1. Florentina Eller
8/16/14
New Drug Update
DrugName: Umeclidinium (umeclidinium bromide)
TradeName: Incruse Ellipta
Manufacturer: GlaxoSmithKline, LLC
PharmacologicClass: Long-acting anticholinergic agent
FDAApprovedIndications: Maintenance treatment of chronic obstructive
pulmonary disease (COPD)
Pharmacology: Anticholinergic agent that causes
bronchodilation; blocksacetylcholine at
muscarinic receptors (M3) on bronchial smooth
muscle.
DosageandAdministration: 1 inhalation (62.5mcg) once daily (preloaded
with30 doses in a blister strip)
No priming is required; inhaler should not be
shaken; administration similar to Spiriva, except
the dose is already loaded in the device(still
have to listen forthe “click” whencoverof
mouthpiece is pushed away, and inhalation must
be rapidly steadily and deeply);prior to initial use,
inhaler MUST be stored inside the moisture
protectivefoil tray; inhaler should be discarded 6
weeks after opening the foil tray or when the counter
reads “0” (after all blisters have been used)
whichevercomes first.
Availableforms: The anticipated availability date for IncruseEllipta
aerosol powder isthe 4th quarter of 2014
Incruse Ellipta is available in 2 forms (both are
colored light grey an light green) containing
either 30 or 7 blisters of umeclidinium
bromide.
Note: Umeclidinium is also available in combination
with a long acting beta2- adrenergic agonist
(vilanterol) under the trade name Anoro Ellipta
aerosol powder breath activated (light gray and
red inhaler), costs around $95, and has an
identical indication as Incruse Ellipta.

2. Florentina Eller
8/16/14
Note: Anoro Ellipta should not be confused with Breo
Elliptainhalation powder (light gray and pale blue
inhaler) whichis a combination of long acting beta2-
adrenergic agonist (vilanterol)and a corticosteroid
(formoterol).Breo Ellipta has one additional
indication - reduction in COPDexacerbation and
it costs around $124.
BlackBoxedWarnings: None
PrecautionsandSpecial Warnings: Bronchospasm (discontinue); hypersensitivity
(contraindicated in patients withsevere milk protein
allergy); glaucoma (use with caution); prostatic
hyperplasia/bladder neck obstruction (use with
caution);Do not use for acute episodes of COPD;
Do not initiate in patients withsignificant
worsening or acutely deteriorating COPD.
Contraindications: Severe hypersensitivity to milk proteins
AdverseEffects: Common:nasopharyngitis (8%);upper
respiratory tract infections (5%); cough (3%);
Serious:anaphylaxis, worsening of narrow angle-
glaucoma; urinary retention, paradoxical
bronchospasm
Monitoring: FEV1, peak flow,and/or other pulmonary function
tests (forefficacy);signs and symptoms of narrow
angle glaucoma and urinary retention (forsafety)
Interactions:
Drugs Anticholinergics
Food None
Disease/Other Pregnancy category C; lactation (caution)
Pharmacokinetics:
Absorption Lungs; minimal oral absorption
Distribution Volume of distribution (Vd) 86L, followingIV
Metabolism Hepatic via CYP2D6;P-glycoprotein(P-gp) substrate
Elimination Urine <1%; feces92% (after oral administration);
T1/2 11 hours
Clinical Trial Information:
In a multicenter, randomized, double-blind, double-dummy, placebo-controlled, 3-way
cross-over,incomplete blockstudy, Donohue et al, evaluated 5-once daily and 3-twicedaily
doses of GSK573719 (umeclidinium-UMEC) over a 14-days period. The primary objective
of the study was to evaluate the dose-response, safety and efficacy of once-daily UMEC(62.5
μg, 125 μg, 250 μg, 500 μg, and 1000 μg), and the efficacy andsafety of twice-daily UMEC
(62.5 μg, 125 μg, and 250 μg) and once daily tiotropium 18 μg compared withplacebo in
subjects with COPD.All UMECdoses were administered using a dry powder inhaler.

3. Florentina Eller
8/16/14
Open-label tiotropium was included as a positive control.For breakthrough symptoms,
patients were provided with supplemental albuterol to use as required. Eligible patients
were randomized to a sequence of 3 treatments consisting of placeboand 2 of the 9 active
treatments
Eligiblepatients weremales and females aged 40–80 years with a history of COPDand ≥10
pack years smoking history, had a post-albuterol (salbutamol) forced expiratory volume in
1 s (FEV1)/forcedvitalcapacity (FVC) ratio of ≤0.70 and a post-albuterol FEV1 of ≥35 and
≤70% of predicted normal. Some of the ineligibilitycriteria includeda current diagnosis of
asthma, a lowerrespiratory tractinfection or recent COPDexacerbation; concurrent use of
systemic corticosteroids, long-acting bronchodilators, or ipratropium; use of oral or
parenteral corticosteroids for 6 weeks, tiotropium for 14 days, and inhaled long-acting β2-
agonist (LABA) for48 h prior to screening. The primaryefficacy endpoint was the change
from baseline in clinic visit trough FEV1 at the end of each treatment period (Day 15).
(Baseline defined as pre-dose FEV1 value obtained at Day 1; trough FEV1 defined as pre
bronchodilator and 24 h post-dose). Secondaryefficacy endpointswere 0–24 h weighted
mean FEV1 at Day 14 and serial FEV1 values at each time point over 28 h at Day 14.
Safetyevaluations included adverse events, vitalsigns, 12-lead ECGand 24 h Holter
assessments (obtained at screening and at the end of each treatment period), standard
clinical laboratory tests, and COPDexacerbations. Patients recorded any medical problems
on diary cards and these entries were reviewed at each study visit. The authors calculated
that a sample size of 117 evaluable patients is sufficientto have 90% power and a targeted
treatment difference fromplacebo of 159 ml. The sample size was adequate to detect a
significant difference, if it existed, between the activegroups (UMECand tiotropium) and
placebo. The Modified Intent-to-Treat (MITT) population was used for the analysis of
primary endpoint. MITT population included all subjects whowere randomized and
received study medication, and analyzed according to actual treatment received.
Results
176 patients were randomized and received at least 1 dose of study treatment, and 135
(77%) completed all treatment periods. These patients were predominantly Caucasians and
had moderate-to-severe disease with post-albuterol FEV1 values ranging from 35 to 72% of
predicted normal. 21-39% of patients concurrently used inhaled corticosteroids(ICS), and
the majority (70%) of patients were current smokers.
EfficacyResults
All once-daily doses of UMEC significantly increased trough FEV1 at 24 h on Day 15
compared with placebo with adjusted mean differences of 128, 147, 95, 140 and 186 mL for
62.5 μg, 125 μg, 250 μg, 500 μg, and 1000 μg, respectively (p≤ 0.006).
Twice-daily dosing of UMECresulted in similar differences (79, 134, and 172 mL for 62.5 μg,
125 μg, and 250 μg, respectively;p ≤ 0.0300). Tiotropium also significantly increased trough
FEV1 compared with placebo (105 mL, p = 0.003).
Compared to placebo, all once-daily doses of UMEC (withthe exception of the 500 and
1000 μg once-daily doses at 1 h showed significant improvements in FEV1 (p ≤ 0.033) at all
time points over 28 h.
SafetyResults
Once or twice-daily 62.5 μg and 125 μg UMECand tiotropium had similar incidence of on-
treatment adverse events (AEs):(17%-23%) vs (16%) with placebo. Higher doses of UMEC
were associated withincreased incidence of AEs (30%–41%). The most common AE was
headache and cough across treatments. Once-daily UMEC 250 μg resulted in 2 serious
adverse events (COPDexacerbation and concussion), while125 μg twice-daily resulted in 1
serious (COPDexacerbation).

4. Florentina Eller
8/16/14
None of these events were fatal or considered related to study treatment. The incidence of
on-treatment COPDexacerbations was low and similar across the treatment groups (0%–
3% with UMEC and 2% withplacebo).
Conclusion
Eventhough this study was limited by the use of an incomplete blockcross-over design
resulting in a relatively small number of subjects receiving each combination of treatments,
the FEV1 serial values obtained over 28 h were very useful in the thorough assessment of
the bronchodilator activity of UMEC.Additionally the study used an adequate sample size to
identify dose-related trends foradverse events related to tolerability.
In conclusion, once daily 62.5 μg, 125 μg, 250 μg, 500 μg, and 1000 μg umeclidinium were
well tolerated and provided significant improvement in lung functionfor up to 28 h in
subjects with COPD.The efficacy iscomparable to tiotropium. Doses of once-daily 62.5 and
125 μg umeclidinium should be considered foruse in practice, along with further long-term
safety and efficacy studies.
Donohueetal 4 conducteda double blind, placebo-controlled,randomized, parallel-
group study to evaluate the efficacy andsafety of a 24-weektreatment with once-daily
umeclidinium/vilanterol (UMEC/VI) (62.5/25 μg) compared withUMEC 62.5 μg and VI25
μg monotherapies in 1,532 patients. Symptomatic COPDS patients ≥40 years (based on the
Medical Research Council Dyspnea Scale and spirometry testing) wereeligible for
participation in the study. Exclusioncriteria includeda current asthma diagnosis, other
respiratory diseases, or significantly abnormal clinical laboratory findings. Maximum
allowable dose of ICS was ≤ 1000 mcg/day of fluticasone propionate or equivalent. Eligible
patients were randomized 3:3:3:2 to treatment with UMEC/VI 62.5/25 mcg, UMEC
62.5 mcg, VI 25 mcg or placebo administered once daily via dry powder inhaler.
Theprimaryefficacy endpoint was pre-dose trough FEV1 on treatment Day 169, (23 h and
24 h after dosing on Day 168). Secondaryendpoints included weighted mean FEV1 over 0–
6 h post-dose on Day 168; trough and 0–6 h weighted mean FEV1 at other visits and serial
FEV1 assessments.
Results
Out of 1,532 patients included in the ITTpopulation, 1178 patients completed the study.
58–64% of patients in all 4 groups had cardiovasculardisease, and 49–52% of patients used
ICSs.
EfficacyResults
All patients randomized to UMEC/VI 62.5/25 mcg, UMEC62.5 mcg or VI 25 mcg obtained
statistically significant improvements in their trough FEV1 at Day 169 compared to placebo
(0.167 L, 0.115 L, and 0.072 L; all p < 0.001). Patients randomized to UMEC/VI62.5/25 mcg
obtained statistically significant improvements in their FEV1 at Day 168, compared to
UMEC62.5 mcg (0.052 L;p = 0.004) and VI 25 mcg (0.095 L; p < 0.001).
Additionally, the use of UMEC/VI62.5/25 mcg, UMEC 62.5 mcg and VI 25 mcg resulted in
greater increases from baseline in 0–6 h weighted mean FEV1 at Day 168 compared with
placebo (0.242 L, 0.150 L and 0.122 L; all p < 0.001). Among the 4 groups, greater increases
in weighted mean FEV1 wereobserved forUMEC/VI62.5/25 mcg compared with UMEC
62.5 mcg (0.092 L; p < 0.001) and VI 25 mcg (0.120 L; p < 0.001) at Day 168
Safety
The most common AEs were headache (8%, 6%, 8%,9% -UMEC/VI,VI, UMEC, placebo
respectively),nasopharyngitis (9%, 6% 7%, 6%) upper respiratory tract infection(3%, 4%,
5%, 5%) and cough (1%, 4%, 4%, 3%); these incidence rates were not significantly
different. Worsening COPDwas the only serious AEs/AE leading to withdrawal of ≥1% of
patients in any of the study group.

5. Florentina Eller
8/16/14
Fatal AEs occurredin 9 patients: 3 in the VI 25 mcg group (sudden death, COPD
exacerbation, COPDexacerbation/renal failure), 3 in the UMEC/VI62.5/25 mcg group
(COPDexacerbation/respiratory failure, myocardial infarction,unknown cause) and 3 in
the UMEC 62.5 mcg group (COPD/acuterespiratory failure, sudden death, cholecystitisand
peritonitis).
Results
UMEC/VI62.5/25 mcg is more effectivein treating COPDcompared to UMEC62.5 mcg or VI
25 mcg monotherapies over 24 weeks in patients withCOPD, withsimilar adverse effects.
Additionally, compared to placebo, both UMEC62.5 mcg and VI 25 mcg were more
efficacious.In conclusion, umeclidinium/vilanterol 62.5mg/25 mg is an effectiveand safe
treatment for COPD.
CostComparison:
Incruse Ellipta is not yet available.
Conclusion:
The GOLD 2014 practice guidelines recommend the use of a long acting beta2-
agonists (LABA) or a long acting muscarinic antagonists (LAMA) forsymptom relief in
patients with stable, relatively milder disease (GOLDstage B). The GOLDguidelines also
recommend adding a therapy with an alternate mechanism of action to maximize the effects
of bronchodilation in patients with COPD,not well controlled withlong-acting
bronchodilator therapy. In particular, the guidelines suggest the use of dual therapy
LAMA/LABA treatment alternative for patients in GOLDstage B–D(ICS/LABA +/_ LAMA is
the first line for stage D).LAMA plus LABA (UMEC/VI - Anoro Ellipta) shows greater
improvements in dyspnea symptoms, use of rescue medications, and quality of life,
compared to the drugs used individually (i.e. Incruse Ellipta or vilanterol).
Right now,Incruse Ellipta is the only alternative to Spiriva (tiotropium) - a LAMA. A
main advantage of Incruse Ellipta over Spiriva is the ease of administration. Incruse Ellipta
dry powder inhaler comes already preloaded with a 30-days supply of doses, which is very
useful for an elderly withosteoarthritis or rheumatoid arthritis, who might struggle to open
the Spiriva’s sealed capsule pouches.
Direct comparison of Spiriva and Incruse Ellipta trials are in the pipeline on
ClinicalTrial.gov. Until the results of these studies are published and the cost is known,
Incruse Ellipta should be used as an alternative to Spiriva, withAnoro Ellipta as the
preferred therapy over both.

6. Florentina Eller
8/16/14
References:
1. Lexicomp. Umeclidinium (Lexi-Drugs).http://online.lexi.com.candycorn.lipscomb.edu
Accessed 8/17/2014.
2. GlaxoSmithKline LLC. Incruse Ellipta prescribing information. June 2014.
https://www.gsksource.com/gskprm/htdocs/documents/INCRUSE-ELLIPTA-PI-PIL.PDF.
Accessed 8/17/2014.
3. Donohue JF, Anzueto A, Brooks J, et al. A randomized, double-blind dose-ranging study of
the novel LAMA GSK573719 in patients withCOPD. Respir Med. 2012 Jul; 106(7):970-9. doi:
10.1016/j.rmed.2012.03.012. Epub 2012 Apr 10.
4. Donohue JF, Maleki-YazdiMR, Kilbride S, et al. Efficacy andsafety of once-daily
umeclidinium/vilanterol 62.5/25 mcg in COPD. RespirMed.2013;107(10):1538–1546.