New evidence raises the stakes for treatment of cystic fibrosis, and other highlights of #ATS2015

is Deputy Editor at CMAJ; he recently returned from the American Thoracic Society 2015 in Denver, Colorado


Denver has always presented a striking contrast of natural beauty with urban realism. The two most prominent expressions I saw of the latter are an increased presence of homeless persons and the pungent and almost inescapable aroma of marijuana, both regularly encountered when walking down the pedestrian mall at the heart of the city’s downtown. The two and illustrate one of perhaps many unanticipated consequences of the recent legalization of marijuana in the state of Colorado.

I can’t decide if this made the choice of Denver as host city for the world’s largest lung diseases conference, the , particularly appropriate or particularly ironic. I spoke with colleagues from Denver who assured me that researchers and public health officials are tracking the outcomes of this closely. There were some preliminary data at the meeting, as well as an afternoon of clinical talks chaired by , a professor and senior scientist at UCLA who has published extensively on the health effects of marijuana (including ),but it is early days yet. Canadian policymakers should watch closely…

The conference’s opening ceremony featured a keynote “address” (really a standup routine) from comedian and cast member . After entertaining the audience with his usual skill with jokes about being Indian and a Muslim in America (in a style somewhat reminiscent of Canada’s own ), he accepted on behalf of the Daily Show an award from ATS president recognizing the show’s success in regularly bringing attention to the disconnect between scientific evidence and public policy. An attendee asked him if the Daily Show would do a sketch about lung disease and I was surprised when he was noncommittal about being able to find in this topic an appropriate angle for a comedy routine. How could Mr. Mandvi forget that he once interviewed me as part of a ??

The session on cutting-edge research is always a meeting highlight, hosted again this year by New England Journal of Medicine Editor-in-Chief , along with JAMA Associate Editor (both, appropriately, are respirologists). This featured a presentation by , a pediatric respirologist and associate professor at the University of Queensland in Australia, on the results of the , a pair of randomized trials of a new drug combination, lumacaftor-ivacaftor, for patients with cystic fibrosis. One of its components, ivacaftor, is already available and being used in clinical practice based on in patients with a specific mutation in the CFTR gene, but who comprise only about 5% of all cystic fibrosis patients. The present study evaluated the new combination’s efficacy in patients homozygous for the commonest mutation, Phe508del (a.k.a. delta-F508). While the treatment was effective, the improvement in lung function was much less than that shown in the earlier ivacaftor study. More impressive was a 30-40% reduction in exacerbations, which represent a major burden for patient quality of life and for health services utilization.

These results will pose a major challenge for public drug formularies, given the . Ivacaftor alone caused some and . This debate has already anticipated the arrival of the lumacaftor/ivacaftor combination, which extends this class of therapy to a much broader population. A key question, unanswered as of yet, is whether giving these drugs from the time of diagnosis could largely or completely prevent expression of the disease. What price should society place on having a normal life, in place of a future of progressive respiratory symptoms and premature death? Given that treatments for orphan diseases like cystic fibrosis are invariably very expensive because they are rare, is it discriminatory to deny such patients access to beneficial treatment while patients with more common diseases receive treatment? Yet how are we going to pay for all this? And what role should the , who funded the development of this treatment and , have in directly ensuring that patients are not denied treatment based on cost?

The story above illustrates how therapeutic advances for chronic disease are being increasingly driven by more personalized therapies targeting specific mechanisms or phenotypes. Another such advance exemplifies the progress that has been made in our understanding of asthma. Typically, the clinical features of asthma are driven by a distinct pattern of inflammation directed by a specific subset of helper T-lymphocytes (Th2 cells). These Th2 cells release cytokines (in particular, IL-4, IL-5 and IL-13) that recruit other inflammatory cells such as eosinophils and mast cells – the familiar direct agents of allergy and asthma. Several new biologics that target these cytokines individually are already well under development, with some promising early results. However, , a professor at the Universities Giessen and Marburg Lung Center in Germany, presented data at the meeting on a new treatment that instead targets the entire pathway. He and his collaborators studied a molecule called hgd40, a DNAzyme – a synthetic antisense DNA molecule designed to match, bind to and catalyze the breakdown of a specific sequence of messenger RNA – in this case directed at GATA3, a transcription factor that acts as a “master control switch” for the Th2 inflammatory pathway. In contrast to most biologics, hgd40 is given daily by the inhaled route. In of 21 allergic asthma patients, hgd40 attenuated both the early-phase and late-phase responses to an allergen challenge. Although not reported in the published report of the study, which was released shortly after his talk, Dr. Renz said that treatment response seemed to increase in proportion to blood eosinophilia. While much more work needs to be done before this specific drug is ready for clinical use, the findings provide unprecedented proof of concept for our modern approach to asthma therapy.

The emphasis on “typical” asthma in the context above is salient. At another session, , a professor at the University of Pittsburgh and a renowned researcher in severe asthma, reminded us in a keynote address about the heterogeneity of clinical asthma. She argues that “asthma” should be regarded like “arthritis” or “anemia” – that is, not a single disease but a category of related but distinct conditions. She reviewed evidence from cluster analyses, biomarker studies and molecular phenotypes that support dividing asthma into subtypes, defined primarily by age of onset (early or late) and severity of obstruction, as well as steroid responsiveness and expression of different inflammatory patterns. Among these subtypes is one repeatedly identified group who lack the Th2-predominant inflammation described above. Such patients tend to be obese, have late-onset disease, and respond poorly to steroids. This raises the obvious question as to whether optimal asthma management may differ according to phenotype, which as noted above is where asthma therapy increasingly seems to be going.

The future of medical therapy: incremental, personalized, expensive. A challenge for patients, physicians, and payers alike. Let’s hope we’re all up to it.