MABA, and novel LAMA
MABA, and novel LAMA
MABA: dual mechanism of action
“The newly developed compound AZD8871 works both as a LABA, and as a LAMA”, declared Dr Ioannis Psallidas (Medical Science Director, AstraZeneca, and University of Oxford, UK) . It is a long-acting, bi-functional bronchodilator agent, combining muscarinic antagonist and β2-adrenoceptor agonist activities in a single molecule (MABA, Figure 4) .
Figure 4: MABA: molecular structure concept with 3 elements 
Until now, four phase 1 studies have been performed to study this new MABA. Single and multiple doses of AZD8871 administered in healthy volunteers and patients with asthma or COPD showed that AZD8871 is safe and efficacious in terms of lung function. Especially in COPD patients, a single dose of AZD8871 (400 µg or 1800 μg) demonstrated a sustained bronchodilation after 36 hours. AZD8871 1800 μg showed greater bronchodilation compared to market products (indacaterol and tiotropium) for both peak and trough FEV1. These results were already presented last year at the ERS 2017 meeting .
Improved lung function and symptoms
During the ERS 2018 meeting, Dr Psallidas and others reported results from a phase 2a randomised, double-blind, placebo-controlled trial of repeated doses of AZD8871 100 µg and 600 μg in COPD patients. Patients were treated for 14 days. The primary objective was to evaluate the efficacy of inhaled AZD8871 in patients with moderate-to-severe COPD. Repeated once-daily doses of AZD8871 100 µg and 600 μg exhibited statistically significant and clinically relevant dose-ordered differences vs placebo in trough FEV1 (primary endpoint). The bronchodilation was sustained over 24 hours with both AZD8871 doses after 14 days of repeated administration. Peak FEV1 with both doses was clinically and statistically significantly greater than placebo. Furthermore, there was a significant improvement in symptoms for AZD8871 600 μg on days 8 and 14 and a significant reduction of daily rescue medication usage for both doses. The safety and tolerability outcomes were not shown during this presentation, but Dr Psallidas reassured that the overall observed safety and tolerability profile was good for both dose levels.
Novel LAMA under development
Revefenacin is a novel once-daily, lung-sensitive LAMA under development for the nebulised long-term maintenance treatment of COPD. Increased trough FEV1 has been demonstrated for nebulised revefenacin 88 μg and 175 μg once-daily in patients with moderate-to-severe COPD over 12 weeks . Safety and tolerability were also demonstrated for nebulised revefenacin 88 μg and 175 μg once-daily for up to 52 weeks in patients with moderate-to-severe stable COPD . At ERS 2018, Dr James Donohue (University of North Carolina at Chapel Hill, USA) presented a post-hoc analysis assessing COPD exacerbation data associated with revefenacin 88 μg and 175 μg once-daily in patients with moderate-to-severe COPD who participated in the phase 3 revefenacin clinical trial program . In total, 40-51% of patients in these trials were on LABA or ICS/LABA. Pooled data analysis showed that revefenacin 88 μg and 175 μg once-daily nominally reduced COPD exacerbations relative to placebo. Although the sample size was small, nebulised revefenacin 175 μg once-daily reduced the frequency of exacerbations similar to other LAMAs . Afterwards, Dr Donohue mentioned some limitations of this analysis. Firstly, the design of the 12-month trial was open label, so differential withdrawal may have biased the results. Furthermore, some factors must be accounted for when interpreting these positive trends: the absence of selection for exacerbation-prone patients and the small sample sizes, and therefore the lack of statistical power.
- Psallidas I, et al. Abstract OA1656, ERS 2018.
- Aparici M, et al. Pulm Pharmacol Ther. 2017;46:1-10.
- Singh D, et al. Eur Respir J 2017;50:PA1798.
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- Kerwin EM, et al. Am J Respir Crit Care Med. 2018;197:A4239.
- Donohue JF, et al. Abstract OA1655, ERS 2018.
- Aaron SD. BMJ. 2014;349:g5237.
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