Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease characterised by irreversible airflow limitation and associated with significant morbidity and mortality. In 2014, COPD was ranked the 10th leading cause of death in Singapore. The 2020 GOLD COPD guidelines define inhaled bronchodilator therapy as the mainstay of stable COPD management, with no distinction between choice of agent. Most commonly, β2-agonists and muscarinic antagonists are used, with longer-acting bronchodilators conferring more convenient and effective symptom relief compared to short-acting agents.
Revefenacin is a potent lung-selective long-acting muscarinic antagonist (LAMA) labelled for the maintenance treatment of patients with COPD. It was approved for use by HSA in September 2021 and is available in Singapore as a unit dose vial containing 175mcg/3mL solution for nebulisation. A single vial is administered once daily via a standard jet nebuliser with a mouthpiece connected to an air compressor. Of note, the safety and efficacy of revefenacin was studied using the PARI LC® Sprint nebuliser and the PARI Trek® S compressor. Other non-compressor-based nebuliser systems have not been evaluated.
Efficacy: Phase II and III studies
Early Phase II studies demonstrated revefenacin’s rapid onset and sustained duration of bronchodilator effect over 24h following once-daily administration. Bronchodilation with revefenacin was evident within the first hour of administration, with a similar onset and peak profile to ipratropium. Study 0091 [NCT01704404] evaluated drug administration over a period of 7 days and determined that dose response flattens at a revefenacin dose of 175mcg. Limited accumulation of revefenacin or its major metabolite were observed in plasma, and steady-state concentrations were achieved by Day 7. In Study 0117 [NCT02040792], revefenacin 175mcg significantly improved Day 28 trough FEV1 compared to placebo, with a difference of 166.6mL.
The Phase II findings paved the way for Phase III randomised controlled trials (RCTs) that evaluated the safety and efficacy of revefenacin against placebo and active comparator, tiotropium. Primary efficacy outcomes are reported in this section while outcomes of the safety studies are reported in the Safety section further below.
Study 0126 [NCT02459080] and Study 0127 [NCT02512510]
Both trials were double-blind, placebo-controlled 12-week studies that compared revefenacin against placebo. The primary efficacy endpoint was change from baseline in trough FEV1 on Day 85. At baseline, half the population were current smokers, and the mean age was 63-64 years with a mean baseline post-bronchodilator percent predicted FEV1 of 54-56%. Compared with placebo, revefenacin produced significant improvements in trough FEV1 in both studies, with a least-squares (LS) mean increase of 146.3-147.0 mL (p<0.001) at Day 85.
Study 0149 [NCT03095456]
The randomised double-blind 28-day Phase IIIb trial evaluated the efficacy of revefenacin against tiotropium (administered via Handihaler) in patients with moderate to very severe COPD. The primary endpoint was change from baseline in trough FEV1 at Day 29. Both revefenacin and tiotropium improved trough FEV1 from baseline on Day 29, with better improvements seen in the revefenacin arm. The difference however, was not significant (LS mean difference FEV1 17.0 mL, p= 0.4461). In the subgroup of COPD patients with severe to very severe airflow limitation where predicted FEV1 <50%, benefits were similarly seen in both treatment arms, with revefenacin demonstrating greater improvements. This was however not clinically significant.
Safety
In general, the AEs reported across literature were coherent and minimal. On a molecular level, revefenacin’s safety profile and in particular its low risk of antimuscarinic AEs, may be explained by its functional selectivity for M3 over M2 muscarinic acetylcholine receptors and rapid systemic clearance as determined in preclinical studies. COPD exacerbation/ worsening was a prominent serious AE, although its incidence was comparable to alternative LAMA therapy, tiotropium.
Study 0128 [NCT02518139]
The randomised 52-week safety trial compared revefenacin administered in a double-blind fashion against open-label tiotropium (administered via Handihaler) in patients with moderate to severe COPD. At baseline, 45-47% were current smokers and the mean age was 64.5 years with a mean baseline post-bronchodilator percent predicted FEV1 of 53-54%. The primary endpoint was drug safety and tolerability. The incidence of adverse events (AEs) and serious AEs were similar between both revefenacin and tiotropium (AE: 72.2% vs 77.2%, Serious AE: 12.8% vs 16.3% respectively). COPD exacerbation was the most frequent AE, which occurred to a lesser extent in the revefenacin arm. The rate of antimuscarinic-related AEs was generally low in both groups and occurred to a lesser extent in the revefenacin group (2.1% vs 4.2%).
Study 0167 [NCT03573817]
The randomised, double-blind, 2-period, 42-day Phase IIIb study evaluated the safety and tolerability of revefenacin when given either before or combined with formoterol 20mcg, a long-acting β2-agonist (LABA), in patients with moderate to very severe COPD. At baseline, the postbronchodilator FEV1 was 55%. AEs were minimal across all groups, with no serious AEs or clinically relevant haemodynamic changes. This study was limited by its short-follow-up duration.
Place in Therapy
Revefenacin has proven clinical efficacy in improving FEV1 relative to placebo and tiotropium among patients with moderate to severe COPD. In general, patients receiving revefenacin therapy in the trials had a baseline post-bronchodilator FEV1 of <50-56%. The drug’s safety and tolerability in this population has also been demonstrated for up to 52-weeks.
Inhaled bronchodilators for COPD today are available as either dry powder inhalers, pressurised metered-dose inhalers or nebulisers. The clinician must consider the practicality of revefenacin’s nebuliser posology in the context of patient preference, disease severity and functional ability. Nebulised administration has portability limitations but may be better suited in elderly patients as well as those with physical or cognitive limitations. Notwithstanding, nebulised therapy is inherently associated with contamination and stability issues that may result in local irritation or infections. Administration must thus be supported by strict safety and decontamination protocols.
When selecting patients that may benefit from therapy, the clinician can consider post-hoc subgroup analyses of the various Phase III clinical studies where factors such as markers of more severe COPD, older age (>65 and >75 years) were found to be associated with significant improvements from baseline in trough FEV1 relative to placebo.
