Throwing bricks at a brick wall?
Lets change gears a bit. I hardly know how to tag this, as I’d say this disease is certainly immunological, a twist on fibrosis, a failure of tissue remodeling, certainly a clinical practice mess, and a nightmare for drug development. I know you’re thinking, aha, Lupus Nephritis! That’s a good guess, and a subject for another time. I want to talk instead about Chronic Obstructive Pulmonary Disease (COPD), a huge disease area with a startling degree of unmet need. Formally known as chronic bronchitis and emphysema, COPD covers a spectrum of often co-existing pathologies, found almost exclusively in smokers and other individuals whose lungs are exposed to hazardous environmental insults.
Just a very brief primer: in the emphysema form of COPD, the walls between many of the bronchial alveoli are damaged, and can break down entirely. As one might expect, the gradual loss of the structural integrity of the alveoli causes an equally gradual loss in the capacity of gas exchange, i.e. less oxygen can cross into the lung capillaries.
In the chronic bronchitis form of COPD, the airway lining is inflamed, causing thickening of the airway walls and constant mucus production. As less air can be drawn into the inflamed lung, gas exchange is again reduced. Since most patients present with both types of pathological processes underway in their lungs, lung function is greatly compromised.
Emphysema is a pathology term referring to the destruction of the alveolar walls. Bronchitis is a clinical term referring to unrelenting cough of 3 or more months in duration, unrelated to other causes (e.g., infection).
A recently recognized component of COPD is an asthmatic phenotype, whereby allergic responses to key environmental antigens further induces inflammation, but also triggers the classical asthma symptoms of airway constriction, airway thickening over time, and mucus production.
Of major concern is the chronic and irreversible nature of this disease. Patients diagnosed with COPD often experience continual decline in lung function even if they stop smoking. In some patients decline in lung function can be acute (rapid) while in other patients lung function declines slowly over many years. Why the course of disease development is so variable is not well understood.
The pathophysiology of this disease is complex. For cigarette smokers (90%+ of the total patient population) the initial response is certainly combinatorial. Airway epithelial cells, airway dendritic cells (DC) and alveolar macrophages respond to injury induced by tobacco smoke, triggering innate immune responses designed to deal with injury and to recruit the adaptive immune system; this adds a second layer of complexity as a host of different cell types traffic into the lung. Of note is the influx of inflammatory macrophages, neutrophils, and cytotoxic T cells (CD8+) that contribute to lung damage. The damage itself is caused by a potent mix of free radicals which are directly cytotoxic (from cigarette smoke, and also as produced by inflammatory cells), expression of proteases which destroy cell:cell adhesion and break down extracellular matrix, and the secretion of pro-inflammatory and cytotoxic proteins that exacerbate the inflammation and also cause cell death. As the airway epithelium is damaged and inflammatory cells flood the vasculature and interstitial space, “alarmed” endothelial cells further contribute to the developing pathology, loosening endothelial cell tight junctions and secreting additional pro-inflammatory mediators. Dead and dying cells accumulate, eventually overwhelming the ability of phagocytic macrophages to clear them. To top it all off, epigenetic changes in various cells in the lung have been described, locking these cells into a pathogenic state. I think we can agree that there are enough bricks here to build a very intractable wall.
So, the lungs of these patients by the time they present are heavily damaged, and there is very little to do other than relieve symptoms. The drugs used for symptomatic relief include bronchodilators such as beta2 agonists and anti-cholinergics (which antagonize the muscarinic receptor). In long acting formulation, beta2 agonists and muscarinic receptor antagonists (called LABAs and LAMAs, respectively) can provide symptomatic relief for many patients. Additional treatment options include inhaled or systemic corticosteroids, to reduce inflammation. These treatment options are considered palliative, and do not significantly change disease course or slow progression in most patients.
Given the complexity of disease presentation it is not too surprising that the number of genes claimed in one study or another to be associated with risk of COPD is huge and fraught with contradictory data (for a recent review see Bossé, 2012, Intl J COPD 7: 607-631). The list of clinical stage candidate therapeutics is also large and diverse, illustrating the challenge of where to start in tackling this disease. A list of therapeutics in development is available online (http://www.phrma.org/research/new-medicines-COPD) although somewhat out of date.
I want to highlight several pathways (and therefore drug targets) of particular interest. Note we are going to skip over any new LABAs and LAMAs as COPD really needs disease-modifying drugs, not better palliatives.
Here’s a short table of interesting potential therapeutics, sorted by related pathways (modified from the on-line list cited above):
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roflumilast
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oral PDE4 inhibitor
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Takeda/Nycomed/Forest Labs
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registry
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Approved
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MK-0359
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oral PDE4 inhibitor
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Merck
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2
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completed 2007: no results reported
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GSK256066
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inhaled PDE4 inhibitor
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GSK
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2
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completed, GSK has requested delay in reporting results
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AZD1981
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CRTH2R antagonist (PGD2 inhibitor)
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Astra Zeneca
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2
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phase 2 completed 2009, no efficacy seen in 1o or 2o endpoints
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MK-7123
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CXCR2
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Merck/Ligand
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2b
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terminated in 2011, no results available
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AZD5069
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CXCR2
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Astra Zeneca
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2
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completed 2011, no results available
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GSK1325756
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CXCR2
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GSK
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1
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dose finding and formulation
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AZD2423
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CCR2b
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Astra Zeneca
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2
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completed 2011, safety, tolerability, biomarkers: no results available
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canakinumab
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anti-IL-1b
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Novartis
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1/2
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completed 2011, see text
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MEDI-8968
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anti-IL-1 receptor
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Medimmune/Astra Zeneca
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2
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ongoing
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MEDI-2338
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anti-IL-18
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Medimmune/Astra Zeneca
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1
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completed: dose escalation with safety, PK: no results available
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MEDI-7814
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C5/C5a
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Medimmune/Astra Zeneca
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1
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completed 2012: dose escalation with safety, PK: no results available
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MEDI-563
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anti-IL-5 receptor
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Medimmune/Astra Zeneca
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2a
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ongoing
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GSK610677
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inhaled p38 inhibitor
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GSK
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1
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completed 2011; dose escalation with safety, PK: no results available
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PF-03715455
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inhaled p38 inhibitor
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Pfizer
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1
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dose escalation study; neutrophil response to LPS
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PH-797804
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p38alpha inhibitor
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Pfizer
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2
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recruiting
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The focus here is on anti-inflammatory pathways that may provide some hope for disease modification rather than simply targeting symptoms. The PDE4 inhibitors and related compounds include rofumilast, the first targeted anti-inflammatory agent approved for use in COPD. Rofumilast provides notable proof of concept that inflammation is a valid target in this disease even though it is only a modestly useful drug (see Cazzola et al. 2012. Eur. Respir. J. 40: 724-741, for an exhaustive review of this and other drug classes). Indeed, its modest efficacy led to rejection in the EU. Nonetheless this is a large and growing area of clinical study and may yet yield breakthrough medicines.
Of note are three CXCR2 antagonists: MK-7123, AZD5069, and GSK1325756. CXCR2 is a chemokine receptor (in the GPCR family) that regulates the migration of neutrophils and monocytes into the lung. Since neutrophils express pro-inflammatory mediators, cytotoxic agents and free radicals, they are a prime target cell type in COPD. CXCR2 expression is upregulated in COPD, and expression is correlated with disease exacerbation. No clinical results are available from these trials to date, and one drug (MK-7123) appears to have been terminated, for reasons unknown. Other reagents targeting cell trafficking include the selectin antagonists, such as bimosiamose. Recently published data show that bimosiamose inhalation twice daily reduced neutrophil and macrophage counts in sputum but had little effect on lung function (Watz et al. 2012.
doi: 10.1016/j.pupt.2012.12.003).
Interleukin-1 beta (Il-1beta) and the interleukin-1 receptor (Il-1R) are targeted by canikinumab and MEDI-8968, respectively. The canikinumab clinical data is instructive. Patients dosed up, starting with 1 mg/kg canakinumab, i.v., then a dose of 3 mg/kg 4 weeks later, and another dose of 3 mg/kg two weeks after that. Thereafter, doses of 6 mg/kg were given every four weeks until completion of the 45-week treatment period. Outcomes included change from baseline measures of forced expiratory volume, 1 second (FEV1) and forced vital capacity (FVC). Results were mixed at best and unfavorable on balance. The adverse event profile was about what you would expect with multiple bacterial and fungal infection, but also a scattering of neoplasms, including several lung cancers, CLL and others. The canikinumab data suggest that targeting this pathway, at least with this specific reagent, has unintended effects in the context of COPD. Recent work has emphasized the role of IL-1alpha, independently of IL-1beta, in COPD. Results from the MEDI-8968 trial will provide more information, since blockade of the receptor should inhibit signaling from both cytokines.
I was surprised to see multiple p38 inhibitor programs active in COPD, since nearly everyone I know seems to have given up on this MAPK pathway, which is even more out of favor than the NF-kB pathway (I’ve done hard time in both fields of study, and know how frustrating it is). Still, it is hard to find a more pleotropic pro-inflammatory signaling pathway. The p38 MAP Kinases transduce signals from diverse receptors, including those signaling exposure to oxidative stress and cytokine receptors. p38 inflammatory cell activity has been demonstrated in COPD samples, and it has been proposed that p38 activation correlates with disease progression. So, I like the therapeutic hypothesis – that inhaled p38 inhibition will provide local efficacious exposure while avoiding systemic toxicity. It will be very interesting to watch the progress of these compounds as they work their way through clinical trials.
Other programs listed target T cell biology (CRTH2, Il-5), innate immune responses (C5/C5a, perhaps IL-18) and other chemokine pathways (CCR2b). It remains to be seen which if any of these approaches will significantly alter the disease course for COPD patients. Of course this is just a very small sample of the approaches being pursued. Many other trials are visible on www.clinicaltrials.gov and many earlier programs are listed in Cazzola et al., referenced above.
We should note in closing that the COPD patient population is above 13MM in the US, with a similar number in the EU. There are huge numbers of patients in the BRIC and other developing countries. Healthcare costs for these patients are staggering, as they have a chronic degenerative disease, requiring in some cases hospitalization, in-home care, hospice care, in short, these patients require life-long medical treatment. With health care spending on COPD in the US approaching 60BB per annum, drug development in this area will continue to grow. Large programs are underway in some of the major pharmaceutical companies, and novel therapies will emerge. We just have to hit the right brick, or more likely, bricks. Stay tuned, and follow @PDRennert