Data from The Asthma Report - Curated by EPG Health - Last updated 31 October 2018
Two of the sessions we selected for The Asthma Report today cover important developments in the asthma treatment landscape, including a detailed look at the new biologics for asthma.
The first section of our report takes a look at how many IL-5 therapies for severe asthma are now available and are of similar efficacy. We therefore pose the question as to whether selection should be based in patient priorities including safety and dosing.
New biologics for asthma
Professor Wenzel, Pittsburgh, United States of America presented the first session: The basic science behind asthma biologics. Looking at a selection of biologics, Professor Wenzel highlighted that current biologics all target T2 systems.
IgE was the first biologic target, gradually moving upstream through IL-5 and IL5R, IL-4/IL-13 and up to Thymic stromal lymphopoietin (TSLP) and alarmins. Initial work on Xolair demonstrated amelioration of early and late allergic response, likely partially via broad effects on mast cells/basophils through the high affinity IgE receptor.
Dupilumab affects the IL-4Ra receptor, blocking the effects of IL-4 and IL-13 and subsequent inflammatory and structural pathways. This therefore leads to improvements in FEV1 and inflammation. The rapid FEV1 response suggests an effect through epithelial cells rather than structural proteins and muscle/fibroblasts. FEV1 improvement correlates closely with drop in FeNO.
IL-13 is known to induce MUC5AC which also effects respiratory flow, and this is corroborated by the relationship between high FeNO and MUC5AC expression. Evidence of mucus plugging correlates with lower FEV1, and more mucus seems to be present with more sputum eosinophils. IL-13 alone has no effect on muscle, but it potentiates contractility induced by other agents although this is not seen in methacholine challenge. IL-4R and IL-13 agents lead to increased eosinophilia, thought to be due to reduced eosinophil trafficking but this was disproved in a study with tralokinumab.
Eosinophils are known to be a good target in preventing exacerbations, and IL-5R treatment may also block basophils. More eosinophils result in better response to anti-IL5 therapy. Eosinophils are known to be associated with basement membrane thickness and blockage of TGFb may be the route by which FEV1 is improved with anti IL-5 therapy.
Genome-wide association studies (GWAS) in asthma highlight chromosome 17q which contains multiple epithelial markers, and TSLP blockade appears to reduce FeNO, sputum eos and blood eos, improving allergic response and exacerbations in studies to date.
Professor Bel, (Amsterdam, Netherlands) continued with the translational evidence supporting clinical use of novel biologics. Phenotypes, initially “extrinsic” vs “intrinsic”, have been long recognised, and the three key cells of atopic asthma, IgE producing B cells, Th2 cells and eosinophils must be considered in treatments.
Many potential targets have failed in development in the animal model stage due to lack of efficacy or high risk of blockade. Allergens and viruses are known to activate dendritic cells then GATA3 positive IL-C2 and Th2 followed by release of IL-4, IL-5, IL-9 and IL-13 resulting in activation of the inflammatory cascade. IL-5 was the first assessed cytokine which proved ineffective at ablation of the allergic response or improvement of FEV1 despite depletion of eosinophils. IL-9 inhibitors failed to improve FEV1, ACQ or exacerbations. Initial trials of sIL-4R also failed in larger trials, as did IL-13 studies. Pitrakinra proved effective in amelioration of late response but did not affect eosinophil migration and so was considered a failure. These study failures were likely attributable to incorrect choice of patient and lack of appreciation of heterogeneity of disease.
Finally, in 2009, mepolizumab proved effective at reducing exacerbations and OCS dose leading to reassessment of the IL-5 targeting therapies. Lebrikizumab, targeted based on high periostin, was thought to be effective but larger trials failed to show a good effect and so the program was abandoned, and similar problems were found with tralokinumab. Blocking IL-13 alone therefore looks insufficiently effective, but IL-4/IL-13 blockade appears effective at both exacerbation and OCS dose reduction. Targeting TSLP with tezepelumab reduces allergen response and eosinophils, resulting in a reduction of exacerbations in both T2 high and low patients.
Prof Bull concluded with real world studies on biologics. Long term safety of anti-IL-5 therapy appears good, side effects are mostly mild. Current biologics do not appear to affect the natural course of disease, but the treatments are effective at preventing progression.
Anti IL-5 therapies appear similarly effective, reducing exacerbations and OCS doses by about 50%, but benralizumab depletes eosinophils by ADCC. Benralizumab is suitable for q8w after initial q4w dosing, while resliuzmab requires IV dosing. Response to IL-5 therapy is proportional to eosinophil dose in a continuous fashion, and no clear threshold is present although 300cells/uL may be considered. Treatment effects should be assessed using multiple aspects of response at 4-6 months including exacerbations, symptoms, lung function, side effects etc.
The next session we chose for the Asthma Report came from Professor Pascal Chanez, who highlighted the importance of recognition of disease heterogeneity and patient centred approaches in use of effective novel treatments.
Clinical year in review – asthma
The asthma section of the clinical year in review was presented by Prof Pascal Chanez and covered mechanisms and diagnosis of asthma, mild asthma and severe asthma. Sui et al in Science describe an increase in pulmonary neuroendocrine cells using immunohistochemistry. PNEcs seem to be required for goblet cell hyperplasia. A drop in PNEcs in mouse models reduces GABA and CGRP which are involved in IL-C2 activity. Demenais et al published in Nature Genetics on a GWAS, identifying loci associated with gata3, TSLP, and T2 interleukins. IL-5 and IL-13 showed close linkage with TSLP.
Aaron et al in the Journal of the American Medical Association (JAMA) investigated the diagnosis of asthma, finding 1 in 3 people with a diagnosis of asthma were found not to be asthmatic. They highlight that expert diagnosis and multiple measures are required and treatment step down and stopping rules are key. Studies in mild asthma show a disconnect relative to severe asthma, in that inflammation is not assessed, despite control being rarely achieved. MART therapy investigation by Bateman et al shows the disconnect between daily symptoms [daily budesonide better than PRN MART) and exacerbation (both strategies the same). Adherence was good in MART and standard groups.
Jackson et al report on quintupling of ICS in paediatric patients to attempt to avoid exacerbations. This strategy did not show benefit in preventing events.
A paper in European Respiratory Journal (ERJ) by chupp et al details long term effects of thermoplasty in severe asthma. They report that symptoms and severe exacerbations improve over three years, but FEV1 is not improved.
The best candidates for BT are still unclear, as is whether disease modification is achieved. Castro et al and Rabe et al report on dupilumab in the NEJM. Castro shows that dupilumab decreases exacerbation risk with eosinophilic patients and those with raised FeNO benefit more. Dupilumab therefore still requires T2 activation but long term follow up is needed and the effect of transient increase in blood eos is unclear. Rabe et al show that a drop in long term OCS use is improved by dupilumab: 80% on dupilumab compared to 40% with placebo were able to reduce OCS use significantly, but again dupilumab was associated with more blood eosinophils.
Professor Chanez concluded by highlighting the importance of real world use of biologics, personalised approaches and recognition of treatable traits and disease heterogeneity. Treatment of mild asthma is crucial to prevent severe asthma from developing.