The annual meeting of the European Respiratory Society took place September 3-7 this year in London, and gathered together researchers, pulmonologists, respiratory specialists, primary care physicians, and several major industry players to discuss developments in the respiratory space over the past year. DRG sent me as the on-the-ground expert in COPD, and while I was there several trends emerged. The impressions I formed will help drive DRG’s coverage of developments in COPD over the next year, and will be incorporated into the upcoming Disease Landscape and Forecast, publishing in November 2016.
The Salford Lung Study
The Salford Lung study, researching GlaxoSmithKline’s Breo/Relvar, was completed in mid-2016 and yielded positive top-line results; this study purported to capture real-world behavior in a large and diverse COPD cohort, by loosening exclusion criteria and using electronic health records to follow each patient’s course of treatment in detail. Results from this study were discussed by lead investigator Jorgen Vestbo, and were concomitantly published in the New England Journal of Medicine. Additionally, GlaxoSmithKline’s Industry Evening Symposium provided a forum for additional detail not covered in the regular session talk.
The initial session covered the study design in broad detail, and the initial publication outlining the trial design is available online; exclusion criteria were much less stringent than in traditional randomized clinical trials (RCTs), allowing recruitment of nearly 3000 patients. These were randomized into two treatment arms. The control group did not receive Breo/Relvar at any time during the study period, while the experimental group was initially prescribed this therapy. However, unlike a true RCT, patients were allowed to switch away from Breo/Relvar, or to add or change other therapies received concomitantly. In the Industry Evening Syposium, speakers also noted that patients were followed by their regular physician and had minimal contact with the study authors. Patients also picked up their therapies in the out-patient pharmacy, in an effort to interfere minimally with the current standard of care.
Results from this study showed that patients in the Breo/Relvar arm experienced an 8.4% risk reduction compared to usual care for the primary endpoint of reduced frequency of exacerbations, with no significant increase in severe adverse events (p=0.02). Notably, this difference was attributed to this LABA/ICS specifically, as other LABA/ICS therapies were used in the control arm. Physicians attending ERS appeared to be quite receptive to the total data package, but some key questions focused on perceived weaknesses of the study design. Some physicians noted that patients do not initiate ICS treatment on a random basis, so the randomized patient population was not representative of patients who deserve ICS treatment. The presenters responded by noting that upon enrollment, 86% of patients were receiving an ICS in their treatment regimen, and that this is representative of a real-life COPD cohort and was effectively a feature, not a bug. Additional concerns focused on whether this trial design could be sufficient for regulators to approve a treatment, and how this real-world evidence (RWE) compares to RCT data when developing treatment guidelines. Many of these questions will remain unanswered until additional, similar studies are performed, and presenters noted that these RWE studies are intended to be complimentary to traditional RCTs. Overall, this study appears to have broken ground in the design and implementation of clinical trials for COPD, and physicians seemed largely enthusiastic about the possibility of using such trials to inform their clinical practice.
The Role of Eosinophils in COPD
Two anti-IL-5 drugs (Nucala [mepolizumab] and Cinqair/Cinqaero [reslizumab]) have recently been approved for severe, eosinophilic asthma, and both are in development for COPD. Many pulmonologists eagerly await clinical trial data from ongoing COPD studies; there may be a link between eosinophilic inflammation and the rate of exacerbations, but this was hotly debated at this year’s ERS conference.
The definition of asthma-COPD overlap syndrome, or ACOS, and the size of this patient population remains a subject of discussion, and eosinophils are sometimes mentioned as the critical marker for an ACOS patient (although at this year’s ERS, physicians involved in the GOLD guidelines suggested that this is not a syndrome and should therefore be referred to as ACO. DRG will continue to refer to ACOS, as this suggestion is not anticipated to be incorporated into guidelines). However, the level of eosinophils indicative of this condition is not well-defined, and some physicians diagnose ACOS only when the patient has significant asthma symptoms, while others believe that eosinophils are not involved in COPD pathology.
Despite significant investigation, coming out of this year’s ERS the role of eosinophils in COPD remains unclear. Many retrospective and observational studies presented this year found no statistically significant difference in patients with elevated eosinophil levels in a number of metrics including the annualized rate of exacerbations, the time to first exacerbation, various QOL questionnaires including TDI and SGRQ, and most importantly, mortality regardless of what cutoff was used (data was presenting using cutoffs of >2%, >3%, >4% or >150 mcg/L, >200 mgc/L, >300 mcg/L blood eosinophils). However, these studies collected insufficient data about current use of ICS; during discussion sessions many physicians questioned whether patients had been improperly excluded because current ICS use had driven their eosinophil count below the cutoffs. Additionally, some studies neglected to capture information about the current treatment of included patients. Other sessions presented data hinting that the historic rate of exacerbation, combined with a cutoff of 300 mcg/L blood eosinophils, may be a robust predictor of future exacerbations. This point was made repeatedly, but relied primarily on post-hoc analysis of the TORCH and WISDOM studies. One thing that is clear is that a large-scale, moderate- to long-term prospective rather than retrospective study of the impact of ICS use in high-eosinophil patients would fill a void in the current understanding of this disease.
Other Important Notes
Several other trends emerged at this year’s ERS conference, but there is not sufficient space to cover all of them in detail here. Notably, physicians appear to be largely receptive to data indicating the LABA/LAMAs can reduce exacerbation rates, as indicated by Novartis’s FLAME study. The choice of device will become even more complicated in coming years as generic version of COPD therapies launch, and this drove significant discussion of several posters and oral sessions investigating various aspects of device design. Finally, Phase II clinical trial data on two novel COPD therapies, a p38 inhibitor, and a PDE3/4 inhibitor, generated significant enthusiasm. Phase III results are eagerly awaited, as physicians are anxious to have new treatment options for the COPD patients.
Although trial data and other publications will likely become available over the coming months, there is no substitute for being in the room where it happens. DRG’s experts were able to experience the reaction of physicians, researchers, and key industry leaders to these results in real time, and having boots on the ground will help provide additional context for the evolving COPD market, and understand how clinical definitions, treatment, areas of opportunity, and research may evolve in coming years. Insights gained will be incorporated into forthcoming DRG offerings, including the COPD Disease Landscape & Forecast, and have helped build the expertise DRG is known for.