Revefenacin, a once-daily, long-acting muscarinic antagonist, for nebulized maintenance therapy in patients with chronic obstructive pulmonary disease
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Clinical Review
Revefenacin, a once-daily, long-acting muscarinic
antagonist, for nebulized maintenance therapy in
patients with chronic obstructive pulmonary disease
Supplementary material is Purpose. This article reviews the efficacy and safety of revefenacin, the
available with the full text of this first once-daily, long-acting muscarinic antagonist, when delivered via a
article at AJHP online.
standard jet nebulizer in patients with chronic obstructive pulmonary dis-
ease (COPD).
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Christopher Hvisdas, PharmD, Summary. Revefenacin 175 µg is indicated for the maintenance treat-
Department of Pharmacy, Penn ment of patients with moderate to very severe COPD. Preclinical studies
Presbyterian Medical Center, University
of Pennsylvania, Philadelphia, PA, USA showed that revefenacin is a potent and selective antagonist with simi-
lar affinity for the different subtypes of muscarinic receptors (M1-M5).
Furthermore, prevention of methacholine- and acetylcholine-induced
bronchoconstrictive effects was dose dependent and lasted longer
than 24 hours, demonstrating a long duration of action. In phase 2 and
3 trials, treatment with revefenacin was demonstrated to result in stat-
istical improvements in pulmonary function (≥100 mL, P < 0.05) vs pla-
cebo, including among patients with markers of more severe disease and
those who received concomitant long-acting β-agonists or long-acting
β-agonists together with inhaled corticosteroids. Revefenacin was also
demonstrated to have efficacy similar to that of tiotropium. The clinical
trial findings indicated no significant difference between revefenacin and
tiotropium with regard to rates of adverse events. Overall, revefenacin was
well tolerated, with COPD worsening/exacerbation, dyspnea, headache,
and cough among the most common adverse events noted in the clinical
trials.
Conclusions. Revefenacin treatment delivered via nebulization led to im-
provements in lung function in patients with COPD. It was also generally
well tolerated, with no major safety concerns. Revefenacin provides a vi-
able treatment option for patients with COPD and may be a suitable alter-
native for those with conditions that may impair proper use of traditional
handheld inhalers.
Keywords: anticholinergics, bronchodilators, chronic obstructive pul-
monary disease, drug administration, drug development and approval,
revefenacin
Am J Health-Syst Pharm. 2021;78:1184-1194
Address correspondence to Dr. Hvisdas
R
(christopher.hvisdas@pennmedicine. evefenacin is the first once-daily long- The Global Initiative for Chronic
upenn.edu).
acting muscarinic antagonist (LAMA) Obstructive Lung Disease (GOLD) re-
© American Society of Health-System for use with a standard jet nebulizer indi- port offers guidance on the diagnosis
Pharmacists 2021. This is an Open cated for the maintenance treatment of pa- and management of COPD. Inhaled
Access article distributed under the terms
of the Creative Commons Attribution tients with chronic obstructive pulmonary bronchodilators are recommended as
License (http://creativecommons. disease (COPD).1 In the United States, first-line therapy for the treatment of
org/licenses/by/4.0/), which permits approximately 16.4 million adults have a COPD.5 Although GOLD does not rec-
unrestricted reuse, distribution, and
reproduction in any medium, provided the confirmed diagnosis of COPD, and it is the ommend a particular bronchodilator
original work is properly cited. fourth leading cause of mortality, with an over another, evidence suggests that
estimated annual cost of $49.9 billion.2-4 LAMAs offer clinical and economic
DOI 10.1093/ajhp/zxab154
1184 AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 13 | July 1, 2021REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE Clinical Review
benefits, compared with long-acting phase 1 trials (ClinicalTrials.gov
β-agonists (LABAs). Long-acting in- KEY POINTS identifiers, NCT02581592 and
haled bronchodilators are most • Revefenacin is the only NCT02578082).15 Study volunteers
often administered with pressurized once-daily nebulized long- received a single 175-µg dose of
metered-dose inhalers or dry powder acting muscarinic antagonist revefenacin via nebulization.
inhalers (DPIs). However, patients with approved by the Food and Systemic exposure to revefenacin
cognitive or physical limitations or Drug Administration for the was modestly increased by severe
with suboptimal peak inspiratory flow maintenance treatment of renal impairment, while exposure
rate (PIFR) may have challenges with chronic obstructive pulmonary to THRX-195518 was approximately
inhalers.6,7 These patients may benefit disease. 2-fold higher than in healthy volun-
from nebulized therapy, which may im- teers. In individuals with moderate
• Compared with placebo,
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prove symptom control, compared with hepatic impairment, systemic exposure
revefenacin demonstrated
other delivery devices.8 Until recently, to revefenacin was similar to that in
statistically clinically important
there was only 1 nebulized LAMA individuals with normal hepatic func-
improvements in pulmonary
available for twice-daily administra- tion, while exposure to THRX-195518
function.
tion, glycopyrrolate bromide (Lonhala was approximately 3-fold higher.
Magnair, Pari, Munich, Germany).9 • Revefenacin was well tolerated; The increase in systemic exposure to
The Food and Drug Administration worsening/exacerbation of THRX-195518 in individuals with se-
(FDA) approved the use of revefenacin chronic obstructive pulmonary vere renal or moderate hepatic impair-
(Yupelri, Theravance Biopharma, disease, cough, dyspnea, and ment was considered unlikely to be
South San Francisco, CA) in November headache were among the most of clinical consequence given its low
2018.1 Clinical trial data for revefenacin common adverse events noted antimuscarinic potency, low systemic
were obtained using the Pari LC Sprint in clinical trials. levels after inhaled revefenacin, and fa-
nebulizer (Pari, Starnberg, Germany) vorable safety profile.15
and the Pari Trek S compressor (Pari, Cardiac safety was assessed in
Midlothian, VA). The pharmacology, healthy volunteers in a random-
pharmacokinetics (PK), efficacy, safety, ized, 4-way crossover phase 1 trial
and clinical application of revefenacin (NCT02820311).16 Each healthy vol-
are reviewed in this article, with a focus bronchoconstriction; thus, in theory, unteer received a single dose of the
on the FDA-approved 175-µg dose. M3 antagonism results in bronchodila- following 4 treatments in separate
Information on the data selection, tion. In preclinical studies, prevention treatment periods: blinded revefenacin
revefenacin dosage and administra- of methacholine- and acetylcholine- 175 µg, revefenacin 700 µg, placebo
tion, and revefenacin drug interactions induced bronchoconstrictive effects via nebulization, and open-label oral
is provided in the eAppendix. was dose dependent and lasted more moxifloxacin 400 mg (positive con-
Pharmacology and PK profile. than 24 hours,13 demonstrating a long trol). Revefenacin did not have a clin-
Revefenacin is a nonester, non duration of action. ically meaningful effect on cardiac
quaternary ammonium–based LAMA. After inhaled administration of repolarization or cardiac conduction
The terminal amide in revefenacin’s revefenacin in patients with COPD, and was generally well tolerated.16
structure provides a metabolically la- conversion to the metabolite THRX- Clinical trials. The methodology
bile functionality, which appears to be 195518 occurred rapidly, and plasma and results of 4 phase 2 studies and 5
stable in the lung but readily hydro- exposures of THRX-195518 were ap- phase 3 studies are summarized and
lyzed to its active metabolite in sys- proximately 3- to 6-fold greater than discussed in Table 1 and Table 2.14,17-23
temic circulation,10 thus potentially those for revefenacin.14 THRX-195518 The results of 2 post hoc/prespecified
minimizing systemically mediated ad- is produced by hepatic metabolism and studies are summarized and dis-
verse events (AEs). has lower activity (approximately one cussed in Table 3.24,25 Eligibility cri-
Similar to tiotropium,11 revefenacin third to one tenth) at target muscarinic teria and definitions for phase 2 and
is a potent and selective antagonist, receptors than revefenacin.1,14 3 clinical trials are discussed in the
with similar affinity to the subtypes Dosing in renal, hepatic, and eAppendix.
of muscarinic receptors (M1-M5).12 cardiac disease. The effects of severe Phase 2 studies. In 2 randomized,
Revefenacin exhibits pharmacological renal impairment (estimated glomerular double-blind, placebo-controlled phase
effects through the inhibition of the filtration rateClinical Review REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Table 1. Summary of Phase 2 and Phase 3 Clinical Trialsa
Clinical Trial Study Design Intervention Duration Baseline Characteristics
Study 0091 Phase 2 REV 22, 44, 88, 175, 350, or 7 days Men: 56%
(NCT01704404)14 Randomized, double-blind, 700 μg or PBO OD Mean age: 64 years
placebo-controlled, Mean FEV1 (percentage of
multiple-dose, incomplete predicted normal): 47%
block, 5-way crossover
design
n = 59
Study 0116 Phase 2 REV 44 BID or 175 μg OD or 7 days Information not available
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(NCT02109172)17 Randomized, double-blind, PBO OD or BID online
placebo-controlled,
dose-ranging, crossover
design
n = 64
Study 0117 Phase 2 REV 44, 88, 175, or 350 μg 28 days Men: 50%
(NCT02040792)18 Randomized, double-blind, or PBO OD Mean age: 62 years
placebo-controlled, dose- Mean FEV1 (percentage of
ranging design predicted normal): 44%
n = 355
Study 0126 Phase 3 REV 88 or 175 μg or PBO 12 weeks Men: 47%-52%
(NCT02459080)19 Randomized, double-blind, OD Mean age: 64 years
placebo-controlled, multiple- Mean FEV1 (percentage
dose, parallel-group design of predicted normal):
n = 619 54-56%
Current smoker: 48%-49%
Study 0127 Phase 3 REV 88 or 175 μg or PBO 12 weeks Men: 47%-52%
(NCT02512510)19 Randomized, double blind, OD Mean age: 63-64 years
placebo-controlled, multiple- Mean FEV1 (percentage of
dose, parallel-group design predicted normal): 54%
n = 611 Current smoker: 45%-48%
Study 0128 Phase 3 REV 88 or 175 μg or TIO 52 weeks Men: 56%-61%
(NCT02518139)20,21 Randomized, partially 18 μg via HandiHaler OD Mean age: 64-65 years
double-blinded, Mean FEV1 (percentage
parallel-group design of predicted normal):
n = 1,020 53-54%
Current smoker: 45%-47%
Study 0149 Phase 3b REV 88 or 175 μg or TIO 28 days Men: 60%
(NCT03095456)22 Randomized, double-blind, 18 μg via HandiHaler OD Mean age: 65 years
active comparator, Mean FEV1 (percentage of
parallel-group design predicted normal): 37%
n = 206 Current smoker: 47%
Study 0167 Phase 3b REV 175 μg OD, FOR 20 μg 42 days Men: 56%-58%
(NCT03573817)23 Randomized, double-blind, BID Mean age: 63-64 years
2-period, parallel-group Sequential administration Mean FEV1 (percentage of
design for 21 days (days 1-21): predicted normal): 55%
n = 122 REV administered in the Current smoker: 54%-59%
morning followed by
FOR in the morning; FOR
alone administered in the
evening
Combined administration for
21 days (days 22-42): REV
and FOR administered
together in the morning
as a mixed solution; FOR
administered alone in the
evening
Abbreviations: BID, twice daily; FEV1, forced expiratory volume in 1 second; FOR, formoterol; OD, once daily; PBO, placebo; REV, revefenacin;
TIO, tiotropium.
a
See the eAppendix for information on eligibility criteria, definitions, and criteria for clinical relevance.
1186 AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 13 | July 1, 2021REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE Clinical Review
Table 2. Summary Data From Phase 2 and Phase 3 Clinical Trials of Revefenacin 175 µg for Moderate to Very
Severe COPDa
Phase Trial Key Efficacy Outcomes Safety Outcomes
Phase 2 Study 0091 Significant improvement in trough Frequency of AEs was lower for REV (45.9%) vs
(NCT01704404)14 FEV1 at day 7 (114.2 mL, P < 0.001) PBO (54.1%)
Most common AEs:
• Headache (REV, 10.8%; PBO, 14.8%)
• Cough (REV, 5.4%; PBO, 1.6%)
• Dyspnea (REV, 5.4%; PBO, 6.6%)
No antimuscarinic AEs were observed
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Study 0116 Improvement in weighted mean Not assessed
(NCT02109172)17 (0-24 hours) FEV1 at day 7 (113 mL)
Study 0117 Significant improvement in trough Frequency of AEs was the same for REV
(NCT02040792)18 FEV1 at day 28 (166.6 mL, P < 0.001) (31.0%) and PBO (31.0%)
Most common AEs:
• Headache (REV, 1.4%; PBO, 2.8%)
• Dyspnea (REV, 4.2%; PBO, 2.8%)
• Cough (REV, 4.2%; PBO, 1.4%)
No antimuscarinic AEs were observed
Phase 3 Study 0126 Significant improvements in trough Frequency of AEs was similar for REV (51.0%)
(NCT02459080)19 FEV1 at day 85: and PBO (51.7%)
Study 0127 • Study 0126: 146.3 mL, P < 0.0001 Most common AEs:
(NCT02512510)19 • Study 0127: 147.0 mL, P < 0.0001 • Worsening/exacerbation of COPD
Significant improvement in peak FEV1 (REV, 10.6%; PBO, 11.0%)
at day 85 (pooled studies 0126 and • Dyspnea (REV, 2.0%; PBO, 5.3%)
0127: 129.5 mL, P < 0.0001) • Headache (REV, 4.0%; PBO, 2.4%)
• Cough (REV, 3.5%; PBO, 3.8%)
Antimuscarinic AEs (constipation and dry
mouth) occurred in ≤1% of patients who
received REV
Study 0128 Sustained significant improvements Frequency of AEs was lower with REV (72.2%)
(NCT02518139)20,21 from baseline in trough FEV1 over vs TIO (77.2%)
52 weeks for REV (52.3-124.3 mL, Most common AEs:
P < 0.0003) and TIO • Worsening/exacerbation of COPD (REV,
(79.7-112.8 mL, P < 0.0003) 21.8%; TIO, 28.1%)
Sustained significant improvements • Nasopharyngitis (REV, 7.8%; TIO, 4.8%)
(P < 0.05) in SGRQ, CAT, CCQ, BDI, • Upper respiratory tract infection (REV, 6.0%;
and TDI from 3 months on for REV TIO, 6.8%)
and TIO • Cough (REV, 7.5%; TIO, 5.6%)
Antimuscarinic AEs were lower with REV (2.1%)
vs TIO (4.2%):
• Dry mouth (REV, ≤0.9%; TIO, 2.8%)
• Constipation (REV, 0.9%; TIO, 2.0%)
Study 0149 Significant improvement in trough Frequency of AEs was lower with REV (11.1%)
(NCT03095456)22 FEV1 from baseline for REV vs TIO vs TIO (37.5%)
(17.0 mL, P = 0.4461) at day 29 Antimuscarinic AEs were lower in patients who
Improvement in trough FVC from received REV vs TIO:
baseline for REV vs TIO (71.5 mL) • Constipation (REV, 0%; TIO, 3.8%)
at day 29 • Dry mouth (REV, 1.9%; TIO, 1.0%)
For patients with predicted FEV1 Discontinuations resulting from AEs were onlyClinical Review REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Continued from previous page
Table 2. Summary Data From Phase 2 and Phase 3 Clinical Trials of Revefenacin 175 µg for Moderate to Very
Severe COPDa
Phase Trial Key Efficacy Outcomes Safety Outcomes
Study 0167 Improvements from baseline in trough Frequency of AEs was lower with REV/FOR
(NCT03573817)23 FEV1 for REV/FOR during sequen- (sequential, 4.8%; combined, 8.1%) vs PBO/
tial (157.1 mL) and combined FOR (sequential, 11.9%; combined, 10.9%)
(115.6 mL) administration at days 21 The most common AEs (≥2%) occurred in the
and 42, respectively PBO/FOR groups:
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• Cough (3.6%)
• Worsening of COPD (3.4%)
• Dizziness (3.4%)
AEs that led to discontinuation for REV/FOR
occurred in ≤1.6% of patients
Abbreviations: AE, adverse event; BDI, Baseline Dyspnea Index; CAT, COPD Assessment Test; CCQ, Clinical COPD Questionnaire; COPD, chronic
obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FOR, formoterol; FVC, forced vital capacity; PBO, placebo; REV,
revefenacin; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO, tiotropium.
a
See the eAppendix for information on eligibility criteria, definitions, and criteria for clinical relevance.
or 700 μg) revefenacin in patients with evaluated once-daily (175 µg) and Phase 3 studies. Based on the phase
moderate to severe COPD.14 The FDA- twice-daily (44 µg) revefenacin.16 The 2 data, the pivotal phase 3 studies in
approved 175-µg dose is discussed. In primary endpoint was change from patients with moderate to very se-
study 0091, patients were randomized baseline in weighted mean FEV1 during vere COPD evaluated the efficacy and
to receive once-daily revefenacin (22, 0 to 24 hours on day 7. Compared with safety of revefenacin 88 and 175 µg once
44, 88, 175, 350, or 700 µg) or placebo placebo, revefenacin produced clin- daily. The FDA-approved 175-µg dose is
for 7 days in a double-blind, incom- ically significant improvements from discussed.
plete block, 5-way crossover design. The baseline in day 7 weighted mean FEV1, Studies 0126 (NCT02459080) and
primary efficacy endpoint was trough with a difference of 113 mL for the FDA- 0127 (NCT02512510) were random-
forced expiratory volume in 1 second approved 175-μg dose.17 ized, double-blind, placebo-controlled,
(FEV1) after the final dose (day 7). At Study 0117 (NCT02040792) was a parallel-group, 12-week studies.19 The
baseline, 56% of patients were men, the randomized, double-blind, placebo- primary efficacy endpoint was change
mean age was 64 years, and the mean controlled, parallel-group, dose- from baseline in trough FEV1 on day 85.
percentage predicted FEV1 was 47%.14 ranging (44-350 µg), 28-day trial.18 Secondary efficacy endpoints included
The mean trough FEV1 on day 7 was The primary endpoint was change overall treatment effect on trough FEV1
significantly higher for patients receiving from baseline in day 28 trough FEV1; and peak FEV1 (0-2 hours after the first
revefenacin vs placebo, with a differ- inhaled corticosteroids (ICS) and dose) on day 1. Concomitant LABA-
ence of 114 mL (P < 0.001) for the FDA- short-acting bronchodilators were containing therapy (with or without
approved dose of 175 μg. Revefenacin permitted. At baseline, 50% of patients ICS) was permitted in up to 40% of the
demonstrated a long-lasting (≥24 hours) were men, the mean age was 62 years, study population to ensure robust as-
bronchodilator effect and was rap- and the mean percentage predicted sessments of concurrent therapies used
idly absorbed and extensively metabol- FEV1 was 44%. by the participants. Stable doses of ICS
ized, with minimal accumulation after Revefenacin 175 µg clinically and without concomitant LABAs were per-
repeated dosing. Revefenacin was well significantly improved day 28 trough mitted, but LAMAs and short-acting
tolerated, and AEs were generally mild. FEV1 vs placebo, with a difference muscarinic antagonists were prohib-
The most common AEs were dyspnea, of 166.6 mL. On day 28, the 24-hour ited. At baseline, 47% to 52% of patients
headache, and cough.14 weighted mean difference from placebo were men, nearly half were current
Researchers evaluated the effi- for FEV1 was numerically similar to the smokers (46%-49%), the mean age was
cacy and safety of revefenacin in 2 respective trough FEV1 value, indicating 63 to 64 years, and the mean baseline
dose-ranging phase 2b studies among that bronchodilation was sustained for postbronchodilator percent predicted
patients with moderate to severe 24 hours after the dose. Furthermore, FEV1 was 54% to 56%.19
COPD.17,18 Study 0116 (NCT02109172) revefenacin 175 µg decreased albuterol Compared with placebo, reve
was a randomized, double-blind, rescue medication usage, by at least 1 fenacin resulted in clinically signifi-
placebo-controlled, 7-day trial that albuterol puff per day.18 cant improvements in trough FEV1 at
1188 AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 13 | July 1, 2021REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE Clinical Review
Table 3. Summary of Phase 3 Post Hoc/Prespecified Subgroup Analysesa
Patient Population/
Study Design Treatments Efficacy/Health Status Outcomes Safety Outcomes
Post hoc subgroup REV 175 µg (n = 395) Clinically significant improvements Not assessed
efficacy analysis PBO (n = 417) in day 85 trough FEV1 (mL) for
of phase 3 studies The following subgroups of pa- REV vs PBO across all sub-
0126 and 012724 tients with severe markers of groups:
COPD were analyzed: • Severe airflow limitation (131.2,
• Severe airflow limitation (per- P < 0.001)
cent predicted FEV1 of 30% • Very severe airflow limitation
to 75 years (129.2, P = 0.0217)
• Background LABA and/or • History of cardiovascular disease
ICS (140.7, P = 0.0242)
• Older age: • History of diabetes mellitus
◦ >65 years (101.6, P = 0.0077)
◦ >75 years • History of cognitive/mental im-
• History of comorbidity risk pairments (149.5, P = 0.0006)
factors: For the SGRQ responders,
◦ Cardiovascular disease the odds of response (odds
◦ Diabetes mellitus ratio >2.0) were significantly
o Cognitive/mental impair- greater (and of clinical import-
ments ance) in the REV arm vs the
PBO arm among the following
subgroups:
• Percent predicted FEV1 of 30%
toClinical Review REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE
Continued from previous page
Table 3. Summary of Phase 3 Post Hoc/Prespecified Subgroup Analysesa
Patient Population/
Study Design Treatments Efficacy/Health Status Outcomes Safety Outcomes
Prespecified subgroup 0126/0127 REV led to similar improvements Incidence of AEs
efficacy analysis REV or PBO and concomitant from baseline in trough FEV1 • REV only: 37.5%
(studies 0126 and LABA or LABA/ICS across subgroups • REV and concomitant LABA or
0127) and safety REV 175 µg (n = 153), PBO Trough FEV1 (LS mean difference) LABA/ICS: 50.2%
analysis (studies (n = 147) at day 85: Exacerbation of COPD was the
0126, 0127, and REV or PBO only • REV only: 150.9 mL, P < 0.0001 most commonly reported AE:
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0128)25 REV 175 µg (n = 242), PBO • REV and concomitant LABA or • Incidence was higher in the sub-
(n = 270) LABA/ICS: 139.2 mL, P < 0.0001 group with REV and concomi-
0128 Similar improvements were ob- tant LABA or LABA/ICS (25.0%)
REV or TIO and concomitant served in SGRQ scores between vs the REV only subgroup
LABA or LABA/ICS subgroups: (11.8%)
REV 175 µg (n = 158), TIO • REV only: –3.3 Antimuscarinic-related AEs were
18 µg (n = 177) • REV and concomitant LABA or reported more frequently in the
REV or TIO only LABA/ICS: –3.4 subgroup with concomitant
REV 175 µg (n = 161), TIO LABA or LABA/ICS (2.5%) vs the
18 µg (n = 174) REV only subgroup (1.4%)
Dry mouth:
• REV and concomitant LABA or
LABA/ICS: 1.1%
• REV only: 1.0%
Constipation:
• REV and concomitant LABA or
LABA/ICS: 1.2%
• REV only: 0.6%
Abbreviations: AE, adverse event; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; GOLD, Global
Initiative for Chronic Obstructive Lung Disease; ICS, inhaled corticosteroid; LABA, long-acting β-agonist; LS, least squares;
PBO, placebo; REV, revefenacin; SABA, short-acting β-agonist; SGRQ, St. George’s Respiratory Questionnaire; TDI, Transition Dyspnea Index; TIO,
tiotropium.
a
See the eAppendix for information on eligibility criteria, definitions, and criteria for clinical relevance.
AEs were considered to be related to compared with placebo, revefenacin in of cardiovascular disease, diabetes
treatment with revefenacin (0126, 1 SAE the pooled analysis increased trough mellitus, and cognitive/mental impair-
of worsening/exacerbation of COPD; FEV1 by more than 100 mL, which sug- ments). There was a greater number of
0127, 1 SAE of pneumonia).19 In terms gests a minimal clinically important St. George’s Respiratory Questionnaire
of cardiovascular AEs, the incidence of difference for FEV1.19 (SGRQ) and Transition Dyspnea Index
prolonged QT interval was low (pooled A post hoc subgroup study was (TDI) responders in the majority of
0126 and 0127: revefenacin, 5.9%; pla- conducted using data from the phase the patient subgroups who received
cebo, 5.3%). One major adverse cardio- 3 studies 0126 and 0127 (Table 3).24 revefenacin vs placebo. For the SGRQ
vascular event (MACE) was identified Revefenacin use was associated responders, the odds of response (odds
for revefenacin (myocardial infarction/ with significant improvements from ratio >2.0) were significantly greater
unstable angina); however, this was not baseline in trough FEV1 vs placebo for patients receiving revefenacin vs
deemed related to treatment.26 While (≥100 mL, P < 0.05) among patients placebo among subgroups with severe
the length of these replicate studies with markers of more severe COPD. airflow obstruction, very severe airflow
(approximately 12 weeks) does not Markers of more severe COPD in- obstruction, and 2011 GOLD D classi-
allow for conclusions on long-term cluded severe and very severe airflow fication. For the TDI responders, the
treatment, results from study 0128 help limitation (percent predicted FEV1 of odds of response (odds ratio >2.0) were
elucidate the long-term safety profile. 30% to 75 years), 3 studies 0126 and 0127 (Table 3).25
idity to their outcomes. Furthermore, and comorbidity risk factors (history Patients receiving concomitant
1190 AM J HEALTH-SYST PHARM | VOLUME 78 | NUMBER 13 | July 1, 2021REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE Clinical Review
revefenacin and LABA or LABA/ICS vs than in those who received tiotropium treatment groups (revefenacin, 48%;
those receiving revefenacin only were (4.2%).20 In terms of cardiovascular AEs, tiotropium, 47%). Clinically relevant
evaluated. Revefenacin produced clin- the incidence of prolonged QT interval improvements in SGRQ and TDI scores
ically significant improvements from was low with revefenacin (7.7%) and were demonstrated with use of either
baseline in trough FEV1, and these im- tiotropium (7.3%). Only 1 MACE was revefenacin or tiotropium. However,
provements were similar in patients who considered to be possibly/probably changes in CAT and CCQ scores did not
received LABA or LABA/ICS and those related to revefenacin (atrial fibrilla- reach the predetermined thresholds
who received concomitant revefenacin tion).26 AEs that led to permanent dis- for clinical significance in any group
only (day 85 trough FEV1, 150.9 and continuation were more frequent for at any time point.21 Study limitations
139.2 mL, respectively; P < 0.0001). patients who received revefenacin included the open-label design for the
Similar improvements in SGRQ scores (12.2 %) than for those who received tiotropium group. Additionally, the
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were observed among patients who re- tiotropium (9.3%); however, no emer- ability to draw conclusions on the effi-
ceived revefenacin only and those who gent AE pattern was identified be- cacy of revefenacin vs tiotropium was
received concomitant LABA or LABA/ tween treatment groups for the patients limited because the study was not de-
ICS (–3.3 and –3.4, respectively).25 discontinuing.20 A similar percentage signed or powered to demonstrate stat-
Study 0128 (NCT02518139) was a of patients who received revefenacin istically significant differences between
randomized, parallel-group, 52-week or tiotropium (Clinical Review REVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE
from baseline in trough FEV1 at day 29. of study drug were only reported in the its clinical efficacy (in terms of im-
A prespecified subgroup analysis was tiotropium group (4.8%).22 proved FEV1) relative to both placebo
planned to compare efficacy based on Study 0167 (NCT03573817) was a and tiotropium among patients with
airflow obstruction severity in patients randomized, double-blind, 2-period, moderate to very severe COPD.14,17-23
with severe to very severe disease. Key parallel-group, 42-day phase 3b study Overall, the data suggested that FEV1
secondary efficacy endpoints were the that evaluated the safety and toler- was not significantly different be-
effect of revefenacin vs tiotropium on ability of revefenacin 175 µg when tween revefenacin and tiotropium.21,22
trough forced vital capacity (FVC) and given either sequentially before or The clinical studies showed that
inspiratory capacity at day 29 and peak combined with formoterol 20 µg via revefenacin was well tolerated and was
FEV1 and FVC at day 29 (0-4 hours). a Pari LC Sprint jet nebulizer using generally similar to tiotropium.21,22 In
Patients were permitted to continue the Pari Trek S compressor in patients addition, revefenacin demonstrated a
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concurrent LABA or LABA/ICS therapy. with moderate to very severe COPD.23 low incidence of antimuscarinic AEs,
At baseline, most patients were men The primary endpoint was the safety which is consistent with revefenacin’s
(60%), 47% of patients were current and tolerability of revefenacin when pharmacological properties of com-
smokers, the mean age of the patients dosed sequentially with formoterol for petitive antagonism of the M3 receptor,
was 65 years, and the mean baseline 21 days. The secondary endpoint was unique molecular class (ie, the absence
postbronchodilator percent predicted the safety and tolerability of combined of a quaternary ammonia), and lung-
FEV1 was 37%.22 dosing as a mixture of revefenacin and selective design.10,13
Revefenacin and tiotropium im- formoterol for 21 days. Other LAMAs Revefenacin may be a suitable al-
proved trough FEV1 and FVC from or LABAs were prohibited during ternative to inhalers in certain patient
baseline on day 29, with better im- the trial. At baseline, most patients populations. A post hoc subgroup study
provements among those receiving were men (56%-58%) and/or current of patients with markers of severe dis-
revefenacin vs tiotropium; however, smokers (54%-59%), the mean age was ease demonstrated that revefenacin
the difference in FEV1 was not sig- 63 to 64 years, and the mean baseline via nebulization could benefit elderly
nificant (LS mean difference: FEV 1, postbronchodilator FEV1 was 55%.23 patients, as well as those with cogni-
17.0 mL [P = 0.4461]; FVC, 71.5 mL). AEs were minimal across all groups, tive or physical limitations.24 Additional
In patients with severe to very severe and there were no SAEs or clinically treatment considerations include pa-
airflow limitation (predicted FEV 1 relevant changes in heart rate, QT tient adherence. Revefenacin is theREVEFENACIN FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE Clinical Review
important to consider infection control patients reach catastrophic coverage. 4. Centers for Disease Control and
with nebulizers across all healthcare Revefenacin has the advantage of Prevention. COPD. Accessed May 22,
2020. https://www.cdc.gov/dotw/copd/
settings, given that bacteria grow in wet being able to be billed under Medicare
index.html
and moist environments. Nebulizers part B through a pharmacy or dur- 5. Golden Initiative for Chronic
can be protected from contamination able medical equipment supplier, un- Obstructive Lung Disease. Global
by following the manufacturers’ instruc- like glycopyrrolate, which can only be strategy for the diagnosis, manage-
tions for care and cleaning. However, billed under Medicare part D. This re- ment, and prevention of chronic
obstructive pulmonary disease.
additional factors should be taken into sults in a 20% copayment for patients,
Published 2020. Accessed May
consideration given the current ongoing which is mitigated by supplemental 19, 2020. https://goldcopd.org/
coronavirus disease 2019 (COVID-19) Medicare plans (F, N, etc) that reduce wp-content/uploads/2019/11/
pandemic. Aerosol nebulization is con- the copayment to $0 for patients. GOLD-2020-POCKET-GUIDE-FINAL-
Downloaded from https://academic.oup.com/ajhp/article/78/13/1184/6210056 by guest on 05 December 2021
sidered to have a high risk of spreading Conclusion. Revefenacin, a pgsized-wms.pdf
6. Taffet G, Donohue J, Altman P.
COVID-19 to healthcare personnel. once-daily LAMA for use with a
Considerations for managing chronic
For inpatient use, guidance states to standard jet nebulizer, represents an obstructive pulmonary disease in the
use personal protective equipment important advance in the treatment elderly. Clin Interv Aging. 2014;9:23-30.
(including N95 masks and eyewear) of COPD. Revefenacin use has been doi:10.2147/CIA.S52999
and negative pressure rooms when shown to result in improvements in 7. Yawn B, Colice G, Hodder R. Practical
aspects of inhaler use in the manage-
possible.29 Additionally, placing a filter lung function and health status in
ment of chronic obstructive pulmonary
on the exhalation component of a nebu- patients with moderate to very se- disease in the primary care setting. Int J
lizer may provide protection against vere COPD, including in patients with Chron Obstruct Pulmon Dis. 2012;7:495-
infection and minimize secondhand markers of more severe disease and 502. doi:10.2147/COPD.S32674
aerosol inhalation in hospitals and patients who received concomitant 8. Pritchard JN. Nebulized drug de-
livery in respiratory medicine: what
outpatient clinics.30 If these conditions LABA or LABA/ICS. Additionally, it
does the future hold? Ther Deliv.
cannot be met, then the use of inhalers was well tolerated, and AEs were gen- 2017;8(6):391-399. doi:10.4155/
may be preferred. Additionally, the erally mild without evidence of car- tde-2017-0015
American College of Asthma, Allergy, diovascular toxicity. 9. US Food and Drug Administration.
and Immunology released guidance Highlights of prescribing information
Lonhala Magnair (glycopyrrolate) in-
for managing patients on nebulizers at
Disclosures halation solution, for oral inhalation
home who have confirmed or suspected use. Published 2017. Accessed July 9,
Medical writing support was funded by
COVID-19. This guidance recommends Theravance Biopharma US Inc (South San 2020. https://www.lonhalamagnair.
using a nebulizer in an area where the Francisco, CA) and Mylan Inc, a Viatris com/LonhalaMagnair-Prescribing-
air is not recirculated.31 Company (Canonsburg, PA). The authors ac- Information.pdf
knowledge Gráinne Faherty, MPharm, for 10. Ji Y, Husfeld C, Pulido-Rios MT, et al.
In terms of cost, the wholesale ac-
medical writing and Frederique H. Evans, MBS, Duration by design: discovery of
quisition cost for a monthly supply is revefenacin, the first-in-class nebu-
for editorial assistance (both from Ashfield
$1,323.90 for revefenacin (Yupelri), MedComms, an Ashfield Health Company) in lized once-daily bronchodilator for
which is similar to that for glycopyrrolate the preparation of the manuscript. The author the treatment of patients with COPD.
(Lonhala Magnair) at $1,359.60.32 This has declared no potential conflicts of interest. Chest. 2016;150:970A. doi:https://doi.
org/10.1016/j.chest.2016.08.1074
price is the most readily available ref-
11. Drugbank. Tiotropium. Updated May
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Accessed July 9, 2020. https://www. revefenacin (TD-4208), a novel, nebu-
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