At this year’s ERS conference, ICS therapies in COPD were a hot topic, along with changes to the GOLD international guidelines.
Last week, DRG sent two analysts from our respiratory team to attend the annual European Respiratory Society Congress. This year the congress was held in Milan and ran from September 9th - 13th, 2017. With over 25,000 attendees, this conference is often a preferred forum for the release of high-profile clinical trial results, and an outlet for varied and interesting science ranging from early-to late-stage drug development along with basic research. Additionally, this year the conference sponsored a mobile pulmonology clinic which offered free assessments. Located near the Sforzesco Castle, a major tourist location, this clinic attracted out-the-door lines for several days running, indicating a high level of interest in respiratory health from the Milanese, not just the physicians attending the conference.
This year in COPD, the main theme that emerged was that of unanswered questions around ICS use, the role of eosinophils in COPD, novel therapeutic pathways, and even how to define and treat this disease. The GOLD (Global Initiative for Chronic Obstructive Lung Disease) international consensus guidelines underwent another revision this year, sparking much discussion in and of themselves. For many years, the guidelines recommended grading COPD severity on a scale of I-IV based on the patient’s spirometric assessment using FEV1. The 2011 update introduced the ABCD scoring system, which combined a symptomatic evaluation, a spirometric test, and a history of exacerbation frequency in an attempt to predict which patients are at a higher risk of additional exacerbations. The 2016 update removed FEV1 from this assessment, causing significant consternation; as a result, the 2017 update re-introduced the I-IV scale to assess airflow limitation and continues to recommend the ABCD framework to evaluate exacerbation risk.
The removal of FEV1 from the ABCD grading shifted many patients with low FEV1 and few exacerbations from group D to group B; much research has established that past exacerbations are the best indicator of future exacerbations and that airflow limitation is not necessarily predictive for these events. Several posters presented at ERS 2017 performed comparative and retroactive analysis of the two different GOLD classification systems on substantial healthcare data sets. Most of these found that the guideline changes enlarged the patient population within group B and validated the separation of risk assessment from FEV1, finding that group D patients under the 2017 guidelines had a higher and more homogenous level of risk for exacerbations.
Despite the retroactive demonstrations of the usefulness of these guidelines, many pulmonologists have channeled their frustration with this moving target into an ongoing discussion of personalized treatment for COPD patients. Some researchers advocated for the usefulness of an emphysema or chronic bronchitis diagnosis, and Boehringer Ingelheim was eager to reinforce this paradigm, devoting a well-attended evening symposium to a forward-looking consideration of personalized medicine for COPD patients. Speakers for this session emphasized a multi-factorial assessment of COPD patients, including evaluation of emphysema, but the paucity of alternatives to LABAs and LAMAs leaves pulmonologists with limited options to truly personalize COPD treatment.
Another interesting evening symposium, hosted by Novartis, had several high-profile researchers explaining and defending the changes made to the severity classification and recommendations. The incorporation of a LABA plus a LAMA as a preferred treatment for grade B, C, and even many D COPD patients, due to their high level of safety and efficacy in many clinical trials, was an important point made by all panelists. Interestingly, the Q&A portion of this session included several questions about the role of ICS therapies and elicited varied answers from the panelists. Novartis has welcomed the removal of ICS from the treatment algorithm in many cases since their respiratory portfolio does not include either a LABA/ICS FDC or triple therapy for COPD, although label extensions of their asthma therapies remain a possible future direction.
However, other manufacturers were more resistant to the removal of ICS as a recommended therapy in B and C patients. Notably, Cheisi performed a retroactive re-evaluation of their large TRILOGY and TRINITY clinical trials on their triple combination, Trimbow, in line with the newer guidance. The diminished size of the GOLD D population has decreased the p-value of some of their results, but their formoterol/glycopyrronium/beclomethasone triple therapy still delivered a statistically significant decreased in exacerbations when compared to either LAMA or LABA/ICS treatment. Chiesi also hosted an evening symposium, in this case with panelists giving an overview of the importance of small airways when considering COPD treatment, highlighting the good lung deposition profile delivered by the extrafine formulation of Cheisi’s Trimbow and other inhaled therapies. Additionally, they presented data showing that their ICS did not increase the rate of pneumonia when compared to LABA/ICS FDCs.
As a consequence of both Chiesi’s data and some additional posters and presentations from GlaxoSmithKline which demonstrated that triple therapies are safe and effective when compared with LABA/ICS FDCs, many of the high-profile pulmonologists present continued to advocate for the use of ICSs in some COPD patients, especially those whose disease remains unstable on dual bronchodilator therapy. However, many eagerly await the results of GlaxoSmithKline’s IMPACT study, the first to compare a triple therapy directly to a LABA/LAMA FDC, which will hopefully answer many important questions about the utility of ICS as an add-on to maximal bronchodilation. A GlaxoSmithKline representative indicated results can be expected towards the end of 2017.
Additionally, many pulmonologists are interested in whether an elevated eosinophil count is indicative of a patient who will respond to ICS therapy since many of the analyses showing this effect were post-hoc evaluations of clinical trials powered to demonstrate other outcomes. Notably, more retrospective analysis of data from the WISDOM study was presented at this year’s conference. Some smaller prospective studies on eosinophil counts were presented, but many experts agree that larger prospective studies are needed. However, one particularly interesting research presentation reported that a majority of COPD patients had eosinophil levels that ranged both above and below the 300 cells/uL cutoff often used in clinical trials within a year-long investigative period and argued that multiple time points will be necessary to evaluate a patient’s eosinophil-linked exacerbation risk. Other researchers showed that sputum eosinophils and blood eosinophils are not necessarily related. However, they also emphasized that sputum is often difficult to induce and may not yield usable cell counts, making it impractical in the clinical setting. These results call into question the utility of blood eosinophils as a biomarker for COPD patients, especially if only a single data point is available for a particular patient.
However, if eosinophils are finally validated as a biomarker for COPD, this will likely help bolster the usefulness of the anti-IL-5 therapy mepolizumab, which has been shown to decrease eosinophil counts and exacerbations in asthmatic patients. At this year’s ERS conference, the first compelling results in COPD were presented, showing that this drug decreased exacerbations by 18-20% in patients with eosinophils higher than 150 cells/uL at enrollment or higher than 300 cells/uL in the previous year. Although these results will likely secure regulatory approval for this drug, which would represent a welcome and novel treatment pathway, the reception at ERS was somewhat cool. The biologic therapy is likely to be quite expensive, and with the role of eosinophils remaining somewhat unclear, physicians may have difficulty justifying the high price except for a very small proportion of patients.
In addition to these major presentations, many other results were presented and interesting discussions had at this year’s ERS conference. DRG’s respiratory analysts will continue to follow exploration of novel and early-phase drugs, along with investigations into additional possible biomarkers for COPD, and as always, this knowledge and experience gained at high-profile industry conferences will help inform our reports. Stay tuned for the upcoming annual refresh of the COPD Disease Landscape and Forecast, which will incorporate many of the themes discussed here.