Category Archives: fibrosis

Holiday Reading

some of the stuff we’re reviewing over the holiday break. N.b. paywalls ahead!  And at the very end, some current non-science favorites.

Tumor Mutational Landscape

Age related variants of variants occurred in three genes (DNMT3A, TET2, and ASXL1) are associated with hematological malignancy risk and

News and Views on the NEJM papers

using siRNA to identify driver genes in breast cancer


a primer on the role of PD-1 pathway inhibitors in Hodgkin’s Lymphoma, from Nat Rev Clin Oncol

the role of TILs and TIL-associated TNF in the survival of CRC patients

nivolumab in metastatic RCC, published data

resistance to T cells in melanoma (hint: they lose MHC expression)

interesting look at PD-L1 expression of the response of RCC to targeted therapies

it’s hard to control ipilimumab-induced tox 2353.abstract

IO combination review

tumor/microenvironment cross-talk mediated by microRNAs

functional blockade of miR-23a releases TILs in an ex vivo NSCLC assay

neutrophils, T cells and lung cancer

Given the new immunotherapy data in bladder cancer, a review of the molecular drivers of this tumor type is most welcome

MDSC requirements for survival

Gene Therapy and CAR T

Novel gene therapy methods puts a safety brake on a retrovirus-based vector

a new review of the CRISPR, Talen, and ZFN technologies for gene editing

NY-ESO-1 CAR T P1 results in solid tumors: long term follow-up and correlates of response

Targeted Therapies

A very timely primer of the role of different PI3K isoforms in diverse cancers

a Notch in the cancer treatment belt? Nope, a bit of a toxic mess made with anti-DLL4 antibody Demcizumab from OncoMed

IL-17 and colon cancer?

Hematological Malignancies

von Adrian and Sharpe tease apart Follicular Lymphoma

the role of one of gp130 in multiple myeloma

Fibrosis, Inflammation, Metabolism, MS

a brand new fibrosis review

the TRPV4 pathway, TGFbeta and IPF

The role of novel branched fatty acid esters of hydroxy fatty acids in Type 2 diabetes

will STING finally yield a useful target in lupus?

an animal model of JCV infection and PML

Investment and Deals

Pharma funding to pull programs out of the academic space

some color from NRDD on the Genentech + NewLink IDO-1 inhibitor deal

Also notable

300,000,000. A violent graphic lurid hypnotic novel of the dissolution of consciousness and the consequence of multiple realities converging within our unprepared empty minds and upon our decadent culture. Horrific and wonderful, but not for the squeamish.

Thug Kitchen – eat like you give a #$%@^. Fun, but you get the idea.

Death & Co: Modern Classic Cocktails. Drink like an adult.

Creating a New Therapeutic Focus

In 2012 we were engaged by a large local biotech company to evaluate a new therapeutic area. This effort was driven by the desire of the client to move aggressively into a new suite of diseases. We began by doing a deep dive into the client’s existing portfolio in order to identify assets already in development that could be directed to novel diseases. Concurrently we began a comprehensive review of preclinical and clinical stage assets available for partnering or in-licensing. Finally we engaged in pathological pathway analysis to identify novel targets for discovery programs. This effort, initiated and completed within two quarters, led to the eventual acquisition of a private company and its Phase 2 clinical stage assets, for nearly 100MM $USD. Based on our analyses the client also started several new discovery and preclinical development programs to complement the clinical stage acquisition.

Cells underlying fibrosis: emerging themes

by Paul D. Rennert, 28 December 2013
A few weeks ago a paper describing the origin of cells responsible for dermal wound healing showed up in Nature, with a beautiful cover picture showing distinct cell lineages in skin. I actually missed the paper when it came out, so thanks to my friend Katherine Turner (ex-GI, ex-Biogen, now at Scholar Rock) for pointing it out.
The abstract is here, the full text requires a subscription. The paper is from Fiona Watt’s group at the Center for Stem Cells and Regenerative Medicine, King’s College, London.
The paper convincingly shows that the dermal layer of the skin is comprised of two distinct fibroblast lineages. Some context: the dermis is the layer of the skin that lies below the epidermis and includes the upper dermis (the dermal papilla) and the hypodermis (lower dermis). The major cells types residing in the dermis are fibroblasts, which along with the extracellular matrix they produce, form the connective tissue. Other prominent cells include macrophages and adipocytes (fat cells). There are also resident dendritic cells, Mast cells, T cells and other immune system cell types. Other structures include the hair follicles, sweat glands, oil glands, blood vessel endothelium, lymphatic vessels, and nerve endings.
Ok, so why is this paper interesting?
What the authors demonstrate is that the upper and lower dermis originate from distinct lineages of fibroblasts. This is shown using lineage tracing techniques and cell transfer assays. The lineage tracing assays required the use of multiple promoter/expression transgenic mice, and is elegantly and robustly done. The data show that late in mouse embryonic development (day 16.5) the dermis becomes fate-restricted: the Lrig1+ fibroblasts become the cells of the upper dermis and Dlk1+ cells give rise to the lower dermis. Here I’ve just picked a few of the markers they used and have grossly simplified the developmental story because I’m more interested in what they did next.
Having established that there are 2 different fibroblast lineages in the mouse dermis, the investigators asked a pretty simple question: what happens when you wound the skin in the adult mouse? Cellular wound-healing models have been widely used as in vitro models of fibroblast migration, ECM production and differentiation into myofibroblasts (so called because they express smooth muscle actin, a marker of myocytes/smooth muscle cells). Wound healing more broadly is a process of local repair and remodeling. “Deranged” or unregulated wound-healing is one model of fibrosis.
Skin or dermal fibrosis is a highly active area of study. Important fibrotic diseases of the skin include systemic sclerosis (scleroderma), amyloidosis, nephrogenic systemic fibrosis, mixed connective tissue disease, wound-healing fibrosis and others. Scleroderma is modeled in mouse by creating chemical insults on the skin, for example with bleomycin. Such models mimic the effect of chronic wounding, thus the connection to wound healing assays. It has been further demonstrated that many of the processes and pathways involved in dermal wound-healing are dysregulated in skin fibrosis, for example ECM production, TGFbeta production, and CTGF activity among many others.
While there is a good deal of consensus as to the mediators of the fibrotic process, the source of the activated cells that drive fibrosis has been controversial. This is a critical question to address, as effective anti-fibrotic therapies should target the pathogenic cell types. Without getting into immune cells, resident macrophages and Mast cells and the like, we can now at least carefully address this question regarding the source of activated fibroblasts. One model proposes that migrating fibrocytes traffic into wounded/fibrotic sites from the circulation. Another model, widely held, proposes that pericytes, which are mesenchymal cells that support blood vessels, somehow migrate away from endothelium and become myofibroblasts, thus supporting wound healing (and by extension contributing to fibrotic diseases). Finally, it has been proposed that myofibroblasts are derived from local (resident) fibroblasts that migrate into the wound and differentiate.
The Watt’s paper shows clearly that the Dlk1+ fibroblasts of the lower dermis migrate into the wound and that a proportion of these cells express smooth muscle actin and are therefore myofibroblasts. These cells produce collagen, the classic ECM protein that characterizes fibrosis, in this case simply deployed to help close the wound. After the wound is closed the epidermal layer is reformed and only then does the upper dermis reform.
These findings allow for the formulation of specific questions regarding the lower dermal fibroblasts:
- what signals activate and then shut down the lower dermal fibroblast to myofibroblast differentiation process?
- are these signals dysregulated in fibrosis?
- do these same cells deploy in response to fibrotic injury (e.g. with bleomycin)?
- do these cells interact with inflammatory cells, thought to contribute to the pathogenic fibrotic response?
- can we identify actionable targets on this cell type to prevent or decrease the fibrotic response?
Importantly this paper encourages us to ask whether similar resident fibroblast or other mesenchymal cell populations contribute to fibrotic disease in other organs such as the kidney, liver, heart and perhaps even lung. If so, the validity of the circulating fibrocyte and differentiating pericyte models might be reevaluated. Notably, linage tracking was used in support of a pericyte model of myofibroblast differentiation in a similar dermal/muscle injury model as detailed in a paper published in 2012 in Nature Medicine (abstract here). I suspect that squaring these studies will take a careful review of the markers used to identify different cell populations and a detailed look at the injury protocols. I’ll update as more info becomes available.
This is a classic example of the beautiful work that comes from an active and competitive research area and we can and look forward to further studies that will illuminate the processes of wound healing and fibrosis. Such work will certainly support and advance successful fibrosis drug development.
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Cool Science: Pathways Driving Fibrosis and Related Drug Development

December 10, 2013, by P.D. Rennert
Some recent interesting papers reveal new mechanisms for the regulation of fibrotic pathways, and suggest drug discovery opportunities.
Fibrosis is a huge medical problem and encompasses many different diseases across most organs and tissues: lung, kidney, liver, gut, vasculature, skin, ocular, cardiac, etc. Lets just assume upfront that we recognize that TGFbeta (TGFb) signaling is a critical pathologic pathway in the induction and persistence of the fibrotic state. I want to take that as a given. TGFb is also showing up more and more often in the context of tumor genetics, as befits a critical growth factor. From the drug development perspective, TGFb antagonism not yet been successful due to the toxicities encountered: TGFb is very pleiotropic and controls many normal functions as well. As a result several alternative means to target the TGFb pathway are under development for the treatment of fibrosis.
A very clever strategy for targeting TGFb was developed by researchers at Biogen, along with a top notch group of outside collaborators (see for example Horan et al. 2008). It was determined that activation of TGFb at sites of inflammation and injury, which are sites for the initiation or promotion of fibrosis, depended on an integrin, namely alphavbeta6 (avb6). Biogen developed a monoclonal antibody (mAb) to avb6 and subsequently outlicensed this mAb to Stromedix. I helped bring that mAb back into Biogen 5 years later (early 2012). By then the mAb, now called STX-100, was Phase 2 ready, a testament to the strength of the Stromedix team. Stromedix was acquired for 75MM upfront, plus milestones: a good deal for both companies. 
On the science side, how avb6 activated TGFb was not well understood, but this was thought to involve a conformational change in the beta6 strand of the integrin.
So lets jump ahead, or sideways anyway.
A parallel basic research and drug discovery effort had uncovered an interesting role for the bioactive lipid lysophosphatidic acid (LPA), and for the LPA receptors, in fibrosis. LPA receptor gene-deficient mice (LPAR knock-out or KO) were resistant to the development of fibrosis in a variety of models, and across diseases in different organ systems. This was interesting since it suggested that somehow LPA and the LPARs were regulating the TGFb pathway (see here, and here). How this occurred was not known, and the available data were correlative: when LPARs were blocked, disease was lessened and there was less TGFb, but was this specific to the LPA pathway or was it due to reduced disease activity? It turned out that the LPA/LPAR pathway interacted with integrin biology, in a couple of interesting ways. The first concerned signaling through one of the LPARs, LPAR2. LPARs are G-protein-coupled receptors, that is, they signal using G proteins. We won’t go into these, but its enough to say that signaling from LPAR2 through a specific G-protein induced a conformational change in the beta chain of avb6, and that this conformational change was associated with the ability of avb6 to activate TGFb. The second way has to do with the manner in which LPA is produced by the enzyme autotaxin, and we’ll come back to that later. This is not the only manner in which LPA impacts fibrosis, as was demonstrated by the Amira drugs that are selective antagonists for LPAR1 and perhaps also LPAR3 (see for example, here). This drug also blocked the development of fibrosis in multiple models, and showed activity in early clinical development for idiopathic pulmonary fibrosis (IPF). The data were suggestive enough that Bristol-Myers Squibb bought the company for $325MM upfront in 2011.
Now lets jump ahead.
In 2011 Tim Springer’s lab published a remarkable paper (Shi et al). What this paper explored, using structural biochemical and biophysical techniques, was how TGFb was kept in an inactive state by its own protein structure (called the “straightjacket”). Breaking this inactive state required distinct and critical interactions, one in which TGFb was embedded into the cell membrane in complex with latent TGFb binding proteins (LTBP), which in turn bound to the extracellular matrix, and the other by which TGFb interacted with the avb6 integrin. Productive binding of the integrin required interaction with cell’s the actin filaments, the protein fibers that hold the cell together and also rearrange themselves in order to allow the cell to move. We should note here that integrin:actin interaction is most often mediated by talins, the proteins that sort of cross link the actin filaments (think of rungs on a ladder as a simple picture). This complex interaction of TGFb, avb6, the cell membrane and the actin fibers imposed enough force on TGFb to break its lock, and free it for activation and release from the cell surface. Its as if you had to rearrange the walls of your house in order to open a window. This is a highly regulated system. So, how did avb6 accomplish this trick? Spinger’s lab didn’t give an answer – they were intently focused on the TGFb structure. But a recent paper on a different integrin provides a clue, and maybe brings us back to the LPAR pathway.
A few weeks ago Shen et al (in Nature) elucidated differential signaling by the integrin alphaIIb-beta3 (aIIb-b3), focusing on the interaction of the b3 subunit with talin and with a G-protein, Galpha13 (Ga13). They found a specific amino acid motif – EXE – mediated binding to the G-protein. This motif is found in many beta subunits, including b6. The protein domain in which this motif is found is within a region known to mediate binding to talin, and Shen et al. go on to show that the two binding phenomena are mutually exclusive. Importantly, interaction with the G-protein required binding to fibrinogen, a ligand for the aIIb-b3 integrin. Integrins transmit signals bidirectionally. Inside-out signalling, the process by which an integrin undergoes conformational change in response to ligand binding, is a talin-dependent mechanism. aIIb-b3 integrin ligation mediates platelet aggregation and triggers outside-in signalling, which requires Ga13 and greatly expands thrombus formation. Switching back to interaction with the G-protein corresponds to clot retraction. So this model proposes waves of signaling controlled in part by which component of the cellular machinery – talin or G-protein – is engaged.
It has been demonstrated in lung and kidney fibrosis models that avb6-mediated activation of TGFb can be triggered by the LPAR2 signaling through Galphaq (Gaq) to the Rho/Rac kinase pathway (see here, and here). The connecting dots from Rho/Rac kinase to avb6 activation are not yet described, by may work by regulating the interaction of avb6 with a G-protein (eg. Ga13) v talin or actin. In KO mouse experiments, Ga12/13 were shown to be required for basal TGFb activation in embryonic fibroblasts (MEFs), but not in LPAR2 transfected MEFs. The relevance of this data to the fibrotic condition however is unclear, and I think it remains worth exploring this link further.
There is an independent link between the LPA/LPAR2/avb6/TGFb pathway and integrin biology. The production of LPA is controlled by the enzyme autotaxin. In settings of tissue injury and inflammation, autotaxin and the LPARs are upregulated by various cells. In this way the LPA production machinery (autotaxin) and the responding receptors are operating in tandem. More remarkably, autotaxin is carried into the inflamed or injured tissue by activated cells – platelets, T cells, and likely other cells types. The manner in which autotaxin is transported is by binding to integrins with b1 or b3 subunits, carried on the cell surface and maneuvered into place by the coordinated action of the activated cell (see a review here). This has likely evolved to maximize the production of LPA at sites where it is required – the half life of LPA in circulation is very short, minutes only. Indeed the half-life of TGFb is even shorter, less than one minute.

So, this is a highly coordinated and highly regulated system, as might be expected when dealing with a potent growth factor like TGFb. The implications of the model for drug development are several. First it seems clear that LPA receptor antagonists that can target LPAR2 would be therapeutic and differentiated from the Amira assets now owned by BMS. The benefit of targeting avb6 was discussed earlier in the context of the Stromedix/Biogen deal. Another target that appears here is autotaxin, and several companies are pursuing autotaxin antagonists – I developed a beautiful compound series at X-Rx Discovery, as one example. Finally, there is the very exciting prospect of using the new structural information about TGFb and related proteins (its a big family) to design drugs that selectively block TGFb activation in the context of an activated cell response. This may be one of the things that Scholar Rock Therapeutics, a venture-company founded by Tim Springer and colleagues, is up to now. We’ll have to wait and see.
Bottom line: we are learning a lot about fibrosis pathophysiology, only a little of which is touched on here. With that knowledge will come a new wave of drug development, and ultimately we hope to provide relief for patients suffering from these chronic and very serious diseases.
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Anti-inflammatory therapeutics for COPD

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 ( 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):

Drug Name






oral PDE4 inhibitor

Takeda/Nycomed/Forest Labs




oral PDE4 inhibitor



completed 2007: no results reported


inhaled PDE4 inhibitor



completed, GSK has requested delay in reporting results


CRTH2R antagonist (PGD2 inhibitor)

Astra Zeneca


phase 2 completed 2009, no efficacy seen in 1o or 2o endpoints





terminated in 2011, no results available



Astra Zeneca


completed 2011, no results available





dose finding and formulation



Astra Zeneca


completed 2011, safety, tolerability, biomarkers: no results available





completed 2011, see text


anti-IL-1 receptor

Medimmune/Astra Zeneca





Medimmune/Astra Zeneca


completed: dose escalation with safety, PK: no results available



Medimmune/Astra Zeneca


completed 2012: dose escalation with safety, PK: no results available


anti-IL-5 receptor

Medimmune/Astra Zeneca




inhaled p38 inhibitor



completed 2011; dose escalation with safety, PK: no results available


inhaled p38 inhibitor



dose escalation study; neutrophil response to LPS


p38alpha inhibitor




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 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