“…A number of other MABAs have been in development for the treatment of COPD including batefenterol, AZD8999, AZD2115, CHF6366 and THRX200495 [ 33 ]. The majority of these are no longer in active clinical development.…”
Section: Discussionmentioning
confidence: 99%
“…Batefenterol completed phase 2b clinical trials, but has not progressed to phase 3. In terms of β 2 -adrenoceptor agonist/muscarinic antagonist activity ratios, batefenterol has a stronger β 2 -adrenoceptor agonist function whereas navafenterol has a stronger M 3 muscarinic antagonist activity [ 33 ]. In a phase 2 trial, batefenterol 300 μg in combination with fluticasone furoate 100 μg showed improvements in change from baseline in FEV 1 compared with placebo over 42 days of treatment [ 34 ].…”
BackgroundNavafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and beta agonist (MABA), being developed for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD.MethodsThis phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol [UMEC/VI]; 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough FEV1 on day 15. Secondary endpoints included: change from baseline in peak FEV1; change from baseline in breathlessness, cough and sputum scale (BCSS); change from baseline in COPD assessment tool (CAT); adverse events; and pharmacokinetics.ResultsSeventy-three participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares [LS] mean difference 0.202 L; p<0.0001). There was no significant difference in FEV1 between navafenterol and UMEC/VI (LS mean difference −0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period.ConclusionOnce-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.
“…A number of other MABAs have been in development for the treatment of COPD including batefenterol, AZD8999, AZD2115, CHF6366 and THRX200495 [ 33 ]. The majority of these are no longer in active clinical development.…”
Section: Discussionmentioning
confidence: 99%
“…Batefenterol completed phase 2b clinical trials, but has not progressed to phase 3. In terms of β 2 -adrenoceptor agonist/muscarinic antagonist activity ratios, batefenterol has a stronger β 2 -adrenoceptor agonist function whereas navafenterol has a stronger M 3 muscarinic antagonist activity [ 33 ]. In a phase 2 trial, batefenterol 300 μg in combination with fluticasone furoate 100 μg showed improvements in change from baseline in FEV 1 compared with placebo over 42 days of treatment [ 34 ].…”
BackgroundNavafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and beta agonist (MABA), being developed for the treatment of chronic obstructive pulmonary disease (COPD). This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD.MethodsThis phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol [UMEC/VI]; 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough FEV1 on day 15. Secondary endpoints included: change from baseline in peak FEV1; change from baseline in breathlessness, cough and sputum scale (BCSS); change from baseline in COPD assessment tool (CAT); adverse events; and pharmacokinetics.ResultsSeventy-three participants were randomised. After 14 days, trough FEV1 was significantly improved with navafenterol compared with placebo (least-squares [LS] mean difference 0.202 L; p<0.0001). There was no significant difference in FEV1 between navafenterol and UMEC/VI (LS mean difference −0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p<0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period.ConclusionOnce-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.
“… 33 Moreover, lower expression of M 2 muscarinic acetylcholine receptor (mAChR) was found in women than in men, leading to a greater M 3 /M 2 mAChR receptor ratio. 33 Indeed, the inhibition of M 2 mAChR expressed at the level of cardiovascular system is related to adverse events such as such as tachycardia and prolonged QT, 34 thus administering a triple FDC including a LAMA should be well assessed in those asthmatic patients that may have an altered response to muscarinic antagonists.…”
Introduction
Inhaled corticosteroid/long-acting β
2
-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) fixed-dose combination (FDC) is currently recommended as controller option at asthma Step 4 and as preferred treatment at asthma Step 5, but no research investigated the potential drawbacks of this therapeutic option in a large asthmatic population. Thus, the aim of this study was to quantify the potential drawbacks of triple FDC therapy in asthma.
Methods
A pairwise meta-analysis was performed according to PRISMA-P guidelines to assess the risk of overall serious adverse events (SAEs), cardiovascular SAEs, and pneumonia reported as SAE in asthmatic patients treated with ICS/LABA/LAMA FDC vs ICS/LABA FDC. A pooled analysis was performed to calculate the frequency of SAEs.
Results
Data from 7204 asthmatic patients were extracted from the CAPTAIN, IRIDIUM, TRIMARAN, and TRIGGER studies. Triple FDC vs ICS/LABA FDC did not increase the risk of total SAEs (RR 0.99 95% CI 0.83–1.18) and cardiac SAEs (RR 0.74 95% CI 0.39–1.40), whereas the sensitivity analysis performed to resolve heterogeneity resulted in increased risk of vascular SAEs (RR 3.23 95% CI 1.05–9.90, P<0.05). The level of ICS dose did not modulate the risk of pneumonia, in any case pneumonia was the most frequent SAE (0.57%). These results were not affected by significant risk of bias.
Conclusion
Triple FDC is a safe pharmacological therapy in severe asthmatic patients; it is characterized by a favourable safety profile and few potential drawbacks, namely, the increased risk of vascular SAEs, that certainly are worthy of future investigations.
“…1 ) represent the main innovation currently under investigation in the field of bronchodilation. However, their clinical development is extremely slow, although there are several MABAs (batefenterol, navafenterol, CHF6366, AZD8999/LAS190792, AZD2115, and THRX200495) that are in clinical development ( Ora et al., 2020b ). Fig.…”
Section: Evolution In Pulmonary Drug Delivery Devicesmentioning
confidence: 99%
“…As knowledge about the pathogenesis and evolution of COPD has expanded, it has become increasingly obvious that the treatment of COPD cannot be limited to the use of classical inhaled bronchodilators (β 2 agonists and muscarinic antagonists) and corticosteroids ( Cazzola and Matera, 2021 ). Some new drugs are in development ( Cazzola et al., 2019a ; Rogliani et al., 2020 ; Matera et al., 2021a , 2021b , 2021c ; Ora et al., 2020a ), but it is difficult to predict which ones will be approved for clinical use because the translation to humans of interventions that are effective in animal models is always not easy and often unreliable ( Cazzola and Matera, 2021 ).…”
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