alpha, and IFN-gamma, plus a variety of conventional clinical endpoints. A subset of patients will undergo a separate procedure to collect cells from inside a forearm vein for analysis. The experimental phase of the trial was due to complete in December 2010. (NCT00835289)
Rosuvastatin (Crestor®). This is a Phase II randomized, placebo-controlled trial of the statin in stable COPD. Like the previous study, the primary outcome will be a vascular one, namely “peripheral vasodilator function expressed as PAT-RH ratio”, (no details provided).Secondary outcomes are circulatory proinflammatory markers, leucocyte counts in sputum, and spirometric indexes. The sponsors, University Hospital, Akershus in Norway and AstraZeneca describe the study as a proof-of-concept study. (NCT00929734).
NVC-422. NovaBay, a biotechnology company, is developing new molecular “anti-infective compounds for the treatment and prevention of antibiotic-resistant infections” which it calls the Aganocide® compounds. They are claimed to have the advantage of being fast acting, broad spectrum in activity, effective against multi-drug resistant bacteria and biofilm, and to have a good safety profile. One of these, NVC-422, is active in vitro against the “superbug” strain of Klebsiella pneumoniae which encodes the New Delhi Metallo-beta-lactamase-1 (NDM-1). It has previously shown efficacy against multidrug-resistant strains of E. coli and K. pneumoniae encoded with the NDM-1 gene. It is presently in trials for urinary tract and catheter-associated infection trials and wound infections. The website states it will be tested in cystic fibrosis. http://www.novabaypharma.com/technology/aganocides.
New Drug Approvals in 2010. According to monthly drug-approval reports on the FDA's website www.fda.gov, 21 new drugs were approved in 2010. This number, which excludes me-toos, new formulations or combinations of previously approved molecules, etc., is fewer than the usual 25 to 30 new molecular entities (NMEs) of previous years. The press takes this as an indication that FDA is becoming more concerned about safety issues (Wall Street Journal Dec 31, 2010). As in every year for about 2 decades, no NME for COPD was approved in 2010. However, the Nycomed/Forest PDE4 inhibitor roflumilast was approved for an acute COPD exacerbation indication in March this year. Its brand name in USA will be Daliresp®.
The Next 50 years… Attendees of the 50th annual meeting of the American Society for Cell Biology last year were invited to predict what the next 50 years in biology would bring. Apart from much grievance-venting about research grants, post-doc stipends, and irreverent (but also relevant) remarks about current politics, some interesting and quite imaginative predictions were made. –Identification of what “junk” DNA does, the solution to the mystery of protein folding, a computer that could be implanted in the brain, and a drug that replaces the need for sleep (but would FDA approve it for use by ICU attendings on call?). Nobody predicted the discovery of a way to change the natural history of COPD. Sadly, it seems 50 years would not be sufficient for that. The closest was the development of bioartificial organs. http://www.the-scientist.com/news/display/57865/#ixzz18b9NBrph.
Addendum: In the previous “COPD Pipeline VIII” that was published in the February 2011 issue of the journal, I discussed the impact of genomics on the flow of new therapies. I stated “knowledge of the molecular defects in cystic fibrosis that were discovered in 1989, 10 years before the first human genome publication, has not brought a single new treatment for that disease to the clinic at the time of writing.” I am happy to report that that statement is now about to become obsolete, http://www.vrtx.com/current-projects/drug-candidates/vx-770.html. On February 23 this year, Vertex Pharmaceuticals announced the results of a late phase trial of one of their experimental agents, VX-770, which they call a CFTR potentiator. The agent significantly improved lung function in patients with cystic fibrosis. Its nature and mechanism of action are described in http://www.pnas.org/content/106/44/18825.long, and its action is specific for CF due to the relatively rare G551D mutation, in which instance VX-770 “increases the function of defective CFTR proteins by increasing the gating activity…of CFTR at the cell surface.”
Some of the information found in this column was made available to the author through Citeline's Trial Trove©. For more information on Trial Trove, please visit www.citeline.com