This issue's column attempts to look far into the future to try to anticipate some of the dividends that basic research might bring to COPD management in the next decade or two. As there is more to say than can be squeezed into a single column, I will deal with just a few topics here, and address others in future columns.
Sirtuins The “French paradox” referred to the fact that the French seemed to be relatively tolerant of a diet that would be considered far too dangerous for American arteries. Research suggested that the likely explanation was the presence of the phytoalexin trans-resveratrol in red wine, of which the French are justly famously for being both excellent producers and large consumers. Resveratrol has indeed been shown to increase the life span of many animals in controlled studies, e.g., mice, fruit flies and nematodes. Longevity in many animal species can also be brought about by calorie restriction. The common link between the latter and resveratrol is that they both activate a family of enzymes that is almost ubiquitous in the animal kingdom, the sirtuins, which lengthen life span in yeast and most animal species. The sirtuins are homologous with the SIRT1-7 family in humans.
Perhaps not surprisingly, accounts of an agent that could prolong human lifespan—and a naturally occurring one at that—has resulted in exaggerated claims and threatened for a while to become a popular fad. The biotech company that was developing resveratrol, Sirtris, sold the rights to GlaxoSmithKline for $720M. Resveratrol congeners with one or two orders of magnitude greater activity have been synthesized, and there is talk of “blocking tumors, healing inflammation, and eliminating toxin.” However, parallel research claims that the assay was flawed and that the activation of sirtuin by resveratrol is an artifact (J Biol Chem 2010; 285:8340–51).
Why is any of this of interest to readers of the Journal? Although the biological effects of resveratrol itself remain controversial and some of the claims for it seem quite unrealistic, sirtuins have important potential for diseases of ageing such as COPD. There are seven human sirtuins, SIRT1–7, and the action of almost all is deacetylation of histone proteins, promoting gene transcription, down-regulating p53 activity, (http://www.ncbi.nlm.nih.gov/pubmed/20226541) and inhibiting the expression of NF-kappaB, (http://anti-agingfirewalls.com/2010/03/24/sirt1-mtor-nf-kappab-and-resveratrol/). Activation of SIRT1 in experimental animal models prolongs life, reduces the incidence of type 2 diabetes, and prevents the development of autoimmunity.
To cite the last link, “..three different theories of longevity seem to be collapsing into one: suppression of mTOR signaling, activation of SIRT1, and inhibition of expression of NF-kappaB. Activating SIRT1 does all of these things.” How it does all these, if it does, is unknown. One theory is that its anti-ageing and cancer protection effects are due to the prevention of “…abnormal angiogenesis –the formation of damaged or mutated blood vessels..” If all this is correct, sirtuins are remarkable molecules and one can see why ways to activate them would be of great interest to the pharmaceutical industry.
Using the search terms “SRT” or “sirtuin”, clinicaltrials.gov currently lists just 4 trials, 2 completed, only one of which is for a COPD indication. The Imperial College group in UK published a report suggesting that SIRT1 is a negative regulator of MMP-9 expression (which has been implicated in the pathogenesis of COPD inflammation). They found that SRT1 levels were decreased in the peripheral lung of patients with COPD, that oxidative injury led to reductions in SRT1, and that restoration of SRT1 activity with the sirtuin activator SRT-2172 blocked the increase in MMP-9 and inhibited neutrophilic inflammation in the lungs of mice exposed to cigarette smoke (Nakamaru et al. FASEB J. 2009;23:2810–9). One assumes industry must also be working in this area; the latest GSK web site's Product Pipeline page (February 2010, Respiratory and Immuno-Inflammatory Section), lists “2245840, a SIRT1 activator in Phase I for COPD.” I have not been able to discover if 2245840 is resveratrol, or a synthetic congener, or an entirely different molecule. Nor have I found a SIRT1 activator on any other company's published COPD pipeline.
There is, however, much ongoing basic research. Of the 129 publications yielded by “SRT” or “sirtuin” on Medline in just the first 6 months of 2010, the following is a small fraction of the investigational areas where its actions are being investigated: airway hyperresponsiveness, protection against oxidative injury, energy expenditure, insulin sensitivity, maintenance of T cell tolerance, apoptosis, ageing and disorders of ageing. Whether the basic research will yield any clinically useful products, and if so when, one cannot say. It will be several years at least, but patents are being issued and the subject seems well worth following. (I thank Prof. Peter Barnes of Imperial College, London UK for assistance with the “Sirtuin” section.)
Can we expect to see the first clinical dividends from the Human Genome Project any time soon? The answer is “definitely maybe”, as someone used to say. Ten years after the first draft of the human genome, we're still waiting for the plethora of significant therapeutic developments that seemed to be just around the corner. But genomics turned out to be much, much more complicated than we expected. We know a lot more about the genetics of diseases and genetic testing is showing how protean what we thought was a single disease can be, explaining many phenotypic differences and variable responses to treatments of some diseases. For instance, one thinks of the just-reported heterogeneity of patient responses to clopidogrel that are due to variations in the CYP-2C19 gene.
In previous columns I referred to studies of the genomics of matrix metalloproteases that make some sense of asthma and COPD susceptibilities (Gross NJ. COPD V. 2010; 7: 307–309), and to the genomics of nicotine dependence (Gross NJ. COPD VII. 2010; 7:437–439). These payoffs of genomics are important, but it's hard to think of a single new therapy based on genomics. 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. Knowing the sequence of a defective gene, even if the defect is “druggable”, to use pharmaceutical jargon, is only the first step in a long, long process of discovery and testing. Completely unexpected adverse effects and the extra regulatory and safety review resulting from a few bad unanticipated outcomes are only part of the problem.
However, some promising new therapeutic approaches are emerging, -some cancer treatments, and the recently approved osteoporosis treatment denosumab (ProliaTM), for example. We may be nearing the end of the dry spell and one novel approach based on genomics, RNA interference, seems worthy of attention if only because the first clinical trials of these agents for COPD are now being designed. Clinical proof of the small interfering RNA (siRNA) concept has just been provided by a Phase I trial in a malignancy (Davis ME et al. Nature 2010. Doi: 10.1038/nature08956). In addition, the first “COPD Pipeline” column (Gross NJ. COPD 2009;6:488-89) referred to an inhaled RNA-silencing oligonucleotide that inhibits expression of specific PDE isoforms, PI1100 (Topigen), which was in Phase II.
The rationale of RNA interference is that the expression of specific genes can be nullified, -silenced, by introducing a double stranded RNA one of whose strands is complementary to the target gene's mRNA sequence. After some intermediate intra-cellular reactions, the anti-sense strand combines with the mRNA resulting in cleavage of the target mRNA and its inactivation. The process is described in some detail with figures that may be useful for teaching purposes in the following link http://www.google.com/images? rlz=1T4SKPB_enUS339US340&q=sirna+mechanism&um =1&ie=UTF-8&source=univ&ei=Mq8iTOyLNsOblgf8_6y MCA&sa=X&oi=image_result_group&ct=title&resnum=4 &ved=0CEEQsAQwAw
Although the phenomenon of RNA interference has been known since at least 1998 (and yielded the 2006 Nobel Prize), one major difficulty of applying it to development and clinical exploitation has been delivery into the human cell. In the Phase I study cited above in Nature, a preparation using a nanoparticle vehicle was administered by frequent intravenous infusions. As pulmonologists we might be in the happier position of being able to send an siRNA directly to the target by inhalation, which is the strategy for Topigen's PI1100 mentioned previously.
Using the search terms “siRNA” or “RNA interference”, clinicaltrials.gov lists 18 trials mostly involving macular degeneration or a malignancy, but none for a COPD indication. One hopes that will change by the time this column is published.
Clinical Trials Initiated in May 2010. The total number for all indications was 160, only 4 for COPD. LABA-LAMA combinations are coming. Pearl Therapeutics, Vectura Group, and Novartis each have new trials with such combinations. Pearl's is a formoterol/glycopyrrolate HFA formulation; Vectura and Novartis have the indacaterol/glycopyrrolate combination, the filing of which is anticipated in 2012 and, if approved, will probably be the first once-a-day LABA-LAMA combination. Parenthetically, Novartis's indacaterol or QAB149 which was approved in EU in late 2009 as a DPI at 2 doses, 150 and 300mg qd (Onbrez Breezhaler™), was sent back to Phase II by FDA reportedly because the agency was not convinced that the doses were the appropriate ones.
Nexbio, a San Diego biotech, has initiated a Phase I study of Fludase® in the category “Respiratory (general)”. The company states “Fludase is a first-in-class broad-spectrum prophylactic and therapeutic agent for influenza-like illness caused by all annual and pandemic variations of influenza virus (IFV), including Pandemic Influenza A(H1N1) and avian H5N1, as well as parainfluenza. Fludase® is currently undergoing a Phase II clinical trial for the treatment of community acquired influenza”. According to the Nexbio website, Fludase® is a recombinant fusion protein that inactivates viral receptors on the cells of the human respiratory tract, thereby preventing influenza and other viruses such as parainfluenza from both infecting the human body and amplifying in already-infected individuals.
The UnPipeline: Phase-out of CFC inhalers
FDA has informed healthcare practitioners and patients that certain metered-dose inhalers used to treat asthma and chronic pulmonary obstructive disease will be gradually removed from the market because they use CFC propellants. They have been banned from consumer aerosol products for a long time.
Seven inhalers are affected by this action. Four of them are no longer being made. The remaining 3, to be phased out over the next few years, are Aerobid, Combivent and Maxair. Aerobid cannot be sold in the United States after June 30, 2011. Combivent and Maxair cannot be sold after December 31, 2013. Manufacturers of these inhalers could stop selling them prior to these deadlines. (I understand that Boehringer-Ingelheim is working with the FDA to ensure that the CFC-propellant version of Combivent will only be discontinued when a formulation of a similar albuterol-ipratropium combination to be delivered via BI's forthcoming Respimat® inhalation device becomes available. It is not known when that is expected to occur). For more see http://www.fda.gov/Drugs/DrugSafety/InformationbyDrug Class/ucm193896.htm
Another UnPipeline item—the dearth of new antibiotics. In the 1980s, new antibiotics were being introduced at the rate of about 3 per year. In the last decade the approval rate has dropped to one per year on average. One recent industry report calls the antibiotic pipeline “bone dry”. The reason, it is said, is the market. As I alluded to in a previous “Pipeline”, returns for a drug that may only be used for a week or two and that may well become ineffective in a few years are less attractive for developers than are drugs that will be used continuously by many patients for many years, even if it's a “me too”. Dr. Anthony S. Fauci, NIAID director, addressing one aspect of the problem stated “…new drugs to treat them [new virulent strains of MRSA] are urgent public health priorities.” Nevertheless, when Congress reauthorized the FDA last Fall (2009) they removed a provision that would have made antibiotic development more attractive to Pharmaceutical companies. “Plus ca change. …”