Download 1 - Surrey PAD

Evidence Review for Prescribing Clinical Network
®
Treatment: Anoro Ellipta
Prepared by: Noreen Devanney
Topic Submitted by: Noreen Devanney
Date: October 2014
Summary page
®1
Anoro Ellipta is a LAMA/LABA combination comprising of umeclidinium 55mcg (LAMA) and
®
vilanterol 22mcg (LABA). Umeclidinium (Incruse Ellipta ) as a separate inhaler has been
granted a licence in the UK, date of availability has not been confirmed. Vilanterol is currently
unlicensed in the UK.
 How strong is the evidence for claimed efficacy?
(Grade A = > 1 RCT or meta-analysis;

Potential advantages in terms of: efficacy, compliance, pharmacokinetics, drug interactions and
adverse effects?
This combination provides an option for improved compliance for patients who are
2
3
indicated to have treatment with combined LAMA/LABA as per NICE or GOLD
Guidelines.

Is there a clear place in therapy / treatment pathway?
(E.g. patient type / characteristics, and relationship to other therapies)
A) as per NICE when ICS are declined or not tolerated
(NB NICE indicates: Be aware of the potential risk of developing side effects (including nonfatal pneumonia) in people with COPD treated with inhaled corticosteroids and be prepared to
discuss this with patients.)
B) as per GOLD when is preferred option to LABA/ICS in patients at low
risk of exacerbations (≤ 1 exacerbation per year) but with significant symptoms.
Is monitoring for toxicity required? No


Is monitoring for efficacy required? Desirable to assess efficacy. Review patients with mild or
moderate COPD at least once a year and those with severe COPD at least twice a year.

Financial implications? Possible cost benefit if used where clinically appropriate as per
2
3
NICE and GOLD guidelines, instead of initiating LABA/ICS combination.

National Guidance available - NICE / GOLD as above

Precedent Setting? SMC JULY 2014: GSK did not present a sufficiently robust clinical and
economic analysis to gain acceptance by the SMC and has submitted further data which is
scheduled for SMC in January 2015.

Similar products? Ultibro (glycopyrronium/indacaterol) is currently licensed in the UK,
®
date available TBC. Duaklir (aclidinium/formoterol) date available 26/1/2015.
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3
®
Recommendation:
Option 1
®
Anoro Ellipta to be used as an option:
2
 as per NICE in patients who are still symptomatic on LAMA alone when ICS are
declined or not tolerated NB patients who have had pneumonia with ICS.
4
 as per GOLD in preference to LABA/ICS in patients at low risk of exacerbations (≤ 1
exacerbation per year) but with significant symptoms.
OR
Option 2
The PCN may wish to defer and consider additional LAMA /LABA evidence for aclidinium /formoterol
(Duaklir®) together with Anoro Ellipta® and SMC statement due in January 2015.
1

VERSION CONTROL SHEET
Version
1
Date
21/9/14
Author
Status
Noreen
Devanney
2
Comment
Short Summary of Scottish Medicines Consortium Review4 for PCN
1/10/14
(P. 3-5 taken fromSMC. Please read in conjunction with full review)
Anoro Ellipta® is a LAMA/LABA combination comprising of umeclidinium 55mcg
(LAMA) and vilanterol 22mcg (LABA). Umeclidinium (Incruse Ellipta®) as a separate
inhaler has been granted a licence in the UK, date of availability has not been
confirmed. Vilanterol is currently unlicensed in the UK.
Summary of evidence on comparative efficacy
(P.2 of SMC review)
Head to head Anoro Ellipta v Tiotropium studies
 Three randomised controlled studies demonstrated that after 24 weeks of
treatment, umeclidinium/vilanterol statistically significantly improved lung
function(trough FEV1) compared with tiotropium monotherapy in patients with
moderate to very severe COPD
 The improvement was clinically significant in two of the three studies.
 The submitting company has acknowledged that there was no difference
between umeclidinium/vilanterol and tiotropium monotherapy in dyspnoea or
health status.
There are a number of limitations to the available evidence.
 The European Medicines Agency recommends that lung function parameters alone
(surrogate outcomes) are insufficient to assess therapeutic effect and that, if selected
as a primary endpoint, additional evidence of efficacy must be demonstrated through
the use of a co-primary endpoint, which should either be a symptom-based endpoint
or a patient-related endpoint.
 The only direct comparative evidence is against tiotropium monotherapy which is not
considered as a relevant comparator to dual LABA/LAMA therapy. Despite the
expectation that dual therapy with umeclidinium/vilanterol would be superior to
tiotropium monotherapy, the differences were not always significant in terms of the
important patient-related outcomes (reduced breathlessness, use of rescue
medication and improved quality of life).
 It is unclear how the efficacy of the umeclidinium/vilanterol combination inhaler
compares to existing LABA/LAMA therapy.
Indirect Treatment Comparison: Anoro Ellipta v tiotropium + indacaterol
 An indirect treatment comparison (Bucher method) of the combined inhaler
umeclidinium/vilanterol 55/22 micrograms (delivered dose) versus separate inhalers
of indacaterol 120 micrograms (delivered dose) plus tiotropium 10 micrograms
(delivered dose). The common comparator was tiotropium 10 micrograms (delivered
dose). Two outcomes were assessed. The primary outcome was change in trough
FEV1 at 12 weeks and included five studies, three of which were the pivotal studies.
 The secondary outcome of the indirect comparison was change in rescue medication
use at 12 weeks and this analysis included four of these five studies.
 The submitting company concluded that umeclidinium/vilanterol is comparable
to indacaterol plus tiotropium.
There are a number of limitations to the available evidence:
 This conclusion may not be valid due to differences among the individual studies in
primary outcome, study duration, patient numbers and COPD severity, and the fact
that the common control arms had differences in outcomes (or the data were not
available).
3



A limitation of the Bucher indirect comparison method is that it only includes studies
with two treatment arms and therefore does not allow for evidence from other studies
to be taken into account.
The indacaterol plus tiotropium comparator is the only one used in the economic case
for this submission, thereby excluding several other relevant comparators.
A network meta-analysis including all studies with relevant treatment arms (all
available LABAs, LAMAs or combinations of these) may have been a more
appropriate method of indirectly comparing umeclidinium/vilanterol with relevant
comparators.
In general, clinical experts consulted by SMC consider that the place of
umeclidinium/vilanterol in treatment is as an alternative to separate inhalers of tiotropium and
a LABA with the potential advantage of improving patient adherence.
The submitting company has advised that the delivery device for umeclidinium/vilanterol is a
new type of dry powder inhaler (Ellipta®) which has been designed to be simple to use. It
requires only that the lid be opened for it to be primed and has all 30 doses contained within
it, avoiding the need for subsequent loading. The in-use shelf life of the inhaler is six weeks.
Summary of evidence on comparative safety
(P.4 of SMC review)
Adverse events (AE) reported in umeclidinium/vilanterol 55/22 micrograms versus tiotropium
10 micrograms groups were 51% versus 39%, 59% versus 59%, and 44% versus 42% in
studies DB2113360, DB2113374 and ZEP117115, respectively. These led to discontinuation
of study drug in 4.7% versus 4.3%, 9.2% versus 5.1% and 4.0% versus 3.1% of patients in
the respective studies.6, 8, 10
Drug-related AE reported in ≥1% of patients/study were ventricular extrasystoles (n=3 in
DB2113374) and headache (n=6 in ZEP117115) in the umeclidinium/vilanterol 55/22
micrograms group and dry mouth (n=3 in DB2113360 and n=3 DB2113374), dysphonia (n=3
DB2113374) and headache (n=3 in ZEP117115) in the tiotropium group.6, 8, 10
Serious adverse events reported in the umeclidinium/vilanterol 55/22 micrograms and
tiotropium 10 micrograms groups were 3.3% versus 6.2%, 10% versus 4.2% and 3.5%
versus 3.8% of patients in studies DB2113360, DB2113374 and ZEP117115, respectively.
No drug-related deaths were reported in any of these studies.5, 7, 10
Safety concerns for umeclidinium/vilanterol include cardiac effects, such as arrhythmias e.g.
atrial fibrillation and tachycardia, and an increased risk of vascular events. Long-term safety
data for the licensed dose of umeclidinium/vilanterol are not yet available.
Cost of relevant comparators
(P.9 of SMC review)
Drug
Umeclidinium/vilanterol
Dose Regimen
55/22 micrograms once daily
Cost per year (£)
394
Long acting beta2 agonists
Indacaterol
Salmeterol
Formoterol
150 to 300 micrograms once daily
50 micrograms twice daily
12 micrograms twice daily*
355
337
144
Long acting muscarinic antagonists
Tiotropium (Spiriva Handihaler®)
Tiotropium (Spiriva Respimat®)
Aclidinium
Glycopyrronium
18 micrograms once daily
5 micrograms once daily
322 micrograms twice daily
44 micrograms once daily
4
406
406
347
334
Summary of comparative health economic evidence
(P.6 of SMC review)
A complex modeling structure using risk equations was used; however, the results indicated
that the resulting QALY gains were very small and the overall cost difference was driven
overwhelmingly by drug costs only (£2,831 of the overall difference in costs of £2,834). It
could have been argued that a simpler analytical approach such as a cost- minimisation
analysis could have been adopted for this comparison. The submitting company did provide
some additional analysis including a naïve indirect comparison against salmeterol and
tiotropium and an associated cost-minimisation analysis. However, there are concerns
regarding the robustness of this naïve comparison as a basis for the analysis.
Owing to the uncertainties surrounding the clinical evidence, the economic case has not
been made.
Additional information: budget impact
(P.9 of SMC review)
The submitting company estimated the population eligible for treatment to be 955 in year 1
and 5,014 in year 5, with an estimated uptake rate of 3% in year 1 and 15% in year 5.
The gross impact on the medicines budget was estimated to be £378k in year 1 and £1,983k
in year 5. As other drugs were assumed to be displaced, the net medicines budget impact is
estimated to be savings of £61k in year 1 and £320k in year 5. These figures assume that
85% of the displacement is from patients receiving treatment with tiotropium alone and 15%
from patients receiving separate inhalers of indacaterol and tiotropium. As noted above,
tiotropium monotherapy may not be an appropriate comparator treatment.
Outcome of SMC Review
Umeclidinium/vilanterol (Anoro®) is not recommended for use within NHS Scotland.
Indication under review: As a maintenance bronchodilator treatment to relieve symptoms in
adult patients with chronic obstructive pulmonary disease.
Three randomised controlled studies demonstrated that after 24 weeks of treatment,
umeclidinium/vilanterol significantly improved lung function compared with an inhaled longacting antimuscarinic in patients with moderate to very severe COPD. However there was no
difference between treatments in dyspnoea or health status.
The submitting company did not present a sufficiently robust clinical and economic analysis
to gain acceptance by SMC.
The licence holder has indicated their intention to resubmit.
5
Additional information for PCN: guidelines and protocols
4. Summary of Key Points for Consideration
4.1a National guidance:
NICE2 and GOLD3 guidance for COPD. Long acting bronchodilators (LABA and LAMA) are
included in both guidance recommendations.
NICE May 20102
FEV1 ≥ 50 advice is to use
LABA or LAMA if breathless or exacerbations on short acting bronchodilators
If still symptomatic or exacerbations then use combination LABA/ICS.
If still symptomatic or exacerbations use LAMA + LABA/ICS
LABA+ LAMA used if ICS is declined or not tolerated
FEV1<50% advice is to use LAMA or LABA/ICS, then LAMA + LABA/ICS if still symptomatic
GOLD December 2013 4 advises that combining bronchodilators of different pharmacological
classes may improve efficacy and decrease the risk of side effects compared to increasing
the dose of a single bronchodilator.
GOLD has segmented patients into four groups according to whether the risk of exacerbation
is low or high and whether the symptomatic impact of the disease in the patient is low or high
in relation to the patients’ spirometric classification.
Patient
A
B
C
D
Characteristic
Low risk
Less symptoms
Low risk *
More symptoms
High Risk
Less symptoms
High Risk
More symptoms
Spirometric
Classification
Exacerbations
Per year
≤1
mMRC
(Medical research
Council )
0-1
CAT
(COPD
assessment test)
<10
GOLD1-2
GOLD1-2
≤1
≥2
≥10
GOLD 3-4
≥2
0-1
<10
GOLD 3-4
≥2
≥2
≥10
Group A: Low risk of exacerbations and fewer symptoms:
first choice - shorting-acting bronchodilators as required or SAMA;
second choice - LAMA or LABA or SAMA + SABA
Group B: Low risk of exacerbations and more symptoms:
first choice - LAMA or LABA
second choice -LAMA + LABA
Group C: High risk of exacerbations and fewer symptoms:
first choice - LAMA or ICS+ LABA
second choice - LAMA + LABA
Group D: High risk of exacerbations and more symptoms:
first choice - LAMA or ICS +LABA;
second choice - ICS + LAMA or ICS + LABA +LAMA or
ICS +LABA +phosphodiesterase inhibitor or
LAMA + LABA or LAMA + phosphodiesterase inhibitor
6
*NB Group (B) patients who are at low risk of exacerbations and more symptoms are
indicated for LAMA+LABA prior to ICS/LABA.
4.2 Efficacy
See P. 3
4.3 Potential Benefits over existing therapy
1) Anoro Ellipta® is the first available combination LAMA/LABA treatment option for patients
who may benefit from increased bronchodilation and who may not be indicated for LABA/ICS
therapy as per or NICE or GOLD guidelines
A) as per NICE when ICS are declined or not tolerated (may include
patients with COPD at risk of pneumonia on steroid)
B) as per GOLD when is preferred option over LABA/ICS in patients at
low risk of exacerbations (≤ 1 exacerbation per year) but with
significant symptom
2) After 6 weeks of use 98-99% of patients of Ellipta patients found their inhaler “easy” or
“very easy” to use 6
4.4 Potential disadvantages: two new drugs to UK market .lack of experience with use
4.5 Budgetary Impact
4.5.1 Cost:
Table 1: Compared to other bronchodilators
Prices from MIMS July 14 *Cost for tiotropium includes one device.
Drug
Umeclidinium/vilanterol
(AnoroEllipta®)
Glycopyrronium
(Seebri Breezhaler®)
Aclidinium
(Eklira Genuair®)
Tiotropium
(Spiriva Handihaler®)*refill
Formoterol Easyhaler ®
Dose Regimen
Cost per 30 days (£)
32.50
Cost
year(£)
394
per
Saving with Anoro®(£)
44 micrograms inhaled
once daily
322
micrograms
inhaled twice daily
18 micrograms inhaled
once daily
27.50
334
(+60)
28.60
347
(+47)
33.50
403
-9
144
(+250)
12mcg BD
11.87
Table 2: Compared to existing LAMA plus LABA individual
Drug
Dose Regimen
Cost per 30 days (£)
Spiriva
Handihaler®+Formoterol
Easyhaler®
Seebri Breezhaler® +
Formoterol Easyhaler®
Eklira Genuair®+
Formoterol Easyhaler®
As licensed
NB Easyhaler is bd
47.37
Cost
year(£)
576
39.37
479
40.47
492
As licensed
NB Easyhaler is bd
per
Saving with Anoro®(£)
-182
-85
-98
Table 3: compared to licensed ICS/LABA combinations and triple therapy (not
considered by SMC)
Drug
Dose Regimen
Cost per 30 days (£)
Seretide 500 Accuhaler®
Symbicort 400 Turbohaler
One puff bd
One puff bd
40.92
38
Cost
year(£)
498
462
As licensed
71.50
869
As licensed
74.42
905
®
Relvar Ellipta 55/22
Symbicort 400 Turbohaler
®
+Spiriva Handihaler
Seretide Accuhaler ® 500
+Spiriva Handihaler ®
per
Saving with Anoro®(£)
-96
-68
110/50 once daily
-475
-511
NB potential cost saving of £475 to £511 per annum per patient if, where indicated as per
NICE or GOLD4, patient is successfully initiated on LAMA +LABA combination instead of
going straight from LAMA only to LAMA + (ICS/LAMA) combination.
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4.5.2 Precedent setting:
SMC ADVICE July 16: following a full submission
Umeclidinium/vilanterol (Anoro®) is not recommended for use within NHS Scotland.
Indication under review: As a maintenance bronchodilator treatment to relieve symptoms in
adult patients with chronic obstructive pulmonary disease.
Three randomised controlled studies demonstrated that after 24 weeks of treatment,
umeclidinium/vilanterol significantly improved lung function compared with an inhaled longacting antimuscarinic in patients with moderate to very severe COPD. However there was no
difference between treatments in dyspnoea or health status.
The submitting company did not present a sufficiently robust clinical and economic analysis
to gain acceptance by SMC.
The licence holder has indicated their intention to resubmit.
SMC will consider again in January following submission of indirect comparison data for
Anoro Ellipta® v tiotropium and salmeterol.
AWMG has not yet given date for review.
4.5.3 Additional Considerations
NEJM Article Re ICS withdrawal: September 2014
Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD Helgo Magnussen,
et al, September 8, 2014, at NEJM.org Supported by Boehringer Ingelheim Pharma.
In conclusion, we found that in patients with severe but stable COPD who were receiving
combination therapy with tiotropium, salmeterol, and glucocorticoids, the stepwise withdrawal
of glucocorticoids was noninferior to the continuation of such therapy, with respect to the risk
of moderate or severe exacerbations. The effect of withdrawal on symptoms and lung
function also needs to be considered when making decisions regarding maintenance therapy
in patients with severe but stable COPD.
NICE Medicines Evidence Commentary Published: March 2014
COPD: risk of pneumonia with inhaled corticosteroids
https://arms.evidence.nhs.uk/resources/hub/1033610/attachmentSummary
Availability of other LABA/LAMA combination
Almirall is due to launch Aclidinium/formoterol (Duaklir®) in January 2014
8
Novartis has not yet specified date for Glycopyrronium/Indacaterol (Ultibro®) which is
currently licensed in UK.
Conclusions and Recommendations







Three randomised controlled studies demonstrated that after 24 weeks of
treatment, umeclidinium/vilanterol statistically significantly improved lung
function(trough FEV1) compared with tiotropium monotherapy in patients with
moderate to very severe COPD
In these studies there was no statistically significant difference between
umeclidinium/vilanterol and tiotropium monotherapy in dyspnoea or health
status.
An indirect treatment of the combined inhaler umeclidinium/vilanterol 55/22
micrograms versus separate inhalers of indacaterol 120 micrograms (delivered
dose) plus tiotropium 10 micrograms concluded that umeclidinium/vilanterol is
comparable to indacaterol plus tiotropium, the primary outcome was change in
trough FEV1 at 12 weeks, the secondary outcome of the indirect comparison
was change in rescue medication use at 12 weeks.
There is a place in both NICE and GOLD guidelines for a group of patients who
may benefit from this combination rather than LABA/ICS or triple therapy.
It has been established that there is a risk of pneumonia with inhaled
corticosteroids in some patients with COPD. LABA/LAMA therapy may be an
option for those patients.
Evidence is emerging re stepping patients with COPD down from triple therapy
to LABA/LAMA
LABA/LAMA combination is significantly more cost effective that LABA/ICS or
triple therapy (this economic evaluation was not considered by SMC) and may
be suitable is some patients.
Option 1
Anoro Ellipta ® to be used as an option
 as per NICE in patients who are still symptomatic on LAMA alone when ICS are
declined or not tolerated (including in patients at risk of pneumonia on ICS)
 as per GOLD in preference to LABA/ICS in patients at low risk of exacerbations
(≤ 1 exacerbation per year) but with significant symptoms.
Option 2
The PCN may wish to defer and consider additional LAMA /LABA evidence for
aclidinium /formoterol (Duaklir®) together with Anoro Ellipta® and SMC statement due
in January 2015.
References:
Appendix 3: References
1. Summary of Product Characteristics (SPC): Anoro Ellipta
https://www.medicines.org.uk/emc/medicine/28949
9
2. NICE quick reference guidance (CG101) COPD (update): Management of COPD in
adults
in
primary
and
secondary
care;
June
2010.
http://www.nice.org.uk/nicemedia/live/13029/49399/49399.pdf
3. GOLD Guideline (2011) updated 2013. Global Strategy for the Diagnosis
.Management and Prevention of COPD. Global Initiative for Chronic Obstructive Lung
Disease (GOLD) 2011 updated 2013
www.goldcopd.org
4. Withdrawal of Inhaled Glucocorticoids and Exacerbations of COPD
Helgo Magnussen, M.D., Bernd Disse, M.D., Ph.D., Roberto Rodriguez-Roisin, M.D.,
Anne Kirsten, M.D., Henrik Watz, M.D., Kay Tetzlaff, M.D., Lesley Towse, B.Sc., Helen
Finnigan, M.Sc., Ronald Dahl, M.D., Marc Decramer, M.D., Ph.D., Pascal Chanez, M.D.,
Ph.D., Emiel F.M. Wouters, M.D., Ph.D., and Peter M.A. Calverley, M.D. for the WISDOM
Investigators
September 8, 2014DOI: 10.1056/NEJMoa1407154Mims
5. NICE Evidence Review: COPD: Risk of pneumonia with inhaled corticosteroids
https://arms.evidence.nhs.uk/resources/hub/1033610/attachmentSummary
6. Riley, J. Use of a new dry powder inhaler to deliver umeclidinium/vilanterol in the
treatment of COPD. Eur Respir J. 42 ,880s 2013
10