The COPD Pipeline XX

The problem of antibiotic resistance is a worsening headache, especially for our hospitalized and ICU patients and our COPD patients who are also huge users. We are aware that new antibiotics are becoming rarer and rarer largely because, for the pharmaceutical company, they are costly to develop, and do not have as much long-term usage as another anti-diabetic or bronchodilator drug. The antibiotic pipeline has been described as “bone dry”, and microorganisms are getting smarter at evading their efficacy. But the good news is that a number of really ingenious new ways of attacking microorganisms are being developed. Here are some:

Lipopolysaccharide Synthesis Inhibitor Gram negative rods (GNR) are amongst our worst foes for the sepsis they cause. A group at Albert Einstein has found that, in mice, the pathogenesis of these organisms, specifically Acinetobacter baumannii, is largely due to the lipopolysaccharide (LPS) they shed. LPS's, as we know, are highly inflammatory molecules and are lethal in mice. Blocking the micro-organisms’ ability to synthesize LPS with an inhibitor prevents the death of A. baumannii-infected mice by inhibiting the activation of the sepsis cascade. The LPS synthesis inhibitor (which is a small molecule but not otherwise described) is not inherently antibacterial and GNR can survive its presence in vitro. But if the infected mouse is treated with the LPS synthesis inhibitor, the GNR's inability to shed LPS disarms the GNR and stacks the odds in favor of the host's opsinophagocytic killing (1). Two observations, -an entirely new class of antibiotic, a LPS synthesis inhibitor, has thus been discovered. Secondly, standard antibiotic screening which is based on in vitro killing of the GNR would fail to detect the antibiotic activity of a LPS synthesis inhibitor. More is at http://mbio.asm.org/content/3/5/e00312-12. One looks forward to the development of such agents for clinical purposes.

Bacteriophage Bacteriophages that infect and kill Ps. aerogenosa are being developed by Ampliphi Biosciences. The rationale for the use of bacteriophages for that purpose is many-fold. Bacteriophages have very selective targets. Unlike antibiotics, they do not eliminate beneficial non-pathogens. Bacteriophages are effective in very small numbers and in single doses. In animal studies they can effect elimination of bacteria in a matter of hours as they replicate themselves. They are not subject to the development of resistance and are effective against biofilms which often limit the efficacy of conventional antibiotics. The bacteriophages being developed by Ampliphi are specific for Ps. aeruginosa and addressed to the treatment of cystic fibrosis and chronic otits media. The otitis media product has completed a Phase I-II trial, and the cystic fibrosis product is in pre-clinical. Clinical trials with the latter are scheduled to begin in 2013. Clinicaltrials.gov does not list other similar products. If successful the principle is sure to be applied to other micro-organisms. Further information is available at http://www.businesswire.com/news/home/20121018005766/en/Ampliphi-Presents-Encouraging-Pre-Clinical-Data-Phage-Based-Therapies

“Fecal transplants” or more discreetly, intestinal microbiota transplant or IMT, are a novel way of addressing the C. difficile problem. In a single-center study, the latest of several reports, 49 patients infected with recurrent multiply resistant C. diff received IMT and 46 of them responded completely within days. Recurrences were rare, -only 4 of the 46 responders, and there were no treatment-related adverse effects. The rationale for IMT seems to be that the use of potent antibiotics, or perhaps other factors, has altered the intestinal microbiome in a way that allows C.diff to become the dominant gastro-intestinal flora. The inoculation of the affected GI tract with a diverse healthy population of many billions of normal GI micro-organisms from healthy GI tracts aims to replace or at least compete with the C. diff population. Over-the-counter ‘probiotics’, a $20 billion market, have the same rationale but usually contain very few different microbial strains. The source of IMT varies but usually starts with the collection of feces from relatives, but unrelated donors have also been used. The feces are made into a slurry which is filtered and the supernatant delivered to the patient's GI tract by enema or colonoscope, but naso-gastric tube delivery has also been used. One site has pooled and frozen the transplant in aliquots. The long term success, at between 85% and 95%, is remarkable, as is the low risk of adverse events. One anticipates that a large prospective trial will be performed and that the Infectious Disease community will recommend a standard procedure for the indication of IMT use, and acquisition and delivery of the agent (3, 4, 5).

TCN-032 Theraclone has an influenza program that is developing 2 agents for the treatment of severe influenza, and the national pandemic stockpile. TCN-032 is a fully human IgG monoclonal that binds to an epitope on the well-conserved M2e protein of the influenza A virus, including avian and swine strains. A phase I trial was completed last year and was reported to show no dose-limiting or serious adverse events, with a good immunogenic response. A safety and efficacy phase II randomized placebo- controlled trial is underway. Subjects in the active arm will be challenged with H3N2 influenza A, and the primary efficacy outcome will be based on clinical manifestations (NCT01719874). Results are expected in Spring 2013.

HA Theraclone's second anti-influenza agent is a hemagglutinin still in preclinical. Their website states they are “.. screening human donors for broadly neutralizing, cross-reactive human antibodies to hemagglutinin. To date, several candidates have been identified that bind and broadly neutralize Group 1 as well as the H3 subtype of Group 2 influenza strains.” A search of the Clinicaltrials.gov website using “hemagglutinin” and “influenza” as search terms reveals 114 studies about two thirds of which are completed studies. Obviously, the field is highly active.

On the subject of influenza, in UK there is controversy over the reliability of trial results of Roche's Tamiflu. The editor of the BMJ has asked the Board of that company to respond to concerns raised by a Cochrane review of neuraminidase inhibitors in healthy adults. That study “took the view that, since eight of the 10 [randomized controlled trials] on which effectiveness claims were based, were never published, and because the only two that had been published were funded by Roche and authored by Roche employees and Roche-paid external experts, the evidence could not be relied upon,” writes Dr. Fiona Godlee Editor of the BMJ.

RPL554 This is a dual PDE3 + 4 inhibitor, the lead drug being developed by Verona Pharma. Besides being a combination PDE inhibitor that is, in theory, likely to be more efficacious than an inhibitor of the sole PDE4 enzyme (2), another novel feature is that the agent will be given by nebulization. A recently reported phase II cross-over trial in 12 COPD patients showed a rapid bronchodilator response, reaching an increase in FEV1 of 15% that was equivalent to that of the albuterol response in the same patients. The treatments were well tolerated. (This study was reported as a poster at ERS last year). The company has also studied the agent in asthmatic patients. Additional studies are ongoing in UK. Verona has a portfolio of drugs in development for the treatment of a variety of respiratory problems, their website is http://www.veronapharma.com/s/Home.asp

MN-221 This is a novel, selective ß2-adrenergic receptor agonist being developed by MediciNova for the treatment of acute exacerbations of asthma and COPD. It is proposed to be administered intravenously in patients where airflow is so limited that inhalation therapy would be ineffective. Animal and in vitro studies indicate that its ß1-adrenergic receptor stimulating activity is less than that of other ß2-adrenergic receptor agonists suggesting, it is claimed, greater cardiac safety than other β2 agonists. Studies also suggested that MN-221 may act as only a partial ß1-adrenergic receptor agonist in cardiac tissue, while acting as a full ß2-agonist in lung tissue. Clinicaltrials.gov lists 2 trials of this agent in acute exacerbations of COPD and 3 trials in acute asthma.

Riociguat We have 3 classes of drugs that treat pulmonary hypertension (PH) but they are not considered to be entirely satisfactory even when used in combinations (6). Riociguat, a Bayer product in development, is the first in a new class of agents for the treatment of PH. Its action is to stimulate soluble guanylate cyclase, a key signaling transduction enzyme, which together with nitric oxide promotes the synthesis of cyclic GMP, leading to relaxation of vascular smooth muscle. The effect of Riociguat is preferentially upon the pulmonary rather than the systemic vasculature. As impairment of the NO-sGC signaling pathway has been implicated in the pathogenesis of PH, the action of Riociguat in promoting cGMP seems physiologically appropriate.

Two phase III randomized placebo-controlled studies of Riociguat were recently completed and preliminary data were presented at the ACCP annual meeting last year. The primary outcomes were the 6-minute walk at 12 weeks and showed 36 meters (10%) and 46 meters (13%) improvements which exceed the currently accepted MCID. In addition, significant improvements in pulmonary vascular resistance, pulmonary artery pressure and WHO functional class were observed. Adverse events included a higher incidence than in the placebo group of headache, dyspepsia, dizziness, diarrhea and hypotension. The agent is taken orally 3 times daily. Three dosages were included in the trials and there was a tendency for higher dosages to result in greater outcome benefits, and for the benefits to increase with time.

Clinicaltrials.gov lists 12 trials of this agent, 6 of which were still active at time of writing. Enrollment criteria for these studies, where stated, excluded subjects with WHO group III which is PH secondary to COPD. This is entirely appropriate as previously stated (6).

Accelerating Drug Approvals

According to a recent study from the Tufts Center for the Study of Drug Development, development and approval times in the US are decreasing, namely from an average of 8.0 years in 2002-2006 to 7.4 years in 2007-2011. Most of the decrease was due to drugs spending less time under review, -credit the FDA for this. Oncology drugs tend to take longer in development but less time in review than other classes. Compared to the European agency (EMA) FDA is twice as fast as reviewing oncology drugs, 7 months versus 15; but a little slower at reviewing non-oncology drugs, 17 months versus 13.

Accelerating Drug Trials

Three drug companies are collaborating in an attempt to get clinical trials up and running faster. Johnson & Johnson, Merck and Eli Lilly are joining forces to streamline the study sites and study-subject recruitment and enrollment processes. http://www.dddmag.com/news/2012/11/drugmakers-collaborate-facilitate-tests?et_cid = 2949857&et_rid = 227339699&linkid = http%3a%2f%2fwww.dddmag.com%2fnews%2f2012%2f11%2fdrugmakers-collaborate-facilitate-tests

They will create a databank from which the companies can readily identify and recruit sites and subjects. “The goal is to eliminate duplicative, time-wasting steps that increase drugmakers’ costs and stretch out the time it takes to get a new medicine approved,” -a goal we all share. Anything that accelerates the entire approval process must be welcomed.

One wonders if and how the HIPPA and protection of patient data confidentiality will be addressed. One also wonders how much the databank will streamline the process. For instance, I can contribute my experienced COPD subjects to a databank, but how will that facilitate a partner company that is developing oncology agents? And is their roster of oncology patients likely to provide any appropriate subjects for my COPD trials? Will those oncology subjects have a recorded spirometry that will readily identify suitable subjects for my COPD study?

In addition, one has to wonder how much the collaboration will shorten the overall drug and device development process. Our experience from both the investigator and pharmaceutical company perspectives is that identification and recruitment of sites and subjects is not a major component of the time needed to take a product to approval. Most of the 5-10 years that a product typically requires are spent in trial data management and interpretation, strategic planning, planning trials, and repeating studies that turn out to have unexpected outcomes, -typically in Phases II and III.

Nevertheless, as stated above, anything that shortens the time from start to finish must be welcomed. Pharmaceutical companies must have considered this approach to be worthwhile as another group of 10 US and European companies called TransCelerate BioPharma recently decided to do a similar thing.

More information is available at http://www.forbes.com/sites/matthewherper/2012/09/20/ten-pharmas-aim-to-cut-red-tape-to-speed-drug-development/

Acknowledgements

I thank Eugene Colice MD for assistance with the topic ‘Accelerating Drug Trials’. Some of the information presented in this column was made available through Citeline's Trial Trove©. For more information on Trial trove, visit www.citeline.com