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Dr. Paul O'Bryne from @McMasterU: "Asthma - Update on New Therapies". Paul O'Byrne to kick off the morning symposium with a talk on new and emerging asthma therapies. From @lee_jasonk: An honour & pleasure to introduce my personal hero Dr. Paul O'Byrne, Chair of Medicine @McMasterU & Director of the Firestone.
GINA 2015 update - stepwise approach to therapy - before any 'step up' confirm diagnosis, adherence and inhaler technique (DAT).
5-8% with severe or refractory asthma despite "maximal" guideline therapy, responsible for large fraction of costs. Dr O'Byrne: severe refractory asthma: 5 to 8% of asthmatics in Canada. 5-8% of severe asthmatics will not respond to standard asthma therapy.
Potential biologics for asthma treatment - anti-IL5 (meoplizumab and resulizumb), IL5R, IL4R, IL13, anti-TSLP. Several current/potential biological targets for asthma tx, IL-4, 5, 13, IgE, TSLP, receptors.
Reduction in severe asthma exacerbations has to be the most important outcome measure. Asthma exacerbations and reduced oral steroid use are probably the most important outcomes for biological agents. Biologics, though expensive, might be very useful in severe asthma, reducing oral corticosteroid use and asthma exacerbation.
Use the lowest effective dose given least frequently - this is important for biologics given the high costs.
Mepolizumab substantially improves exacerbation a in steroid dependent asthma, according to NEJM. Nair paper https://t.co/htjSFYEgJf - pivotal trial showing benefit of mepolizumab for prednisone dependent eosinophilic asthma. Mepolizumab (anti-IL5) has been shown to significantly decrease exacerbations in well-selected asthma pts.
DREAM study of mepolizumab showed reduction in severe exacerbations for eosinophilic asthma - Lancet 2012.
Use the lowest effective dose given least frequently - this is important for biologics given the high costs. Example: 75mg of mepolizumab IV shown to be equivalent to 100mg subcutaneously by Ortega et al in 2014.
Current FDA-approved dose of mepo (100mg) may not fully control airway eosinophilia, may be insufficient for some patients.
Benralizumab (IL5-receptor alpha mAb)
Benralizumab (IL5-receptor alpha mAb) effective in preventing relapse after acute severe asthma. Benralizumab is an anti-IL5 receptor antibody - shown to reduce exacerbations/admissions to hospital in the 0.3mg/kg dose.
Reslizumab (different anti-IL5 drug) also shown to reduce severe exacerbations, especially in those older than 40 yo. Reslizumab given to patients with late-onset asthma with elevated blood eosinophils reduced exacerbations and improved FEV1.
IL4R alpha subunit is the common receptor for both IL4 and IL13. Lebrikizumab is an anti-IL13 mab - benefit is seen entirely in patients with elevated periostin. Lebrikizumab (anti-IL13) effective for improved lung function, but only in those with high periostin (marker of IL13 activity).
De Boever study of an anti-IL13 Mab showed an increase in blood eosinophil counts - unexplained. Surprising, using anti-IL13 increases eosinophils, an unexplained finding. No improvement in ACQ-7 or FEV1 in another study of anti-IL13.
Tralokinuab (anti-IL13) for moderate to severe asthma - those with high periostin sputum levels were the only ones to benefit .
Dr. O'Bryne points out that neither of the previous two studies looked at rates of severe exacerbations. Hanania et al Thorax 2015 - able to show significant reductions in severe exacerbations with anti-IL13 in the periostin-high group. Striking reduction in exacerbations with lower doses of lebrikizumab (not with higher dose) in those with high periostin.
Dupilumab is an anti-IL4R alpha Mab - showed reductions in exacerbations in asthmatics with elevated eosinophils. Dupilumab (anti-IL4Ra) prevented loss of control/exacerbations as meds decreased in asthma with elevated eosinophils.
Dupilumab given q2 wks improved FEV1 and reduced exacerbations, irrespective of eosinophil counts - Wenzel study.
Dupilumab significantly decreased severe exacerbations in a recent trial in a dose-dependant fashion.
QGE031 - new anti-IgE MAb that has much higher affinity binding to IgE than omalizumab. High affinity anti IgE may be better than omalizumab in asthma.
New trial is studying a new high affinity anti-IgE monoclonal antibody, reportedly better than Omalizumab.
AMG 157 is a MAb against TSLP - marked reduction in FENO levels, sputum eosinophils and blocked responses to allergen challenge. AMG157 (anti-TSLP) recently shown to have beneficial effects as well, but very preliminary data.
Inflammatory phenotyping most useful way to identify asthma pts who may benefit from novel therapeutics (ie Anti-IL-5).
Bronchial thermoplasty - Dr Nair/Cox think it is best for persistent non-inflammatory asthma with high degree of variable hyperresponsiveness.